Clomiphene citrate plus tamoxifen versus laparoscopic ovarian drilling in women with clomiphene-resistant polycystic ovary syndrome.

PubMed

Zakherah, Mahmoud S; Nasr, Ahmed; El Saman, Aly M; Shaaban, Omar M; Shahin, Ahmed Y

2010-03-01

To compare the efficacy of clomiphene citrate (CC) plus tamoxifen with that of laparoscopic ovarian drilling in clomiphene-resistant women with polycystic ovary syndrome (PCOS). We randomly allocated 150 women with CC-resistant PCOS to a combined medication group (group 1) or a laparoscopic surgery group (group 2). The primary outcome was the live birth rate in each group; secondary outcomes were the rates of ovulation, clinical pregnancy and miscarriage. There were no significant differences between the groups regarding rates of ovulation (81.3% vs 85.3%), pregnancy (53.3% vs 50.7%), or live births (49.3% vs 44.0%), but the mean endometrium thickness was significantly greater on the day of human chorionic gonadotropin administration in group 1 (P<0.001). Clomiphene citrate plus tamoxifen was as effective as laparoscopic ovarian drilling in promoting ovulation and pregnancy.

Letrozole versus clomiphene citrate for unexplained infertility: a systematic review and meta-analysis.

PubMed

Liu, Aihai; Zheng, Chao; Lang, Junzhe; Chen, Wenbing

2014-05-01

The objective of this study is to investigate and compare the effectiveness of letrozole and clomiphene citrate for improving fertility outcomes, including pregnancy rate, miscarriage rate, multiple pregnancy rate, and incidence rate of adverse events, number of dominant follicles, endometrial thickness at hCG day and serum E2 on hCG day. MEDLINE, EMBASE, CENTRAL, CNKI and CBMdisc databases were searched up to March 2013. Randomized controlled trials comparing letrozole with clomiphene in women with unexplained infertility were included. Pooled relative risk, mean difference and 95% confidence intervals were calculated. We found that there are no differences in pregnancy, miscarriage and multiple pregnancy rates, incidence rate of adverse events, number of dominant follicles (>18 mm) and endometrial thickness at hCG day in women with unexplained infertility between letrozole and clomiphene regimens. The mean (±standard deviation) concentration of serum E2 on hCG day was lower in those treated with letrozole than those with clomiphene. The subgroup of 2.5 mg letrozole displayed a statistically significant higher rate of clinical pregnancy as compared with 100 mg of clomiphene. The results of this study conclude that letrozole is as effective as clomiphene in women with unexplained infertility. Letrozole at a dose of 2.5 mg seems more effective. Further high-quality studies assessing the possible effectiveness of letrozole in selected groups of patients are warranted. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.

PubMed

Legro, Richard S; Brzyski, Robert G; Diamond, Michael P; Coutifaris, Christos; Schlaff, William D; Casson, Peter; Christman, Gregory M; Huang, Hao; Yan, Qingshang; Alvero, Ruben; Haisenleder, Daniel J; Barnhart, Kurt T; Bates, G Wright; Usadi, Rebecca; Lucidi, Scott; Baker, Valerie; Trussell, J C; Krawetz, Stephen A; Snyder, Peter; Ohl, Dana; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

2014-07-10

Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).

Comparison of the effects of letrozole and clomiphene citrate for ovulation induction in infertile women with polycystic ovary syndrome.

PubMed

Nahid, L; Sirous, K

2012-06-01

Ovulation dysfunction is one of the most common causes of reproductive failure in infertile couples. The prevalence of this disorder in infertile women is about 30 to 40%. Polycystic ovary syndrome is a common disease that is closely related to ovulation dysfunction and 7% of women of childbearing age are afflicted with it. Ovulation induction is a way to treat infertility in PCOS which is possible through medication or surgery. This study was conducted to compare the effects of Letrozole and Clomiphene citrate for ovulation induction in women with PCOS. This intervention is a clinical trial study carried out on 100 infertile women with polycystic ovary syndrome who were referred to gynecologist's office and Oslian hospital. The subjects were randomly divided in to two groups including 50 patients who received letrozole and Clomiphene Citrate. Abdominal ultrasound was performed on the day 14 of the menstrual cycle to monitor the number and size of developed follicles and endometrial thickness.%age of ovulation was compared between the two groups receiving medication with χ2 test and t-test was used to compare the average number and size of follicles and endometrial thickness. Twenty-three cases (46%) in group receiving clomiphene citrate had thin endometrium and thin endometrium was observed in 1 case (2%) of group receiving letrozole. Among 50 subjects who received clomiphene citrate, 10 people (20%) reported blurred vision, 9 patients (18%) headache, 6 patients (12%) nausea and 2 patients (4%) reported vomiting and one (2%) twin pregnancies was observed, but no complications were reported in group receiving letrozole. Mean age, parity, and the duration of infertility were similar in all patients. Ovulation rate was 88%; similar in both groups. The average number of follicles in the group receiving clomiphene citrate was 58/1±32/2 and in the group receiving letrezole it was 50/0±30/1. Average follicle size in both groups was almost similar. Endometrial thickness in the group receiving letrezole was 27/1±71/9 and in the group receiving clomiphene citrate it was 06/3±08/6. Pregnancy rate in both groups was almost similar. This study showed that stimulation of letrozole and clomiphene citrate on ovulation and was almost the same and clomiphene citrate caused endometrial thinning more often than letrozole. Also the side effects reported by patients in the group receiving clomiphene citrate were higher, while in the group receiving letrozole no complication was reported. Based on these findings letrozole can be considered an appropriate alternative for clomiphene citrate without side effects.

Clomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles: A randomized trial.

PubMed

Pourali, Leila; Ayati, Sedigheh; Tavakolizadeh, Shirin; Soleimani, Hourieh; Teimouri Sani, Fatemeh

2017-01-01

Clomiphene citrate is one of the effective drugs for infertility treatment due to oligo-ovulation or anovulation. Intrauterine insemination (IUI) is one of more adherent methods for treatment of infertile cases which is followed by controlled ovarian hyperstimulation (COH). the aim of this study was to evaluate Clomiphene citrate versus letrozole with gonadotropins in IUI cycles. In this prospective randomized trial, 180 infertile women who were referred to Milad Hospital were selected. The first group received 5 mg/day letrozole on day 3-7 of menstrual cycle. The second group received 100 mg/day Clomiphene in the same way as letrozole. In both groups, human menopausal gonadotropin was administered every day starting on day between 6-8 of cycle. Ovulation was triggered with urinary Human Chorionic Gonadotropin (5000 IU) when have two follicles of ≥16 mm. IUI was performed 36 hr later. The number of matured follicles, cycle cancellation, and abortion were the same in both groups. Endometrial thickness was higher at the time of human menopausal gonadotropin administration in letrozole group. Chemical and clinical pregnancy rates were much higher in letrozole group. Ovarian hyperstimulation was significantly higher in clomiphene group. Letrozole appears to be a good alternative to clomiphene citrate with fewer side effects.

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

PubMed Central

Legro, Richard S.; Brzyski, Robert G.; Diamond, Michael P.; Coutifaris, Christos; Schlaff, William D.; Casson, Peter; Christman, Gregory M.; Huang, Hao; Yan, Qingshang; Alvero, Ruben; Haisenleder, Daniel J.; Barnhart, Kurt T.; Bates, G. Wright; Usadi, Rebecca; Lucidi, Scott; Baker, Valerie; Trussell, J.C.; Krawetz, Stephen A.; Snyder, Peter; Ohl, Dana; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

2014-01-01

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P = 0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P = 0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.) PMID:25006718

Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome

PubMed Central

Hajishafiha, Masomeh; Dehghan, Meisam; Kiarang, Nazila; Sadegh-Asadi, Nahideh; Shayegh, Seyed Navid; Ghasemi-Rad, Mohammad

2013-01-01

Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age (6.8%–18%), is among the most common causes of infertility due to ovulation factors, and accounts for 55%–70% of infertility cases caused by chronic anovulation. In this study, we used a combination of letrozole and clomiphene in patients resistant to both drugs individually, and studied the effects of this combination in ovulation and pregnancy in resistant PCOS patients. Methods The study population included infertile couples diagnosed as PCOS in the wife. The women used clomiphene for at least six cycles in order to ovulate after failure to form the dominant follicle, and were then put on letrozole for four cycles. Patients who were unable to form the dominant follicle were enrolled on letrozole and clomiphene combination therapy. Results One hundred enrolled patients underwent 257 cycles of a combination of letrozole and clomiphene, in which 213 were able to form the dominant follicle (82.9%) and 44 were unable to do so (17.1%). The number of mature follicles was 2.3±1.1. The mean endometrial thickness in patients on the day of human chorionic gonadotropin administration was 8.17±1.3 mm. The pregnancy rate was 42%. Conclusion According to the results of this study, it can be proposed that in PCOS patients resistant to clomiphene and letrozole used as single agents, a combination of the two drugs can be administered before using more aggressive treatment that may have severe complications or surgery. This combination may also be used as a first-line therapy to induce ovulation in severe cases of PCOS in order to save time and expense. PMID:24348019

Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome.

PubMed

Hajishafiha, Masomeh; Dehghan, Meisam; Kiarang, Nazila; Sadegh-Asadi, Nahideh; Shayegh, Seyed Navid; Ghasemi-Rad, Mohammad

2013-01-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age (6.8%-18%), is among the most common causes of infertility due to ovulation factors, and accounts for 55%-70% of infertility cases caused by chronic anovulation. In this study, we used a combination of letrozole and clomiphene in patients resistant to both drugs individually, and studied the effects of this combination in ovulation and pregnancy in resistant PCOS patients. The study population included infertile couples diagnosed as PCOS in the wife. The women used clomiphene for at least six cycles in order to ovulate after failure to form the dominant follicle, and were then put on letrozole for four cycles. Patients who were unable to form the dominant follicle were enrolled on letrozole and clomiphene combination therapy. One hundred enrolled patients underwent 257 cycles of a combination of letrozole and clomiphene, in which 213 were able to form the dominant follicle (82.9%) and 44 were unable to do so (17.1%). The number of mature follicles was 2.3±1.1. The mean endometrial thickness in patients on the day of human chorionic gonadotropin administration was 8.17±1.3 mm. The pregnancy rate was 42%. According to the results of this study, it can be proposed that in PCOS patients resistant to clomiphene and letrozole used as single agents, a combination of the two drugs can be administered before using more aggressive treatment that may have severe complications or surgery. This combination may also be used as a first-line therapy to induce ovulation in severe cases of PCOS in order to save time and expense.

Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary syndrome.

PubMed

He, Donghong; Jiang, Fengyan

2011-07-01

The aim of this study was to systematically compare the clinical efficacy and safety of letrozole with clomiphene citrate for ovulation induction in women with polycystic ovary syndrome (PCOS). The Cochrane Central Register of Controlled Trials, PubMed, EMbase, CBMdisc and CNKI were searched for eligible randomized controlled trials (RCT) comparing letrozole with clomiphene citrate in PCOS patients. Two reviewers independently extracted information and evaluated methodological quality according to the Cochrane Handbook 5.0. Meta-analysis was performed with the fixed-effects model or random-effects model according to the heterogeneity. Six eligible RCT involving 841 patients were included. Letrozole was associated with a number of lower mature follicles per cycle (standardized mean difference (SMD) -1.41; 95% confidence intervales (CI) -1.54 to -1.28; P<0.00001) compared with clomiphene citrate. There were no significant differences in pregnancy rate (relative risk (RR) 0.97; 95% CI 0.79 to 1.18), abortion rate (RR 1.38; 95% CI 0.48 to -3.96) and multiple pregnancy rate (RR 0.34; 95% CI 0.07 to -1.72) between the two groups. The evidence from ovulation rates was not enough to support either letrozole or clomiphene citrate. In conclusion, letrozole is as effective as clomiphene citrate for ovulation induction in patients with PCOS. Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Cost-effectiveness of treatment strategies in women with PCOS who do not conceive after six cycles of clomiphene citrate.

PubMed

Moolenaar, Lobke M; Nahuis, Marleen J; Hompes, Peter G; van der Veen, Fulco; Mol, Ben Willem J

2014-05-01

This study evaluated the cost-effectiveness of treatments for women with polycystic ovary syndrome (PCOS) who ovulate on clomiphene citrate but do not conceive after six cycles. A decision-analytic framework was developed for six scenarios: (1) three cycles of IVF; (2) continuation of clomiphene citrate for six cycles, followed by three cycles of IVF in case of no birth; (3) six cycles of gonadotrophins and three cycles of IVF; (4) 12 cycles of gonadotrophins and three cycles of IVF; (5) continuation of clomiphene citrate for six cycles, six cycles of gonadotrophins and three cycles of IVF; (6) continuation of clomiphene citrate for six cycles, 12 cycles of gonadotrophins and three cycles of IVF. Two-year cumulative birth rates were 58%, 74%, 89%, 97%, 93% and 98% and costs per couple were € 9518, € 7530, € 9711, € 9764, € 7651 and € 7684 for scenarios 1-6, respectively. Scenario 2 was the lowest cost option. The extra cost for at least one live birth in scenario 5 was € 629 and in scenario 6 € 630. In these subjects, continuation of treatment for six cycles of clomiphene citrate, 6 or 12 cycles of gonadotrophins and IVF is potentially cost-effective. These results should be confirmed in a randomized clinical trial. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents

PubMed Central

Jungheim, Emily S.; Odibo, Anthony O.

2010-01-01

Study objective To compare different oral ovulation induction agents in treating infertile women with polycystic ovary syndrome Design Decision-analytic model comparing three treatment strategies using probability estimates derived from literature review and sensitivity analyses performed on the baseline assumptions Setting Outpatient reproductive medicine and gynecology practices Patients Infertile women with polycystic ovary syndrome Interventions Metformin, clomiphene citrate, or metformin with clomiphene citrate Main Outcome Measures Live birth Results Within the baseline assumptions, combination therapy with metformin and clomiphene citrate was the preferred therapy for achieving live birth in women with polycystic ovary syndrome. Sensitivity analysis revealed the model to be robust over a wide range of probabilities. Conclusions Combination therapy with metformin and clomiphene citrate should be considered as first-line treatment for infertile women with polycystic ovary syndrome PMID:20451181

Clomiphene citrate increases nitric oxide, interleukin-10 and reduces matrix metalloproteinase-9 in women with polycystic ovary syndrome.

PubMed

Sylus, Angel Mercy; Nandeesha, Hanumanthappa; Sridhar, Magadi Gopalakrishna; Chitra, Thyagaraju; Sreenivasulu, Karli

2018-06-08

Matrix metalloproteinase-9, Nitric oxide and inflammation plays a role in the pathogenesis of poly cystic ovary syndrome (PCOS). Even though these parameters are altered in PCOS, the effect of clomiphene citrate on them has not been studied till date. The present study was done to assess the effect of clomiphene citrate on matrix metalloproteinase-9, nitric oxide and interleukin-10 levels in women with PCOS. 72 women diagnosed with PCOS were enrolled in the study. Matrix metalloproteinase-9, nitric oxide and interleukin-10 levels were compared at baseline and after three weeks following Clomiphene citrate treatment. Clomiphene citrate increases both nitric oxide (p = 0.03) and interleukin-10 (p < 0.001) levels and reduces matrix metalloproteinase-9 levels (p < 0.001) in women with PCOS. It also improves the ovulation rate (52.8%) and clinical pregnancy rate (19.4%) in PCOS. Also there was a significant reduction in matrix metalloproteinase-9 levels in both the ovulatory (p < 0.001) and conceived groups (p = 0.024) compared to non ovulatory and non conceived group. There was no difference in nitric oxide and interleukin-10 levels in ovulatory and conceived groups compared to non ovulatory and non conceived group. We conclude that clomiphene citrate increases the levels of nitric oxide and interleukin-10 and decreases the matrix metalloproteinase - 9 levels and improves the ovulation rate and clinical pregnancy rate in PCOS. Copyright © 2018 Elsevier B.V. All rights reserved.

Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: A randomized controlled trial

PubMed Central

2011-01-01

Background The aim of this randomized controlled trial was to compare the efficacy of extended letrozole regimen with clomiphene citrate in women with unexplained infertility undergoing superovulation and intrauterine insemination (IUI). Methods Two hundred and fourteen patients with unexplained infertility were randomized into two equal groups using computer generated list and were treated by either letrozole 2.5 mg/day from cycle day 1 to 9 (extended letrozole group, 211 cycles) or clomiphene citrate 100 mg/day from cycle day 3 to 7 (clomiphene citrate group,210 cycles). Intrauterine insemination was performed 36 to 40 hours after HCG administration. Results Both groups were comparable with regard to number of mature follicles (2.24 +/- 0.80 Vs 2.13 +/- 0.76) and the day of HCG administration. Serum estradiol was significantly greater in clomiphene citrate group (356 +/- 151 Vs 822 +/- 302 pg/ml, P = < 0.001) and the endometrial thickness was significantly greater in extended letrozole group (9.10 +/- 1.84 Vs 8.18 +/- 1.93 mm, P = < 0.001).The pregnancy rate per cycle and cumulative pregnancy rate were significantly greater in extended letrozole group (18.96% Vs 11.43% and 37.73% Vs 22.86%, respectively). Conclusion The extended letrozole regimen had a superior efficacy as compared with clomiphene citrate in patients of unexplained infertility undergoing superovulation and IUI. Trial registration ClinicalTrials.gov, NCT01232075 PMID:21693030

Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome.

PubMed

Leanza, V; Coco, L; Grasso, F; Leanza, G; Zarbo, G; Palumbo, M

2014-06-01

Polycystic ovary syndrome (PCOS) is one of the most common causes of ovulatory infertility. It is an endocrine disorders characterized by a high level of male hormones (androgens) and frequent anovulatory cycles associated with multiple ovarian microcysts. The aim of this paper was to evaluate effects of a Clomiphene citrate alone versus a combined treatment (Metformin and Clomiphene citrate). A total of 60 women with PCOS and infertility were evaluated. Inclusions criteria were: age 26-34 years, nulliparity, above 3 years of sterility, multiple ovarian microcysts, BMI>27.5, oligomenorrhea/amenorrhea, hyperandrogenism and normal male fertility. Four patients were excluded (renal damage 2, tubal occlusion 1 and Pelvic Inflammatory Disease 1). The remaining 56 were divided into 2 groups: group A were inducted with Clomiphene Citrate alone, while group B were inducted with Clomiphene citrate and Metformin. In group A we obtained ovulation in 20 women (71.4%), 8 pregnancies (28.5%) and one (3.5%) spontaneous abortion. In group B we obtained ovulation in 24 women (85.7%), 15 pregnancies (53.5%) and no spontaneous abortions. Combined treatment was found to be more effective (53.5) in improving pregnancy rate compared to monotherapy (28.5%).

The laparoscopic ovarian electrocautery versus gonadotropin therapy in infertile women with clomiphene citrate-resistant polycystic ovary syndrome; a randomized controlled trial.

PubMed

Mehrabian, Ferdous; Eessaei, Fatemeh

2012-03-01

This study aimed to compare two methods of treatment of infertility with gonadotropin with laparoscopic ovarian electrocauterization in patients with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). A number of 104 nulipara patients with polycystic ovary syndrome, who were resistant to clomiphene citrate were randomly assigned to two groups. One group received gonadotropin; after the bleeding withdrawal and from the third day of the cycle, the injection of human menopausal gonadotropin (HMG) was started with 10 mg medroxy progesterone. The patients were followed with serial trans-vaginal sonographies. When the diameter of follicles reached to 18 mm, human chorionic gonadotropin (HCG) was prescribed. The other group was treated with laparoscopic ovarian electrocauterization under general anesthesia. If after 3 cycles, the anovulation was established with progesterone measurement, the clomiphene citrate was prescribed. Gonadotropin was administered, if the lack of ovulation persisted. No significant difference was documented between the two groups in terms of the obesity indexes, duration of infertility, age, sonographic and laboratory findings. In the gonadotropin group, 37 cases (71%) of pregnancy occurred. The rate of pregnancy was the same in the other group consisting of 18 cases treated by electrocautery, 9 cases with cautery + clomiphene, and 10 cases with clomiphene + cautery + gonadotropin. In the group treated with gonadotropin, there were 1 triple and 4 twins pregnancies. In the group treated with ovarian electrocautery, one twin pregnancy was observed. In the group treated with gonadotropin, 2 cases of ovarian hyperstimulation syndrome, 1 case of ectopic pregnancy and 6 cases of miscarriage occurred; the corresponding figure in the ovarian electrocautery group consisted of 5 cases of miscarriage. Our findings suggest that ovarian electrocauterization is an appropriate method with good efficacy and low complication rate for infertility treatment of women with clomiphene citrate-resistant polycystic ovary syndrome.

Predictors of patient responses to ovulation induction with clomiphene citrate in patients with polycystic ovary syndrome experiencing infertility.

PubMed

Ellakwa, Hamed E; Sanad, Zakaria F; Hamza, Haitham A; Emara, Mohamed A; Elsayed, Mohamed A

2016-04-01

To identify predictors of clomiphene citrate-induced ovulation in patients with polycystic ovary syndrome (PCOS). A prospective observational study of patients 18-40 years of age with PCOS experiencing infertility was conducted at Menoufia University Hospital between January 2011 and January 2013. A range of potential predictors of ovulation were recorded before patients received a 50-mg dose of clomiphene citrate. Following ovulation or no response to increasing clomiphene-citrate doses, correlations between predictors and treatment responses were analyzed. In total, 150 patients with PCOS experiencing infertility were enrolled. Following treatment, 110 (73.3%) patients ovulated. Highly significant differences were observed between treatment responders and non-responders in baseline amenorrhea, body mass index (BMI), waist circumference, total testosterone, anti-Müllerian hormone, fasting insulin, homeostatic model assessment of insulin resistance, and visceral fat area (P<0.001). Significant differences in mean ovarian volume (P<0.009) and ovarian stromal artery pulsatility index (P<0.003) were also observed. Total testosterone was the best individual predictor of clomiphene citrate treatment response. The area under the receiver operating characteristic curve in a multivariate prediction model was 0.98. A combination of patient amenorrhea, BMI, total testosterone, anti-Müllerian hormone, ovarian volume, ovarian stromal artery pulsatility index, and visceral fat area could be used to predict clomiphene-citrate treatment response in patients with PCOS experiencing infertility. ClinicalTrials.gov: NCT02269306. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial.

PubMed

Badawy, Ahmed; State, Omnia; Abdelgawad, Soma

2007-01-01

To compare clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for inducing ovulation in patients with polycystic ovary syndrome. Prospective cross-over trial. University teaching hospital and a private practice setting. Five hundred and seventy-three patients were treated with clomiphene citrate for one menstrual cycle among which 470 patients were treated with clomiphene citrate plus N-acetyl cysteine for another cycle. All women suffered from polycystic ovary syndrome. Patients had clomiphene citrate 50-mg tablets twice daily alone or with N-acetyl cysteine 1,200 mg/day orally for 5 days starting on day 3 of the menstrual cycle. Primary outcomes were number of mature follicles, serum E2, serum progesterone, and endometrial thickness. Secondary outcome was the occurrence of pregnancy. Ovulation rate improved significantly after the addition of N-acetyl cysteine (17.9% versus 52.1%). Although the number of mature follicles was more in the N-acetyl cysteine group (2.1+/-0.88 versus 3.2+/-0.93), the difference was not statistically significant. The mean E2 levels (pg/ml) at the time of human chorionic gonadotropine injection, serum progesterone levels (ng/ml) on days 21-23 of the cycle, and the endometrial thickness were significantly improved in the N-acetyl cysteine group. The overall pregnancy rate was 11.5% in the N-acetyl cysteine group. Insulin resistance occurred in 260 patients (55.4%). There was no significant difference between the insulin resistance group (n = 260) and non-insulin resistance group (n = 210) as regards ovulation rate, number of follicles, serum E2 (pg/ml), serum progesterone (ng/ml), endometrial thickness (mm), or pregnancy rate. N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients.

Effectiveness of electroacupuncture for polycystic ovary syndrome: study protocol for a randomized controlled trial.

PubMed

Chen, Jiao; Feng, Shuwei; Zeng, Jiuzhi; Wu, Xi; Yang, Mingxiao; Tang, Hongzhi; Fan, Huaying; Yang, Jie; Liang, Fanrong

2016-05-21

Whether electroacupuncture is effective for patients with polycystic ovary syndrome is still inconclusive. Therefore, this study aims to evaluate the add-on effects of electroacupuncture to conventional drugs for the treatment of polycystic ovary syndrome. This study is a two-center, open-labeled, randomized, controlled trial. A total of 116 eligible patients with polycystic ovary syndrome will be randomly allocated in a 1:1 ratio to the electroacupuncture plus clomiphene citrate group or to the clomiphene citrate group. Participants in the electroacupuncture plus clomiphene citrate group will receive electroacupuncture treatment in addition to clomiphene citrate capsules, whereas participants in the clomiphene citrate group will be prescribed clomiphene citrate capsules only. Electroacupuncture treatment will be performed from the fifth day of menstruation or withdrawal bleeding until the next menstruation, in three sessions per week for three menstrual cycles. The primary outcome is the ovulation rate. The secondary outcomes include the dominant follicle rate, mean number of dominant follicles, endometrial thickness, time point of ovulation, follicular size before ovulation, luteinizing hormone, estradiol level, and pregnancy rate. The measuring points for outcomes will be baseline and the completion of treatment. Any adverse events occurring during the trial process will be recorded. In addition, a quality-monitoring group independent from the research team will be set up to control the quality of the trial. The design and methodological rigor of this trial will allow for the collection of valuable data to evaluate the effectiveness of electroacupuncture for treating polycystic ovary syndrome. Therefore, this trial will contribute reliable evidence for use in clinical decision-making in acupuncture therapy of polycystic ovary syndrome as well as to future research in acupuncture for polycystic ovary syndrome. Chinese Clinical Trial Registry, ChiCTR-IOR-15007358 , registered on 26 October 2015.

Does metformin augment the ovulation inducing effects of clomiphene in non-obese women with polycystic ovary syndrome?

PubMed

Chaudhury, Kalyansree; Chaudhury, Sudeshna; Chowdhury, Subhankar

2008-10-01

To decide if metformin augments clomiphene response for ovulation induction in non-obese women with polycystic ovary syndrome, a prospective randomised placebo-controlled trial was undertaken among 27 patients, who were found eligible for this study following clinical assessment and basic investigations. Women with polycystic ovary syndrome, even when non-obese, has increased insulin-resistance and do not respond favourably when treated with clomiphene for ovulation induction. The hypothesis is that by improving insulin- resistance and thus reversing from hyperinsulinaemia towards normal insulin secretion will enhance the responsiveness of these women to ovulation inducing effects of clomiphene. In the metformin group there were 15 patients who were given metformin 500mg orally 8 hourly daily for initial 3 months whereas in the placebo group there were 12 patients who were given folic acid (as placebo) 5mg orally once daily for initial 3 months. Thereafter, all the 27 patients in both groups were treated with clomiphene 50mg orally once daily from day 2 for 5 days in each month for subsequent 3 months. However, metformin and folic acid was continued in the metformin group and placebo group respectively for these subsequent 3 months when these patients were being treated with clomiphene for ovulation induction. Ovulation, as the outcome measure, was assessed by serial transvaginal ultrasound scanning from day 8/ day 9 and serum progesterone estimation on the 7th or 8th day following the ultrasound evidence of ovulation. Ovulation is taken to have occurred when serum progesterone was > or =8 ng/ml. Ovulation was noted to have occurred in 71.11% of the 45 cycles studied in 15 patients in the metformin group whereas ovulation occurred in 11.11% of the 36 cycles studied in 12 patients in the placebo group. This difference was highly statistically significant (p < 0.001) by Fisher's exact test. It can be conducted that metformin augments the ovulation inducing effects of clomiphene in non-obese women with polycystic ovary syndrome.

Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial

PubMed Central

Bayram, Neriman; van Wely, Madelon; Kaaijk, Eugenie M; Bossuyt, Patrick M M; van der Veen, Fulco

2004-01-01

Objective To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with polycystic ovary syndrome. Design Randomised controlled trial. Setting Secondary and tertiary hospitals in the Netherlands. Participants 168 patients with clomiphene citrate resistant polycystic ovary syndrome: 83 were allocated electrocautery and 85 were allocated recombinant follicle stimulating hormone. Intervention Laparoscopic electrocautery of the ovaries followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or induction of ovulation with recombinant follicle stimulating hormone. Main outcome measure Ongoing pregnancy within 12 months. Results. The cumulative rate of ongoing pregnancy after recombinant follicle stimulating hormone was 67%. With only electrocautery it was 34%, which increased to 49% after clomiphene citrate was given. Subsequent recombinant follicle stimulating hormone increased the rate to 67% at 12 months (rate ratio 1.01, 95% confidence interval 0.81 to 1.24). No complications occurred from electrocautery with or without clomiphene citrate. Patients allocated to electrocautery had a significantly lower risk of multiple pregnancy (0.11, 0.01 to 0.86). Conclusion The ongoing pregnancy rate from ovulation induction with laparoscopic electrocautery followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or recombinant follicle stimulating hormone, seems equivalent to ovulation induction with recombinant follicle stimulating hormone, but the former procedure carries a lower risk of multiple pregnancy. PMID:14739186

Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome

PubMed Central

Stener-Victorin, Elisabet; Kuang, Hong-Ying; Ma, Hong-Li; Gao, Jing-Shu; Xie, Liang-Zhen; Hou, Li-Hui; Hu, Zhen-Xing; Shao, Xiao-Guang; Ge, Jun; Zhang, Jin-Feng; Xue, Hui-Ying; Xu, Xiao-Feng; Liang, Rui-Ning; Ma, Hong-Xia; Yang, Hong-Wei; Li, Wei-Li; Huang, Dong-Mei; Sun, Yun; Hao, Cui-Fang; Du, Shao-Min; Yang, Zheng-Wang; Wang, Xin; Yan, Ying; Chen, Xiu-Hua; Fu, Ping; Ding, Cai-Fei; Gao, Ya-Qin; Zhou, Zhong-Ming; Wang, Chi Chiu; Wu, Tai-Xiang; Liu, Jian-Ping; Ng, Ernest H. Y.; Legro, Richard S.; Zhang, Heping

2017-01-01

Importance Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures The primary outcome was live birth. Secondary outcomes included adverse events. Results Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, −0.6%; 95% CI, −5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration clinicaltrials.gov Identifier: NCT01573858 PMID:28655015

Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial.

PubMed

Wu, Xiao-Ke; Stener-Victorin, Elisabet; Kuang, Hong-Ying; Ma, Hong-Li; Gao, Jing-Shu; Xie, Liang-Zhen; Hou, Li-Hui; Hu, Zhen-Xing; Shao, Xiao-Guang; Ge, Jun; Zhang, Jin-Feng; Xue, Hui-Ying; Xu, Xiao-Feng; Liang, Rui-Ning; Ma, Hong-Xia; Yang, Hong-Wei; Li, Wei-Li; Huang, Dong-Mei; Sun, Yun; Hao, Cui-Fang; Du, Shao-Min; Yang, Zheng-Wang; Wang, Xin; Yan, Ying; Chen, Xiu-Hua; Fu, Ping; Ding, Cai-Fei; Gao, Ya-Qin; Zhou, Zhong-Ming; Wang, Chi Chiu; Wu, Tai-Xiang; Liu, Jian-Ping; Ng, Ernest H Y; Legro, Richard S; Zhang, Heping

2017-06-27

Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. The primary outcome was live birth. Secondary outcomes included adverse events. Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. clinicaltrials.gov Identifier: NCT01573858.

Scleroderma renal crisis and ovarian hyperstimulation syndrome related to the use of clomiphene in a patient with scleroderma.

PubMed

Kobak, Senol; Hacivelioglu, Servet; Gungor, Selen

2014-01-01

This paper presented a 28-year-old female with systemic sclerosis who developed scleroderma renal crisis and ovarian hyperstimulation syndrome following clomiphene administration. Urgent therapy including angiotensin-converting enzyme (ACE) inhibitors and supportive care resulted in regression and eventually resolution of all the clinical and laboratory symptoms. Although scleroderma renal crisis is a fatal complication of high-dose corticosteroids, rarely is this seen with the use of ACE inhibitors. This case report aimed to investigate the potential capacity of the selective oestrogen receptor modulator clomiphene to induce scleroderma renal crisis as well as corticosteroids. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Pregnancy following laparoscopic ovarian drilling for clomiphene resistant polycystic ovarian syndrome.

PubMed

Ikechebelu, J I; Mbamara, S U; Okeke, C A F

2010-06-01

We present a case of a 29 year old nulliparous woman with clomiphene resistance polycystic ovarian syndrome. She had a successful laparoscopic ovarian drilling (LOD) in a private fertility centre in Nnewi Southeast Nigeria. She achieved a pregnancy four months later following clomiphene citrate ovulation induction. The pregnancy was complicated with 1st trimester threatened abortion, pre-term PROM and later pre-term labour at 34 weeks gestation with breech presentation. She had a successful caesarean delivery of a 1.75 kg life female baby that was nursed in the incubator for 2 weeks before discharge. This is the first reported successful LOD in Southeast Nigeria with good pregnancy outcome.

The significance of anthropometric and endocrine parameters in ovulation induction with clomiphene citrate in women with polycystic ovary syndrome.

PubMed

Akpinar, Funda; Dilbaz, Berna; Cırık, Derya A; Yilmaz, Saynur; Kiykac, Sadiman; Karahanoglu, Ertugrul; Mollamahmutoglu, Leyla

2016-11-01

To investigate factors associated with the response to ovarian stimulation in patients with polycystic ovary syndrome. Methods: The records of patients with polycystic ovary syndrome and infertility who underwent ovulation induction with clomiphene citrate were reviwed between January 2011 and December 2014 in Etlik Zübeyde Hanim Women's Health Training and Research Hospital Ankara, Turkey. The anthropometric and endocrine factors of patients who were resistant to treatment at a dose of 150 mg/day (n=84) were compared with those who responded with growth of at least one graaffian follicle at a dose of 50 mg/day (n=342). Results: Of the parameters examined, body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio were significantly higher in the clomiphene citrate-resistant group compared with the responsive group. Conclusion: Reproductive treatment in patients with polycystic ovary syndrome show different outcomes. Significantly higher body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio observed in clomiphene citrate resistant group can be a possible explanation for this impedance.

The significance of anthropometric and endocrine parameters in ovulation induction with clomiphene citrate in women with polycystic ovary syndrome

PubMed Central

Akpinar, Funda; Dilbaz, Berna; Cirik, Derya A.; Yılmaz, Saynur; Kıykac, Sadıman; Karahanoglu, Ertugrul; Mollamahmutoglu, Leyla

2016-01-01

Objectives: To investigate factors associated with the response to ovarian stimulation in patients with polycystic ovary syndrome. Methods: The records of patients with polycystic ovary syndrome and infertility who underwent ovulation induction with clomiphene citrate were reviwed between January 2011 and December 2014 in Etlik Zübeyde Hanim Women’s Health Training and Research Hospital Ankara, Turkey. The anthropometric and endocrine factors of patients who were resistant to treatment at a dose of 150 mg/day (n=84) were compared with those who responded with growth of at least one graaffian follicle at a dose of 50 mg/day (n=342). Results: Of the parameters examined, body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio were significantly higher in the clomiphene citrate-resistant group compared with the responsive group. Conclusion: Reproductive treatment in patients with polycystic ovary syndrome show different outcomes. Significantly higher body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio observed in clomiphene citrate resistant group can be a possible explanation for this impedance. PMID:27761570

Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis.

PubMed

Misso, Marie L; Costello, Michael F; Garrubba, Marie; Wong, Jennifer; Hart, Roger; Rombauts, Luk; Melder, Angela M; Norman, Robert J; Teede, Helena J

2013-01-01

BACKGROUND Recent studies suggest that metformin may be more effective in women with polycystic ovary syndrome (PCOS) who are non-obese. The objective here is to determine and compare the effectiveness of metformin and clomiphene citrate for improving fertility outcomes in women with PCOS and a BMI < 32 kg/m(2) (BMI 32 kg/m(2) was used to allow for international differences in BMI values which determine access to infertility therapy through the public health system). METHODS Databases were searched for English language articles until July 2011. women of any age, ethnicity and weight with PCOS diagnosed by all current criteria, who are infertile; at least 1000 mg of any type of metformin at any frequency, including slow release and standard release, compared with any type, dose and frequency of clomiphene citrate. rates of ovulation, live birth, pregnancy, multiple pregnancies, miscarriage, adverse events, quality of life and cost effectiveness. Data were extracted and risk of bias assessed. A random effects model was used for meta-analyses of data, using risk ratios (relative risk). RESULTS The search returned 4981 articles, 580 articles addressed metformin or clomiphene citrate and four randomized controlled trials (RCTs) comparing metformin with clomiphene citrate were included. Upon meta-analysis of the four RCTs, we were unable to detect a statistically significant difference between the two interventions for any outcome in women with PCOS and a BMI < 32 kg/m(2), owing to significant heterogeneity across the RCTs. CONCLUSIONS Owing to conflicting findings and heterogeneity across the included RCTs, there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI < 32 kg/m(2). However, a lack of superiority of one treatment is not evidence for equivalence, and further methodologically rigorous trials are required to determine whether there is a difference in effectiveness between metformin and placebo (or no treatment) or between metformin and clomiphene citrate for ovulation induction in women with PCOS who are non-obese. Until then, caution should be exercised when prescribing metformin as first line pharmacological therapy in this group of women.

Heterotopic pregnancy following induction of ovulation with clomiphene citrate.

PubMed

Ghandi, Sedigheh; Ahmadi, Raheleh; Fazel, Mahmoud

2011-01-01

Although heterotopic gestation is common in assisted reproductive techniques, it is very rare in natural conception and clomiphene induced pregnancy. Diagnosis and appropriate intervention of heterotopic pregnancy requires a high index of suspicious. In this paper a case of heterotopic pregnancy in a 30-year old woman with hemoperitoneum from ruptured tubal pregnancy with live intrauterine gestation at 9 weeks of gestation is reported. This case suggests that a heterotopic pregnancy must always be considered particularly after the induction of ovulation by clomiphene citrate or assisted reproductive technology. Every clinician treating women of reproductive age should keep this diagnosis in mind. It also demonstrates that early diagnosis is essential in order to salvage the intrauterine pregnancy and avoid maternal morbidity and mortality.

Heterotopic pregnancy following induction of ovulation with clomiphene citrate

PubMed Central

Ghandi, Sedigheh; Ahmadi, Raheleh; Fazel, Mahmoud

2011-01-01

Background: Although heterotopic gestation is common in assisted reproductive techniques, it is very rare in natural conception and clomiphene induced pregnancy. Diagnosis and appropriate intervention of heterotopic pregnancy requires a high index of suspicious. Case: In this paper a case of heterotopic pregnancy in a 30-year old woman with hemoperitoneum from ruptured tubal pregnancy with live intrauterine gestation at 9 weeks of gestation is reported. Conclusion: This case suggests that a heterotopic pregnancy must always be considered particularly after the induction of ovulation by clomiphene citrate or assisted reproductive technology. Every clinician treating women of reproductive age should keep this diagnosis in mind. It also demonstrates that early diagnosis is essential in order to salvage the intrauterine pregnancy and avoid maternal morbidity and mortality. PMID:26396583

Clomiphene Stair-Step Protocol for Women With Polycystic Ovary Syndrome.

PubMed

Jones, Tiffanny; Ho, Jacqueline R; Gualtieri, Marc; Bruno-Gaston, Janet; Chung, Karine; Paulson, Richard J; Bendikson, Kristin A

2018-01-01

To compare time to ovulation, ovulation rates, and side effect profile of traditional and the stair-step protocol for ovulation induction using clomiphene citrate in women with polycystic ovary syndrome (PCOS). We performed a retrospective study of women seeking care for infertility with a diagnosis of PCOS at a university-based infertility clinic from July 2012 to July 2014. We included patients who were resistant to the initial starting dose of 50 mg clomiphene. The primary outcome was time to ovulation. Secondary outcomes included ovulation rates, clinical pregnancy rates, and mild and moderate-to-severe side effects based on dose. For the traditional protocol, higher doses of clomiphene were used each subsequent month if no ovulation occurred. For the stair-step protocol, higher doses of clomiphene were given 7 days after the last dose if no dominant follicles were seen on ultrasonography. Our study had 80% power to detect a 20% difference in ovulation. One hundred nine patients were included in the analysis with 66 (60.6%) in the traditional and 43 (39.4%) in the stair-step protocol. Age and body mass index were similar between groups. The time to ovulation was decreased in the stair-step protocol group compared with the traditional protocol group (23.1±0.9 days vs 47.5±6.3 days). Ovulation rates were increased in the stair-step group compared with the traditional group at 150 mg (16 [37%] vs 8 [12%], P=.004) and at 200 mg (9 [21%] vs 3 [5%], P=.01). Pregnancy rates were similar between groups once ovulation was achieved (12 [18.1%] vs 7 [16.3%], P=.08). The stair-step protocol had an increased incidence of mild side effects (vasomotor flushes, headaches, gastrointestinal disturbance, mastalgia, changes in mood; 18 [41%] vs 8 [12%]), but there was no difference in the incidence of severe side effects (headaches, visual disturbances). For women with PCOS, the stair-step clomiphene protocol is associated with decreased time to ovulation and increased ovulation rates at higher doses when compared with the traditional protocol.

Polycystic ovarian disease.

PubMed

Raj, S G; Talbert, L M

1984-01-01

Polycystic ovarian disease (PCOD) was first described as a single disease by Stein and Leventhal in 1935, but now has been separated into several distinct entities, comprising a symptom complex. The most frequent presenting symptoms associated with PCOD are obesity, hirsutism, amenorrhea or anovulation, dysfunctional uterine bleeding, irregular menses, and infertility. The common finding of hirsutism in PCOD patients is a reflection of the hyperandrogenism resulting from elevation of all the androgens, including testosterone, androstenediol, dehydroepiandrostrone sulfate (DHEA-S), and androstenedione. Some patients with all the clinical features of PCOD can be shown, through appropriate testing, to have an attenuated form of classic congenital adrenal hyperplasia (CAH). Serum follicle stimulating hormone (FSH) levels are usually low or in the normal range, and serum luteinizing hormone (LH) levels are usually elevated in patients with PCOD, resulting in an altered LH/FSH ratio. Treatment for PCOD must be based on the needs and desires of the individual patient, and on the pathophysiology of the patient's particular abnormalities. When pregnancy is desired, ovulation induction with clomiphene is indicated. Clomiphene is a weak estrogen that induces a transient rise in serum LH and FSH, followed by a gonadotropic pattern similar to normal cycles. A 72% ovulation rate and a 41.8% conception rate have been reported after treatment with clomiphene. In patients who do not respond to clomiphene, or clomiphene with added human chorionic gonadotropin (hCG), human menopausal gonadotropin (hMG) can be used to induce ovulation, but the patient should be closely monitored for multiple ovulation, multiple pregnancy, or hyperstimulation syndrome. For patients not interested in conception, regular menstrual cyclicity can be restored and hyperandrogenism reduced with oral contraceptives (OCs).

Intrauterine insemination versus timed intercourse with clomiphene citrate in polycystic ovary syndrome: a randomized controlled trial.

PubMed

Abu Hashim, Hatem; Ombar, Osama; Abd Elaal, Ibrahim

2011-04-01

To compare the efficacy of intrauterine insemination vs. timed intercourse with clomiphene citrate as a first-line treatment for anovulatory infertility associated with polycystic ovary syndrome. A randomized controlled trial following the CONSORT criteria. A university hospital and a private practice setting. 188 women (525 cycles) with polycystic ovary syndrome. Women received three consecutive cycles of ovulation induction with clomiphene citrate and intrauterine insemination (n=93, 259 cycles) or three consecutive cycles of clomiphene citrate with timed intercourse (n=95, 266 cycles). Clinical pregnancy rate per cycle, number of growing and mature follicles, serum estradiol, endometrial thickness at the hCG day, serum progesterone, ovulation, miscarriage and live birth rates. There were no differences between the two groups regarding the clinical pregnancy rate per cycle or per woman (8.49 vs. 7.89% and 23.6 vs. 22.1%; p=0.26 and p=0.33, respectively). Two twin pregnancies occurred in each group. Miscarriage and live birth rates were comparable (18.1 vs. 19% and 19.35 vs. 17.89%; p=0.31 and p=0.33, respectively). No ectopic, higher-order pregnancies or cases of ovarian hyperstimulation syndrome occurred. No differences were found regarding the number of follicles, serum progesterone, ovulation rates, estradiol levels or endometrial thickness at the hCG day (7.7±0.4 vs. 7.5±0.6mm; p=0.54). Ovulation induction with clomiphene citrate and timed intercourse is as effective as that with intrauterine insemination for achieving pregnancy in polycystic ovary syndrome and could represent the initial treatment option, being less invasive and less expensive than intrauterine insemination. © 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.

How do red and infrared low-level lasers affect folliculogenesis cycle in rat's ovary tissue in comparison with clomiphene under in vivo condition.

PubMed

Naseri, Paria; Alihemmati, Alireza; Rasta, Seyed Hossein

2017-12-01

Folliculogenesis is a cycle that produces the majority of oocyte. Any disruption to this cycle leads to ovulation diseases, like polycystic ovarian syndrome (PCOS). Treatments include drugs and surgery; lasers have also been used complementarily. Meanwhile, still there is no definite treatment for PCOS. This study investigated the photo-bio stimulation effect of near-infrared and red low-level laser on producing follicles and compared the result with result of using common drug, clomiphene. Therefore, the aim of this study was to propose the use of lasers autonomously treatment. So, there was one question: how do lasers affect folliculogenesis cycle in rat's ovary tissue? In this study, 28 rats were assigned to four groups as follows: control (CT), clomiphene drug (D), red laser (RL), and near-infrared laser (NIRL). Afterwards, 14 rats of RL and NIRL groups received laser on the first 2 days of estrous cycle, each 6 days, for 48 days. During treatment period, each rat received energy density of 5 J/cm 2 . Seven rats in D group received clomiphene. After the experiment, lasers' effects at two wavelengths of 630 and 810 nm groups have been investigated and compared with clomiphene and CT groups. Producing different follicles to complement folliculogenesis cycle increased in NIRL and RL groups, but this increase was significant only in the NIRL group. This indicates that NIRL increases ovarian activity to produce oocyte that certainly can be used in future studies for finding a cure to ovarian negligence to produce more oocyte and treat diseases caused by it like PCOS.

Congenital malformations among babies born following letrozole or clomiphene for infertility treatment.

PubMed

Sharma, Sunita; Ghosh, Sanghamitra; Singh, Soma; Chakravarty, Astha; Ganesh, Ashalatha; Rajani, Shweta; Chakravarty, B N

2014-01-01

Clomiphene citrate (CC) is the first line drug for ovulation induction but because of its peripheral antiestrogenic effect, letrozole was introduced as the 2nd line drug. It lacks the peripheral antiestrogenic effect and is associated with similar or even higher pregnancy rates. Since letrozole is a drug for breast cancer, its use for the purpose of ovulation induction became controversial in the light of studies indicating an increased incidence of congenital malformations. To evaluate and compare the incidence of congenital malformations among offsprings of infertile couples who conceived naturally or with clomiphene citrate or letrozole treatment. A retrospective cohort study done at a tertiary infertility centre. A total of 623 children born to infertile women who conceived naturally or following clomiphene citrate or letrozole treatment were included in this study. Subjects were sorted out from medical files of both mother and newborn and follow up study was done based on the information provided by parents through telephonic conversations. Babies with suspected anomaly were called and examined by specialists for the presence of major and minor congenital malformations. Other outcomes like multiple pregnancy rate and birth weight were also studied. Overall, congenital malformations, chromosomal abnormalities were found in 5 out of 171 (2.9%) babies in natural conception group and 5 out of 201 babies in the letrozole group (2.5%) and in 10 of 251 babies in the CC group (3.9%). There was no significant difference in the overall rate of congenital malformations among children born to mothers who conceived naturally or after letrozole or CC treatment. Congenital malformations have been found to be comparable following natural conception, letrozole and clomiphene citrate. Thus, the undue fear against letrozole may be uncalled for.

Switch to restoration therapy in a testosterone treated central hypogonadism with erythrocytosis.

PubMed

Cangiano, B; Cacciatore, C; Persani, L; Bonomi, M

2017-01-01

We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic-pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion. Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.

Metformin versus chromium picolinate in clomiphene citrate-resistant patients with PCOs: A double-blind randomized clinical trial.

PubMed

Amooee, Sedigheh; Parsanezhad, Mohammad Ebrahim; Ravanbod Shirazi, Maryam; Alborzi, Saeed; Samsami, Alamtaj

2013-08-01

Chromium picolinate could be effective in clomiphen citrate resistant PCOS patients. To compare the effects of chromium picolinate vs. metformin in clomiphen citrate resistant PCOS patients. The present randomized clinical trial was performed on 92 women with clomiphen citrate-resistant PCOS at the clinics which were affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The subjects were randomly assigned to two groups receiving either chromium picolinate (200µg daily) or metformin (1500mg daily) for 3 months. Anthropometric and hormonal profile were measured and compared both before and after the treatment. Ovulation and pregnancy rate was measured in the two study groups, as well. Chromium picolinate significantly decreased fasting blood sugar (FBS) after 3 months of treatment (p=0.042). In the same way, the serum levels of fasting insulin had significantly decreased leading to an increase in insulin sensitivity as measured by QUICKI index (p=0.014). In comparison to the patients who received chromium picolinate, those who received metformin had significantly lower levels of testosterone (p=0.001) and free testosterone (p=0.001) after 3 months of treatment. Nevertheless, no significant difference was found between the two study groups regarding ovulation (p=0.417) and pregnancy rates (p=0.500). Chromium picolinate decreased FBS and insulin levels and, thus, increased insulin sensitivity in clomiphene citrate-resistance PCOS women. These effects were comparable with metformin; however, metformin treatment was associated with decreased hyperandrogenism. Overall, chromium picolinate was better tolerated compared to metformin; nonetheless, the two study groups were not significantly different regarding ovulation and pregnancy rates. Registration ID in IRCT: IRCT201203139281N1.

DNA synthesis in the pituitary gland of the rat: effect of sulpiride and clomiphene.

PubMed

Burdman, J A; Szijan, I; Jahn, G A; Machiavelli, G; Kalbermann, L E

1979-09-15

Sulpiride administration to rats releases prolactin and increases DNA replication in the anterior pituitary gland. Clomiphene prevents the stimulation of DNA synthesis produced by sulpiride, but does not affect prolactin release from the gland. These findings suggest that the intracellular prolactin content of the anterior pituitary gland plays a role in the regulation of DNA synthesis through a mechanism mediated by oestrogens.

Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence?

PubMed

Abu Hashim, Hatem

2016-01-01

The potential reproductive benefits of metformin, a drug endowed with the capacity to ameliorate insulin resistance in polycystic ovary syndrome (PCOS), has garnered much interest over the past 2 decades. In this review, randomized-controlled trials (RCT) and meta-analyses of RCT comparing metformin are critically appraised and summarized. PubMed and CENTRAL databases were consulted. Evidence is insufficient to favour the use of metformin or metformin plus clomiphene citrate instead of clomiphene citrate for ovulation induction in women with newly diagnosed PCOS. Evidence is also insufficient to recommend metformin as a primary treatment for non-obese women with PCOS. Metformin plus clomiphene citrate should be considered as an effective option in clomiphene citrate-resistant PCOS. In women with PCOS undergoing gonadotrophin ovulation induction, metformin significantly increased pregnancy and live birth rates (P < 0.0001 and P = 0.020, respectively) with reduced risk of cancelled cycles. A beneficial effect of metformin co-treatment in increasing clinical pregnancy rates and reducing the risk of OHSS in PCOS patients undergoing assisted reproduction techniques has been shown. No evidence was found of reduced risk of spontaneous abortion or increased risk of major anomalies in women with PCOS taking metformin during the first trimester. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Frequency of rate of body temperature chart at mid cycle in pregnant women and the subsequent effect on pregnancy.

PubMed

Kawamura, M; Ezawa, M; Onodera, T; Nagashima, T; Toyooka, R; Yagishita, M

2008-01-01

To determine if changes in basal body temperature (BBT) during the ovuratory phase are related to subsequent effects on pregnancy. BBT records from 216 pregnant women in a spontaneous cycle or a clomiphene citrate cycle during a recent 6-year period were studied. The last day of low phase (LDLP) and the number of days until high phase (NDHP) were determined for all subjects. In the spontaneous cycle group, medium-cycle cases were most frequent and long-cycle cases were most frequent in the clomiphene cycle group. The NDHP ranged between one and three days in 82.8% of the subjects in the spontaneous cycle group and in 86.1% of the subjects in the clomiphene cycle group. Our findings demonstrate the importance of properly evaluating an NDPH of two or even three days in a BBT-based assessment of ovarian function in the ovulatory phase.

[Flying needling therapy combined with clomiphene for ovulation failure in polycystic ovary syndrome:a randomized controlled trial].

PubMed

Ma, Hong; Quan, Xiaohong; Chen, Xiuhua; Dong, Ying

2016-11-12

To compare the efficacy among the combined treatment of flying needling therapy and clomiphene, the simple application of flying needling therapy and simple clomiphene in the treatment of ovulation failure in polycystic ovary syndrome (PCOS). Ninety patients of PCOS were randomized into a flying needling therapy group, a medication group and a combined treatment group, 30 cases in each one. In the flying needling therapy group, the flying needling therapy was simply applied to Ganshu (BL 18), Shenshu (BL 23), Zhongwan (CV 12), Shuifen (CV 9), Guanyuan (CV 4) and Zhongji (CV 3). The unilateral back- shu points were used alternatively in each treatment. The needles were inserted rapidly with rotation technique and even-needling manipulation. The needles were retained for 30 min. The treatment was given once every two days, 3 times a week. In the medication group, clomiphene was taken orally on the 5th day of menstruation, continuously for 5 days. In the combined treatment group, the flying needling therapy and clomiphene were used in combination. All of the patients were treated for 3 months and followed up for 1 month. The ovulation rates were compared among the three groups. The levels of androgen testosterone were compared before and after treatment. In the combined treatment group, the ovulation rate was 86.2% (100/116), better than 66.7% (80/120) in the flying needling therapy group and 69.6% (78/112) in the medication group (both P <0.05). The efficacy was similar between the fly needling therapy group and the medication group ( P >0.05). After treatment, the level of testosterone was reduced in the three groups (all P <0.05). In the combined treatment group, the improvement in androgen level was better than those in the flying needling therapy group and the medication group (both P <0.05). The efficacy was similar between the flying needling therapy group and the medication group ( P >0.05). The adverse reactions in the combined treatment group and the flying needling therapy group were lower than those in the medication group (both P <0.05). The flying needling therapy effectively improves in the ovulation failure of PCOS and its effect is similar to clomiphene. The allied treatment of them apparently improves the clinical efficacy and alleviates the adverse reactions.

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS

PubMed Central

Dodson, William C.; Kunselman, Allen R.; Stetter, Christy M.; Kris-Etherton, Penny M.; Williams, Nancy I.; Gnatuk, Carol L.; Estes, Stephanie J.; Allison, Kelly C.; Sarwer, David B.; Diamond, Michael P.; Schlaff, William D.; Casson, Peter R.; Christman, Gregory M.; Barnhart, Kurt T.; Bates, G. Wright; Usadi, Rebecca; Lucidi, Scott; Baker, Valerie; Zhang, Heping; Eisenberg, Esther; Coutifaris, Christos; Dokras, Anuja

2016-01-01

Context: In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. Objective: We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. Design, Setting, and Participants: This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18–40 years of age who were overweight/obese and infertile with PCOS. Intervention: We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). Main Outcome Measures: Live birth, pregnancy loss, and ovulation were measured. Results: In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1–1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2–1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3–4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3–4.8; P = .01). Conclusions: These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment. PMID:27172435

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS.

PubMed

Legro, Richard S; Dodson, William C; Kunselman, Allen R; Stetter, Christy M; Kris-Etherton, Penny M; Williams, Nancy I; Gnatuk, Carol L; Estes, Stephanie J; Allison, Kelly C; Sarwer, David B; Diamond, Michael P; Schlaff, William D; Casson, Peter R; Christman, Gregory M; Barnhart, Kurt T; Bates, G Wright; Usadi, Rebecca; Lucidi, Scott; Baker, Valerie; Zhang, Heping; Eisenberg, Esther; Coutifaris, Christos; Dokras, Anuja

2016-07-01

In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS. We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). Live birth, pregnancy loss, and ovulation were measured. In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01). These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance.

PubMed

Kamenov, Zdravko; Kolarov, Georgi; Gateva, Antoaneta; Carlomagno, Gianfranco; Genazzani, Alessandro D

2015-02-01

Insulin resistance plays a key role in the pathogenesis of polycystic ovarian syndrome (PCOS). One of the methods for correcting insulin resistance is using myo-inositol. The aim of the present study is to evaluate the effectiveness of myo-inositol alone or in combination with clomiphene citrate for (1) induction of ovulation and (2) pregnancy rate in anovulatory women with PCOS and proven insulin resistance. This study included 50 anovulatory PCOS patients with insulin resistance. All of them received myo-inositolduring three spontaneous cycles. If patients remained anovulatory and/or no pregnancy was achieved, combination of myo-inositol and clomiphene citrate was used in the next three cycles. Ovulation and pregnancy rate, changes in body mass index (BMI) and homeostatic model assessment (HOMA) index and the rate of adverse events were assessed. After myo-inositol treatment, ovulation was present in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 myo-inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant. During follow-up, a reduction of body mass index and HOMA index was also observed. Myo-inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients.

Comparing the Effect of Metformin and Acarbose Accompanying Clomiphene on the Successful Ovulation Induction in Infertile Women with Polycystic Ovary Syndrome.

PubMed

Rezai, Masomeh; Jamshidi, Mohmmad; Mohammadbeigi, Robabeh; Seyedoshohadaei, Fariba; Mohammadipour, Somaye; Moradi, Ghobad

2016-09-01

The aim of this study was to compare the effects of Metformin and Acarbose accompanying Clomiphene on the successful ovulation induction in infertile women with polycystic ovary syndrome.This randomized double blind clinical trial study was performed on 60 women with polycystic ovary syndrome. Women were selected and randomly divided in two control and intervention groups. Intervention group received Acarbose 100 mg/day for 3 months. In the first, second, and third weeks, they received 1 tablet, 2 tablets, and 3 tablets per day respectively. In addition, they received 100 mg Clomiphene from third to seventh day of menstruation, during the 3 month treatment period. The control group received Metformin 500 mg/day for 3 months. In the first, second, and third weeks, they received 1 tablet, 2 tablets, and 3 tablets per day respectively. In addition, they received 100 mg Clomiphene from third to seventh day of menstruation, during the 3 month treatment period. All the subjects in both groups before and after the treatment were examined for hirsutism, acne, oral glucose tolerance test, serum triglycerides, cholesterol, LDL, HDL. Also, induction of ovulation was assessed by vaginal ultrasound. The Mean of BMI and fasting glucose tolerance test in Acarbose group was less than Metformin group (P = 0.05). The mean of triglycerides, LDL and HDL levels did not differ between the two groups after the intervention (P > 0.05). The mean of cholesterol levels were different in the two groups after the intervention (P = 0.04). Frequency of ovulation induction in those who received Acarbose (78.5%) was more than those who received Metformin (46.6) (P = 0.012). Comparing with Metformin, Acarbose accompanying Clomiphene was more effective in ovulation induction and decreasing body mass index in infertile women with polycystic ovary syndrome.

CLOMIPHENE CITRATE IN THE TREATMENT OF IDIOPATHIC OR FUNCTIONAL HYPOGONADOTROPIC HYPOGONADISM IN MEN: A CASE SERIES AND REVIEW OF THE LITERATURE.

PubMed

Liel, Yair

2017-03-01

Late-onset hypogonadotropic hypogonadism (LOH) is a complex, heterogeneous entity. Whenever treatment is indicated, the endocrine literature has recommend testosterone replacement. We present our experience with clomiphene citrate treatment in patients with LOH and a review of the literature. This retrospective case series included 18 male patients with hypogonadotropic hypogonadism, roughly according to the European Male Aging Study criteria for LOH, attended at an academic hospital outpatient clinic. Data were retrieved from the patients' electronic medical records. The patients' mean age (±SD) was 44.3 ± 6.3 years (range 21-67 years) referred for evaluation of low testosterone together with decreased libido, erectile dysfunction, fatigue or tiredness, anxiety, and osteoporosis. Clomiphene was initially prescribed at doses between 25 mg 3 times a week and 50 mg/day. At 6 to 8 weeks following initiation of treatment, mean basal total-testosterone increased from 7.6 ± 2.6 to 19.3 ± 5.2 nmol/L (P<.0001). Mean basal luteinizing hormone (LH) increased from 2.7 ± 2.1 to 8.3 ± 3.5 nmol/L (P<.0001). Mean basal follicle-stimulating hormone (FSH) increased from 4.2 ± 3.6 to 8.6 ± 6.2 nmol/L (P = .007). Testosterone and LH responses were invariably observed, including 2 patients with history of nonpituitary cranial pathologies, 2 with somewhat elevated FSH, and 1 with an eating disorder. Twelve (67%) patients reported improvement in symptoms. Side effects included transient nipple tenderness in 1 patient. Available data suggest that clomiphene is an efficient and convenient alternative to testosterone replacement therapy in a substantial subset of patients with LOH. Additional long-term controlled studies should further establish the role of clomiphene in LOH. FSH = follicle-stimulating hormone LH = luteinizing hormone LOH = late-onset hypogonadotropic hypogonadism.

Altering Hirsutism Through Ovulation Induction in Women With Polycystic Ovary Syndrome

PubMed Central

Roth, Lauren W.; Huang, Hao; Legro, Richard S.; Diamond, Michael P.; Coutifaris, Christos; Carson, Sandra A.; Steinkampf, Michael P.; Carr, Bruce R.; McGovern, Peter G.; Cataldo, Nicholas A.; Gosman, Gabriella G.; Nestler, John E.; Myers, Evan R.; Zhang, Heping; Schlaff, William D.

