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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Human eggs grown to maturity in the lab first time could unlock future fertility options

image credit: Prof David Albertini

In an extraordinary scientific feat, researchers were successful in growing human oocytes from the earliest follicular stage in the laboratory in just 20 days instead of 5 months in the body. The eggs fertility potential is unknown yet, and it remains to be seen whether they can produce healthy babies. 

The study was carried out in collaboration with the Royal Infirmary Edinburgh, The Center for Human Reproduction in New York and the Royal Hospital for Sick Children in Edinburgh, and published January 2018 in Journal of molecular human reproduction.

This process of oocytes maturation in lab could find potential applications in fertility preservation of cancer patients during the chemotherapy treatments. Immature eggs recovered from patients’ ovarian tissue could be matured in the lab and stored for later fertilization without the fear of reintroducing cancer.

Professor Evelyn Telfer from School of Biological Sciences said, “Being able to fully develop human eggs in the lab could widen the scope of available fertility treatments. We are now working on optimizing the conditions that support egg development in this way and studying how healthy they are. We also hope to find out, subject to regulatory approval, whether they can be fertilized.”

Till now researchers have successfully produced live offspring in mouse from in vitro grown (IVG) oocytes from primordial follicles. They have also grown human oocytes from secondary/multi-laminar stage to obtain fully grown oocytes capable of meiotic maturation.

However, this is the first report of in vitro complete human oocyte growth from immature primordial/unilaminar follicles using two-step culture system.

A series of magnified images show human eggs in development stages. Prof. Evelyn Telfer and Dr. Marie McLaughlin/University of Edinburgh/Handout via REUTERS

The scientist obtained fresh ovarian cortical pieces of approximate size 5 mm × 4 mm from women undergoing elective cesarean section. Fragments were cultured for 8 days according to the institute predetermined protocols.

Follicles ranging in diameter from 100–150 μm were dissected for further isolated culture. After about 8 days cumulus-oocyte complexes (COCs) were retrieved by gentle pressure on the cultured follicles. These COCs were further cultured for 4 more days when complexes containing oocytes >100 μm diameter were selected for in vitro maturation (IVM) in SAGE medium and subsequently fixed for analysis.

Confocal immuno-histochemical analysis of oocytes more than 100 μm diameter showed the presence of a Metaphase II spindle confirming that these IVG oocytes had resumed meiosis but their developmental potential is unknown.

Other scientists are looking at this process with great concern because of the shortened maturation process and lack of genetic analysis of the matured egg.

Telfer agrees that much work needed to be done and said, “We had no great expectations. To see at least one [egg reaching maturity], we thought, ‘Wow, that’s actually quite incredible.’”

The eggs fertility potential is unknown yet because of lack of regulatory approval, and even if they have can be fertilized much research is needed to see whether they can produce healthy babies.

But, the study has given new insights on human egg development that could be very useful in fertility treatment and regenerative therapies.

Her team is working on improving the process and getting an approval from the United Kingdom’s Human Fertilization and Embryology Authority—to try fertilizing the lab-matured eggs to create human embryos.

Full Text

University of Edinburgh press release

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News from ACOG 2018: Aspirin cuts down the risk of superimposed preeclampsia in women with chronic hypertension

Keeping up with the American College of Obstetricians and Gynecologists (ACOG) 2016 practice guideline of supplementing low-dose aspirin to pregnant women with chronic hypertension was associated with a 57% decrease in superimposed preeclampsia.

Investigators at Thomas Jefferson University presented the results of this retrospective study in a poster presentation at the ACOG 2018 annual meeting (April 27–30, 2018, Austin, Texas).

The study participants included 715 women with chronic hypertension carrying singleton pregnancy, who delivered at Thomas Jefferson University Hospital between January 2008 to July 2017.

The women were divided into 2 groups based on whether they delivered before and after ACOG recommendations. The pre-ACOG group included 635 women while the post-ACOG group had 80 women.

The cohort was further stratified based on additional risk factor for the development of superimposed preeclampsia (SIP) like a previous history of preeclampsia or pregestational diabetes. The primary outcome of interest was the development of preeclampsia, while the secondary outcomes studied were the incidence of SIP with severe features (SIPSF), small for gestational age, and preterm birth was also studied.

The incidence of SIP was dramatically reduced by 57% in women with chronic HT who received low dose aspirin (OR 0.43 (95% CI 0.26-0.73).

Women who had no other risk factor for the development of SIP, the incidence of SIP and SIP with severe features decreased by 75% and 77% respectively.

The incidence of secondary outcomes did not show any significant changes. Aspirin showed the highest benefits in women with chronic hypertension who did not have any additional risk factor for preeclampsia.

Hence the authors concluded that this study showed that ACOG guidelines have a significant positive impact on bringing down the incidence of superimposed preeclampsia in patients with chronic hypertension.

Abstract

ACOG Practice Advisory on Low-Dose Aspirin and Prevention of Preeclampsia

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