The therapeutic dilemma in PCOS patients not desiring pregnancy: A systematic review and meta-analysis

Combined oral contraceptive (COC) and anti-androgens (AA) are more effective than metformin for treating the symptoms of excess androgens and offer endometrial protection in adult women with polycystic ovary syndrome (PCOS) as compared to metformin alone. Addition of metformin to the treatment regimen improves glucose sensitivity and bring about weight loss report the results of a systematic review and metanalysis published in current issue of Journal of Human Reproduction Update.

PCOS is common endocrine disorder in women of the reproductive age and beyond. Most treatments are directed towards achieving conception in younger women who desire fertility but the treatment of women with PCOS who do not desire pregnancy is not standardized.

COC and anti-androgens with or without insulin sensitizers are commonly used.  But, the efficacy and safety of these treatments in treating hyperandrogenemia and its effect on cardiometabolic risk factor are not well documented.

This review of RCTs was conducted to seek better therapeutic approach in this subset of women who do not desire fertility in terms of efficacy and safety.

The authors found 1522 articles abstract after going through PubMed and EMBASE until September 2017. After exclusion, 33 studies and 1521 women were included in the quantitative synthesis and in the meta-analyses. After statistical analysis, the outcomes were:

• COC and/or AA significantly improved the hirsutism score as compared to metformin alone.

• COC and/or AA also was more effective in preventing endometrial hyperplasia as compared to metformin alone.

• COC was also found more effective in regularizing the menstrual cycle.

• Metformin helped in improving the cardiometabolic profile in these women because of its favorable effect on BMI.

• The use of COC and/or AA along with metformin did not affect the mean glucose levels but it did help bring down the fasting glucose levels.

• Both the therapies were comparable in terms of the effect on lipid profile, blood pressure or prevalence of hypertension, but the quality of evidence was low when these effects were explored.

The results of this systematic review and metanalysis provide scientific evidence to choose between treatment for adult women with PCOS based on symptoms and desired goal of therapy.

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Stair-step ovulation induction protocols are not just limited to Clomiphene

Stair-step ovulation induction protocol with Letrozole is also as effective as stair-step method using Clomiphene Citrate, and has a slight edge over CC in obese patients reports the result of study published in March issue of Fertility and Sterility.

Stair-step ovulation induction protocols have shown to achieve ovulation induction in shorter time as compared to traditional protocols in women with PCOS. But, so far studies and clinical trials have mainly focused on Clomiphene Citrate(CC).

Letrozole has shown to have superior ovulation rates over CC in women with PCOS, but no study has so far evaluated the stair-step method for Letrozole in cases of absent follicular recruitment after the initial dose.

This Retrospective cohort study recruited 92 infertile PCOS patients, 49 patients completed a letrozole stair-step from Jan 2015-Oct 2016 while 43 patients received stair-step protocols from July 2013-2014.

Letrozole protocol used in the study

CC protocol used in the study 

The demographics of both the groups were nearly similar, except patients in the Letrozole group were obese with a mean BMI of 30.8 as compared to 26.3 in CC group.

Ovulation rates were comparable in both groups (95.9% vs 88.1%, p=0.09), as also time to attain pregnancy, clinical pregnancy rates and side effects.

Thus, letrozole can also be effectively used in stair-step doses for achieving ovulation and pregnancy in PCOS women resistant to traditional protocols.

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Stair-step clomiphene protocols shortens time to ovulation in women with PCOS

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 Stair-step clomiphene protocol shortens induction time and brings about more ovulation in women with PCOS says the results of a retrospective cohort study published in January issue of Journal Obstetrics and Gynecology.

The researchers looked at traditional and step-up protocol in terms of ovulation rates and time to ovulation in women who have not responded to initial dose of 50mg of clomiphene citrate(CC).

Over a period of 2 years, the study included 109 patients attending a university hospital infertility clinic, with 66 women receiving traditional treatment and 43 were given the stair-step dose of clomiphene.  

The women were monitored for time to ovulation, as well as ovulation rates, clinical pregnancy rates and mild to moderate side effects.

The traditional protocol was used in 2012, in which CC 50mg was given between days 5-9. If no ovulation occurred, the dose was increased by 50mg after a spontaneous menses or a progestin induced bleed.

The stair-step protocol was used in 2013, in which CC 50mg was given between days 5-9. If no developing follicle >10mm was noted between days 11-14, the dose was increased to100mg immediately for 5 days and an ultrasound was repeated 12 days later. The dose was increased in increments of 50mg until a dose of 250mg was achieved.

It was seen that time to ovulation was nearly 50% less with stair-step method as compared with that of traditional method (23±1.8 vs 47.5±12.5 days, p<0.001). With 100 mg of CC, ovulation rates were comparable with both methods but was nearly 3 times with 150 mg CC (37% vs 12%, p=0.004) and 4 times with 200mg CC (21% vs 5%, p=0.01), with stair-step method as compared to traditional one.

Once ovulation was achieved, clinical and overall pregnancy rates did not differ between both the methods (16% vs 17%, p>0.05).

Women with stair-step method did experience mild side effects like headaches, vasomotor flushing, mastalgia and GI more frequently; however, incidence of severe side effects were similar in both the groups.

The authors concluded that stair-step method is an efficient and effective method for ovulation induction with CC at significantly decreased time. Authors of a prospective cohort study even cited the stair-step protocol as an alternative to gonadotrophin therapy with similar efficacy.

The abstract was also presented as 70th Annual Meeting of the American Society for Reproductive Medicine, October 18-22, 2014, Honolulu, Hawaii and could be accessed here.

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