2012-01-01

Objective Many women with polycystic ovary syndrome (PCOS) experience infertility and hirsutism and often seek treatment for both concurrently. We investigated whether women who ovulate in response to treatment with clomiphene citrate), metformin, or both would have greater improvement in hirsutism compared to those who did not ovulate. Methods This is a secondary analysis evaluating the change in Ferriman-Gallwey score for the hirsute women (n = 505, 80.7%) from the Pregnancy in Polycystic Ovary Syndrome 1 study. This was a prospective, randomized, doubled-blind trial of 626 women with PCOS and infertility recruited from 12 university sites. They were treated with clomiphene citrate, metformin, or both (combination) for up to six cycles, and hirsutism evaluators were blinded to group assignment. Results There was a significant decrease in the Ferriman-Gallwey score between baseline and completion of the study in each of the three individual groups (clomiphene citrate, p=0.024; metformin, p=0.005; combination, p<0.001). There was no significant difference in the degree to which the hirsutism score changed when comparing the three groups (p=0.44). The change in hirsutism was not associated with the duration of treatment or with the presence or absence of ovulation. Conclusions In infertile hirsute women with PCOS, treatment with clomiphene citrate, metformin, or both for up to 6 cycles does not alter hirsutism. Clinical Trial Registration ClinicalTrials.gov, www.clinicaltrials.gov, NCT00068861. PMID:22617579

The comparision of effect of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients.

PubMed

Ozcan Cenksoy, Pinar; Ficicioglu, Cem; Kizilkale, Ozge; Suhha Bostanci, Mehmet; Bakacak, Murat; Yesiladali, Mert; Kaspar, Cigdem

2014-07-01

To compare the effects of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients. Of 225 patients, 83 patients were in microdose flare-up group (Group 1), 70 patients were in GnRH antagonist/letrozole group (Group 2) and 72 patients were in GnRH antagonist/clomiphene citrate group (Group 3). Demographic and endocrine characteristics, the total number of oocytes retrieved, cancellation rate and clinical pregnancy rate were collected Results: Total dosage of gonadotropins (p=0.002) and serum E2 levels on the day of hCG administration (p=0.010) were significantly higher and duration of stimulations (p=0.03) was significantly longer in group 1. The number of oocytes retrieved was significantly greater in group 1 and 2 when compare to those of group 3 (p=0,000). There was a trend towards increasing cycle cancellation rates with GnRH antagonist/clomiphene citrate and GnRH antagonist/letrozole. Our finding suggest that the results of microdose flare-up protocol are better than other two used treatment protocols, in terms of maximum estradiol levels, number of mature oocytes retrieved, and cancellation rate and it still seems to be superior the ovarian stimulation regime for the poor responder patients.

Evaluation of tumor necrosis factor alpha serum level in obese and lean women with clomiphene citrate-resistant polycystic ovary disease.

PubMed

Seyam, Emaduldin; Hasan, Momen; Khalifa, Eissa M; Ramadan, Ahmad; Hefzy, Enas

2017-11-01

The aim of this work was to investigate the level of the serum level of tumor necrosis factor alpha (TNF-α) as an inflammatory biomarker in lean and obese women with polycystic ovary disease (PCOD), who are resistant to clomiphene citrate (CCR-PCOD). It is a case-controlled study, where 150 (n = 150) PCOD women (study group), who are resistant to clomiphene citrate (CCR-PCOD) had been recruited, in addition to 100 (n = 100) women with PCOD, who are not resistant to clomiphene citrate (NCCR-PCOD) as the first control group, and another 100 women (n = 100) fertile women with normal reproductive health, as the second control group. All the recruited subjects had been divided into subgroups according to the BMI: One obese group with BMI ≥ 27 and the second lean group with BMI < 27. TNF-α had been measured in all women groups recruited, in addition to the other essential, basic and PCOD-relevant biochemical and hormonal tests. TNF-α level was found to be higher in all PCOD women, either the study or control PCOD groups, than the fertile control group (49.93 ± 3.39 versus 35.83 ± 2.47 pg/ml, p < 0.001). The level of TNF-α has come highest in the obese clomiphene citrate-resistant PCOD women (obese CCR-PCOD), while the lowest has come in the lean PCOD women, who are not resistant to clomiphene citrate (NCCR-PCOD). Free Androgen Index (FAI) and androgenic obesity with higher W/H ratio were clearly going with TNF-α pattern and have come higher in all PCOD compared to the fertile control group. Insulin resistance (IR) shows a positive correlation with BMI regardless off PCOD status and androgen level as well. The level of other basic and PCOD-relevant hormones like FSH, TSH and prolactin have never shown statistically significant differences between all the study and control groups, except LH serum level which has shown a nonsignificant higher level in all PCOD women included either resistant to CC or not. TNF-α serum level has come significantly higher in all women with PCOD, especially in those resistant to CC. Androgenic obesity with higher W/H ratio has shown a positive correlation with TNF-α level, which could consider it a good severity index of PCOD status and an informative predictor of CCR before its use.

Cancer Risk in Women Treated with Fertility Drugs According to Parity Status-A Registry-based Cohort Study.

PubMed

Reigstad, Marte Myhre; Storeng, Ritsa; Myklebust, Tor Åge; Oldereid, Nan Birgitte; Omland, Anne Katerine; Robsahm, Trude Eid; Brinton, Louise Annette; Vangen, Siri; Furu, Kari; Larsen, Inger Kristin

2017-06-01

Background: Long-term safety of assisted reproductive techniques (ART) is of interest as their use is increasing. Cancer risk is known to be affected by parity. This study examined the risk of cancer after fertility treatment, stratified by women's parity. Methods: Data were obtained from all women ( n = 1,353,724) born in Norway between 1960 and 1996. Drug exposure data (2004-2014) were obtained from the Norwegian Prescription Database (drugs used in ART and clomiphene citrate). The Medical Birth Registry of Norway provided parity status. HRs were calculated for all site cancer, breast, cervical, endometrial, ovarian, colorectal, central nervous system, thyroid cancer, and malignant melanoma. Results: In 12,354,392 person-years of follow-up, 20,128 women were diagnosed with cancer. All-site cancer risk was 1.14 [95% confidence interval (95% CI), 1.03-1.26] and 1.10 (95% CI, 0.98-1.23) after clomiphene citrate and ART exposure, respectively. For ovarian cancer, a stronger association was observed for both exposures in nulliparous (HR, 2.49; 95% CI, 1.30-4.78; and HR, 1.62; 95% CI, 0.78-3.35) versus parous women (HR, 1.37; 95% CI, 0.64-2.96; and HR, 0.87; 95% CI, 0.33-2.27). Elevated risk of endometrial cancers was observed for clomiphene citrate exposure in nulliparous women (HR, 4.49; 95% CI, 2.66-7.60 vs. HR, 1.52; 95% CI, 0.67-3.42). Risk was elevated for breast cancer in parous women exposed to clomiphene citrate (HR, 1.26; 95% CI, 1.03-1.54) for thyroid cancer and among nulliparous women after ART treatment (HR, 2.19; 95% CI, 1.08-4.44). Conclusions: Clomiphene citrate appears associated with increased risk of ovarian and endometrial cancer. Elevations in risks of breast and thyroid cancer were less consistent across type of drug exposure and parity. Impact: Continued monitoring of fertility treatments is warranted. Cancer Epidemiol Biomarkers Prev; 26(6); 953-62. ©2017 AACR . ©2017 American Association for Cancer Research.

The effect of clomiphene on disuse bone loss

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeBlanc, A.; Marsh, C.; Spira, M.

1984-01-01

Clomiphene is a synthetic estrogen agonist/antagonist used for many years to induce ovulation in anovulatory women. A recent study demonstrated that clomiphene had a protective effect against bone loss in ovariectomized aged rats. The purpose was to determine if this drug retards resorption of bone associated with disuse in rats with intact ovaries. Eleven adult (300-350g) female rats received a pedicle bone graft (disuse) in one femur with the opposite limb serving as control. Of these, 6 received weekly 10 mg injections of clomiphone (Rx). Three Rx and three untreated (unRx) were sacrificed at 6 weeks while the remainder (3more » Rx, 2 unRx) were sacrificed at 10 weeks after surgery. All received quantitative injections of MDP 24 hrs. before sacrifice and labeled microspheres (5) just prior to sacrifice. The % uptakes of MDP and S, total bone mineral (BMC) and regional BMC (RBMC) were determined. Results are expressed as a ratio of the pedicle bone to the bone from the opposite limb. At 6 weeks, MDP and S are elevated in both groups indicating that metabolic activity is elevated. The Rx group shows no change in BMC while the unRx lost 13%. At 10 weeks, MDP and S are close to one in both groups. The Rx group lost 13% BMC while the unRx lost 29%. The RBMC indicates that the early loss of mineral is located primarily in the metaphysis, a region rich in trabecular bone. These results indicate that clomiphene retards resorption of bone resulting from disuse.« less

Metformin and/or clomiphene do not adversely affect liver or renal function in women with polycystic ovary syndrome.

PubMed

Aubuchon, Mira; Kunselman, Allen R; Schlaff, William D; Diamond, Michael P; Coutifaris, Christos; Carson, Sandra A; Steinkampf, Michael P; Carr, Bruce R; McGovern, Peter G; Cataldo, Nicholas A; Gosman, Gabriella G; Nestler, John E; Myers, Evan R; Legro, Richard S

2011-10-01

Nonalcoholic fatty liver disease is common to insulin-resistant states such as polycystic ovary syndrome (PCOS). Metformin (MET) is often used to treat PCOS but information is limited as to its effects on liver function. We sought to determine the effects of MET on serum hepatic parameters in PCOS patients. This was a secondary analysis of a randomized, doubled-blind trial from 2002-2004. This multi-center clinical trial was conducted in academic centers. Six hundred twenty-six infertile women with PCOS with serum liver function parameters less than twice the upper limit of normal were included. Clomiphene citrate (n = 209), MET (n = 208), or combined (n = 209) were given for up to 6 months. The percent change from baseline in renal and liver function between- and within-treatment arms was assessed. Renal function improved in all treatment arms with significant decreases in serum blood urea nitrogen levels (range, -14.7 to -21.3%) as well as creatinine (-4.2 to -6.9%). There were similar decreases in liver transaminase levels in the clomiphene citrate and combined arms (-10% in bilirubin, -9 to -11% in transaminases) without significant changes in the MET arm. When categorizing baseline bilirubin, aspartate aminotransferase, and alanine aminotransferase into tertiles, there were significant within-treatment arm differences between the tertiles with the highest tertile having the largest decrease from baseline regardless of treatment arm. Women with PCOS can safely use metformin and clomiphene even in the setting of mildly abnormal liver function parameters, and both result in improved renal function.

[The use of clomiphene citrate in ambulatory medicine practice in the Midi-Pyrénées area: compliance to national guidelines applicable to infertility diagnosis and to prescription and monitoring rules applicable to clomiphene citrate treatments].

PubMed

Bigouroux, V; Roussel, H; Souche, A; Bourrel, R; Sciortino, V

2004-11-01

Evaluate the compliance to the national guidelines from ANDEM (1996) and AFSSAPS (2003) concerning the diagnosis of infertility, the prescription of clomiphene and the monitoring of these treatments. Retrospective study of female patients from 16 to 50 y.o. having benefited from reimbursement of clomiphene citrate treatment between 1st April 2002 and 30th June 2002. After random sampling stratified on age, data on diagnosis procedures and treatments were extracted from the Social Security reimbursement database. These data were validated and completed by patients' interviews. A total of 283 women were included. 30% were subject to the basic hormonal tests (FSH, LH, estradiol). The proportion of patients explored by hysterosalpingogram, post-coital test and echography were respectively 50%, 35% and 68%. A semen analysis was found in 60% of the partners. The complete set of recommended tests before start of treatment was realised in 1.5% of women. In 7% of cases, women were treated without prior exploration. The proportion of tests performed was comparable below and above the age of 35. 77% of treatments were initiated after at least one year of waiting for a spontaneous conception. 69% of women were monitored during treatment by other methods than clinical follow-up. Prescription of clomifene citrate is too frequently realised without compliance to guidelines applicable to infertility investigations and therefore without persuasive diagnosis. These practices can lead to loss of childbearing opportunities and complications.

Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: a randomized clinical trial.

PubMed

Rezk, Mohamed; Shaheen, Abd-Elhamid; Saif El-Nasr, Ibrahim

2018-04-01

A total of 202 patients with clomiphene citrate (CC) -resistant polycystic ovary syndrome (PCOS) were randomly allocated into two arms of induction of ovulation; the first group (n = 102) received CC 100 mg and metformin 500 mg while the second group (n = 100) received letrozole 2.5 mg with ovulation rate, clinical pregnancy rate, adverse effects, and acceptability were assessed. Patients in the letrozole arm experienced higher rate of ovulation (82% versus 43.1%, p < .001), more dominant follicles (p < .05), better endometrial thickness (p < .001), higher clinical pregnancy rate (36% versus 9.8%, p < .001), higher multiple pregnancy rate (p < .05), lesser adverse effects (p < .05) and higher acceptability (p < .001) compared to patients in the CC and metformin arm. In conclusion; letrozole is better and more acceptable than combined CC and metformin for inducing ovulation in patients with CC-resistant PCOS with higher clinical pregnancy rate and unexpectedly higher multiple pregnancy rate.

[Infertility in polycystic ovary syndrome treated with acupuncture and clomiphene: a randomized controlled trial].

PubMed

Jiang, Duosheng; Zhang, Yingchun; Wu, Xianqun; Wu, Song

2015-02-01

To explore the best therapy for infertility caused by polycystic ovary syndrome (PCOS). One hundred and twenty patients were randomized into three groups, a clomi-phene group (group A), an acupuncture-moxibustion + Chinese medicine group (group B) and a clomiphene + acupuncture-moxibustion+ Chinese medicine group (group C), 40 cases in each one. In the group A, since the 5th day of menstruation, clomiphene was prescribed for oral administration. In the group B, on the 5th day of menstruation, warm needling therapy was applied at Zhongji (CV 3), Guanyuan (CV 4), Guilai (ST 29), etc. Additionally, the Chinese herbal medication for tonifying the kidney and activating blood circulation was provided. In the group C, the therapy as the group B was combined on the basis of the treatment as the group A. The treatment lasted continuously for 3 menstrual cycles. The endometrial thickness, endometrial type and cervical mucus score on human chorionic gon adotropin (HCG) day, and ovulatory cycle rate, clinical pregnancy rate and abortion rate after treatment were observed in the patients of the three groups. 1) HCG day cervical mucus score, endometrial thickness and endometrial morphology (A type rate): the results in the group C were better than those in the group A (all P<0.01); the results in the group B were better than those in the group A (all P<0.05). The difference in the endometrial thickness was not significant in comparison between the group C and the group B (P>0.05). The cervical mucus score and endometrial morphology (A type rate) in the group C were better than those in the group B (both P<0.05). 2) The ovulatory cycle rates in the group A and group (C were higher than that in the group B (both P<0.05), the pregnancy rate in the group C was higher than that in the other groups (both P<0.05), and the early abortion rate in the group C was lower than that in the group A and group B (both P<0.01). 3) Follicle diameter from 18 mm to 20 mm and endometrial thickness: the differences were not significant between the normal pregnancy patients and the early abortion patients (both P>0.05). The endometrial morphology A type rate in the normal pregnancy patients was higher than that in the early abortion patients (P<0.05). The combined therapy of acupuncture, herbal medicine and clomiphene improves the pregnancy rate and reduces early abortion rate by effectively improving HCG day cervical mucus, endometrial thickness and morphology. The efficacy is apparently superior to the simple medication with clomiphene and the combined application of acupuncture and herbal medicine.

Metformin and/or Clomiphene Do Not Adversely Affect Liver or Renal Function in Women with Polycystic Ovary Syndrome

PubMed Central

Aubuchon, Mira; Kunselman, Allen R.; Schlaff, William D.; Diamond, Michael P.; Coutifaris, Christos; Carson, Sandra A.; Steinkampf, Michael P.; Carr, Bruce R.; McGovern, Peter G.; Cataldo, Nicholas A.; Gosman, Gabriella G.; Nestler, John E.; Myers, Evan R.

2011-01-01

Context: Nonalcoholic fatty liver disease is common to insulin-resistant states such as polycystic ovary syndrome (PCOS). Metformin (MET) is often used to treat PCOS but information is limited as to its effects on liver function. Objective: We sought to determine the effects of MET on serum hepatic parameters in PCOS patients. Design: This was a secondary analysis of a randomized, doubled-blind trial from 2002–2004. Setting: This multi-center clinical trial was conducted in academic centers. Patients: Six hundred twenty-six infertile women with PCOS with serum liver function parameters less than twice the upper limit of normal were included. Interventions: Clomiphene citrate (n = 209), MET (n = 208), or combined (n = 209) were given for up to 6 months. Main Outcome Measure: The percent change from baseline in renal and liver function between- and within-treatment arms was assessed. Results: Renal function improved in all treatment arms with significant decreases in serum blood urea nitrogen levels (range, −14.7 to −21.3%) as well as creatinine (−4.2 to −6.9%). There were similar decreases in liver transaminase levels in the clomiphene citrate and combined arms (−10% in bilirubin, −9 to −11% in transaminases) without significant changes in the MET arm. When categorizing baseline bilirubin, aspartate aminotransferase, and alanine aminotransferase into tertiles, there were significant within-treatment arm differences between the tertiles with the highest tertile having the largest decrease from baseline regardless of treatment arm. Conclusion: Women with PCOS can safely use metformin and clomiphene even in the setting of mildly abnormal liver function parameters, and both result in improved renal function. PMID:21832111

Use of letrozole and clomiphene citrate combined with gonadotropins in clomiphene-resistant infertile women with polycystic ovary syndrome: a prospective study

PubMed Central

Xi, Wenyan; Liu, Shankun; Mao, Hui; Yang, Yongkang; Xue, Xiang; Lu, Xiaoning

2015-01-01

Background Gonadotropin has been used to stimulate ovulation in clomiphene-resistant infertile women with polycystic ovary syndrome (PCOS), but it is associated with overstimulated cycles with the development of many follicles. The aim of the study was to evaluate the effectiveness and efficacy of letrozole and clomiphene citrate (CC) combined with human menopausal gonadotropin (HMG) in CC-resistant infertile women with PCOS. Methods Ninety-four women received the letrozole + HMG, 90 women received CC + HMG, and 71 women received HMG only. All women received one treatment regimen in one treatment cycle. All patients were given HMG 75 IU on alternate days daily starting on day 3 or day 7 until the day of administration of human chorionic gonadotropin. Results The rate of monofollicular development was 80.2% in the letrozole + HMG group, 65.3% in the CC + HMG group, and 54.7% in the HMG-only group (P<0.05 for letrozole + HMG vs the other two groups). The number of developing follicles (≥14 mm follicles) and the cycle cancellation rate due to ovarian hyperresponse were the lowest in the letrozole + HMG group, but the difference was not significant. The ovulation and pregnancy rate were similar among the three protocols. The HMG dose needed and the mean duration of treatment were significantly lower in the letrozole + HMG and CC + HMG groups compared with the HMG-only group. Conclusion Letrozole in combination with HMG is an effective protocol for reducing the risks of hyperstimulation for ovarian induction in CC-resistant women with PCOS. This combination may be more appropriate in patients who are particularly sensitive to gonadotropin. PMID:26648691

Pretreatment and co-administration of oral anti-diabetic agent with clomiphene citrate or rFSH for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome.

PubMed

Begum, Mosammat Rashida; Akhter, Sayeba; Ehsan, Mariya; Begum, Mosammat Shahina; Khan, Farzana

2013-05-01

The objective of this study was to explore the result of pretreatment and concomitant use of metformin with clomiphene citrate (CC) and rFSH for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome (PCOS). This randomized controlled trial was done in the Dhaka Medical College and Hospital and the Infertility Care and Research Centre, Dhaka, Bangladesh. A total of 165 infertile patients with CC-resistant PCOS who attended for treatment were the target population for this study. Patients were divided into three groups: groups A and B were given metformin and group C was the control. Along with metformin, group A received CC and group B received rFSH. Group C was treated with only rFSH. Metformin was given 1500 mg daily for 4 weeks. Afterwards CC or rFSH were added for induction of ovulation along with metformin. Six ovulatory cycles were assessed. Treatment was terminated when there was no response with maximum dose of CC and rFSH or after six ovulatory cycles without pregnancy or after achieving pregnancy. A P-value of <0.5 was considered as significant. Ovulation (89.09%) and pregnancy (54.55%) rates were higher in group B. Ovulation (74.55%) and pregnancy (29.09%) rates were also satisfactory in group C but a dose of rFSH requirement was significantly higher (P = 0.000). In group A, both ovulation and pregnancy rate were much lower than the other two groups (27.27% and 12.73%, respectively). Use of metformin increases the response of ovulation-inducing agents and can be used safely in PCOS. © 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.

Therapeutic effects of metformin and clomiphene in combination with lifestyle intervention on infertility in women with obese polycystic ovary syndrome.

PubMed

Zhang, Jing; Si, Qinqin; Li, Jinqiong

2017-01-01

To evaluate the therapeutic effects of metformin and clomiphene in combination with lifestyle adjustment on infertility in women with obese polycystic ovarian syndrome (PCOS). A total of 101 infertile women with obese PCOS admitted to our hospital from July 2013 to July 2015 were randomly divided into an observation group (n=51) and a control group (n=50). The control group was treated with metformin plus clomiphene, based on which the observation group was also subjected to lifestyle adjustment. The body weight, body mass index (BMI) and waist-to-hip ratio (WHR) were measured before and after treatment. The changes of reproductive hormones, ovaries and endometrium were detected, and the rates of menstrual recovery, ovulation and pregnancy were observed. The body weight and BMI of the observation group after treatment were significantly lower than those before treatment and of the control group (P<0.05). There was no significant difference in WHR between the two groups. In the observation group, there were significant differences in LH, T, LH/FSH, FINS and TG levels before and after treatment and from those of the control group after treatment (P<0.05). Both the left and right ovarian volumes of the observation group after treatment were significantly lower than those before treatment and of the control group after treatment (P<0.05). The menstrual recovery, ovulation and pregnancy rates of the observation group were significantly higher than those of the control group (P<0.05). Lifestyle adjustment combined with metformin and clomiphene can improve the reproductive endocrine and lipid metabolism of obese PCOS patients, decrease the volumes of left and right ovaries, and increase the menstrual recovery, ovulation and pregnancy rates.

Use of letrozole and clomiphene citrate combined with gonadotropins in clomiphene-resistant infertile women with polycystic ovary syndrome: a prospective study.

PubMed

Xi, Wenyan; Liu, Shankun; Mao, Hui; Yang, Yongkang; Xue, Xiang; Lu, Xiaoning

2015-01-01

Gonadotropin has been used to stimulate ovulation in clomiphene-resistant infertile women with polycystic ovary syndrome (PCOS), but it is associated with overstimulated cycles with the development of many follicles. The aim of the study was to evaluate the effectiveness and efficacy of letrozole and clomiphene citrate (CC) combined with human menopausal gonadotropin (HMG) in CC-resistant infertile women with PCOS. Ninety-four women received the letrozole + HMG, 90 women received CC + HMG, and 71 women received HMG only. All women received one treatment regimen in one treatment cycle. All patients were given HMG 75 IU on alternate days daily starting on day 3 or day 7 until the day of administration of human chorionic gonadotropin. The rate of monofollicular development was 80.2% in the letrozole + HMG group, 65.3% in the CC + HMG group, and 54.7% in the HMG-only group (P<0.05 for letrozole + HMG vs the other two groups). The number of developing follicles (≥14 mm follicles) and the cycle cancellation rate due to ovarian hyperresponse were the lowest in the letrozole + HMG group, but the difference was not significant. The ovulation and pregnancy rate were similar among the three protocols. The HMG dose needed and the mean duration of treatment were significantly lower in the letrozole + HMG and CC + HMG groups compared with the HMG-only group. Letrozole in combination with HMG is an effective protocol for reducing the risks of hyperstimulation for ovarian induction in CC-resistant women with PCOS. This combination may be more appropriate in patients who are particularly sensitive to gonadotropin.

Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: in vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation.

PubMed

Soliman, Ghareb M; Fetih, Gihan; Abbas, Ahmed M

2017-03-01

The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness. Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic ® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (T sol-gel ), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725). The T sol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28-37 °C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration. Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.

A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin.

PubMed

Shigiyama, Fumika; Kumashiro, Naoki; Rikitake, Takayuki; Usui, Shuki; Saegusa, Michiko; Kitamura, Mamoru; Uchino, Hiroshi; Hirose, Takahisa

2016-01-01

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

Early pregnancy factor (EPF) as a marker for detecting subclinical embryonic loss in clomiphene citrate-treated women.

PubMed

Shahani, S K; Moniz, C L; Gokral, J S; Meherji, P K

1995-05-01

A discrepancy exists between the apparently normal ovulation and the pregnancy rates in women treated with clomiphene citrate (CC). Our previous studies have indicated that immuno-suppressive "early pregnancy factor" (EPF) is a novel marker to detect subclinical embryonic loss in infertile women. In the present study EPF was used as a marker to detect subclinical embryonic loss in women treated with CC with/without gonadotropins. In some of the women treated with CC, conception was assisted by artificial insemination with husband's semen (AIH). Our results have indicated that fertilization occurred (EPF + ve) in 47.7% (52/109) of women treated with CC with/without gonadotropins; 13.46% (7/52) retained the fetus and continued pregnancy till full term, whereas 78.9% (41/52) did not retain the fetuses. In the group where after stimulation, conception was assisted by AIH, fertilization was observed in 38.24% (26/68), retention in 11.54% (3/26) but subclinical embryonic loss was observed in 80.8% (21/26) cases. Thus, our results have indicated that subclinical embryonic loss may account for some of the discrepancy observed between the apparently normal ovulation and the pregnancy rates in women treated with clomiphene citrate.

Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome.

PubMed

de Paula Guedes Neto, Ernesto; Savaris, Ricardo Francalacci; von Eye Corleta, Helena; de Moraes, Gisele Silva; do Amaral Cristovam, Rafael; Lessey, Bruce A

2011-09-01

To compare the ovulation rate between raloxifene and clomiphene citrate (CC) in patients with polycystic ovary syndrome (PCOS). Double-blind, randomized, superiority clinical trial. Tertiary university hospital. Women with ovulatory dysfunction and PCOS based on the Rotterdam criteria. One of two oral treatments: 5 days of 100 mg/day of CC or R. Ovulation, based on follicle collapse on serial ultrasound and midsecretory serum progesterone concentration (≥3 ng/dL). The women with PCOS (n = 82) were randomized to receive CC (n = 40) or raloxifene (n = 42). From these, 68 patients finished the trial according to the protocol (CC: n = 37; raloxifene: n = 31). There were no statistically significant differences between the groups in ovulation rates per an intention-to-treat analysis based on ultrasound alone (CC: 21 of 40 vs. raloxifene: 17 of 42) or on progesterone levels (CC: 16 of 40 vs. raloxifene: 11 of 42). No serious adverse events were observed in either group. No statistically significant difference in ovulation was observed between raloxifene and clomiphene citrate in patients with PCOS with ovulatory dysfunction. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Smart coumarin-tagged imprinted polymers for the rapid detection of tamoxifen.

PubMed

Ray, Judith V; Mirata, Fosca; Pérollier, Celine; Arotcarena, Michel; Bayoudh, Sami; Resmini, Marina

2016-03-01

A signalling molecularly imprinted polymer was synthesised for easy detection of tamoxifen and its metabolites. 6-Vinylcoumarin-4-carboxylic acid (VCC) was synthesised from 4-bromophenol to give a fluorescent monomer, designed to switch off upon binding of tamoxifen. Clomiphene, a chlorinated analogue, was used as the template for the imprinting, and its ability to quench the coumarin fluorescence when used in a 1:1 ratio was demonstrated. Tamoxifen and 4-hydroxytamoxifen were also shown to quench coumarin fluorescence. Imprinted and non-imprinted polymers were synthesised using VCC, methacrylic acid as a backbone monomer and ethylene glycol dimethacrylate as cross-linker, and were ground and sieved to particle sizes ranging between 45 and 25 μm. Rebinding experiments demonstrate that the imprinted polymer shows very strong affinity for both clomiphene and tamoxifen, while the non-imprinted polymer shows negligible rebinding. The fluorescence of the imprinted polymer is quenched by clomiphene, tamoxifen and 4-hydroxytamoxifen. The switch off in fluorescence of the imprinted polymer under these conditions could also be detected under a UV lamp with the naked eye, making this matrix suitable for applications when coupled with a sample preparation system.

Effects of Letrozole-HMG and Clomiphene-HMG on Incidence of Luteinized Unruptured Follicle Syndrome in Infertile Women Undergoing Induction Ovulation and Intrauterine Insemination: A Randomised Trial.

PubMed

Azmoodeh, Azra; Pejman Manesh, Mansoureh; Akbari Asbagh, Firouzeh; Ghaseminejad, Azizeh; Hamzehgardeshi, Zeinab

2015-09-01

Luteinized unruptured follicle (LUF) syndrome is considered a cause of ovulation failure and a subtle cause of infertility. Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome, but it has also occurred after the induction of ovulation with clomiphene/HMG and HCG. This study was designed for evaluation and comparison of LUF incidence in eligible infertile women undergoing two stimulation protocols (clomiphene + HMG and letrozole + HMG) in addition to intrauterine insemination (IUI). Some related factors were compared between LUF and non-LUF cycles as secondary outcomes. The study was designed as a prospective randomized controlled trial. Patients were randomized using a table of random numbers into two equal protocol groups. For group A, (n = 90) clomiphene citrate was administrated orally in doses of 100 mg/day, and group B (n = 90) orally received letrozole 5 mg/day from day 3 to 7 of the menstrual cycle. Then HMG 75IU/day was administered intramuscularly in both groups on day 8 of the menstrual cycle and the dose was adjusted on the basis of ovarian response. The optimum size of preovulatory follicles for the injection of HCG (10,000 IU) was considered 18-23 mm. The number and size of preovulatory follicles were assessed by vaginal ultrasound 12 h before HCG (D0). Endometrial thickness was measured as well. IUI was performed on all patients 38-40 h after HCG. The second ultrasound examination was performed to observe the evidence of oocyte releasing at the time of IUI (D1). If the follicles were unruptured, a third sonography was performed on day 7 after HCG (D7) to observe LUF syndrome. There was a significant difference between clomiphene-HMG and letrozole-HMG in LUF (p = 0.021) and pregnancy (p = 0.041). The complete LUF in letrozole-HMG was lower than the alternative group and the pregnancy rate was higher. The patients in the non-LUF group had higher midluteal progesterone and a thicker endometrium compared to LUF cycles (p = 0.039) and (p < 0.001). The results of our multivariate logistic regression indicate that size 18-19.9 mm leads to the complete LUF  less than ≥22 mm [AOR: 0.25, P = 0.005], and  in size 20- 21.9 mm  as well [AOR: 0.17, P = 0.002]. Letrozole, with lower incidences of LUF, is more effective than clomiphene citrate for the induction of ovulation in IUI cycles. In our study, we illustrated that larger follicles of ≥22 mm diameter were associated with higher incidences of LUF. We recommend that further studies investigate and focus on the relationship between follicular size and/or full hormonal profiles and LUF.

The cycle characteristics of clomiphene with clomiphene and menotropins in polycystic ovary syndrome and non polycystic ovary syndrome infertile patients.

PubMed

Ghasemi, M; Ashraf, H; Koushyar, H; Mousavifar, N

2013-06-01

This study compares the cycle characteristics of clomiphene (CC) with CC+HMG (Human Menopausal Gonadotropin or Menotropins) in Polycystic Ovary Syndrome (PCOS) and non-PCOS infertile patients. Patients were treated by CC + minimal HMg protocol. The cancellation rate, the mean number of different follicle sizes and endometrial thickness and pattern were compared. The cancelled cycles due to non-responsiveness were significantly higher in CC compared to CC+ minimal HMg protocol. PCOS patients are significantly nonresponsive in CC cycle and hyperresponsive in CC+ minimal HMg cycles. The mean number of different sizes of follicles and the endometrial thickness were significantly higher in CC+ minimal HMg. PCOS patients were significantly different from non-PCOS regarding the number of mature follicle and endometrial thickness. The pregnancy rate was 11% (10.2% in non-PCOS and 12.2% in PCOS). CC+ minimal HMg is a viable alternative to HMg /FSH only protocol in CC failure or resistant patients, and its efficacy can be mostly attributed to improvement of endometrial quality and increase in follicle number. Moreover, due to high cancellation of PCOS patients treated by this protocol, seemingly other alternatives should be found; perhaps sequential letrozole+HMg/FSH that have been shown to improve the ovarian response in this group of patients.

Comparison of letrazole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation.

PubMed

Sharief, Maysoon; Nafee, Najlaa Rasmee

2015-11-01

To compare the efficacy of letrazole in the induction of ovulation with clomiphene citrate in patients with polycystic ovary syndrome and primary infertility. The prospective clinical trial was conducted at Basrah Maternity and Child Hospital, Basrah, Iraq, between January 2012 and April 2013, and comprised women with polycystic ovarian syndrome and primary infertility who were randomised into 2 groups. Group A received100-200mg clomiphene citrate daily while group 2 received letrazole (2.5-5mg) daily. Both groups were followed by ultrasound until the dominant follicle reached a diameter >18mm, human chorionic gonadotropin10.000 U/L was given and timed intercourse was advised. Of the 75 subjects in the study, 40(53.3%) were in group A and 35(46.6%) in group B. The mean age in group A was 25.3+2.1 years versus 26.1+1.3 years in group B (p=0.05). The number of mature follicles was significantly lower, but the endometrial thickness and ovulation were significantly higher in group B than in group A (p<0.05 each). There was no significant difference in pregnancy rate between the two groups (p>0.05). Letrazole may have a role as the first-line treatment for unovulatory patients with polycystic ovary syndrome.

The effect of clomiphene citrate on human preovulatory oocyte maturation in vivo.

PubMed

Seibel, M M; Smith, D M

1989-02-01

Sixty-four infertile women underwent diagnostic laparoscopy in the periovulatory period at time-bracketed intervals following their endogenous luteinizing hormone (LH) surge. Forty-eight of these women were studied during natural cycles and 16 had mild oligoovulation and were administered clomiphene citrate (CC) to regulate their cycles. No patient received human chorionic gonadotropin. No patient was undergoing either in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT). Follicle puncture was performed and the oocytes were observed immediately for stage of maturation. Oocytes obtained from follicles exposed to CC were found to require an increased interval of time to reach metaphase I compared to oocytes obtained from natural cycles (27.75 +/- 2.2 vs 22.5 hr; mean +/- SE). Furthermore, the interval of time required for metaphase I oocytes to achieve metaphase II was statistically significantly shortened for CC cycles (2.4 hr for CC vs 10 hr for natural cycles. Nevertheless, there was no difference between natural and CC cycles in the time interval between LH surge onset and ovulation. These in vivo findings suggest a direct effect of CC on human oocyte maturation and may help explain the well-established discrepancy between the relatively high ovulation rate and the relatively low conception rate in clomiphene-induced cycles.

Luteal Phase Support in the Intrauterine Insemination (IUI) Cycles: A Randomized Double Blind, Placebo Controlled Study

PubMed Central

Hossein Rashidi, Batool; Davari Tanha, Fatemeh; Rahmanpour, Haleh; Ghazizadeh, Mahya

2014-01-01

Objective: To evaluate the impact of luteal phase support with vaginal progesterone on pregnancy rates in the intrauterine insemination (IUI) cycles, stimulated with clomiphene citrate and human menopausal gonadotropin (hMG), in sub fertile couples. Materials and methods: This prospective, randomized, double blind study was performed in a tertiary infertility center from March 2011 to January 2012. It consisted of 253 sub fertile couples undergoing ovarian stimulation for IUI cycles. They underwent ovarian stimulation with clomiphene citrate (100 mg) and hMG (75 IU) in preparation for the IUI cycle. Study group (n = 127) received luteal phase support in the form of vaginal progesterone (400 mg twice a day), and control group (n = 126) received placebo. Clinical pregnancy and abortion rates were assessed and compared between the two groups. Results: The clinical pregnancy rate was not significantly higher for supported cycles than that for the unsupported ones (15.75% vs. 12.69%, p = 0.3). The abortion rate in the patients with progesterone luteal support compared to placebo group was not statistically different (10% vs. 18.75%, p = 0.45). Conclusion: It seems that luteal phase support with vaginal progesterone was not enhanced the success of IUI cycles outcomes, when clomiphene citrate and hMG were used for ovulation stimulation. PMID:25530766

Characterization of the biotransformation pathways of clomiphene, tamoxifen and toremifene as assessed by LC-MS/(MS) following in vitro and excretion studies.

PubMed

Mazzarino, Monica; Biava, Mariangela; de la Torre, Xavier; Fiacco, Ilaria; Botrè, Francesco

2013-06-01

The use of selective oestrogen receptor modulators has been prohibited since 2005 by the World Anti-Doping Agency regulations. As they are extensively cleared by hepatic and intestinal metabolism via oxidative and conjugating enzymes, a complete investigation of their biotransformation pathways and kinetics of excretion is essential for the anti-doping laboratories to select the right marker(s) of misuse. This work was designed to characterize the chemical reactions and the metabolizing enzymes involved in the metabolic routes of clomiphene, tamoxifen and toremifene. To determine the biotransformation pathways of the substrates under investigation, urine samples were collected from six subjects (three females and three males) after oral administration of 50 mg of clomiphene citrate or 40 mg of tamoxifen or 60 mg of toremifene, whereas the metabolizing enzymes were characterized in vitro, using expressed cytochrome P450s and uridine diphosphoglucuronosyltransferases. The separation, identification and determination of the compounds formed in the in vivo and in vitro experiments were carried out by liquid chromatography coupled with mass spectrometry techniques using different acquisition modes. Clomiphene, tamoxifen and toremifene were biotransformed to 22, 23 and 18 metabolites respectively, these phase I reactions being catalyzed mainly by CYP3A4 and CYP2D6 isoforms and, to a lesser degree, by CYP3A5, CYP2B6, CYP2C9, CYP2C19 isoforms. The phase I metabolic reactions include hydroxylation in different positions, N-oxidation, dehalogenation, carboxylation, hydrogenation, methoxylation, N-dealkylation and combinations of them. In turn, most of the phase I metabolites underwent conjugation reaction to form the corresponding glucuro-conjugated mainly by UGT1A1, UGT1A3, UGT1A4, UGT2B7, UGT2B15 and UGT2B17 isoenzymes.

Long-term follow-up of laparoscopic electrocautery of the ovaries versus ovulation induction with recombinant FSH in clomiphene citrate-resistant women with polycystic ovary syndrome: an economic evaluation.

PubMed

Nahuis, M J; Oude Lohuis, E; Kose, N; Bayram, N; Hompes, P; Oosterhuis, G J E; Kaaijk, E M; Cohlen, B J; Bossuyt, P P M; van der Veen, F; Mol, B W; van Wely, M

2012-12-01

Laparoscopic electrocautery of the ovaries and ovulation induction with gonadotrophins are both second line treatments for women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Long-term follow-up after electrocautery versus ovulation induction with gonadotrophins has demonstrated at least comparable chances for a first live born child with a reduced need for ovulation induction or assisted reproduction treatment and increased chances for a second live born child. In this study, we report on the long-term economic consequences of both treatment modalities. Between February 1998 and October 2001, we performed a multi-centre randomized controlled trial (RCT) comparing a strategy of laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and gonadotrophins when anovulation persisted, and a strategy of ovulation induction with gonadotrophins in women with clomiphene citrate-resistant PCOS. Eight to twelve years after randomization we performed a follow-up study on reproductive outcome in these women and the fertility treatments they had needed including data on direct medical costs of pregnancy and delivery. Clinical data included number of treatment cycles, live births, miscarriages, ectopic pregnancies and multiple pregnancies. We calculated mean costs per woman after randomization until the first live birth. Confidence intervals (CIs) were estimated by bootstrapping. We obtained data for an economic analysis on 159 of the 168 randomized women (95%). In total, 71 of 83 women (86%) allocated to the electrocautery strategy and 69 of 85 women (81%) allocated to the gonadotrophin strategy had at least one live birth. Given the equivalence between the two treatment strategies in terms of a first live birth-the primary outcome measure-our analysis focused on the cost difference between the two strategies within a mean follow-up time of 8-12 years. The mean costs per first live birth after randomization were €11 176 (95% CI: €9689-€12 549) for the electrocautery group and €14 423 (95% CI: €12 239-€16 606) for the recombinant FSH group, resulting in significantly lower costs (P < 0.05) per first live birth for women allocated to the electrocautery group (mean difference €3247; 95% CI: €650-€5814). In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries results in significantly lower costs per live birth than ovulation induction with gonadotrophins for an at least equal effectiveness.

[Therapeutic effects on ovulation and reproduction promotion with acupuncture and clomiphene in polycystic ovary syndrome].

PubMed

Yu, Liqing; Cao, Lianying; Xie, Jing; Shi, Yin

2018-03-12

To compare the difference in the therapeutic effects on ovulation disorder in polycystic ovary syndrome (PCOS) between the combined therapy of electroacupuncture and clomiphene and the single medication of clomiphene and to explore the effect mechanism. A total of 80 patients of PCOS were randomized into an acupuncture plus medication group (40 cases) and a medication group (40 cases). In the medication group, since the 5th day of menstruation or medicine-withdrawal bleeding, clomiphene was prescribed for oral administration, continuously for 5 days. In the acupuncture plus medication group, the medication was the same as the medication group. Additionally, 30 min electroacupuncture (continuous wave, 2 Hz) was applied to Qihai (CV 6), Guanyuan (CV 4), Zigong (EX-CA 1), Dahe (KI 12), Sanyinjiao (SP 6), Zhongji (CV 3), Diji (SP 8), Shenshu (BL 23), Sanjiaoshu (BL 22) and Ciliao (BL 32), etc. The treatment started on the 5th day of menstruation or medicine-withdrawal bleeding, once every two days, 3 times a week. One cycle of menstruation or 1 month was taken as one course. The treatment cycles were 3 months in the two groups. The level of estradiol (E 2 ) and progesterone (P) in the serum, the endometrial thickness and morphology, ovulation rate and clinical pregnancy rate, as well as the clinical therapeutic effects were compared after treatment in the two groups. Two cases were dropped out because the herbal medicine was taken simultaneously in the acupuncture plus medication group. In the medication group, the medication was discontinued in 3 cases due to gastrointestinal adverse reactions. The total effective rate was 86.8% (33/38) in the acupuncture plus medication group, better than 64.9% (24/37) in the medication group ( P <0.05). The ovulation rate in the acupuncture plus medication group was higher than that in the medication group [(86.8%, 33/38) vs (64.9% 24/37), P <0.05]. The pregnancy rate in the acupuncture plus medication group was higher than the medication group in tendency, without significant difference [21.1% (8/38) vs 16.2% (6/37), P >0.05]. After treatment, the results of endometrial thickness and morphology (A-type rate) in the acupuncture plus medication group were better than those in the medication group ( P <0.01, P <0.05). After treatment, regarding the levels of E 2 and P in the serum in the window period of implantation, the results in the acupuncture plus medication group were higher remarkably than those in the medication group (both P <0.01). The combined intervention of electroacupuncture and clomiphene achieves the definite effects of ovulation and pregnancy promotion in PCOS. It remarkably increases the levels of E 2 and P in the serum, the endometrial thickness and A-type rate. The therapeutic effects of the combined intervention are remarkably better than those of the simple application of clomiphene. This combined intervention is safe and tolerable for the adverse reactions. The effect mechanisms may be related to the improvements of estrogen, progestin and endometrial receptivity.

Aromatase inhibitors for subfertile women with polycystic ovary syndrome.

PubMed

Franik, Sebastian; Kremer, Jan A M; Nelen, Willianne L D M; Farquhar, Cindy

2014-02-24

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS. We searched the following sources from inception to 24/10/2013 to identify relevant randomised controlled trials (RCTs): the Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organisation (WHO) clinical trials register and Clinicaltrials.gov. Furthermore, we manually searched the references of relevant articles.The search was not restricted by language or publication status. We included all RCTs of aromatase inhibitors used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed trial quality. Studies were pooled where appropriate using a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were pregnancy, miscarriage and multiple pregnancy. The quality of the evidence for each comparison was assessed using GRADE methods. We included 26 RCTs (5560 women). In all studies the aromatase inhibitor was letrozole. Live birth (12 RCTs) One RCT compared letrozole with placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Nine RCTs compared letrozole with clomiphene citrate (with or without adjuncts) followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.63, 95% CI 1.31 to 2.03, n=1783, I²=3%)Two RCTs compared letrozole with laparoscopic ovarian drilling. There was no evidence of a difference between the groups in live birth rate (OR 1.19, 95% CI 0.76 to 1.86, n=407, I²=0%) OHSS (16 RCTs) There was no evidence of a difference in OHSS rates when letrozole was compared with placebo (one RCT, n=36), clomiphene citrate (with or without adjuncts) followed by timed intercourse (nine RCTs, n=2179), clomiphene citrate (with or without adjuncts) followed by intrauterine insemination (IUI) (two RCTs, n=1494), laparoscopic ovarian drilling (one RCT, n=260) or anastrozole (one RCT, n=220). Events were absent or very rare, and no study had more than 2 cases of OHSS. Clinical pregnancy (25 RCTs) One RCT compared letrozole versus placebo in women who were clomiphene resistant and the results were inconclusive (OR 3.17, 95% CI 0.12 to 83.17, n=36)Fourteen RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by timed intercourse. The pregnancy rate was higher in the letrozole group (OR 1.32, 95% CI 1.09 to 1.60, n=2066, I²=25%)Three RCTs compared letrozole versus clomiphene citrate (with or without adjuncts) followed by IUI. The pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30 to 2.25, n=1597)Three RCTs compared letrozole versus laparoscopic ovarian drilling. There was no evidence of a difference in the clinical pregnancy rate (OR 1.14, 95% CI 0.80 to 1.65, n=553, I²=0%)Two RCTs compared letrozole versus anastrozole, one RCT compared a five day versus a 10 day administration protocol for letrozole and another RCT compared 5 mg of letrozole versus 7.5 mg of letrozole. There was no evidence of a difference in the clinical pregnancy rate in these comparisons.The quality of the evidence was rated as low for live birth and pregnancy outcomes. The reasons for downgrading the evidence were poor reporting of study methods, possible publication bias and the tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth (suggesting that results might be somewhat less favourable to letrozole if all studies reported live birth). Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. The quality of this evidence is low and findings should be regarded with some caution. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, though there were few relevant studies. OHSS was a very rare event, with no occurrences in most studies.

Administration of clomiphene citrate in patients with polycystic ovary syndrome, without inducing withdrawal bleeding, achieves comparable treatment characteristics and outcome.

PubMed

Farhi, Jacob; Orvieto, Raoul; Homburg, Roy

2010-04-01

In an attempt to evaluate the effect of random timing of the start of clomiphene citrate (CC) treatment in anovulatory patients with polycystic ovary syndrome on treatment characteristics and outcome, with no regard to time of menstruation, we studied 291 women in their first CC treatment cycle. Duration of treatment was shorter by 2 days and number of leading follicles was higher when treatment was started late (7-29 days from starting a bleed, as compared with day 5), but no effect of starting day was observed on response rate to CC, maximal E(2) level, endometrial thickness, and pregnancy rate. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Treatment strategies in PCOS patients.

PubMed

Tauchert, Sascha; Ludwig, Annika K; Diedrich, K; Weiss, Juergen M

2005-06-01

Polycystic ovary syndrome (PCOS), with a prevalence of up to 7%, is the most common endocrinopathy in women of reproductive age. It is a complex metabolic-endocrine disorder with severe long-term health consequences, such as a higher risk of type 2 diabetes and cardiovascular diseases. According to prospective studies, women with PCOS have abnormal glucose tolerance and diabetes mellitus in 31.0-35.0% and 7.5-10.0% respectively. This risk is 2-3 times higher than normal. Insulin resistance plays a key role in the pathophysiology of this syndrome, and this makes the use of oral antidiabetic drugs most compelling. The majority of studies have shown amelioration of typical symptoms such as hyperandrogenism and cycle irregularities following the use of oral anti-diabetics, and ovulation and pregnancy rates increased. Furthermore, these drugs might be cardioprotective by improving insulin sensitivity and reducing the risk for type 2 diabetes. The best-investigated drug is metformin. Metformin is not approved for PCOS treatment in Germany and is a class B drug in pregnancy. In sterile PCOS patients, clomiphene citrate is still the first choice. The combination of clomiphene with metformin and lifestyle changes such as weight reduction and exercise might be superior to clomiphene alone. This article covers the use of different oral anti-diabetic drugs in the treatment of PCOS, and their influence on fertility and long-term health.

Treatment strategies and cumulative live birth rates in WHO-II ovulation disorders.

PubMed

Braam, Sanne C; de Bruin, Jan Peter; Buisman, Erato T I A; Brandes, Monique; Nelen, Willianne L D M; Smeenk, Jesper M J; van der Steeg, Jan Willem; Mol, Ben Willem J; Hamilton, Carl J C M

2018-04-10

To assess the live birth rate in women with WHO II anovulation and the proportion of women that need second or third line treatments if the initial therapy fails. In this multicenter cohort study we included couples with unfulfilled child wish who were referred to three fertility clinics in the Netherlands and selected women with a WHO II ovulation disorder as the only final infertility diagnosis (n = 468). The cumulative live birth rate of the total group was 82% (383/468). The majority started with clomiphene-citrate as first-line treatment (n = 378) resulting in 180 (48%) live births. There were 153 couples (40%) who underwent a second-line treatment (recombinant-FSH or laparoscopic electrocoagulation of the ovaries, LEO) and 52 couples (14%) a third-line treatment (IVF/ICSI), resulting in 44% and 63% treatment dependent live births rates, respectively. Of all couples, 92 (20%) conceived naturally, 186 (40%) after clomiphene-citrate, 60 (13%) after recombinant-FSH, nine (2%) after LEO and 36 (8%) after IVF. Subfertile women with a WHO II ovulation disorder have a good prognosis on live birth, and most did so after ovulation induction with clomiphene-citrate. If first-line ovulation induction has failed ovulation induction with gonadotrophins or IVF still result in a live birth in about half of the cases. Copyright © 2018 Elsevier B.V. All rights reserved.

A randomized controlled trial of the effect of rosiglitazone and clomiphene citrate versus clomiphene citrate alone in overweight/obese women with polycystic ovary syndrome.

PubMed

Mohsen, Iman Abdel

2012-04-01

In women suffering from polycystic ovary syndrome, correction of hyperinsulinemia results in enhanced responsiveness to ovulation induction agents. The effect of rosiglitazone was investigated on ovulation induction in obese women with PCOS. A randomized controlled trial was set up. One hundred women were randomly assigned. Group A (n = 46) received rosiglitazone 4 mg b.i.d. plus clomiphene citrate (CC) 100 mg on cycle days 3-7. Group B (n = 45) received CC only. Primary outcome was ovulation. Secondary outcomes included pregnancy as well as changes in fasting glucose and insulin. Both groups were similar with respect to background and hormonal characteristics (age, duration of infertility, BMI, WHR, FSH, LH, E2, testosterone, fasting glucose and insulin). The cumulative ovulation rate over 12 weeks was significantly higher in group A (81.8%) than in group B (55.2%) (p < 0.001), whereas the difference in cumulative pregnancy rate was not statistically significant (30.4% versus 28.8%, respectively) in groups A and B (p = 0.946). Fasting insulin levels significantly declined after rosiglitazone therapy (p < 0.001) without change in glucose levels this resulted in normalization of the mean glucose to insulin ratio. Short term administration of rosiglitazone to overweight and obese PCOS women results in enhancement of CC induced ovulation as well as improvement of insulin sensitivity.

Chinese herbal medicine for subfertile women with polycystic ovarian syndrome.

PubMed

Zhou, Kunyan; Zhang, Jing; Xu, Liangzhi; Wu, Taixiang; Lim, Chi Eung Danforn

2016-10-12

Polycystic ovarian syndrome (PCOS) is one of the most common reproductive endocrinology abnormalities, and affects 5% to 10% of women of reproductive age. Western medicines, such as oral contraceptives, insulin sensitizers and laparoscopic ovarian drilling (LOD), have been used to treat PCOS. Recently, many studies have been published that consider Chinese herbal medicine (CHM) as an alternative treatment for women with PCOS. To assess the efficacy and safety of CHM for subfertile women with PCOS. We searched sources, including the following databases, from inception to 9 June 2016: the Cochrane Gynaecology and Fertility Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Allied and Complementary Medicine (AMED), PsycINFO, Chinese National Knowledge Infrastructure (CNKI), VIP, Wanfang and trial registries. In addition, we searched the reference lists of included trials and contacted experts in the field to locate trials. Randomized controlled trials (RCTs) that considered the use of CHM for the treatment of subfertile women with PCOS. Two review authors independently screened appropriate trials for inclusion, assessed the risk of bias in included studies and extracted data. We contacted primary study authors for additional information. We conducted meta-analyses. We used the odds ratios (ORs) to report dichotomous data, with 95% confidence intervals (CI). We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. We included five RCTs with 414 participants. The comparisons in the included trials were as follows: CHM versus clomiphene, CHM plus clomiphene versus clomiphene (with or without ethinyloestradiol cyproterone acetate (CEA)), CHM plus follicle aspiration plus ovulation induction versus follicle aspiration plus ovulation induction alone, and CHM plus laparoscopic ovarian drilling (LOD) versus LOD alone. The overall quality of the evidence for most comparisons was very low.None of the included studies reported live birth rate, and only one study reported data on adverse events.When CHM was compared with clomiphene (with or without LOD in both arms), there was no evidence of a difference between the groups in pregnancy rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 0.78 to 5.06; two studies, 90 participants, I² statistic = 0%, very low quality evidence). No study reported data on adverse events. When CHM plus clomiphene was compared with clomiphene (with or without CEA), there was low quality evidence of a higher pregnancy rate in the CHM plus clomiphene group (OR 2.62, 95% CI 1.65 to 4.14; three RCTs, 300 women, I² statistic = 0%,low quality evidence). No data were reported on adverse events.When CHM with follicle aspiration and ovulation induction was compared with follicle aspiration and ovulation induction alone, there was no evidence of a difference between the groups in pregnancy rates (OR 1.60, 95% CI 0.46 to 5.52; one study, 44 women, very low quality evidence), severe luteinized unruptured follicle syndrome (LUFS) (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence), ovarian hyperstimulation syndrome (OHSS) (OR 0.16, 95% CI 0.00 to 8.19; one study, 44 women, very low quality evidence) or multiple pregnancy (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence).When CHM with LOD was compared with LOD alone, there was no evidence of a difference between the groups in rates of pregnancy (OR 3.50, 95% CI 0.72 to 17.09; one study, 30 women, very low quality evidence), No data were reported on adverse events.There was no evidence of a difference between any of the comparison groups for any other outcomes. The quality of the evidence for all other comparisons and outcomes was very low. The main limitations in the evidence were failure to report live birth or adverse events, failure to describe study methods in adequate detail and imprecision due to very low event rates and wide CIs. There is insufficient evidence to support the use of CHM for women with PCOS and subfertility. No data are available on live birth, and there is no consistent evidence to indicate that CHM influences fertility outcomes. However there is very limited low quality evidence to suggest that the addition of CHM to clomiphene may improve pregnancy rates. There is insufficient evidence on adverse effects to indicate whether CHM is safe.

Clomiphene

MedlinePlus

... is in a class of medications called ovulatory stimulants. It works similarly to estrogen, a female hormone ... your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting ...

Effect of haloperidol on the synthesis of DNA in the pituitary gland of the rat.

PubMed

Machiavelli, G A; Jahn, G A; Kalbermann, L E; Szijan, I; Alonso, G E; Burdman, J A

1982-03-01

The administration of haloperidol increased serum prolactin and decreased the pituitary concentration of prolactin 15 min after its administration. Concomitantly there was a stimulation in the synthesis of DNA and the activity of DNA polymerase alpha in the anterior pituitary gland that was greater in oestrogenized than in non-oestrogenized male rats. Both these effects were greatly reduced by clomiphene in the oestrogenized male rats, although it did not affect the release of prolactin produced by haloperidol. In non-oestrogenized animals clomiphene abolished the stimulatory effect of haloperidol on the synthesis of DNA. These results suggest that the reduction in the intracellular levels of prolactin are a primary event in the oestrogen mediated stimulation of cell proliferation by prolactin releasing agents.

Live Birth after Rescue In vitro Maturation-intracytoplasmic Sperm Injection in Type 1 Diabetes, Polycystic Ovary Syndrome Patient Using Clomiphene-antagonist Protocol.

PubMed

Sankari, Samundi; Elanchezhian, M; Selvamani, Divya; Nagarajan, M; Gopikrishnan, D

2018-01-01

Infertility in patients with polycystic ovary syndrome (PCOS) associated with diabetes leads to challenging situations seeking alternative treatments. In vitro maturation (IVM) followed by intracytoplasmic sperm injection (ICSI) could overcome the challenges with promising pregnancies in such patients. In the treatment of a 32-year-old diabetic woman who also had PCOS, single immature oocyte was retrieved. Rescue IVM followed by ICSI yielded a grade 1 day 3 embryo which on transferring resulted in pregnancy and a healthy infant was delivered. Rescue IVM-ICSI could help in achieving pregnancy and live birth. Stimulation involving clomiphene and gonadotropin-releasing hormone antagonist is an effective and patient-friendly protocol for women with PCOS and diabetes and also for poor responders.

The effect of clomiphene-citrate on broody turkey hens.

PubMed

Robinzon, B; Shafir, Z; Perek, M; Snapir, N

1984-11-01

The effect of clomiphene-citrate (CC) on broody turkey hens was examined in three experiments. Turkey hens were categorized as broody if found in the laying nest during 6 successive checks per day, if they were reluctant to leave the nest for a period of 24 hr or more, if they had ruffled feathers, and if their cloacal orifices were contracted so as to prevent vaginal exposure by abdominal massage during artificial insemination. In each experiment, 20 hens, selected as broody from commercial breeding flocks, were treated; half were treated with CC at a dosage of 6 mg/kg body weight/day (per os) for 5 consecutive days, and the rest (control) received parallel treatment with a placebo (CaCO3). In all experiments, the CC administration alleviated brooding behavior and increased egg production.

The relationship of the oestrogen and progestin receptors in the abnormal uterus of the adult anovulatory rat. Effects of neonatal treatment with testosterone propionate or clomiphene citrate.

PubMed Central

White, J O; Moore, P A; Elder, M G; Lim, L

1981-01-01

The neonatal administration of testosterone propionate to Wistar rats resulted in anovulatory adults in persistent vaginal oestrus. Clomiphene citrate had a similar effect. In both groups of adults, hyperplasia of the uterine epithelium and occasional metaplasia was observed. The uterine nuclear and cytosol oestrogen and progestin receptors of these anovulatory rats were found to have affinities for their respective ligands similar to those of normal females. The nuclear oestrogen receptor comprised occupied and unoccupied components, as in normal females. The content of the nuclear oestrogen receptor was comparable with that of females in the late dioestrous or pro-oestrous phase. This content was higher in the clomiphene-treated group. Despite the relatively high nuclear oestrogen receptor content the content of progestin receptors, a putative index of the oestrogenic response, was lower in the treated rats than in normal adult females throughout the cycle. Administration of oestradiol to both treatment groups resulted in depletion of cytosol oestrogen receptor content 1 h later, which, however, was not reflected by an increase in the content of nuclear oestrogen receptors. There was no measurable increase in progesterone receptor content in treated rats after daily administration of oestrogen (5 microgram/rat) for 3 days. These changes in sex-hormone-receptor interactions involving an impairment of the normal oestrogenic response may be associated with the abnormal differentiation of the uterus in these sterile, anovulatory animals. Images Fig. 1. Fig. 2. PMID:7316994

Combined metformin and clomiphene citrate versus laparoscopic ovarian diathermy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial.

PubMed

Abu Hashim, Hatem; El Lakany, Naser; Sherief, Lotfy

2011-03-01

To compare the effect of combined metformin and clomiphene citrate (CC) with laparoscopic ovarian diathermy (LOD) meant for ovulation induction in CC-resistant women with polycystic ovary syndrome (PCOS). Two-hundred and eighty-two anovulatory women with CC-resistant PCOS were selected in this randomized controlled trial. Patients (n = 138) received combined metformin-CC for up to six cycles or underwent LOD (n = 144) with six months follow up. The outcome measures were: ovulation rate, midcycle endometrial thickness, pregnancy and miscarriage rates. Ovulation occurred in 386/576 cycles (67%) in the combined metformin-CC group and 381/558 cycles (68.2%) in LOD group without a significant difference between the groups. Resumption of regular menstruation was similar in both groups. A significant increase in midcycle endometrial thickness was observed in the combined metformin-CC group (9.2 ± 1.2 mm vs 7.6 ± 1.1 mm) (P < 0.05). The pregnancy rate was similar in both groups (15.4% vs 17%), and there were no statistically significant differences regarding the miscarriage rate between both groups. Four twin pregnancies occurred in the metformin-CC group. No ovarian hyperstimulation occurred in either group. Combined metformin-CC and LOD are equally effective for inducing ovulation and achieving pregnancy in CC-resistant PCOS patients. © 2010 The Authors. Journal of Obstetrics and Gynaecology Research © 2010 Japan Society of Obstetrics and Gynecology.

Adding the phytoestrogen Cimicifugae Racemosae to clomiphene induction cycles with timed intercourse in polycystic ovary syndrome improves cycle outcomes and pregnancy rates - a randomized trial.

PubMed

Shahin, Ahmed Y; Mohammed, Safwat A

2014-07-01

Owing to their potential to act as estrogen receptor modulators and interfere with aromatase enzyme in animal studies, phytoestrogens (PE) may be useful as part of ovulation induction for polycystic ovary syndrome (PCOS). Patients <35 years, presenting with infertility and PCOS, were included and randomly allocated to either group I (clomiphene citrate; CC) or group II (CC plus Cimicifugae racemosae; CR). Primary outcome was pregnancy rate. Secondary outcomes included ovulation, midcycle serum estradiol and luteinizing hormone (LH) as well as mid-luteal serum progesterone. Analysis included 98 patients in group I versus 96 patients in group II. Both groups were matched regarding demographics and basic data. Significant differences were elicited when comparing days until HCG injection (15.0 ± 1.7 versus 12.0 ± 1.9, p=0.91), endometrial thickness (mm) (8.5 ± 1.9 versus 12.5 ± 1.9, p<0.001), serum levels of mid-luteal and midcycle estradiol (p<0.001; Figure 2), LH (IU/ml) (p<0.001) as well as mid-luteal progesterone (p<0.001). PE plus CC group had significantly higher clinical pregnancies per cycle (33/192 (17.2%) versus 71/204 (34.8%), p<0.01), compared to the CC only group. Adding CR to clomiphene-induction cycles with timed intercourse in polycystic ovarian syndrome improves cycle outcomes and pregnancy rates.

Comparison of pregnancy rates in PCOS patients undergoing clomiphene citrate and IUI treatment with different leading follicular sizes.

