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

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 now  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 multi-factorial 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]

Considering all the associated co-morbidities American College of Obstetricians and Gynecologists and the Endocrine Society recommend that all women diagnosed with PCOS should undergo screening for Dyslipidemias and Impaired Glucose Tolerance Test in a recent paper published in November issue of American Journal of  Obstetrics and Gynecology.[4]

The women are advised to have a full 2 hour 75 g oral glucose tolerance test and fasting lipid profile at the time of diagnosis and every 2-5 years and 2 years respectively.

The study also stressed that gynecologists under-utilize the opportunity to screen these women for metabolic abnormalities. In an internet survey with ACOG fellows and junior obstetricians it was seen that 1 in 5 physicians will not order any test in nearly half of their patients diagnosed with PCOS. 

Nearly half of the patients of PCOS patients received hemoglobin A1C test  and about 40% were ordered to have  fasting glucose. Only 7% of the patients were ordered to have 2-hour oral glucose tolerance test.

ACOG and the Endocrine Society advocates the use of CME and other educational activity to educate the obstetricians to address the metabolic abnormalities in their PCOS patients because, they may be the only physician to come in contact with  these patients in the reproductive years.  So, no opportunities should be lost to educate these patients about the screening for future metabolic disorders.

This promotes effective preventive health care and early diagnosis in these at-risk women.

According to Endocrine society clinical practice guidelines:[5]

·         The Task Force recommends that a physical examination should document cutaneous manifestations of PCOS: terminal hair growth acne, alopecia, acanthosis nigricans, and skin tags

·         The Task Force recommends screening adolescents and women with PCOS for increased adiposity, by BMI calculation (Overweight = 25 to 29.9 kg/m^2, ,Obese = ≥30 kg/m²⁾ and measurement of waist circumference. (Abnormal>35 inches)

·         The Task Force recommends the use of an oral glucose tolerance test (OGTT) consisting of a fasting (Fasting glucose >126 mg/dL or 2-hour glucose >200 mg/dL) and 2-hour glucose level using a 75-g oral glucose load to screen for impaired glucose tolerance (IGT) and T2DM ( Fasting glucose 110 to 125 mg/dL or 2-hour glucose 140 to 199 mg/dL)  in adolescents and adult women with PCOS because they are at high risk for such abnormalities. A hemoglobin A1c (HgbA1c) test may be considered if a patient is unable or unwilling to complete an OGTT. Rescreening is suggested every 3–5 years, or more frequently if clinical factors such as central adiposity, substantial weight gain, and/or symptoms of diabetes develop.

·         The Task Force recommends that adolescents and women with PCOS be screened for the following cardiovascular disease risk factors : family history of early cardiovascular disease, cigarette smoking, IGT/T2DM, hypertension, dyslipidemia, OSA, and obesity (especially increased abdominal adiposity). Abnormal values are: HDL <50 mg/dL,TG >150 mg/dL and LDL >130 mg/dL.

·         The Task Force suggests screening women and adolescents with PCOS for depression and anxiety by history and, if identified, providing appropriate referral and/or treatment.

·         The Task Force suggests screening overweight/obese adolescents and women with PCOS for symptoms suggestive of OSA and, when identified, obtaining a definitive diagnosis using polysomnography. If OSA is diagnosed, patients should be referred for institution of appropriate treatment.

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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] http://www.ajog.org/article/S0002-9378(16)30478-1/fulltext

[5] National Guideline Clearinghouse (NGC). Guideline summary: Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. In: National Guideline Clearinghouse (NGC) [Web site]. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2013 Dec 01. [cited 2016 Nov 01]. Available: https://www.guideline.gov

Vitamin D and Human Reproduction—Evolving perspectives

We are all well versed with the role of Vitamin D in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. Its deficiency is linked to many chronic diseases of the cardiovascular and metabolic systems.

Evidence from animal and human studies suggests that vitamin D plays a very important role in human fertility and neonatal development. This steroid hormone has Vitamin D receptors (VDR) at multiple sites in the body including ovary, particularly the granulosa cells, endometrium and placenta.

It plays a very important role in ovarian steroidogenesis. [1] It deficiency contribute to development of insulin resistance and impaired glucose metabolism in patients with Polycystic Ovary Syndrome (PCOS). Therapeutic efficacy of supplementation with Vitamin D to improve insulin resistance, bring about ovulation and regularize menstruation in PCOs patients have been documented.[2] [3]

Observations also shows that lower 25(OH)D levels put women at higher risk of developing uterine fibroids, both in black and white ethnicities. In these women, the growth and size of the fibroid is also directly related to decreased levels of Vitamin D. Animal studies and human in vitro studies have shown the beneficial effect Vitamin D supplementation in inhibition of development and/or growth of uterine fibroids.[4] [5]

A recent study by Harris HR et al demonstrated that women within the highest quintile of Vitamin D blood values have one fourth the risk of developing endometriosis as compared to those in lowest quintile.[6]

It also plays a role in Body Mass Index (BMI) as per a recent meta-analysis, every 10% increase in BMI leads to 4% decrees in Vitamin D concentration.[7]

It’s role in male reproductive physiology is well documented by the fact that it’s level directly correlate with sperm motility and morphology.

