Polycystic ovary syndrome (PCOS) is more common than we think! Listen as our esteemed guest Dr Katherine Sherif (@katherinesherif) reviews common patient complaints that should trigger PCOS in the differential, its pathophysiology, key physical exam findings, an algorithm for lab evaluation for PCOS diagnosis, and common treatments (OCPs, metformin, spironolactone and more!).
Written and Produced by: Molly Heublein, MD
Cover Art and Infographic: Kate Grant MBChB DipGUMed
Hosts: Matthew Watto MD, FACP; Molly Heublein, MD
Editor: Emi Okamoto MD (written materials); Clair Morgan of Nodderly.com (audio)
Guest: Katherine Sherif, MD
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2003 Rotterdam Criteria: to diagnose PCOS a patient needs any 2 of 3: 1. irregular periods (oligomenorrhea/amenorrhea); 2. Signs of hyperandrogenism or laboratory evidence of hyperandrogenism; and/or 3. polycystic ovaries seen on imaging. (Williams 2016)
Patients can have normal ovarian imaging (no polycystic ovaries on ultrasound) or no obesity and still have PCOS if they have irregular periods and hyperandrogenism.
Over 10-20% of women in the US meet criteria for PCOS, this incidence is significantly increasing as we see rises in obesity. (Abbara 2019)
We don’t exactly know what drives the development of PCOS. There are several ideas about the underlying pathophysiology. (Witchel 2019)
It may be disordered hypothalamic function drives the pituitary to release excess luteinizing hormone (LH) over follicle stimulating hormone (FSH). High LH will trigger production of more androgens, inhibiting folliculogenesis in the ovary.
Dr Sherif believes the more important driving factor is insulin resistance. Insulin itself directly stimulates the thecal cells in the ovary causing increased androgen production. Insulin goes to hypothalamus increasing pulses of gonadotropin releasing hormone, causing the pituitary to produce more LH, which then impacts ovarian function. Insulin decreases sex hormone binding globulin (SHBG) which releases free testosterone which inhibits folliculogenesis. Insulin resistance contributes to central weight gain, from increased androgens and direct signals to adipocytes.
Missed/irregular menses, hirsutism, and difficulty losing weight are common presenting complaints that should make you think of PCOS. Most often patients won’t come to PCP for infertility, since they will more likely be directing this complaint to a gynecologist. The irregular menses should be more than 6 weeks apart (oligomenorrhea), not irregular spotting.
Hirsutism: Midline terminal hair (darker, coarser) is more related to androgen excess- midline chest hair, midline lower abdominal hair below umbilicus/above pubis, and hair down the inner thighs are signs of hirsutism. Upper arm hair or upper back terminal hair is a strong sign of hyperandrogenism. Hair around nipples or facial hair can be normal and are genetically dependent. (Martin 2018)
Alopecia tends to be the most distressing symptom of PCOS in Dr Sherif’s experience because this is hard to treat and hair is highly socially valued. The hyper-androgen driven alopecia is diffuse– so you see a wider visible scalp part (not patchy like alopecia areata). (Martin 2018)
Severe acne is a sign of hyperandrogenism, especially when it spreads onto upper chest, upper arms, and/or buttocks. Use of isotretinoin treatment in adolescence is significantly correlated with high androgens/PCOS. (Goodman 2015)
Other skin findings including hidradenitis suppurativa, acanthosis nigricans, keratosis pilaris, and skin tags are associated with insulin resistance and PCOS. (Misitzis 2019)
Difficulty with weight loss is common in patients with PCOS, though in Dr Sherif’s experience, about 20% of women with PCOS are lean.
Evaluate causes of oligo/amenorrhea by checking a pregnancy test, prolactin, and thyroid stimulating hormone. (Williams 2016)
Non-classical congenital adrenal hyperplasia (CAH) can look very similar to PCOS in adolescence/early adulthood. Recall that classical CAH manifests at birth with ambiguous genitalia. With non-classical adrenal hyperplasia, patients may not present until puberty, but may note early breast development or clitoromegaly, and have may hirsutism, shorter statute, and/or a more muscular frame. It is more common among Meditteranean, Jewish, and Hispanic ethnic groups (Trakakis, 2008). An elevated 17-alpha hydroxyprogesterone is suggestive of CAH, but can be normal due to variable lab processing. If suspicion remains high, genetic evaluation of the 21-hydroxylase enzyme can be confirmatory. (Choi 2016)
If a patient has clear hyperandrogenism on exam (without more significant virilization to make you concerned about an androgen tumor), it is not necessary to check laboratory makers of hyperandrogenism, but these can be helpful. Also, Dr Sherif reminds sex hormone should not be tested when women are on hormonal birth control.
