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

Episona.com

Healthy infertile women with no polycystic ovarian syndrome have the same ongoing pregnancy and live birth rates from IVF irrespective of whether the embryo was fresh or frozen reports the results of two recent clinical trials published in JAMA. 

Recent clinical trials have documented higher pregnancy and live birth rates with the transfer of frozen embryos as compared to fresh ones. A clinical review published in the Journal of Human Reproduction Update also favored “elective frozen embryo transfer (eFET) not only in terms of achieving higher pregnancy rates but, more importantly, also in terms of lower maternal and infant morbidity and mortality.”

The two current studies were conducted to see whether fresh frozen embryo transfer resulted in higher birthrates in women who do not have PCOS.

The first multicenter, randomized trial recruited 2157 women who were scheduled to undergo their first IVF cycles. They were randomly assigned to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. The maximum embryo transferred in each participant was two with the live birth rate as the primary outcome after the first embryo transfer.

There was no significant difference in terms of live birth rates in the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%; P=0.50) respectively. Both the groups were also similar in terms of risks of obstetrical and neonatal complications, rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy.

But, frozen embryo transfer did result in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%; P=0.005).

The second study randomly assigned 782 healthy infertile women with no PCOS to receive either a frozen embryo or a fresh embryo on day 3 during their first or second IVF. In this study also, the pregnancy rates were comparable in both the groups, 36.3% in the frozen-embryo group 34.5% in the fresh-embryo group (P = .65).

The authors concluded that in women who do not have PCOS, the pregnancy rates are similar with fresh or frozen embryos. In healthy infertile women, probably the uterine environment was favorable for fresh embryos transfer. 

Abstract-NEJM

Abstract-NEJM

Abstract-JAMA

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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

Photo of the day: Three-dimensional sonography-based automated follicle count (SonoAVC) in polycystic ovarian morphology

Automated Volume Count software in three-dimensional volume of left ovary, depicting 67 antral follicles

Three-dimensional Sonography-based Automated Volume Count, GE Medical Systems (SonoAVC) could be a useful adjunct for follicular monitoring in patients with Polycystic ovarian syndrome (PCOS), with a significant saving in time and an accurate prediction over manual counts. 

SonoAVC was introduced in 2008 (GE Medical Systems, Zipf, Austria), and automatically identifies and counts follicles in a given ovarian volume because of hypoechoic nature against hyperechoic ovarian tissue background.

SonoAVC software is either integrated into the ultrasound device or it can be installed separately on a PC for the offline analysis of data sets obtained using an ultrasound device from the same manufacturer. Each volume has its own color, making SonoAVC an ideal tool for studying follicular development within the ovary.

Here is a beautiful picture of the day published on January 3, 2018 in the Journal Ultrasound in Obstetrics and Gynecology, which depicts the stark contrast between Grayscale two-dimensional ultrasound images showing follicles vs. automated follicle counting using Sonography-based Automated Volume Count software in three-dimensional volume of left ovary, depicting 67 antral follicles.  

Grayscale two-dimensional ultrasound images showing follicles

automated follicle counting using Sonography-based Automated Volume Count software

Technique of using SonoAVC on the Voluson E8 ultrasound system:

• A transvaginal ultrasound is performed using a 3D imaging probe (RIC 5-9 or RIC 6-12)

• Optimize the gain and harmonics for optimum image quality

• Select 3D imaging mode, adjust quality settings

• Adjust volume angle to include entire ovary and acquire volume

• Adjust 3D box over area of interest

• Select SonoAVC to evaluate the ovarian follicles

• Increase or decrease growth or follicular separation

• Select follicles manually if they are not identified

• Display report and chart

Full-Text of Journal Article 

In case you missed it: Here are the top 5 posts this month

September was a very busy month with lots of good research papers and systematic reviews published on various topics. We also saw many guidelines and recommendations updates from ACOG, ASRM and USPSTF. Here are the top 5 most read posts for the month of September.

USPSTF simplifies cervical cancer screening recommendations: Dual testing no longer advised

The US Preventive Services Task Force (USPSTF) has issued new draft recommendations for cervical cancer screening with a major change that it recommends either cervical cytology (CC) or high-risk HPV (hrHPV) test as a screening procedure every 3 years for women aged 30-65 years, and not both ( Grade A)  

https://obgynupdated.blogspot.com/2017/09/uspstf-simplifies-cervical-cancer.html

ACOG issues clinical practice guidelines for Gestational Diabetes Mellitus

The American College of Obstetricians and Gynecologists (ACOG) has issued clinical practice guidelines for the diagnosis and treatment of gestational diabetes mellitus (GDM).