As per Hill’s criteria a causal relationship between Vitamin D deficiency and negative outcome in IVF is explained but further research into knowing the magnitude of association is needed.[8]

A systemic review and meta-analysis by Lerchbaum E and Obermayer-Pietsch B published in Eur J Endocrinol May 1, 2012 concludes that Vitamin D plays an important role in Human reproduction and advocates the need of further research in therapeutic benefits of Vitamin D supplementation in such patients.  

Another review by Vanni et al published in the Reproductive Biology and Endocrinology, 2014 emphasizes the importance of supplementation of Vitamin D in IVF settings because consisting evidence documenting the increase incidence of gestational diabetes, IUGR, pre-eclampsia and preterm births in patients deficient in Vitamin D.[9]

The authors opine that although drastic improvements in reproductive failure may not be achieved solely by supplementing Vitamin D, but its addition to any fertility regimen is cheap, effective and without any side effects. It is easily correctable by simple oral supplementation.

Dosage up to 4000 IU is safe, without any side effects and effectively improve maternal vitamin D status. [10]

Results of double blind randomized trial entitled “Vitamin D during IVF” is still awaited.[11]

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[1]Anagnostis P, Karras S, Goulis DG: Vitamin D in human reproduction: a narrative review. Int J Clin Pract. 2013, 67 (3): 225-235

[2] Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S: The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010, 33 (4): 234-238.

[3] Wehr E, Pieber TR, Obermayer-Pietsch B: Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011, 34 (10): 757-63.

[4] Bläuer M, Rovio PH, Ylikomi T, Heinonen PK: Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro. Fertil Steril. 2009, 91 (5): 1919-1925.

[5] Halder SK, Osteen KG, Al-Hendy A: Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and −9 in human uterine fibroid cells. Hum Reprod. 2013, 28 (9): 2407-2416.

[6]  Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA: Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013, 177 (5): 420-430.

[7] Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Kiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, et al: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013, 10 (2): e1001383-

[8] Hill AB: The environment and disease: association or causation?. Proc R Soc Med. 1965, 58: 295-300.

[9] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM: Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013, 26 (346): f1169-

[10] Wagner CL, McNeil R, Johnson DD, Husley TC, Ebeling M, Robinson C, Hamilton SA, Hollis BW: Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013, 136: 313-320.

[11] https://clinicaltrials.gov/ct2/show/NCT01019785

Metformin or Oral Contraceptives for treatment of Polycystic Ovarian Syndrome in Adolescents: A Meta-analysis

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder in adolescent and adult women affecting 1 in 15 women worldwide and have important metabolic and reproductive implication.  

The diagnosis of PCOS is challenging specially in adolescent as normal pubertal changes can mimic the signs of PCOS. The Rotterdam criteria are widely in use for diagnosis. These criteria require that patients have at least two of the following conditions: ovulatory dysfunction, androgen excess, and polycystic ovaries. It is also necessary to rule out other causes of androgen excess and ovulatory dysfunction before a diagnosis of PCOS is made. 

The treatment approach varies according to the age of the patient, desire for pregnancy and the presenting symptoms.  

The Endocrine Society guidelines for the treatment of adults with PCOS recommends using oral contraceptive pills (OCPs) to control symptoms of androgen excess, while reserving metformin for cases with impaired glucose tolerance or features of metabolic syndrome.

However, evidence is sparse to support the best first-line medication in adolescents with PCOS.

Investigators Dr. Reem A. Al Khalifah and colleagues of King Saud University in Saudi Arabia published a metaanalysis and systemic review of randomized, controlled trials (RCTs) to evaluate the use of metformin versus OCPs for the treatment of PCOS in adolescents ages 11 to 19 years in the Pediatrics, online April 28.

The team searched the literature through Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials, and gray literature resources, up to January 29, 2015. Only four RCTs met the inclusion and exclusion criteria’s amounting to 170 patients in total. 

It was seen that OCP treatment resulted in improvement in menstrual irregularities with a modest improvement in the acne scores.  On the other hand, metformin improved the BMI, decreased dysglycemia prevalence and improved total cholesterol and low-density lipoprotein levels. Both treatment modalities have a similar effect on hirsutism. 

However, the evidence quality was very low, so "treatment choice should be guided by patient values and preferences, while balancing potential side effects" said Dr. Al Khalifah

But, as PCOS is a spectrum with many girls presenting with obesity and hairiness while others have normal body weight and just have menstrual irregularities. So, depending upon the symptoms, the treatment is tailored according to the patient need, with either OCP or metformin being the first line of treatment. 

Concurrently, the importance of life style modification and statin is also stressed to provide long term cardiac protection in these patients.

References:
http://womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html#b
http://www.ncbi.nlm.nih.gov/pubmed/26280343
http://press.endocrine.org/doi/abs/10.1210/jc.2013-2350