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

Ob/Gyn Updated Facebook page

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

Ovulation induction with Clomiphene Citrate (CC) in women with WHO group II ovulatory disorders results in lower endometrial thickness (EMT) as compared to other regimens. The regimen also resulted in lower number of pregnancies and live births reports the results of systematic review and meta-analysis published in Journal Ultrasound in Obstetrics and Gynecology.

WHO group II ovulation disorders are defined as dysfunctions of the hypothalamic-pituitary-ovarian axis. This category includes conditions such as polycystic ovary syndrome (PCOS) and hyperprolactinaemic amenorrhoea. Around 85% of women with ovulation disorders have a group II ovulation disorder.

This systematic review and meta-analysis only focused on randomized control trials(RCTs) and included all those studies comparing CC with any other regimens and looked at EMT and rates of ovulation, pregnancy and live births.

The other regimens included in the study were Letrozole, CC plus metformin, CC plus N-acetyl cysteine (NAC), CC + nitric oxide (NO) donor and Tamoxifen.

The researchers selected 33 RCTs from 1718 articles that fitted the inclusion criteria amounting a total of 4349 women and 7210 ovulation induction cycle.

Maximum number (15) of RCTs compared CC with Letrozole. Overall the mean EMT was 1.39mm lower in CC group as compared to Letrozole. (WMD, −1.39; 95% CI, −2.27 to −0.51; I² = 100%), and women on CC had a 22% lower chance of pregnancy and 30% lower chance of live births. The ovulation rates were comparable between the two groups.

Only 2 RCTS were found comparing CC with CC plus metformin and no significant difference were noted in any of the outcome parameters between the groups.

When comparing CC with CC plus N-acetyl cysteine (NAC) and CC plus nitric oxide (NO) donor, EMT was lower in CC only group, along with ovulation and pregnancy rates.

When the CC regimen was compared with Tamoxifen, lower EMT and comparable ovulation and pregnancy rates were noted.

The authors concluded that in women with WHO group II ovulatory disorders, Letrozole seems to benefit these women more in terms of increased EMT, ovulation, pregnancy rates and live births. 

Whether the increase pregnancy rates and live births rates are due to increase in EMT has not been looked at in this study.

Abstract

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

Novartis Breast Cancer drug Kisqali wins market approval in European Union as first-line treatment for HR+/HER2-

European Medicines Agency (EMA) panel approves Kisqali (CDK4/6 inhibitor ribociclib) in combination with hormone therapy as a first-line treatment for hormone receptor positive, human epidermal growth factor receptor-2 negative locally advanced or metastatic breast cancer.

FDA has already cleared Kisqali in March 2017.

This approval challenges the market share of rival, Pfizer's Ibrance which is in market since 2015.

Kisqali is sold in US packaged with aromatase inhibitor letrozole but, the Committee for Medicinal Products for Human Use (CHMP) recommends combining Kisqali with any aromatase inhibitor like letrozole, anastrozole or exemestane, giving the physician the discretion to select the therapy they believe is most appropriate for each individual patient.

This approval is based on results of a pivotal Phase III  MONALEESA-2 trial that showed Kisqali plus letrozole reduced risk of disease progression or death by 44% over letrozole alone among postmenopausal women with HR+/HER2- advanced breast cancer.

After nearly one year of additional follow-up, Kisqali plus letrozole demonstrated median progression-free survival (PFS) of 25.3 months compared to 16.0 months for placebo in combination with letrozole.

Bruno Strigini, CEO, Novartis Oncology said, "This positive CHMP opinion brings us one step closer to improving the lives of women diagnosed with advanced or metastatic breast cancer throughout Europe. There is currently no cure for advanced breast cancer, and approximately 30 percent of those affected by early-stage breast cancer will go on to develop advanced disease.”

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. 

---

[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