Although prevalence of GDM is directly proportional to prevalence of type 2 DM in a given population, it is estimated that GDM accounts for 90% of cases diabetes in pregnancy. The prevalence of DM in pregnancy is around 6-9%.

https://obgynupdated.blogspot.com/2017/09/acog-issues-clinical-practice.html

ASRM guidelines update: Metformin alone is not the first line of treatment for ovulation induction in women with PCOS

Practice Committee of the American Society for Reproductive Medicine does not recommend Metformin alone for ovulation induction as a first line therapy in women with PCOS. The guidelines were published in Journal Fertility and Sterility Epub ahead of print.

Metformin is a biguanide used as an oral insulin lowering agent in type2 diabetes, but also used enthusiastically in women with PCOS because of shared pathophysiology of insulin resistance in both.

https://obgynupdated.blogspot.com/2017/09/asrm-guidelines-update-metformin-alone.html

Oral Nifedipine parallels IV hydralazine in lowering down BP in acute hypertensive emergency in pregnancy

Intravenous hydralazine and oral nifedipine both exhibit the same efficacy in lowering the blood pressure in acute hypertensive emergency of pregnancy reports the results of small randomized trial published online in journal American Journal of Obstetrics and Gynecology.

https://obgynupdated.blogspot.com/2017/09/oral-nifedipine-parallels-iv.html

Oral diclofenac potassium plus cervical lidocaine cream eases the pain during hysterosalpingography

Oral diclofenac potassium tab 30 minutes before hysterosalpingography (HSG) and cervical lidocaine cream 5% significantly relieves pain and eases patient anxiety during the procedure and for half an hour after reports the results of a randomized trial published in September issue of journal Fertility and Sterility.

https://obgynupdated.blogspot.com/2017/09/oral-diclofenac-potassium-plus-cervical.html 

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

Preconception Impaired Glucose Tolerance (IGT) in women with Polycystic Ovarian Syndrome (PCOS), is associated with adverse pregnancy as compared to women with normoglycemia or isolated impaired fasting glucose (i-IFG) reports the results of multi-center randomized trial published ahead of print in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism. 

These results were independent of prepregnancy BMI.

PCOS is prevalent in 7-8% of women of childbearing age and it is the most common cause of infertility. This study was also a secondary analysis of data from RCT that was designed to compare the obstetric outcomes between fresh and frozen embryo transfer.

Baseline fasting and 2-hour glucose and insulin levels following 75-g OGTT were measured in 1508 women with PCOS.

Women who had IGT before they become pregnant faced 3 times and 8 times increased odds of developing Gestational Diabetes in singleton pregnancy and twin pregnancy respectively.

These women also faced twice the risk of large for gestational age babies and singleton pregnancy loss as compared to women with normal blood sugar levels. All these associations were true even after the data was adjusted for confounder like age, body mass index (BMI), duration of infertility, total testosterone level, and treatment groups (frozen vs. fresh embryo transfer).

The researchers concluded that preconception impaired glucose tolerance is associated with adverse pregnancy outcomes in women with PCOS.

Abstract

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

Women with Polycystic Ovarian Syndrome (PCOS) are diagnosed with diabetes 4 years earlier and are at 4 times higher the risk of getting the disease as compared to controls, reports the result of a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.  

PCOS is prevalent in 7-8% of women of childbearing age and it is the most common cause of infertility. In USA, an estimated 5 to 6 million women have PCOS.

Dorte Glintborg, M.D., Ph.D., of the Odense University Hospital in Denmark said, “Many women with PCOS are obese, but the risk for the development of diabetes in PCOS is unknown.”

In this Prospective population-based cohort study researchers studied two groups of women with PCOS. The larger cohort consisted of all pre-menopausal women with a diagnosis of PCOS (18,477 women) picked up from National Patient Register, Denmark and a smaller local cohort of 1,162 women with PCOS who were examined at Odense University Hospital in Denmark. 

Women in the local group were examined and tested for insulin and glucose levels, cholesterol, triglycerides and testosterone levels.

Three age matched women were included as control for each study participant with a diagnosis of PCOS. The main outcome of interest was time and number of participants to develop diabetes.

The women were followed up for median 11.1 years.

The Hazard Ratio for development of T2D was 4.0 in PCOS Denmark (p<0.001), while the total event rate of T2D was 8.0 per 1000 patient years in PCOS Denmark vs. 2.0 per 1000 patient years in controls (p<0.001).

The women also developed diabetes 4 years earlier as compared to controls (31 years vs. 35 years).

BMI, fasting blood glucose, HbA1c, 2-hour blood glucose, insulin resistance, and triglycerides all were good predictors of risk of developing diabetes in future while having multiple children was protective against development of T2D.