PubMed

Seckin, Berna; Pekcan, Meryem Kuru; Bostancı, Esra Isci; Inal, Hasan Ali; Cicek, Mahmut Nedim

2016-04-01

The objective of the study was to compare the pregnancy rates in PCOS patients undergoing clomiphene citrate (CC) and intrauterine insemination (IUI) treatment with different leading follicular sizes. A total of 358 infertile women with PCOS who underwent 563 clomiphene citrate and IUI treatment cycles were included in this prospective study. Treatment cycles were divided into three groups according to leading follicular size on the day of hCG administration: Group I: follicular size 17-18 mm (n = 177), Group II: 19-22 mm (n = 321), and Group III : >22 mm (n = 65). Pregnancy rates were evaluated. Treatment outcomes of the groups were further analyzed related to endometrial thickness measurement on the day of hCG. For this purpose, cycles were placed into three subgroups as follows: endometrial thickness <7, 8-9, and >9 mm. There was no statistically significant difference in clinical pregnancy rate per cycle between the groups (8.5, 10, and 9.2 % for Group I, II, and III, respectively, p = 0.86). In further analyses related to endometrial thickness, no significant difference was also found in pregnancy rate among the groups. This results suggest that pregnancy rate is not related to leading follicle size on the day of hCG administration in PCOS patients treated with CC and IUI. In addition, pregnancy rate in women with different follicular sizes is not influenced by the endometrial thickness.

Ovulation induction: a mini review.

PubMed

Messinis, Ioannis E

2005-10-01

Ovulation induction is the method for treating anovulatory infertility. For patients with hypogonadotrophic hypogonadism, the treatment involves administration of both FSH and LH, while HCG is injected for follicle rupture. Pulsatile GnRH has the same effectiveness as gonadotrophins and the advantage of the low multiple pregnancy rate. In polycystic ovary syndrome (PCOS), the first treatment choice is clomiphene citrate. With this drug, in properly selected patients, the cumulative pregnancy rate approaches that of normal women. Low-dose protocols of FSH are the second line of treatment, effective in inducing monofollicular development. Laparoscopic ovarian drilling can be an alternative but not as a first choice treatment in clomiphene-resistant patients. Other treatments, such as pulsatile GnRH and GnRH agonists, are hardly used today in PCOS. However, in obese women with PCOS, weight loss and exercise should be recommended as the first line of therapy. Newer agents including aromatase inhibitors and insulin sensitizers, although promising, need further evaluation.

[Perinatal clomiphene citrate treatment changes sexual orientations of male mice].

PubMed

He, Feng-Qin; Zhang, Heng-Rui

2013-10-01

Perinatal period and adolescence are critical for brain development, which is the biological basis of an individual's sexual orientation and sexual behavior. In this study, animals were divided into two groups and their sexual orientations were observed: one group experienced drug treatments during the perinatal period, and the other group was castrated at puberty. The results showed that estradiol treatment had no effect on mature male offspring's sexual orientations, but 9 days and 14 days of clomiphene citrate treatment significantly increased the chance of homosexuality and effeminized behavior. In addition, the sexual orientation of mature normal male offspring, which were castrated when they were 21 days old,was not significant different from the control animals. These findings suggest that the inhibition of perinatal estrogen activities could suppress individual male-typical responses, enhance female-typical responses and induce homosexual orientations. Moreover, the masculinizing effects of estrogen were more obvious during perinatal period than adolescence.

An economic evaluation of laparoscopic ovarian diathermy versus gonadotrophin therapy for women with clomiphene citrate-resistant polycystic ovarian syndrome.

PubMed

Farquhar, Cynthia M

2005-08-01

Women with polycystic ovarian syndrome are typically anovulatory and require ovulation induction. Ovarian wedge resection was the first treatment for anovulation but was eventually abandoned because of the increased risk of postsurgical adhesions and as medical ovulation induction with clomiphene and gonadotrophins was introduced. However, with the advent of laparoscopy, there has been a return to surgical approaches. The potential advantages of laparoscopic surgery include avoidance of hyperstimulation and the lowered costs make ovarian surgery an attractive alternative to gonadotrophins. Clinical trials in New Zealand and the Netherlands have compared costs of laparoscopic ovarian drilling with gonadotrophins. The total cost of treatment in the Netherlands study for the ovarian drilling group was euro 4664 and for the gonadotrophins group was euro 5418. Without the cost of monitoring and the diagnostic laparoscopy then the difference was euro 2110 in favour of ovarian drilling. It was estimated that the cost per term pregnancy would be euro 14,489 for gonadotrophin and euro 11,301 for ovarian drilling (22% lower). The higher rates of multiple pregnancy in the gonadotrophin group were considered to be responsible for the increased costs. In the New Zealand trial the costs of a live birth were one-third lower in the group that underwent laparoscopic ovarian diathermy compared with those women who received gonadotrophins (NZ$19,640 and 29,836, respectively). Treating women with clomiphene-resistant polycystic ovarian syndrome with laparoscopic ovarian diathermy results in reduced direct and indirect costs. The reduction in multiple pregnancies makes the alternative of surgery particularly attractive.

Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis.

PubMed

Yu, QingAn; Lv, XiaoYing; Liu, KunPeng; Ma, DaKun; Wu, YaoHua; Dai, WenJie; Jiang, HongChi

2018-01-01

Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas. The purpose of this study was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroid cancer. To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecified fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35; 95% confidence interval [CI] 1.12-1.64; P = 0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12-1.88; P = 0.005). After pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61-1.58, P = 0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.

Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins.

PubMed

Nahuis, M J; Kose, N; Bayram, N; van Dessel, H J H M; Braat, D D M; Hamilton, C J C M; Hompes, P G A; Bossuyt, P M; Mol, B W J; van der Veen, F; van Wely, M

2011-07-01

Long-term effects of laparoscopic electrocautery of the ovaries are unknown. To study the long-term effects of laparoscopic electrocautery of the ovaries and gonadotrophins, we followed women with clomiphene-resistant polycystic ovary syndrome (PCOS) randomly allocated to one of these treatments until 8-12 years after their initial treatment. Between February 1998 and October 2001 168 women with clomiphene citrate-resistant PCOS were included in a randomized controlled trial comparing an electrocautery strategy to a strategy starting with rFSH. In 2009 these women were contacted about their reproductive outcome and menstrual cycle regularity. Analysis was by intention-to-treat. We compared time to conception resulting in live birth, subsequent pregnancies, ectopic and multiple pregnancies, menopause, as well as minimal and maximal menstrual cycle length. After 8-12 years, the cumulative proportion of women with a first child was 86% in women who had been allocated to electrocautery versus 81% in women who had been allocated to immediate rFSH [relative ratio (RR): 1.1; 95% confidence interval (CI): 0.92-1.2]. Treatment with electrocautery resulted in a significantly lower need for stimulated cycles to reach a live birth; 53% after electrocautery versus 76% after rFSH (RR: 0.69; 95% CI: 0.55-0.88).The cumulative proportion of women with a second child was 61% after electrocautery versus 46% after immediate rFSH (RR: 1.4; 95% CI: 1.00-1.9). Overall, there were 7 twins out of 134 deliveries (5%) after electrocautery versus 10 twins out of 124 deliveries (8%) in the rFSH group (RR: 0.65; 95% CI: 0.25-1.6). Fifty-four per cent of the women allocated to electrocautery had a regular menstrual cycle 8-12 years after randomization versus 36% in those allocated to rFSH (RR: 1.5; 95% CI: 0.87-2.6). In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries is as effective as ovulation induction with FSH treatment in terms of live births, but reduces the need for ovulation induction or ART in a significantly higher proportion of women and increases the chance for a second child. Clinicians may use these data when informing clomiphene-resistant anovulatory women about treatment options.

Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility.

PubMed

Skalkidou, Alkistis; Sergentanis, Theodoros N; Gialamas, Spyros P; Georgakis, Marios K; Psaltopoulou, Theodora; Trivella, Marialena; Siristatidis, Charalampos S; Evangelou, Evangelos; Petridou, Eleni

2017-03-25

Medical treatment for subfertility principally involves the use of ovary-stimulating agents, including selective oestrogen receptor modulators (SERMs), such as clomiphene citrate, gonadotropins, gonadotropin-releasing hormone (GnRH) agonists and antagonists, as well as human chorionic gonadotropin. Ovary-stimulating drugs may act directly or indirectly upon the endometrium (lining of the womb). Nulliparity and some causes of subfertility are recognized as risk factors for endometrial cancer. To evaluate the association between the use of ovary-stimulating drugs for the treatment of subfertility and the risk of endometrial cancer. A search was performed in CENTRAL, MEDLINE (Ovid) and Embase (Ovid) databases up to July 2016, using a predefined search algorithm. A search in OpenGrey, ProQuest, ClinicalTrials.gov, ZETOC and reports of major conferences was also performed. We did not impose language and publication status restrictions. Cohort and case-control studies reporting on the association between endometrial cancer and exposure to ovary-stimulating drugs for subfertility in adult women were deemed eligible. Study characteristics and findings were extracted by review authors independently working in pairs. Inconsistency between studies was quantified by estimating I 2 . Random-effects (RE) models were used to calculate pooled effect estimates. Separate analyses were performed, comparing treated subfertile women versus general population and/or unexposed subfertile women, to address the superimposition of subfertility as an independent risk factor for endometrial cancer. Nineteen studies were eligible for inclusion (1,937,880 participants). Overall, the quality of evidence was very low, due to serious risk of bias and indirectness (non-randomised studies (NRS), which was reflected on the GRADE assessment.Six eligible studies, including subfertile women, without a general population control group, found that exposure to any ovary-stimulating drug was not associated with an increased risk of endometrial cancer (RR 0.96, 95% CI 0.67 to 1.37; 156,774 participants; very low quality evidence). Fifteen eligible studies, using a general population as the control group, found an increased risk after exposure to any ovary-stimulating drug (RR 1.75, 95% CI 1.18 to 2.61; 1,762,829 participants; very low quality evidence).Five eligible studies, confined to subfertile women (92,849 participants), reported on exposure to clomiphene citrate; the pooled studies indicated a positive association ( RR 1.32; 95% CI 1.01 to 1.71; 88,618 participants; very low quality evidence), although only at high dosage (RR 1.69, 95% CI 1.07 to 2.68; two studies; 12,073 participants) and at a high number of cycles (RR 1.69, 95% CI 1.16 to 2.47; three studies; 13,757 participants). Four studies found an increased risk of endometrial cancer in subfertile women who required clomiphene citrate compared to a general population control group (RR 1.87, 95% CI 1.00 to 3.48; four studies, 19,614 participants; very low quality evidence). These data do not tell us whether the association is due to the underlying conditions requiring clomiphene or the treatment itself.Using unexposed subfertile women as controls, exposure to gonadotropins was associated with an increased risk of endometrial cancer (RR 1.55, 95% CI 1.03 to 2.34; four studies; 17,769 participants; very low quality evidence). The respective analysis of two studies (1595 participants) versus the general population found no difference in risk (RR 2.12, 95% CI 0.79 to 5.64: very low quality evidence).Exposure to a combination of clomiphene citrate and gonadotropins, compared to unexposed subfertile women, produced no difference in risk of endometrial cancer (RR 1.18, 95% CI 0.57 to 2.44; two studies; 6345 participants; very low quality evidence). However, when compared to the general population, an increased risk was found , suggesting that the key factor might be subfertility, rather than treatment (RR 2.99, 95% CI 1.53 to 5.86; three studies; 7789 participants; very low quality evidence). The synthesis of the currently available evidence does not allow us to draw robust conclusions, due to the very low quality of evidence. It seems that exposure to clomiphene citrate as an ovary-stimulating drug in subfertile women is associated with increased risk of endometrial cancer, especially at doses greater than 2000 mg and high (more than 7) number of cycles. This may largely be due to underlying risk factors in women who need treatment with clomiphene citrate, such as polycystic ovary syndrome, rather than exposure to the drug itself. The evidence regarding exposure to gonadotropins was inconclusive.

Efficacy of combined metformin–clomiphene citrate in comparison with clomiphene citrate alone in infertile women with polycystic ovarian syndrome (PCOS)

PubMed Central

Ayaz, A; Alwan, Y; Farooq, MU

2013-01-01

Background. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women and is associated with the reproductive and metabolic disorders. Objectives. To compare the ovulation and conception rates after the treatment with Clomiphene Citrate (CC) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome (PCOS). Material & Methods. This randomized controlled trial of independent cases and controls was conducted in the Department of Obstetrics and Gynecology, Hera General Hospital, Makkah, Saudi Arabia, during 2008. The 42 subjects diagnosed as PCOS were divided into group A and B (21 subjects in each) for the management with CC + metformin and CC alone, respectively. Group A received 500mg of metformin continuously, three times a day from the first cycle, for 6 months or until the pregnancy was confirmed. In both groups, CC was started with a dose of 50 mg from day-2 until day-6 of the menstrual cycle. The dose of CC was increased to 100 mg in the second and 150 mg in the third cycle, and then 150 mg remained for the rest of three cycles. With ovulation, the dose of CC was unaltered in both groups. Data were analyzed by using SPSS version 16. Results. More than 50% of the females in both groups had a body mass index of >25. Group A achieved a higher rate of regular cycles, ovulation success, and conception than group B (71.4% vs. 38.1%; p=0.03), (76.2% vs. 38.1%; p=0.021) and (66.6% vs. 28.6%, p=0.01), respectively. Conclusion. Management with metformin + CC increased the ovulation and conception rates. PMID:23904883

Endometrial Shedding Effect on Conception and Live Birth in Women With Polycystic Ovary Syndrome

PubMed Central

Diamond, Michael P.; Kruger, Michael; Santoro, Nanette; Zhang, Heping; Casson, Peter; Schlaff, William; Coutifaris, Christos; Brzyski, Robert; Christman, Gregory; Carr, Bruce R.; McGovern, Peter G.; Cataldo, Nicholas A.; Steinkampf, Michael P.; Gosman, Gabriella G.; Nestler, John E.; Carson, Sandra; Myers, Evan E.; Eisenberg, Esther; Legro, Richard S.

2013-01-01

Objective To estimate whether progestin-induced endometrial shedding, prior to ovulation induction with clomiphene citrate, metformin, or a combination of both, affects ovulation, conception, and live birth rates in women with polycystic ovary syndrome (PCOS). Methods A secondary analysis of the data from 626 women with PCOS from the National Institutes of Child Health and Human Development Cooperative Reproductive Medicine Network trial was performed. Women had been randomized to up to six cycles of clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin. Women were assessed for occurrence of ovulation, conception, and live birth in relation to prior bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed). Results While ovulation rates were higher in cycles preceded by spontaneous endometrial shedding than after anovulatory cycles (with or without prior progestin withdrawal), both conception and live birth rates were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding (live birth per cycle: spontaneous menses 2.2%; anovulatory with progestin withdrawal 1.6%; anovulatory without progestin withdrawal 5.3%; p<0.001). The difference was more marked when rate was calculated per ovulation (live birth per ovulation: spontaneous menses 3.0%; anovulatory with progestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%; p < .001). Conclusion Conception and live birth rates are lower in women with PCOS after a spontaneous menses or progestin-induced withdrawal bleeding as compared to anovulatory cycles without progestin withdrawal. The common clinical practice of inducing endometrial shedding with progestin prior to ovarian stimulation may have an adverse effect on rates of conception and live birth in anovulatory women with PCOS. PMID:22525900

Efficacy of combined metformin-clomiphene citrate in comparison with clomiphene citrate alone in infertile women with polycystic ovarian syndrome (PCOS).

PubMed

Ayaz, A; Alwan, Y; Farooq, M U

2013-06-15

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women and is associated with the reproductive and metabolic disorders. To compare the ovulation and conception rates after the treatment with Clomiphene Citrate (CC) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome (PCOS). This randomized controlled trial of independent cases and controls was conducted in the Department of Obstetrics and Gynecology, Hera General Hospital, Makkah, Saudi Arabia, during 2008. The 42 subjects diagnosed as PCOS were divided into group A and B (21 subjects in each) for the management with CC + metformin and CC alone, respectively. Group A received 500mg of metformin continuously, three times a day from the first cycle, for 6 months or until the pregnancy was confirmed. In both groups, CC was started with a dose of 50 mg from day-2 until day-6 of the menstrual cycle. The dose of CC was increased to 100 mg in the second and 150 mg in the third cycle, and then 150 mg remained for the rest of three cycles. With ovulation, the dose of CC was unaltered in both groups. Data were analyzed by using SPSS version 16. More than 50% of the females in both groups had a body mass index of >25. Group A achieved a higher rate of regular cycles, ovulation success, and conception than group B (71.4% vs. 38.1%; p=0.03), (76.2% vs. 38.1%; p=0.021) and (66.6% vs. 28.6%, p=0.01), respectively. Management with metformin + CC increased the ovulation and conception rates.

Laparoscopic ovarian drilling for clomiphene-resistant polycystic ovary syndrome.

PubMed

Flyckt, Rebecca L; Goldberg, Jeffrey M

2011-03-01

Laparoscopic ovarian drilling (LOD) is an alternative to ovulation induction with gonadotropins for polycystic ovarian syndrome (PCOS) patients unresponsive to clomiphene. It is quick and easy to perform, although the number of punctures and energy doses has not been standardized. The mechanism of LOD is unclear, but it is likely mediated by a reduction in intraovarian androgen production. Serum luteinizing hormone and testosterone levels are rapidly normalized, and these changes are sustained over long-term follow-up. Studies have shown that ovulation and pregnancy rates are comparable between ovulation induction with gonadotropins and LOD, but LOD avoids the risks of multiple pregnancy and ovarian hyperstimulation syndrome. LOD is also more cost effective and better tolerated than gonadotropin therapy. Concerns regarding clinically significant adhesion formation and premature ovarian failure are not supported by the available data. Transvaginal hydrolaparoscopy and ultrasound guidance are less invasive techniques for performing ovarian drilling and may encourage LOD earlier in the course of treatment for PCOS. © Thieme Medical Publishers.

Therapeutic effects of metformin and laparoscopic ovarian drilling in treatment of clomiphene and insulin-resistant polycystic ovary syndrome.

PubMed

Wang, Xiao-Hong; Wang, Jun-Qing; Xu, Yan; Huang, Li-Ping

2015-05-01

To compare the therapeutic effects of metformin (Met) and laparoscopic ovarian drilling (LOD) in clomiphene and insulin-resistant patients with polycystic ovary syndrome (CIRPCOS). A total of 110 patients were randomly divided into two groups. One group was administered Met (n = 55), while the other group underwent LOD (n = 55). Rates of ovulation, pregnancy, and abortion were compared between both groups. Rates of normal menstruation, ovulation, and pregnancy in the LOD group were higher than in the Met group: 76.4% (42/55) vs. 58.2% (32/55), P < 0.04; 50.8% (11/258) vs. 33.5% (94/281), P < 0.001; 38.2% (21/55) vs. 20.0% (11/55), P < 0.03. The difference in the early abortion rate between both groups was not statistically significant. Although Met can significantly improve a patient's insulin resistance, we found that in patients diagnosed with CIRCPOS, LOD can be much more effective in improving rates of normal menstruation, ovulation, and pregnancy.

[Therapeutic effect of metformin for clomiphene-resistant infertility patients with polycystic ovary syndrome: a systematic analysis].

PubMed

Wang, Ling-li; Ren, Wei; Cheng, Qing-feng; Fan, Xiao-dong

2012-09-01

To evaluate the efficacy of metformin (MTF) in treatment of clomiphene (CC)-resistant patients with polycystic ovary syndrome (PCOS). The published articles of randomized controlled trial (RCT) of comparison of MTF combined with CC and CC alone in treatment of CC-resistant PCOS were searched in PubMed, EMBASE, OVID, EBSCO databases and Cochrane Library, and these studies were screened under inclusion and exclusion criteria. The quality of included studies and extract data of comparison of ovulation rates and pregnancy rates were evaluated. And the Meta-analysis using statistic software RevMan 5.0 was completed. Total of 333 patients in total 8 trials were included. Meta analysis showed that MTF plus CC led to a significantly higher clinical ovulation rate (OR = 7.31, 95%CI: 2.57 - 20.76, P < 0.05) and pregnancy rate (OR = 7.93, 95%CI: 2.45 - 25.63, P < 0.05) than that of CC alone. MTF can increase ovulation and pregnancy rates of CC-resistant PCOS women.

Protein concentration in pre-ovulatory follicular fluid related to ovarian stimulation.

PubMed

Suchanek, E; Mujkic-Klaric, A; Grizelj, V; Simunic, V; Kopjar, B

1990-05-01

Sixty follicular fluids obtained from 26 women with either clomiphene citrate and human menopausal gonadotropins (hMG) or hMG-induced ovulation were analyzed for the contents of total proteins, fibrinogen, plasminogen, antithrombin III, ceruloplasmin, alpha-2 macroglobulin, alpha-1 antitrypsin and immunoglobulins (IgG, IgA, IgM). Concentrations of these proteins was correlated to the type of ovarian follicle growth induction. Follicular fluids from patients stimulated with clomiphene citrate-hMG contained significantly higher concentrations of ceruloplasmin than those treated with hMG alone. No significant differences in the concentrations of other proteins were noted between the two types of ovarian induction. A multivariate data analysis resulted in three Varimax factors (VRX I) suggesting that proteins with antiprotease activity in the follicular fluid may play a role in human follicle maturation. Follicular fluid Ig may reflect the degree of follicular wall permeability under hMG treatment. Accordingly, it may be assumed that a combination of different proteins described by VRX factors could be used for evaluation of ovarian stimulation.

[Which ovarian stimulation to which women: The polycystic ovary syndrome (PCOS)].

PubMed

Merviel, P; Bouée, S; Ménard, M; Le Martelot, M-T; Roche, S; Lelièvre, C; Chabaud, J-J; Jacq, C; Drapier, H; Beauvillard, D

2017-11-01

Polycystic ovarian syndrome (PCOS) is a frequent pathology in the young woman, linking infertility to a metabolic disease. Initial support will include a plan (in the case of overweight or obesity) to lose at least 5 to 10% of the weight. Subsequently, clomiphene citrate is the first treatment for ovulation induction with pregnancy rates of 40 to 80% after 6 cycles. If there is resistance to clomiphene citrate, the choice will be between the ovarian drilling (50-60% of pregnancy in the year following, including the half spontaneous) or ovarian stimulation with gonadotropins. The risk of ovarian stimulation in these women is hyperstimulation and multiple pregnancies. We also discuss the place of the GnRH pulsatile administration, insulin-sensitizers, in vitro fertilization and in vitro maturation in these women. Once infertility support, these women should be long-term followed because of the neoplasic and cardiovascular risks they present. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Enclomiphene Citrate for the Treatment of Secondary Male Hypogonadism

PubMed Central

Rodriguez, Katherine M.; Pastuszak, Alexander W.; Lipshultz, Larry I.

2016-01-01

Introduction Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches. Areas Covered Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency. Expert Opinion Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option. PMID:27337642

[Qilin Pills combined with clomiphene for idiopathic oligoasthenozoospermia].

PubMed

Yang, Ming-gen; Zheng, Gou-da; Xu, Zhen-qiang; Lin, Hai-li; Zhuang, Zhi-ming; Zhang, Chao-xian

2015-06-01

To observe the therapeutic effect of Qilin Pills combined with clomiphene on idiopathic oligoasthenospermia. We randomly assigned 300 patients with idiopathic oligoasthenospermia to a trial (n = 156) and a control group (n = 144) to be treated with Qilin Pills (6 g, tid) combined with clomiphene (50 mg, qd) and clomiphene alone (50 mg, qd), respectively, both for a course of 12 weeks. Before and after 4, 8, and 12 weeks of medication, we determined sperm concentration, the percentages of grade a and grade a + b sperm, sperm motility, and the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T), followed by evaluation of the clinical efficacy of Qilin Pills with the pregnancy rate in the patients' spouses as the secondaty therapeutic indexes. Compared with the baseline, both groups of patients showed remarkably improved semen parameters and hormone levels after treatment (all P < 0.01). After 4, 8, and 12 weeks of medication, statistically significant differences were observed between the trial and control groups in sperm concentration ([17.06 ± 2.24] vs [15.07 ± 2.48], [22.10 ± 2.65] vs [18.11 ± 2.97], and [28.13 ± 3.59] vs [21.21 ± 3.60] x 10(6)/mL, P < 0.01), the percentage of grade a sperm ([15.03 ± 2.39] vs [13.08 ± 2.51], [21.08 ± 3.16] vs [16.04 ± 3.05], and [28.08 ± 4.70] vs [20.14 ± 4.74]%, P < 0.01), the percentage of grade a + b sperm ([30.10 ± 5.07] vs [26.21 ± 3.96], [38.08 ± 5.64] vs [30.07 ± 4.80], and [48.04 ± 6.49] vs [35.28 ± 4.77]%, P < 0.01), sperm motility ([42.04 ± 4.86] vs [40.29 ± 4.19], [52.05 ± 5.58] vs [48.03 ± 4.40], and [65.03 ± 5.13] vs [56.67 ± 4.99]%), the FSH level ([7.75 ± 1.38] vs [7.20 ± 1.17], [10.83 ± 1.23] vs [9.10 ± 1.32], and [14.22 ± 0.84] vs [12.06 ± 1.45] IU/L, P < 0.01), the LH level ([10.05 ± 1.68] vs [9.18 ± 1.54], [13.96 ± 1.68] vs [11.99 ± 1.71], and [19.01 ± 2.42] vs [15.86 ± 2.08] IU/L, P < 0.01) and the T level ([19.19 ± 192] vs [18.34 ± 1.79] [21.06 ± 1.63] vs [20.06 ± 1.56], and [24.63 ± 1.06] vs [22.03 ± 1.49] nmol/L, P < 0.01). The pregnancy rate in the patients' spouses was significantly higher in the trial than in the control group at 4, 8, and 12 weeks (1.92 vs 0.69, 4.81 vs 3.47, and 11.54 vs 8.33%, P < 0.01). There were no statistically significant differences in drug tolerance between the two groups (P > 0.05). No obvious adverse reactions were observed. Qilin Pills combined with clomiphene can evidently improve the seminal quality and hormone level of oligoasthenospermia patients with no obvious adverse events. However, its long-term efficacy and tolerance deserve further clinical investigation.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

PubMed

Morley, Lara C; Tang, Thomas; Yasmin, Ephia; Norman, Robert J; Balen, Adam H

2017-11-29

Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I 2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology. We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I 2 = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I 2 = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I 2 = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I 2 = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I 2 = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I 2 = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I 2 = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I 2 = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I 2 = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I 2 = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I 2 = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I 2 = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I 2 = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I 2 = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I 2 = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I 2 = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I 2 = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I 2 = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I 2 =0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I 2 = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes. Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.

Use of serum lutenizing hormone in the clinical management of short-term amenorrhea.

PubMed

Bloch, S K

1975-04-15

Serum luteinizing hormone (LH) values determined by radioimmunoassay can be of aid in evaluating patients with short-term amenorrhea. These values have proved useful in ruling out pregnancy in cases of hypothalamic amenorrhea and amenorrhea occuring during treatment with contraceptive pills and also in diagnosing early pregnancy after clomiphene therapy.

Malignant tumors of the ovary or the breast in association with infertility: a report of thirteen cases.

PubMed

Unkila-Kallio, L; Leminen, A; Tiitnen, A; Lehtovirta, P; Wahlström, T; Ylikorkala, O

1997-02-01

Many questions have been raised recently about the relationship between infertility, fertility drugs and cancer. This prompted us to evaluate our patients having ovarian or breast cancer with a known history of infertility. We report thirteen women who had been examined and/or treated for infertility before the occurrence of malignant tumors of the ovary or the breast at an age under 50 years in 1990-1995 in our unit. Mean age of the patients was 35 years (s.d. 5.9 years, range 28-47 years). Of the 11 ovarian tumors, one was a malignant teratoma, two were granulosa cell tumors and eight epithelial ovarian cancers. Ten women had received either clomiphene citrate alone or together with gonadotrophins, one had used only gonadotrophins, and in two patients ovarian cancer was detected during an infertility work-up but before any treatment. Four women had used clomiphene for more than twelve cycles. Two patients had ductal breast cancer. Our patients emphasize the need for follow-up and long-term prospective studies in infertile women who have been evaluated or treated for infertility.

Clomiphene citrate alternatives for the initial management of polycystic ovary syndrome: an evidence-based approach.

PubMed

Abu Hashim, Hatem

2012-06-01

Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous condition affecting 4-8% of reproductive age women. It is the most common cause of chronic anovulation and is associated with hyperandrogenemia. Clomiphene citrate (CC) is considered as the first-line therapy for ovulation induction in these patients. Despite progress in understanding the pathophysiology of PCOS over the past 20 years, many questions persist to the extent that PCOS was described as "A Riddle Wrapped in a Mystery inside an Enigma". On the other hand, a recent publication from the Centers for Disease Control suggested that CC may be associated with an increased risk of birth defects. The purpose of this review is to critically evaluate and summarize the current literature regarding CC alternatives for the initial management of PCOS focusing specifically on the roles of weight loss and other approaches to ovulation induction as insulin-sensitizing drugs, aromatase inhibitors, minimal stimulation protocol, gonadotrophins and surgery (laparoscopic ovarian drilling). Finally, the efficacy of intrauterine insemination with CC for the initial management of PCOS will be evaluated.

[Comments on "Effect of acupuncture and clomiphene in Chinese women with polycystic ovary syndrome: a randomized clinical trial" published in Journal of the American Medical Association].

PubMed

Gang, Weijuan; Jing, Xianghong

2017-11-12

In recent years, more and more patients of polycystic ovary syndrome (PCOS) have strong desire to be treated with acupuncture. In "Effect of acupuncture and clomiphene in Chinese women with polycystic ovary syndrome: a randomized clinical trial" published in Journal of the American Medical Association ( JAMA ) on June 27, 2017, the finding of this research does not support acupuncture for such infertility women. The questions and doubts are proposed in the paper from the regimen of acupuncture treatment, the determination of primary outcome and the explanation of the results. It is found by comparison that the trigger point treatment in the article is different from traditional acupuncture, there is doubt in live birth rate as the primary outcome, 4-month treatment is not enough for the change of live birth rate, difference without statistic significance between acupuncture and control acupuncture does not mean invalid acupuncture because the control acupuncture is not invalid, the research and statistic method are not those planned. As a result, we consider that the conclusion is unreasonable.

Cost effectiveness of letrozole and purified urinary FSH in treating women with clomiphene citrate-resistant polycystic ovarian syndrome: a randomized controlled trial.

PubMed

Hassan, AbdelGany; Shehata, Nesreen; Wahba, Amr

2017-04-01

We aimed to compare the cost effectiveness of letrozole versus purified urinary follicle stimulating hormone (FSH) in treating patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). This was a randomized trial conducted in Cairo University and Beni-Suef University Hospitals, Egypt. A cohort of 140 eligible women was randomized to receive either letrozole 2.5 mg twice daily for five days, or FSH using a graduated regimen starting with a dose of 75 IU. Treatment was repeated for three months if pregnancy did not occur. There were no significant differences between the two treatments in the cumulative clinical pregnancy rate (30% vs. 34%; p = 0.578), cumulative ovulation rate (47% vs. 57%; p = 0.236), miscarriage rate (9% vs. 4%, p > 0.999) or multiple pregnancy rate (0% and 8%, p = 0.491) but the FSH cycles were 4.8 times more expensive. Letrozole and FSH were both effective in treating women with CC-resistant PCOS but letrozole was more cost effective.Study registration number: NCT02304107.

Comparison of mild and microdose GnRH agonist flare protocols on IVF outcome in poor responders.

PubMed

Karimzadeh, Mohammad Ali; Mashayekhy, Mehri; Mohammadian, Farnaz; Moghaddam, Fatemeh Mansoori

2011-05-01

To compare the IVF outcome of clomiphene citrate/gonadotropin/antagonist (mild protocol) and microdose GnRH agonist flare protocols for poor responders undergoing in vitro fertilization. 159 poor responder patients were randomized and ovarian stimulation was performed with clomiphene citrate, gonadotropin and antagonist (group I) or microdose GnRH agonist flare (group II) protocols. Main outcome was clinical pregnancy rate and secondary outcomes were doses of gonadotropin administration and duration of stimulation. There were no significant differences in age, causes of infertility, basal FSH, BMI, duration of infertility, E(2) level on the day of hCG injection in both groups. Although the cancellation, fertilization, and clinical pregnancy rates were similar in both groups, the endometrial thickness, number of retrieved oocytes, mature oocytes and implantation rate were significantly higher in mild protocol. The doses of gonadotropin administration and duration of stimulation were significantly lower in mild protocol. We recommend mild protocol in assisted reproductive technology cycles for poor responders based on our results regarding less doses of used gonadotropin and a shorter duration of stimulation.

[Comparative study on Chinese medical syndrome typing and treatment combined different surgical methods for treating clomiphene-resistant polycystic ovary syndrome].

PubMed

Zeng, Lei; Zeng, Cheng; Tao, Li-Li

2012-11-01

To observe the therapeutic efficacy of Chinese medical syndrome typing and treatment combined cold needle puncture drainage operation or unipolar electrocoagulation drilling technique under laparoscope for treating clomiphene-resistant polycystic ovary syndrome (PCOS). Forty infertility patients with clomiphene-resistant PCOS were assigned to two groups using stratified random sampling method according to age, infertility time, and body mass index, 20 in each group. Patients in Group A were treated with Chinese medical syndrome typing and treatment combined cold needle puncture drainage operation, while those in Group B were treated with Chinese medical syndrome typing and treatment combined unipolar electrocoagulation drilling technique. After operation Chinese herbal treatment was administered to all patients according to syndrome typing. The serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), androgen (T), estradiol (E2), and prolactin (PRL) were determined before and after operation. The ovulation was monitored. The pregnancy rate and the pregnancy outcomes were recorded after operation. There was no statistical difference in the 3-month spontaneous ovulation rate or the 1-year pregnancy rate (P > 0.05). The levels of LH, T, and PRL were significantly lower after operation than before operation in the two groups (P < 0.05). The menstruation and ovulation were obviously improved after operation. The total ovulation rate was 95% (19/20) in Group A. Successful pregnancy occurred in 15 cases of Group A. Ovarian hyperstimulation syndrome (OHSS) occurred in 1 case of Group A. The total ovulation rate was 90% (18/20) in Group B. Successful pregnancy occurred in 13 cases of Group B. Hypovaria occurred in 1 case of Group B. Luteinized unruptured follicle (LUFS) occurred in 2 cases of Group A and 1 case of Group B. Chinese medical syndrome typing and treatment combined cold needle puncture drainage operation or unipolar electrocoagulation drilling technique could effectively promote the ovulation. The two methods showed similar therapeutic effects.

The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome.

PubMed

Legro, Richard S; Kunselman, Allen R; Brzyski, Robert G; Casson, Peter R; Diamond, Michael P; Schlaff, William D; Christman, Gregory M; Coutifaris, Christos; Taylor, Hugh S; Eisenberg, Esther; Santoro, Nanette; Zhang, Heping

2012-05-01

Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50mg every day for 5 days (days 3-7 of cycle), or B) letrozole 2.5mg every day for 5 days (days 3-7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (×5 days) or 7.5mg of letrozole a day (×5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms. Copyright © 2012 Elsevier Inc. All rights reserved.

THE PREGNANCY IN POLYCYSTIC OVARY SYNDROME II (PPCOS II) TRIAL: RATIONALE AND DESIGN OF A DOUBLE-BLIND RANDOMIZED TRIAL OF CLOMIPHENE CITRATE AND LETROZOLE FOR THE TREATMENT OF INFERTILITY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME

PubMed Central

Legro, Richard S.; Kunselman, Allen R.; Brzyski, Robert G.; Casson, Peter R.; Diamond, Michael P.; Schlaff, William D.; Christman, Gregory M.; Coutifaris, Christos; Taylor, Hugh S.; Eisenberg, Esther; Santoro, Nanette; Zhang, Heping

2012-01-01

Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50 mg every day for 5 days (day 3–7 of cycle), or B) letrozole 2.5 mg every day for 5 days (day 3–7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (× 5 days) or 7.5 mg of letrozole a day (× 5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms. PMID:22265923

Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome.

PubMed

Franik, Sebastian; Eltrop, Stephanie M; Kremer, Jan Am; Kiesel, Ludwig; Farquhar, Cindy

2018-05-24

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI). We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status. We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods. This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I 2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I 2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I 2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I 2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I 2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I 2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I 2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I 2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I 2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

Insulin resistance in clomiphene responders and non-responders with polycystic ovarian disease and therapeutic effects of metformin.

PubMed

Parsanezhad, M E; Alborzi, S; Zarei, A; Dehbashi, S; Omrani, G

2001-10-01

To evaluate the clinical features, endocrine and metabolic profiles in clomiphene (CC) responders and non-responders with polycystic ovarian disease (PCOD), and to examine the effects of metformin (MTF) on the above parameters of CC resistance. A prospective clinical trial was undertaken at the infertility division of a university teaching hospital. Forty-one CC responders were selected and their hormonal and clinical features were determined. Forty-one CC-resistant PCOD women were also selected and clinical features; metabolic and hormonal profiles before and after treatment with MTF 1500 mg/day for 6-8 weeks were evaluated. Women who failed to conceive were treated by CC while continuing to take MTF. CC responders had higher insulin levels while non-responders were hyperinsulinemic. Menstrual irregularities improved in 30%. Mean+/-S.D. area under curve of insulin decreased from 297.58+/-191.33 to 206+/-0.1 mIU/ml per min (P=0.005). Only 39.39% ovulated and 24.24% conceived. PCOD is associated with insulin resistance (IR) particularly in CC-resistant women. Insulin resistance and androgen levels are significantly higher in obese patients. MTF therapy improved hyperandrogenemia, IR, and pregnancy rate.

Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice

PubMed Central

Melo, Anderson Sanches; Ferriani, Rui Alberto; Navarro, Paula Andrea

2015-01-01

Polycystic ovary syndrome represents 80% of anovulatory infertility cases. Treatment initially includes preconception guidelines, such as lifestyle changes (weight loss), folic acid therapy to prevent the risk of fetal neural tube defects and halting the consumption of tobacco and alcohol. The first-line pharmacological treatment for inducing ovulation consists of a clomiphene citrate treatment for timed intercourse. The second-line pharmacological treatment includes the administration of exogenous gonadotropins or laparoscopic ovarian surgery (ovarian drilling). Ovulation induction using clomiphene citrate or gonadotropins is effective with cumulative live birth rates of approximately 70%. Ovarian drilling should be performed when laparoscopy is indicated; this procedure is typically effective in approximately 50% of cases. Finally, a high-complexity reproduction treatment (in vitro fertilization or intracytoplasmic sperm injection) is the third-line treatment and is recommended when the previous interventions fail. This option is also the first choice in cases of bilateral tubal occlusion or semen alterations that impair the occurrence of natural pregnancy. Evidence for the routine use of metformin in infertility treatment of anovulatory women with polycystic ovary syndrome is not available. Aromatase inhibitors are promising and longer term studies are necessary to prove their safety. PMID:26602525

Subclinical hypothyroidism is associated with metabolic syndrome and clomiphene citrate resistance in women with polycystic ovary syndrome.

PubMed

Lu, Yue-Hong; Xia, Zhou-Lan; Ma, Ying-Ying; Chen, Hui-Juan; Yan, Li-Ping; Xu, Hui-Fang

2016-10-01

To evaluate the possible relationship between subclinical hypothyroidism (SCH) and metabolic syndrome (MS) and the response to clomiphene citrate (CC) stimulation in women with polycystic ovary syndrome (PCOS). One hundred and ninety-six women with PCOS were divided into two groups: (1) the SCH group with 92 patients; (2) the euthyroid (EU) group with 104 patients. Physical characteristics and metabolic parameters as well as the reaction to CC stimulating test were compared between these two groups. (1) In the SCH group, significantly higher body mass index, Ferriman-Gallwey score, serum triglyceride, insulin and glucose of oral glucose tolerance test, homeostatic model assessment-insulin resistance (HOMA-IR) and significantly lower serum high-density lipoprotein cholesterol was observed in comparison with those in the EU group (p < 0.05). (2) The prevalence of CC resistance (30.4%), IR (43.5%) and MS (34.8%) in the SCH group was significantly higher than that in the EU group (p < 0.05). SCH was found associated with IR, MS and CC resistance in women with PCOS. PCOS patients with SCH may have a poorer treatment response to ovulation induction with CC.

In vitro fertilization treatments with the use of clomiphene citrate or letrozole.

PubMed

Haas, Jigal; Casper, Robert F

2017-10-01

There has been increasing interest in combining the oral agents clomiphene citrate (CC) and letrozole with gonadotropins in IVF: for poor responders to reduce the amount of gonadotropins used, and in normal responders to reduce the incidence of ovarian hyperstimulation (OHSS). In normal responders, mild stimulation with the use of CC and gonadotropins was found to decrease the number of oocytes retrieved and result in good pregnancy rates, but in most studies the cumulative pregnancy rate was lower compared with conventional ovarian stimulation when frozen embryo transfers were considered. Coadministration of letrozole and gonadotropins has mainly been used in patients with breast cancer to prevent the massive elevation of serum E 2 concentrations with the use of standard controlled ovarian hyperstimulation. CC and letrozole have both been used with gonadotropins in poor responders and have been shown to reduce the amount of gonadotropin used without reducing the pregnancy rate. Letrozole use with gonadotropins in IVF cycles may increase endometrial receptivity by increasing integrin expression in the endometrium and by lowering estrogen concentrations to more physiologic levels. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea.

PubMed

Borges, Lavinia Estrela; Morgante, Giuseppe; Musacchio, Maria Concetta; Petraglia, Felice; De Leo, Vincenzo

2007-06-01

To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. This was an open-label study. Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.

Long-term effects of ovulation-stimulating drugs on cancer risk.

PubMed

Brinton, Louise

2007-07-01

Although nulliparity has been extensively related to the risk of ovarian, breast and endometrial cancers, with many studies showing the relationship largely attributable to infertility, treatment effects on cancer risk are poorly understood. Two early studies raised substantial concern when ovulation-stimulating drugs were linked with large increases in ovarian cancer, supporting the notion of an important aetiological role of incessant ovulation. Subsequent studies have been mainly reassuring, although some have suggested possible risk increases among nulligravid women, those with extensive follow-up, and those developing borderline tumours. Results regarding effects of fertility drugs on breast cancer risk are conflicting, with some showing no associations and others demonstrating possible risk increases, although for varying subgroups. In contrast, endometrial cancer results are more consistent, with two recent studies showing increased risks related to clomiphene usage. This is of interest given that clomiphene is structurally similar to tamoxifen, a drug extensively linked with this cancer. Given the recent marketing of fertility drugs and the fact that exposed women are only beginning to reach the cancer age range, further follow-up is necessary. This will also be important to fully resolve effects of exposures such as gonadotrophins, used more recently in conjunction with IVF.

Cycle regimens for frozen-thawed embryo transfer.

PubMed

Ghobara, T; Vandekerckhove, P

2008-01-23

Pregnancy rates following frozen-thawed embryo transfer (FET) treatment have always been found to be lower than following embryo transfer using fresh embryos. Nevertheless, FET increases the (cumulative) pregnancy rate, reduces cost, is relatively simple to undertake and can be accomplished in a shorter time period compared to repeated 'fresh' cycles. FET is performed using different cycle regimens: spontaneous ovulatory cycles, cycles in which ovulation is induced by drugs and cycles in which the endometrium is artificially prepared by oestrogen (O) and progesterone (P) hormones, with or without a gonadotrophin releasing hormone agonist (GnRHa). To determine whether there is a difference in outcome between natural cycle FET, artificial cycle FET and ovulation induction cycle FET. Our search included CENTRAL,DARE, MEDLINE (1950 to 2007), EMBASE (1980 to 2007) and CINAHL (1982 to 2007). Randomised controlled trials (RCTs) comparing the various cycle regimens and different methods used to prepare the endometrium during FET in assisted reproductive technology (ART). The two authors independently extracted data. Dichotomous outcomes results (e.g. clinical pregnancy rate) were expressed as an odds ratio (OR) with 95% confidence intervals (CI) for each study. Continuous outcome results (endometrial thickness) were expressed as weighted mean difference (WMD). Where suitable, results were combined for meta-analysis with RevMan software using the Peto-modified Mantel-Haenszel method. Seven randomised controlled studies assessing six comparisons and including 1120 women in total were included in this review.1) O + P FET versus natural cycle FET: this comparison demonstrated no significant differences in outcomes but confidence intervals remain wide, and therefore moderate differences in either direction remain possible (OR 1.06, 95% CI 0.40 to 2.80, P 0.91).2) GnRHa + O + P FET versus O + P FET: this comparison showed that the live birth rate per woman was significantly higher in the former group (OR 0.38, 95% CI 0.17 to 0.84, P 0.02). The clinical pregnancy rate was also higher but not significantly so (OR 0.76, 95% CI 0.52 to 1.10, P 0.14).3) O + P FET versus follicle stimulating hormone (FSH) FET, 4) O + P FET versus clomiphene FET and 5) GnRHa + O + P FET versus clomiphene FET: there were no differences in the outcomes in the comparison of these cycle regimens.6) Clomiphene + human menopausal gonadotrophin (HMG) FET versus HMG FET: in a comparison of two ovulation induction regimes the pregnancy rate was found to be significantly higher in the HMG group (OR 0.46, 95% CI 0.23 to 0.92). There were also fewer cycle cancellations and a lower multiple pregnancy rate when HMG was used without clomiphene but these did not reach statistical significance. At the present time there is insufficient evidence to support the use of one intervention in preference to another.

Fertility drugs and endometrial cancer risk: results from an extended follow-up of a large infertility cohort.

PubMed

Brinton, Louise A; Westhoff, Carolyn L; Scoccia, Bert; Lamb, Emmet J; Trabert, Britton; Niwa, Shelley; Moghissi, Kamran S

2013-10-01

Do fertility drugs influence the subsequent risk of endometrial cancer in a manner that is independent of other risk predictors, such as parity? In this follow-up of a large cohort of women evaluated for infertility and for whom information was captured on fertility drugs, indications for usage and other risk factors that might influence cancer risk, we found no evidence for a substantial relationship between fertility drug use and endometrial cancer risk. Although the hormonal etiology of endometrial cancer has been well established, it remains unclear whether the use of fertility drugs has an influence on risk. Results regarding the effects of fertility drugs on endometrial cancer risk have been inconsistent, although several studies have shown some evidence for possible increases in risk. The relationship is of particular interest given that clomiphene, a commonly prescribed drug, is a selective estrogen receptor modulator, with chemical properties similar to tamoxifen, another drug linked to an increase in endometrial cancer risk. In a retrospective cohort of 12 193 women evaluated for infertility between 1965 and 1988 at five US sites, follow-up was pursued through 2010 via both passive as well as active (questionnaire) means. Among the 9832 subjects for whom follow-up was allowed and achieved, 259 346 at-risk person-years (i.e. prior to hysterectomy) were accrued, and 118 invasive endometrial cancers identified. Cox regression determined hazard ratios (HRs) and 95% confidence intervals (CIs) for fertility treatments adjusted for endometrial cancer risk factors and causes of infertility. Although we observed slight increases in endometrial cancer risk associated with clomiphene (HR = 1.39, 95% CI: 0.96-2.01) and the less commonly prescribed gonadotrophins (1.34, 0.76-2.37), there were no convincing relationships of risk with either cycles of use or cumulative exposures for either drug. A statistically significant risk associated with the use of clomiphene among women who began use at younger ages (<30) (1.93, 1.24-3.00) may have reflected indications for drug usage rather than the effect of the drug itself. Women who received clomiphene followed by gonadotrophins were at a non-significantly elevated risk (1.77, 0.98-3.19). Like most studies of endometrial cancer, we were limited by sample sizes, particularly for evaluating subgroup associations. We were also unable to follow all women and were not able to obtain complete risk factor information (including hysterectomy status) for the entire cohort. Although we found no support for a relationship between fertility drugs and endometrial cancer risk, the association should continue to be monitored given that our study population was still young and had not yet reached the age of peak endometrial cancer incidence. This project was supported in part by funds from the intramural research program of the National Cancer Institute, National Institutes of Health. None of the authors has any conflicting interests to declare.

Could transvaginal, ultrasound-guided ovarian interstitial laser treatment replace laparoscopic ovarian drilling in women with polycystic ovary syndrome resistant to clomiphene citrate?

PubMed

Api, Murat

2009-12-01

A number of novel surgical modalities that destroy or remove some ovarian tissue to restore ovarian function in patients with polycystic ovary syndrome have been described in the most recent literature. Although these modalities were reported to have easy applicability and low cost with shorter hospital stay, the efficacy and safety concerns need to be discussed extensively.

Adrenal hormones in human follicular fluid.

PubMed

Jimena, P; Castilla, J A; Peran, F; Ramirez, J P; Vergara, F; Molina, R; Vergara, F; Herruzo, A

1992-11-01

Considerable evidence indicates that adrenal hormones may affect gonadal function. To assess the role of some adrenal hormones in human follicular fluid and their relationship with the ability of the oocyte to be fertilized and then to cleave in vitro, cortisol and dehydroepiandrosterone sulfate were measured in follicular fluid obtained at the time of oocyte recovery for in vitro fertilization from cycles stimulated by clomiphene citrate, human menopausal gonadotropin and human chorionic gonadotropin. Thirty-six follicular fluid containing mature oocyte-corona-cumulus complexes and free of visible blood contamination were included in this study. There was no significant difference in follicular fluid dehydroepiandrosterone sulfate concentration between follicles with oocytes which did or did not fertilize (5.1 +/- 1.1 vs 5.8 +/- 2.0 mumol/l). However, follicular fluid from follicles whose oocytes were not fertilized had levels of cortisol significantly higher than those in follicular fluid from follicles containing successfully fertilized oocytes (406.0 +/- 75.9 vs 339.2 +/- 37.0 nmol/l; p < 0.005). No significant correlations were found between rates of embryo cleavage and cortisol and dehydroepiandrosterone levels in follicular fluid. We conclude that cortisol levels in follicular fluid may provide an index of fertilization outcome, at least in stimulated cycles by clomiphene citrate, human menopausal gonadotropin and human chorionic gonadotropin.

Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies.

PubMed

Hull, M G

1987-09-01

The frequency of polycystic ovarian disease (PCOD) as a cause of oligo-amenorrhea and infertility was determined, first by characterizing clinically occult PCOD using endocrinological methods, and secondly by estimating the frequency of overt and occult PCOD amongst infertile women residing in a particular area. Four groups of infertile women with oligo-amenorrhea due to 'functional' disorder were compared. The results show that by contrast with the groups having hyperprolactinemia or hypothalamic disorder the group with hirsutism (and therefore presumed PCOD) was closely resembled by a non-hirsute group in terms of estrogenization, LH level, LH/FSH ratio, prolactin level, body mass and responsiveness to clomiphene. The last group was therefore concluded to have a mild occult form of PCOD. The population studies revealed, first, that overt and occult PCOD accounted for 90% of patients with oligomenorrhea and 37% with amenorrhea, or 73% with oligo- or amenorrhea. Oligo- or amenorrhea accounted for 21% of couples with infertility and the annual incidence was 247 patients per million of the general population. The annual incidence of infertility due to PCOD per million was 41 with overt PCOD and 139 with occult PCOD (total 180). Of those, 140 appeared to respond well to clomiphene (78%) but 40 (22%) failed, requiring alternative therapy.

Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial.

PubMed

Liu, Chang; Feng, Guimei; Huang, Wei; Wang, Qiuyi; Yang, Shiyuan; Tan, Jing; Fu, Jing; Liu, Dong

2017-11-01

To compare the therapeutic efficacy of clomiphene citrate (CC) and letrozole (LE) on ovulation, pregnancy, and live birth in women with polycystic ovary syndrome (PCOS); and to ensure if LE can replace CC as the first-line therapy for ovulation induction in these women. This is a prospectively, randomized, controlled trial in the tertiary hospital. Two-hundred and sixty-eight anovulatory PCOS patients were treated by CC or CC plus metformin and LE or LE plus metformin for three continuous cycles or conception; their ovulation rates, pregnancy rates, and live birth rates were calculated and compared. No significant difference was noted among the four groups regarding to the baseline data of clinical manifestations, serum sex hormone levels, and serum insulin levels. A total of 240 patients completed the therapies. The ovulation rate was significantly higher in the group LE than the group CC; however, no significant difference was noted between the groups LE and CC, CC, and CC + MET, or LE and LE + MET in the pregnancy rate, abortion rate, and live birth rate. No birth defect was found in the total of 63 newborns. CC regimen was still recommended to be the first-line therapy of ovulation induction for PCOS.

Laparoscopic ovarian diathermy vs clomiphene citrate plus metformin as second-line strategy for infertile anovulatory patients with polycystic ovary syndrome: a randomized controlled trial.

PubMed

Palomba, Stefano; Falbo, Angela; Battista, Lucia; Russo, Tiziana; Venturella, Roberta; Tolino, Achille; Orio, Francesco; Zullo, Fulvio

2010-06-01

The purpose of this study was to compare the effectiveness of laparoscopic ovarian diathermy (LOD) vs clomiphene citrate (CC) plus metformin in infertile patients with CC-resistant polycystic ovary syndrome (PCOS). Fifty primary infertile patients with CC-resistant PCOS were assigned randomly to receive LOD followed by a 6-month observation (group A) or 6-cycle course of CC plus metformin (group B). Reproductive and safety outcomes were analyzed. No significant difference between 2 groups in pregnancy (15/92 women [16.3%] vs 14/107 women [13.1%]; P = .521) and live-birth (13/92 women [14.1%] vs 12/107 women [11.2%]; P = .536) rates per cycle was observed. With the use of a Cox regression analysis, patients under medical treatment, compared with patients who received surgical treatment, had a relative risk of pregnancy of 1.2 (95% confidence interval, 0.61-2.44; P = .582) and a relative risk of live-birth of 1.4 (95% confidence interval, 0.63-2.96; P = .425). LOD and CC plus metformin seem to be 2 effective approaches to treat infertility in patients with CC-resistant PCOS. Copyright 2010 Mosby, Inc. All rights reserved.

Efficacy of combined metformin-letrozole in comparison with bilateral ovarian drilling in clomiphene-resistant infertile women with polycystic ovarian syndrome.

PubMed

Abd Elgafor, Ibrahim

2013-07-01

To compare the hormonal-metabolic profiles and reproductive outcomes between women receiving metformin plus letrozole and women undergoing bilateral ovarian drilling in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS). In this randomized study, 146 patients were randomly allocated into group 1 (n = 73) who received metformin plus letrozole, and group 2 (n = 73) who underwent bilateral ovarian drilling. Comparison was done between the basal and after treatment biochemical values for each group, in addition reproductive outcomes after treatment were compared between both groups. There was significant reduction in testosterone (p ≤ 0.001), fasting insulin (p ≤ 0.001), and fasting glucose/fasting insulin ratio (p = 0.029) in metformin plus letrozole group, while there was significant reduction in FSH, LH and LH/FSH ratio in bilateral drilling group (p ≤ 0.001, 0.001 and 0.001). No significant difference in cycle regularity (p = 0.82), ovulation (p = 0.24), pregnancy rate (p = 0.32) and abortion rate (p = 0.51) between both groups. Both metformin plus letrozole and bilateral ovarian drilling are similarly effective as second-line strategies for the treatment of women with PCOS who do not conceive with CC.

Parameters for calcium metabolism in women with polycystic ovary syndrome who undergo clomiphene citrate stimulation: a prospective cohort study.

PubMed

Ott, J; Wattar, L; Kurz, C; Seemann, R; Huber, J C; Mayerhofer, K; Vytiska-Binstorfer, E

2012-05-01

To evaluate whether parameters for calcium metabolism were associated with characteristics of polycystic ovary syndrome (PCOS). A prospective cohort study. Ninety-one anovulatory, infertile women with PCOS patients underwent clomiphene citrate (CC) stimulation. Main outcome measures were parathyroid hormone (PTH); 25-hydroxyvitamin D3 (25OHD3); serum levels of calcium, phosphorus, magnesium, albumin, and total protein; the serum calcium-phosphorus product; LH; FSH; sexual hormone binding globulin; testosterone; and androstenedione. PTH correlated inversely with serum calcium (r=-0.235; P=0.004) and 25OHD3 (r=-0.664; P<0.001), whereas positive correlations were found between PTH and body mass index (BMI; r=0.270; P=0.010) and between PTH and testosterone (r=0.347; P=0.001). After stimulation with 50 mg CC, 57.1% (52/91) developed a follicle, whereas 26.4% (24/91) became pregnant. In a multivariate model to predict both follicle development and pregnancy, BMI and 25OHD3 deficiency were significant predictive parameters. 25OHD3 deficiency was an independent predictive parameter of CC stimulation outcome, in terms of follicle development and pregnancy. Our results suggest a substantial role of vitamin D in PCOS and infertility treatment in these patients.

Letrozole versus clomiphene citrate in polycystic ovary syndrome: a meta-analysis of randomized controlled trials.

PubMed

Hu, Shifu; Yu, Qiong; Wang, Yingying; Wang, Mei; Xia, Wei; Zhu, Changhong

2018-05-01

Polycystic ovary syndrome (PCOS) is a common endocrine disturbance affecting women in the reproductive age group. The present study aimed to compare the effects of letrozole (LE) and clomiphene citrate (CC) for ovulation induction in women with PCOS. The PUBMED, Web of Science, and EMBASE databases were screened systematically for randomized controlled trials (RCTs) published from database inception to July 2017. Eleven RCTs involving 2255 patients were included, and data were independently extracted and analyzed using 95% risk ratios (RRs) and confidence intervals (CIs) based on a random- or fixed-effect model (as appropriate). Meta-analyses of nine RCTs comparing LE and CC ovulation induction, followed by timed intercourse, indicated that the former significantly increased the ovulation rate (RR = 1.18; 95% CI 1.03-1.36, P = 0.01), pregnancy rate (RR = 1.34; 95% CI 1.09-1.64, P = 0.006), and live birth rate (RR = 1.55; 95% CI 1.28-1.88, P < 0.00001). However, LE and CC did not differ significantly in terms of the multiple pregnancy and abortion rates. Furthermore, LE for ovulation induction significantly improved the pregnancy rate after IUI. LE is superior to CC for ovulation induction in patients with PCOS.

The effect of luteal-phase support with vaginal progesterone on pregnancy rates in gonadotropin and clomiphene citrate/intra-uterine insemination cycles in unexplained infertility: A prospective randomised study.

PubMed

Karadag, Burak; Dilbaz, Berna; Karcaaltincaba, Deniz; Sahin, Elif Gulsah; Ercan, Fedi; Karasu, Yetkin; Tonyalı, Nazan Vanlı

2016-08-01

The purpose of this study is to analyse the effect of luteal-phase support on pregnancy rates in gonadotropin + intra-uterine insemination (Gn/IUI) and clomiphene citrate (CC) +IUI (CC/IUI) cycles in patients with unexplained infertility. Equal numbers of patients were recruited in two treatment arms (CC/IUI and Gn/IUI) (n = 100, n = 100, respectively). In each group, 50 patients received vaginal progesterone for 14 days (Crinone 8% vaginal gel, 90 mg per day) for luteal-phase support from the day after IUI and continued until menstruation or the 10th week of gestation if pregnant. There were 29 clinical pregnancies among 200 patients. Pregnancy rates were 12% in CC/IUI cycles, 10% in luteal-phase-supported CC/IUI cycles 16% in Gn/IUI cycles and 20% in luteal-phase-supported Gn/IUI cycles. Although pregnancy rates were higher in Gn/IUI cycles compared to CC/IUI cycles, luteal-phase support did not significantly affect the pregnancy rates in both groups. This study implies that luteal-phase support with progesterone has no pronounced beneficial effect on pregnancy rates in either CC/IUI or Gn/IUI cycles in patients with unexplained infertility.

Association of increased total antioxidant capacity and anovulation in nonobese infertile patients with clomiphene citrate-resistant polycystic ovary syndrome.

PubMed

Verit, Fatma Ferda; Erel, Ozcan; Kocyigit, Abdurrahim

2007-08-01

To investigate whether total antioxidant capacity (TAC) could predict the response to ovulation induction to clomiphene citrate (CC) in nonobese women with polycystic ovary syndrome. Prospective longitudinal follow-up study. Academic hospital. Fifty-five nonobese, oligomenorrheic women with polycystic ovary syndrome and normal indices of insulin sensitivity. None. Standard clinical examinations and ultrasonographic and endocrine screening, including FSH, LH, E(2), P, total T, sex hormone-binding globulin, DHEAS, and TAC were performed before initiation of CC medication. Within the total group, 27 (49%) of the patients did not ovulate at the end of follow-up. TAC, free androgen index, and ovarian volume were all significantly different in CC nonresponders from those in responders. Total antioxidant capacity was found to be the best predictor in univariate analysis (odds ratio, 171.55; 95% confidence interval, 10.61-2,772.93), and it had the highest area in the receiver operating characteristics analysis (0.91). In a multivariate prediction model, TAC, free androgen index, and ovarian volume showed good predictive power, with Hosmer-Lemeshow goodness of fit test of 0.80. Total antioxidant capacity was the strongest predictor of ovarian response during CC induction of ovulation in these patients. It can be concluded that TAC can be used as a routine screening test.

FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection

PubMed Central

Johansen, Lisa M.; Brannan, Jennifer M.; Delos, Sue E.; Shoemaker, Charles J.; Stossel, Andrea; Lear, Calli; Hoffstrom, Benjamin G.; DeWald, Lisa Evans; Schornberg, Kathryn L.; Scully, Corinne; Lehár, Joseph; Hensley, Lisa E.; White, Judith M.; Olinger, Gene G.

2014-01-01

Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections. PMID:23785035

A randomized controlled trial evaluating the effect of ethinyl estradiol during clomiphene citrate cycles among women with polycystic ovary syndrome.

PubMed

Moini, Ashraf; Ahmadi, Firoozeh; Jahangiri, Nadia; Ahmadi, Jila; Akhoond, Mohammad Reza

2015-11-01

To investigate the effects of low-dose ethinyl estradiol (EE) on the clinical pregnancy rate among women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with clomiphene citrate (CC). Between March 12, 2011, and February 10, 2013, a randomized, double-blind, placebo-controlled trial was conducted at the Royan Institute Research Center, Tehran, Iran, among women with PCOS who were aged 25-30 years, were undergoing their first intrauterine insemination cycle, and had a history (≥2 years) of infertility, oligomenorrhea, or amenorrhea. Participants were randomly allocated to receive EE (0.05 mg daily for 5 days) or placebo, co-administered with CC cycles (100 mg daily for 5 days). The primary outcome was clinical pregnancy rate. Analyses were per protocol: patients who discontinued the intervention were excluded. Analyses included 45 women who received CC and EE, and 50 women who received CC and placebo. The number of women who achieved a clinical pregnancy was higher among participants who received CC and EE (13 [29%]) than among those in the control group (5 [10%]; P =0 .02). No adverse effects of EE were reported. The combination of CC and EE seems to increase the clinical pregnancy rate among women with PCOS undergoing intrauterine insemination. ClinicalTrials.gov:NCT01219101. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Minimal stimulation or clomiphene citrate as first-line therapy in women with polycystic ovary syndrome: a randomized controlled trial.

