ACOG update: Letrozole is the first line therapy for ovulation induction in PCOS

The American College of Obstetricians and Gynecologists (ACOG) now recommends Letrozole (aromatase inhibitor) as the first-line treatment for ovulation induction in women with Polycystic Ovarian Syndrome (PCOS) due to data demonstrating increased ovulation rates, clinical pregnancy rates and live-birth rate vs clomiphene citrate. The guidelines are published as Practice Bulletin No. 194 in the June issue of Journal Obstetrics and Gynecology.

This replaces the Practice Bulletin Number 108, published October 2009, which recommends letrozole as first-line therapy for ovulation induction only in women with PCOS and a BMI greater than 30.

It is estimated that polycystic ovary syndrome (PCOS) affects 1 in 10 women of childbearing age and it is the most common cause of ovulatory infertility. If lifestyle modifications and weight loss are unable to achieve conception, currently clomiphene citrate (CC) is usually prescribed as the first-line treatment for ovulation induction.

  

The gonadotropin-stimulating action of letrozole has been used off-label in the treatment of patients with ovulatory dysfunction, such as polycystic ovary syndrome.

The results of recent double-blind, multicenter trial show that letrozole was associated with higher live-birth (27.5% vs 10.1%) and ovulation rates (61.7% vs 48.3%) among infertile women with the polycystic ovary syndrome as compared to CC.

Women on letrozole also had a 40% higher clinical pregnancy rate (OR 1.40 95% CI, 1.18-1.65) and 64% increased live birth rate (OR 1.64 (95% CI, 1.32-2.04) as compared to CC.

If prescribing letrozole, the starting dose is 2.5 mg/day for 5 days typically starting on day 3, 4, or 5 after a spontaneous menses or progestin-induced bleed. If ovulation does not occur, the dose can be increased to 5 mg/day for 5 days with a maximum dose of 7.5 mg/day. Doses higher than 7.5 mg/day have been associated with thinning of the endometrium as seen with clomiphene citrate.

Lifestyle modification and weight loss are strongly encouraged along with letrozole therapy.

Several studies have also shown that letrozole is also the drug of choice in clomiphene non-responders with 50–80% women ovulating on letrozole.

Letrozole and clomiphene citrate are pregnancy category X drugs, and studies have demonstrated similar rates of congenital malformation in mothers who achieved pregnancy because of ovulation induction using these drugs.

When prescribing letrozole for ovulation induction, patients should be counseled that unlike clomiphene citrate, letrozole is not approved by the U.S. Food and Drug Administration for ovulation induction.

More recent papers on PCOS:

Fresh or frozen-embryo transfer results in similar pregnancy rates in women without PCOS

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

Clomiphene compared with other drugs in terms of ovulation, EMT, pregnancy and live births: systematic review and meta-analysis

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

Preconception IGT in PCOS results in adverse pregnancy outcome, independent of BMI

New study quantifies the risk of developing type 2 Diabetes in women with PCOS

Polycystic ovarian syndrome increases the risk of subsequent early ovarian aging later in life

PCOS is often underdiagnosed as the common cause of Abnormal Uterine Bleeding in Adolescents

Letrozole does not increase the risk of adverse pregnancy or neonatal outcomes and major congenital anomalies in patients conceived by ARTs

ACOG calls upon all obstetrician-gynecologists to screen PCOS patients for metabolic abnormalities.

Current options for ovulation induction in Polycystic Ovarian Syndrome (PCOS)

PCOS and Infertility: Pretreatment Weight loss hikes the live birth and ovulation rate in overweight and obese patients. 

PracticeBulletin No. 194

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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.

Abstract

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.

Abstract

Current options for ovulation induction in Polycystic Ovarian Syndrome (PCOS).

Image courtesy: pcosdatabase.org

Polycystic Ovarian Syndrome (PCOS) affects 1 in 10 women of childbearing age and have important metabolic and reproductive repercussion.[1] The treatment approach varies per the age of the patient, desire for pregnancy and the presenting symptoms.  

Approximately 80% of women who suffer from anovulatory infertility have PCOS. The treatment approaches towards ovulation induction varies per efficacy, patient BMI and other associated metabolic abnormalities.

A recent paper published in the December issue of Human Reproduction Update summarizes the evidence based recommendations for the management of anovulatoryinfertility in PCOS patients.[2] 

The evidence will form the basis for WHO to develop global guidelines. Management includes lifestyle changes, pharmacotherapy, bariatric surgery and laparoscopic surgery.

Lifestyle management, weight loss and exercise is recommended as the first line of treatment to improve general health and decrease insulin resistance. Morbidly obsess women should seek expert advice. At present, there is no evidence supporting the role of bariatric surgery in PCOS associated infertility. [3]

courtesy: iconfinder.com

Clomiphene citrate is recommended as primary agent to bring about ovulation. It is simple, inexpensive and induces ovulation in 75% of the patients.[4] Letrozole, an aromatase inhibitor is fast catching on clomiphene citrate as first place option.[5]

Metformin alone is not very effective in improving the live birth rates. It is added to clomiphene citrate regimen in older women with visceral obesity.  

Gonadotrophins and laparoscopic ovarian drilling are reserved as second line of treatment in patients who do not respond to lifestyle modification and oral therapies. Gonadotropin releasing hormone (GnRH) antagonist protocol is safe and combined with IVF. When GnRH agonist is the choice for treatment, metformin should be used as an adjunct to reduce the risk of ovarian hyperstimulation syndrome(OHSS).

Laparoscopic ovarian drilling is specifically used when there are other indications for laparoscopic surgery. It should not be used as first line of treatment. Concerns about long term effect of drilling on ovarian functions are still unanswered. [6]

IVF can be of use in those patients who do not respond to lifestyle modifications and oral ovulation induction drugs. It is specifically useful in those patients who also have additional causes for infertility.