Total and free testosterone and DHEA Sulfate are good markers of biochemical hyperandrogenism, but there can be significant laboratory variation and a lack of standardized reference ranges. Dr Sherif suggests most women have a DHEA sulfate around 100 ug/dL, in PCOS DHEA sulfate levels are typically 200-400. If DHEA-S level is over 500, it is important to rule out congenital adrenal hyperplasia.
Anti Mullerian Hormone (AMH) >1ng/mL can rule out premature ovarian insufficiency as cause for missed menses. AMH is easy to check since it is not affected by exogenous hormones (ie OCPs) or phase in menstrual cycle. AMH is secreted by immature ovarian follicles (so is low in menopause); in PCOS AMH levels are often high because of lack of follicular atresia and ovarian stimulation/enlargement. (Abbara 2019)
No need to check luteinizing hormone/follicle stimulating hormone. No need for a transvaginal ultrasound/follicle counts on ultrasound if your patient already meets criteria for PCOS with hyperandrogenism and oligomenorrhea. These add little value. (Williams 2016).
Women with PCOS are at long term risk for metabolic syndrome, fatty liver, dyslipidemia and type 2 diabetes. Regular screening and treatment of these conditions is recommended. (Goodman 2015)
First line treatment is oral contraceptive pills which work best for severe acne, hirsutism, and alopecia. Of course these are not appropriate for women who are trying to get pregnant or who have contraindications to estrogen use. In appropriate women, use a standard estrogen dose- ethinyl estradiol 35mcg- and a low androgen progesterone (no norethindrone or levonorgestrel as they have androgenic properties). Norgestimate (in ortho cyclen) or drospirenone (in Yaz) are good progesterone choices as they do not have any androgenic properties. (Goodman 2015)
Metformin is commonly prescribed to address insulin resistance– improves ovulation, regulates menses, and boosts fertility. (Williams 2016)
Thiazolidinediones like pioglitazone can be used as insulin sensitizers to help improve ovulation– seem to work well in slender patients (expert opinion). Can be used in combination with metformin, or if a patient does not tolerate metformin (Xu 2017). Pioglitazone should be stopped with conception. Targeting the incretin system (DPP4 inhibitors and GLP-1 agonists) has had promising signals in recent trials (Devin, 2020).
Clomiphene or letrozole are used to treat anovulation/infertility, though these are most often prescribed by a fertility specialist. (Williams 2016)
Spironolactone helps block androgens- reducing acne and hirsutism– standard dose is 50-100mg BID. If this is unsuccessful, finasteride can be an alternative androgen blocker. Both of these can take months to show improvement in acne/hirsutism. (Goodman 2015)
Topical minoxidil is FDA approved for use in female hair loss, but Dr Sherif finds oral minoxidil (off label) more helpful, some small studies have shown benefit of oral minoxidil (Ramos 2020). Bicalutamide and flutamide are androgen blockers used in prostate cancer treatment that can be used to treat hirsutism in patients who are resistant. (Moretti 2018, Williams 2016)
Kashlak Pearl: Dr Sherif’s recommends that we partner with the patients to offer different choices of medication options, as some women may choose multiple treatments at once.
Menstrual periods and infertility should be considered a vital sign. As internists/primary care we must pay more attention to these important signs that are relegated to gynecology, but can tell us important clues about our patients’ health.
Listeners will explain the basic pathophysiology, diagnosis, and management of PCOS.
After listening to this episode listeners will…
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Dr Sherif reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Sherif K, Heublein M, Grant K, Okamoto E, Watto MF. “#198 PCOS: Polycystic Ovary Syndrome with Katherine Sherif MD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. March 9, 2020.
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