The increased risk of developing T2D in PCOS is an important finding,” Glintborg said. “Diabetes may develop at a young age and screening for diabetes is important, especially in women who are obese and have PCOS.”

Access Abstract, Press Release by Endocrine Society

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

Women with polycystic ovarian syndrome (PCOS) have 8.64 fold increase in risk of developing premature ovarian failure as compared to women who did not have PCOS according to a population based study in forthcoming issue of Journal Menopause. Metformin was found to be effective in reducing such risk. 

The study authors reviewed data across a period of 14 years (1998 to 2012) from Taiwan National Health Insurance Research Database.

The study group consisted of women with PCOS (exposure group; n=7,049), each woman with PCOS was age matched with 10 other women without PCOS. (contrast group; n = 70,490).

The cohort was followed up for 10 years. The diagnosis of POI and PCOD was confirmed by blood test and ultrasonography.

Polycystic ovary syndrome (PCOS) is an endocrinopathy that affects approximately 10% of reproductive-aged women throughout their lives and POI affects 1-3% of women by age 40.

It was seen that POI was nearly 8 times more common in women with PCOD. Kaplan-Meier survival analysis showed that POI free survival rates of women were significantly more in contrast group than exposure group (P < 0.001).

After adjustment of covariates, it was seen that women with PCOD have 8.31 fold increase in risk of developing premature ovarian failure, this was 9.93 fold for women who did not receive metformin treatment for PCOS.

Metformin was significantly effective in lowering the risk to nearly half (5.66).

However, well-designed, prospective, long-term, large-scale, randomized clinical trials are necessary to elucidate the efficacy and safety of long term metformin in patients with PCOS.  

The results of this study are in contrast to the earlier hypothesis that women with polycystic ovaries (PCO) are protected against POI because they may have actually been born with a larger pool of resting follicles.

Currently, PCOS and POI are both being investigated as diseases of autoimmune origin.

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

Image courtesy: University of Utah.

 Abnormal uterine bleeding(AUB) is very frequent in adolescents and generally lasts for 4-5 years after menarche. It is an important cause of visit to emergency room or healthcare provider in pediatric patients. Although DUB due to immaturity of hypothalamic pituitary ovarian (HPO) axis is a common cause of AUB in healthy adolescent, it is also important to rule out other pathological causes.

PCOS as a cause of AUB in adolescent’s patients is often underdiagnosed and poses a diagnostic dilemma as normal pubertal changes like acne, menstrual irregularities and hyperinsulinemia can mimic several features of PCOS.

Prompt diagnosis and treatment of PCOS is very important because of future reproductive and metabolic repercussions.[1] Evidence suggests that adolescents diagnosed with PCOS have elevated risk of Metabolic Syndrome (MetS) and premature cardiovascular dysfunction and cardiovascular disease.[2]

Adolescents with AUB are mostly managed as outpatients but some require hospitalization because of hemodynamic instability. A recent paper published in Journal of Pediatricand Adolescent Gynecology evaluated the most common etiology for AUB in hospital admitted adolescent patients with severe anemia.[3]

This retrospective study was conducted by Dr. Sofya Maslyanskaya, Assistant Professor of Pediatrics, Albert Einstein College of Medicine, Bronx, New York and her colleague at Children's Hospital at Montefiore in New York City.

The researchers identified 125 females aged 8 to 20 years admitted to the hospital for anemia with AUB from January 2000 to December 2014.

As per hospital protocols, all the subjects underwent hormonal testing for PCOS and other endocrinal disorders. Hence the data could be accessed and reviewed by the researchers for laboratory test results, treatment and final diagnosis.

The demographics of the study subjects were: mean age at the time of admission was 16 years, mean Hb 7gm/dl, nearly half were obese and 41% sexually active.

PCOS was diagnosed as the leading cause (33%) for hospital admissions for severe bleeding, followed by HPO axis immaturity in 31% of cases. Endometritis was responsible for 13% of admissions while bleeding disorder accounted for 10%.

Nearly three-fourth of teenagers diagnosed with PCOS were obese while subjects with HPO axis immaturity have the lowest Hb level as compared to other etiologies.

The lead author stressed the need for ruling out PCOS as the cause of AUB before any form of treatment is started, especially in adolescent girls admitted for anemia with AUB. Once hormonal treatment is started the diagnosis becomes more difficult.

The study results cannot be generalized to patients with less severe DUB. Also, the participants were mostly from Asian and Latino communities, so the results may not apply to other demographics.

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[1] http://contemporaryobgyn.modernmedicine.com/contemporary-obgyn/content/tags/adolescent-gynecology/pcos-adolescents-beyond-reproductive-implicati

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703718/

[3] http://www.jpagonline.org/article/S1083-3188(16)30284-4/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

Preliminary study indicates that Resveratrol is effective in correcting PCOS Abnormalities.

