Oral agents for ovulation induction – clomiphene citrate versus aromatase inhibitors

The purpose of this review is to compare clomiphene citrate (CC) with aromatase inhibitors (AI) as the first-line therapy for WHO Group II (eu-oestrogenic) infertility. For the past 45 years CC has been the first-line therapy, as it is a simple, cheap treatment, almost devoid of side effects, and yields ovulation in 73%, pregnancy in 36% and a singleton live birth rate of 25%. The gap between ovulation and pregnancy rates has mainly been attributed to its anti-oestrogen effects on endometrium. AI block oestrogen production, not oestrogen receptors, and would therefore be expected to produce superior conception rates and less multiple pregnancies. AI have yet to undergo further large, robust clinical trials in order to fulfill this promise as a feasible alternative to CC in this role, but some preliminary trials have shown at least equality and some superiority.     

The role of anti-Müllerian hormone in predicting clomiphene citrate resistance in women with polycystic ovarian syndrome

Clomiphene citrate (CC) is the agent of first choice in polycystic ovarian syndrome; however, anovulation problem does not resolve in a quarter of them. Thus, we investigated the value of anti-Müllerian hormone (AMH) in the prediction of ovarian response to CC in women with the polycystic ovarian syndrome (PCOS). This prospective cohort study included 90 anovulatory women with PCOS who were given 50?mg/d CC. The patients who ovulated occupied the group of responders and the patients who did not ovulate in three cycles included in the CC-resistant group. AMH levels of both groups were compared. p?<?.05 was considered statistically significant. Patients who ovulated had significantly lower serum AMH concentrations compared with the resistant group (p?=?.001). After analyzing the ROC curve, serum AMH concentration was found to be a useful predictor of CC resistance with the sensitivity of 66% and the specificity of 89%, when the threshold AMH concentration was >12.38?ng/ml in PCOS patients. In the present study, we revealed that the higher the AMH level the poorer the CC response would be in PCOS patients, therefore we recommend measuring the AMH levels of all PCOS patients before planning any ovulation induction treatment to achieve the desired success.     

Anastrozole versus clomiphene citrate: which is better for ovulation induction?

Although anastrozole may be used as an oral therapeutic agent in ovulation induction, it is not recommended as a replacement for clomiphene citrate. On the basis of two phase 2 studies, anastrozole should be viewed as a second-tier therapy after clomiphene citrate in anovulatory patients.     

Letrozole versus clomiphene citrate: which is better for ovulation induction?

Letrozole is at least as effective as clomiphene for inducing ovulation and achieving pregnancy in patients with polycystic ovarian syndrome. Potential advantages of letrozole include reduced multiple pregnancies, absence of antiestrogenic adverse effects, and the subsequent need for less intensive monitoring.     

Response to ovulation induction treatments in women with polycystic ovary syndrome as a function of serum anti-Müllerian hormone levels

Journal of Assisted Reproduction and Genetics - To assess whether anti-Müllerian hormone (AMH) can predict response to ovulation induction (OI) with clomiphene citrate (CC), letrozole (LET),...     

Evaluation of ovarian function in 35–40-year-old women with polycystic ovary syndrome

Objective

To assess gonadotrophin secretion, ovarian steroid production and ovarian reserve in PCOS women during the onset of reproductive decline, in order to characterize their ovarian function at this age.

Study design

Forty PCOS patients and 35 healthy women (35–40 years of age) were included. Clinical history, anthropometry, transvaginal ultrasound and a leuprolide acetate test (10 μg/kg s.c.) were performed. Gonadotrophins, steroid hormones, SHBG, inhibin B and AMH were determined.

Results

Basal and peak LH levels were similar in both groups. Basal and peak FSH levels were significantly higher in the control group. Androgens, peak oestradiol, ovarian volume, antral follicle count and AMH levels were significantly higher in PCOS patients.

Conclusion

These observations suggest that during late reproductive age, gonadotrophin secretion in women with PCOS is clearly different from that observed in control women and may also differ from that of younger PCOS patients. New features like normal LH and lower FSH levels associated with a higher ovarian reserve may give a different reproductive profile to these women.     

Anti-Müllerian hormone and fertility disturbances in obese women and women with polycystic ovary syndrome

Anti-Müllerian hormone (AMH) belongs to a family of growth and differentiation factors beta (TGF-beta). In male fetuses AMH induces regression of Müller's ducts whereas in female ones this hormone plays an important role during adolescence and reproductive period. AMH participates in regulation of folliculogenesis by inhibiting the recruitment of prenatal and antral follicles. The aim of the present study was to summarize the current knowledge of the role of AMH in menstrual and fertility disturbances in obese women and those with polycystic ovary syndrome.     

Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome?

Insulin resistance is an important pathophysiological feature of the polycystic ovary syndrome (PCOS). Insulin resistance and its compensatory hyperinsulinemia contribute to the anovulation, hyperandrogenism, infertility and early pregnancy loss suffered by women with PCOS. Current evidence supports the role of metformin in the treatment of anovulation in PCOS, both in monotherapy and concomitantly with clomiphene in clomiphene-resistant patients. In addition, novel evidence suggests that insulin sensitizers may also play a role in reducing the risk of early pregnancy loss. The insulin-sensitizing agents available commercially include metformin, rosiglitazone and pioglitazone. Compared with the thiozolidinediones, metformin is the agent that has been most frequently studied in PCOS, and has the most favorable pregnancy safety profile. In conclusion, there is strong evidence supporting the use of metformin as a primary ovulatory agent in women with PCOS.     