PubMed

Abu Hashim, Hatem; Bazeed, Mohamed; Abd Elaal, Ibrahim

2012-02-01

To compare the efficacy of minimal stimulation and clomiphene citrate (CC) as a first-line treatment for anovulatory infertility associated with polycystic ovary syndrome (PCOS). One hundred and thirteen women with PCOS were selected in this randomized controlled trial. Patients received minimal stimulation protocol consisted of 5 days CC (100 mg/day) then 150 IU of highly purified uFSH on cycle day 9 (n = 58, 159 cycles) or CC only (n = 55, 153 cycles) for up to three cycles. Outcome measures were: clinical pregnancy rate per cycle, number of growing and mature follicles, serum E2, endometrial thickness at the hCG day, serum P, ovulation and miscarriage rates. There were no differences between both groups regarding the clinical pregnancy rate per cycle and per woman (8.8% vs. 7.8 % and 24.1% vs. 21.8%; p = 0.23, p = 0.36, respectively). One twin pregnancy occurred in each group. Miscarriage rate was comparable (14.3% vs. 16.7%; p = 0.38). No differences were found regarding the number of follicles, serum P, ovulation rate, E2 and endometrial thickness at the hCG day (7.8 ± 0.5 vs. 7.6 ± 0.6 mm; p = 0.52). Ovulation induction with minimal stimulation is not more effective than CC alone for achieving pregnancy when used as initial treatment in PCOS patients.

The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome.

PubMed

Maged, Ahmed M; Elsawah, Heba; Abdelhafez, Aly; Bakry, Ahmed; Mostafa, Walaa Ai

2015-01-01

To assess the adjuvant effect of metformin and N-acetylcysteine (NAC) to clomiphene citrate (CC) in induction of ovulation in Polycystic Ovary Syndrome (PCOS) patients. 120 women with PCOS were randomly divided into three equal groups: group I received CC only, group II received CC plus NAC and group III received CC plus metformin. There was a significant difference between group II and other two groups regarding average number of ovulatory follicles >18 mm (2.25 versus 1.75 and 1.89, respectively), but no significant difference between the three study groups regarding number of intermediate follicles 14-18 mm (4, 10 and 4, respectively). There was no significant difference between the three study groups regarding occurrence and laterality of ovulation, pregnancy rate per cycle but a significant difference between group II and other two groups regarding pregnancy rate per patient (20% versus 10% and 10%, respectively, p value 0.05). There was a highly statistically significant difference between group II and other two groups regarding peak endometrial thickness (7.3 ± 1.1 versus 5.4 ± 0.6 and 5.3 ± 0.6, respectively). NAC as an adjuvant to CC for induction of ovulation improves ovulation and pregnancy rates in PCOS patients with beneficial impacts on endometrial thickness.

Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome.

PubMed

Wallace, Kedra L; Johnson, Venessia; Sopelak, Victoria; Hines, Randall

2011-10-01

To compare the effect of clomiphene citrate (CC) and letrozole on endometrial receptivity in women with polycystic ovary syndrome (PCOS). A randomized controlled trial. University teaching hospital. Ten anovulatory women with PCOS and 5 fertile ovulatory women. Patients received 2.5 mg of letrozole on cycle days 3-7 (5 patients, 1 cycle) or 50 mg of CC on cycle days 5-9 (5 patients, 1 cycle). Serum estrogen (E) and progesterone (P) endometrial protein and messenger RNA (mRNA) expression of leukemia inhibitory factor (LIF), dickkhopf homolog 1 (DKK-1), fibroblast growth factor 22 (FGF-22), and endometrial mRNA expression of LIF/GP130 receptor (LIFR). No statistically significant differences were observed between groups compared with fertile ovulatory women when serum E and P were examined, or between body mass index (BMI), and cycle day at time of biopsy. Letrozole increased mRNA expression of LIF, DKK1, LIFR, and FGF-22, whereas CC only increased endometrial mRNA expression of LIF. Letrozole mRNA expression directly translated into increased protein expression of like genes in the endometrium. The CC protein expression of DKK-1 was significantly decreased compared with controls. Letrozole positively influences a number of markers of endometrial receptivity compared with CC. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Clomiphene citrate before and after withdrawal bleeding for induction of ovulation in women with polycystic ovary syndrome: Randomized cross-over trial.

PubMed

Elbohoty, Ahmed E H; Amer, Mohamed; Abdelmoaz, Mohamed

2016-08-01

To compare the ovarian response to early versus late clomiphene citrate (CC) in women with polycystic ovary syndrome (PCOS). This cross-over randomized controlled clinical trial included 90 infertile amenorrheic women with PCOS. After inducing withdrawal bleeding, patients were randomly divided into two equal groups to receive ovulation induction with CC 100 mg/day for 5 days. Group I started treatment the next day after finishing medroxyprogesterone acetate course for a menstrual cycle, and after a washout period of another menstrual cycle, the treatment was shifted to start on day 2 of withdrawal bleeding. Group II received a reversed protocol: late then early treatment. Women were followed up on transvaginal ultrasonography to monitor follicular growth, endometrial thickness and evidence of ovulation. Human chorionic gonadotropin 10 000 IU was given i.m. to trigger ovulation when at least one mature follicle measured ≥18 mm at day 14. In all cases, early induction protocol resulted in significantly higher proportion of ovulating patients, thicker endometrium and higher number of follicles 14-17 mm in diameter, ≥ 18 mm in diameter and total number of follicles (P < 0.001 for all comparisons). In women with PCOS, early initiation of CC before withdrawal bleeding or during the last days of the luteal phase can achieve a better ovulatory response. © 2016 Japan Society of Obstetrics and Gynecology.

Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study.

PubMed

Zhao, Yue; Ruan, Xiangyan; Mueck, Alfred O

2017-06-01

There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS). Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3 months. All patients got LTZ on day 3 for 5 d in combination with Hp-HMG, starting with 75 IU from cycle day 7 and maintained for up to 3 d. The maximum dose was 150 IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events. Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen. LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.

Gonadotropin Therapy versus Laparoscopic Ovarian Drilling in Clomiphene Citrate-Resistant Polycystic Ovary Syndrome Patients: A Retrospective Cost-Effectiveness Analysis.

PubMed

De Frène, Veerle; Gerris, Jan; Weyers, Steven; Dhont, Marc; Vansteelandt, Stijn; Annemans, Lieven; De Sutter, Petra

2015-01-01

Gonadotropin therapy and laparoscopic ovarian drilling (LOD) are treatment options for ovulation induction (OI) in clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients. The current evidence of the cost-effectiveness of both treatments is scarce, conflicting and performed from different health-economic perspectives. A retrospective health-economic evaluation was performed from a societal perspective in which human menopausal gonadotropin (hMG) therapy (n = 43) was compared with LOD (n = 35), followed by OI with CC and/or hMG if spontaneous ovulation did not occur within 2 months. Data were collected until the patients were pregnant, with a time limit of 6 months after the onset of treatment. Outcomes were expressed as ongoing pregnancy rate and number of live-born children. The ongoing pregnancy rate was 21/35 (60%) after LOD and 30/43 (69.8%) after hMG treatment (relative risk 0.85, 95% CI 0.61-1.19). The societal cost per patient, up to an ongoing pregnancy, was significantly higher after LOD versus hMG treatment (adjusted mean difference EUR 1,073, 95% CI 180-1,967). This economic evaluation based on real-life data shows that the societal cost up to an ongoing pregnancy is less after hMG treatment when compared with LOD surgery in CC-resistant PCOS patients. © 2015 S. Karger AG, Basel.

Ultra-short term clomiphene citrate in high responder women with polycystic ovary syndrome: a case series.

PubMed

Kelekci, Sefa; Eris, Serenat; Demirel, Emine

2014-04-01

To evaluate a new trial of short-term clomiphene citrate (CC) in high responder women with polycystic ovary syndrome (PCOS). This case series was conducted in the infertility outpatient clinics of two centres. Ovulation induction was performed with CC 50-100mg a day in six high-responder women with PCOS who had a history of cancellation of treatment because of ≥3 mature follicles between March 2010 and June 2013. Induction was initiated on the third day of their cycles and the duration of induction was only two days. Demographic data of the patients, number of mature follicles on hCG day, ovulation rate, luteal phase length, pregnancy rate, and type of pregnancy were recorded. All data were analysed by SPSS packet programme (SPSS, 17.0, SPSS Inc., Chicago, IL, USA). The median number of mature follicles and duration of the follicular phase were 1.3 (1-2) and 11.9 (11-14) days, respectively. The ovulation rate was 80% (12/15) and pregnancy rate per cycle was 26.6%. If this hypothesis is supported by large prospective randomised controlled studies, ultra-short term ovulation induction with CC may provide an alternative approach for high-responder women with PCOS who have a history of treatment cycle cancellations. Copyright © 2014. Published by Elsevier Ireland Ltd.

Clomiphene Citrate versus Letrozole for Ovarian Stimulation in Therapeutic Donor Sperm Insemination.

PubMed

El Hachem, Hady; Antaki, Roland; Sylvestre, Camille; Kadoch, Isaac-Jacques; Lapensée, Louise; Bouet, Pierre Emmanuel

2017-01-01

To compare clomiphene citrate (CC) and letrozole for ovarian stimulation (OS) in therapeutic donor sperm insemination (TDI) cycles. Retrospective cohort study between January 2011 and June 2014 at a University-affiliated private IVF clinic in Montreal, Canada. 257 normo-ovulatory women ≤40 years of age with no history of infertility undergoing 590 TDI cycles in the absence of a male partner (single women and same-sex couples) or azoospermia were included. Patients received 100 mg CC daily (145 women, 321 cycles) or letrozole 5 mg daily (112 women, 269 cycles), from days 3 to 7. Only the first 3 cycles were included per patient. Our main outcome measure was cumulative live birth rates (LBR). Baseline characteristics were comparable between the 2 groups. There were no differences in LBR per cycle (16.5% (53/321) vs. 11.5% (31/269), p = 0.08) and cumulative LBR (36.6% (53/145) vs. 27.7% (31/112), p = 0.13), between CC and letrozole, respectively. Multiple pregnancy rate (11.6% (8/69) vs. 8.7% (4/46), p = 0.6) and miscarriage rate (21.7 vs. 21.7%, p = 1) were also comparable between CC and letrozole, respectively. In normo-ovulatory women undergoing TDI, OS with CC or letrozole resulted in similar live birth and twin pregnancy rates. © 2016 S. Karger AG, Basel.

Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic review and meta-analysis.

PubMed

Roque, Matheus; Tostes, Ana C I; Valle, Marcello; Sampaio, Marcos; Geber, Selmo

2015-01-01

The objective of the present systematic review and meta-analysis was to examine the literature and to identify the results of randomized controlled trials (RCTs) comparing the use of letrozole to clomiphene citrate (CC) for ovulation induction in patients with polycystic ovary syndrome (PCOS). An exhaustive electronic literature search was performed using the MEDLINE and EMBASE databases until October 2014. Seven prospective RCTs comparing the use of letrozole to CC in PCOS patients met the inclusion criteria. Overall, the seven included studies accounted for 1833 patients (906 in the letrozole group and 927 in the CC group) and for 4999 ovulation induction cycles (2455 in the letrozole group and 2544 in the CC group). Five of the included studies reported data on live birth rates. There was a statistically significant increase in the live birth and pregnancy rates in the letrozole group when compared to the CC group, with a relative risk (RR) = 1.55 (95% confidence interval (CI): 1.26-1.90; I(2) = 0%) and RR = 1.38 (95% CI: 1.05-1.83; I(2) = 61%), respectively. There were no differences in the multiple pregnancy, miscarriage and ovulation rates between the two groups. Our study found that letrozole is superior to CC when considering the live birth and pregnancy rates in patients with PCOS.

The effects of letrozole and clomiphene citrate on ligands expression of Wnt3, Wnt7a, and Wnt8b in proliferative endometrium of women with Polycystic ovarian syndrome.

PubMed

Mehdinejadiani, Shayesteh; Amidi, Fardin; Mehdizadeh, Mehdi; Barati, Mahmood; Safdarian, Leili; Aflatoonian, Reza; Alyasin, Ashraf; Aghahosseini, Marzieh; Pazhohan, Azar; Hayat, Parisa; Mohammadzadeh Kazorgah, Farzaneh; Sobhani, Aligholi

2018-03-06

Polycystic ovarian syndrome (PCOS) is a common endocrinologic disorder in women of reproductive age characterized by polycystic ovaries, oligo/anovulation, and hyperandrogenism. Not only anovulation but also endometrial dysfunction can reduce fertility in PCOS patients. Wnt pathway is responsible for endometrial proliferation which be strongly regulated by estradiol. To determine the effects of clomiphene citrate (CC) and letrozole, we measured the expression of some main ligands of Wnt/β-catenin signaling including Wnt7a, Wnt3, and Wnt8b in the endometrial samples taken from PCOS women on day 12 of the menses who received 100 mg CC or 5 mg letrozole as well as from women without treatment. Significantly, the mean estrogen and progesterone concentration were lower and higher, respectively, in letrozole than CC. The mean endometrial thickness (ET) was significantly greater in letrozole compared to CC. Assessment of the mRNA and protein expression of Wnt7a, Wnt3, and Wnt8b showed significantly lower expression in CC than the letrozole and control groups. Collectively, letrozole provided a better molecular response in the endometrium of PCOS patients during the proliferative phase, similar to natural cycles, compared to CC. CC decreased the ligands expression of Wnt3, Wnt7a, and Wnt8b, resulting in endometrial dysfunction.

[Effect of clomiphene citrate and Dingkun Dan on ovulation induction and clinical pregnancy of polycystic ovary syndrome].

PubMed

Chen, Lan; Tan, Yong; Chen, Shu-Ping

2017-10-01

The evaluation is based on clomiphene citrate (CC)+gonadotropin (Gn), clinical study on CC and Dingkun Dan's treatment on ovulation induction and clinical pregnancy effect of PCOS, and to provide ideas and methods for traditional Chinese medicine assisted reproductive treatment. This study selected 60 PCOS infertility patients treated with ovulation induction in reproductive medicine clinic, Jiangsu Province Hospital of traditional Chinese medicine during 2015-10-01-2017-04-23. They were randomly divided into two groups： Group A (CC+Gn+HCG) and Group B (CC+Gn+Dingkun Dan). These results were observed and compared including cycle ovulation rate, cycle cancellation rate, cycle pregnancy rate, cumulative pregnancy rate, endometrial thickness, duration of Gn, total amount of Gn, the occurring rate of luteinized unruptured follicle syndrome and ovarian hyperstimulation syndrome. Group A had lower cycle ovulation rate, cycle pregnancy rate, cumulative pregnancy rate and endometrial thickness, compared with Group B, the difference was statistically significant(P＜0.05). However, Group A had higher cycle cancellation rate, duration of Gn and total amount of Gn, compared with Group B, the difference was statistically significant(P＜0.05). In this study, no case of LUFS or OHSS was found in all patients. CC and Dingkun Dan had the effect of promoting ovulation on PCOS infertility patients, and CC+Gn+Dingkun Dan could elevate clinical pregnancy rate. Copyright© by the Chinese Pharmaceutical Association.

Anti-Müllerian hormone as a predictor of polycystic ovary syndrome treated with clomiphene citrate.

PubMed

Hestiantoro, Andon; Negoro, Yuwono Sri; Afrita, Yohana; Wiweko, Budi; Sumapradja, Kanadi; Natadisastra, Muharam

2016-12-01

This study aimed to determine the threshold of anti-Müllerian hormone (AMH) as predictor of follicular growth failure in polycystic ovary syndrome (PCOS) patients treated with clomiphene citrate (CC). Fifty female subjects with PCOS were recruited and divided into two groups based on successful and unsuccessful follicular growth. Related variables such as age, infertility duration, cigarette smoking, use of Moslem hijab, sunlight exposure, fiber intake, body mass index, waist circumference, AMH level, 25-hydroxy vitamin D level, and growth of dominant follicles were obtained, assessed, and statistically analyzed. The AMH levels of patients with successful follicular growth were significantly lower ( p =0.001) than those with unsuccessful follicular growth (6.10±3.52 vs. 10.43±4.78 ng/mL). A higher volume of fiber intake was also observed in the successful follicular growth group compared to unsuccessful follicular growth group ( p =0.001). Our study found the probability of successful follicle growth was a function of AMH level and the amount of fiber intake, expressed as Y=-2.35+(-0.312×AMH level)+(0.464×fiber intake) (area under the curve, 0.88; 95% confidence interval, 0.79-0.98; p <0.001). The optimal threshold of AMH level in predicting the failure of follicle growth in patients with PCOS treated with CC was 8.58 ng/mL.

Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

PubMed Central

Crosnoe-Shipley, Lindsey E; Elkelany, Osama O; Rahnema, Cyrus D; Kim, Edward D

2015-01-01

The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. The article is designed as a review of published literature. We conducted a PubMed literature search for the time period of 1989-2014, concentrating on 26 studies investigating the efficacy of various therapeutic options on semen analysis, pregnancy outcomes, time to recovery of spermatogenesis, as well as serum and intratesticular testosterone levels. Our results demonstrated that exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Cessation of exogenous testosterone should be recommended for men desiring to maintain their fertility. Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. Off-label use of SERMs, such as clomiphene citrate, are effective for maintaining testosterone production long-term and offer the convenience of representing a safe, oral therapy. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. We concluded that exogenous testosterone supplementation decreases sperm production. It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment. PMID:25949938

Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation.

PubMed

Kamath, Mohan S; Maheshwari, Abha; Bhattacharya, Siladitya; Lor, Kar Yee; Gibreel, Ahmed

2017-11-02

Gonadotropins are the most commonly used medications for controlled ovarian stimulation in in vitro fertilisation (IVF). However, they are expensive and invasive, and are associated with the risk of ovarian hyperstimulation syndrome (OHSS). Recent calls for more patient-friendly regimens have led to growing interest in the use of clomiphene citrate (CC) and aromatase inhibitors with or without gonadotropins to reduce the burden of hormonal injections. It is currently unknown whether regimens using CC or aromatase inhibitors such as letrozole (Ltz) are as effective as gonadotropins alone. To determine the effectiveness and safety of regimens including oral induction medication (such as clomiphene citrate or letrozole) versus gonadotropin-only regimens for controlled ovarian stimulation in IVF or intracytoplasmic sperm injection (ICSI) treatment. We searched the following databases: Cochrane Gynaecology and Fertility Group Specialised Register (searched January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL CRSO), MEDLINE (1946 to January 2017), Embase (1980 to January 2017), and reference lists of relevant articles. We also searched trials registries ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch/Default.aspx). We handsearched relevant conference proceedings. We included randomized controlled trials (RCTs). The primary outcomes were live-birth rate (LBR) and OHSS. Three review authors independently assessed trial eligibility and risk of bias. We calculated risk ratios (RR) and Peto odds ratio (OR) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MD) for continuous outcomes. We analyzed the general population of women undergoing IVF treatment and (as a separate analysis) women identified as poor responders. We assessed the overall quality of the evidence using the GRADE approach. We included 27 studies in the updated review. Most of the new trials in the updated review included poor responders and evaluated Ltz protocols. We could perform meta-analysis with data from 22 studies including a total of 3599 participants. The quality of the evidence for different comparisons ranged from low to moderate. The main limitations in the quality of the evidence were risk of bias associated with poor reporting of study methods, and imprecision.In the general population of women undergoing IVF, it is unclear whether CC or Ltz used with or without gonadotropins compared to use of gonadotropins along with gonadotropin-releasing hormone (GnRH) agonists or antagonists resulted in a difference in live birth (RR 0.92, 95% CI 0.66 to 1.27, 4 RCTs, n = 493, I 2 = 0%, low-quality evidence) or clinical pregnancy rate (RR 1.00, 95% CI 0.86 to 1.16, 12 RCTs, n = 1998, I 2 = 3%, moderate-quality evidence). This means that for a typical clinic with 23% LBR using a GnRH agonist regimen, switching to CC or Ltz protocols would be expected to result in LBRs between 15% and 30%. Clomiphene citrate or Ltz protocols were associated with a reduction in the incidence of OHSS (Peto OR 0.21, 95% CI 0.11 to 0.41, 5 RCTs, n = 1067, I 2 = 0%, low-quality evidence). This means that for a typical clinic with 6% prevalence of OHSS associated with a GnRH regimen, switching to CC or Ltz protocols would be expected to reduce the incidence to between 0.5% and 2.5%. We found evidence of an increase in cycle cancellation rate with the CC protocol compared to gonadotropins in GnRH protocols (RR 1.87, 95% CI 1.43 to 2.45, 9 RCTs, n = 1784, I 2 = 61%, low-quality evidence). There was moderate quality evidence of a decrease in the mean number of ampoules used,) and mean number of oocytes collected with CC with or without gonadotropins compared to the gonadotropins in GnRH agonist protocols, though data were too heterogeneous to pool.Similarly, in the poor-responder population, it is unclear whether there was any difference in rates of live birth (RR 1.16, 95% CI 0.49 to 2.79, 2 RCTs, n = 357, I 2 = 38%, low-quality evidence) or clinical pregnancy (RR 0.85, 95% CI 0.64 to 1.12, 8 RCTs, n = 1462, I 2 = 0%, low-quality evidence) following CC or Ltz with or without gonadotropin versus gonadotropin and GnRH protocol. This means that for a typical clinic with a 5% LBR in the poor responders using a GnRH protocol, switching to CC or Ltz protocols would be expected to yield LBRs between 2% to 14%. There was low quality evidence that the CC or Ltz protocols were associated with an increase in the cycle cancellation rate (RR 1.46, 95% CI 1.18 to 1.81, 10 RCTs, n = 1601, I 2 = 64%) and moderate quality evidence of a decrease in the mean number of gonadotropin ampoules used and the mean number of oocytes collected, though data were too heterogeneous to pool. The adverse effects of these protocols were poorly reported. In addition, data on foetal abnormalities following use of CC or Ltz protocols are lacking. We found no conclusive evidence indicating that clomiphene citrate or letrozole with or without gonadotropins differed from gonadotropins in GnRH agonist or antagonist protocols with respect to their effects on live-birth or pregnancy rates, either in the general population of women undergoing IVF treatment or in women who were poor responders. Use of clomiphene or letrozole led to a reduction in the amount of gonadotropins required and the incidence of OHSS. However, use of clomiphene citrate or letrozole may be associated with a significant increase in the incidence of cycle cancellations, as well as reductions in the mean number of oocytes retrieved in both the general IVF population and the poor responders. Larger, high-quality randomized trials are needed to reach a firm conclusion before they are adopted into routine clinical practice.

The prevalence of metabolic syndrome in clomiphene citrate resistant polycystic ovary syndrome.

PubMed

Verit, Fatma Ferda

2012-05-01

To investigate the prevalence of metabolic syndrome in clomiphene citrate (CC) resistant polycystic ovary syndrome (PCOS) patients. 58 CC resistant PCOS patients, 52 CC responders, 53 fertile PCOS and 53 age and body mass index-matched normoandrogenic ovulatory fertile women were evaluated for metabolic syndrome. Metabolic syndrome prevalence was 41.4% in CC resistants, in 23.1% of CC responders, in 11.3% of PCOS fertiles and 0% of controls (p < 0.0001). Waist circumference (WC) > 88 cm was 44.8%, systolic blood pressure (BP) ≥ 130 mmHg and diastolic BP ≥85 mmHg were 27.6%, TG (triglyceride) ≥150 mg/dL was 36.2%, HDL(high density lipoprotein) < 50 mg/dL was 63.8%, fasting glucose levels ≥ 100 mg/dL was 20.7% in CC resistant PCOS women. There were positive associations between CC resistance and WC >88 cm, BP ≥ 130 ≥ 85 mmHg, TG ≥ 150 mg/dL, HDL < 50 mg/dL, fasting glucose ≥ 100 mg/dL, and presence of metabolic syndrome (p < 0.05, for all). Moreover, WC > 88 cm, and HDL < 50 mg/dL were independent variables that were associated by CC resistance by multivariate regression analysis. CC resistant PCOS patients have high prevalence of metabolic syndrome. These women have an increased risk of future cardiovascular disease.

Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome.

PubMed

Amer, S A; Li, T C; Metwally, M; Emarh, M; Ledger, W L

2009-01-01

Laparoscopic ovarian diathermy (LOD) is currently accepted as a successful second-line treatment for ovulation induction (OI) in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS). The aim of this study was to test the hypothesis that LOD may be superior to CC as a first-line treatment. The study included 72 anovulatory women with PCOS who were randomized to LOD (n = 36) or CC (n = 36). Women who remained anovulatory after LOD were offered CC. Similarly, women receiving CC who failed to ovulate or conceive were offered LOD. Pregnancy rates were compared between the two groups using chi(2) and odds ratio with 95% confidence interval (OR, 95% CI). After randomization, six women conceived before starting treatment and another patient postponed treatment. The remaining 65 women received the treatment (33 underwent LOD and 32 received CC). After the primary treatment, more pregnancies (44%) occurred in women receiving CC than in those undergoing LOD (27%), although the difference did not reach statistical significance [P = 0.13, OR 2.1 (0.7 - 5.8)]. After adding the second treatment, the pregnancy rate was still higher, but to a less extent, in the CC group [63% versus 52%, P = 0.2, OR 1.6 (0.6 - 4.2)]. LOD is not superior to CC as a first-line method of OI in women with PCOS. The trial is registered with ClinicalTrials.gov with an identifier number NCT00220545.

Prognostic value of total testosterone for pregnancy during treatment in patients with clomiphene-citrate-resistant polycystic ovary syndrome: a pilot study.

PubMed

Li, Chunyang; Cheng, Jing; Wang, Jianguang; Xue, Yamei; Huang, Zhaoxia; Zhang, Shengkun; Lv, Jieqiang

2011-09-01

Reduction of serum total testosterone (TT) is associated with pregnancy rate in polycystic ovary syndrome (PCOS) women receiving metformin, but most of the studies focus on the changes of basal levels of TT. The aim of this study was to evaluate whether the TT level around the ovulation period is related to the outcome of pregnancy in women with PCOS. In total, 30 non-obese PCOS women with clomiphene citrate (CC) resistance from the Medical College's Reproductive Health Center were enrolled and randomly assigned to be treated with placebo (Group 1) or metformin (850 mg) (Group 2) twice daily for 3 months as the pre-treatment. Then, metformin alone was administered with CC, human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG) to induce ovulation for 3 months in Group 1. In Group 2, CC/HMG/HCG was used to induce ovulation for 3 months without metformin. Follicle-stimulating hormone, luteinizing hormone, estradiol and TT levels before and after ovulation in pregnant cycles and non-pregnant cycles were evaluated over the course of treatment. A total of 26 subjects completed 65 cycles. The TT levels after ovulation in the pregnant cycles were significantly lower than in the non-pregnant cycles in both groups (P = 0.001 and P < 0.001, respectively). The level of TT after ovulation may be of prognostic value for pregnancy in non-obese women with PCOS and CC resistance during treatment.

Comparison of the pregnancy outcomes and the incidence of fetal congenital abnormalities in infertile women treated with letrozole and clomiphene citrate.

PubMed

Akbari Sene, Azadeh; Ghorbani, Selma; Ashrafi, Mahnaz

2018-06-01

The aim of the study was to evaluate the incidence of congenital fetal anomalies reported among infertile Iranian women treated with letrozole compared to those treated with Clomiphene Citrate (CC). This retrospective case-control study was performed based on information available from infertile patients referred to the Akbar-Abadi Hospital IVF Center, Tehran, Iran, undergoing ovulation induction (OI) or intrauterine insemination (IUI) cycles from 2007 to 2014.We compared sonographic findings, fertility results, pregnancy complications and congenital anomalies in two groups of women treated with letrozole and CC. Overall, the results of the 2009 cycles including 1237 CC cycles and 772 letrozole cycles were evaluated. In spite of a higher chance of ovulation following CC treatment, overall fertility rates were similar in the two treatment groups. The frequency of adverse outcomes of pregnancy was similar in the two groups, except for the incidence of first trimester abortion, which was significantly higher in the CC-treated group. The frequency of fetal anomalies and major chromosomal abnormalities in the Letrozole group was 4.76% (five cases), and in the CC group, it was 2.12% (three cases). This difference was not statistically significant. Based on the findings of this study, it seems that the incidence of congenital anomalies in offspring after OI with letrozole is not increased compared to the CC group. © 2018 Japan Society of Obstetrics and Gynecology.

Anti-Müllerian hormone as a predictor of polycystic ovary syndrome treated with clomiphene citrate

PubMed Central

Negoro, Yuwono Sri; Afrita, Yohana; Wiweko, Budi; Sumapradja, Kanadi; Natadisastra, Muharam

2016-01-01

Objective This study aimed to determine the threshold of anti-Müllerian hormone (AMH) as predictor of follicular growth failure in polycystic ovary syndrome (PCOS) patients treated with clomiphene citrate (CC). Methods Fifty female subjects with PCOS were recruited and divided into two groups based on successful and unsuccessful follicular growth. Related variables such as age, infertility duration, cigarette smoking, use of Moslem hijab, sunlight exposure, fiber intake, body mass index, waist circumference, AMH level, 25-hydroxy vitamin D level, and growth of dominant follicles were obtained, assessed, and statistically analyzed. Results The AMH levels of patients with successful follicular growth were significantly lower (p=0.001) than those with unsuccessful follicular growth (6.10±3.52 vs. 10.43±4.78 ng/mL). A higher volume of fiber intake was also observed in the successful follicular growth group compared to unsuccessful follicular growth group (p=0.001). Our study found the probability of successful follicle growth was a function of AMH level and the amount of fiber intake, expressed as Y=–2.35+(–0.312×AMH level)+(0.464×fiber intake) (area under the curve, 0.88; 95% confidence interval, 0.79–0.98; p<0.001). Conclusion The optimal threshold of AMH level in predicting the failure of follicle growth in patients with PCOS treated with CC was 8.58 ng/mL. PMID:28090459

Use of fertility drugs and risk of uterine cancer: results from a large Danish population-based cohort study.

PubMed

Jensen, Allan; Sharif, Heidi; Kjaer, Susanne K

2009-12-01

Some epidemiologic studies have indicated that uterine cancer risk may be increased after use of fertility drugs. To further assess this association, the authors used data from a large cohort of 54,362 women diagnosed with infertility who were referred to Danish fertility clinics between 1965 and 1998. In a case-cohort study, rate ratios and 95% confidence intervals were used to assess the effects of 4 groups of fertility drugs on overall risk of uterine cancer after adjustment for potentially confounding factors. Through mid-2006, 83 uterine cancers were identified. Ever use of any fertility drug was not associated with uterine cancer risk (rate ratio (RR) = 1.10, 95% confidence interval (CI): 0.69, 1.76). However, ever use of gonadotropins (follicle-stimulating hormone and human menopausal gonadotropin) increased uterine cancer risk (RR = 2.21, 95% CI: 1.08, 4.50); the risk was primarily observed after 10 years of follow-up. Furthermore, uterine cancer risk increased with number of cycles of use for clomiphene (for > or =6 cycles, RR = 1.96, 95% CI: 1.03, 3.72) and human chorionic gonadotropin (for > or =6 cycles, RR = 2.18, 95% CI: 1.16, 4.08) but not for other gonadotropins. Use of gonadotropin-releasing hormone analogs was not associated with risk. Gonadotropins, and possibly clomiphene and human chorionic gonadotropin, may increase the risk of uterine cancer, with higher doses and longer follow-up leading to greater risk.

Effects of human chorionic gonadotropin combined with clomiphene on Serum E2, FSH, LH and PRL levels in patients with polycystic ovarian syndrome.

PubMed

Yonggang, Huang; Xiaosheng, Lu; Zhaoxia, Huang; Yilu, Chen; Jiqiang, Lv; Huina, Zhang

2017-02-01

Effects of human chorionic gonadotropin combined with clomiphene on serum E 2 , FSH, LH and PRL levels in patients with polycystic ovarian syndrome were analyzed. 90 patients with polycystic ovarian syndrome treated from January 2015 to March 2016 were randomly and evenly divided into control group and observation group. Patients in the control group were only treated with clomiphene. On the basis of the treatment in control group, human chorionic gonadotropin was added in the treatment of observation group. The changes of E 2 , FSH, LH, PRL levels were compared between two groups before and after the treatment. Clinical curative effects of patients in the two groups was evaluated. Adverse reactions during treatment in two groups were observed and recorded. The incidence of adverse reactions was calculated. Serum E 2 , FSH, LH and PRL levels in the two groups decreased significantly after treatment compared with that before treatment. The difference is statistical significant ( P  < 0.05). After the treatment, E 2 , FSH, LH and PRL levels in the observation group were lower than that in the control group and the difference is statistical significant ( P  < 0.05). Total effective rate was 64.44% in the control group and 93.33% in the observation group. There were statistically significant difference in clinical curative effects in the two groups ( P  < 0.05). Different degrees of adverse reactions were found in both groups during treatment, such as nausea, vomiting, anorexia, liver dysfunction. There were 2 cases of nausea, 2 cases of vomiting, 3 cases of anorexia and 1 case of liver dysfunction from the 45 patients in control group. The total incidence of adverse reactions was 17.78% (8/45). There were 1 case of nausea, 1 case of vomiting, 1 case of anorexia and no liver dysfunction from the 45 patients in observation group. The total incidence of adverse reactions was 6.67% (3/45). The total incidence of adverse reactions in the observation group was significantly higher than that in the control group and the difference was not statistically significant ( P  > 0.05). Combined use of human chorionic gonadotropin can significantly reduce serum E 2 , FSH, LH and PRL levels, improve clinical curative effects and reduce the incidence of adverse reactions. Human chorionic gonadotropin has high application value on the treatment of polycystic ovary syndrome.

Current medical management of endocrine-related male infertility

PubMed Central

Ring, Joshua D; Lwin, Aye A; Köhler, Tobias S

2016-01-01

Male factor contributes to 50%–60% of overall infertility but is solely responsible in only 20% of couples. Although most male factor infertility is ascertained from an abnormal semen analysis, other male factors can be contributory especially if the sample returns normal. Male infertility can be due to identifiable hormonal or anatomical etiologies that may be reversible or irreversible. This manuscript will highlight existing guidelines and our recommendations for hormone evaluation for male infertility and empiric therapies including multivitamins, estrogen receptor modulators (clomiphene), estrogen conversion blockers (anastrozole), and hormone replacement. PMID:27098657

Pregnancy outcome in women with polycystic ovary syndrome comparing the effects of laparoscopic ovarian drilling and clomiphene citrate stimulation in women pre-treated with metformin: a retrospective study

PubMed Central

2010-01-01

Background Ovarian stimulation in women with polycystic ovary syndrome (PCOS) increases the risk for perinatal complications. Ovulation induction by laparoscopic ovarian drilling (LOD) might improve the overall pregnancy outcomes. The aim of our study was to assess the adverse events or effects on pregnancy of LOD and clomiphene citrate (CC) stimulation in patients who received metformin. Methods Setting: Academic research institution. We retrospectively analyzed the courses of 40 spontaneous pregnancies after LOD for CC-resistance, 40 pregnancies after CC stimulation, and 40 pregnancies after metformin treatment alone. Patients in the LOD and the CC groups had been pre-treated with Metformin. Primary outcome parameters were: the rate of multiple pregnancies; the rate of early pregnancy losses/miscarriages; the development of gestational diabetes, pregnancy-induced hypertension, and preeclampsia/HELLP-syndrome; premature delivery; and birth weight. Results The rate of twin pregnancies did not differ between the CC group (12.5%), the LOD group (7.5%), and the metformin only group (2.5%, p = 0.239). Seventeen women suffered an early miscarriage. There were no differences with regard to the rates of gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm delivery. By analyzing all pregnancy complications together, the overall pregnancy complication rate was highest in the CC group (70.0%, 28/40), followed by the LOD group (45.0%, 18/40), and the metformin only group (47.5%, 19/40; p = 0.047). Conclusions CC, but not LOD, increases the complication rate in pregnant patients who received metformin. PMID:20465786

Pregnancy outcome in women with polycystic ovary syndrome comparing the effects of laparoscopic ovarian drilling and clomiphene citrate stimulation in women pre-treated with metformin: a retrospective study.

PubMed

Ott, Johannes; Kurz, Christine; Nouri, Kazem; Wirth, Stefan; Vytiska-Binstorfer, Elisabeth; Huber, Johannes C; Mayerhofer, Klaus

2010-05-13

Ovarian stimulation in women with polycystic ovary syndrome (PCOS) increases the risk for perinatal complications. Ovulation induction by laparoscopic ovarian drilling (LOD) might improve the overall pregnancy outcomes. The aim of our study was to assess the adverse events or effects on pregnancy of LOD and clomiphene citrate (CC) stimulation in patients who received metformin. Academic research institution. We retrospectively analyzed the courses of 40 spontaneous pregnancies after LOD for CC-resistance, 40 pregnancies after CC stimulation, and 40 pregnancies after metformin treatment alone. Patients in the LOD and the CC groups had been pre-treated with Metformin. Primary outcome parameters were: the rate of multiple pregnancies; the rate of early pregnancy losses/miscarriages; the development of gestational diabetes, pregnancy-induced hypertension, and preeclampsia/HELLP-syndrome; premature delivery; and birth weight. The rate of twin pregnancies did not differ between the CC group (12.5%), the LOD group (7.5%), and the metformin only group (2.5%, p=0.239). Seventeen women suffered an early miscarriage. There were no differences with regard to the rates of gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm delivery. By analyzing all pregnancy complications together, the overall pregnancy complication rate was highest in the CC group (70.0%, 28/40), followed by the LOD group (45.0%, 18/40), and the metformin only group (47.5%, 19/40; p=0.047). CC, but not LOD, increases the complication rate in pregnant patients who received metformin.

Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a systematic review and meta-analysis.

PubMed

Ding, Nan; Chang, Jianbo; Jian, Qiliang; Liang, Xuefei; Liang, Zhongzhen; Wang, Fang

2016-11-01

To assess the efficacy of late luteal phase clomiphene citrate (CC) administration relative to early follicular phase CC for ovulation induction for polycystic ovary syndrome (PCOS). Review. A complete electronic databases including PubMed, Embase, The Cochrane Library, Web of Science, and CBM were searched for relevant randomized controlled trials (RCTs). The search was not restricted by language and publication time. Two reviewers selected trials and assessed trial quality by the Cochrane Handbook 5.1.0 independently. Four eligible RCT studies involving 708 women (934 cycles) were included. The results of the Meta-analysis: Late luteal phase group was associated with a number of higher total follicles (MD 1.82; 95% CI 0.86-2.78, p < 0.00001) and significant higher endometrial thickness on the day of HCG (MD 0.88; 95% CI 0.78-0.99, p < 0.00001) compared with early follicular group. There were no significant differences in the rate of pregnancy (RR 1.29; 95% CI 0.83-2.01, p = 0.26), ovulation rate (RR 0.99; 95% CI 0.86-1.14, p = 0.87), and abortion rate (RR 1.12; 95% CI 0.38 to 3.29, p = 0.84) between the two groups. It appeared that late luteal phase CC for ovulation induction might be an effective method for ovulation induction in women with PCOS compared to conventional CC administration. Further intensive randomized-controlled studies should be warranted to define the efficacy of CC used in late luteal phase.

Identification of human flavin-containing monooxygenase 3 substrates by a colorimetric screening assay.

PubMed

Catucci, Gianluca; Polignano, Isabelle; Cusumano, Debora; Medana, Claudio; Gilardi, Gianfranco; Sadeghi, Sheila J

2017-04-01

Human hepatic flavin-containing monooxygenase 3 is a phase I drug-metabolizing enzyme that is responsible for the oxidation of a variety of drugs and xenobiotics. This work reports on a high throughput rapid colorimetric assay for the screening of substrates or inhibitors of this enzyme. The method is based on the competition of two substrates for access to the active site of hFMO3 whereby the enzymatic product of the first drug converts nitro-5-thiobenzoate (TNB, yellow) to 5,5'-dithiobis (2-nitrobenzoate) (DTNB, colourless). Upon addition of a competing substrate, the amount of detected DNTB is decreased. The assay is validated testing three known substrates of hFMO3, namely benzydamine, tozasertib and tamoxifen. The latter drugs resulted in 41%-55% inhibition. In addition, two other drugs also classified as doping drugs, selegiline and clomiphene, were selected based on their chemical structure similarity to known substrates of hFMO3. These drugs showed 21% and 60% inhibition in the colorimetric assay and therefore were proven to be hFMO3 substrates. LC-MS was used to confirm their N-oxide products. Further characterisation of these newly identified hFMO3 substrates was performed determining their K m and k cat values that resulted to be 314 μM and 1.4 min -1 for selegiline and, 18 μM and 0.1 min -1 for clomiphene. This method paves the way for a rapid automated high throughput screening of nitrogen-containing compounds as substrates/inhibitors of hFMO3. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of laparoscopic ovarian drilling on serum anti-mullerian hormone levels in patients with anovulatory Polycystic Ovarian syndrome.

PubMed

Paramu, Sobhana

2016-12-01

Anti-mullerian hormone (AMH) is a marker of the activity of recruitable ovarian follicles. It is useful in the prediction of ovarian reserve. Women with polycystic ovarian syndrome (PCOS) have elevated circulating and intrafollicular AMH levels. Laparoscopic ovarian drilling (LOD) in patients with PCOS destroys ovarian androgen-producing tissue and reduces their peripheral conversion to estrogens. Identifying factors that determine the response of patients with PCOS to LOD will help in selecting the patients who would likely benefit from this treatment. AMH is one such marker that can predict the response to LOD. To evaluate the effect of LOD on serum AMH levels among PCOS responders and non-responders and the usefulness of AMH as a tool in predicting the response to LOD, and to whether there was loss of ovarian function after LOD. This is a prospective cohort study including 30 clomiphene-resistant women with anovulatory PCOS undergoing LOD. Statistical analysis was performed to evaluate the effect of LOD on serum levels of AMH on these women. A significant fall in the levels of AMH was observed after LOD in both responders and non-responders (p<0.001). Women with AMH >8.3 ng/mL showed a significantly lower ovulation rate (33.3%). LOD was not associated with a risk of diminished ovarian reserve. LOD is an effective first-line treatment for women with PCOS who are clomiphene resistant. LOD has no negative effect on ovarian reserve. AMH is a useful marker in predicting the outcome of LOD.

Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease.

PubMed

Tiitinen, A E; Laatikainen, T J; Seppälä, M T

1993-07-01

To study the serum levels of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) in relation to clomiphene citrate (CC) responsiveness in women with polycystic ovarian disease (PCOD). Prospective. PATIENTS, SETTING: Twenty-three women with PCOD admitted consecutively to the University Infertility Clinic, a tertiary referral center. Blood samples were taken at fasting state and during oral glucose tolerance test (OGTT) for the determination of insulin, IGF-I, and IGFBP-1. A dose of 50 to 200 mg/d CC was given for ovulation induction. With CC treatment, ovulation was achieved in 13 of 23 PCOD patients. The IGFBP-1 concentration was lower in CC nonresponders than in CC responders (20.5 +/- 4.0 ng/mL versus 41.0 +/- 8.5 ng/mL) (P < 0.05). This difference was accentuated in 13 lean PCOD patients. Lean CC nonresponders (n = 7) had almost threefold lower serum IGFBP-1 levels than lean CC responders (n = 6) (24.0 +/- 3.1 ng/mL versus 61.8 +/- 8.6 ng/mL) (P < 0.01). By contrast, among 10 obese PCOD patients, the IGFBP-1 levels were low irrespective of CC responsiveness (14.8 +/- 8.0 ng/mL versus 16.7 +/- 7.2 ng/mL). The differences remained during OGTT. The concentrations of IGF-I, insulin, sex hormone-binding globulin, LH, FSH, and androgens showed no significant differences between CC responders and nonresponders. There was an inverse correlation between serum insulin and IGFBP-1 levels in obese PCOD patients, whereas this was not seen in lean patients. In lean PCOD patients, low serum IGFBP-1 concentration is related to CC unresponsiveness by a mechanism unrelated to insulin.

Clomiphene citrate 'stair-step' protocol vs. traditional protocol in patients with polycystic ovary syndrome: a randomized controlled trial.

PubMed

Deveci, Canan Dura; Demir, Berfu; Sengul, Ozlem; Dilbaz, Berna; Goktolga, Umit

2015-01-01

To evaluate the efficacy of the stair-step protocol using clomiphene citrate (CC) and to assess the uterine and systemic side effects in patients with polycystic ovary syndrome (PCOS). A total of 60 PCOS patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle were randomly allocated to the control (traditional protocol) and study (stair-step protocol) groups. In the stair-step protocol,patients were treated with CC 50 mg/day for 5 days and then in nonresponsive patients, the dosage was increased to 100 mg/day for 5 days in the same cycle. Patients who failed the 50 mg/day CC treatment in the previous cycle were stimulated with 100 mg/day CC and were accepted as the control group. Ovulation and pregnancy rates, duration of treatment and uterine and systemic side effects were evaluated. Ovulation and pregnancy rates were similar between the stair-step and the control group (43.3 vs. 33.3 %, respectively) (16.7 vs. 10 %, respectively). The duration of treatment was significantly shorter in stair-step compared to traditional protocol (20.5 ± 2.0 vs. 48.6 ± 2.4 days, respectively). There were no significant differences in the systemic side effects between the groups. Uterine side effects were evaluated with endometrial thickness and uterine artery Doppler ultrasound; no significant differences were observed in stair-step compared to traditional protocol. The stair-step protocol was determined to have a significantly shorter treatment period without any detrimental effect on the ovulation and pregnancy rates.

Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome.

PubMed

Kosar, Ozlem; Ozaksit, Gulnur; Taskin, Mine Islimye

2014-10-01

The aim was to test a new protocol of luteal phase administration of clomiphene citrate (CC) for ovulation induction in women with polycystic ovary syndrome (PCOS). This was a prospective, randomized, controlled trial. Two hundred and fifty-two women (cycles) with PCOS were utilized to create two groups. Patients in Group 1 (126 patients) received 100 mg of CC daily for 5 days starting on day 5 of menses, and patients in Group 2 (126 patients) received 100 mg of CC daily for 5 days starting the next day after finishing medroxyprogesterone acetate (MPA) (before withdrawal bleeding). The main outcome measures were the number of growing and mature follicles, serum E2 (in pg/mL), serum progesterone (in ng/mL) levels, endometrial thickness (in mm), pregnancy, and miscarriage rates. The total number of follicles and the number of follicles ≥14 mm during stimulation were significantly greater in Group 2. The endometrial thickness at the time of human chorionic gonadotrophin (hCG) administration was significantly greater in Group 2 as compared to Group 1 (7.84 ± 1.22 and 8.81 ± 0.9, respectively). Serum E2 levels were also significantly higher (p < 0.05) in Group 2 as compared to Group 1 (449.61 ± 243.45 vs. 666.09 ± 153.41 pg/mL). Pregnancy occurred in 13 patients (10.3 %) in Group 2 and in 11 patients (8.7 %) in Group 1. The difference was not statistically significant. Luteal phase administration of CC in patients with PCOS leads to increased follicular growth and endometrial thickness, which might result in a higher pregnancy rate.

Outcomes from a university-based low-cost in vitro fertilization program providing access to care for a low-resource socioculturally diverse urban community.

PubMed

Herndon, Christopher N; Anaya, Yanett; Noel, Martha; Cakmak, Hakan; Cedars, Marcelle I

2017-10-01

To report on outcomes from a university-based low-cost and low-complexity IVF program using mild stimulation approaches and simplified protocols to provide basic access to ART to a socioculturally diverse low-income urban population. Retrospective cohort study. Academic infertility center. Sixty-five infertile couples were enrolled from a county hospital serving a low-resource largely immigrant population. Patients were nonrandomly allocated to one of four mild stimulation protocols: clomiphene/letrozole alone, two clomiphene/letrozole-based protocols involving sequential or flare addition of low-dose gonadotropins, and low-dose gonadotropins alone. Clinical fellows managed all aspects of cycle preparation, monitoring, oocyte retrieval, and embryo transfer under an attending preceptor. Retrieval was undertaken without administration of deep anesthesia, and laboratory interventions were minimized. All embryo transfers were performed at the cleavage stage. Sociomedical demographics, treatment response, and pregnancy outcomes were recorded. From August 2010 to June 2016, 65 patients initiated 161 stimulation IVF cycles, which resulted in 107 retrievals, 91 fresh embryo transfers, and 40 frozen embryo transfer cycles. The mean age of patients was 33.3 years, and mean reported duration of infertility was 5.3 years; 33.5% (54/161) of cycles were cancelled before oocyte retrieval, with 13% due to premature ovulation. Overall, cumulative live birth rates per retrieval including subsequent use of frozen embryos was 29.0%; 44.6% (29/65) of patients enrolled in the program achieved pregnancy. Use of mild stimulation protocols, simplified monitoring, and minimized laboratory handling procedures enabled access to care in a low-resource socioculturally diverse infertile population. Copyright © 2017. Published by Elsevier Inc.

Combination therapy with clomiphene citrate and anastrozole is a safe and effective alternative for hypoandrogenic subfertile men.

PubMed

Alder, Nathan J; Keihani, Sorena; Stoddard, Gregory J; Myers, Jeremy B; Hotaling, James M

2018-06-06

To assess the efficacy and safety of combination therapy with clomiphene citrate (CC) and anastrozole (AZ) for male hypoandrogenism. We identified patients treated with a combination of CC + AZ in the period 2014 to 2017. Data were gathered on patient characteristics and laboratory values at baseline. Total testosterone, bioavailable testosterone, oestradiol and testosterone:oestradiol ratio were measured before combination therapy (treatment with CC only) and at CC + AZ combination therapy follow-ups. Treatment side effects were recorded; prostatic-specific antigen and haematocrit levels were measured to assess safety after 6 months. As a secondary outcome, semen characteristics were compared at baseline and after at least 3 months of combination therapy when these data were available. Data were analysed using a paired t-test and Wilcoxon's signed-rank test. A total of 51 men were included, with a mean age of 35.4 ± 7.4 years and a mean body mass index of 35.0 ± 8.0 kg/m 2 . After CC treatment, total testosterone, bioavailable testosterone, and oestradiol levels all significantly increased. AZ was added in all patients with hyperoestrogenaemia (oestradiol >50 pg/mL) or a testosterone:oestradiol ratio <10. CC + AZ therapy maintained therapeutic total testosterone and bioavailable testosterone levels while also normalizing oestradiol levels and testosterone:oestradiol ratio. Eleven patients experienced side effects: anxiety/irritability, n = 5; decreased libido, n = 4; elevated (>54%) haematocrit, n = 2. Combination therapy with CC + AZ is an effective and safe alternative for patients with elevated oestradiol level or low testosterone:oestradiol ratio. © 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.

Pregnancy complications and metabolic disease in women with clomiphene citrate-resistant anovulation randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotropins: a 10-year follow-up.

PubMed

Nahuis, Marleen J; Oude Lohuis, Eefje J; Bayram, Neriman; Hompes, Peter G A; Oosterhuis, G Jurjen E; van der Veen, Fulco; Mol, Ben Willem J; van Wely, Madelon

2014-01-01

To assess long-term effects of laparoscopic electrocautery of the ovaries compared with ovulation induction with gonadotropins in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) on the incidence of pregnancy complications like gestational diabetes, hypertensive disorders, and metabolic or cardiovascular disease. Long-term follow-up study. Twenty-eight hospitals within the Netherlands. One hundred sixty-eight CC-resistant women who had participated in a randomized controlled trial between 1998 and 2001 comparing electrocautery and gonadotropins. Postal questionnaire, search in medical files. Pregnancy complications, metabolic or cardiovascular disease. Eighty-two percent of follow-up data were obtained. Thirteen of 68 women (19%) allocated to electrocautery, and 14 of 63 women (22%) allocated to gonadotropins had evidence for pregnancy complications (relative risk 0.86; 95% confidence interval 0.43-1.7). At follow-up, 12 of 69 (17%) women allocated to electrocautery, and 13 of 69 (19%) women allocated to gonadotropins had evidence for metabolic or cardiovascular disease (relative risk 0.90; 95% confidence interval 0.39-2.1). The risk of these was modified by body mass index (BMI), but not by female age or treatment allocation. This study is based on questionnaires and data from medical files. In the absence of routine screening, under-reporting in our follow-up study is likely. Electrocautery in women with CC-resistant PCOS does not affect pregnancy complications or metabolic or cardiovascular disease later in life compared with ovulation induction with gonadotropins. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Comparison between Unilateral and Bilateral Ovarian Drilling in Clomiphene Citrate Resistance Polycystic Ovary Syndrome Patients: A Randomized Clinical Trial of Efficacy

PubMed Central

Zahiri Sorouri, Ziba; Sharami, Seyede Hajar; Tahersima, Zinab; Salamat, Fatemeh

2015-01-01

Background Laparoscopic ovarian drilling (LOD) is an alternative method to induce ovulation in polycystic ovary syndrome (PCOS) patients with clomiphene citrate (CC) resistant instead of gonadotropins. This study aimed to compare the efficacy of unilateral LOD (ULOD) versus bilateral LOD (BLOD) in CC resistance PCOS patients in terms of ovulation and pregnancy rates. Materials and Methods In a prospective randomized clinical trial study, we included 100 PCOS patients with CC resistance attending to Al-Zahra Hospital in Rasht, Guilan Province, Iran, from June 2011 to July 2012. Patients were randomly divided into two ULOD and BLOD groups with equal numbers. The clinical and biochemical responses on ovulation and pregnancy rates were assessed over a 6-month follow-up period. Results Differences in baseline characteristics of patients between two groups prior to laparoscopy were not significant (p>0.05). There were no significant differences between the two groups in terms of clinical and biochemical responses, spontaneous menstruation (66.1 vs. 71.1%), spontaneous ovulation rate (60 vs. 64.4%), and pregnancy rate (33.1 vs. 40%) (p>0.05). Following drilling, there was a significant decrease in mean serum concentrations of luteinizing hormone (LH) (p=0.001) and testosterone (p=0.001) in both the groups. Mean decrease in serum LH (p=0.322) and testosterone concentrations (p=0.079) were not statistically significant between two groups. Mean serum level of follicle stimulating hormone (FSH) did not change significantly in two groups after LOD (p>0.05). Conclusion Based on results of this study, ULOD seems to be equally efficacious as BLOD in terms of ovulation and pregnancy rates (Registration Number: IRCT138903291306N2). PMID:25918587

Multiple Cationic Amphiphiles Induce a Niemann-Pick C Phenotype and Inhibit Ebola Virus Entry and Infection

PubMed Central

Shoemaker, Charles J.; Schornberg, Kathryn L.; Delos, Sue E.; Scully, Corinne; Pajouhesh, Hassan; Olinger, Gene G.; Johansen, Lisa M.; White, Judith M.

2013-01-01

Ebola virus (EBOV) is an enveloped RNA virus that causes hemorrhagic fever in humans and non-human primates. Infection requires internalization from the cell surface and trafficking to a late endocytic compartment, where viral fusion occurs, providing a conduit for the viral genome to enter the cytoplasm and initiate replication. In a concurrent study, we identified clomiphene as a potent inhibitor of EBOV entry. Here, we screened eleven inhibitors that target the same biosynthetic pathway as clomiphene. From this screen we identified six compounds, including U18666A, that block EBOV infection (IC50 1.6 to 8.0 µM) at a late stage of entry. Intriguingly, all six are cationic amphiphiles that share additional chemical features. U18666A induces phenotypes, including cholesterol accumulation in endosomes, associated with defects in Niemann–Pick C1 protein (NPC1), a late endosomal and lysosomal protein required for EBOV entry. We tested and found that all six EBOV entry inhibitors from our screen induced cholesterol accumulation. We further showed that higher concentrations of cationic amphiphiles are required to inhibit EBOV entry into cells that overexpress NPC1 than parental cells, supporting the contention that they inhibit EBOV entry in an NPC1-dependent manner. A previously reported inhibitor, compound 3.47, inhibits EBOV entry by blocking binding of the EBOV glycoprotein to NPC1. None of the cationic amphiphiles tested had this effect. Hence, multiple cationic amphiphiles (including several FDA approved agents) inhibit EBOV entry in an NPC1-dependent fashion, but by a mechanism distinct from that of compound 3.47. Our findings suggest that there are minimally two ways of perturbing NPC1-dependent pathways that can block EBOV entry, increasing the attractiveness of NPC1 as an anti-filoviral therapeutic target. PMID:23441171

Maitake mushroom (Grifola frondosa) extract induces ovulation in patients with polycystic ovary syndrome: a possible monotherapy and a combination therapy after failure with first-line clomiphene citrate.

PubMed

Chen, Jui-Tung; Tominaga, Kunihiko; Sato, Yoshiaki; Anzai, Hideo; Matsuoka, Ryo

2010-12-01

Insulin resistance is a prominent feature of polycystic ovary syndrome (PCOS), and insulin-sensitizing drugs are used to induce ovulation. Recently, it was reported that an extract from Maitake mushroom (Grifola frondosa) improves insulin resistance. The objective was to explore the effects of Maitake extract (SX-fraction: MSX) to induce ovulation in patients with PCOS in comparison with and in combination with clomiphene citrate (CC). We conducted an open trial with 80 patients with PCOS at three clinics in Japan. Seventy-two (72) new patients were randomly assigned to receive MSX or CC monotherapy for up to 12 weeks. Eighteen (18) patients who did not respond to MSX or CC were subjected to combination therapy of MSX and CC for up to 16 weeks. Eight (8) patients with documented history of failure to CC received combination therapy from the beginning. Ovulation was assessed by ultrasonography. Twenty-six (26) patients in the MSX group and 31 in the CC group were evaluated for ovulation. The ovulation rates for MSX and CC were as follows: 76.9% (20/26) and 93.5% (29/31), respectively by the patients (NS), and 41.7% (30/72) and 69.9% (58/83), respectively, by the cycles (p = 0.0006). In the combination therapy, 7 of 7 patients who failed in MSX monotherapy and 6 of 8 patients who failed in CC monotherapy showed ovulation. The present study suggests that MSX alone may induce ovulation in PCOS patients and may be useful as an adjunct therapy for patients who failed first-line CC treatment.

Unilateral or bilateral laparoscopic ovarian drilling in polycystic ovary syndrome: a meta-analysis of randomized trials.

PubMed

Abu Hashim, Hatem; Foda, Osama; El Rakhawy, Mohamed

2018-04-01

This systematic review and meta-analysis aimed to compare the effectiveness of unilateral vs. bilateral laparoscopic ovarian drilling (ULOD vs. BLOD) for improving fertility outcomes in infertile women with clomiphene-resistant polycystic ovary syndrome (PCOS) as well as its effect on ovarian reserve. Searches were conducted on PubMed, ScienceDirect, ClinicalTrials.gov, and CENTRAL databases from January 1984 to January 2017. Only randomized trials comparing ULOD with BLOD were included. The PRISMA Statement was followed. Main outcomes were ovulation and clinical pregnancy rates per woman randomized. Secondary outcomes were; live birth and miscarriage rates as well as postoperative serum anti-mullerian hormone (AMH) concentration and antral follicle count (AFC). Quality assessment was performed by the Cochrane Collaboration risk of bias tool. Eight eligible trials (484 women) were analyzed. No significant difference was found in rates of ovulation (OR 0.73; 95% CI 0.47-1.11), clinical pregnancy (OR 0.56; 95% CI 0.22-1.41), live birth (OR 0.77; 95% CI 0.28-2.10), or miscarriage (OR 0.90; 95% CI 0.33-2.84) when ULOD was compared with BLOD. The reduction in AMH was comparable between the two procedures (MD 0.64 ng/ml; 95% CI - 0.08 to 1.36). A significantly higher AFC at 6-month follow-up was found with dose-adjusted ULOD (MD 2.20; 95% CI 1.01-3.39). After carefully weighing up the well-known benefits of BLOD against a potential risk to ovarian reserve, clinicians could be advised to offer the fixed-dose ULOD to their infertile patients with clomiphene-resistant PCOS. This is concordant with the "primum non nocere" principal if LOD will be envisaged.

Effects of fertility drugs on cancers other than breast and gynecologic malignancies.

PubMed

Brinton, Louise A; Moghissi, Kamran S; Scoccia, Bert; Lamb, Emmet J; Trabert, Britton; Niwa, Shelley; Ruggieri, David; Westhoff, Carolyn L

2015-10-01

To examine the relationship of ovulation-stimulating drugs to risk of cancers other than breast and gynecologic malignancies. Retrospective cohort study, with additional follow-up since initial report. Reproductive endocrinology practices. Among a cohort of 12,193 women evaluated for infertility between 1965 and 1988, a total of 9,892 women (81.1% of the eligible population) were followed through 2010, via passive and active (questionnaire) approaches. None. Hazard ratios (HRs) and 95% confidence intervals (CIs) for various fertility treatment parameters for select cancers. During 30.0 median years of follow-up (285,332 person-years), 91 colorectal cancers, 84 lung cancers, 55 thyroid cancers, and 70 melanomas were diagnosed among study subjects. Clomiphene citrate (CC), used by 38.1% of patients, was not associated with colorectal or lung cancer risks, but was related significantly to melanoma (HR = 1.95; 95% CI: 1.18-3.22), and non-significantly to thyroid cancer risks (HR = 1.57; 95% CI: 0.89-2.75). The highest melanoma risks were seen among those with the lowest drug exposure levels, but thyroid cancer risk was greatest among the heavily exposed patients (HR = 1.96; 95% CI: 0.92-4.17 for those receiving >2,250 mg). Clomiphene citrate-associated risks for thyroid cancer were somewhat higher among nulligravid, compared with gravid, women, but did not differ according to distinct causes of infertility. Gonadotropins, used by only 9.7% of subjects, were not related to risk of any of the assessed cancers. Our results provide support for continued monitoring of both melanoma and thyroid cancer risk among patients receiving fertility drugs. Published by Elsevier Inc.

In vitro fertilisation for unexplained subfertility.