Courtesy: www.pexels.com

Clinical pearls:

• Resveratrol in a dose of 1500 mg/day reduced the levels of Testosterone and DHES by 23.1% and 22.1% in a small pilot study of patients with PCOS.
• It also improved the insulin resistance and decreased serum insulin levels significantly.

Resveratrol found in grapes and red wine can help to reverse the hormonal imbalance found in women with PCOS says the results of small pilot study published online October 18,2016 in  The Journal of Clinical Endocrinology& Metabolism.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder and affects 1 in 15 women worldwide with less than  50% of women diagnosed. [1] It is responsible for 70 percent of infertility issues in women who have difficulty ovulating, per the PCOS Foundation.[2] It has been recognized and diagnosed for 75 years. Genetic and environmental factors play a part in its causation, but the exact etiology remains unknown.

It has a multifactorial etiology that involves genetic, environmental and hormonal imbalance. Androgen excess is clearly the culprit but insulin resistance also plays a major role in its causation. 

Although large number of women with obesity have PCOS, not all obese women have PCOS. Apart from infertility, PCOS is responsible for many chronic conditions. As per NIH, women with PCOS constitute the largest group at risk for developing CVD and Type 2 DM. More than half will be diagnosed with prediabetic or diabetic before the age of 40 years. [3]

Treatment is currently directed at symptoms rather than treating the pathophysiology which remains largely unknown. Lifestyle modification, weight loss and metformin have all shown to decrease androgen, improve insulin sensitivity and bring about ovulation.

Resveratrol is an antioxidant compound found in many foods like dark chocolate, blueberries, raspberries, including peanuts and pistachio beside grapes and red wine.  It is known to have anti-inflammatory and anti-proliferative property well known to cause apoptosis in cancer cells. In 2010 a study by researchers at University of California School of Medicine, Department of Gynecology and Obstetrics, showed that in-vitro animal studies resveratrol could counteract the negative effect of insulin on ovarian cells and preventing excess proliferation of the theca interstitial ovarian cells.

The recent study is a randomized, double-blind, placebo-controlled trial that evaluated the effects of resveratrol over a period of 3 months at Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA.

The study included 34 patients diagnosed with PCOS as per the Rotterdam criteria,[4] each having at least 2 of the following three clinical or chemical hyperandrogenism; oligo- or amenorrhea; and/or polycystic ovaries as viewed by transvaginal ultrasound.

All study participants were evaluated at baseline and after 3 months for BMI, hirsutism, acne score, Insulin levels, OGTT and other metabolic and endocrine abnormalities.

Participants were then randomly assigned to receive either placebo or 1500 mg/day of oral micronized transresveratrol. Over the course of the studies 3 women were lost to follow-up and one became pregnant, so the final analysis includes 15 women in each arm.

The primary endpoint of the study was changes in testosterone levels (T).

It was seen that resveratrol was significantly effective in bringing down the serum testosterone levels in the study group. Women on resveratrol experienced an average of 23.1% decline of total T levels (.53 ng/mL at baseline to 0.41 ng/ml) which was significantly more than what was observed by use of OC pills and metformin (19%)  over a 12-month period.[5] For women in placebo group no change in T levels was seen. Similarly, serum DHES levels decreased by 22.1% for women taking resveratrol (8.05 μmol/L at baseline to 6.26 μmol/L after 3 months).

Resveratrol also decreased the serum fasting insulin levels and exert a positive increase in Insulin Sensitivity Index of by 66%.

“It is apparent that resveratrol significantly reduces serum levels of T and DHEAS, suggesting an effect on ovarian as well as adrenal androgen production” the authors quoted.

In a press releases accompanying the article, the study’s senior author Dr.  Antoni J. Duleba said “Our study is the first clinical trial to find resveratrol significantly lowers PCOS patients’ levels of testosterone as well as dehydroepiandrosterone sulfate (DHEAS), another hormone that the body can convert into testosterone. This nutritional supplement can help moderate the hormone imbalance that is one of the central features of PCOS.”

He also stated the need for more studies before a recommendation can be made for its use in clinical practice.

The authors reported having no relevant conflicts of interest.

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[1] http://www.pcosfoundation.org/what-is-pcos

[2] http://www.pcosfoundation.org/about-pcos

[3] https://prevention.nih.gov/docs/programs/pcos/FinalReport.pdf

[4] Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41– 47

[5] Glintborg D, Altinok ML, Mumm H, Hermann AP, Ravn P, Andersen M. Body composition is improved during 12 months’ treatment with metformin alone or combined with oral contraceptives compared with treatment with oral contraceptives in polycystic ovary syndrome. J Clin Endocrinol Metab. 2014;99:2584 –2591