The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia

Objective.?To assess the impact of metformin and of two different oral contraceptives (OCs) containing cyproterone acetate and drospirenone, on serum anti-Müllerian hormone (AMH) levels, in a cohort of women with polycystic ovary syndrome (PCOS) with hyperandrogenism.

Design.?Prospective randomised study.

Setting. Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki.

Patients.?Forty-five (45) women with PCOS diagnosed according to the criteria proposed in 1990 by the NIH.

Interventions.?Women with PCOS were randomised into three groups, all treated for 6 months: Group A received an OC containing 35?μg ethinylestradiol plus 2?mg cyproterone acetate, Group B received an OC containing 30?μg ethinylestradiol plus 3?mg drospirenone and Group C received metformin 850?mg?×?2.

Main outcome measure(s).?Anti-Müllerian hormone levels were measured by a specific ELISA.

Results.?AMH was significantly decreased under treatment with 35?μg ethinylestradiol plus 2?mg cyproterone acetate (p?=?0.002 at 3 months and p?<?0.001 at 6 months). Treatment with 30?μg ethinylestradiol plus 3?mg drospirenone, and treatment with metformin 850?mg?×?2 did not significantly affect serum AMH levels. AMH was significantly decreased under OCs treatment compared to metformin 850?mg?×?2 (p?=?0.005).

Conclusion(s).?AMH serum levels were significantly decreased under treatment with 35?μg ethinylestradiol plus 2?mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins.     

Can metformin reduce the incidence of gestational diabetes mellitus in pregnant women with polycystic ovary syndrome? Prospective cohort study

Background.?Women with polycystic ovary syndrome (PCOS) are at a high risk to develop Gestational Diabetes mellitus (GDM). We hypothesized that metformin due to its metabolic, endocrine, vascular, and anti-inflammatory effects may reduce the incidence of GDM in PCOS women.

Patient and method.?We carried out a prospective cohort study to determine the beneficial effects of metformin on PCOS patients during pregnancy. Three-hundred and sixty non-diabetic PCOS patients were included who were conceived on metformin by different treatment modalities. Two-hundred pregnant women continued on metformin at a dose of 1000–2000?mg daily throughout pregnancy (study group) and 160 women discontinued metformin use at the time of conception (control group).

Results.?There is a statistically significant reduction in the incidence of GDM in favor of metformin group (OR: 0.17, 95% CI: 0.07–0.37). There is a statistically significant reduction in the incidence of pre-eclampsia in favor of metformin group (OR: 0.35, 95% CI: 0.13–0.94).

Conclusion.?Metformin is a promising medication for the prevention or reduction of the incidence of GDM and pre-eclampsia in PCOS women.     

Are there differences in ultrasound parameters between Chinese women with polycystic ovaries only and with polycystic ovary syndrome?

OBJECTIVE: We aimed to compare antral follicle count (AFC), ovarian volume, ovarian stromal blood flow between Chinese women with polycystic ovary (PCO) only and polycystic ovary syndrome (PCOS) and to evaluate the effect of age on these ultrasound parameters in these women. STUDY DESIGN: In the second to fourth day of the period, they underwent a transvaginal three-dimensional scanning with power Doppler to determine total AFC, total ovarian volume, total ovarian vascularization index (VI), flow index (FI) and vascularization flow index (VFI). Hormonal profile was also measured. RESULTS: A total of 71 Chinese women were recruited in the study: 39 women with PCO only and 32 women with PCOS. Women with PCO only had significantly lower AFC, ovarian volume, ovarian VI, serum LH, testosterone and DHEAS concentrations but higher serum SHBG concentration when compared with PCOS women. When women with PCO only and PCOS were considered together, the rate of decline of AFC over age was 0.905 follicle per year (95% CI=0.008-1.803, p=0.048) and there was no significant decline of ovarian volume and total ovarian VI, FI and VFI over age. CONCLUSION: PCO only represents a milder end of the PCOS spectrum.     

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

Objectives

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).

Methods

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.

Results

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.

Conclusion

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.     

Is subclinical hypothyroidism contributing dyslipidemia and insulin resistance in women with polycystic ovary syndrome?

We aimed to analyze lipid parameters and determine the need for a 2-hour oral glucose tolerance test (OGTT) for the identification of IR and impaired glucose tolerance test (IGT) in subclinical hypothyroidism (SCH) women with and without polycystic ovary syndrome (PCOS). 20 patients with PCOS and SCH consisted of Group I and 39 patients with PCOS and normal thyroid function consisted of Group II and 53 healthy women with normal thyroid function consisted of Group III. Triglyceride levels were 143.26?±?99.86?mg/dL in group 1 and 88.56?±?37.56?mg/dL in group 2 and 83.71?±?31.94?mg/dL in group 3 which were statistically significant. Total cholesterol, HDL- cholesterol, LDL-cholesterol were found similar between the groups. Fasting insulin levels were 12.45?±?8.62 µU/mL in group 1 and 8.60?±?5.35 µU/mL in group 2 and 7.04?±?3.55 µU/mL in group 3 which were statistically significant (P?=?0.027). HOMA-IR were 2.92?±?2.34 in group 1 and 1.95?±?1.52 in group 2 and 1.60?±?0.86 in group 3 which were statistically significant (P?=?0.046). This study showed that women with PCOS and subclinical hypothyroidism should be evaluated for dyslipidemia and Insulin resistance.