PubMed

Pandian, Zabeena; Gibreel, Ahmed; Bhattacharya, Siladitya

2015-11-19

One-third of subfertile couples have no identifiable cause for their inability to conceive. In vitro fertilisation (IVF) is a widely accepted treatment for this condition; however, this treatment is invasive and expensive and is associated with risks. To evaluate the effectiveness and safety of IVF compared with expectant management, unstimulated intrauterine insemination (IUI) or intrauterine insemination along with ovarian stimulation with gonadotropins (IUI + gonadotropins) or clomiphene (IUI + CC) or letrozole (IUI + letrozole) in improving pregnancy outcomes. This review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, first quarter), MEDLINE (1946 to May 2015), EMBASE (1985 to May 2015), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (May 2015) and reference lists of articles. We searched the following trial registries: clinicaltrials.gov (http://www.clinicaltrials.gov) and the World Health Organization International Trials Registry Platform search portal (http://www.who.int/trialsearch/Default.aspx). We searched the Web of Science (http://wokinfo.com/) as another source of trials and conference abstracts, OpenGrey (http://www.opengrey.eu/) for unpublished literature from Europe and the Latin American Caribbean Health Sciences Literature (LILACS) database (http://regional.bvsalud.org/php/index.php?lang=en). Moreover, we handsearched relevant conference proceedings and contacted study authors to ask about additional publications.Two review authors independently assessed trial eligibility, extracted data and assessed risk of bias. The primary review outcome was cumulative live birth rate. Multiple pregnancy and other adverse effects were secondary outcomes. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity by using the I(2) statistic. We assessed the overall quality of evidence for the main comparisons using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. We included randomised controlled trials (RCTs) in which the effectiveness of IVF in couples with unexplained subfertility was compared with that of other treatments, including expectant management, unstimulated IUI and stimulated IUI using gonadotropins or clomiphene or letrozole.Live birth rate (LBR) per woman was the primary outcome. Two review authors independently assessed the eligibility and quality of trials and evaluated the quality of the evidence by using GRADE criteria. IVF versus expectant management (two RCTs):Live birth rate per woman was higher with IVF than with expectant management (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, one RCT, 51 women, very low quality evidence). Multiple pregnancy rates (MPRs), ovarian hyperstimulation syndrome (OHSS) and miscarriage were not reported. IVF versus unstimulated IUI (two RCTs):Live birth rate was higher with IVF than with unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12, two RCTs, 156 women, I(2) = 60%, low quality evidence). There was no evidence of a difference between the groups in multiple pregnancy rates (OR 1.03, 95% CI 0.04 to 27.29, one RCT, 43 women, very low quality evidence) IVF versus IUI + ovarian stimulation with gonadotropins (three RCTs) or clomiphene (one RCT) or letrozole (no RCTs):Data from these trials could not be pooled because of high statistical heterogeneity (I(2) = 93.3%). Heterogeneity was eliminated when studies were stratified by pretreatment status.In trials comparing IVF versus IUI + gonadotropins among treatment-naive women, there was no conclusive evidence of a difference between the groups in live birth rates (OR 1.27, 95% CI 0.94 to 1.73, four RCTs, 745 women, I(2) = 8.0%, moderate-quality evidence). In women pretreated with IUI + clomiphene, a higher live birth rate was reported among those who underwent IVF than those given IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57, one RCT, 280 women, moderate-quality evidence).There was no conclusive evidence of a difference in live birth rates between IVF and IUI + CC in treatment-naive women (OR 2.51, 95% CI 0.96 to 6.55, one RCT, 103 women, low quality evidence).In treatment-naive women, there was no evidence of a difference in rates of multiple pregnancy between women who underwent IVF and those who received IUI + gonadotropins (OR 0.79, 95% CI 0.45 to 1.39, four RCTs, 745 women, I(2) = 0%, moderate quality evidence). There was no evidence of a difference in MPRs between women who underwent IVF compared with those given IUI + CC (OR 1.02, 95% CI 0.20 to 5.31, one RCT, 103 women, low-quality evidence).There was no evidence of a difference in ovarian hyperstimulation syndrome rate between treatment-naive women who underwent IVF and those given IUI + gonadotropins (OR 1.23, 95% CI 0.36 to 4.14, two RCTs, 221 women, low quality evidence). There was no evidence of a difference in OHSS rates between groups receiving IVF versus those receiving IUI + CC (OR 1.02, 95% CI 0.20 to 5.31, one RCT, 103 women, low-quality evidence).In treatment naive women, there was no evidence of a difference in miscarriage rates between IVF and IUI + CC (OR 1.16, 95% CI 0.44 to 3.02, one RCT, 103 women, low-quality evidence), nor between women treated with IVF versus those receiving IUI+ gonadotropins (OR 1.16, 95% CI 0.44 to 3.02, one RCT, 103 women).No studies compared IVF with IUI + letrozole.The quality of the evidence ranged from very low to moderate. The main limitation was serious imprecision resulting from small study numbers and low event rates. IVF may be associated with higher live birth rates than expectant management, but there is insufficient evidence to draw firm conclusions. IVF may also be associated with higher live birth rates than unstimulated IUI. In women pretreated with clomiphene + IUI, IVF appears to be associated with higher birth rates than IUI + gonadotropins. However in women who are treatment-naive there is no conclusive evidence of a difference in live birth rates between IVF and IUI + gonadotropins or between IVF and IUI + clomiphene. Adverse events associated with these interventions could not be adequately assessed owing to lack of evidence.

Polycystic ovarian syndrome management options.

PubMed

Bates, G Wright; Propst, Anthony M

2012-12-01

Polycystic ovarian syndrome (PCOS) is a disorder of androgen excess and ovarian dysfunction. Hirsutism and elevated free testosterone levels are the most consistent signs of the androgen excess. Irregular, infrequent, or absent menses and infertility are symptoms of ovulatory dysfunction. Obesity is also a feature of this syndrome and contributes to associated metabolic abnormalities. Lifestyle modification should be the first treatment and is effective in reducing the signs and symptoms. The ovulatory infertility associated with PCOS can be overcome in most cases with oral (clomiphene citrate or letrozole) or injectable (gonadotropins) agents. Surgical intervention is reserved for cases resistant to medical management. Copyright © 2012 Elsevier Inc. All rights reserved.

Ultrastructure of the human preovulatory oocyte.

PubMed

Szöllösi, D; Mandelbaum, J; Plachot, M; Salat-Baroux, J; Cohen, J

1986-08-01

The ultrastructure of preovulatory human oocyte-cumulus complexes was described after inducing maturation by clomiphene, human menopausal gonadotropin (hMG), human chorionic gonadotropin (hCG) treatment. The majority of the oocytes was at metaphase II of meiosis, with a radially orientated spindle. The oocyte surface was covered by a multitude of microvilli. Cortical granules were nonuniformly distributed along the cortex. A cytoplasmic polarization was observed. The cytoplasmic organelles were in general uniformly dispersed, with the exception of a narrow segment within which cytoplasmic membranes and mitochondria formed clusters. The spindle was usually found at the borderline between the two regions of the cytoplasm. The functional significance of this polarization is not yet known.

Familial trend in polycystic ovarian syndrome: report of two cases.

PubMed

Joe-kechebelu, N N; Mbamara, S U; Ikechebelu, J I

2013-01-01

Polycystic ovarian syndrome (PCOS) is an endocrine disorder with a strong genetic component. The affected females present with anovulatory cycles, a spectrum of menstrual disorders, and features of androgen excess. We present the case of two sisters who were diagnosed with PCOS and have a family history of oligomenorrhoea in their grandmother and PCOS in their mother and sisters. They also have a family history of hypertension, diabetes mellitus, and breast mass which are known co-morbidities associated with PCOS. Both were managed successfully with ovulation induction using clomiphene citrate. PCOS could be familial as in our patients and further research is required to define the exact genetic pattern of inheritance.

Laparoscopic ovarian drilling: An alternative but not the ultimate in the management of polycystic ovary syndrome

PubMed Central

Mitra, Subarna; Nayak, Prasanta Kumar; Agrawal, Sarita

2015-01-01

Since its introduction in 1984, laparoscopic ovarian drilling has evolved into a safe and effective surgical treatment for anovulatory, infertile women with polycystic ovary syndrome (PCOS), unresponsive to clomiphene citrate. It is as effective as gonadotropins in terms of pregnancy and live birth rates, but without the risks of ovarian hyperstimulation syndrome and multiple pregnancies. It improves ovarian responsiveness to successive ovulation induction agents. Its favorable reproductive and endocrinal effects are sustained long. Despite its advantages, its use in unselected cases of PCOS or for non-fertility indications is not prudent owing to the potential risks of iatrogenic adhesions and ovarian insufficiency. PMID:25810633

Altered Circulating Inflammatory Cytokines Are Associated with Anovulatory Polycystic Ovary Syndrome (PCOS) Women Resistant to Clomiphene Citrate Treatment.

PubMed

Wang, LianLian; Qi, HongBo; Baker, Philip N; Zhen, QianNa; Zeng, Qing; Shi, Rui; Tong, Chao; Ge, Qian

2017-03-01

BACKGROUND Polycystic ovary syndrome (PCOS) is a common gynecological disease characterized by chronic oligoanovulation, clinical/biochemical hyperandrogenism, polycystic ovaries, and insulin resistance. Accumulating evidence has shown that PCOS-related ovarian dysfunction is the main cause of anovulatory infertility. Clomiphene citrate (CC) is the first-line therapy for PCOS patients; however, approximately 15-40% PCOS patients are resistant to CC treatment. It has been demonstrated that PCOS is a chronic pro-inflammatory state, as some pro-inflammatory cytokines were elevated in the peripheral circulation of PCOS patients, but whether altered inflammatory cytokines expression in PCOS patients is associated with blunted response to CC remains unknown. MATERIAL AND METHODS We recruited 44 CC-resistant PCOS patients, along with 55 age and body mass index (BMI)-matched CC-sensitive PCOS patients. Ovulation was induced by administrating 50-100 mg/day CC on days 5 to 9 of each menstrual cycle. The cytokine profiles were detected by cytokine antibody microarrays and further validated by ELISAs. RESULTS CC-resistant patients had higher levels of high-sensitivity C-reactive protein (hsCRP) than the CC-sensitive individuals. A growth factor, angiopoietin-2, was significantly reduced [1.64 (0.93-1.95) vs. 1.08 (0.85-1.34), p<0.05], while a chemokine CXCL-16 was significantly increased (9.10±2.35 vs. 10.41±2.82, p<0.05) in CC-resistant patients compared to the CC-sensitive subjects. CXCL-16 was positively correlated with hsCRP (r=0.33, p<0.01). Logistic regression analysis showed that angiopoietin-2 and CXCL-16 are associated with CC resistance. CONCLUSIONS Circulating cytokines are disturbed in CC-resistant PCOS patients. Altered angiopoietin-2 and CXCL-16 levels might compromise the responsiveness of the ovary to CC through up-regulating angiogenesis and inflammation.

Intrauterine insemination versus fallopian tube sperm perfusion in non-tubal infertility

PubMed Central

Shekhawat, G.S.

2012-01-01

Background Controlled ovarian hyperstimulation (COH) combined with intrauterine insemination (IUI), using a volume of 0.5 ml of inseminate is commonly offered to couples with non-tubal sub fertility. Another method is Fallopian tube sperm perfusion (FSP) which is based on a pressure injection of 4 ml of sperm suspension while attempting to seal the cervix to prevent semen reflux. This technique ensures the presence of higher sperm density in the fallopian tubes at the time of ovulation than standard IUI. The aim of this study was to compare the efficiency of standard intrauterine insemination (IUI) and Fallopian tube sperm perfusion (FSP) in the treatment of non-tubal infertility. Methods 200 consecutive patients with infertility in 404 stimulated cycles were included in the study. Those randomized to standard IUI included 100 patients in 184 cycles [158 clomiphene citrate/human menopausal gonadotrophin cycles and 26 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group A). Patients subjected to FSP included 100 patients in 220 cycles (193 clomiphene citrate/human menopausal gonadotrophin cycles and 27 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group B). Swim up semen preparation technique was used in all cases. Insemination was performed in both groups 34–37 h after hCG administration. Standard IUI was performed using 0.5 ml of inseminate. In FSP 4 ml inseminate was used. Results In group A (184 IUI cycles in 100 patients), 22 clinical pregnancies (presence of gestational sac with fetal cardiac activity) occurred (11.95% per cycle over four cycles). In group B, (220 cycles of FSP in 100 patients), 48 clinical pregnancies occurred (21.81% per cycle over four cycles) and this difference was statistically significant (p < 0.05). Conclusions For non-tubal sub fertility, the results indicate clear benefit for FSP (Fallopian tube sperm perfusion) over IUI (Intrauterine insemination). PMID:24532873

Women with clomiphene citrate resistant polycystic ovarian disease: predictors of spontaneous ovulation after laparoscopic ovarian drilling.

PubMed

Abuelghar, Wessam M; Bayoumy, Hassan A; Ellaithy, Mohamed I; Khalil, Marian S

2014-04-01

To evaluate the role of different clinical, biochemical and sonographic factors as predictors of spontaneous ovulation after laparoscopic ovarian drilling (LOD) in women with clomiphene citrate resistant polycystic ovarian disease (CCR-PCOD). This prospective study recruited 251 infertile women with CCR-PCOD. Several clinical, biochemical and sonographic criteria were tested as possible predictors of spontaneous ovulation after LOD using multivariate analysis. Women with higher preoperative levels of LH, FSH and/or androstenedione had significantly higher rates of spontaneous ovulation within the first eight weeks after LOD, but only FSH and androstenedione were found to be independent predictors. Other factors including age, BMI, type of infertility, duration of infertility, menstrual pattern, testosterone level, ovarian volume and SHBG were insignificant predictors. Receiver-operating characteristic (ROC) curves derived from FSH, LH, androstenedione, and a logistic regression model showed that the best cut-off values were 4.1IU/l, 7.8IU/l, 1.2ng/ml, and 0.4897, respectively, with sensitivity of 91.18%, 100%, 73.53%, and 88.24% and specificity of 69.57%, 69.57%, 65.22%, and 73.91% for FSH, LH, androstenedione, and logistic regression model respectively. An extended follow up (9 months after LOD) was conducted for the anovulatory and the non-pregnant ovulatory women, who were treated individually according to their clinical situation. Of these women, 53.5% (69/129) got pregnant, resulting in a cumulative pregnancy rate of 48% (82/171). Of these pregnancies, 16/82 (19.5%) were spontaneous while 35.4% (29/82) and 45.1% (37/82) occurred after ovulation induction by CC and gonadotropins, respectively. This study supports the use of androstenedione, LH and FSH as a simple reliable tool in triaging patients with CCR-PCOD to select the ideal candidates for LOD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of Effectiveness of Different Protocols Used for Controlled Ovarian Hyperstimulation in Intrauterine Insemination Cycle.

PubMed

Banker, Manish; Patel, Azadeh; Deshmukh, Ashwini; Shah, Sandeep

2018-02-01

Intrauterine insemination (IUI) is one of the most commonly performed procedure of assisted reproductive technology, for the treatment of infertility. Controlled ovarian hyperstimulation is an important first step while performing IUI. This study aims at establishing a relationship between stimulation protocol and pregnancy outcome following IUI. This is a retrospective study of 1001 cycles of IUI in which the patients were divided into two groups: Group A Clomiphene citrate (CC only) and Group B Clomiphene citrate and Gonadotropin or Gonadotropin alone(CC+GN OR GN alone). The primary outcome assessed was clinical pregnancy rates (CPRs), and the secondary outcomes were miscarriage rate (MR), multiple pregnancy rates (MPRs), follicle numbers and endometrial thickness (ET). Significantly, higher CPR was observed in Group B in comparison with Group A (14.55 vs. 7.82%; p  = 0.05). MR was much higher in Group A in comparison with Group B, (14.29 vs. 5.43%; p  = 0.94), but it was non-significant. The follicle number and the ET of the Group A versus Group B are (1.54 ± 0.69 vs. 1.90 ± 1.04; p  = 0.0003) and (8.56 ± 1.33 vs. 8.39 ± 1.29; p  = 0.1784), respectively; and for subgroups, Group B1 and Group B2 are 1.92 ± 0.99 versus 1.65 ± 0.92; p  = 0.0008 and 8.32 ± 1.27 vs. 8.69 ± 1.24; p  = 0.0004, respectively. GN, either alone or the combination with CC, gives a higher CPR and a lower abortion rate following IUI, thus increasing the multiple pregnancy rate.

Clomiphene citrate or anastrozole for ovulation induction in women with polycystic ovary syndrome? A prospective controlled trial.

PubMed

Badawy, Ahmed; Abdel Aal, Ibrahim; Abulatta, Mohamed

2009-09-01

To compare the effects of anastrozole (1 mg) and clomiphene citrate (CC; 100 mg) used for ovulation induction in women with polycystic ovary syndrome. Prospective controlled trial. University teaching hospital and private-practice setting. The study comprised a total of 216 infertile women (469 cycles) with polycystic ovary syndrome. Patients received anastrozole (1 mg/d; 115 patients, 243 cycles) for 5 days, starting on day 3 of menses. A matched historical group of patients with polycystic ovary syndrome who were treated with CC (100 mg/d; 101 patients, 226 cycles) was used as a control group. Timed intercourse was advised 24-36 hours after hCG injection. Number of follicles, serum E(2), serum P, endometrial thickness, and pregnancy and miscarriage rates. The mean age, parity, and duration of infertility in both groups were similar, but statistically significantly more polycystic ovaries were found in the anastrozole group (odds ratio = 2.44; 95% confidence interval = 1.19-5.02). The total numbers of follicles were significantly higher in the CC group (3.8 +/- 0.6 vs. 3.4 +/- 0.5). Endometrial thickness at the time of hCG administration was significantly greater in the anastrozole group (10.1 +/- 0.22 mm vs. 8.2 +/- 0.69 mm). The duration of stimulation was similar in the two groups. Ovulation occurred in 165 (67.9%) of 243 cycles in the anastrozole group and in 150 (68.6%) of 226 cycles in the CC group without significant difference. Serum P was significantly higher in the CC group (7.1 +/- 1.11 vs. 8.1 +/- 0.88 ng/mL). The pregnancy and miscarriage rates were similar in the two groups. Anastrozole was associated with significantly fewer mature and growing follicles, thicker endometrium, and slightly higher pregnancy rate. Anastrozole may be helpful in situations in which multiple pregnancy is not desirable or the risk of ovarian hyperstimulation syndrome is high.

Altered Circulating Inflammatory Cytokines Are Associated with Anovulatory Polycystic Ovary Syndrome (PCOS) Women Resistant to Clomiphene Citrate Treatment

PubMed Central

Wang, LianLian; Qi, HongBo; Baker, Philip N.; Zhen, QianNa; Zeng, Qing; Shi, Rui; Tong, Chao; Ge, Qian

2017-01-01

Background Polycystic ovary syndrome (PCOS) is a common gynecological disease characterized by chronic oligoanovulation, clinical/biochemical hyperandrogenism, polycystic ovaries, and insulin resistance. Accumulating evidence has shown that PCOS-related ovarian dysfunction is the main cause of anovulatory infertility. Clomiphene citrate (CC) is the first-line therapy for PCOS patients; however, approximately 15–40% PCOS patients are resistant to CC treatment. It has been demonstrated that PCOS is a chronic pro-inflammatory state, as some pro-inflammatory cytokines were elevated in the peripheral circulation of PCOS patients, but whether altered inflammatory cytokines expression in PCOS patients is associated with blunted response to CC remains unknown. Material/Methods We recruited 44 CC-resistant PCOS patients, along with 55 age and body mass index (BMI)-matched CC-sensitive PCOS patients. Ovulation was induced by administrating 50–100 mg/day CC on days 5 to 9 of each menstrual cycle. The cytokine profiles were detected by cytokine antibody microarrays and further validated by ELISAs. Results CC-resistant patients had higher levels of high-sensitivity C-reactive protein (hsCRP) than the CC-sensitive individuals. A growth factor, angiopoietin-2, was significantly reduced [1.64 (0.93–1.95) vs. 1.08 (0.85–1.34), p<0.05], while a chemokine CXCL-16 was significantly increased (9.10±2.35 vs. 10.41±2.82, p<0.05) in CC-resistant patients compared to the CC-sensitive subjects. CXCL-16 was positively correlated with hsCRP (r=0.33, p<0.01). Logistic regression analysis showed that angiopoietin-2 and CXCL-16 are associated with CC resistance. Conclusions Circulating cytokines are disturbed in CC-resistant PCOS patients. Altered angiopoietin-2 and CXCL-16 levels might compromise the responsiveness of the ovary to CC through up-regulating angiogenesis and inflammation. PMID:28246376

Clomiphene citrate is associated with favorable cycle characteristics but impaired outcomes of obese women with polycystic ovarian syndrome undergoing ovarian stimulation for in vitro fertilization

PubMed Central

Jiang, Shutian; Kuang, Yanping

2017-01-01

Abstract The aim of this study was to explore the effect of clomiphene citrate (CC) on the cycle characteristics and outcomes of obese women with polycystic ovarian syndrome (PCOS) undergoing ovarian stimulation for in vitro fertilization (IVF). This is a retrospective cohort study, and it was conducted at the tertiary-care academic medical center. This study included 174 obese PCOS patients undergoing IVF. In the study group (n = 90), CC and human menopausal gonadotropin (HMG) were administered simultaneously beginning on cycle day 3, while in control group (n = 84) HMG was used only. Both of the 2 groups used medroxyprogesterone acetate (MPA) for preventing premature luteinizing hormone (LH) surges. Ovulation was cotriggered by a GnRH agonist and hCG when dominant follicles matured. The primary outcome measure was the number of oocytes retrieved. Secondary outcomes included the number of top-quality embryos, maturation rate, fertilization rate, cleavage rate, incidence of premature LH surge, and OHSS. The study group received obviously lower total HMG dose [1650 (975–4800) vs 2025 (1350–3300) IU, P = 2.038E–4] but similar HMG duration. While the antral follicle count (AFC) is higher in study group, the number of oocytes retrieved and top-quality embryos are remarkably less [5 (0–30) vs 13 (0–42), P = 6.333E–5; 2 (0–14) vs 3.5 (0–15), P = .003; respectively]. The mature oocyte rate is higher in study group (P = .036). No significant differences were detected in fertilization rate and cleavage rate between 2 groups. CC has a positive influence on cycle characteristics, but might be correlated with the impaired IVF outcomes (less oocytes retrieved and top quality embryos, lower oocyte retrieval rate) in obese PCOS patients undergoing IVF, when HMG and MPA are used simultaneously. PMID:28796038

[Optimal Ovulation Induction in Polycystic Ovary Syndrome Resistant to Clomiphene Citrate or Letrozole.

PubMed

Chen, Ying; Zhang, Dan

2016-11-01

To investigate the optimal ovulation induction with the combination of combining letrozole(LE),clomiphene citrate (CC),and human menopausal gonadotropin (HMG) in polycystic ovary syndrome(PCOS) patients resistant to CC or LE. Two hundreds nine PCOS patients (209 cycles) resistant to CC or LE were randomly divided into three groups: CC+HMG group (59 cycles),LE+HMG group (72 cycles) and LE+CC group (78 cycles).The patients in LE+CC group unable to form the dominant follicle after 54 cycles were enrolled into LE+CC+HMG group.Maximum follicle diameter (MFD),endometrial thickness,number of follicles (diameter>1.4 cm),the level of serum estradiol (E2) were measured on the day of HMG administration.Also these results were observed and compared including the duration of treatment,dosage of HMG,number of ovulated follicles,clinical pregnancy rate,biochemical pregnancy rate,early abortion rate,twinning rate,and ectopic pregnancy rate. The ovulation rate was significantly lower in LE+CC group (30.77%) ( P <0.05),but similar in the other three groups.The number of >1.4 cm follicles and ovulated follicles,ovulation duration and E2 concentration in LE+CC group were also at a lower level ( P <0.05).The patients in LE+CC+HMG group showed higher E2 level and more HMG consumption ( P <0.05).There was no statistical difference in endometrial thickness,MFD,clinical pregnancy rate,biochemical pregnancy rate,early abortion rate and twinning rate among these groups ( P >0.05).No severe ovarian hyperstimulation syndrome (OHSS) or luteinized unruptured follicle (LUF) occurred. Combintion of LE with CC could achieve 1/3 ovulation induction in PCOS resistant to CC or LE alone.When both combined with HMG,the induction of ovulation could be significantly higher than LE+HMG and CC+HMG,while the risk of multiple pregnancy and OHSS was reduced.

Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost.

PubMed

Taylor, Frederick; Levine, Laurence

2010-01-01

The efficacy of oral clomiphene citrate (CC) in the treatment of male hypogonadism and male infertility (MI) with low serum testosterone and normal gonadotropin levels has been reported. The aim of this article is to evaluate CC and testosterone gel replacement therapy (TGRT) with regard to biochemical and clinical efficacy and cost. The main outcome measures were change in serum testosterone with CC and TGRT therapy, and change in the androgen deficiency in aging male (ADAM) questionnaire scores with CC therapy. Men receiving CC or TGRT with either Androgel 1% or Testim 1% for hypogonadism (defined as testosterone < 300 ng/mL) or MI were included. Serum values were collected 1-2 months after treatment initiation and semi-annually thereafter. Retrospective data collection was performed via chart review. Subjective follow up of patients receiving CC was performed via telephone interview using the ADAM questionnaire. A hundred and four men (65 CC and 39 TGRT) were identified who began CC (50 mg every other day) or TGRT (5 g). Average age (years) was 42(CC) vs. 57 (TGRT). Average follow up was 23 months (CC, range 8-40 months) vs. 46 months (TGRT, range 6-149 months). Average posttreatment testosterone was 573 ng/dL in the CC group and 553 ng/dL in the TGRT group (P value < 0.001). The monthly cost of Testim 1% (5 gm daily) is $270, Androgel 1% (5 gm daily) is $265, and CC (50 mg every other day) is $83. Among CC patients, the average pretreatment ADAM score was 4.9 vs. 2.1 at follow up (P < 0.05). Average pretreatment ADAM sexual function domain score was 0.76 vs. 0.23 at follow up (P < 0.05). There were no adverse events reported. CC represents a treatment option for men with hypogonadism, demonstrating biochemical and clinical efficacy with few side effects and lower cost as compared with TGRT.

[Management of functional sterility using clomiphene and cyclophenyl at the Karl-Marx-Stadt District Hospital Gynecologic Clinic].

PubMed

Neubert, S; Melzer, H

1977-01-01

We report on 39 barren patients suffering from anovulatory cycle disturbances or corpus luteum inadequacies. Them were given treatment in the Gynecological Hospital of Karl-Marx-Stadt County at Karl-Marx-Stadt in the past few years and were administered Clomiphendihydrogencitrate or Cyclophenyl to provoke ovulation. Before and during therapy, the total of estrogenes and pregnanediol were determined in the 24h-urine every two days. The clinical data and the results of the hormone investigations were analysed, and an attempt was made to derive a forecast from the estrogene and pregnanediol secretion so as to be able to form an opinion on the positive or negative result of the treatment.

Anovulation and ovulation induction

PubMed Central

Katsikis, I; Kita, M; Karkanaki, A; Prapas, N; Panidis, D

2006-01-01

Conventional treatment of normogonadotropic anovulatory infertility is ovulation induction using the antiestrogen clomiphene citrate, followed by follicle-stimulating hormone. Multiple follicle development, associated with ovarian hyperstimulation, and multiple pregnancy remain the major complications. Cumulative singleton and multiple pregnancy rate data after different induction treatments are needed. Newer ovulation induction interventions, such as insulin-sensitizing drugs, aromatase inhibitors and laparoscopic ovarian electrocoagulation, should be compared with conventional treatments. Ovulation induction efficiency might improve if patient subgroups with altered chances for success or complications with new or conventional techniques could be identified, using multivariate prediction models based on initial screening characteristics. This would make ovulation induction more cost-effective, safe and convenient, enabling doctors to advise patients on the most effective and patient-tailored treatment strategy. PMID:20351807

Survival and growth in a woman with untreated hypothalamic panhypopituitarism of 21 years' duration.

PubMed

Tolis, G; Cruess, S; Goldstein, M; Friesen, H G; Rochefort, J G

1974-09-21

A 29-year-old woman with evidence of a craniopharyngioma and documented panhypopituitarism is described. Clinical and laboratory evaluation revealed deficiencies of follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, growth hormone, prolactin, adrenocorticotropic hormone and antidiuretic hormone. Prompt release of several pituitary hormones was noticed after administration of the hypothalamic releasing hormones FSH/LH-RF and thyrotropin-releasing hormone, whereas insulin-induced hypoglycemia, levodopa, chlorpromazine and clomiphene citrate, all of which act at the level of the hypothalamus, did not alter basal pituitary secretion. The patient's height of 60 inches, despite panhypopituitarism, and the interpretation of the above data are discussed in the light of current concepts regarding the dynamics of the hypothalamic-hypophyseal system.

Survival and growth in a woman with untreated hypothalamic panhypopituitarism of 21 years' duration

PubMed Central

Tolis, G.; Cruess, S.; Goldstein, M.; Friesen, H. G.; Rochefort, J. G.

1974-01-01

A 29-year-old woman with evidence of a craniopharyngioma and documented panhypopituitarism is described. Clinical and laboratory evaluation revealed deficiencies of follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, growth hormone, prolactin, adrenocorticotropic hormone and antidiuretic hormone. Prompt release of several pituitary hormones was noticed after administration of the hypothalamic releasing hormones FSH/LH-RF and thyrotropin-releasing hormone, whereas insulin-induced hypoglycemia, levodopa, chlorpromazine and clomiphene citrate, all of which act at the level of the hypothalamus, did not alter basal pituitary secretion. The patient's height of 60 inches, despite panhypopituitarism, and the interpretation of the above data are discussed in the light of current concepts regarding the dynamics of the hypothalamic-hypophyseal system. ImagesFIG. 1 PMID:4370418

Ovulation induction in women with polycystic ovary syndrome: an update.

PubMed

Bhagavath, Balasubramanian; Carson, Sandra A

2012-03-01

Infertility is frequently caused by anovulation. The affected women present with irregular menstrual cycles and the most common diagnosis is polycystic ovary syndrome. Ovulation induction is commonly used to treat these women. Clomiphene citrate (a selective estrogen receptor modulator or SERM) remains the most used medication for treating this condition. Alternatives that have been used include other SERMs such as tamoxifen, aromatase inhibitors, insulin sensitizing agents, and ovarian drilling. Evidence for and against the effectiveness of these agents has fluctuated over the last decade. Controversies surrounding the use of ovulation induction such as development of functional cysts, high-order multiple births, and development of ovarian cancer have been further studied and some controversies have almost been laid to rest in the last decade. Copyright © 2012 Mosby, Inc. All rights reserved.

Stress and fertility: some modalities of investigation and treatment in couples with unexplained infertility in Dublin.

PubMed

Harrison, R F; O'Moore, R R; O'Moore, A M

1986-01-01

The role of stress in infertility, and its treatment, is reviewed in various groups of couples labeled "unexplained infertile." A simplified profile of stress markers based upon basal prolactin estimations and psychological measurements found infertile couples more stressed than fertile controls and revealed a sub-group of women characterized as having significantly high psychological stress scores and intermittent elevations of prolactin (spikers). This group was effectively treated with a combination of clomiphene citrate and bromocriptine. However, attention to the failures as well as the successes suggests optimum benefit to the patients might involve not only provision of a good clinic ambiance and pharmacological preparations, but also relaxation therapies such as Autogenic Training, which significantly lowered psychological and biochemical stress marker scores.

Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel.

PubMed

Kaminetsky, Jed; Werner, Michael; Fontenot, Greg; Wiehle, Ronald D

2013-06-01

Clomiphene citrate is employed off-label in men who have low testosterone and for the restoration of sperm counts in men who have used exogenous testosterone. Clomiphene is a mixture of two diastereoisomers: zuclomiphene and enclomiphene. We evaluated enclomiphene citrate in men with secondary hypogonadism. Our aim was to compare oral enclomiphene citrate as an alternative to topical testosterone. Blood levels of total testosterone (TT), estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, thyroid stimulation hormone, prolactin, and insulin-like growth factor 1 IGF-1 were measured at certain times after treatment with each agent. Sperm parameters were determined at the same visits. Free testosterone (FT) was calculated. This was a proof-of-principle, randomized, open-label, fixed dose, active-control, two-center phase IIB study in 12 men with secondary hypogonadism treated previously with topical testosterone. After discontinuation of topical testosterone, morning TT values averaged 165 ± 66 pg/dL. After 3 months, there was a significant rise in men receiving enclomiphene citrate and gel that was sustained for 3 months. At 6 months, TT levels were 545 ± 268 and 525 ± 256 pg/dL for groups receiving the gel and enclomiphene citrate, respectively. Only men in the enclomiphene citrate group demonstrated increased LH and FSH. TT decreased one month posttreatment to pretreatment values. Enclomiphene citrate elevated sperm counts in seven out of seven men at 3 months and six out of six men at 6 months with sperm concentrations in the 75-334 × 10(6) /mL range. The gel was ineffective in raising sperm counts above 20 × 10(6) /mL for all five men at 3 months and raised counts in only two or five men at 6 months. At follow-up, only enclomiphene citrate treatment was associated with elevated sperm counts. Enclomiphene citrate increased testosterone and sperm counts. Concomitant changes in LH and FSH suggest normalization of endogenous testosterone production and restoration of sperm counts through the hypothalamic-pituitary-testicular axis. © 2013 Repros Therapeutics. Journal of Sexual Medicine © 2013 International Society for Sexual Medicine.

Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial.

PubMed

Palomba, S; Falbo, A; Giallauria, F; Russo, T; Rocca, M; Tolino, A; Zullo, F; Orio, F

2010-11-01

Clomiphene citrate (CC) is the first-line therapy for the induction of ovulation in infertile women with polycystic ovary syndrome (PCOS), but ∼20% of patients are unresponsive. The aim of the current study was to test the hypothesis that a 6-week intervention that consisted of structured exercise training (SET) and hypocaloric diet increases the probability of ovulation after CC in overweight and obese CC-resistant PCOS patients. A cohort of 96 overweight and obese CC-resistant PCOS patients was enrolled consecutively in a three-arm randomized, parallel, controlled, assessor-blinded clinical trial. The three interventions were: SET plus hypocaloric diet for 6 weeks (Group A); 2 weeks of observation followed by one cycle of CC therapy (Group B); and SET plus hypocaloric diet for 6 weeks, with one cycle of CC after the first 2 weeks (Group C). The primary end-point was the ovulation rate. Other reproductive data, as well as anthropometric, hormonal and metabolic data, were also collected and considered as secondary end points. After 6 weeks of SET plus hypocaloric diet, the ovulation rate was significantly (P =0.008) higher in Group C [12/32 (37.5%)] than in Groups A [4/32 (12.5%)] and B [3/32 (9.4%)] with relative risks of 3.9 [95% confidence interval (CI) 1.1-8.3; P = 0.035] and 4.0 (95% CI 1.2-12.8; P = 0.020) compared with Groups A and B, respectively. Compared with baseline, in Groups A and C, a significant improvement in clinical and biochemical androgen and insulin sensitivity indexes was observed. In the same two groups, the insulin sensitivity index was significantly (P < 0.05) better than that in Group B. In overweight and obese CC-resistant PCOS patients, a 6-week intervention of SET and a hypocaloric diet was effective in increasing the probability of ovulation under CC treatment. The study was registered at Clinicaltrials.gov:NCT0100468.

Ficus platyphylla promotes fertility in female Rattus norvegicus Wistar strain: a preliminary study.

PubMed

Ugwah-Oguejiofor, Chinenye J; Bello, Shaibu O; Okolo, Raymond U; Etuk, Emmanuel U; Ugwah, Michael O; Igbokwe, Vincent U

2011-11-02

Ficus platyphylla Delile (family-Moracea) commonly called gutta percha tree is a deciduous plant found in savannah areas. It grows widely in the Northern part of Nigeria, up to 60 ft. high and is known as 'gamji' by the Hausas. The seeds, bark and leaves have been used traditionally in combination to promote fertility. Scientifically, the plant has been shown to have analgesic, anti-inflammatory and CNS effects. The present study was to validate the use of this plant to promote fertility in female Rattus norvegicus Wistar strain using various fertility parameters. Female Rattus norvegicus Wistar strain weighing between 150-180 g were randomly selected and divided into two major groups. Each group was subdivided into 5 treatment groups of 100, 200, 400 mg/kg BW of aqueous extract of F. platyphylla and a control group of 5 ml/kg of distilled water. A positive control of clomiphene citrate was used. Treatment of the first group was discontinued after 15 days prior to mating (pre-mating treatment group), while the other was treated continuously till delivery (continuous treatment group). At the 10th day, females were sacrificed and implantation sites were checked and embryos counted. Upon delivery, litter sizes were determined and the pups weighed and checked for deformities. Other reproductive indices were calculated. Data were analyzed by one-way analysis of variance and students T-test. Proportions were analysed by Chi square. Statistical evaluations were performed using STATS programs and Graphpad prism, and a difference was considered statistically significant at P < 0.05. There was a significant reduction in the percentage post implantation losses of both the pre-treatment and the continuous treatment groups when compared to their distil water controls. The litter size of the pre-treatment group was similar to the distil water group while at 400 mg/kg, the continuous treatment group showed an increase in the litter size similar to that of the clomiphene group. There were no observed external deformities in the pups. Administration of aqueous extract of F. platyphylla promotes fertility by reducing post implantation loss and by increasing litter size in female Rattus norvegicus Wistar strain.

Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment.

PubMed

Helo, Sevann; Mahon, Joseph; Ellen, Joseph; Wiehle, Ron; Fontenot, Gregory; Hsu, Kuang; Feustel, Paul; Welliver, Charles; McCullough, Andrew

2017-01-01

To determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in men with hypogonadism on long-term clomiphene citrate (CC) therapy, and to determine whether patient age, body mass index (BMI) or duration of therapy were predictive of relative concentrations of ENC and ZUC. Men already receiving CC 25 mg daily therapy for secondary hypogonadism for a minimum of 6 weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone, free testosterone, oestradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) before initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, BMI and medical comorbidites were recorded. Serum samples were obtained at the time of enrolment to determine ENC and ZUC concentrations. A total of 15 men were enrolled in the period from June 2015 to August 2015. The median (range) patient age was 36 (22-70) years, BMI 32.0 (21.1-40.3) kg/m 2 and duration of treatment 25.9 (1.7-86.6) months. Baseline median total testosterone, oestradiol and LH levels were 205.0 ng/dL, 17.0 pg/mL and 4.0 mlU/mL, respectively. The post-treatment median total testosterone, oestradiol and LH level increased to 488.0 ng/dL, 34.0 pg/mL and 6.1 mIU/mL, respectively (all P<0.001). The median ENC and ZUC concentrations were 2.2 and 44.0 ng/mL, respectively. After at least 6 weeks of CC therapy, the median ZUC: ENC serum concentration ratio was 20:1. On linear regression analysis. patient age, BMI, duration of treatment and serum testosterone levels were not predictive of ENC or ZUC concentrations. Long-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for the development of a pure selective oestrogen receptor antagonist for the treatment of men with hypogonadism. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

The role of ovarian surgery in polycystic ovary syndrome.

PubMed

Farquhar, Cynthia M

2004-10-01

Problems in inducing ovulation in women with polycystic ovary syndrome (PCOS) and anovulation are well recognized. In 1935, Stein and Leventhal first described surgical treatment by ovarian wedge resection at laparotomy for women with anovulation and PCOS. Ovarian wedge resection was eventually abandoned because of the significant risk of postsurgical adhesion formation, which resulted in tubal adhesions, and because of the advent of medical ovulation induction with clomiphene and gonadotrophins. However, since the arrival of minimally invasive surgical techniques, laparoscopic ovarian surgery has become feasible. The potential advantages of laparoscopic ovarian surgery include repeated single ovulations and less adhesion formation. Lowered costs make ovarian surgery an attractive alternative to gonadotrophins. However, although many case series have suggested that ovarian surgery is an effective strategy, few randomized, controlled trials have been undertaken comparing the success rates of surgery with gonadotrophins. The long-term concerns with surgery include adhesion formation and premature ovarian failure.

Treatment strategies for the infertile polycystic ovary syndrome patient.

PubMed

Tannus, Samer; Burke, Yechiel Z; Kol, Shahar

2015-11-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Infertility is a prevalent presenting feature of PCOS, and approximately 75% of these women suffer infertility due to anovulation. Lifestyle modification is considered the first-line treatment and is associated with improved endocrine profile. Clomiphene citrate (CC) should be considered as the first line pharmacologic therapy for ovulation induction. In women who are CC resistant, second-line treatment should be considered, as adding metformin, laparoscopic ovarian drilling or treatment with gonadotropins. In CC treatment failure, Letrozole could be an alternative or treatment with gonadotropins. IVF is considered the third-line treatment; the 'short', antagonist-based protocol is the preferred option for PCOS patients, as it is associated with lower risk of developing ovarian hyperstimulation syndrome (specifically by using a gonadotropin--releasing hormone agonist as ovulation trigger), but with comparable outcomes as the long protocol.

Ovulation induction in normogonadotropic anovulation (PCOS).

PubMed

van Santbrink, Evert J P; Fauser, Bart C J M

2006-06-01

Treatment of normogonadotropic anovulatory infertility (World Health Organization class 2, or WHO2) is by induction of ovulation using clomiphene citrate (CC), followed by follicle-stimulating hormone (FSH) in cases of treatment failure. Not all patients will become ovulatory or will conceive with this treatment. Others, exhibiting multifollicular instead of monofollicular development, may encounter complications such as ovarian hyperstimulation and multiple pregnancy. Recently introduced alternative treatment interventions-such as insulin-sensitizing drugs, aromatase inhibitors, or laparoscopic electrocautery of the ovaries-may offer the possibility of improving the efficacy of the classical ovulation induction algorithm. Based on initial patient characteristics, it may be possible to identify specific patient subgroups with altered chances of success or complications while using one of these interventions. Regarding CC and FSH ovulation induction, this has been performed using multivariate prediction models. This approach may enable us to improve safety, cost-effectiveness, and patient convenience in future ovulation induction.

Ovulation induction in polycystic ovary syndrome.

PubMed

Tanbo, Tom; Mellembakken, Jan; Bjercke, Sverre; Ring, Eva; Åbyholm, Thomas; Fedorcsak, Peter

2018-06-11

The objective of this narrative review is to suggest a rational order of treatment choices in anovulatory women with polycystic ovary syndrome (PCOS), for whom a multitude of treatment options exist. In obese/overweight PCOS patients the importance of weight reduction should be stressed. Inositol, a dietary supplement with a documented effect on ovulation and without side effects in the doses recommended, may be suggested. Additional first line medical alternatives include insulin sensitizers, selective estrogen receptor modulators and aromatase inhibitors. Of these, the aromatase inhibitor letrozole and the combination of clomiphene citrate and metformin have the highest rates of ovulation and live birth. Second line treatments are ovarian electrocautery and low-dose follicle stimulating hormone stimulation. Controlled ovarian stimulation with in vitro fertilization, should be considered the last option since it carries a significant risk of ovarian hyperstimulation syndrome in patients with PCOS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Melatonin in human preovulatory follicular fluid

NASA Technical Reports Server (NTRS)

Brzezinski, Amnon; Seibel, Machelle M.; Lynch, Harry J.; Deng, Mei-Hua; Wurtman, Richard J.

1987-01-01

Melatonin, the major hormone of the pineal gland, has antigonadotrophic activity in many mammals and may also be involved in human reproduction. Melatonin suppresses steroidogenesis by ovarian granulosa and luteal cells in vitro. To determine if melatonin is present in the human ovary, preovulatory follicular fluids (n = 32) from 15 women were assayed for melatonin by RIA after solvent extraction. The fluids were obtained by laparoscopy or sonographically controlled follicular puncture from infertile women undergoing in vitro fertilization and embryo transfer. All patients had received clomiphene citrate, human menopausal gonadotropin, and hCG to stimulate follicle formation. Blood samples were obtained by venipuncture 30 rain or less after follicular aspiration. All of the follicular fluids contained melatonim, in concentrations substantially higher than those in the corresponding serum. A positive correlation was found between follicular fluid and serum melatonin levels in each woman; these observations indicate that preovulatory follicles contain substantial amounts of melatonin that may affect ovarian steroidogenesis.

Changes in ovarian reserve and ovarian blood flow in patients with polycystic ovary syndrome following laparoscopic ovarian drilling.

PubMed

Kamal, Nasser; Sanad, Zakaria; Elkelani, Osama; Rezk, Mohamed; Shawky, Mohamed; Sharaf, Abd-Elbar

2018-04-10

This prospective cohort study was conducted on 80 patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome undergoing laparoscopic ovarian drilling (LOD). Pre- and post-LOD ovarian reserve parameters (anti-Mullerian hormone: AMH, ovarian volume: OV, and antral follicle count: AFC) and ovarian stromal blood flow indices (Vascularization index: VI, flow index: FI, and vascularization flow index: VFI) were measured to explore the effect of LOD and to find out the correlation between serum AMH and different clinical, hormonal, and ultrasonic variables. There was a highly significant reduction of the serum AMH (p < .001) after LOD with significant reduction in OV, AFC and vascular indices (VI, FI and VFI) of the right and left ovaries (p < .05). LOD significantly reduced ovarian reserve parameters (AMH, OV and AFC) and ovarian stromal blood flow indices (VI, FI and VFI) with no observed correlation between AMH levels and Doppler indices.

The diagnosis and therapy of luteal phase deficiency.

PubMed

Soules, M R; Wiebe, R H; Aksel, S; Hammond, C B

1977-10-01

Between 1973 and 1975, 16 patients evaluated for infertility at Duke University Medical Center were diagnosed as having luteal phase deficiency. A majority had had prior infertility surveys, and the average duration of their infertility exceeded 2 years. The diagnosis was suspected after study of basal body temperature charts and menstrual patterns in more than 80% of the patients. This diagnosis was established by timed endometrial biopsy. The primary method of therapy was supplementation of the luteal phase with progesterone vaginal suppositories. The pregnancy rate after therapy was 50% and pregnancy occurred after a mean of five treatment cycles. The minimal follow-up of patients who failed to conceive was 8 months. To date, the majority of these pregnancies have been completed without complication and the remainder are progressing satisfactorily. Two additional patients developed luteal phase deficiency while taking clomiphene citrate and became pregnant with progesterone supplementation.

Luteal phase deficiency and infertility: difficulties encountered in diagnosis and treatment.

PubMed

Annos, T; Thompson, I E; Taymor, M L

1980-06-01

Uncertainty concerning the importance of luteal phase defects as a cause of female infertility is closely related to problems of diagnosis. A study was undertaken of the consistency of the parameters used in daignosing luteal phase deficiency in 14 patients; results of randomized treatment regimens were also compared. Specific diagnostic criteria utilizing the basal body temperature (BBT) chart, endometrial biopsy, and progesterone levels were used. Prolactin and luteinizing hormone levels were measured at the time of progesterone determinations. Of the 29 cycles studied, only one third showed consistent abnormalities in BBT chart, endometrial biopsy, and progesterone levels. Discrepancy between the endometrial biopsy and the progesterone level occurred in at least 50% of all cycles studied. Prolactin levels were elevated in only 1 patient, suggesting a minor role for altered prolactin metabolism in luteal phase deficiency. Randomized treatment with progesterone vaginal suppositories, clomiphene citrate, and no treatment resulted in pregnancy in 5 of 14 patients (36%).

Tumor necrosis factor alpha versus LH and androstendione as a reliable predictor of spontaneous ovulation after laparoscopic ovarian drilling for women with clomiphene citrate resistance polycystic ovarian disease.

PubMed

Seyam, Emaduldin; Hefzy, Enas

2018-03-01

Laparoscopic ovarian drilling (LOD) is still a controversial decision; due to the long term hazards; so short and long term predictors after the procedure should be taken in consideration. The aim of this work was to investigate the role of the serum level of tumor necrosis factor alpha (TNF-α) and other polycystic ovarian disease (PCOD) relevant clinical and biochemical factors as a predictor of spontaneous ovulation after laparoscopic ovarian drilling (LOD) in women with clomiphene citrate resistant polycystic ovarian disease (CCR-PCOD). It was a prospective research work, where 150 infertile women with CCR-PCOD had been recruited. TNF-α serum level, which is an inflammatory biomarker, was investigated in addition to other PCOD relevant clinical and biochemical parameters as possible predictors of successful spontaneous ovulation and subsequent pregnancy after LOD. Recruited women with higher preoperative levels of TNF-α, LH, and androstenedione had significantly higher rates of spontaneous ovulation within the first three months follow up after LOD, in contrast to obese women with BMI ≥ 25 kg/m2, long duration of infertility ≥3 years, marked biochemical hyperandrogenism (testosterone levels ≥4.5 nmol/L, free androgen index ≥15), and high insulin resistance (IR). Ninty five (95 = 63.3%) women in between women regularly menstruated (105 = 70%) had spontaneous ovulation, and of those spontaneously ovulated, 35(36.8%) women got pregnant spontaneously during the first 3 months follow up. Extended follow up for 12 months period revealed that 61 women got pregnant, with cumulative pregnancy rate of 58%. Logistic regression showed that the best cut-off values for spontaneous ovulation after LOD were 65.1 pg/ml, 11.5 IU/l, and 3.1 ng/ml and with a sensitivity of 91%, 88%, 55%, and with a specificity of 85%, 79%, 78%, for TNF-α, LH, androstenedione serum level respectively. TNF-α, LH, and Androstenedione could be considered as reliable predictors to depend on for recruiting the ideal women candidates with CCR-PCOD; to have the maximum benefits after LOD treatment option. Copyright © 2018 Elsevier B.V. All rights reserved.

Brachial-to-ankle pulse wave velocity as an independent prognostic factor for ovulatory response to clomiphene citrate in women with polycystic ovary syndrome.

PubMed

Takahashi, Toshifumi; Igarashi, Hideki; Hara, Shuichiro; Amita, Mitsuyoshi; Matsuo, Koki; Hasegawa, Ayumi; Kurachi, Hirohisa

2014-01-01

Polycystic ovary syndrome (PCOS) has a risk for cardiovascular disease. Increased arterial stiffness has been observed in women with PCOS. The purpose of the present study was to investigate whether the brachial-to-ankle pulse wave velocity (baPWV) is a prognostic factor for ovulatory response to clomiphene citrate (CC) in women with PCOS. This study was a retrospective cohort study of 62 women with PCOS conducted from January 2009 to December 2012 at the university hospital, Yamagata, Japan. We analyzed 62 infertile PCOS patients who received CC. Ovulation was induced by 100 mg CC for 5 days. CC non-responder was defined as failure to ovulate for at least 2 consecutive CC-treatment cycles. The endocrine, metabolic, and cardiovascular parameters between CC responder (38 patients) and non-responder (24 patients) groups were analyzed. In univariate analysis, waist-to-hip ratio, level of free testosterone, percentages of patients with dyslipidemia, impaired glucose tolerance, and diabetes mellitus, blood glucose and insulin levels at 60 min and 120 min, the area under the curve of glucose and insulin after 75-g oral glucose intolerance test, and baPWV were significantly higher in CC non-responders compared with responders. In multivariate logistic regression analysis, both waist-to-hip ratio (odds ratio, 1.77; 95% confidence interval, 2.2-14.1; P=0.04) and baPWV (odds ratio, 1.71; 95% confidence interval, 1.1-2.8; P=0.03) were independent predictors of ovulation induction by CC in PCOS patients. The predictive values of waist-to-hip ratio and baPWV for the CC resistance in PCOS patients were determined by the receiver operating characteristic curves. The area under the curves for waist-to-hip ratio and baPWV were 0.76 and 0.77, respectively. Setting the threshold at 0.83 for waist-to-hip ratio offered the best compromise between specificity (0.65) and sensitivity (0.84), while the setting the threshold at 1,182 cm/s for baPWV offered the best compromise between specificity (0.80) and sensitivity (0.71). Both metabolic and cardiovascular parameters were predictive for CC resistance in PCOS patients. The measurement of baPWV may be a useful tool to predict ovulation in PCOS patients who receive CC.

Ovarian size and response to laparoscopic ovarian electro-cauterization in polycystic ovarian disease.

PubMed

Alborzi, S; Khodaee, R; Parsanejad, M E

2001-09-01

To evaluate endocrine and ovulatory changes in polycystic ovarian disease (PCOD) in relation to patients' ovarian size. Three hundred and seventy-one women with clomiphene citrate-resistant PCOD underwent laparoscopic ovarian cauterization [type I or typical with ovarian volume >8 cm(3) or cross-sectional area >10 cm(2) (n=211), type II with normal size ovary (n=160)]. Serum levels of LH, FSH, DHEAS, PRL, and T before and 10 days after ovarian cautery, spontaneous and induced ovulation and pregnancy rates were compared. Both groups responded to therapy in a similar manner, with a marked decrease in LH, FSH, DHEAS and T levels, with ovulation rates in type I 90.99%, type II 88.75% and pregnancy rates, 73.45% and 71.25%, respectively, with no statistical differences. Hormonal changes, ovulation and pregnancy rates were similar in the two types of PCOD, therefore it can be concluded that ovarian size is not a prognostic factor for response of PCOD patients to laparoscopic ovarian electro-cauterization.

Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus.

PubMed

Georgopoulos, N A; Markou, K B; Pappas, A P; Protonatariou, A; Vagenakis, G A; Sykiotis, G P; Dimopoulos, P A; Tzingounis, V A

2001-12-01

Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge, while thyroid-stimulating hormone (TSH) response to TRH was diminished, and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus, with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.

Analysis of confiscated black market drugs using chromatographic and mass spectrometric approaches.

PubMed

Thevis, Mario; Schrader, Yvonne; Thomas, Andreas; Sigmund, Gerd; Geyer, Hans; Schänzer, Wilhelm

2008-04-01

In the context of house searches in Germany, numerous drugs were confiscated and subjected to chemical analysis, including anabolic agents such as various anabolic-androgenic steroids (stanozolol, testosterone derivatives, trenbolone esters, etc.) and clenbuterol, as well as agents with anti-estrogenic activity (tamoxifen, clomiphene), drugs stimulating virility (sildenafil, tadalafil), and unlabeled plastic bags. Liquid chromatography-tandem mass spectrometry, gas chromatography-mass spectrometry with nitrogen-phosphorus specific detection, gel electrophoresis, and immunological tests were employed to test for the effective content of 70 products. In 18 cases (25.7%), the declared ingredients differed from the actual content, in particular concerning anabolic-androgenic steroids. Nandrolone and trenbolone esters, for instance, were frequently substituted or complemented by various testosterone derivatives, and several testosterone depot formulations originally composed of four different esters were found to contain fewer or wrong components. Except for those drugs supposedly originating from so-called underground labs, fake packings were hardly or not distinguishable from original boxes by visual inspection.

Hormonal Changes After Laparoscopic Ovarian Diathermy in Patients with Polycystic Ovarian Syndrome.

PubMed

Elnaggar, Elsayed A; Elwan, Youssef Abo; Ibrahim, Safaa A; Abdalla, Mena M

2016-10-01

To assess the changes in hormonal profile (serum FSH, LH, prolactin and total testosterone) following laparoscopic ovarian drilling (LOD) in patients with polycystic ovarian syndrome. Fifty patients with PCOS have been included in this study. Serum prolactin, total testosterone, follicular-stimulating hormone (FSH) and luteinizing hormone (LH) levels have been used as biochemical markers, before and after procedures. Laparoscopic ovarian drilling was successfully employed without any surgical complications and on an average follow-up time of 24 weeks after the procedure. During the follow-up serum values for prolactin, total testosterone and LH have decreased significantly and FSH levels remained unchanged after the procedure. The LOD in patients with PCOS may avoid or reduce the risk of OHSS and the multiple pregnancy rate induced by gonadotropin therapy. The high pregnancy rate and the economic aspect of the procedure offer an attractive management for patients with PCOS. However, LOD can be considered as second-line treatment after clomiphene citrate treatment failure and/or resistance.

Effects of previous ovarian surgery on the follicular response to ovulation induction in an in vitro fertilization program.

PubMed

Hornstein, M D; Barbieri, R L; McShane, P M

1989-04-01

This study examined the effects of previous ovarian surgery on the clinical response to ovulation induction with clomiphene citrate-human menopausal gonadotropin in an in vitro fertilization program. Patients were divided into five clinical groups: group A (n = 63), no previous ovarian surgery; B (n = 9), unilateral cystectomy; C (n = 6), unilateral oophorectomy with no contralateral ovarian surgery; D (n = 7), bilateral ovarian surgery with both ovaries present; and E (n = 4), unilateral oophorectomy and contralateral cystectomy. Patients in group E demonstrated significantly lower serum estradiol on cycle days 9-11 (P less than or equal to .05) and fewer follicles on cycle days 11-12 (P less than or equal to .05) than did patients in groups A-D. The percentage of cancelled cycles increased with increasing amounts of ovarian surgery (P less than or equal to .03). The study suggests that one cause of a poor response to ovulation induction for in vitro fertilization may be prior extensive ovarian surgery.

Brachial-to-ankle pulse wave velocity as an independent prognostic factor for ovulatory response to clomiphene citrate in women with polycystic ovary syndrome

PubMed Central

2014-01-01

Background Polycystic ovary syndrome (PCOS) has a risk for cardiovascular disease. Increased arterial stiffness has been observed in women with PCOS. The purpose of the present study was to investigate whether the brachial-to-ankle pulse wave velocity (baPWV) is a prognostic factor for ovulatory response to clomiphene citrate (CC) in women with PCOS. Methods This study was a retrospective cohort study of 62 women with PCOS conducted from January 2009 to December 2012 at the university hospital, Yamagata, Japan. We analyzed 62 infertile PCOS patients who received CC. Ovulation was induced by 100 mg CC for 5 days. CC non-responder was defined as failure to ovulate for at least 2 consecutive CC-treatment cycles. The endocrine, metabolic, and cardiovascular parameters between CC responder (38 patients) and non-responder (24 patients) groups were analyzed. Results In univariate analysis, waist-to-hip ratio, level of free testosterone, percentages of patients with dyslipidemia, impaired glucose tolerance, and diabetes mellitus, blood glucose and insulin levels at 60 min and 120 min, the area under the curve of glucose and insulin after 75-g oral glucose intolerance test, and baPWV were significantly higher in CC non-responders compared with responders. In multivariate logistic regression analysis, both waist-to-hip ratio (odds ratio, 1.77; 95% confidence interval, 2.2–14.1; P = 0.04) and baPWV (odds ratio, 1.71; 95% confidence interval, 1.1–2.8; P = 0.03) were independent predictors of ovulation induction by CC in PCOS patients. The predictive values of waist-to-hip ratio and baPWV for the CC resistance in PCOS patients were determined by the receiver operating characteristic curves. The area under the curves for waist-to-hip ratio and baPWV were 0.76 and 0.77, respectively. Setting the threshold at 0.83 for waist-to-hip ratio offered the best compromise between specificity (0.65) and sensitivity (0.84), while the setting the threshold at 1,182 cm/s for baPWV offered the best compromise between specificity (0.80) and sensitivity (0.71). Conclusions Both metabolic and cardiovascular parameters were predictive for CC resistance in PCOS patients. The measurement of baPWV may be a useful tool to predict ovulation in PCOS patients who receive CC. PMID:25024746

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial

PubMed Central

2013-01-01

Background Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. Methods/Design We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI. Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included. Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total). An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). Discussion The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women. Trial registration number Netherlands Trial register NTR1449 PMID:24160333

Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal pregnancy outcomes compared with the standard progestin-primed ovarian stimulation in infertile women with polycystic ovarian syndrome.

PubMed

Ye, Hongjuan; Tian, Hui; He, Wen; Lyu, Qifeng; Kuang, Yanping; Chen, Qiuju; Sun, Lihua

2018-05-28

Oral progestin has recently been used to prevent premature LH surges in ovarian stimulation, and this progestin-primed ovarian stimulation (PPOS) is effective and safe in patients with different ovarian reserves. The current data are lacking regarding how to individualize the gonadotropin dose and regimen for women with polycystic ovarian syndrome (PCOS). A retrospective cohort trial was performed to evaluate the efficacy of progestin-primed milder stimulation with clomiphene citrate (CC) compared to the standard progestin-primed ovarian stimulation (PPOS) protocol for infertile women with PCOS. A total of 220 PCOS women were collected and classified into the study group (HMG 150 IU/d + CC 50 mg/d + MPA 10 mg/d) and control group (HMG 225 IU/d + MPA 10 mg/d). Ovulation was triggered by GnRH agonist 0.1 mg and hCG 1000 IU when dominant follicles matured. Viable embryos were cryopreserved for later transfer. The primary endpoint was the ongoing pregnancy rate. Secondary outcomes included the cycle characteristics and the live birth rate. The study group consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± 372.0 IU, P < 0.001) and harvested fewer oocytes than the control group (12.2 ± 7.4 vs 18.2 ± 9.7, P < 0.001). The study group showed a higher mid-follicular LH concentration (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 mIU/ml, P < 0.05) but no endogenous LH surge. No between-group difference was found in the incidence of ovarian hyperstimulation syndrome (OHSS) (0.91% vs 0.91%, P > 0.05). The cumulative ongoing pregnancy rate and live birth rate per patient were lower but did not reach significance compared with the control group (71.8% vs 81.8 and 64.5% vs 75.5%, respectively, both P > 0.05). The milder PPOS with CC in PCOS women led to lower oocyte yields and suboptimal pregnancy outcomes compared to the standard PPOS treatment. The two regimens both achieved a low incidence of OHSS. The results from the CC combination regimen provide a new insight for developing a more patient-friendly protocol for PCOS women.

Prolactin release, oestrogens and proliferation of prolactin-secreting cells in the anterior pituitary gland of adult male rats.

PubMed

Pérez, R L; Machiavelli, G A; Romano, M I; Burdman, J A

1986-03-01

Relationships among the release of prolactin, the effect of oestrogens and the proliferation of prolactin-secreting cells were studied under several experimental conditions. Administration of sulpiride or oestradiol released prolactin and stimulated cell proliferation in the anterior pituitary gland of adult male rats. Clomiphene completely abolished the rise in cell proliferation, but did not interfere with the sulpiride-induced release of prolactin. Treatment with oestradiol plus sulpiride significantly increased serum prolactin concentrations and the mitotic index compared with the sum of the stimulation produced by both drugs separately. Bromocriptine abolished the stimulatory effect of oestradiol on the serum prolactin concentration and on cell proliferation. In oestradiol- and/or sulpiride-treated rats, 80% of the cells in mitoses were lactotrophs. The remaining 20% did not stain with antisera against any of the pituitary hormones. The number of prolactin-secreting cells in the anterior pituitary gland significantly increased after the administration of oestradiol or sulpiride. The results demonstrate that treatment with sulpiride and/or oestradiol increases the proliferation and the number of lactotrophs in the anterior pituitary gland of the rat.

Dexamethasone in unexplained infertility.