No evidence supported the use of acupuncture or herbal remedies in ovulation induction. 

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[1] https://www.womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html

[2] https://humupd.oxfordjournals.org/content/22/6/687.abstract

[3] https://www.ncbi.nlm.nih.gov/pubmed/27965894

[4] https://www.ncbi.nlm.nih.gov/pubmed/27151490

[5] https://www.ncbi.nlm.nih.gov/pubmed/27866938

[6] https://www.ncbi.nlm.nih.gov/pubmed/22696324

PCOS and Infertility: Pretreatment Weight loss hikes the live birth and ovulation rate in overweight and obese patients.

Couples are often puzzled when they face infertility as well as modifiable morbidity (overweight and obesity) limiting the chances of successful conception and healthy pregnancy thereof.   It’s   a tough choice to opt between starting the infertility treatment or correcting the underlying morbidity.

Obesity is associated with delayed conception, increased pregnancy loss, higher rates of preeclampsia and preterm labor and metabolic syndrome leading to perinatal and neonatal morbidity and mortality.

Expert opinion have always advocated that obese women with PCOS delay infertility therapy and pursue lifestyle modification, but has lacked high quality evidence in support of the claim. There are no data on the optimum weight loss as well as duration of preconception treatment.

Dr. Richard S. Legro, MD, from Penn State College of Medicine, Hershey, Pennsylvania, and colleagues recently  published their study findings in online edition of the Journal of Clinical Endocrinology and Metabolism.

“We found that pretreatment lifestyle modification for weight loss, with or without concurrent OC therapy, was associated with a significant improvement in the rate of ovulation and an even greater increase in live birth rate than immediate fertility treatment with clomiphene. Further, ovulation and live birth rates were nearly identical between pretreatment with oral contraceptives vs immediate treatment with clomiphene, suggesting that there is little fertility benefit to pretreatment with hormonal suppression, alone or in combination with lifestyle modification” opined the researchers.

Two very good trials recently were concurrently conducted to demonstrate significant benefits of lifestyle modification on ovulation and live births rate in obese women with PCOS.  The trials are The Treatment of Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women or OWL PCOS study and The Pregnancy in Polycystic Ovary Syndrome II or PPCOS II study.

Both the trials were multicentric conducted concurrently by the researchers.

The OWL PCOS was a randomized open labeled two site study constituting 149 women, diagnosed with PCOS by Modified Rotterdam criteria. The women were assigned to 3 groups to receive either 16-week Preconception treatment with continuous oral contraception, lifestyle modification or combination of both before going to receive 4 cycles of clomiphene and timed intercourse.

The PPCOS II study was double blind, with 750 women receiving   either 5 cycles of ovulation induction with letrozole or clomiphene citrate and timed intercourse. No study participants received any life style modification earlier.

A secondary post hoc analysis was done by combining data from both the studies. An intentional similar design, with same inclusion/exclusion criteria’s and use of clomiphene for ovulation induction made it feasible to combine the data from the two trials.

The researchers extracted the data for all women in the PPCOS II study in the clomiphene arm who met the BMI criteria of the OWL PCOS study. So, they had data on 187 women from the PPCOS II study and 142 women from the OWL PCOS study.

The primary outcome was live birth, while predetermined secondary outcomes were conception, ovulation and pregnancy loss rates.

It was seen that earlier lifestyle modification leading to weight loss, irrespective of hormonal treatment with OCP resulted in significant improvement in ovulation rate and greater increase in live birth rates as compared to starting immediate clomiphene treatment.

In those patients who only received clomiphene the ovulation rate was 44.7% (277/619), and the live birth rate was 10.2% (19/187) while patients who underwent weight loss before fertility treatment the ovulation rate was 62.0% (80/129), and the live birth rate was 25.0% (12/48).

Patients who underwent lifestyle modification (In the OWL PCOS study, as well as patients in the Combined group of the OWL PCOS study) had 2.5-fold increase in live births. Patients in the Lifestyle modification and Combined groups also had a 1.4-fold increase in cumulative ovulation rate (P .003 and P .001, respectively) compared to treatment with only clomiphene in PPCOS II.

Use of OCP before starting clomiphene did not have any significant effect on ovulation or live birth rates.

Comparing the results at the end of first cycle, only patients who lost weight in OWL PCOS had a significantly improved chance of pregnancy and live birth in the first ovulation induction cycle compared to the first ovulation induction cycle in direct clomiphene group. The study also demonstrated that improving the quality of ovulation is as important as improving the rate of ovulation to achieve a higher live birth rate.  

"Our research holds significant implications for current practice, and supports the concept of delaying fertility treatment to pursue lifestyle modification in overweight/obese women with PCOS. It provides momentum to test this concept more completely and prospectively in properly designed and adequately powered multicenter studies to generate Level I evidence for the practice," the authors explain.

"Future studies may also want to utilize other ovulation induction agents in the infertility treatment phase such as low dose gonadotropin or letrozole, which tend to have greater success rates combined with comparable rates of multiple pregnancy and congenital anomalies as clomiphene," the authors conclude. 

Disclosure Statement: Dr. Legro reports consulting fees from Euro screen, Astra Zeneca, Clarus Therapeutics, Takeda, Kindex and research funding from Ferring and Astra Zeneca. Dr. Estes and Dr. Schlaff reports research funding from AbbVie. Dr. Dokras reports consulting fees from JDS Therapeutics. Mr. Kunselman reports ownership of Merck stock. Dr. Sarwer reports consulting fees from BAROnova, EnteroMedics, and Ethicon. The other investigators report no disclosures. 

References:

http://press.endocrine.org/doi/pdf/10.1210/jc.2016-1659