PubMed

Moradan, Sanam; Ghorbani, Raheb

2009-08-01

To determine if dexamethasone could be a suitable option in the treatment of patients with unexplained infertility. This study was carried out in the Obstetrics Department of Amir University Hospital, Semnan, Iran, from April 2001 to May 2008. One hundred and twenty-four cases of unexplained infertility that underwent ovulation induction and intrauterine insemination (IUI) (only one cycle) were evaluated, and divided into 2 groups. Sixteen cases were excluded, as they were unresponsive to the induction ovulation regimen. Group I (n=42) received clomiphene citrate (CC) + dexamethasone, and the control group (group II, n=66) received CC alone. These groups were the same in age, duration of infertility, and body mass index. The clinical pregnancy rates were evaluated in 2 groups by using statistical tests. The clinical pregnancy rate was 21.4% in group I, and 4.5% in group II. There was a significant statistical difference between the groups (relative risk=4.71, 95% confidence interval=1.35-16.42, p=0.0085). The pregnancy rate in women with unexplained infertility that underwent ovulation induction with CC + dexamethasone + IUI was significantly higher than those who underwent ovulation induction with CC alone + IUI.

Melatonin in human preovulatory follicular fluid

NASA Technical Reports Server (NTRS)

Brzezinski, Amnon; Seibel, Machelle M.; Lynch, Harry J.; Deng, Mei-Hua; Wurtman, Richard J.

1987-01-01

Melatonin, the major hormone of the pineal gland, has antigonadotrophic activity in many mammals and may also be involved in human reproduction. Melatonin suppresses steroidogenesis by ovarian granulosa and luteal cells in vitro. To determine if melatonin is present in the human ovary, preovulatory follicular fluids (n = 32) from 15 women were assayed for melatonin by RIA after solvent extraction. The fluids were obtained by laparoscopy or sonographically controlled follicular puncture from infertile women undergoing in vitro fertilization and embryo transfer. All patients had received clomiphene citrate, human menopausal gonadotropin, and hCG to stimulate follicle formation. Blood samples were obtained by venipuncture 30 min or less after follicular aspiration. All of the follicular fluids contained melatonin, in concentrations (35.6 plus or minus 4.8 (plus or minus SEM) pg/mL) substantially higher than those in the corresponding serum (10.0 plus or minus 1.4 pg/mL). A positive correlation was found between follicular fluid and serum melatonin levels in each woman (r = 0.770; P less than 0.001). These observations indicate that preovulatory follicles contain substantial amounts of melatonin that may affect ovarian steroidogenesis.

The function of the corpus luteum of pregnancy in ovulatory dysfunction and luteal phase deficiency.

PubMed

Soules, M R; Hughes, C L; Aksel, S; Tyrey, L; Hammond, C B

1981-07-01

Relatively little knowledge exists of corpus luteum function in early pregnancy after the successful treatment of ovulatory dysfunction or luteal phase deficiency. To assess the activity of the corpus luteum of such patients, human chorionic gonadotropin (hCG) and 17-hydroxyprogesterone (17-OH-P) levels were determined in serum samples obtained from normal women (44 patients), women with ovulatory dysfunction (10 patients), and women with luteal phase deficiency (7 patients); all determinations were made during conceptive cycles, and sampling continued into the first trimester of pregnancy. There were no statistically significant abnormalities of hCG levels when infertility patients were compared with control patients. According to the premise that 17-OH-P levels reflect corpus luteal function, there appeared to be adequate function in pregnancies after progesterone treatment of luteal phase deficiency. In pregnancies following ovulation induction with clomiphene, the corpus luteum function, on the basis of 17-OH-P levels, was significantly increased in magnitude and duration. These results have clinical implications with regard to supplemental hormone therapy in early pregnancy.

[Electroacupuncture Combined with Clomiphene Promotes Pregnancy and Blastocyst Implantation Possibly by Up-regulating Expression of Insulin Receptor and Insulin Receptor Substrate 1 Proteins in Endometrium in Rats with PCOS].

PubMed

Lai, Mao-Hua; Ma, Hong-Xia; Song, Xing-Hua

2016-10-25

To observe the effect of electroacupuncture (EA) intervention combined with clomiphene critate (CC) on the blastocyst implantation and pregnancy rate and expression of insulin receptor (INSR) and insulin receptor substrate 1 (IRS 1) proteins in the endometrium in rats with polycystic ovary syndrome (PCOS), so as to reveal its mechanisms underlying improvement of PCOS. One hundred and twenty-five female SD rats were randomly divided into normal control, PCOS model, medication (CC), EA and EA+CC groups ( n =25 in each group, 15 for checking blastocyst implantation, and 10 for Western blot). The PCOS model was established by subcutaneous injection of Dehydroepiandrosterone (DHEA) and fed with high-fat diet. Rats of the normal control group were treated by subcutaneous injection of sesame oil and fed with the normal forage. EA stimulation was applied to "Zhongwan" (CV 12), "Guanyuan" (CV 4) and bilateral "Tianshu" (ST 25) for 30 min, 3 times a week, 5 weeks altogether. Rats of the CC and EA+CC groups were fed with CC (100 mg·kg -1 ·d -1 ) for 2 days after regular restriction (30 min, 3 times a week, 5 weeks altogether). The pregnancy was determined by vaginal smear tests and the number of blastocyst implantation determined by examination of the uterus after execution. The expression of INSR and IRS 1 proteins in the endometrium was detected by Western blot. The pregnancy rate and the number of blastocyst implantation were significantly lower in the model group than in the normal control group ( P <0.05), and remarkably increased after EA and EA+CC interventions ( P <0.05). The effects of EA+CC were obviously superior to those of simple EA and simple medication in raising the pregnancy rate and the number of blastocyst implantation ( P <0.05). No significant differences were found between the EA and CC groups in the pregnancy rate and the number of blastocyst implantation ( P >0.05). The relative expression levels of both INSR and IRS 1 proteins were markedly lower in the model group than in the normal control group ( P <0.05), and significantly higher in both EA and EA+CC groups than in the model group ( P <0.05). No significant differences were found between the model and the CC groups and between the EA and EA+CC groups in the expression levels of INSR and IRS 1 proteins ( P >0.05). EA intervention can improve pregnancy rate and the number of blastocyst implantation in PCOS rats, which may be related to its effects in up-regulating the expression of INSR and IRS 1 proteins in the endometrium.

Intra-uterine insemination: pregnancy rate in relation to number, size of pre-ovulatory follicles and day of insemination.

PubMed

Karuppaswamy, J; Smedley, Mamin; Carter, Lindsay

2009-03-01

The objective of the study was to analyse the pregnancy rate in intra-uterine insemination (IUI) in relation to pre-ovulatory follicular number, size and day of insemination. A retrospective analysis of 216 completed IUI cycles was used in an attempt to identify significant variables predictive of treatment success. Couples with unexplained infertility and male factor infertility underwent IUI with or without ovarian stimulation. The mean number of IUI cycles per patient was 4.1, the overall pregnancy rate was 27.3% per patient, and the pregnancy rate per cycle was 6.9%. The pregnancy rate was 4.4% when one follicle was produced, whereas with more than two follicles, the rate increased to 21.2%. Hormonal stimulation using clomiphene citrate and/or human menopausal gonadotrophin/follicle stimulating hormone yielded a significant higher pregnancy rate compared to IUI in natural cycles (10.3% versus 3.3%). Although not statistically significant, the pregnancy rate decreased with advancing age of woman. The results suggest that IUI is a useful method of assisted conception in unexplained infertility and higher pregnancy rates can be achieved with good patient selection and ovarian stimulation.

Cryosurgery of genital warts in cases in which podophyllin treatment failed or was contraindicated.

PubMed Central

Ghosh, A K

1977-01-01

A total of 56 cases with warts in which podophyllin treatment was either contraindicated or a failure, were treated with nitrous oxide using a Keymed 500 cryosurgical appliance. Forty-three patients who completed treatment were followed-up for three months. Thirty-seven of these had received applications of podophyllin twice weekly for an average period of three months before cryosurgery. The remaining cases in whom podophyllin was considered to be contraindicated included five with vulval warts (two were pregnant, two were bronchial asthmatics taking oral prednisolone, and one was taking oral clomiphene citrate), and a diabetic patients with penile warts. Thirty-two were cured and 11 relapsed. The latter were re-treated at the end of the follow-up period with two freezing cycles of 45 seconds at an interval of 30 minutes. Seven were cured and the remaining four men who failed to respond belonged to the podophyllin-resistant group and included three with metal warts and one homosexual with anogenital warts. Cryosurgery gave a cumulative success rate of 91%. A single freezing cycle was free from complications but a double freezing cycle was often followed by severe local reaction. Images PMID:843897

Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study

PubMed Central

Giagulli, Vito Angelo; Baccini, Margherita; Fanelli, Flaminia; Mezzullo, Marco; Fazzini, Alessia; Bianchi, Nicola; Carbone, Matteo Domenico; De Pergola, Giovanni; Mastroroberto, Marianna; Morselli Labate, Antonio Maria; Pasquali, Renato

2017-01-01

Context Low testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate. Objective To evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET). Design Cross-over, randomized, double-blind, placebo-controlled study. Methods 24 obese men, aged 47.3 ±. 6.3 (range 35–55 years), with low T level (≤3 ng/mL) and naïve diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment. Results Of 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03±0.80 to 5.99±1.67 ng/mL P<0.001) but not after the Plac treatment (2.87±0.78 to 3.09±0.84 ng/mL P<0.001 between the treatments). T changes were similar in IGT and T2DM subjects. Gonadotropins as well raised significantly after CC treatment (LH 3.83±1.45 to 8.53±6.40 mU/mL; FSH 4.84±1.67 to 10.15±5.08 mU/mL P<0.001 respectively), whereas no changes for LH (3.51±1.59 to 3.63±1.39 mU/mL) but a smooth increased for FSH (4.61±2.49 to 5.39±2.65 mU/mL; P = 0.004) were shown after Plac treatment (LH P = 0.001 and FSH P = 0.002 between treatments). Furthermore, fasting glucose (106.8±23.2 to 101.1±25.7 mg/dL; P = 0.004), insulin (19.3±12.1 to 15.6±10.1 μU/mL; P = 0.010) and HOMA-IR (4.94±2.89 to 3.69±2.12; P = 0.001) decreased significantly during the CC treatment period, whereas no significant changes were observed in any of these parameters in the Plac treatment. Conclusions A low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters. Trial registration EudraCT 2011-000439-10 PMID:28886024

Effect of simultaneously started clomiphene citrate and gonadotropins in antagonist regimes, on cumulative live births, fresh-cycle live births and cost of stimulation in IVF cycles.

PubMed

Satwik, Ruma; Kochhar, Mohinder

2018-04-11

The aim of the study was to compare simultaneously started clomiphene citrate (CC) and gonadotropins (Gn) with gonadotropins alone in conventional antagonist regimes with respect to fresh-cycle live births, cumulative live births and cost of ovarian stimulation per started cycle. This was a single-center prospective cohort study conducted over 1 year. Women undergoing autologous in vitro fertilization (IVF) treatment in antagonist protocols and who consented to participate in the study were divided into two cohorts. The CC cohort (n = 86) received 50 mg CC for 5 days and individualized Gn daily until the hCG trigger, both starting from day 2 and antagonist daily from day 8 of menstrual cycle. The Gn-only cohort (n = 349) received individualized Gn from day 2 and the antagonist from day 7 of menstrual cycle. IVF outcomes and cost of stimulation were compared between two cohorts across expected ovarian response categories. The CC cohort used a mean lower dose of Gn (1741.38 ± 604.46 vs 1980.54 ± 686.42; MD = -239.16; 95%CI = -348.03 to -189.24; P = 0.003) over fewer days (8.54 ± 1.86 vs 9.25 ± 1.97; MD =-0.71;95% CI = -1.17 to -0.25; P = 0.0026) to achieve similar retrieved oocytes, (9.19 ± 5.92 vs 9.36 ± 6.96; MD = -0.17; 95%CI -1.77 to + 1.43; P = 0.83), positive bhCG rates (40% vs 29.6%, MD = 10.4%; OR = 1.65, 95%CI = 0.95-2.86; P = 0.078) and live births in fresh cycles (32.31% vs 21.30%; MD = 11.01%; OR = 1.76; 95%CI = 0.97-3.19; P = 0.06) and cumulative live births per initiated cycle (30.23% vs 20.34%; MD = 9.89%; OR = 1.697; 95%CI = 0.99-2.88; P = 0.0501). The dose lowering achieved a 28-40% reduction in the cost of stimulation, which was most noticeable in the hyper-responder category for both hMG cycles, (Rs.11 602.3 ± 3365.9 vs 19615 ± 2677.1; MD = -8012.7; %age reduction: 40.8%; P = 0.0007) and recombinant FSH cycles (Rs. 22 459.6 ± 6255.3 vs 33 022.1 ± 9891.2; MD: -10 562; %age reduction: -32%; P = 0.0001). CC started simultaneously with Gn in antagonist regimes helps lower the cost of stimulation without affecting IVF outcomes. © 2018 Japan Society of Obstetrics and Gynecology.

Therapeutic approach for metabolic disorders and infertility in women with PCOS.

PubMed

Morgante, G; Massaro, M G; Di Sabatino, A; Cappelli, V; De Leo, V

2018-01-01

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10% of women of reproductive age. It generally shows with oligo/amenorrhea, anovulatory cycles, clinical o biochemical hirsutism, polycystic ovaries and, in a significant percentage of cases, insulin resistance. PCOS is defined as a multifactorial pathology, determined by the association of many factors: genetic, endocrine and environmental. The first and most effective treatment of PCOS is to change life-style and lose weight. The use of oral contraceptives has been shown effective in reducing acne and hirsutism and regulates the menstrual cycle. For women with severe hirsutism, the addition of antiandrogens to estrogen-progestin therapy has significantly improved the results. In cases of anovulatory infertility, the drug of first choice is clomiphene citrate, followed by low-dose gonadotropins. Recently, insulin-sensitizing drugs have been widely prescribed for PCOS patients. They are particularly effective in reducing insulin resistance and improving ovulatory performance. Besides insulin-sensitizing drugs, natural substances, such as inositol, seems to have good efficacy, similar to metformin with fewer side effects. New substances that could be used include statins and natural statins, such as monakolin, alone or combined with myo-inositol. These substances do not have side effects and greatly reduce the hyperandrogenic component in these patients.

Endometrial Scratch Injury Induces Higher Pregnancy Rate for Women With Unexplained Infertility Undergoing IUI With Ovarian Stimulation: A Randomized Controlled Trial.

PubMed

Maged, Ahmed M; Al-Inany, Hesham; Salama, Khaled M; Souidan, Ibrahim I; Abo Ragab, Hesham M; Elnassery, Noura

2016-02-01

To explore the impact of endometrial scratch injury (ESI) on intrauterine insemination (IUI) success. One hundred and fifty four infertile women received 100 mg of oral clomiphene citrate for 5 days starting on day 3 of the menstrual cycle. Patients were randomized to 2 equal groups: Group C received IUI without ESI and group S had ESI. Successful pregnancy was confirmed by ultrasound. 13, 21, and 10 women got pregnant after the first, second, and third IUI trials, respectively, with 28.6% cumulative pregnancy rate (PR). The cumulative PR was significantly higher in group S (39%) compared to group C (18.2%). The PR in group S was significantly higher compared to that in group C at the second and third trials. The PR was significantly higher in group S at the second trial compared to that reported in the same group at the first trial but nonsignificantly higher compared to that reported during the third trial, while in group C, the difference was nonsignificant. Eight pregnant women had first trimester abortion with 18.2% total abortion rate with nonsignificant difference between studied groups. The ESI significantly improves the outcome of IUI in women with unexplained infertility especially when conducted 1 month prior to IUI. © The Author(s) 2015.

Malignant melanoma risk after exposure to fertility drugs: results from a large Danish cohort study.

PubMed

Hannibal, Charlotte Gerd; Jensen, Allan; Sharif, Heidi; Kjaer, Susanne Krüger

2008-09-01

The aim was to examine the effects of fertility drugs on malignant melanoma risk using data from the largest cohort of infertile women to date. A cohort of 54,362 women with infertility problems referred to Danish fertility clinics in the period 1963-1998 was established. A detailed data collection including information about type and amount of treatment was conducted. Using case-cohort techniques, we calculated rate ratios (RRs) of malignant melanoma associated with different fertility drugs after adjustment for parity status. 112 malignant melanomas were identified during follow-up through 2000. Use of clomiphene, gonadotrophins, hCG or GnRH did not affect risk of malignant melanoma significantly. When stratifying for parity, however, use of gonadotrophins (RR = 2.29; CI: 1.16-4.52) or GnRH (RR = 3.26; 95% CI: 1.50-7.09) among parous women was associated with a significant increased risk. For all groups of fertility drugs, we found no association with number of cycles of use or years since first use (latency). Our findings showed no strong association between malignant melanoma risk and use of fertility drugs, although the results indicated that use of gonadotrophins or GnRH might increase risk in parous women. Longer follow-up is needed to confirm our findings.

Emerging medication for the treatment of male hypogonadism.

PubMed

Aydogdu, Aydogan; Swerdloff, Ronald S

2016-09-01

Male hypogonadism is characterized by inadequate production of Testosterone (T) (hypoandrogenism) and deficiencies in spermatogenesis. The main treatment of male hypogonadism is T replacement therapy (TRT), but for some of the patients, alternative drugs may be more suitable. The available literature of T and alternative treatments for male hypogonadism are discussed. Transdermal application of T gels are the most commonly used route of T administration. Some oral T formulations are either associated with hepatic toxicity (i.e. methyltestosterone) or short half-lives that require multiple doses per day (i.e. oral testosterone undecanoate). Short acting, injectable T formulations are also available. If the patient prefers not to use daily drugs or short acting injectable formulations, depot formulations such as injectable testosterone undecanoate (TU) may be a good alternative. If the patient has hypogonadotropic hypogonadism and desires fertility or if he is adolescent, instead of TRT, gonadotropins can be started to stimulate testicular growth and spermatogenesis. In obese patients or for the patients having high risks for TRT, off label aromatase inhibitors (AI) and clomiphene citrate (CC), may be considered to stimulate LH, FSH and T levels. In patients with high prostate disease risk, selective androgen receptor modulators may be an alternative treatment but these latter treatments have not had high level evidence.

Impact of transvaginal hydrolaparoscopy ovarian drilling on ovarian stromal blood flow and ovarian volume in clomiphene citrate-resistant PCOS patients: a case-control study.

PubMed

Giampaolino, Pierluigi; Morra, Ilaria; De Rosa, Nicoletta; Cagnacci, Angelo; Pellicano, Massimiliano; Di Carlo, Costantino; Nappi, Carmine; Bifulco, Giuseppe

2017-09-01

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in gynecology. In PCOS patients vascularization parameters are altered. Transvaginal hydrolaparoscopy (THL) is a mini-invasive approach for ovarian drilling in PCOS patients. In this study, we assessed the effect of ovarian drilling using THL on ovarian volume (OV) and vascularization index (VI) using 3D power Doppler ultrasonography in CC-resistant PCOS patients. A case-control study on 123 CC-resistant PCOS women who underwent THL ovarian drilling was performed. Patients underwent 3D ultrasound and power Doppler to measure VI, flow index (FI), vascularization flow index (VFI) and to evaluate OV before and after the procedure, at six months, and on the early follicular phase of the menstrual cycle. After THL ovarian drilling, OV and power Doppler flow indices were significantly reduced compared to pre-operative values (OV: 7.85 versus 11.72 cm 3 , p < 0.01; VI: 2.50 versus 4.81, p < 0.01; VFI: 1.10 versus 2.16, p < 0.01; FI: 32.05 versus 35.37, p < 0.01). In conclusion, THL ovarian drilling seems to reduce OV and 3D power Doppler indices, and could therefore be a viable alternative to LOD in PCOS patients resistant to medical therapy.

Extrauterine Choriocarcinoma in the Fallopian Tube Following Infertility Treatment: Implications for the Management of Early-Detected Ectopic Pregnancies.

PubMed

Jwa, Seung Chik; Kamiyama, Shigeru; Takayama, Hisako; Tokunaga, Yoshimitsu; Sakumoto, Tetsuro; Higashi, Masahiro

Extrauterine choriocarcinoma in the fallopian tube is very rare and is often diagnosed and treated as an ectopic tubal pregnancy. A 34-year-old woman who initially became pregnant after infertility treatment using ovulation induction with clomiphene citrate and intrauterine insemination was later diagnosed with an extrauterine choriocarcinoma in the left fallopian tube. Because of suspected left ectopic tubal pregnancy based on ultrasonography findings and a high level of β-human chorionic gonadotropin (β-hCG; 7054.3 mIU/mL), the patient underwent diagnostic laparoscopy at a gestational age of 6 weeks. Left salpingectomy was performed based on the operative diagnosis of an ectopic tubal pregnancy. No signs of tubal rupture or leakage of contents from the fallopian tube were observed during the operation. Her serum β-hCG dropped to 10.3 mIU/mL at 15 days postoperatively. Histopathology demonstrated an extrauterine choriocarcinoma in the removed fallopian tube, and the patient was referred to a regional oncologic hospital to receive additional adjuvant chemotherapy. This case indicates that conservative treatment for ectopic pregnancy should be chosen carefully, and that histopathology diagnosis and appropriate β-hCG monitoring following treatment are important not only to diagnose persistent ectopic pregnancy, but also to rule out the possibility of a tubal choriocarcinoma. Copyright © 2017 AAGL. Published by Elsevier Inc. All rights reserved.

Metabolic Syndrome: Polycystic Ovary Syndrome.

PubMed

Mortada, Rami; Williams, Tracy

2015-08-01

Polycystic ovary syndrome (PCOS) is a heterogeneous condition characterized by androgen excess, ovulatory dysfunction, and polycystic ovaries. It is the most common endocrinopathy among women of reproductive age, affecting between 6.5% and 8% of women, and is the most common cause of infertility. Insulin resistance is almost always present in women with PCOS, regardless of weight, and they often develop diabetes and metabolic syndrome. The Rotterdam criteria are widely used for diagnosis. These criteria require that patients have at least two of the following conditions: hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The diagnosis of PCOS also requires exclusion of other potential etiologies of hyperandrogenism and ovulatory dysfunction. The approach to PCOS management differs according to the presenting symptoms and treatment goals, particularly the patient's desire for pregnancy. Weight loss through dietary modifications and exercise is recommended for patients with PCOS who are overweight. Oral contraceptives are the first-line treatment for regulating menstrual cycles and reducing manifestations of hyperandrogenism, such as acne and hirsutism. Clomiphene is the first-line drug for management of anovulatory infertility. Metformin is recommended for metabolic abnormalities such as prediabetes, and a statin should be prescribed for cardioprotection if the patient meets standard criteria for statin therapy. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Epidemiology, diagnosis, and management of polycystic ovary syndrome.

PubMed

Sirmans, Susan M; Pate, Kristen A

2013-12-18

Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism, and polycystic ovaries. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but is as high as 15%-20% when the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria are used. Clinical manifestations include oligomenorrhea or amenorrhea, hirsutism, and frequently infertility. Risk factors for PCOS in adults includes type 1 diabetes, type 2 diabetes, and gestational diabetes. Insulin resistance affects 50%-70% of women with PCOS leading to a number of comorbidities including metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes. Studies show that women with PCOS are more likely to have increased coronary artery calcium scores and increased carotid intima-media thickness. Mental health disorders including depression, anxiety, bipolar disorder and binge eating disorder also occur more frequently in women with PCOS. Weight loss improves menstrual irregularities, symptoms of androgen excess, and infertility. Management of clinical manifestations of PCOS includes oral contraceptives for menstrual irregularities and hirsutism. Spironolactone and finasteride are used to treat symptoms of androgen excess. Treatment options for infertility include clomiphene, laparoscopic ovarian drilling, gonadotropins, and assisted reproductive technology. Recent data suggest that letrozole and metformin may play an important role in ovulation induction. Proper diagnosis and management of PCOS is essential to address patient concerns but also to prevent future metabolic, endocrine, psychiatric, and cardiovascular complications.

Rapid determination of anti-estrogens by gas chromatography/mass spectrometry in urine: Method validation and application to real samples.

PubMed

Gerace, E; Salomone, A; Abbadessa, G; Racca, S; Vincenti, M

2012-02-01

A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone) plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid-liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS) after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4 min, allowing a processing rate of 10 samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti-estrogenic drug administration.

Rapid determination of anti-estrogens by gas chromatography/mass spectrometry in urine: Method validation and application to real samples

PubMed Central

Gerace, E.; Salomone, A.; Abbadessa, G.; Racca, S.; Vincenti, M.

2011-01-01

A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone) plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid–liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS) after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4 min, allowing a processing rate of 10 samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti-estrogenic drug administration. PMID:29403714

The Pregnancy in Polycystic Ovary Syndrome Study II: Baseline Characteristics and Effects of Obesity from a Multi-Center Randomized Clinical Trial

PubMed Central

Legro, Richard S.; Brzyski, Robert G.; Diamond, Michael P.; Coutifaris, Christos; Schlaff, William D.; Alvero, Ruben; Casson, Peter; Christman, Gregory M.; Huang, Hao; Yan, Qingshang; Haisenleder, Daniel J.; Barnhart, Kurt T.; Bates, G. Wright; Usadi, Rebecca; Lucidi, Richard; Baker, Valerie; Trussell, J.C.; Krawetz, Stephen A.; Snyder, Peter; Ohl, Dana; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

2014-01-01

Objective To summarize baseline characteristics from a large multi-center infertility clinical trial. Design Cross-sectional baseline data from a double-blind randomized trial of 2 treatment regimens (letrozole vs. clomiphene). Setting Academic Health Centers throughout the U.S. Interventions None Main Outcome Measure(s) Historical, biometric, biochemical and questionnaire parameters. Participants 750 women with PCOS and their male partners took part in the study. Results Females averaged ~30 years old and were obese (BMI 35) with ~20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). . Most of the females had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH:FSH ratio (~2), and AMH levels (8.0 ng/mL). Additionally, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH:FSH levels, AMH levels and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Males were obese (BMI 30) and had normal mean semen parameters. Conclusions The treatment groups were well-matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators. PMID:24156957

Effect of rejuvenation hormones on spermatogenesis.

PubMed

Moss, Jared L; Crosnoe, Lindsey E; Kim, Edward D

2013-06-01

To review the current literature for the effect of hormones used in rejuvenation clinics on the maintenance of spermatogenesis. Review of published literature. Not applicable. Men who have undergone exogenous testosterone (T) and/or anabolic androgenic steroid (AAS) therapies. None. Semen analysis, pregnancy outcomes, and time to recovery of spermatogenesis. Exogenous testosterone and anabolic androgenic steroids suppress intratesticular testosterone production, which may lead to azoospermia or severe oligozoospermia. Therapies that protect spermatogenesis involve human chorionic gonadotropin (hCG) therapy and selective estrogen receptor modulators (SERMs). The studies examining the effect of human growth hormone (HGH) on infertile men are uncontrolled and unconvincing, but they do not appear to negatively impact spermatogenesis. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. The use of hormones for rejuvenation is increasing with the aging of the Baby Boomer population. Men desiring children at a later age may be unaware of the side-effect profile of hormones used at rejuvenation centers. Testosterone and anabolic androgenic steroids have well-established detrimental effects on spermatogenesis, but recovery may be possible with cessation. Clomiphene citrate, human growth hormone (HGH)/insulin-like growth factor-1 (IGF-1), human chorionic gonadotropin (hCG), and aromatase inhibitors do not appear to have significant negative effects on sperm production, but quality data are lacking. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evaluation of filovirus entry inhibitors.

PubMed

Chen, Qing; Tang, Ke; Zhang, Xiaoyu; Chen, Panpan; Guo, Ying

2018-03-01

Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4 (BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and drugs. An HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here, we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day 4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious in vitro . The pseudo-filovirus-infection mouse models can be used for in vivo activity evaluation of anti-filovirus drugs. This sequential in vitro and in vivo evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities.

Novel strategies in the management of polycystic ovary syndrome.

PubMed

Spritzer, P M; Motta, A B; Sir-Petermann, T; Diamanti-Kandarakis, E

2015-09-01

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting reproductive-aged women. PCOS has been recognized as a syndrome combining reproductive and metabolic abnormalities with lifelong health implications. Cardiometabolic alterations require regular screening and effective and targeted lifestyle advice to lose weight as well as to prevent weight gain. Pharmacological therapy includes insulin-sensitizer drugs and agents that act directly on metabolic comorbidities, such as statins and antiobesity drugs. Bariatric surgery may be an option for severely obese women with PCOS Regarding reproductive aspects, ovulation induction with antiestrogens such as clomiphene citrate or letrozole is the first-line medical treatment. Exogenous gonadotropins and in vitro fertilization (IVF) are recommended as second-line treatment for anovulatory infertility. Laparoscopic ovarian diathermy may be used in special cases and metformin is no longer recommended for ovulation induction. Combined oral contraceptives (OCs) are the first-line treatment for the management of menstrual irregularities in women not seeking pregnancy, also providing endometrial protection and contraception. Progestin-only pills or cyclical progestins are recommended for those with contraindications to OCs. Metformin is also considered a second-line choice for improving menstrual cycles in women presenting insulin-resistance and dysglicemia. Hirsutism requires cosmetic procedures and medical treatment with OCs. More severe cases may need anti-androgen drugs added to the OCs. In conclusion, strategies regarding the management of reproductive issues in PCOS encompass a tailored approach to individual needs of each patient.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis.

PubMed

Gadalla, M A; Huang, S; Wang, R; Norman, R J; Abdullah, S A; El Saman, A M; Ismail, A M; van Wely, M; Mol, B W J

2018-01-01

To compare the impact of clomiphene citrate (CC) vs other drug regimens on mid-cycle endometrial thickness (EMT), ovulation, pregnancy and live birth rates in women with World Health Organization (WHO) group II ovulatory disorders. We searched MEDLINE, EMBASE, Scopus, Web of Science, The Cochrane Central Register of Clinical Trials (CENTRAL) and the non-MEDLINE subset of PubMed from inception to December 2016 and cross-checked references of relevant articles. We included only randomized controlled trials (RCTs) comparing CC used alone vs other drug regimens for ovulation induction in women with WHO group II anovulation. Outcomes were mid-cycle EMT, ovulation, pregnancy and live birth rates. We pooled weighted mean differences (WMD) with 95% confidence intervals (CI) for continuous variables (EMT) and risk ratios (RR) with 95% CI for binary variables (ovulation, pregnancy and live birth rates). We retrieved 1718 articles of which 33 RCTs (4349 women, 7210 ovulation induction cycles) were included. In 15 RCTs that compared CC with letrozole, EMT was lower in the CC group (1957 women, 3892 cycles; WMD, -1.39; 95% CI, -2.27 to -0.51; I 2  = 100%), ovulation rates after CC and letrozole were comparable (1710 women, 3217 cycles; RR, 0.97; 95% CI, 0.90-1.04; I 2  = 47%), while CC led to a lower pregnancy rate (1957 women, 3892 cycles; RR, 0.78; 95% CI, 0.63-0.95; I 2  = 43%) and a lower live birth rate (RR, 0.70; 95% CI, 0.49-0.98; I 2  = 35%). In two RCTs that compared CC with CC plus metformin, EMT, ovulation and pregnancy rates were comparable (101 women, 140 cycles; WMD, -0.23; 95% CI, -0.92 to 0.45; I 2  = 78%; RR, 0.84; 95% CI, 0.67-1.06; I 2  = 0%; and RR, 0.79; 95% CI, 0.33-1.87; I 2  = 0%). In three studies that compared CC with CC plus N-acetyl cysteine (NAC), EMT was lower in the CC group (340 women, 300 cycles; WMD, -1.51; 95% CI, -1.98 to -1.04; I 2  = 45%). In two studies that compared CC with CC + nitric oxide (NO) donor, EMT was lower in the CC group (120 women, 304 cycles; WMD, -1.75; 95% CI, -2.08 to -1.41; I 2  = 0%). Compared with CC plus NO donor or NAC, CC showed statistically significant lower ovulation and pregnancy rates. Compared with tamoxifen in three studies, CC showed a tendency towards lower EMT (571 women, 844 cycles; WMD, -1.34; 95% CI, -2.70 to 0.01; I 2  = 96%) with comparable ovulation and pregnancy rates. In women with WHO group II ovulatory disorders, ovulation induction with CC might result in lower EMT than other ovulation induction regimens. Whether the lower EMT caused the lower pregnancy and live birth rates remains to be elucidated. Letrozole seems to be beneficial for these women. However, our findings should be interpreted with caution as the quality of evidence was very low. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Circulating anti-mullerian hormone as predictor of ovarian response to clomiphene citrate in women with polycystic ovary syndrome.

PubMed

Xi, Wenyan; Yang, Yongkang; Mao, Hui; Zhao, Xiuhua; Liu, Ming; Fu, Shengyu

2016-02-11

To investigate the impact of high circulating AMH on the outcome of CC ovulation induction in women with PCOS. This prospective cohort observational study included 81 anovulatory women with PCOS who underwent 213 cycles of CC ovarian stimulation. Serum AMH concentrations were measured on cycle day 3 before the commencement of CC in the first cycle, which were compared between responders and CC-resistant anovulation (CRA). Logistic regression analysis was applied to study the value of serum AMH for the prediction of ovarian responsiveness to CC stimulation. The receiver-operating characteristic (ROC) curve was used to evaluate the prognostic value of circulating AMH. Serum AMH levels. Women who ovulated after CC therapy had a significantly lower AMH compared with the CRA (5.34 ± 1.97 vs.7.81 ± 3.49, P < 0.001). There was a significant gradient increase of serum AMH levels with the increasing dose of CC required to achieve ovulation (P < 0.05). In multivariate logistic regression analysis, AMH was an independent predictor of ovulation induction by CC in PCOS patients. ROC curve analysis showed AMH to be a useful predictor of ovulation induction by CC in PCOS patients, having 92 % specificity and 65 % sensitivity when the threshold AMH concentration was 7.77 ng/ml. Serum AMH may be clinically useful to predict which PCOS women are more likely to respond to CC treatment and thus to direct the selection of protocols of ovulation induction.

Menstrual restoration in severe panhypopituitarism many years after cranial irradiation for suprasellar germinoma.

PubMed

Ito, Masanobu; Iwamoto, Ichiro; Hirano, Hirofumi; Douchi, Tsutomu

2015-07-01

We report a very rare case showing menstrual restoration in severe pan-hypopituitarism many years after cranial irradiation for suprasellar germinoma. A 30-year-old, almost primarily amenorrheic woman with severe panhypopituitarism presented with cyclic genital bleeding for the previous five months. She had menstruated once, when she was 13 years old. When she was 14 years old, she was diagnosed with a suprasellar germinoma measuring 10 mm in diameter, which led to diabetes insipidus. Cranial irradiation with a total dose of 24 Gy and chemotherapy resulted in complete tumor remission. She developed severe hypopituitarism [luteinizing hormone (LH) = 0.4 mIU/mL, follicle-stimulating hormone (FSH) = 1.7 mIU/mL, and serum estradiol (E2) level < 10 pg/mL]. She had received multiple hormone replacement therapies for many years. When she was 29 years old, she expressed a desire to become pregnant. Serum gonadotropin and E2 levels increased (LH = 5.8 mIU/mL, FSH = 5.9 mIU/mL, and E2 = 58 pg/mL). She conceived with clomiphene therapy, and then delivered a healthy baby. Eight months after parturition, her basal body temperature and serum progesterone levels indicated recovery of ovulatory cycles. Ten months after parturition, she also spontaneously conceived. Menstrual restoration is very rare in severe panhypopituitarism after cranial irradiation. A relatively low dose of irradiation and small tumor size may have contributed to the recovery of menstruation in our patient.

Epidemiology, diagnosis, and management of polycystic ovary syndrome

PubMed Central

Sirmans, Susan M; Pate, Kristen A

2014-01-01

Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism, and polycystic ovaries. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but is as high as 15%–20% when the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria are used. Clinical manifestations include oligomenorrhea or amenorrhea, hirsutism, and frequently infertility. Risk factors for PCOS in adults includes type 1 diabetes, type 2 diabetes, and gestational diabetes. Insulin resistance affects 50%–70% of women with PCOS leading to a number of comorbidities including metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes. Studies show that women with PCOS are more likely to have increased coronary artery calcium scores and increased carotid intima-media thickness. Mental health disorders including depression, anxiety, bipolar disorder and binge eating disorder also occur more frequently in women with PCOS. Weight loss improves menstrual irregularities, symptoms of androgen excess, and infertility. Management of clinical manifestations of PCOS includes oral contraceptives for menstrual irregularities and hirsutism. Spironolactone and finasteride are used to treat symptoms of androgen excess. Treatment options for infertility include clomiphene, laparoscopic ovarian drilling, gonadotropins, and assisted reproductive technology. Recent data suggest that letrozole and metformin may play an important role in ovulation induction. Proper diagnosis and management of PCOS is essential to address patient concerns but also to prevent future metabolic, endocrine, psychiatric, and cardiovascular complications. PMID:24379699

IVF endocrinology: the Edwards era.

PubMed

Hillier, Stephen G

2013-12-01

Through pioneering human IVF as a global infertility treatment, Robert Edwards and his clinical partner Patrick Steptoe launched the field of IVF endocrinology. Following repeated failures with oocytes collected in human menopausal gonadotrophin (HMG) primed cycles timed to injection of human chorionic gonadotrophin (HCG), the first successful IVF pregnancy came from a spontaneous menstrual cycle. Intensive endocrine monitoring was used to track pre-ovulatory follicular development and collect a single ripe egg timed to the natural LH surge. Despite this groundbreaking achievement, ovulation induction was clearly required to make IVF treatment clinically robust and reliable. Ovarian stimulation with clomiphene citrate was used to achieve the first maternity from a superovulated human IVF cycle in 1980. HMG/HCG regimens were then successfully introduced-including substitution of 'pure' follicle-stimulating hormone as the principal ovarian stimulant. The application and success of IVF treatment were dramatically enhanced by the introduction of gonadotrophin-releasing hormone analogues that enabled elective control of endogenous gonadotrophin release during ovarian stimulation. Programmed gonadotrophin regimes yielding double-digit oocyte numbers became normal: 'more is better' was the ethos. Bob Edwards expressed increasing concern over the cost, complexity and potential long-term health risks of such high-order ovarian stimulation. In later life he repeatedly called for a return to minimalist approaches based on the natural menstrual cycle to improve oocyte quality over quantity. This article reviews the application of ovulation induction to human IVF and celebrates Edwards' abiding impact on the field, which firmly grounds him in the reproductive endocrinology pantheon.

Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer.

PubMed

Vlahos, Nikos F; Economopoulos, Konstantinos P; Fotiou, Stylianos

2010-02-01

There is evidence that endometriosis as well as drugs used in the process of in vitro fertilisation appear to associate with increased risk for gynaecological cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation. There are data to support that ovarian endometriosis could have the potential for malignant transformation. Epidemiologic and genetic studies support this notion. It seems that endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). There is no clear association between endometriosis and breast or endometrial cancer. More studies are needed to establish the risk factors that may lead to malignant transformation of this condition and to identify predisposed individuals who may require closer surveillance. Currently, there is no proven relationship between any type of gynaecological cancer and drugs used for infertility treatment. In principle, infertile women have increased risk for gynaecologic malignancies. Nulligravidas who received treatment are at increased risk for malignancy compared with women who had conceived after treatment. There is limited evidence that clomiphene citrate use for more than six cycles or 900mg or treatment of women over the age of 40 could increase their risk for ovarian and breast cancer. More studies with the appropriate statistical power and follow-up time are required to evaluate accurately the long-term effects of these drugs and procedures.

[Does fertility treatment increase the risk of breast cancer? Current knowledge and meta-analysis].

PubMed

Gabriele, V; Benabu, J-C; Ohl, J; Youssef, C Akladios; Mathelin, C

2017-05-01

The objective of this review was to assess the level of risk of breast cancer for women exposed to ovulation-inducing therapy (OIT). The 25 selected studies were extracted from the PUBMED database from January 2000 until March 2016 with the following key-words: "fertility agents", "infertility treatments", "clomiphene citrate", "buserelin", "ovarian stimulation", "assisted reproductive technology" and "breast cancer". Our meta-analysis was performed using Review Manager software, Cochrane Collaboration, 2014. The results were calculated by type of OIT, as well as globally. The analysis of these published epidemiological studies confirms that exposition to OIT is not a breast cancer risk factor, but the results are contradictory. Two studies have shown a significantly increased risk of breast cancer in a population of infertile women, while two others have found a significant decrease of this risk. The twenty others did not show any impact of IOT over this risk. Our meta-analysis of 20 selected studies has not identified a significant association between exposition to OIT and breast cancer risk (relative risk=0,96; IC 95: (0,81-1,14) for cohort studies and odds ratio=0,94; IC 95% (0,81-1,10) for case-control studies). Exposition to OIT is not an identified risk factor for breast cancer. A message reassuring about a possible risk of OIT-related breast cancer should be given to these women. Exposition to OIT is therefore not an indication of increased breast surveillance. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatory infertility (WHO group 2).

PubMed

Eijkemans, Marinus J C; Polinder, Suzanne; Mulders, Annemarie G M G J; Laven, Joop S E; Habbema, J Dik F; Fauser, Bart C J M

2005-10-01

Conventional treatment in normogonadotrophic anovulatory infertility (WHO 2) consists of clomiphene citrate (CC), followed by exogenous gonadotrophins (FSH) and IVF. Response to these treatments may be predicted on the basis of individual patient characteristics. We aimed to devise a patient-tailored, cost-effective treatment algorithm involving the above-mentioned treatment modalities, based on individual patient characteristics. Sixteen prognostic groups are defined, according to the presence or absence of: age >30 years, amenorrhea, elevated androgen levels and obesity. The chances of response with each of the three treatments were calculated using prediction models. Treatment costs were based on the data of 240 patients visiting a specialist academic fertility unit. Outcome was an ongoing pregnancy within 12 months after initiation of treatment. The costs per pregnancy of three different strategies were compared, with a threshold for cost-effectiveness of 10 000. The strategy CC + FSH + IVF compared with FSH + IVF generated more pregnancies against lower costs. Compared with CC + IVF, it also produced more pregnancies, but at higher costs. For <30 years of age with normal androgen levels, costs per pregnancy were less than 10 000. For women >30 years old, costs per pregnancy were 25 000 and over 200 000, when presenting with normal or elevated androgen levels, respectively. The conventional treatment protocol is efficient for women aged <30 years with normal androgen levels. For women >30 years old with elevated androgen levels, FSH may be skipped.

Insulin resistance is associated with depression risk in polycystic ovary syndrome.

PubMed

Greenwood, Eleni A; Pasch, Lauri A; Cedars, Marcelle I; Legro, Richard S; Eisenberg, Esther; Huddleston, Heather G

2018-06-13

To test the hypothesis that insulin resistance is associated with depression risk in polycystic ovary syndrome (PCOS). Secondary analysis of data from a multicenter randomized trial. Multicenter university-based clinical practices. Seven hundred thirty-eight women with PCOS by modified Rotterdam criteria seeking pregnancy enrolled in a randomized clinical trial comparing clomiphene citrate versus letrozole. The Primary Care Evaluation of Mental Disorders Patient Health Questionnaire was self-administered to identify depression using a validated algorithm at enrollment. Demographic and anthropometric data were collected, and serum assays were performed. Insulin resistance was estimated using the homeostatic model of insulin resistance (HOMA-IR), with a cutoff of >2.2 considered abnormal. Demographic, endocrine, and metabolic parameters associated with depression. In a univariate logistic regression analysis, elevated HOMA-IR was associated with 2.3-fold increased odds of depression (odds ratio [OR] = 2.32; 95% confidence interval [CI], 1.28-4.21). This association remained significant after controlling for age and body mass index (adjusted OR [aOR] = 2.23; 95% CI, 1.11-4.46) and in a model including additional potential confounders (aOR = 2.03; 95% CI, 1.00-4.16). Insulin resistance has a strong and independent association with depression in PCOS and may serve as a physiologic mediator. Our findings corroborate a growing body of evidence linking insulin resistance to depressed mood. The association between insulin resistance and depressed mood warrants further investigation to elucidate mechanisms and identify potential therapeutic targets. Copyright © 2018 American Society for Reproductive Medicine. All rights reserved.

Diagnosis and Treatment of Polycystic Ovary Syndrome.

PubMed

Williams, Tracy; Mortada, Rami; Porter, Samuel

2016-07-15

Polycystic ovary syndrome is the most common endocrinopathy among reproductive-aged women in the United States, affecting approximately 7% of female patients. Although the pathophysiology of the syndrome is complex and there is no single defect from which it is known to result, it is hypothesized that insulin resistance is a key factor. Metabolic syndrome is twice as common in patients with polycystic ovary syndrome compared with the general population, and patients with polycystic ovary syndrome are four times more likely than the general population to develop type 2 diabetes mellitus. Patient presentation is variable, ranging from asymptomatic to having multiple gynecologic, dermatologic, or metabolic manifestations. Guidelines from the Endocrine Society recommend using the Rotterdam criteria for diagnosis, which mandate the presence of two of the following three findings- hyperandrogenism, ovulatory dysfunction, and polycystic ovaries-plus the exclusion of other diagnoses that could result in hyperandrogenism or ovulatory dysfunction. It is reasonable to delay evaluation for polycystic ovary syndrome in adolescent patients until two years after menarche. For this age group, it is also recommended that all three Rotterdam criteria be met before the diagnosis is made. Patients who have marked virilization or rapid onset of symptoms require immediate evaluation for a potential androgen-secreting tumor. Treatment of polycystic ovary syndrome is individualized based on the patient's presentation and desire for pregnancy. For patients who are overweight, weight loss is recommended. Clomiphene and letrozole are first-line medications for infertility. Metformin is the first-line medication for metabolic manifestations, such as hyperglycemia. Hormonal contraceptives are first-line therapy for irregular menses and dermatologic manifestations.

Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan.

PubMed

Cevher, Erdal; Sensoy, Demet; Taha, Mohamed A M; Araman, Ahmet

2008-01-01

The aim of this study was to design and evaluate of mucoadhesive gel formulations for the vaginal application of clomiphene citrate (CLM) for local treatment of human papilloma virus (HPV) infections. Chitosan (CHI) and polycarbophil (PC) were covalently modified using the thioglycolic acid and L-cysteine, respectively. The formation of thiol conjugates of chitosan (CHI-TG) and polycarbophil (PC-CYS) were confirmed by FT-IR analysis and PC-CYS and CHI-TG were found to have 148.42 +/- 4.16 and 41.17 +/- 2.34 micromol of thiol groups per gram of polymer, respectively. One percent CLM gels were prepared by combination of various concentrations of PC and CHI with thiolated conjugates of these polymers. Hardness, compressibility, elasticity, adhesiveness and cohesiveness of the gels were measured by Texture profile analysis and the vaginal mucoadhesion was investigated by mucoadhesion test. The increasing in the amount of the thiol conjugates was found to enhance the elasticity, cohesiveness, adhesiveness and mucoadhesion of the gel formulations but not their hardness and compressibility when compared to gels prepared using their respective parent formulations. Slower release rate of CLM from gels was achieved when the polymer concentrations were increased in the gel formulations. PC and its thiol conjugate were found to prolong the release of CLM longer than 70 h unlike gel formulations prepared using CHI and its thiol conjugate which were able to release CLM up to 12 h. Stability of CLM was preserved during the 3 month stability analysis under controlled room temperature and accelerated conditions.

Three decades after Gjönnaess's laparoscopic ovarian drilling for treatment of PCOS; what do we know? An evidence-based approach.

PubMed

Abu Hashim, Hatem; Al-Inany, Hesham; De Vos, Michel; Tournaye, Herman

2013-08-01

The introduction of laparoscopic ovarian drilling (LOD) by Gjönnaess in 1984 as a substitute for ovarian wedge resection created opportunities for extensive research given its worldwide application for ovulation induction in women with polycystic ovary syndrome (PCOS). To critically evaluate and summarize the current body of literature regarding the role of LOD for the management of PCOS entailing its different preoperative, operative and postoperative aspects. In addition, long-term efficacy, cost-effectiveness, patient preference and health-related quality of life issues will be evaluated together with other available alternatives of ovulation induction treatments. A PubMed search was conducted looking for the different trials, reviews and various guidelines relating to the role of LOD in the management of PCOS. LOD whether unilateral or bilateral is a beneficial second-line treatment in infertile women with clomiphene citrate (CC)-resistant PCOS. It is as effective as gonadotrophin treatment but without the risk of multiple pregnancy or ovarian hyperstimulation and does not require intensive monitoring. Increased responsiveness of the ovary to CC especially in patients who remain anovulatory following LOD is another advantage. Recent evidence suggests that relatively novel oral methods of ovulation induction, e.g. CC plus metformin, CC plus tamoxifen, rosiglitazone plus CC and aromatase inhibitors represent a successful alternative to LOD in CC-resistant PCOS. Meanwhile current evidence does not support LOD as a first-line approach in PCOS-related anovulation or before IVF. LOD is currently recommended as a successful and economical second-line treatment for ovulation induction in women with CC-resistant PCOS.

Therapeutic and fertility restoration effects of Ionidium suffruticosum on sub-fertile male albino Wistar rats: effects on testis and caudal spermatozoa.

PubMed

Chenniappan, Kuppusamy; Murugan, Kadarkari

2017-12-01

Ionidium suffruticosum (L.) Ging (Violaceae) is an important medicinal plant widely used as a herbal traditional medicine in Ayurveda for the treatment of infertility. Currently, little pharmacological information is available on its male fertility properties following prolonged use. To investigate I. suffruticosum leaf extracts for male fertility parameters. The ethanol lyophilized fraction was administered orally on carbendazim-induced sub-fertility rats (250 mg/kg body weight for 28 days). The effects of fractions on rat's fertility parameters i.e., body and testes weight, sperm motility, sperm vitality, epididymal sperm counts, its morphology, enzyme and antioxidant stress and histopathology were studied and compared with clomiphene citrate. The sub-fertile male rats treated with I. suffruticosum leaf extract increased the body weight of 7 g, testis weight of 97 mg, increased cauda epididymal sperm counts of 34.2 × 10 6 sperm/mL, motility of sperm 46% and vitality 28% also increased and normal sperm morphology also improved up to 32%. The carbendazim-treated group showed loss in body weight of 33 g, testis weight of 851 mg, decreased epididymal sperm counts of 15 × 10 6 sperm/mL, with sluggish motility and a highly significant fall in the live sperms of about 57%. The leaf fraction of I. suffructicosum increased the testicular weight, spermatogenesis, sperm counts, lessened sperm agglutination, and increased testicular oxidative biomarkers, SOD, and CAT. This study therefore supports the usage of I. suffructicosum in traditional medicine for infertility.

Fertility drugs and the risk of breast cancer: a meta-analysis and review.

PubMed

Zreik, Tony G; Mazloom, Ali; Chen, Yanli; Vannucci, Marina; Pinnix, Chelsea C; Fulton, Stephanie; Hadziahmetovic, Mersiha; Asmar, Nadia; Munkarah, Adnan R; Ayoub, Chakib M; Shihadeh, Ferial; Berjawi, Ghina; Hannoun, Antoine; Zalloua, Pierre; Wogan, Christine; Dabaja, Bouthaina

2010-11-01

The risk of breast cancer has been associated with reproductive history. The purpose of this study was to determine the relationship between fertility drugs used in assisted reproductive procedures and the risk of breast cancer. We performed a literature search using the MEDLINE, the COCHRANE Library, and Scopus to identify studies linking breast cancer to fertility drugs. We excluded case series, case reports, and review articles from our analysis. The study populations included women who were treated for infertility with clomiphene, gonadotropins, gonadotropin-releasing hormones, or other unspecified fertility agents. We extracted information on study design, sample size, type of fertility drugs and number of treatment cycles, breast cancer incidence, and follow-up time from these studies. Eight case-control studies and fifteen cohort studies were included in the quantitative analyses. The Newcastle-Ottawa Quality Assessment Scales were used. Two investigators independently extracted study methods, sources of bias, and outcomes. We found that the risk of breast cancer was not significantly associated with fertility drug treatment. The follow-up periods were short in some of the studies analyzed in our study; however, we proceeded to test the trend in risk estimates across different durations of follow-up and found a trend for association using the nonparametric test; this was interpreted with caution in view of the lack of adjustment with other confounding factors. The current published data do not suggest higher risk of breast cancer in women who receive fertility treatment, but the lack of long-term follow up and the inherent weaknesses in some of the published studies have to be cautiously taken into account.

Maternal use of fertility drugs and risk of cancer in children--a nationwide population-based cohort study in Denmark.

PubMed

Hargreave, Marie; Jensen, Allan; Nielsen, Thor Schütt Svane; Colov, Emilie Palmgren; Andersen, Klaus Kaae; Pinborg, Anja; Kjaer, Susanne Krüger

2015-04-15

Large population-based studies are needed to examine the effect of maternal use of fertility drugs on the risk of cancer in children, while taking into account the effect of the underlying infertility. A cohort of 123,322 children born in Denmark between 1964 and 2006 to 68,255 women who had been evaluated for infertility was established. We used a case-cohort design and calculated hazard ratios (HRs) for cancer in childhood (0-19 years) and in young adulthood (20-29 years) associated with maternal use of six groups of fertility drugs (clomiphene, gonadotropins [i.e., human menopausal gonadotropins and follicle-stimulating hormone], gonadotropin-releasing hormone analogs, human chorionic gonadotropins, progesterone and other fertility drugs). We found no statistically significant association between maternal use of fertility drugs and risk for overall cancer in childhood or young adulthood. However, with regard to specific cancers in childhood, our results showed that maternal use of progesterone before childbirth markedly increased the risks of their offspring for acute lymphocytic leukemia (any use: HR, 4.95; 95% CI, 1.69-14.54; ≥ three cycles of use: HR, 9.96; 95% CI, 2.63-37.77) and for sympathetic nervous system tumors (any use: HR, 5.79; 95% CI, 1.23-27.24; ≥ three cycles of use: HR, 8.51; 95% CI, 1.72-42.19). These findings show that maternal use of progesterone may increase the risk for specific cancers in the offspring. Additional large epidemiological studies are urgently needed to confirm our finding. © 2014 UICC.

Past, Present, and Future Research Avenues for Metformin

PubMed Central

Sparkes, Steven T.; Patel, Dhiren K.

2014-01-01

Objective: To review why metformin is considered first-line therapy for type 2 diabetes mellitus (T2DM) and review newer avenues of research currently being evaluated. Data Sources: The Cochrane Library and Medline (to January 2014) were searched for case–control and cohort studies, clinical trials, and systematic reviews and meta-analyses involving metformin for any indication. Study Selection and Data Extraction: The literature search found 5 major avenues of research for metformin: reduction in mortality, delayed-onset or prevention of T2DM in the presence of prediabetes, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS), and decreased cancer risk. When available, multi-center, double-blind, controlled clinical trials or meta-analyses thereof were selected for review. If these types of studies did not exist, other types of studies were chosen for review. Data Synthesis: Metformin significantly decreases all-cause and diabetes-related mortality in overweight and obese patients with T2DM. It may also decrease risk of progression to T2DM in patients with prediabetes. Metformin has been studied for the treatment of NAFLD though data are limited. Metformin alone or combined with clomiphene may increase pregnancy and ovulation rates but has not yet been shown to increase live-birth rates in patients with PCOS. Metformin may decrease risk of colorectal cancer but not all-cancer risk. Conclusions: Metformin’s clinical role in T2DM and prediabetes is well established. Other avenues of research being evaluated at this time are NAFLD, PCOS, and reduced risk of cancer; more data are needed before it has a clinical role in these indications.

Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome.

PubMed

Amer, S A; Smith, J; Mahran, A; Fox, P; Fakis, A

2017-08-01

Would letrozole as a primary ovulation induction agent generate better pregnancy rates than clomiphene citrate (CC) in subfertile women with anovulatory polycystic ovarian syndrome (PCOS)? Participants receiving letrozole as a primary treatment achieved a significantly (P = 0.022) higher clinical pregnancy rate per patient (61.2%) compared to CC (43.0%). According to a recent Cochrane systematic review (2014), letrozole appears to improve live-birth (LB) and pregnancy rates in anovulatory women with PCOS, compared to CC. However, the review concluded that the quality of evidence was low due to poor reporting of study methods and possible publication bias. This double-blind randomized controlled trial (RCT) included 159 participants between April 2007 and June 2014. Subjects were randomly allocated to either CC (n = 79) or letrozole (n = 80) in a 1:1 ratio. Both drugs were encapsulated to look identical. Randomization was performed in mixed blocks and stratified by patients' BMI (<30 and 30-35 kg/m2). The trial included subfertile women diagnosed with PCOS. Treatment started with one tablet (CC 50 mg, letrozole 2.5 mg) increasing to two in non-responders and continuing until pregnancy or for up to six ovulatory cycles. Non-responders were crossed over to the other treatment after a 6-week break. Cycles were initially monitored with ultrasound follicle tracking then mid-luteal serum progesterone measurement in subsequent cycles. Amongst the 159 participants included in the intention-to-treat analysis, four women conceived before treatment and six were lost-to-follow-up. The remaining 149 participants (74 on CC and 75 on letrozole) completed at least the first treatment. Women receiving letrozole achieved a significantly (P = 0.022; absolute difference [95% confidence interval] 18% [3-33%]) higher pregnancy rate (61.%) than those on CC (43%). The median number of treatment cycles received until pregnancy was significantly (log rank P = 0.038) smaller with letrozole (4[3-5] cycles) compared to CC (6[4-7] cycles). LB rates were not statistically (P = 0.089) different between the two groups, although there was a trend towards higher rates on letrozole (48.8%) compared to CC (35.4%). After the crossover, pregnancy and LB rates on letrozole (n = 45; 28.9 and 24.4%, respectively) were not statistically (P = 0.539 and P = 0.601) different from CC (n = 31; 22.6 and 19.4%). One possible limitation of this trial may be the exclusion of PCOS women with BMI > 35 kg/m2, which would limit the applicability of the results in this subgroup of PCOS. However, this group of women are generally excluded from treatment in the majority of fertility centres, especially in Europe, due to the associated challenges and risks. The results of this trial are consistent with the recent Cochrane systematic review. However, with its robust design, the current RCT provides more valid and compelling evidence for the superiority of letrozole over CC as a primary ovulation induction agent in PCOS women with 40% increase in pregnancy rates and with a shorter time-to-pregnancy. Furthermore, the participants in this RCT are a good representation of subfertile PCOS population receiving fertility treatment in Europe and worldwide. The results are therefore globally generalizable for clinical practice. This RCT was mainly funded by the R&D Funding Scheme of Derby Hospitals NHS Foundation Trust. The study also received funds from School of Medicine, University of Nottingham. The Trust R&D department was involved in the development of the protocol and the running of the trial. The trial was sponsored and monitored by the University of Nottingham. The authors have no conflicts of interest. www.Clinicaltrials.gov: NCT00478504. Registration was verified on 23/05/2007. 25/04/2007. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

The role of obesity in the development of polycystic ovary syndrome.

PubMed

Motta, Alicia Beatriz

2012-01-01

Polycystic Ovary Syndrome (PCOS) is one of the common endocrine diseases that affects women in their reproductive age. PCOS has diverse clinical implications that include reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, cardiovascular diseases) and psychological features (increased anxiety, depression and worsened quality of life). The exact patho-physiology of PCOS is complex and remains largely unclear. The prevalence of PCOS is estimated at 4-18%, depending on diverse factors discussed ahead. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and body weight. During the last decades, obesity and excess weight are major chronic diseases all around the word. Obesity increases some features of PCOS such as hyperandrogenism, hirsutism, infertility and pregnancy complications. Both obesity and insulin resistance increase diabetes mellitus type 2 and cardiovascular diseases. Moreover, obesity impairs insulin resistance and exacerbates reproductive and metabolic features of PCOS. It is well known that obesity is associated with anovulation, pregnancy loss and late pregnancy complications (pre-eclampsia, gestational diabetes). Obesity in PCOS is also linked to failure or delayed response to the various treatments including clomiphene citrate, gonadotropins and laparoscopic ovarian diathermy. It has been reported that, after losing as little as 5 % of initial body weight obese women with PCOS improved spontaneous ovulation rates and spontaneous pregnancy. Therefore, the weight loss prior to conception improves live birth rate in obese women with or without PCOS. The treatment of obesity may include lifestyle therapy (diet and exercise), pharmacological treatment and bariatric surgery. In summary, weight loss is considered the first-line therapy in obese women with PCOS. In the present review, the consequence and treatment of obesity in women with PCOS are discussed.

Maternal Medication and Herbal Use and Risk for Hypospadias: Data from the National Birth Defects Prevention Study, 1997--2007

PubMed Central

Lind, Jennifer N.; Tinker, Sarah C.; Broussard, Cheryl S.; Reefhuis, Jennita; Carmichael, Suzan L.; Honein, Margaret A.; Olney, Richard S.; Parker, Samantha E.; Werler, Martha M.

2014-01-01

Purpose Investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants. Methods We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1,537 infants with second-or third-degree isolated hypospadias and 4,314 liveborn male control infants without major birth defects, with estimated dates of delivery from 1997–2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy BMI, previous live births, maternal sub-fertility, study site, and year. Results We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. Two new associations were observed for venlafaxine (aOR 2.4; 95% CI 1.0, 6.0) and progestin only oral contraceptives (aOR 1.9, 95% CI 1.1, 3.2). The previously reported association for clomiphene citrate was confirmed (aOR 1.9, 95% CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them. Conclusions Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raises the possibility of confounding by underlying subfertility. PMID:23620412

Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens.

PubMed

Zhang, Caiqiao; Fang, Changge; Liu, Li; Xia, Guoliang; Qiao, Huili

2002-01-01

Polychlorinated biphenyls (PCBs) are worldwide persistent pollutants that have produced detrimental effects on endocrine function and reproduction in a variety of species. The present study revealed effects of PCBs on gonadal development and functions in chickens of different ages. Aroclor 1254 (0-100 microg/egg) was injected into Hyline chicken eggs before incubation. The adult chickens received Aroclor 1254 by gavage (50 mg/kg BW). It was observed that in day 5 embryos, PCBs resulted in a dose-dependent decrease of primordial germ cell (PGC) numbers, and caused PGCs pyknosis and vacuolation. Clomiphen failed to block the effects of PCBs. In the newly hatched chicken, PCBs induced a marked decrease in area of the transverse sections, diameter and relative area of the testicular tubules. The differentiation of germ cells was retarded after PCB treatment. In contrast, the area of the left ovarian transverse sections, the thickness of ovarian cortex and the number of oocytes increased dramatically in the female chickens after PCB exposure. In the adult chickens, PCBs caused no significant changes in body weight, respiration, heart rate, body temperature, red and white blood cell number, but induced a marked decrease in the testicular weight, and severe damage of the seminiferous tubules. The number of the spermatogenic cells and serum testosterone level were decreased significantly by PCBs. On the contrary, in the laying hens there was no significant effect of PCB on egg quality except a slight decrease in egg weight. These results indicated that PCBs exerted its disrupting effects on chicken reproduction with a sex and stage-related pattern, and in vivo disruption of gonadal development represents a possible model for risk assessment of environmental endocrine disrupters by in ovo treatment.

Treatment Outcome of Ovulation-inducing Agents in Patients with Anovulatory Infertility: A Prospective, Observational Study

PubMed Central

Prajapati, Kinjal; Desai, Mira; Shah, Samidh; Choudhary, Sumesh; Aggarwal, Rohina; Mishra, Vineet

2017-01-01

Objective: To compare different treatment regimens on pregnancy rate and outcome in patients with anovulatory infertility. Patients and Methods: A prospective observational study was conducted on patients with infertility due to anovulation. Patients treated with clomiphene citrate (CC) 50/100 mg/day from 2nd to 6th day of menstrual cycle (MC) (n = 38), short gonadotropin-releasing hormone (GnRH) agonist regimen (leuprolide [0.5 mg subcutaneous] + recombinant follicle-stimulating hormone [rFSH] [225 IU intramuscular [IM] from 2nd to 10th day of MC [n = 32]), long GnRH agonist regimen (leuprolide from 21st day followed by leuprolide + rFSH from 2nd to 10th day of MC [n = 19]), and antagonist regimen (human menopausal gonadotropin [hMG] [150 IU IM] from 2nd day followed by hMG + cetrorelix from 7th to 10th day of MC) (n = 6) were recruited and followed up for follicular size, endometrial thickness, and pregnancy test. Data were analyzed using appropriate statistical test andP < 0.05 was considered statistically significant. Results: A significant increase in follicular diameter and endometrial thickness was observed in patients treated with gonadotropin regimens as compared to CC alone (P < 0.0001). The highest number of positive pregnancy test with ultrasonographic evidence of gestational sac was observed with leuprolide + rFSH (long regimen) (10/19, 52.6%) followed by leuprolide + rFSH (short regimen) (13/32, 40.6%) while least in antagonist regimen (2/6, 33.3%) and CC (1/38, 2.63%). All regimens were well tolerated. Conclusion: Treatment outcome was better with long agonist regimen. PMID:29081619

Comparison of the effects of ovarian cauterization and gonadotropin-releasing hormone agonist and oral contraceptive therapy combination on endocrine changes in women with polycystic ovary disease.

PubMed

Taskin, O; Yalcinoglu, A I; Kafkasli, A; Burak, F; Ozekici, U

1996-06-01

To study the effects of laparoscopic ovarian cauterization and combination of long-acting GnRH agonist (GnRH-a) and oral contraceptive (OC) therapy on endocrine changes in women with clomiphene citrate (CC)- resistant polycystic ovary disease (PCOD). Prospective, randomized. University-based infertility clinic. Seventeen women with CC-resistant PCOD were included randomly in the study to either laparoscopic ovarian cautery or GnRH-a and OC therapy for 3 months. Serum concentrations of LH, FSH, androstenedione (A), T, and sex hormone-binding globulin (SHBG) were determined before each therapeutic approach and during the follicular phase of first menstrual cycle after the cessation of each treatment. The mean serum concentrations and the clinical profiles were similar in both groups. Both groups showed significant changes in LH, FSH, A, T, and SHBG compared with pretreatment levels. There were no significant differences in the final concentrations of LH, FSH, and A between the two study groups after each treatment, whereas T and SHBG levels were significantly different in the goserelin and OC group. The decrease in LH and increase in SHBG serum concentrations were greater in the goserelin and OC-treated women [-59% and + 5.9% versus - 70% and + 13.5%, respectively]. Although the SHBG concentration increased in both groups, the serum SHBG concentration of the goserelin and OC group was significantly higher than the other group. Both therapeutic modalities revealed similar effects on the endocrine profiles in women with CC-resistant PCOD. Considering the invasiveness, cost, and potential complications of laparoscopic ovarian cauterization, noninvasive medical treatment with GnRH-a and OC combination may be more effective in restoring the optimal follicular environment in women with PCOD.

Office microlaparoscopic ovarian drilling (OMLOD) versus conventional laparoscopic ovarian drilling (LOD) for women with polycystic ovary syndrome.

PubMed

Salah, Imaduldin M

2013-02-01

This was a prospective controlled study to compare the beneficial effects of office microlaparoscopic ovarian drilling (OMLOD) under augmented local anesthesia, as a new modality treatment option, compared to those following ovarian drilling with the conventional traditional 10-mm laparoscope (laparoscopic ovarian drilling, LOD) under general anesthesia. The study included 60 anovulatory women with polycystic ovary syndrome (PCOS) who underwent OMLOD (study group) and 60 anovulatory PCOS women, in whom conventional LOD using 10-mm laparoscope under general anesthesia was performed (comparison group). Transvaginal ultrasound scan and blood sampling to measure the serum concentrations of LH, FSH, testosterone and androstenedione were performed before and after the procedure. Intraoperative and postoperative pain scores in candidate women were evaluated during the office microlaparoscopic procedure, in addition to the number of candidates who needed extra analgesia. Women undergoing OMLOD showed good intraoperative and postoperative pain scores. The number of patients discharged within 2 h after the office procedure was significantly higher, without the need for postoperative analgesia in most patients. The LH:FSH ratio, mean serum concentrations of LH and testosterone and free androgen index decreased significantly after both OMLOD and LOD. The mean ovarian volume decreased significantly (P < 0.05) a year after both OMLOD and LOD. There were no significant differences in those results after both procedures. Intra- and postoperatively augmented local anesthesia allows outpatient bilateral ovarian drilling by microlaparoscopy without general anesthesia. The high pregnancy rate, the simplicity of the method and the faster discharge time offer a new option for patients with PCOS who are resistant to clomiphene citrate. Moreover, ovarian drilling could be performed simultaneously during the routine diagnostic microlaparoscopy and integrated into the fertility workup of these patients.

Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline

PubMed Central

Legro, Richard S.; Arslanian, Silva A.; Ehrmann, David A.; Hoeger, Kathleen M.; Murad, M. Hassan; Pasquali, Renato; Welt, Corrine K.

2013-01-01

Objective: The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS). Participants: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer developed the guideline. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. Conclusions: We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study. PMID:24151290

Use of letrozole in assisted reproduction: a systematic review and meta-analysis

PubMed Central

Requena, Antonio; Herrero, Julio; Landeras, José; Navarro, Esperanza; Neyro, José L.; Salvador, Cristina; Tur, Rosa; Callejo, Justo; Checa, Miguel A.; Farré, Magí; Espinós, Juan J.; Fábregues, Francesc; Graña-Barcia, María

2008-01-01

BACKGROUND Letrozole is the third-generation aromatase inhibitor (AI) most widely used in assisted reproduction. AIs induce ovulation by inhibiting estrogen production; the consequent hypoestrogenic state increases GnRH release and pituitary follicle-stimulating hormone (FSH) synthesis. METHODS A systematic search of the literature was performed for both prospective and retrospective studies. Meta-analyses of randomized clinical trials (RCTs) were performed for three comparisons: letrozole versus clomiphene citrate (CC), letrozole + FSH versus FSH in intrauterine insemination (IUI) and letrozole + FSH versus FSH in IVF. In the absence of RCTs, non-randomized studies were pooled. RESULTS Nine studies were included in the meta-analysis. Four RCTs compared the overall effect of letrozole with CC in patients with polycystic ovary syndrome. The pooled result was not significant for ovulatory cycles (OR = 1.17; 95% CI 0.66–2.09), or for pregnancy rate per cycle (OR = 1.47; 95% CI 0.73–2.96) or for pregnancy rate per patient (OR = 1.37; 95% CI 0.70–2.71). In three retrospective studies which compared L + FSH with FSH in ovarian stimulation for IUI, the pooled OR was 1.15 (95% CI 0.78−1.71). A final meta-analysis included one RCT and one cohort study that compared letrozole + gonadotrophin versus gonadotrophin alone: the pooled pregnancy rate per patient was not significantly different (OR = 1.40; 95% CI 0.67–2.91). CONCLUSIONS Letrozole is as effective as other methods of ovulation induction. Further randomized-controlled studies are warranted to define more clearly the efficacy and safety of letrozole in human reproduction. PMID:18812422

Human antral fluid IGF-I and oocyte maturity: effect of stimulation therapy.

PubMed

Roussi, M; Royère, M; GuillonueauM; Lansac, J; Muh, J P

1989-07-01

Studies in animals have highlighted a possible role for growth factors, particularly IGF-I on cellular replication and cytodifferentiation in the ovary. At this time, few studies have been performed about IGF-I in the human ovary. From 38 women undergoing in Vitro Fertilization 293 antral antral fluids were collected and assessed for steroids (estradiol and progesterone), FSH and IGF-I. Two induction treatments were compared: clomiphene citrate hMG (group A,N = 15), triptoreline/hMG (group B,N = 23). We also studied relationships between quantitative parameters and oocyte collection or oocyte corona cumulus complex maturity, In group B, the highest antral estradiol levels were found in follicles yielding an oocyte (p less than 0.05). Concerning antral progesterone, higher levels were observed in follicles collected from group A than follicles collected from group B (p less than 0.05): for this parameter, the highest levels were observed when an oocyte was harvested, whatever the treatment (p less than 0.05). Highest antral FSH levels were observed in group B (p less than 0.05). IGF-I levels were higher in follicles collected from group B than in follicles collected from group A (p less than 0.05) and antral IGF-I levels differed between mature and immature oocyte corona cumulus complex in group B (p less than 0.05). These results, which are in keeping with studies about biological action of IGF-I in animal or human follicles or granulosa cells, led us to hypothesize a role for IGF-I in human follicular recruitment and maturation, a role that possible is enhanced during GnRH analogue and gonadotropin therapy.

European survey of diagnosis and management of the polycystic ovary syndrome: results of the ESE PCOS Special Interest Group's Questionnaire.

PubMed

Conway, Gerard; Dewailly, Didier; Diamanti-Kandarakis, Evanthia; Escobar-Morreale, Hector F; Franks, Steven; Gambineri, Alessandra; Kelestimur, Fahrettin; Macut, Djuro; Micic, Dragan; Pasquali, Renato; Pfeifer, Marija; Pignatelli, Duarte; Pugeat, Michel; Yildiz, Bulent

2014-10-01

There is evidence for differences between endocrinologists and other specialists in their approach to diagnosis and management of the polycystic ovary syndrome (PCOS). A mailed survey consisting of a simple questionnaire aiming to understand current practice for diagnosis and management of the PCOS by specialists across Europe. The questionnaire consisted of 23 questions grouped to achieve information on i) the general characteristics of the respondents, ii) patients with PCOS seen by endocrinologists, iii) the main diagnostic criteria, iv) biochemical parameters used in the differential diagnosis of hyperandrogenism, v) long-term concerns, and, finally vi) treatment choices. A total of 357 questionnaires representing 13.3% of the members of European Society of Endocrinology (ESE) were available for final analysis; 93% of the respondents were endocrinologists In relation to the diagnostic criteria, respondents were most likely to select menstrual irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that the NIH criteria were followed by the majority of respondents. The most frequent biochemical parameters in the differential diagnosis of hyperandrogenism were total testosterone or free androgen index. Obesity and type 2 diabetes were regarded as the principal long-term concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%), lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility include clomiphene citrate alone or in combination with metformin, prescribed by 9 and 23%, respectively, whereas only 6% used other methods for induction of ovulation. The survey produced by ESE is a good start for evaluating the perspective in the diagnosis and treatment of PCOS by endocrinologists in Europe. © 2014 European Society of Endocrinology.

Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries.

PubMed

Polson, D W; Reed, M J; Franks, S; Scanlon, M J; James, V H

1988-05-01

Serum 11 beta-hydroxyandrostenedione levels (11-OHA) were measured in normal women and women with polycystic ovaries (PCO) to assess their value in localizing the source of excessive androgen production in women with PCO. Serum 11-OHA was undetectable (less than 1.5 nmol/L) in an adrenalectomized woman, a woman with 11-hydroxylase deficiency, and a woman receiving chronic dexamethasone therapy, confirming the specificity of the antiserum used in this study. Serum 11-OHA concentrations were similar in normal women [mean, 5.0 +/- 2.3 (+/- SD) nmol/L] and women with PCO (5.0 +/- 2.1 nmol/L); serum androstenedione concentrations were increased in women with PCO. Thus, the ratio of androstenedione to 11-OHA was significantly higher (P less than 0.001) in women with PCO (2.0 +/- 0.7) than in normal women (1.1 +/- 0.5). Serum 11-OHA levels after adrenal suppression or stimulation were similar in women with PCO who had an ovulatory response and those who failed to ovulate after clomiphene administration. Administration of dexamethasone (1 mg) and injection of ACTH (250 micrograms) were associated with marked suppression and subsequent stimulation of serum 11-OHA levels in both normal women and women with PCO, and the responses were similar in the two groups. Also, the hour to hour and diurnal variations in serum 11-OHA were similar to those of androstenedione and cortisol during a 24-h period, indicating the adrenal origin of 11-OHA. Our finding of similar serum 11-OHA levels in the presence of increased serum androstenedione levels in women with PCO supports the concept that the ovary is the major source of excess androgen production in women with PCO.

Low-dose gonadotropin induction of ovulation in anovulatory women - still needed in the age of IVF.

PubMed

White, Davinia; Hardy, Kate; Lovelock, Suzannah; Franks, Stephen

2018-02-19

Low-dose, step-up gonadotropin is the treatment of choice for women with PCOS who have not conceived after anti-estrogen treatment, and as an effective alternative to pulsatile GnRH in women with hypogonadotropic hypogonadism (HH). There has been, however, no large-scale, comparative study between the two groups using low-dose gonadotropins. Here we performed a retrospective, comparative analysis, in a single clinic database, of efficacy and safety of induction of ovulation using low-dose gonadotropins in 364 Women with PCOS and 80 women with HH. The rate of ovulation was high in both PCOS (83%) and HH (84%) but mono-follicular, ovulatory cycles were more prevalent in PCOS than in HH (77% vs 53%, p<0.0001) and the proportion of cycles that were abandoned was higher in HH than in PCOS (25% vs 15%, p<0.0001). The median threshold dose of gonadotropin required to induce ovulation was 75iu/day in PCOS and 113iu/day in HH (p<0.001) and the range of doses was greater in HH women. Forty-nine percent of women with PCOS and 65% of those with HH conceived (more than 90% within 6 cycles of treatment) and had a least one pregnancy. Multiple pregnancies (all twins) occurred in only 4% of women with PCOS and 5% of those with HH. These findings emphasise the efficacy and safety of low-dose gonadotropin treatment for both clomiphene-resistant women with PCOS and those with HH. These results highlight the importance of choosing the more physiological approach of gonadotropin induction of ovulation in both groups as the most appropriate treatment, in preference to IVF.

A Randomized Clinical Trial to Determine Optimal Infertility Treatment in Older Couples: The Forty and Over Treatment Trial (FORT-T)

PubMed Central

Goldman, Marlene B.; Thornton, Kim L.; Ryley, David; Alper, Michael M.; Fung, June L.; Hornstein, Mark D.; Reindollar, Richard H.

2014-01-01

Objective To determine optimal infertility therapy in women at the end of their reproductive potential. Design Randomized clinical trial. Setting Academic medical centers and private infertility center in a state with mandated insurance coverage. Patients Couples with ≥ 6 months of unexplained infertility; female partner aged 38–42. Interventions Randomized to treatment with 2 cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. Main Outcome Measures Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after 2 treatment cycles and at the end of treatment. Results 154 couples were randomized to receive CC/IUI (N=51), FSH/IUI (N=52), or immediate IVF (N=51); 140 (90.9%) couples initiated treatment. Cumulative clinical pregnancy rates per couple after the first 2 cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatment, 71.4% (110/154) of couples conceived a clinically recognized pregnancy and 46.1% delivered at least one live-born baby. 84.2% of all live born infants resulting from treatment were achieved from IVF. There were 36% fewer treatment cycles in the IVF arm compared to either COH/IUI arm and couples conceived a pregnancy leading to a live birth after fewer treatment cycles. Conclusions An RCT to compare treatment initiated with 2 cycles of COH/IUI to immediate IVF in older women with unexplained infertility demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group. PMID:24796764

Effects of metformin treatment on luteal phase progesterone concentration in polycystic ovary syndrome.

PubMed

Meenakumari, K J; Agarwal, S; Krishna, A; Pandey, L K

2004-11-01

The causes of luteal phase progesterone deficiency in polycystic ovary syndrome (PCOS) are not known. To determine the possible involvement of hyperinsulinemia in luteal phase progesterone deficiency in women with PCOS, we examined the relationship between progesterone, luteinizing hormone (LH) and insulin during the luteal phase and studied the effect of metformin on luteal progesterone levels in PCOS. Patients with PCOS (19 women aged 18-35 years) were treated with metformin (500 mg three times daily) for 4 weeks prior to the test cycle and throughout the study period, and submitted to ovulation induction with clomiphene citrate. Blood samples were collected from control (N = 5, same age range as PCOS women) and PCOS women during the late follicular (one sample) and luteal (3 samples) phases and LH, insulin and progesterone concentrations were determined. Results were analyzed by one-way analysis of variance (ANOVA), Duncan's test and Karl Pearson's coefficient of correlation (r). The endocrine study showed low progesterone level (4.9 ng/ml) during luteal phase in the PCOS women as compared with control (21.6 ng/ml). A significant negative correlation was observed between insulin and progesterone (r = -0.60; P < 0.01) and between progesterone and LH (r = -0.56; P < 0.05) concentrations, and a positive correlation (r = 0.83; P < 0.001) was observed between LH and insulin. The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml) in PCOS women treated with metformin. The results suggest that hyperinsulinemia/insulin resistance may be responsible for low progesterone levels during the luteal phase in PCOS. The luteal progesterone level may be enhanced in PCOS by decreasing insulin secretion with metformin.

Association of uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination for unexplained infertility.

PubMed

Styer, Aaron K; Jin, Susan; Liu, Dan; Wang, Baisong; Polotsky, Alex J; Christianson, Mindy S; Vitek, Wendy; Engmann, Lawrence; Hansen, Karl; Wild, Robert; Legro, Richard S; Coutifaris, Christos; Alvero, Ruben; Robinson, Randal D; Casson, Peter; Christman, Gregory M; Christy, Alicia; Diamond, Michael P; Eisenberg, Esther; Zhang, Heping; Santoro, Nanette

2017-03-01

To investigate the association of non-cavity-distorting uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination (OS-IUI) in couples with unexplained infertility. Secondary analysis from a prospective, randomized, multicenter clinical trial investigating fertility outcomes after OS-IUI. Reproductive Medicine Network clinical sites. Nine hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. Participants were randomized to one of three arms (clomiphene citrate, letrozole, or gonadotropins), and treatment was continued for up to four cycles or until pregnancy was achieved. Conception (serum hCG increase), clinical pregnancy (fetal cardiac activity), and live birth rates. A total of 102/900 participants (11.3%) had at least one documented fibroid and a normal uterine cavity. Women with fibroids were older, more likely to be African American, had a greater uterine volume, lower serum antimüllerian hormone levels, and fewer antral follicles than women without fibroids. In conception cycles, clinical pregnancy rates were significantly lower in participants with fibroids than in those without uterine fibroids. Pregnancy loss before 12 weeks was more likely in African American women with fibroids compared with non-African American women with fibroids. There was no difference in conception and live birth rates in subjects with and without fibroids. No differences were observed in conception and live birth rates in women with non-cavity-distorting fibroids and those without fibroids. These findings provide reassurance that pregnancy success is not impacted in couples with non-cavity-distorting fibroids undergoing OS-IUI for unexplained infertility. NCT01044862. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Effects of letrozole in combination with low-dose intramuscular injection of human menopausal gonadotropin on ovulation and pregnancy of 156 patients with polycystic ovary syndrome.

PubMed

Chen, Zhihua; Zhang, Mengzhen; Qiao, Yuhuan; Yang, Junjuan

2016-01-01

To explore the effects of letrozole (LE) in combination with low-dose intramuscular injection of human menopausal gonadotropin (HMG) on the ovulation induction and pregnancy of patients with polycystic ovary syndrome (PCOS). A total of 156 patients with PCOS infertility were randomly divided into an LE group, a clomiphene citrate (CC) group and an LE + HMG group (n= 52). LE and CC were orally taken according to the prescribed dosage on the 3rd-5th days of menstruation respectively, and 75 IU HMG was given through intramuscular injection. The ovulation induction parameters and pregnancy outcomes were observed. The number of ovulation cycle of LE + HMG group was significantly higher than that of LE group (χ 2 =8.451, P<0.001). After injection of human chorionic gonadotropin, both endometrial thickness and number of mature follicles of LE + HMG group were significantly higher than those of other two groups (P<0.001), and the daily estradiol (E2) level was also higher (q=4.531, P<0.05). The pregnancy rate of LE + HMG group was 55.7%, which exceeded those of other two groups (compared to LE group, χ 2 =4.012, P<0.05). In LE + HMG group, the average medication cycle of clinically pregnant patients was (2.9 ± 0.3) weeks, which was significantly shorter than those of CC and LE groups (F=17.241, P<0.001). The regimen using LE in combination with low-dose intramuscular injection of HMG has satisfactory therapeutic effects on ovulation induction, short medication cycle and high clinical pregnancy rate, which is promising for treating patients with PCOS infertility.

The Role of Infertility Etiology in Success Rate of Intrauterine Insemination Cycles: An Evaluation of Predictive Factors for Pregnancy Rate

PubMed Central

Ashrafi, Mahnaz; Rashidi, Mandana; Ghasemi, Afsaneh; Arabipoor, Arezoo; Daghighi, Sara; Pourasghari, Parisa; Zolfaghari, Zahra

2013-01-01

Background: The objective of this study was to identify the prognostic factors that influence the outcome of ovarian stimulation with intrauterine insemination (IUI) cycles in couples with different infertility etiology. Materials and Methods: This retrospective study was performed in data of 1348 IUI cycles with ovarian stimulation by clomiphene citrate (CC) and/or gonadotropins in 632 women with five different infertility etiology subgroups at Akbarabbadi Hospital, Tehran, Iran. Results: The pregnancy rate (PR)/ cycle was highest (19.9%) among couples with unexplained infertility and lowest (10.6%) in couples with multiple factors infertility. In cases of unexplained infertility, the best PRs were seen after CC plus gonadotropins stimulation (26.3%) and with inseminated motile sperm count>30×106 (21.9%), but the tendency didn’t reach statistical significant. In the ovarian factor group, the best PRs were observed in women aged between 30 and 34 years (20.8%), with 2-3 preovulatory follicles (37.8%) and infertility duration between 1and 3 years (20.8%), while only infertility duration (p=0.03) and number of preovulatory follicles (p=0.01) were statistically significant. Multiple logistic regression analysis determined that number of preovulatory follicles (p=0.02), duration of infertility (p=0.015), age (p=0.019), infertility etiology (p=0.05) and stimulation regimen (p=0.01) were significant independent factors in order to predict overall clinical PR. Conclusion: The etiology of infertility is important to achieve remarkable IUI success. It is worth mentioning that within different etiologies of infertility, the demographic and cycles characteristics of couples did not show the same effect. Favorable variables for treatment success are as follows: age <40, duration of infertility ≤5 years and a cause of infertility except of multiple factors. PMID:24520471

Outcomes after intrauterine insemination are independent of provider type

PubMed Central

Goldman, Randi H.; Batsis, Maria; Hacker, Michele R.; Souter, Irene; Petrozza, John C.

2015-01-01

OBJECTIVE We sought to determine whether the success of intrauterine insemination (IUI) varies based on the type of health care provider performing the procedure. STUDY DESIGN This was a retrospective cohort study set at an infertility clinic at an academic institution. The patients who comprised this study were 1575 women who underwent 3475 IUI cycles from late 2003 through early 2012. Cycles were stratified into 3 groups according to the type of provider who performed the procedure: attending physician, fellow physician, or registered nurse (RN). The primary outcome was live birth. Additional outcomes of interest included positive pregnancy test and clinical pregnancy. Repeated measures log binomial regression was used to estimate the risk ratios (RR) and 95% confidence intervals (CI) for the outcomes and to evaluate the effect of potential confounders. All tests were 2-sided, and P values < .05 were considered statistically significant. RESULTS Of the 3475 IUI cycles, 2030 (58.4%) were gonadotropin stimulated, 929 (26.7%) were clomiphene citrate stimulated, and 516 (14.9%) were natural. The incidences of clinical pregnancy and live birth among all cycles were 11.8% and 8.8%, respectively. After adjusting for female age, male partner age, and cycle type, the incidence of live birth was similar for RNs compared with attending physicians (RR, 0.80; 95% CI, 0.58–1.1) and fellow physicians compared with attending physicians (RR, 0.84; 95% CI, 0.58–1.2). Similar results were seen for positive pregnancy test and clinical pregnancy. CONCLUSION There was no significant difference in live birth following IUI cycles in which the procedure was performed by a fellow physician or RN compared with an attending physician. PMID:24881820

Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome

PubMed Central

Smith, J.; Mahran, A.; Fox, P.; Fakis, A.

2017-01-01

Abstract STUDY QUESTION Would letrozole as a primary ovulation induction agent generate better pregnancy rates than clomiphene citrate (CC) in subfertile women with anovulatory polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER Participants receiving letrozole as a primary treatment achieved a significantly (P = 0.022) higher clinical pregnancy rate per patient (61.2%) compared to CC (43.0%). WHAT IS KNOWN ALREADY According to a recent Cochrane systematic review (2014), letrozole appears to improve live-birth (LB) and pregnancy rates in anovulatory women with PCOS, compared to CC. However, the review concluded that the quality of evidence was low due to poor reporting of study methods and possible publication bias. STUDY DESIGN, SIZE, DURATION This double-blind randomized controlled trial (RCT) included 159 participants between April 2007 and June 2014. Subjects were randomly allocated to either CC (n = 79) or letrozole (n = 80) in a 1:1 ratio. Both drugs were encapsulated to look identical. Randomization was performed in mixed blocks and stratified by patients’ BMI (<30 and 30–35 kg/m2). PARTICIPANTS/MATERIALS, SETTING, METHODS The trial included subfertile women diagnosed with PCOS. Treatment started with one tablet (CC 50 mg, letrozole 2.5 mg) increasing to two in non-responders and continuing until pregnancy or for up to six ovulatory cycles. Non-responders were crossed over to the other treatment after a 6-week break. Cycles were initially monitored with ultrasound follicle tracking then mid-luteal serum progesterone measurement in subsequent cycles. MAIN RESULTS AND THE ROLE OF CHANCE Amongst the 159 participants included in the intention-to-treat analysis, four women conceived before treatment and six were lost-to-follow-up. The remaining 149 participants (74 on CC and 75 on letrozole) completed at least the first treatment. Women receiving letrozole achieved a significantly (P = 0.022; absolute difference [95% confidence interval] 18% [3–33%]) higher pregnancy rate (61.%) than those on CC (43%). The median number of treatment cycles received until pregnancy was significantly (log rank P = 0.038) smaller with letrozole (4[3–5] cycles) compared to CC (6[4–7] cycles). LB rates were not statistically (P = 0.089) different between the two groups, although there was a trend towards higher rates on letrozole (48.8%) compared to CC (35.4%). After the crossover, pregnancy and LB rates on letrozole (n = 45; 28.9 and 24.4%, respectively) were not statistically (P = 0.539 and P = 0.601) different from CC (n = 31; 22.6 and 19.4%). LIMITATIONS, REASONS FOR CAUTION One possible limitation of this trial may be the exclusion of PCOS women with BMI > 35 kg/m2, which would limit the applicability of the results in this subgroup of PCOS. However, this group of women are generally excluded from treatment in the majority of fertility centres, especially in Europe, due to the associated challenges and risks. WIDER IMPLICATIONS OF THE FINDINGS The results of this trial are consistent with the recent Cochrane systematic review. However, with its robust design, the current RCT provides more valid and compelling evidence for the superiority of letrozole over CC as a primary ovulation induction agent in PCOS women with 40% increase in pregnancy rates and with a shorter time-to-pregnancy. Furthermore, the participants in this RCT are a good representation of subfertile PCOS population receiving fertility treatment in Europe and worldwide. The results are therefore globally generalizable for clinical practice. STUDY FUNDING/COMPETING INTEREST(S) This RCT was mainly funded by the R&D Funding Scheme of Derby Hospitals NHS Foundation Trust. The study also received funds from School of Medicine, University of Nottingham. The Trust R&D department was involved in the development of the protocol and the running of the trial. The trial was sponsored and monitored by the University of Nottingham. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER www.Clinicaltrials.gov: NCT00478504. TRIAL REGISTRATION DATE Registration was verified on 23/05/2007. DATE OF FIRST PATIENT'S ENROLMENT 25/04/2007. PMID:28854590

Risk for borderline ovarian tumours after exposure to fertility drugs: results of a population-based cohort study.

PubMed

Bjørnholt, Sarah Marie; Kjaer, Susanne Krüger; Nielsen, Thor Schütt Svane; Jensen, Allan

2015-01-01

Do fertility drugs increase the risk for borderline ovarian tumours, overall and according to histological subtype? The use of any fertility drug did not increase the overall risk for borderline ovarian tumours, but an increased risk for serous borderline ovarian tumours was observed after the use of progesterone. Many epidemiological studies have addressed the connection between fertility drugs use and risk for ovarian cancer; most have found no strong association. Fewer studies have assessed the association between use of fertility drugs and risk for borderline ovarian tumours, and the results are inconsistent. A retrospective case-cohort study was designed with data from a cohort of 96 545 Danish women with fertility problems referred to all Danish fertility clinics in the period 1963-2006. All women were followed for first occurrence of a borderline ovarian tumour from the initial date of infertility evaluation until a date of migration, date of death or 31 December 2006, whichever occurred first. The median length of follow-up was 11.3 years. Included in the analyses were 142 women with borderline ovarian tumours (cases) and 1328 randomly selected sub-cohort members identified in the cohort during the follow-up through 2006. Cases were identified by linkage to the Danish Cancer Register and the Danish Register of Pathology by use of personal identification numbers. To obtain information on use of fertility drugs, hospital files and medical records of infertility-associated visits to all Danish fertility clinics were collected and supplemented with information from the Danish IVF register. We used case-cohort techniques to calculate rate ratios (RRs) and corresponding 95% confidence intervals (CIs) for borderline ovarian tumours, overall and according to histological subtype, associated with the use of any fertility drug or five specific groups of fertility drugs: clomiphene citrate, gonadotrophins (human menopausal gonadotrophins and follicle-stimulating hormone), gonadotrophin-releasing hormone analogues, human chorionic gonadotrophins and progesterone. Analyses within the cohort showed that the overall risk for borderline ovarian tumours was not associated with the use of any fertility drug (RR 1.00; 95% CI 0.67-1.51) or of gonadotrophins (RR 1.32; 95% CI 0.81-2.14), clomiphene citrate (RR 0.96; 95% CI 0.64-1.44), human chorionic gonadotrophins (RR 0.91; 95% CI 0.61-1.36) or gonadotrophin-releasing hormone analogues (RR 1.10; 95% CI 0.66-1.81). Furthermore, no associations were observed between the risk for borderline ovarian tumours and these groups of fertility drugs according to the number of cycles of use, length of follow-up or parity. In contrast, use of progesterone increased the risk for borderline ovarian tumours, particularly serous tumours, for which statistically significantly increased risks were observed with any use of progesterone (RR 1.82; 95% CI 1.03-3.24), among women treated with ≥4 cycles of progesterone (RR 2.63; 95% CI 1.04-6.64) and for all women followed up for ≥4 years after their first treatment with progesterone. Although we tried to minimize the effects of the underlying infertility, the severity of infertility might have affected our risk estimates, as women with more severe fertility problems may receive more treatment. The results from the subgroup analyses, e.g. the findings of an elevated risk for borderline ovarian tumours associated with increased time since first use of progesterone and with increased number of treatment cycles, should be interpreted with caution as these analyses are based on a limited number of women with borderline ovarian tumours. Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and risk for borderline ovarian tumours, the novel observation of an increased risk for serous tumours after use of progesterone should be investigated in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of fertility problems. No conflict of interest was reported. S.M.B. was supported by a research scholarship from the Danish Cancer Society. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ovarian surgery for symptom relief in women with polycystic ovary syndrome.

PubMed

Lepine, Sam; Jo, Junyoung; Metwally, Mostafa; Cheong, Ying C

2017-11-10

Polycystic ovary syndrome (PCOS) is a common endocrine condition, affecting approximately one in 10 women. PCOS is defined by two of three features: oligo- or anovulation, clinical or biochemical hyperandrogenism or both, or polycystic ovaries.Women with PCOS can have a wide range of health problems, including infrequent and irregular periods, unwanted hair growth and acne, and subnormal fertility. Long-term health concerns include an increased risk of heart disease, diabetes and the development of precancerous disease of the womb. To assess the effectiveness and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual irregularity in PCOS. We searched the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL, MEDLINE, Embase and PsycINFO (from inception to 17 October 2016). We handsearched citation lists, registers of ongoing trials and conference proceedings. We included randomized controlled trials (RCTs) of women undergoing ovarian drilling in comparison to no treatment, medical treatment, or other forms of surgical treatment for the symptoms of PCOS. We used standard methodological procedures recommended by Cochrane. The primary outcome measures were improvement in menstrual regularity and androgenic symptoms of PCOS (hirsutism, acne); the secondary outcome measures included harms, change of body mass index (BMI), waist circumference, androgen levels, metabolic measures and quality of life. We assessed the quality of the evidence using GRADE methods. We included 22 RCTs (2278 women analyzed) of participants with PCOS and symptoms of acne, hirsutism or irregular menstrual cycles, all of which included laparoscopic ovarian drilling (LOD) as an intervention.Two studies reported their funding source (Farquhar 2002 - supported in part by the Auckland Medical Research Foundation; Sarouri 2015 - the authors thank the Vice Chancellor for Research of Guilan University of Medical Sciences for funding this project).The quality of the evidence ranged from very low to moderate quality. The main limitations were imprecision associated with the low number of studies, inconsistency and risk of bias associated with the inability to blind participants. There were too few studies to assess risk of publication bias. Menstrual RegularityTwo studies compared LOD versus metformin (n=226) but no conclusions could be drawn with regard to menstrual regularity, as their findings were inconsistent and they were unsuitable for pooling. There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when LOD was compared with medical treatment including metformin + clomiphene (OR 1.02, 95% CI 0.64 to 1.64, 2 studies, 332 women, I 2 = 13%, low-quality evidence), letrozole (OR 1.08, 95% CI 0.64 to 1.84, 1 study, 260 women, low-quality evidence), or metformin + letrozole (OR 0.95, 95% CI 0.49 to 1.81, 1 study, 146 women, low-quality evidence). However, one study reported that LOD was superior to gonadotrophin (OR 19.2, 95% CI 3.17 to 116.45, 1 study, 35 women, very low-quality evidence).There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when bilateral unipolar LOD was compared to unilateral LOD (OR 1.51, 95% CI 0.62 to 3.71, 2 studies, 104 women, I 2 = 0%, moderate-quality evidence), transvaginal ultrasound-guided LOD (OR 1.23, 95% CI 0.64 to 2.37, 1 study, 147 women, low-quality evidence), LOD using adjusted thermal dose in accordance with the ovarian volume (OR 0.42, 95% CI 0.16 to 1.14, 1 study, 115 women, low-quality evidence) or bipolar LOD (OR 1.00, 95% CI 0.05 to 18.57, 1 study, 18 women, low-quality evidence).Four to five punctures per ovary may improve the rate of women reporting menstrual regularity compared with two or fewer (OR 16.04, 95% CI 4.19 to 61.34, 2 studies, 73 women, I 2 = 0%, low-quality evidence). Androgenic SymptomsThere was probably little or no difference in improvement in androgenic symptoms when LOD was compared to metformin (OR 1.00, 95% CI 0.42 to 2.37, 1 study, 126 women, moderate-quality evidence) or gonadotrophins; acne (OR 3.20, 95% CI 0.33 to 30.94, 1 study, 25 women, low-quality evidence), hirsutism (OR 2.31, 95% CI 0.22 to 23.89, 1 study, 25 women, low-quality evidence).There appeared to be little or no difference in improvement of androgenic symptoms when LOD was compared to transvaginal ultrasound-guided LOD, with respect to hirsutism (OR 1.09, 95% CI 0.30 to 3.91, 1 study, 39 women, low-quality evidence) or acne (OR 0.84, 95% CI 0.20 to 3.50, 1 study, 31 women, low-quality evidence). HarmsLOD was associated with fewer gastrointestinal side effects than metformin plus clomiphene (OR 0.05, 95% CI 0.01 to 0.36, 2 studies, 332 women, I 2 = 0%, moderate-quality evidence). One study suggested little or no difference in rates of ovarian hyperstimulation syndrome between LOD and gonadotrophins (OR 0.08, 95% CI 0.00 to 1.61, 1 study, 33 women, low-quality evidence).There were fewer adhesions with transvaginal hydrolaparoscopy compared to LOD (OR 0.10, 95% CI 0.05 to 0.18, 1 study, 246 women, moderate-quality evidence). There appeared to be little or no difference in adhesions when variable energy LOD was compared with standard LOD (OR 0.96, 95% CI 0.32 to 2.88, 1 study, 64 women, low-quality evidence). Another study (44 women) reported that none of the women who returned for surgery following either traditional or unilateral LOD were found to have adhesions. There was no clear evidence that LOD improves menstrual regularity or the androgenic symptoms of PCOS, compared to most of the medical treatments used in the included studies. LOD was associated with fewer gastrointestinal side effects compared to metformin and clomiphene.There was also no clear evidence of different effectiveness between types of LOD, except that LOD with four to five punctures per ovary may be more effective than two or fewer punctures. There was little evidence comparing LOD with different types of surgery, although one study concluded that transvaginal hydrolaparoscopy had a lower risk of adhesions than LOD.There was evidence from one small study of benefit from LOD compared to gonadotrophins for menstrual regulation. However, gonadotrophins are seldom used for this indication.

Unilateral Versus Bilateral Laparoscopic Ovarian Drilling Using Thermal Dose Adjusted According to Ovarian Volume in CC-Resistant PCOS, A Randomized Study.

PubMed

El-Sayed, Mohamed Lotfy Mohamed; Ahmed, Mostafa Abdo; Mansour, Marwa Abdel Azim; Mansour, Shymma Abdel Azim

2017-10-01

This study aimed to evaluate the efficacy of unilateral laparoscopic ovarian drilling versus bilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume in clomiphene citrate (CC)-resistant PCOS patients in terms of endocrine changes, menstrual cycle resumption, ovulation and pregnancy rates. This study was conducted in the Department of Obstetrics and Gynecology, Zagazig university hospitals. One hundred CC-resistant PCOS patients were divided into two groups. Group (I) (50 patients) underwent unilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume (60 J/cm 3 of ovarian tissue), and group (II) (50 patients) underwent bilateral laparoscopic ovarian drilling using the same previously mentioned thermal dose. Endocrinal changes and menstrual cycle resumption were assessed within 8 weeks postoperatively, but the ovulation and pregnancy rates were estimated after 6-month follow-up period. There was no statistically significant difference between the two groups as regards demographic data ( p  > 0.05). As regards menstruation cycle resumption (62.5 vs. 81%) ( p  = 0.047), total ovulation rate (54.2 vs. 78.7%) ( p  = 0.011) and cumulative pregnancy rate (33.3 vs. 55.3%) ( p  = 0.031), there was statistically significant difference between both groups. After drilling, there were highly statistically significant decrease in the mean serum levels of luteinizing hormone (LH) and significant decrease in the mean serum levels of testosterone in both groups. Mean serum level of follicle stimulating hormone (FSH) did not change significantly in both groups after drilling. Bilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume is more effective than the right-sided unilateral technique with thermal dose adjusted according to ovarian volume in terms of menstrual cycle resumption, ovulation and cumulative pregnancy rates in CC-resistant PCOS patients.

Cancer Risk in Women Treated with Fertility Drugs According to Parity status - A Registry-based Cohort Study

PubMed Central

Reigstad, Marte Myhre; Storeng, Ritsa; Myklebust, Tor Åge; Oldereid, Nan Birgitte; Omland, Anne Katerine; Robsahm, Trude Eid; Brinton, Louise Anette; Vangen, Siri; Furu, Kari; Larsen, Inger Kristin

2017-01-01

Background Long-term safety of assisted reproductive techniques (ART) is of interest as use is increasing. Cancer risk is known to be affected by parity. This study examined risk of cancer after fertility treatment, stratified by women’s parity. Methods Data was obtained on all women (n=1 353 724) born in Norway between 1960–1996. Drug exposure data (2004–2014) was obtained from the Norwegian Prescription Database [drugs used in ART and clomiphene citrate (CC)]. The Medical Birth Registry of Norway provided parity status. Hazard ratios were calculated for all site cancer, breast, cervical, endometrial, ovarian, colorectal, central nervous system, thyroid cancer and malignant melanoma. Results In 12 354 392 person-years of follow-up, 20 128 women were diagnosed with cancer. All-site cancer risk was (1.14, 1.03–1.26) and (1.10, 0.98–1.23) following CC and ART exposure respectively. For ovarian cancer, a stronger association was observed for both exposures in nulliparous (HR 2.49, 1.30–4.78, and HR 1.62, 0.78–3.35) versus parous women (HR 1.37, 0.64–2.96, and HR 0.87, 0.33–2.27). Elevated risk of endometrial cancers was observed for CC exposure in nulliparous women (4.59, 2.68–7.84 vs. 1.44, 0.63–3.31). Risk was elevated for breast cancer in parous women exposed to CC (1.26, 1.03–1.54) and among nulliparous women after ART treatment (2.19, 1.08–4.44). Conclusion CC appears associated with increased risk of ovarian and endometrial cancer. Elevations in risks of breast and thyroid cancer were less consistent across type of drug exposure and parity. Impact Continued monitoring of fertility treatments is warranted. PMID:28108444

Review: aromatase inhibitors for ovulation induction.

PubMed

Casper, Robert F; Mitwally, Mohamed F M

2006-03-01

For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking.

Diagnosis and management of polycystic ovary syndrome in the UK (2004–2014): a retrospective cohort study

PubMed Central

Ding, Tao; Baio, Gianluca; Hardiman, Paul J; Petersen, Irene; Sammon, Cormac

2016-01-01

Objective To estimate the incidence and prevalence of polycystic ovary syndrome (PCOS) in UK primary care and investigate prescribing patterns before and after a PCOS diagnosis. Design Retrospective cohort study. Setting UK primary care (2004–2014). Participants Women aged 15–45 years. Primary and secondary outcome measures The incidence and prevalence of diagnosed PCOS and probable PCOS (ie, those without a confirmed diagnosis but with at least 2 PCOS features recorded within 3 years). Among women with diagnosed or probable PCOS, the prevalence of prescribing of drugs typically used to treat PCOS was calculated prior to and in the 24 months after the diagnosis of PCOS. Results We identified 7233 women with PCOS diagnoses and 7057 women with records suggestive of probable PCOS, corresponding to incidence rates of 0.93 and 0.91 per 1000 person-years at risk (PYAR) and an overall rate of 1.84 per 1000 PYAR. Women aged 20–24 years and women living in deprived areas had the highest incidence of PCOS. The prevalence of PCOS in 2014 was ∼2%. The proportion of women with a prescription in the 24 months after their PCOS index date varied by drug type: 10.2% metformin, 15.2% combined oral contraceptives, 18.8% acne-related treatments, 1.93% clomiphene, 1.0% spironolactone, 0.28% cyproterone and 3.11% eflornithine. Acne-related treatments were more commonly used to treat probable (28.3%) than diagnosed (12.3%) cases, while metformin was prescribed much more commonly in diagnosed cases. Conclusions In conclusion, compared to rates estimated in community samples, the incidence and prevalence of women presenting in primary care with PCOS diagnoses and features are low, indicating that PCOS is an under-recognised condition. Although considerable variation is observed in treatments prescribed to women with PCOS, the treatments initiated following a confirmed diagnosis generally reflect the long-term prognostic concerns raised in PCOS consensuses. PMID:27401369

Controlled Ovarian Hyperstimulation with Intrauterine Insemination Is More Successful After r-hCG Administration Than Spontaneous LH Surge.

PubMed

Taerk, Evan; Hughes, Edward; Greenberg, Cassandra; Neal, Michael; Amin, Shilpa; Faghih, Mehrnoosh; Karnis, Megan

2017-01-01

The purpose of this study was to evaluate whether clinical pregnancy rate is affected by timing intrauterine insemination (IUI) according to serum LH surge, r-hCG trigger, or a combination of LH surge and r-hCG trigger in controlled ovarian hyperstimulation (COH) cycles for patients with a variety of infertility etiologies. The last 365 consecutive COH-IUI cycles performed at ONE Fertility Burlington in 2014 were reviewed and categorized according to method of IUI timing. Associations between categorical variables were analyzed using a combination of Chi-square and Fisher's Exact tests, and between continuous variables using independent sample t-tests and logistic regression to a level of significance of p<0.05. The overall clinical pregnancy rate in this sample was 18.1% (66/365). Administration of r-hCG prior to IUI resulted in a higher clinical pregnancy rate compared with spontaneous serum LH surge: 18.2% vs . 5.8%, p=0.012. Patients in whom r-hCG was administered concomitantly with a serum LH surge had a higher clinical pregnancy than the r-hCG trigger group (30.8% vs . 18.2%, p=0.004) and LH surge group (30.8% vs . 5.8%, p<0.001). A sub-group analysis revealed that patients receiving r-FSH, rather than clomiphene or letrozole, had a significantly higher clinical pregnancy rate after r-hCG trigger as compared to the LH surge group (21.7% vs . 2.1%, p=0.01). In subfertile couples undergoing COH-IUI, r-hCG administration was associated with an increased clinical pregnancy rate compared with spontaneous serum LH surge. When r-hCG was administered concomitantly with a serum LH surge, this benefit was amplified. The effect appears to be of particular importance in r-FSH-medicated cycles.

PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

PubMed Central

Oostdijk, Wilma; Idkowiak, Jan; Mueller, Jonathan W.; House, Philip J.; Taylor, Angela E.; O'Reilly, Michael W.; Hughes, Beverly A.; de Vries, Martine C.; Kant, Sarina G.; Santen, Gijs W. E.; Verkerk, Annemieke J. M. H.; Uitterlinden, André G.; Wit, Jan M.; Losekoot, Monique

2015-01-01

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome. PMID:25594860

A case-control pilot study of low-intensity IVF in good-prognosis patients.

PubMed

Gleicher, Norbert; Weghofer, Andrea; Barad, David H

2012-04-01

Low-intensity IVF (LI-IVF) is rapidly gaining in popularity. Yet studies comparing LI-IVF to standard IVF are lacking. This is a case-control pilot study, reporting on 14 first LI-IVF and 14 standard IVF cycles in women with normal age-specific ovarian reserve under age 38, matched for age, laboratory environment, staff and time of cycle. LI-IVF cycles underwent mild ovarian stimulation, utilizing clomiphene citrate, augmented by low-dose gonadotrophin stimulation. Control patients underwent routine ovarian stimulation. LI-IVF and regular IVF patients were similar in age, body mass index, FSH and anti-Müllerian hormone. Standard IVF utilized more gonadotrophins (P<0.001), yielded more oocytes (P<0.001) and cryopreserved more embryos (P<0.001). With similar embryo numbers transferred, after ethnicity adjustments, standard IVF demonstrated better odds for pregnancy (OR 7.07; P=0.046) and higher cumulative pregnancy rates (63.3% versus 21.4%; OR 6.6; P=0.02). Adjustments for age, ethnicity and diagnosis maintained significance but oocyte adjustment did not. Cost assessments failed to reveal differences between LI-IVF and standard IVF. In this small study, LI-IVF reduced pregnancy chances without demonstrating cost advantages, raising questions about its utility. In the absence of established clinical and/or economic foundations, LI-IVF should be considered an experimental procedure. Low-intensity IVF (LI-IVF) is increasingly propagated as an alternative to standard IVF. LI-IVF has, however, never been properly assessed in comparison to standard IVF. Such a comparison is presented in the format of a small pilot study, matching LI-IVF cycles with regular IVF cycles and comparing outcomes as well as costs. The study suggests that LI-IVF, at least in this setting, is clinically inferior and economically at best similar to standard IVF. LI-IVF should, therefore, as of this point not be offered as routine IVF treatment but only as an experimental procedure. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Walnut leaf extract acts as a fertility agent in male Wistar albino rats - A search for herbal male fertility enhancer.

PubMed

Akomolafe, Seun F; Oboh, Ganiyu

2017-11-17

Background Walnut leaf is one of the many medicinal plants used in folklore as male fertility enhancers. The present work was therefore undertaken with an aim to scientifically validate this claim. As such, we evaluated the effect of the aqueous extract from walnut leaves on biomolecules related to fertility in adult male rats and its mode of action as fertility-enhancing agent. Methods Twenty-five rats were randomly divided into five groups of five animals each; Group 1 served as control and received normal (0.9%) saline only; Groups II, III, IV received 50, 500, 1,000 mg/kg body weight (BW) of T. conophorum leaf extract orally, while Group V served as standard and was given suspension of clomiphene citrate orally at the dose of 1.04 mg/kg/ml BW. The extract and drug were given daily and the experiment lasted for 21 consecutive days. Results The testicular biochemical parameters in treated groups showed significant (p<0.05) increase in lactate dehydrogenase activity activity, Glucose-6-phosphate dehydrogenase (G-6PDH) activity, glycogen content, 3β and 17β hydroxysteroid dehydrogenase activities and testicular and epididymal Zn and Se contents with a significant decrease in cholesterol content. A significant increase in testis weight and epididymis weight were also observed. Also, a significant (p<0.05) increase in the level of serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone, sperm count, motility, viability and a decrease in sperm abnormality were observed in the various treated groups when compared with the control group. This increment was concentration dependent, while the extract at the highest concentration showed a more pronounced effect than the standard drug. Also, no sperm DNA fragmentation index was found in all the treatment groups. Photomicrographs from light and scanning electron microscopy showed large fenestrae of interstitial tissue, large fluid space and intact seminiferous epithelium layers fully packed with spermatogenic cells in treated groups than the control group. Conclusions The present study has demonstrated that Tetracarpidium conophorum leaf possesses fertility-enhancing property and have useful effects on spermatogenesis and sperm parameters in rats.

Diagnosis and management of polycystic ovary syndrome in the UK (2004-2014): a retrospective cohort study.

PubMed

Ding, Tao; Baio, Gianluca; Hardiman, Paul J; Petersen, Irene; Sammon, Cormac

2016-07-11

To estimate the incidence and prevalence of polycystic ovary syndrome (PCOS) in UK primary care and investigate prescribing patterns before and after a PCOS diagnosis. Retrospective cohort study. UK primary care (2004-2014). Women aged 15-45 years. The incidence and prevalence of diagnosed PCOS and probable PCOS (ie, those without a confirmed diagnosis but with at least 2 PCOS features recorded within 3 years). Among women with diagnosed or probable PCOS, the prevalence of prescribing of drugs typically used to treat PCOS was calculated prior to and in the 24 months after the diagnosis of PCOS. We identified 7233 women with PCOS diagnoses and 7057 women with records suggestive of probable PCOS, corresponding to incidence rates of 0.93 and 0.91 per 1000 person-years at risk (PYAR) and an overall rate of 1.84 per 1000 PYAR. Women aged 20-24 years and women living in deprived areas had the highest incidence of PCOS. The prevalence of PCOS in 2014 was ∼2%. The proportion of women with a prescription in the 24 months after their PCOS index date varied by drug type: 10.2% metformin, 15.2% combined oral contraceptives, 18.8% acne-related treatments, 1.93% clomiphene, 1.0% spironolactone, 0.28% cyproterone and 3.11% eflornithine. Acne-related treatments were more commonly used to treat probable (28.3%) than diagnosed (12.3%) cases, while metformin was prescribed much more commonly in diagnosed cases. In conclusion, compared to rates estimated in community samples, the incidence and prevalence of women presenting in primary care with PCOS diagnoses and features are low, indicating that PCOS is an under-recognised condition. Although considerable variation is observed in treatments prescribed to women with PCOS, the treatments initiated following a confirmed diagnosis generally reflect the long-term prognostic concerns raised in PCOS consensuses. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovary Syndrome.

PubMed

Legro, Richard S; Dodson, William C; Kris-Etherton, Penny M; Kunselman, Allen R; Stetter, Christy M; Williams, Nancy I; Gnatuk, Carol L; Estes, Stephanie J; Fleming, Jennifer; Allison, Kelly C; Sarwer, David B; Coutifaris, Christos; Dokras, Anuja

2015-11-01

Lifestyle modification is recommended in women with polycystic ovary syndrome (PCOS) prior to conception but there are few randomized trials to support its implementation or benefit. This study aimed to determine the relative efficacy of preconception intervention on reproductive and metabolic abnormalities in overweight/obese women with PCOS. This was a randomized controlled trial of preconception and infertility treatment at Academic Health Centers in women with infertility due to PCOS, age 18-40 y and body mass index 27-42 kg/m(2). Women were randomly assigned to receive either 16 weeks of 1) continuous oral contraceptive pills (OCPs) (ethinyl estradiol 20 mcg/1 mg norethindrone acetate) ("OCP"); 2) lifestyle modification consisting of caloric restriction with meal replacements, weight loss medication (either sibutramine, or orlistat), and increased physical activity to promote a 7% weight loss ("Lifestyle"); or 3) combined treatment with both OCP and lifestyle modification ("Combined"). After preconception intervention, women underwent standardized ovulation induction with clomiphene citrate and timed intercourse for four cycles. Pregnancies were followed with trimester visits until delivery. Weight, ovulation, and live birth were measured. We consented 216 and randomly assigned 149 women (Lifestyle: n = 50; OCP: n = 49; Combined: n = 50). We achieved significant weight loss with both Lifestyle (mean weight loss, -6.2%; 95% confidence interval (CI), -7.4--5.0; and Combined (mean weight loss, -6.4%; 95% CI, -7.6--5.2) compared with baseline and OCP (both P < .001). There was a significant increase in the prevalence of metabolic syndrome at the end of preconception treatment compared with baseline within OCP (odds ratio [OR, 2.47; 95% CI, 1.42-4.27) whereas no change in metabolic syndrome was detected in the Lifestyle (OR, 1.18; 95% CI, 0.63-2.19) or Combined (OR, 0.72; 95% CI, 0.44-1.17) groups. Cumulative ovulation rates were superior after weight loss: OCP, 46%; Lifestyle, 60%; and Combined, 67% (P < .05). Live birth rates were OCP, 12%; Lifestyle, 26%; and Combined, 24% (P = .13). A preconception weight loss intervention eliminates the adverse metabolic oral contraceptive effects and, compared with oral contraceptive pretreatment, leads to higher ovulation rates.

Analysis of Maternal Risk Factors Associated With Congenital Vertebral Malformations

PubMed Central

Hesemann, Jennifer; Lauer, Emily; Ziska, Stephen; Noonan, Kenneth; Nemeth, Blaise; Scott-Schwoerer, Jessica; McCarty, Catherine; Rasmussen, Kristen; Goldberg, Jacob M.; Sund, Sarah; Eickhoff, Jens; Raggio, Cathleen L.; Giampietro, Philip F.

2014-01-01

Study Design A retrospective chart review of cases with congenital vertebral malformations (CVM) and controls with normal spine morphology. Objective To determine the relative contribution of maternal environmental factors (MEF) during pregnancy including maternal insulin dependent diabetes mellitus, valproic acid, alcohol, smoking, hyperthermia, twin gestation, assisted reproductive technology, in-vitro fertilization and maternal clomiphene usage to CVM development. Summary of Background Data Congenital vertebral malformations (CVM) represent defects in formation and segmentation of somites occurring with an estimated incidence of between 0.13–0.50 per 1000 live births. CVM may be associated with congenital scoliosis, Klippel-Feil syndrome, hemifacial microsomia and VACTERL syndromes, and represent significant morbidity due to pain and cosmetic disfigurement. Methods A multicenter retrospective chart review of 229 cases with CVM and 267 controls with normal spine morphology between the ages of 1–50 years was performed in order to obtain the odds ratio (OR) of MEF related to CVM among cases vs. controls. CVM due to an underlying syndrome associated with a known gene mutation or chromosome etiology were excluded. An imputation based analysis was performed in which subjects with no documentation of MEF history were treated as no maternal exposure.” Univariate and multivariate analysis was conducted to calculate the OR. Results Of the 229 total cases, 104 cases had single or multiple CVM without additional congenital malformations (CM) (Group 1) and 125 cases had single or multiple CVM and additional CM (Group 2). Nineteen percent of total cases had an identified MEF. The OR (95% CI, P-value) for MEF history for Group 1 was 6.0 (2.4–15.1, P<0.001) in the univariate analysis. The OR for MEF history in Group 2 was 9.1 (95%CI, P-value) (3.8–21.6, P<0.001) in the univariate analysis. The results were confirmed in the multivariate analysis, after adjusting for age, gender, and institution. Discussion These results support a hypothesis for an association between the above MEF during pregnancy and CVM and have implications for development of prevention strategies. Further prospective studies are needed to quantify association between CVM and specific MEF. PMID:23446706

Fertility drugs and young-onset breast cancer: results from the Two Sister Study.

PubMed

Fei, Chunyuan; Deroo, Lisa A; Sandler, Dale P; Weinberg, Clarice R

2012-07-03

Fertility drugs stimulate hyperovulation, which may have implications for breast cancer. We examined the association between use of fertility drugs (clomiphene citrate [CC] and follicle-stimulating hormone [FSH]) and subsequent risk of young-onset (<50 years at diagnosis) breast cancer. We conducted the Two Sister Study, a sister-matched case-control study, by enrolling 1422 women between September 2008 and December 2010, who were younger than age 50 years at diagnosis with breast cancer and were enrolled within 4 years of diagnosis, and 1669 breast cancer-free control sisters from the Sister Study. Participants reported their use of fertility drugs (CC and FSH) and ever-users reported whether a pregnancy had resulted that lasted 10 or more (10+) weeks. Conditional logistic regression was used to estimate confounder-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for fertility drug use with or without conception of a 10+ week pregnancy. A total of 288 participants reported having used ovulation-stimulating drugs (193 CC only, 29 FSH only, and 66 both). Overall, women who had used fertility drugs showed a non-statistically significantly decreased risk of breast cancer, compared with nonusers (OR = 0.82, 95% CI = 0.63 to 1.08). Women who had used fertility drugs but had not conceived a 10+ week pregnancy under treatment showed a statistically significantly decreased risk of breast cancer compared with nonusers (OR = 0.62, 95% CI = 0.43 to 0.89). Women who had used fertility drugs and conceived a 10+ week pregnancy under treatment showed a statistically significantly increased risk of breast cancer compared with unsuccessfully treated women (OR = 1.82, 95% CI = 1.10 to 3.00), although their risk was not increased compared with women who had not used fertility drugs (OR = 1.13, 95% CI = 0.78 to 1.64). In the absence of a 10+ week pregnancy under treatment, exposure to ovulation-stimulating fertility drugs was associated with reduced risk of young-onset breast cancer. This apparent association was absent in women who conceived a 10+ week pregnancy under treatment, for whom risk was higher than that of unsuccessfully treated women, but similar to that of untreated women.

Fertility-related quality of life from two RCT cohorts with infertility: unexplained infertility and polycystic ovary syndrome

PubMed Central

Santoro, Nanette; Eisenberg, Esther; Trussell, J.C.; Craig, LaTasha B.; Gracia, Clarisa; Huang, Hao; Alvero, Ruben; Casson, Peter; Christman, Gregory; Coutifaris, Christos; Diamond, Michael; Jin, Susan; Legro, Richard S.; Robinson, Randal D.; Schlaff, William D.; Zhang, Heping

2016-01-01

STUDY QUESTION Does fertility-related quality of life (FertiQOL) differ by infertility diagnosis between women with polycystic ovary syndrome (PCOS) and their partners, compared with couples with unexplained infertility (UI)? SUMMARY ANSWER Women with PCOS report lower QOL than those with UI, whereas males with UI report lower QOL than males with PCOS partners. WHAT IS KNOWN ALREADY The fertility-specific QOL survey, FertiQOL, has been used to examine fertility-related QOL in a number of worldwide cohorts. Few data have addressed fertility-related QOL as a function of infertility diagnosis. Overall, men report better QOL than women with infertility, and there is variation in FertiQOL scores across different samples from different countries. STUDY DESIGN, SIZE, DURATION This was a prospective, cohort study derived from two concurrent, randomized clinical trials, and designed to examine QOL in infertile females with PCOS and UI at the time of enrollment compared with each other and their male partners; to compare concordance FertiQOL scores in this study across other worldwide cohorts; and to determine if baseline FertiQOL was associated with pregnancy outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS and their partners (n = 733 and n = 641, respectively), and couples with UI (n = 865 women and 849 men) completed a validated fertility-specific QOL survey (FertiQOL) at the time of the study screening visit. PCOS women were randomized to either clomiphene citrate or letrozole treatment; couples with UI were randomized to clomiphene citrate, letrozole or gonadotrophin plus IUI. FertiQOL results were compiled by diagnosis (PCOS or UI) and compared by diagnosis and sex using Wilcoxon Rank-Sum testing. Relationships between baseline FertiQOL and pregnancy outcomes were examined using logistic regression. Multivariable models were performed to assess the association between FertiQOL scores and key participant characteristics. MAIN RESULTS AND THE ROLE OF CHANCE Women with PCOS had lower total FertiQOL scores (72.3 ± 14.8) than those with UI (77.1 ± 12.8; P < 0.001); this was true for each domain (except Relational). These differences were largely explained by variation in BMI, hirsutism, household income and age. Women had lower overall FertiQOL scores than their male partners. Males with PCOS partners had higher scores than males with UI (84.9 ± 10.2 versus 83.3 ± 10.8; P = 0.003). Scores were not consistently associated with conception or pregnancy outcome. LIMITATIONS, REASONS FOR CAUTION The use of multiple tests of association may have resulted in spurious statistically significant findings. Inherent sociodemographic differences between women with PCOS and those with UI largely account for the lower QOL in women with PCOS. Our study was unable to assess if changes in QOL affected pregnancy outcome as FertiQOL data were collected prior to treatment. Finally, the participants for both studies represent their local communities, but are not a population-based sample and thus firm conclusions about how representative these couples are to the general population must be made with caution. WIDER IMPLICATIONS OF THE FINDINGS Women with PCOS with elevated BMI and hirsutism scores and with lower socioeconomic status may require more, targeted psychosocial support than those with other diagnoses. Possible attribution of infertility to the male partner appears to result in a lower QOL. There appears to be substantial national variation in FertiQOL scores, with US-based cohorts reporting overall higher QOL. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD39005 (to M.D.), U10 HD38992 (to R.S.L.), (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act. N.S., E.E., J.C.T., C.G., H.H., R.A., P.C., G.C., C.C., M.D., S.J., W.D.S. and H.Z. report no conflicts of interests/disclosures. L.B.C. reports research support from Ferring Pharmaceuticals and Roche Diagnostics; R.S.L. reports receipt of consulting fees from AstraZeneca, Euroscreen, Sprout Pharmaceuticals, Taken, Kindex, Clarus and Bayer, Inc., and research support from AstraZeneca and Ferring Pharmaceuticals. R.D.R. reports research support from AbbVie. TRIAL REGISTRATION NUMBER Pregnancy in Polycystic Ovary Syndrome II (PPCOS II), NCT00719186; Assessment of Multiple Intrauterine Gestations in Ovulation Stimulation (AMIGOS) NCT01044862, clinicaltrials.gov. TRIAL REGISTRATION DATE PPCOS II 17 July 2008; AMIGOS 7 January 2010. DATE OF FIRST PATIENT'S ENROLMENT PPCOS II 19 February 2009; AMIGOS 2 August 2010. PMID:27402910

Fertility-related quality of life from two RCT cohorts with infertility: unexplained infertility and polycystic ovary syndrome.

PubMed

Santoro, Nanette; Eisenberg, Esther; Trussell, J C; Craig, LaTasha B; Gracia, Clarisa; Huang, Hao; Alvero, Ruben; Casson, Peter; Christman, Gregory; Coutifaris, Christos; Diamond, Michael; Jin, Susan; Legro, Richard S; Robinson, Randal D; Schlaff, William D; Zhang, Heping

2016-10-01

Does fertility-related quality of life (FertiQOL) differ by infertility diagnosis between women with polycystic ovary syndrome (PCOS) and their partners, compared with couples with unexplained infertility (UI)? Women with PCOS report lower QOL than those with UI, whereas males with UI report lower QOL than males with PCOS partners. The fertility-specific QOL survey, FertiQOL, has been used to examine fertility-related QOL in a number of worldwide cohorts. Few data have addressed fertility-related QOL as a function of infertility diagnosis. Overall, men report better QOL than women with infertility, and there is variation in FertiQOL scores across different samples from different countries. This was a prospective, cohort study derived from two concurrent, randomized clinical trials, and designed to examine QOL in infertile females with PCOS and UI at the time of enrollment compared with each other and their male partners; to compare concordance FertiQOL scores in this study across other worldwide cohorts; and to determine if baseline FertiQOL was associated with pregnancy outcome. Women with PCOS and their partners (n = 733 and n = 641, respectively), and couples with UI (n = 865 women and 849 men) completed a validated fertility-specific QOL survey (FertiQOL) at the time of the study screening visit. PCOS women were randomized to either clomiphene citrate or letrozole treatment; couples with UI were randomized to clomiphene citrate, letrozole or gonadotrophin plus IUI. FertiQOL results were compiled by diagnosis (PCOS or UI) and compared by diagnosis and sex using Wilcoxon Rank-Sum testing. Relationships between baseline FertiQOL and pregnancy outcomes were examined using logistic regression. Multivariable models were performed to assess the association between FertiQOL scores and key participant characteristics. Women with PCOS had lower total FertiQOL scores (72.3 ± 14.8) than those with UI (77.1 ± 12.8; P < 0.001); this was true for each domain (except Relational). These differences were largely explained by variation in BMI, hirsutism, household income and age. Women had lower overall FertiQOL scores than their male partners. Males with PCOS partners had higher scores than males with UI (84.9 ± 10.2 versus 83.3 ± 10.8; P = 0.003). Scores were not consistently associated with conception or pregnancy outcome. The use of multiple tests of association may have resulted in spurious statistically significant findings. Inherent sociodemographic differences between women with PCOS and those with UI largely account for the lower QOL in women with PCOS. Our study was unable to assess if changes in QOL affected pregnancy outcome as FertiQOL data were collected prior to treatment. Finally, the participants for both studies represent their local communities, but are not a population-based sample and thus firm conclusions about how representative these couples are to the general population must be made with caution. Women with PCOS with elevated BMI and hirsutism scores and with lower socioeconomic status may require more, targeted psychosocial support than those with other diagnoses. Possible attribution of infertility to the male partner appears to result in a lower QOL. There appears to be substantial national variation in FertiQOL scores, with US-based cohorts reporting overall higher QOL. This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD39005 (to M.D.), U10 HD38992 (to R.S.L.), (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act. N.S., E.E., J.C.T., C.G., H.H., R.A., P.C., G.C., C.C., M.D., S.J., W.D.S. and H.Z. report no conflicts of interests/disclosures. L.B.C. reports research support from Ferring Pharmaceuticals and Roche Diagnostics; R.S.L. reports receipt of consulting fees from AstraZeneca, Euroscreen, Sprout Pharmaceuticals, Taken, Kindex, Clarus and Bayer, Inc., and research support from AstraZeneca and Ferring Pharmaceuticals. R.D.R. reports research support from AbbVie. Pregnancy in Polycystic Ovary Syndrome II (PPCOS II), NCT00719186; Assessment of Multiple Intrauterine Gestations in Ovulation Stimulation (AMIGOS) NCT01044862, clinicaltrials.gov. PPCOS II 17 July 2008; AMIGOS 7 January 2010. PPCOS II 19 February 2009; AMIGOS 2 August 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Laparoscopic ovarian drilling versus GnRH antagonist combined with cabergoline as a prophylaxis against the re-development of ovarian hyperstimulation syndrome.

PubMed

Seyam, Emaduldin; Hefzy, Enas

2018-07-01

The aim of this work was to investigate the value of laparoscopic ovarian drilling (LOD) compared with GnRH antagonist flexible protocol combined with cabergoline (Cb), as a prophylaxis against the re-development of ovarian hyperstimulation syndrome (OHSS) in women with clomiphene citrate-resistant polycystic ovary disease (CCR-PCOD) who had severe OHSS before in a previous ICSI cycle. It is a prospective controlled study, where 250 CCR-PCOD women (n = 250) with a history of severe OHSS before, had been recruited for the study. LOD had been performed for 120 (n = 120) of the recruited women before ovarian induction, and considered as group A. GnRH antagonist (Cetrotide 0.25 mg) was added when a leading follicle reaches 14-16 mm combined with oral Cb in a dose 0.5 mg a day before hCG, and for 8 d for another 130 (n = 130) women, and considered as group B. Pregnancy was diagnosed with BhCG level ≥25 IU/L, ± 14 d after embryo transfer, followed with transvaginal ultrasound scanning (TVS) 2 weeks later to confirm intra-uterine pregnancy (IUP). Women were followed up weekly for 3 months for the possible development of any signs and symptoms of OHSS. None of the participants in group A developed severe OHSS, and only six women (5%) developed mild to moderate OHSS. The incidence of severe OHSS was significantly higher (n = 3, 15%) in group B compared with group A (p < .001). Another (n = 17, 13.3%) women in group B developed mild to moderate OHSS. The probability of developing severe OHSS was also significantly higher in group B as well (p = .031). Pregnancy rate (PR) was significantly higher in group A more than group B (67% versus 39%, respectively), and all were single intrauterine pregnancies (IUP) and all developed after fresh embryo transfer (ET), compared with frozen embryo transfer (FET) which was performed in 42 cases in group B after postponing ET due to significantly severe OHSS developed. LOD could be considered a good prophylactic measure against OHSS, in addition to improving the total outcome of IVF cycles in women with CCR-PCOS.

Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovary Syndrome

PubMed Central

Dodson, William C.; Kris-Etherton, Penny M.; Kunselman, Allen R.; Stetter, Christy M.; Williams, Nancy I.; Gnatuk, Carol L.; Estes, Stephanie J.; Fleming, Jennifer; Allison, Kelly C.; Sarwer, David B.; Coutifaris, Christos; Dokras, Anuja

2015-01-01

Context: Lifestyle modification is recommended in women with polycystic ovary syndrome (PCOS) prior to conception but there are few randomized trials to support its implementation or benefit. Objective: This study aimed to determine the relative efficacy of preconception intervention on reproductive and metabolic abnormalities in overweight/obese women with PCOS. Design, Setting, and Participants: This was a randomized controlled trial of preconception and infertility treatment at Academic Health Centers in women with infertility due to PCOS, age 18–40 y and body mass index 27–42 kg/m2. Intervention: Women were randomly assigned to receive either 16 weeks of 1) continuous oral contraceptive pills (OCPs) (ethinyl estradiol 20 mcg/1 mg norethindrone acetate) (“OCP”); 2) lifestyle modification consisting of caloric restriction with meal replacements, weight loss medication (either sibutramine, or orlistat), and increased physical activity to promote a 7% weight loss (“Lifestyle”); or 3) combined treatment with both OCP and lifestyle modification (“Combined”). After preconception intervention, women underwent standardized ovulation induction with clomiphene citrate and timed intercourse for four cycles. Pregnancies were followed with trimester visits until delivery. Main Outcome Measures: Weight, ovulation, and live birth were measured. Results: We consented 216 and randomly assigned 149 women (Lifestyle: n = 50; OCP: n = 49; Combined: n = 50). We achieved significant weight loss with both Lifestyle (mean weight loss, −6.2%; 95% confidence interval (CI), −7.4–−5.0; and Combined (mean weight loss, −6.4%; 95% CI, −7.6–−5.2) compared with baseline and OCP (both P < .001). There was a significant increase in the prevalence of metabolic syndrome at the end of preconception treatment compared with baseline within OCP (odds ratio [OR, 2.47; 95% CI, 1.42–4.27) whereas no change in metabolic syndrome was detected in the Lifestyle (OR, 1.18; 95% CI, 0.63–2.19) or Combined (OR, 0.72; 95% CI, 0.44–1.17) groups. Cumulative ovulation rates were superior after weight loss: OCP, 46%; Lifestyle, 60%; and Combined, 67% (P < .05). Live birth rates were OCP, 12%; Lifestyle, 26%; and Combined, 24% (P = .13). Conclusions: A preconception weight loss intervention eliminates the adverse metabolic oral contraceptive effects and, compared with oral contraceptive pretreatment, leads to higher ovulation rates. PMID:26401593

Impact of Male and Female Weight, Smoking, and Intercourse Frequency on Live Birth in Women With Polycystic Ovary Syndrome

PubMed Central

Allshouse, Amanda A.; Casson, Peter R.; Coutifaris, Christos; Diamond, Michael P.; Christman, Gregory M.; Schlaff, William D.; Alvero, Ruben; Trussell, J. C.; Krawetz, Stephen A.; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping; Legro, Richard S.

2015-01-01

Context: Obese men with normal semen parameters exhibit reduced fertility but few prospective data are available. Objective: This study aimed to determine the effect of male factors and body mass among the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) participants. Methods: This is a secondary analysis of the PPCOS II trial. A total of 750 infertile women with polycystic ovary syndrome (PCOS) were randomly assigned to up to receive five cycles of letrozole or clomiphene citrate. Females were 18–39-years-old and had a male partner with sperm concentration of at least 14 million/mL who consented to regular intercourse. Analysis was limited to couples with complete male partner information (n = 710). Results: Male body mass index (BMI) was higher in couples who failed to conceive (29.5 kg/m2 vs 28.2 kg/m2; P = .039) as well as those who did not achieve a live birth (29.5 kg/m2 vs 28.1 kg/m2; P = .047). At least one partner was obese in 548 couples (77.1%). A total of 261 couples were concordant for obesity (36.8%). After adjustment for female BMI, the association of male BMI with live birth was no longer significant (odds ratio [OR] = 0.85; 95 % confidence interval [CI], 0.68–1.05; P = .13). Couples in which both partners smoked had a lower chance of live birth vs nonsmokers (OR = 0.20; 95 % CI, 0.08–0.52; P = .02), whereas there was not a significant effect of female or male smoking alone. Live birth was more likely in couples with at least three sexual intercourse attempts over the previous 4 weeks (reported at baseline) as opposed to couples with lesser frequency (OR = 4.39; 95 % CI, 1.52–12. 4; P < .01). Conclusions: In this large cohort of obese women with PCOS, effect of male obesity was explained by female BMI. Lower chance of success was seen among couples where both partners smoked. Obesity and smoking are common among women with PCOS and their partners and contribute to a decrease in fertility treatment success. PMID:25856211

Fertility after contraception or abortion.

PubMed

Huggins, G R; Cullins, V E

1990-10-01

There is a very small correlation, if any, between the prior use of OCs and congenital malformations, including Down's syndrome. There are few, if any, recent reports on masculinization of a female fetus born to a mother who took an OC containing 1 mg of a progestogen during early pregnancy. However, patients suspected of being pregnant and who are desirous of continuing that pregnancy should not continue to take OCs, nor should progestogen withdrawal pregnancy tests be used. Concern still exists regarding the occurrence of congenital abnormalities in babies born to such women. The incidence of postoperative infection after first trimester therapeutic abortion in this country is low. However, increasing numbers of women are undergoing repeated pregnancy terminations, and their risk for subsequent pelvic infections may be multiplied with each succeeding abortion. The incidence of prematurity due to cervical incompetence or surgical infertility after first trimester pregnancy terminations is not increased significantly. Asherman's syndrome may occur after septic therapeutic abortion. The pregnancy rate after treatment of this syndrome is low. The return of menses and the achievement of a pregnancy may be slightly delayed after OCs are discontinued, but the fertility rate is within the normal range by 1 year. The incidence of postpill amenorrhea of greater than 6 months' duration is probably less than 1%. The occurrence of the syndrome does not seem to be related to length of use or type of pill. Patients with prior normal menses as well as those with menstrual abnormalities before use of OCs may develop this syndrome. Patients with normal estrogen and gonadotropin levels usually respond with return of menses and ovulation when treated with clomiphene. The rate for achievement of pregnancy is much lower than that for patients with spontaneous return of menses. The criteria for defining PID or for categorizing its severity are diverse. The incidence of PID is higher among IUD users than among patients taking OCs or using a barrier method. The excess risk of PID among IUD users, with the exception of the first few months after insertion, is related to sexually transmitted diseases and not the IUD. Women with no risk factors for sexually transmitted diseases have little increased risk of PID or infertility associated with IUD use. There appears to be no increased risk of congenital anomalies, altered sex ratio, or early pregnancy loss among spermicide users. All present methods of contraception entail some risk to the patient. The risk of imparied future fertility with the use of any method appears to be low.(ABSTRACT TRUNCATED AT 400 WORDS)

Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings.

PubMed

Arentz, Susan; Abbott, Jason Anthony; Smith, Caroline Anne; Bensoussan, Alan

2014-12-18

Polycystic ovary syndrome (PCOS) is a prevalent, complex endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility. Evidence based medical management emphasises a multidisciplinary approach for PCOS, as conventional pharmaceutical treatment addresses single symptoms, may be contra-indicated, is often associated with side effects and not effective in some cases. In addition women with PCOS have expressed a strong desire for alternative treatments. This review examines the reproductive endocrine effects in PCOS for an alternative treatment, herbal medicine. The aim of this review was to identify consistent evidence from both pre-clinical and clinical research, to add to the evidence base for herbal medicine in PCOS (and associated oligo/amenorrhoea and hyperandrogenism) and to inform herbal selection in the provision clinical care for these common conditions. We undertook two searches of the scientific literature. The first search sought pre-clinical studies which explained the reproductive endocrine effects of whole herbal extracts in oligo/amenorrhoea, hyperandrogenism and PCOS. Herbal medicines from the first search informed key words for the second search. The second search sought clinical studies, which corroborated laboratory findings. Subjects included women with PCOS, menstrual irregularities and hyperandrogenism. A total of 33 studies were included in this review. Eighteen pre-clinical studies reported mechanisms of effect and fifteen clinical studies corroborated pre-clinical findings, including eight randomised controlled trials, and 762 women with menstrual irregularities, hyperandrogenism and/or PCOS. Interventions included herbal extracts of Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia. Endocrine outcomes included reduced luteinising hormone (LH), prolactin, fasting insulin and testosterone. There was evidence for the regulation of ovulation, improved metabolic hormone profile and improved fertility outcomes in PCOS. There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate (and Cimicifuga racemosa). There was less robust evidence for the complementary combination of spirinolactone and Glycyrrhiza spp. for hyperandrogenism. Preclinical and clinical studies provide evidence that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism and PCOS. However the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable. Further pre-clinical studies are needed to explain the effects of herbal medicines not included in this review with current clinical evidence but an absence of pre-clinical data.

Pulsatile gonadotrophin releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome.

PubMed

Bayram, N; van Wely, M; van der Veen, F

2004-01-01

In normal menstrual cycles, gonadotrophin releasing hormone (GnRH) secretion is pulsatile, with intervals of 60-120 minutes in the follicular phase. Treatment with pulsatile GnRH infusion by the intravenous or subcutaneous route using a portable pump has been used successfully in patients with hypogonadotrophic hypogonadism. Assuming that the results would be similar in women with polycystic ovary syndrome (PCOS), pulsatile GnRH has been used to induce ovulation in these women. Although ovulation and pregnancy have been achieved, the effectiveness of pulsatile GnRH in women with PCOS has not been clearly demonstrated. To assess the effectiveness of pulsatile GnRH administration in women with polycystic ovary syndrome (PCOS), in terms of ongoing pregnancy, ovulation, clinical pregnancy, ovarian hyperstimulation syndrome (OHSS), multiple pregnancy, miscarriage, and multifollicular growth. We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched 13 August 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 2, August 2001), MEDLINE (January 1966 to August 2003), EMBASE (January 1985 to August 2003) and reference lists of articles. We also contacted manufacturers and researchers in the field. All relevant published randomised clinical trials were selected for inclusion if treatment consisted of pulsatile GnRH administration versus another treatment for ovulation induction in subfertile women with PCOS. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomisation, completeness of follow-up, presence or absence of crossover and co-intervention. All trials were screened and analysed for predetermined quality criteria. 2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto method. Four randomised clinical trials involving 57 women were identified comparing four different treatments: GnRH versus HMG, GnRH and FSH versus FSH, GnRH following pretreatment with GnRH agonist (GnRHa) versus GnRH only, GnRH following pretreatment with GnRHa versus clomiphene citrate. This means that there was only one trial in any one comparison. In two studies, data of pre- and post-crossover were not described separately. All trials were small and of too short duration to show any significant differences in pregnancy results. The odds ratio for ongoing pregnancy, only described in one trial, was 7.5 (95% CI 0.44 to 127) in the comparison GnRH following pretreatment with GnRHa versus GnRH only in favour of the first group. Multiple pregnancies were not seen. Ovarian hyperstimulation syndrome was seen only in women allocated to ovulation induction with HMG. The four trials describing four different comparisons with a short follow up (1 to 3 cycles) were too small to either prove or discard the value of pulsatile GnRH treatment in patients with polycystic ovary syndrome.

Low dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis.

PubMed

Youssef, Mohamed Abdel-Fattah; van Wely, Madelon; Mochtar, Monique; Fouda, Usama Mohamed; Eldaly, Ashraf; El Abidin, Eman Zein; Elhalwagy, Ahmed; Mageed Abdallah, Ahmed Abdel; Zaki, Sherif Sameh; Abdel Ghafar, Mohamed Sayed; Mohesen, Mohamed Nagi; van der Veen, Fulco

2018-02-01

To evaluate the effectiveness of low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens in terms of ongoing pregnancy per fresh IVF attempt in women with poor ovarian reserve undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment. A systematic review and meta-analysis of randomized controlled studies that evaluate the effectiveness of low dosing of gonadotropins alone or combined with oral compounds compared with high doses of gonadotropins in women with poor ovarian reserve undergoing IVF/ICSI treatment. Not applicable. Subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment. We searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and the Clinical Trials Registry using medical subject headings and free text terms up to June 2016, without language or year restrictions. We included randomized controlled studies (RCTs) enrolling subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment and comparing low doses of gonadotropins and gonadotropins combined with oral compounds versus high doses of gonadotropins. We assessed the risk of bias using the criteria recommended by the Cochrane Collaboration. We pooled the results by meta-analysis using the fixed and random effects model. The primary outcome was ongoing pregnancy rate (PR) per woman randomized. We retrieved 787 records. Fourteen RCTs (N = 2,104 women) were included in the analysis. Five studies (N = 717 women) compared low doses of gonadotropins versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (2 RCTs: risk rate 0.98, 95% confidence interval 0.62-1.57, I 2 = 0). Nine studies (N = 1,387 women) compared ovarian stimulation using gonadotropins combined with the oral compounds letrozole (n = 6) or clomiphene citrate (CC) (n = 3) versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (3 RCTs: risk rate 0.90, 95% confidence interval 0.63-1.27, I 2 = 0). We found no evidence of a difference in pregnancy outcomes between low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens. Whether low doses of gonadotropins or gonadotropins combined with oral compounds is to be preferred is unknown, as they have never been compared head to head. A health economic analysis to test the hypothesis that an ovarian stimulation with low dosing is more cost-effective than high doses of gonadotropins is needed. CRD42016041301. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Cycle regimens for frozen-thawed embryo transfer.

PubMed

Ghobara, Tarek; Gelbaya, Tarek A; Ayeleke, Reuben Olugbenga

2017-07-05

Among subfertile couples undergoing assisted reproductive technology (ART), pregnancy rates following frozen-thawed embryo transfer (FET) treatment cycles have historically been found to be lower than following embryo transfer undertaken two to five days following oocyte retrieval. Nevertheless, FET increases the cumulative pregnancy rate, reduces cost, is relatively simple to undertake and can be accomplished in a shorter time period than repeated in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles with fresh embryo transfer. FET is performed using different cycle regimens: spontaneous ovulatory (natural) cycles; cycles in which the endometrium is artificially prepared by oestrogen and progesterone hormones, commonly known as hormone therapy (HT) FET cycles; and cycles in which ovulation is induced by drugs (ovulation induction FET cycles). HT can be used with or without a gonadotrophin releasing hormone agonist (GnRHa). This is an update of a Cochrane review; the first version was published in 2008. To compare the effectiveness and safety of natural cycle FET, HT cycle FET and ovulation induction cycle FET, and compare subtypes of these regimens. On 13 December 2016 we searched databases including Cochrane Gynaecology and Fertility's Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. Other search sources were trials registers and reference lists of included studies. We included randomized controlled trials (RCTs) comparing the various cycle regimens and different methods used to prepare the endometrium during FET. We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth rates and miscarriage. We included 18 RCTs comparing different cycle regimens for FET in 3815 women. The quality of the evidence was low or very low. The main limitations were failure to report important clinical outcomes, poor reporting of study methods and imprecision due to low event rates. We found no data specific to non-ovulatory women. 1. Natural cycle FET comparisons Natural cycle FET versus HT FETNo study reported live birth rates, miscarriage or ongoing pregnancy.There was no evidence of a difference in multiple pregnancy rates between women in natural cycles and those in HT FET cycle (odds ratio (OR) 2.48, 95% confidence interval (CI) 0.09 to 68.14, 1 RCT, n = 21, very low-quality evidence). Natural cycle FET versus HT plus GnRHa suppressionThere was no evidence of a difference in rates of live birth (OR 0.77, 95% CI 0.39 to 1.53, 1 RCT, n = 159, low-quality evidence) or multiple pregnancy (OR 0.58, 95% CI 0.13 to 2.50, 1 RCT, n = 159, low-quality evidence) between women who had natural cycle FET and those who had HT FET cycles with GnRHa suppression. No study reported miscarriage or ongoing pregnancy. Natural cycle FET versus modified natural cycle FET (human chorionic gonadotrophin (HCG) trigger)There was no evidence of a difference in rates of live birth (OR 0.55, 95% CI 0.16 to 1.93, 1 RCT, n = 60, very low-quality evidence) or miscarriage (OR 0.20, 95% CI 0.01 to 4.13, 1 RCT, n = 168, very low-quality evidence) between women in natural cycles and women in natural cycles with HCG trigger. However, very low-quality evidence suggested that women in natural cycles (without HCG trigger) may have higher ongoing pregnancy rates (OR 2.44, 95% CI 1.03 to 5.76, 1 RCT, n = 168). There were no data on multiple pregnancy. 2. Modified natural cycle FET comparisons Modified natural cycle FET (HCG trigger) versus HT FETThere was no evidence of a difference in rates of live birth (OR 1.34, 95% CI 0.88 to 2.05, 1 RCT, n = 959, low-quality evidence) or ongoing pregnancy (OR 1.21, 95% CI 0.80 to 1.83, 1 RCT, n = 959, low-quality evidence) between women in modified natural cycles and those who received HT. There were no data on miscarriage or multiple pregnancy. Modified natural cycle FET (HCG trigger) versus HT plus GnRHa suppressionThere was no evidence of a difference between the two groups in rates of live birth (OR 1.11, 95% CI 0.66 to 1.87, 1 RCT, n = 236, low-quality evidence) or miscarriage (OR 0.74, 95% CI 0.25 to 2.19, 1 RCT, n = 236, low-quality evidence) rates. There were no data on ongoing pregnancy or multiple pregnancy. 3. HT FET comparisons HT FET versus HT plus GnRHa suppressionHT alone was associated with a lower live birth rate than HT with GnRHa suppression (OR 0.10, 95% CI 0.04 to 0.30, 1 RCT, n = 75, low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 0.64, 95% CI 0.37 to 1.12, 6 RCTs, n = 991, I 2 = 0%, low-quality evidence) or ongoing pregnancy (OR 1.72, 95% CI 0.61 to 4.85, 1 RCT, n = 106, very low-quality evidence).There were no data on multiple pregnancy. 4. Comparison of subtypes of ovulation induction FET Human menopausal gonadotrophin(HMG) versus clomiphene plus HMG HMG alone was associated with a higher live birth rate than clomiphene combined with HMG (OR 2.49, 95% CI 1.07 to 5.80, 1 RCT, n = 209, very low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 1.33, 95% CI 0.35 to 5.09,1 RCT, n = 209, very low-quality evidence) or multiple pregnancy (OR 1.41, 95% CI 0.31 to 6.48, 1 RCT, n = 209, very low-quality evidence).There were no data on ongoing pregnancy. This review did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for FET in subfertile women with regular ovulatory cycles. The most common modalities for FET are natural cycle with or without HCG trigger or endometrial preparation with HT, with or without GnRHa suppression. We identified only four direct comparisons of these two modalities and there was insufficient evidence to support the use of either one in preference to the other.

Effect of exposure to second-hand smoke from husbands on biochemical hyperandrogenism, metabolic syndrome and conception rates in women with polycystic ovary syndrome undergoing ovulation induction.

PubMed

Li, Jian; Wu, Q; Wu, Xiao-Ke; Zhou, Zhong-Ming; Fu, Ping; Chen, Xiu-Hua; Yan, Ying; Wang, Xin; Yang, Zheng-Wang; Li, Wei-Li; Stener-Victorin, Elisabet; Legro, Richard S; Ng, Ernest Hung-Yu; Zhang, Heping; Mol, Ben Willem J; Wang, Chi Chiu

2018-04-01

Does second-hand smoke (SHS) exposure from husbands have adverse effects on sex hormones, metabolic profiles, clinical phenotypes and fertility outcomes in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction? SHS exposure is associated with worsened biochemical hyperandrogenism, higher incidence of metabolic syndrome and reduced conception rates in women with PCOS. Smoking in women impairs fecundity at some stages of the reproductive process including folliculogenesis, embryo transport, endometrial angiogenesis and uterine blood flow. Yet little is known about the hazard of SHS exposure in women with PCOS. This study was a secondary analysis of the Polycystic Ovary Syndrome Acupuncture and Clomiphene Trial (PCOSAct), a large randomized controlled trial conducted at 27 hospitals from 2012 to 2015 in mainland China. Out of 1000 women with PCOS, SHS exposure status were available in 500 women, of whom 271 women were non-exposed and 229 exposed to cigarette smoke (170 women ≤10 cigarettes per day as low-SHS exposed and 59 women >10 cigarettes per day as high-SHS exposed). We compared circulating sex steroids, glucose and lipid metabolism, metabolic syndrome and phenotypes, fertility and obstetric outcomes between non-exposed and exposed women. Women exposed to SHS, compared to non-exposed women, had a higher serum total testosterone (1.7 vs 1.5 nmol/L, P = 0.01), free androgen index (5.7 vs 4.0, P = 0.001) and lower sex hormone binding globulin (30.1 vs 35.6 nmol/L, P = 0.03). Metabolic syndrome, but not other phenotypes, was more frequent in exposed women as compared to non-exposed women (21.8 vs 13.3%, adjusted odds ratio (OR)=1.66; 95% CI, 1.02-2.71, P = 0.04). Ovulation rates between exposed and non-exposed groups were not significantly different (76.9 vs 82.9%, adjusted OR=0.72; 95% CI, 0.45-1.15, P = 0.17). Conception rates were significant lower in the exposed group (26.6 vs 36.9%; adjusted OR=0.61; 95% CI, 0.41-0.91; P = 0.01), while clinical pregnancy and live birth rates showed a similar trend that was not statistically significant. Gestational age, birth weight and other obstetric outcomes were not affected by SHS exposure. Data on SHS exposure were missing in 50% of the women. We did not assay serum nicotine or cotinine levels to quantify the SHS exposure status. These data suggest that smoking partners of infertile women with PCOS who seek treatment should be advised to quit smoking. Funding was provided by the National Public Welfare Projects for Chinese Medicine (201107005 and 200807002) and the National Clinical Trial Base in Chinese Medicine Special Projects (JDZX2012036 and 2015B009). There are no conflicts of interest. ClinicalTrial.gov number: NCT01573858 and chictr.org.cn number: ChiCTR-TRC-12002081.

[Effect of Transcutaneuos Acupoint Electrostimulation on Serum Sex Hormone Levels and Expression of Ovarian Steroid Hormone Metabolic Enzymes in Polycystic Ovary Syndrome Rats].

PubMed

Zhou, Jian-yong; Zhang, Xiao-yue; Yu, Mei-ling; Lu, Sheng-feng; Chen, Xia

2016-02-01

To observe the effect of transcutaneuos acupoint electrostimulation(TAES) on ovarian serum sex hormone levels and ovarian follicle granular cell aromatase cytochrome P 450 (P 450 arom) protein and follicle theca cell cytochrome P 450 17 α-hydroxylase/c 17-20 lyase cytochrome P 450 (P 450 c 17 α) protein expression in polycystic ovary syndrome (PCOS)rats, so as to explore its mechanisms underlying improvement of PCOS. METHODS Forty SD rats were randomly divided into four groups: normal control, model, medication and TAES (10 rats/group). The PCOS model was established by giving (gavage) the animals with letrozole solution (1.0 mg/kg, once daily for 21 consecutive days). Rats of the medication group were treated with Clomiphene (1 mg/kg) once daily for 7 days, and those of the TAES group were treated with electrical stimulation (2 Hz, 3 mA) of "Guanyuan" (CV 4) and "Sanyinjiao" (SP 6) areas for 30 min, once daily for 7 consecutive days. The rats body weight and bilateral ovarian weight were detected, and the ovarian structure and follicular development degree were observed under light microscope after H. E. stain, and the serum testosterone (T), estradiol (E2), luteotrophic hormone (LH) and follicle-stimulating hormone (FSH) contents were detected using radioimmunoassay. The expression of ovarian P 450 arom (for production of estrogen)protein and P 450 c 17 α (for production of androgen) protein was detected by using immunohistochemical stain and Western blot, respectively. The body weight, bilateral ovary weight, serum T and LH contents, and ratio of LH/FSH, and ovarian P 450 c 17 α immunoactivity and protein expression levels in the model group were all significantly increased compared with the normal control group (P < 0.01), and the levels of serum E2 and ovarian P 450 arom immunoactivity and protein expression were significantly decreased after modeling (P < 0.01). Following the treatment, the increased body weight, ovary weight, serum T and LH contents, ratio of LH/FSH, and ovarian P 450 c 17 α immunoactivity and protein expression levels, and the decreased ovarian P 450 arom immunoactivity and protein expression levels were reversed in the TAES group (P < 0.01, P < 0.05) rather than in the medication group, except serum T and ratio of LH/FSH in the medication group. No significant differences were found between the medication and TAES groups in the serum T and ratio of LH/FSH (P > 0.05). In addition, the increased vesicular follicle number, the decreased corepus luteum number and the thickness of granular cell layer were markedly improved in the TAES group. TAES intervention can reduce both body weight and ovarian weight and regulate the levels of serum sex hormones and ovarian P 450 c 17 α and P 450 arom protein expression levels in PCOS rats, which may contribute to its effect in improving PCOS.

Socioeconomic disparities in access to ART treatment and the differential impact of a policy that increased consumer costs.

PubMed

Chambers, G M; Hoang, V P; Illingworth, P J

2013-11-01

What was the impact on access to assisted reproductive technology (ART) treatment by different socioeconomic status (SES) groups after the introduction of a policy that increased patient out-of-pocket costs? After the introduction of a policy that increased out-of-pocket costs in Australia, all SES groups experienced a similar percentage reduction in fresh ART cycles per 1000 women of reproductive age. Higher SES groups experienced a progressively greater reduction in absolute numbers of fresh ART cycles due to existing higher levels of utilization. Australia has supportive public funding arrangements for ARTs. Policies that substantially increase out-of-pocket costs for ART treatment create financial barriers to access and an overall reduction in utilization. Data from the USA suggests that disparities exist in access to ART treatment based on ethnicity, education level and income. Time series analysis of utilization of ART, intrauterine insemination (IUI) and clomiphene citrate by women from varying SES groups before and after the introduction of a change in the level of public funding for ART. Women undertaking fertility treatment in Australia between 2007 and 2010. Women from higher SES quintiles use more ART treatment than those in lower SES quintiles, which likely reflects a greater ability to pay for treatment and a greater need for ART treatment as indicated by the trend to later childbearing. In 2009, 10.13 and 5.17 fresh ART cycles per 1000 women of reproductive age were performed in women in the highest and lowest SES quintiles respectively. In the 12 months after the introduction of a policy that increased out-of-pocket costs from ∼$1500 Australian dollars (€1000) to ∼$2500 (€1670) for a fresh IVF cycle, there was a 21-25% reduction in fresh ART cycles across all SES quintiles. The absolute reduction in fresh ART cycles in the highest SES quintile was double that in the lowest SES quintile. In this study, SES was based on the average relative socioeconomic advantage and disadvantage of small geographic areas, and therefore may not reflect the SES of an individual. Additionally, the policy impact was limited to the 12 months following its introduction, and may not reflect longer term trends in ART treatment. While financial barriers are an important obstacle to equitable access to ARTs, socioeconomic differences in utilization are likely to persist in countries with supportive public funding, due in part to differences in childbearing patterns and treatment seeking behaviour. Policy makers should be informed of the impact that changes in the level of cost subsidization have on access to ART treatment by different socioeconomic groups. G.M.C. receives grant support to her institution from the Australian Government, Australian Research Council (ARC) Linkage Grant No LP1002165; ARC Linkage Grant Partner Organisations are IVFAustralia, Melbourne IVF and Queensland Fertility Group. V.P.H. is employed as an Economics Research Associate on the same grant. P.J.I. is Medical Director of the IVF Clinic, IVFAustralia and has a financial interest in the parent group, Virtus. N/A.

The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance.

PubMed

Balen, Adam H; Morley, Lara C; Misso, Marie; Franks, Stephen; Legro, Richard S; Wijeyaratne, Chandrika N; Stener-Victorin, Elisabet; Fauser, Bart C J M; Norman, Robert J; Teede, Helena

2016-11-01

Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). The aim of this paper was to present an evidence base for the management of anovulatory PCOS. The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m 2 and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed. This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Does unilateral laparoscopic diathermy adjusted to ovarian volume increase the chances of ovulation in women with polycystic ovary syndrome?

PubMed

Sunj, M; Canic, T; Baldani, D P; Tandara, M; Jeroncic, A; Palada, I

2013-09-01

Does unilateral volume-adjusted laparoscopic diathermy increase the chances of ovulation in women with polycystic ovary syndrome (PCOS)? Although unilateral laparoscopic ovarian drilling (ULOD) using adjusted thermal doses was more efficient than bilateral laparoscopic ovarian drilling (BLOD) using fixed doses, the chances of ovulation were improved in patients irrespective of the technique used. The adjustment of the thermal dose to ovarian volume in BLOD increases ovulation and pregnancy rates compared with fixed-dose treatment, but BLOD causes the formation of adhesions, particularly on the left ovary, and increases the risk of damage to ovarian tissue. In contrast, ULOD with a fixed thermal dose minimizes the risk of ovarian tissue damage, and can increase the activity in both right and left ovaries, although this varies in humans and in other species. This prospective, longitudinal, study, between September 2009 and January 2013, included 96 infertile women with PCOS who were unresponsive to clomiphene citrate treatment and had underwent either ULOD or BLOD. After surgery, the groups were followed up for 6 months to assess ovulatory response. Patients were assigned to two groups; one group underwent laparoscopic ovarian drilling of the right ovary alone, while both ovaries were treated in the second group. The ULOD group (n = 49) received thermal doses adjusted to the volume of the right ovary (60 J/cm³). The BLOD group (n = 47) received fixed doses of 600 J per ovary, regardless of its volume. The two treatment groups were matched by the number of participants, age and baseline parameters. The ovulation rate during the first menstrual cycle after LOD was significantly higher in the ULOD group than in the BLOD group [73 versus 49%; absolute risk reduction (ARR), -0.25; 95% confidence interval (CI), -0.44 to -0.03; P = 0.014]. Treatment with ULOD on the right ovary significantly increased the chances of ovulation in patients with a larger right ovary compared with those who had a smaller right ovary (100 versus 36%; ARR, -0.64; 95% CI, -0.84 to -0.37; P = 0.004). Interestingly, the chances of ovulation were also significantly higher in patients in the BLOD group who had a larger right ovary compared with those who had a smaller right ovary (88 versus 33%; ARR, -0.55; 95% CI, -0.73 to -0.28; P = 0.002). The pregnancy rate was also significantly higher in patients with a larger right ovary compared with those with a smaller right ovary, regardless of the treatment group. The 6-month follow-up was too short to demonstrate any long-term differences in the ovulation rates. Future research should therefore extend the follow-up beyond 6 months. Another limitation is that ULOD was used to treat only the right ovary. Future studies should investigate whether ULOD treatment of the larger ovary, whether left or right, would significantly increase the ovulation rate. This study represents an advance in the determination of the optimal laparoscopic treatment for women with PCOS, as it was shown that improved results can be achieved using less thermal energy in volume-adjusted ULOD.

Pulsatile luteinising hormone releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome.

PubMed

Bayram, N; van Wely, M; Vandekerckhove, P; Lilford, R; van Der Veen, F

2000-01-01

In normal menstrual cycles, gonadotrophin releasing hormone (GnRH) secretion is pulsatile, with intervals of 60-120 minutes in the follicular phase. Treatment with pulsatile GnRH infusion by the intra-venous or subcutaneous route using a portable pump has been used successfully in patients with hypogonadotrophic hypogonadism. Assuming that the results would be similar in polycystic ovary syndrome (PCOS), pulsatile GnRH has been used to induce ovulation in patients with PCOS. But, although ovulation and pregnancy has been achieved, the use of pulsatile GnRH in PCOS patients is controversial. To assess the effectiveness of pulsatile GnRH administration in women with clomiphene-resistant polycystic ovary syndrome (PCOS), in terms of ovulation induction, pregnancy, miscarriage, multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). The search strategy of the Menstrual Disorders and Subfertility review group was used to identify all relevant trials. Please see Review Group details. All relevant published RCTs were selected. Non-randomised controlled trials were eligible for inclusion if treatment consisted of GnRH administration versus another treatment to induce ovulation in subfertile women with PCOS. A computerised MEDLINE and EMBASE search was used to identify randomised and non randomised controlled trials. The reference lists of all studies found were checked for relevant articles. One RCT (Bringer 1985a) and one abstract (Coelingh 1983) were identified this way. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomization, completeness of follow-up, presence or absence of cross-over and co-intervention. All trials were screened and analysed for predetermined quality criteria. 2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. Three RCTs and one non-randomised comparative trial were identified comparing four different treatments: GnRH versus HMG, GnRH following GnRHa pre-treatment versus no pre-treatment, GnRH and FSH versus FSH, and GnRH following GnRHa pre-treatment versus GnRH following oral contraceptive pre-treatment. This means that there was only one trial in any one comparison. In the first two studies, data of pre- and post-cross-over were not described separately. Therefore, these results could not be included in the MetaView analysis. The odds ratio for ovulation rate was 16 (95 % CI: 1.1-239) in the study comparing GnRH and FSH with FSH. When GnRH after GnRHa pre-treatment was compared with GnRH after oral contraceptive pre-treatment, an odds ratio of 7.5 (95 % CI: 1.2-46) was obtained. All trials were small and of too short duration to show any significance in pregnancy results. Per study only one to four pregnancies occurred. Multiple pregnancies were not seen. OHSS was seen only in the patients stimulated with HMG. The four trials describing four different comparisons with a short follow up (1 to 3 cycles) were too small to either prove or discard the value of pulsatile GnRH treatment in patients with polycystic ovary syndrome.

Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles.

PubMed

Venetis, Christos A; Kolibianakis, Efstratios M; Bosdou, Julia K; Lainas, George T; Sfontouris, Ioannis A; Tarlatzis, Basil C; Lainas, Tryfon G

2015-03-01

What is the proper way of assessing the effect of progesterone elevation (PE) on the day of hCG on live birth in women undergoing fresh embryo transfer after in vitro fertilization (IVF) using GnRH analogues and gonadotrophins? This study indicates that a multivariable approach, where the effect of the most important confounders is controlled for, can lead to markedly different results regarding the association between PE on the day of hCG and live birth rates after IVF when compared with the bivariate analysis that has been typically used in the relevant literature up to date. PE on the day of hCG is associated with decreased pregnancy rates in fresh IVF cycles. Evidence for this comes from observational studies that mostly failed to control for potential confounders. This is a retrospective analysis of a cohort of fresh IVF/intracytoplasmic sperm injection cycles (n = 3296) performed in a single IVF centre during the period 2001-2013. Patients in whom ovarian stimulation was performed with gonadotrophins and GnRH analogues. Natural cycles and cycles where stimulation involved the administration of clomiphene were excluded. In order to reflect routine clinical practice, no other exclusion criteria were imposed on this dataset. The primary outcome measure for this study was live birth defined as the delivery of a live infant after 24 weeks of gestation. We compared the association between PE on the day of hCG (defined as P > 1.5 ng/ml) and live birth rates calculated by simple bivariate analyses with that derived from multivariable logistic regression. The multivariable analysis controlled for female age, number of oocytes retrieved, number of embryos transferred, developmental stage of embryos at transfer (cleavage versus blastocyst), whether at least one good-quality embryo was transferred, the woman's body mass index, the total dose of FSH administered during ovarian stimulation and the type of GnRH analogues used (agonists versus antagonists) during ovarian stimulation. In addition, an interaction analysis was performed in order to assess whether the ovarian response (<6, 6-18, >18 oocytes) has a moderating effect on the association of PE on the day of hCG with live birth rates after IVF. Live birth rates were not significantly different between cycles with and those without PE when a bivariate analysis was performed [odds ratio (OR): 0.78, 95% confidence interval (CI): 0.56-1.09]. However, when a multivariable analysis was performed, controlling for the effect of the aforementioned confounders, live birth rates (OR: 0.68, 95% CI: 0.48-0.97) were significantly decreased in the group with PE on the day of hCG. The number of oocytes retrieved was the most potent confounder, causing a 29.4% reduction in the OR for live birth between the two groups compared. Furthermore, a moderating effect of ovarian response on the association between PE and live birth rates was not supported in the present analysis since no interaction was detected between PE and the type of ovarian response (<6, 6-18, >18 oocytes). This is a retrospective analysis of data collected during a 12-year period, and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded. This analysis highlights the need for a multivariable approach when researchers or clinicians aim to evaluate the impact of PE on pregnancy rates in their own clinical setting. Failure to do so might explain why many past studies have failed to identify the detrimental effect of PE in fresh IVF cycles. None. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Management of women with PCOS using myo-inositol and folic acid. New clinical data and review of the literature.

PubMed

Regidor, Pedro-Antonio; Schindler, Adolf Eduard; Lesoine, Bernd; Druckman, Rene

2018-03-02

Introduction The use of 2 × 2000 mg myo-inositol +2 × 200 μg folic acid per day is a safe and promising tool in the effective improvement of symptoms and infertility for patients with polycystic ovary syndrome (PCOS). In addition, PCOS is one of the pathological factors involved in the failure of in vitro fertilization (IVF). Typically, PCOS patients suffer of poor quality oocytes. Patients and methods In an open, prospective, non-blinded, non-comparative observational study, 3602 infertile women used myo-inositol and folic acid between 2 and 3 months in a dosage of 2 × 2000 mg myo-inositol +2 × 200 μg folic acid per day. In a subgroup of 32 patients, hormonal values for testosterone, free testosterone and progesterone were analyzed before and after 12 weeks of treatment. The mean time of use was 10.2 weeks. In the second part of this trial it was investigated if the combination of myo-inositol + folic acid was able to improve the oocyte quality, the ratio between follicles and retrieved oocytes, the fertilization rate and the embryo quality in PCOS patients undergoing IVF treatments. Twenty-nine patients with PCOS, underwent IVF protocols for infertility treatment and were randomized prospectively into two groups. Group A (placebo) with 15 patients and group B (4000 mg myo-inositol +400 μg folic acid per day) with 14 patients were evaluated. The patients of group B used 2 months' myo-inositol + folic acid before starting the IVF protocol. For statistically analyses Student's t-test was performed. Results Seventy percent of the women had a restored ovulation, and 545 pregnancies were observed. This means a pregnancy rate of 15.1% of all the myo-inositol and folic acid users. In 19 cases a concomitant medication with clomiphene or dexamethasone was used. One twin pregnancy was documented. Testosterone levels changed from 96.6 ng/mL to 43.3 ng/mL and progesterone from 2.1 ng/mL to 12.3 ng/mL in the mean after 12 weeks of treatment (p < 0.05) Student's t-test. No relevant side effects were present among the patients. The women in the IVF treatment the group A showed a higher number of retrieved oocytes than group B. Nevertheless, the ratio follicle/retrieved oocyte was clearly better in the myo-inositol group (= group B). Out of the 233 oocytes collected in the myo-inositol group, 136 where fertilized whereas only 128 out of 300 oocytes were fertilized in the placebo group. With regards to the oocytes quality, better data were obtained in the myo-inositol group. More metaphase II and I oocytes were retrieved in relation to the total number of oocytes, when compared with the placebo group. Also, more embryos of grade I quality were observed in the myo-inositol group than in the placebo group. The duration of stimulation was 9.7 days (±3.3) in the myo-inositol group and 11.2 (±1.8) days in the placebo group and the number of used follicle-stimulating hormone (FSH) units was lower in the myo-inositol group in comparison to the placebo group: 1850 FSH units (mean) versus 1850 units (mean). Discussion Myo-inositol has proven to be a new treatment option for patients with PCOS and infertility. The achieved pregnancy rates are at least in an equivalent or even superior range than those reported using metformin as an insulin sensitizer. No moderate to severe side effects were observed when myo-inositol was used at a dosage of 4000 mg per day. In addition, our evidence suggests that a myo-inositol therapy in women with PCOS results in better fertilization rates and a clear trend to a better embryo quality. As by the same way the number of retrieved oocytes was smaller in the myo-inositol group, the risk of a hyperstimulation syndrome in these patients can be reduced. Therefore, myo-inositol also represents an improvement in IVF protocols for patients with PCOS.

Identification and replication of prediction models for ovulation, pregnancy and live birth in infertile women with polycystic ovary syndrome.

PubMed

Kuang, Hongying; Jin, Susan; Hansen, Karl R; Diamond, Michael P; Coutifaris, Christos; Casson, Peter; Christman, Gregory; Alvero, Ruben; Huang, Hao; Bates, G Wright; Usadi, Rebecca; Lucidi, Scott; Baker, Valerie; Santoro, Nanette; Eisenberg, Esther; Legro, Richard S; Zhang, Heping

2015-09-01

Can we build and validate predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome (PCOS)? We were able to develop and validate a predictive model for pregnancy outcomes in women with PCOS using simple clinical and biochemical criteria particularly duration of attempting conception, which was the most consistent predictor among all considered factors for pregnancy outcomes. Predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome have been reported, but such models require validation. This is a secondary analysis of the data from the Pregnancy in Polycystic Ovary Syndrome I and II (PPCOS-I and -II) trials. Both trials were double-blind, randomized clinical trials that included 626 and 750 infertile women with PCOS, respectively. PPCOS-I participants were randomized to either clomiphene citrate (CC), metformin, or their combination, and PPCOS-II participants to either letrozole or CC for up to five treatment cycles. Linear logistic regression models were fitted using treatment, BMI, and other published variables as predictors of ovulation, conception, clinical pregnancy, and live birth as the outcome one at a time. We first evaluated previously reported significant predictors, and then constructed new prediction models. Receiver operating characteristic (ROC) curves were constructed and the area under the curves (AUCs) was calculated to compare performance using different models and data. Chi-square tests were used to examine the goodness-of-fit and prediction power of logistic regression model. Predictive factors were similar between PPCOS-I and II, but the two participant samples differed statistically significantly but the differences were clinically minor on key baseline characteristics and hormone levels. Women in PPCOS-II had an overall more severe PCOS phenotype than women in PPCOS-I. The clinically minor but statistically significant differences may be due to the large sample sizes. Younger age, lower baseline free androgen index and insulin, shorter duration of attempting conception, and higher baseline sex hormone-binding globulin significantly predicted at least one pregnancy outcome. The ROC curves (with AUCs of 0.66-0.76) and calibration plots and chi-square tests indicated stable predictive power of the identified variables (P-values ≥0.07 for all goodness-of-fit and validation tests). This is a secondary analysis. Although our primary objective was to confirm previously reported results and identify new predictors of ovulation and pregnancy outcomes among PPCOS-II participants, our approach is exploratory and warrants further replication. We have largely confirmed the predictors that were identified in the PPCOS-I trial. However, we have also revealed new predictors, particularly the role of smoking. While a history of ever smoking was not a significant predictor for live birth, a closer look at current, quit, and never smoking revealed that current smoking was a significant risk factor. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, and U10 HD055944; and U54-HD29834. Heilongjiang University of Chinese Medicine Grants 051277 and B201005. R.S.L. reports receiving consulting fees from Euroscreen, AstraZeneca, Clarus Therapeutics, and Takeda, and grant support from Ferring, Astra Zeneca, and Toba. K.R.H. reports receiving grant support from Roche Diagnostics and Ferring Pharmascience. G.C. reports receiving Honorarium and grant support from Abbvie Pharmaceuticals and Bayer Pharmaceuticals. M.P.D. holds equity from Advanced Reproductive Care Inc. and DS Biotech, receives fees from Advanced Reproductive Care Inc., Actamax, Auxogyn, ZSX Medical, Halt Medical, and Neomed, and receives grant support from Boehringer-Ingelheim, Abbott, and BioSante, Ferring Pharmaceuticals, and EMD Serono. H.Z. receives research support from the Chinese 1000-scholar plan. Others report no disclosures other than NIH grant support. PPCOS-I and -II were respectively registered at Clinicaltrials.gov: NCT00719186 and NCT00719186. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews.

PubMed

Mourad, Selma; Brown, Julie; Farquhar, Cindy

2017-01-23

Ovarian hyperstimulation syndrome (OHSS) in assisted reproductive technology (ART) cycles is a treatment-induced disease that has an estimated prevalence of 20% to 33% in its mild form and 3% to 8% in its moderate or severe form. These numbers might even be higher for high-risk women such as those with polycystic ovaries or a high oocyte yield from ovum pickup. The objective of this overview is to identify and summarise all evidence from Cochrane systematic reviews on interventions for prevention or treatment of moderate, severe and overall OHSS in couples with subfertility who are undergoing ART cycles. Published Cochrane systematic reviews reporting on moderate, severe or overall OHSS as an outcome in ART cycles were eligible for inclusion in this overview. We also identified Cochrane submitted protocols and title registrations for future inclusion in the overview. The evidence is current to 12 December 2016. We identified reviews, protocols and titles by searching the Cochrane Gynaecology and Fertility Group Database of Systematic Reviews and Archie (the Cochrane information management system) in July 2016 on the effectiveness of interventions for outcomes of moderate, severe and overall OHSS. We undertook in duplicate selection of systematic reviews, data extraction and quality assessment. We used the AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the quality of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables. We included a total of 27 reviews in this overview. The reviews were generally of high quality according to AMSTAR ratings, and included studies provided evidence that ranged from very low to high in quality. Ten reviews had not been updated in the past three years. Seven reviews described interventions that provided a beneficial effect in reducing OHSS rates, and we categorised one additional review as 'promising'. Of the effective interventions, all except one had no detrimental effect on pregnancy outcomes. Evidence of at least moderate quality indicates that clinicians should consider the following interventions in ART cycles to reduce OHSS rates.• Metformin treatment before and during an ART cycle for women with PCOS (moderate-quality evidence).• Gonadotrophin-releasing hormone (GnRH) antagonist protocol in ART cycles (moderate-quality evidence).• GnRH agonist (GnRHa) trigger in donor oocyte or 'freeze-all' programmes (moderate-quality evidence). Evidence of low or very low quality suggests that clinicians should consider the following interventions in ART cycles to reduce OHSS rates.• Clomiphene citrate for controlled ovarian stimulation in ART cycles (low-quality evidence).• Cabergoline around the time of human chorionic gonadotrophin (hCG) administration or oocyte pickup in ART cycles (low-quality evidence).• Intravenous fluids (plasma expanders) around the time of hCG administration or oocyte pickup in ART cycles (very low-quality evidence).• Progesterone for luteal phase support in ART cycles (low-quality evidence).• Coasting (withholding gonadotrophins) - a promising intervention that needs to be researched further for reduction of OHSS.On the basis of this overview, we must conclude that evidence is currently insufficient to support the widespread practice of embryo cryopreservation. Currently, 27 reviews in the Cochrane Library were conducted to report on or to try to report on OHSS in ART cycles. We identified four review protocols but no new registered titles that can potentially be included in this overview in the future. This overview provides the most up-to-date evidence on prevention of OHSS in ART cycles from all currently published Cochrane reviews on ART. Clinicians can use the evidence summarised in this overview to choose the best treatment regimen for individual patients - a regimen that not only reduces the chance of developing OHSS but does not compromise other outcomes such as pregnancy or live birth rate. Review results, however, are limited by the lack of recent primary studies or updated reviews. Furthermore, this overview can be used by policymakers in developing local and regional protocols or guidelines and can reveal knowledge gaps for future research.

Frozen-thawed embryo transfer in a natural or mildly hormonally stimulated cycle in women with regular ovulatory cycles: a RCT.

PubMed

Peeraer, Karen; Couck, Isabelle; Debrock, Sophie; De Neubourg, Diane; De Loecker, Peter; Tomassetti, Carla; Laenen, Annouschka; Welkenhuysen, Myriam; Meeuwis, Luc; Pelckmans, Sofie; Meuleman, Christel; D'Hooghe, Thomas

2015-11-01

Can ovarian stimulation with low dose hMG improve the implantation rate (IR) per frozen-thawed embryo transferred (FET) when compared with natural cycle in an FET programme in women with a regular ovulatory cycle? Both IR and live birth rate (LBR) per FET were similar in the group with mild ovarian stimulation and the natural cycle group. Different cycle regimens for endometrial preparation are used prior to FET: spontaneous ovulatory cycles, cycles with artificial endometrial preparation using estrogen and progesterone hormones, and cycles stimulated with gonadotrophins or clomiphene citrate. At present, it is not clear which regimen results in the highest IR or LBR. More specifically, there are no RCTs in ovulatory women comparing reproductive outcome after FET during a natural cycle and during a hormonally stimulated cycle. A total of 410 women scheduled for FET during 579 cycles (December 2003-September 2013) were enrolled in an open-label RCT to natural cycle (NC FET group, n = 291) or to a cycle hormonally stimulated with s.c. gonadotrophins (hMG FET group, 37.5-75 IU per day, n = 288). A total of 672 embryos were transferred during 434 cycles (332 embryos and 213 cycles in the NC FET group; 340 embryos and 221 cycles in the hMG FET group). Assuming a = 0.05 and 80% power, it was calculated that 219 frozen-thawed embryos were required for transfer in each group to demonstrate a difference of 10% in IR. Women were eligible according to the following inclusion criteria: regular ovulatory cycle, female age ≥21 years and ≤45 years, informed consent. FET cycles with preimplantation genetic screening were excluded. The primary outcome was IR per embryo transferred. Secondary outcomes included IR with fetal heart beat (FHB), LBR per embryo transferred and endometrial thickness on the day of hCG administration. Statistical analysis was by intention to treat and controlled for the presence of multiple measures, as eligible women could be randomized in more than one cycle. Chi-square and independent t-test were used to compare categorical and continuous variables. The relative risk (RR) was estimated using a Poisson model with log link. Hierarchical models with random intercepts for patient and cycle were considered to account for clustering of cycles within patients and of embryos within cycles. The primary outcome, IR per embryo transferred, was not statistically different between the NC FET group (41/332 (12.35%)) and in the hMG FET group (55/340 (16.18%)) (RR 1.3 (95% confidence interval (CI) 0.9-2.0), P = 0.19). Similarly, the secondary outcome, IR with FHB per embryo transferred, was 34/332 (10.24%) in the NC FET group and 48/340 (14.12%) in the hMG FET group (RR 1.4 (95% CI 0.9-2.1), P = 0.15). The LBR per embryo transferred was 32/332 (9.64%) in the NC FET group and 45/340 (13.24%) in the hMG FET group (RR 1.4 (95% CI 0.9-2.2), P = 0.17). Endometrial thickness was also similar in both groups [8.9 (95% CI 8.7-9.1) in the NC FET group and 8.9 (95% CI 8.7-9.1) in the hMG FET group]. The duration of the follicular phase was significantly shorter (P < 0.001) in the hMG FET group [13.7 days (95% CI 13.2-14.2)] than in the NC FET group [15.4 days (95% CI 14.8-15.9)]. Randomization of cycles instead of patients; open-label design; relatively long period of recruitment. Our observation that the IR per embryo transferred is not significantly increased after FET during natural or gonadotrophin stimulated cycle, suggests that the effect of mild hormonal stimulation with gonadotrophins is smaller than what was considered clinically relevant with respect to reproductive outcome after FET. These data suggest that endometrial receptivity is not relevantly improved, but also not impaired after hormonal stimulation with gonadotrophins. Since FET during a natural cycle is cheaper and more patient-friendly, we recommend this regimen as the treatment of choice for women with regular cycles undergoing FET. clinicaltrials.gov NCT00492934. 26 June 2007. 1 December 2003. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME - PART 2.

PubMed

Goodman, Neil F; Cobin, Rhoda H; Futterweit, Walter; Glueck, Jennifer S; Legro, Richard S; Carmina, Enrico

2015-12-01

Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists and the Androgen Excess Society aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2014. Insulin resistance is believed to play an intrinsic role in the pathogenesis of PCOS. The mechanism by which insulin resistance or insulin give rise to oligomenorrhea and hyperandrogenemia, however, is unclear. Hyperinsulinemic-euglycemic clamp studies have shown that both obese and lean women with PCOS have some degree of insulin resistance. Insulin resistance is implicated in the ovulatory dysfunction of PCOS by disrupting the hypothalamic-pituitary-ovarian axis. Given the association with insulin resistance, all women with PCOS require evaluation for the risk of metabolic syndrome (MetS) and its components, including type 2 diabetes, hypertension, hyperlipidemia, and the possible risk of clinical events, including acute myocardial infarction and stroke. Obese women with PCOS are at increased risk for MetS with impaired glucose tolerance (IGT; 31 to 35%) and type 2 diabetes mellitus (T2DM; 7.5 to 10%). Rates of progression from normal glucose tolerance to IGT, and in turn to T2DM, may be as high as 5 to 15% within 3 years. Data suggest the need for baseline oral glucose tolerance test every 1 to 2 years based on family history of T2DM as well as body mass index (BMI) and yearly in women with IGT. Compared with BMI- and age-matched controls, young, lean PCOS women have lower high-density lipoprotein (HDL) size, higher very-low-density lipoprotein particle number, higher low-density lipoprotein (LDL) particle number, and borderline lower LDL size. Statins have been shown to lower testosterone levels either alone or in combination with oral contraceptives (OCPs) but have not shown improvement in menses, spontaneous ovulation, hirsutism, or acne. Statins reduce total and LDL cholesterol but have no effect on HDL, C-reactive protein, fasting insulin, or homeostasis model assessment of insulin resistance in PCOS women, in contrast to the general population. There have been no long-term studies of statins on clinical cardiac outcomes in women with PCOS. Coronary calcification is more prevalent and more severe in PCOS than in controls. In women under 60 years of age undergoing coronary angiography, the presence of polycystic ovaries on sonography has been associated with more arterial segments with >50% stenosis, but the relationship between PCOS and actual cardiovascular events remains unclear. Therapies for PCOS are varied in their effects and targets and include both nonpharmacologic as well as pharmacologic approaches. Weight loss is the primary therapy in PCOS--reduction in weight of as little as 5% can restore regular menses and improve response to ovulation- inducing and fertility medications. Metformin in premenopausal PCOS women has been associated with a reduction in features of MetS. Clamp studies using ethinyl estradiol/drosperinone combination failed to reveal evidence of an increase in either peripheral or hepatic insulin resistance. Subjects with PCOS have a 1.5-times higher baseline risk of venous thromboembolic disease and a 3.7-fold greater effect with OCP use compared with non-PCOS subjects. There is currently no genetic test to screen for or diagnose PCOS, and there is no test to assist in the choice of treatment strategies. Persistent bleeding should always be investigated for pregnancy and/or uterine pathology--including transvaginal ultrasound exam and endometrial biopsy--in women with PCOS. PCOS women can have difficulty conceiving. Those who become pregnant are at risk for gestational diabetes (which should be evaluated and managed appropriately) and the microvascular complications of diabetes. Assessment of a woman with PCOS for infertility involves evaluating for preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes and evaluating the couple for other common infertility issues that may affect the choice of therapy, such as a semen analysis. Women with PCOS have multiple factors that may lead to an elevated risk of pregnancy, including a high prevalence of IGT--a clear risk factor for gestational diabetes--and MetS with hypertension, which increases the risk for pre-eclampsia and placental abruption. Women should be screened and treated for hypertension and diabetes prior to attempting conception. Women should be counseled about weight loss prior to attempting conception, although there are limited clinical trial data demonstrating a benefit to this recommendation. Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or letrozole, an aromatase inhibitor.