#198 PCOS: Polycystic Ovary Syndrome with Katherine Sherif MD

March 9, 2020 | By Molly Heublein

It’s more than just the Ovary

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!).

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Credits

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

Sponsor

AccessMedicine is the acclaimed online medical resource that features Harrison’s Principles of Internal Medicine and more trusted content from the best minds in medicine. Visit  AccessMedicine to learn more: http://bit.ly/MHCurbsiders.

Time Stamps

• 00:00 Sponsors – AccessMedicine.com (McGraw-Hill) http://bit.ly/MHCurbsiders; Primary Care Internal Medicine of Ithaca https://www.primarycareinternalmedicineofithaca.com/
• 00:35 Intro, disclaimer, guest bio
• 03:00 Guest one-liner, book recommendation; Picks of the Week*: The Beginner’s Guide to the End: Practical Advice for Living Life and Facing Death, by Dr BJ Miller and Shoshana Berger; Overdrive App to download audio books and other media from libraries
• 07:58 AccessMedicine.com (McGraw-Hill) http://bit.ly/MHCurbsiders; Primary Care Internal Medicine of Ithaca https://www.primarycareinternalmedicineofithaca.com/
• 09:30 Case of PCOS; Definition; Common presenting complaints
• 14:40 Hirsutism and terminal hair growth
• 17:05 Alopecia
• 20:25 Acne; Hidradenitis suppurativa
• 23:05 Irregular menses; Lab workup; Non-classic congenital adrenal hyperplasia
• 28:38 Hyperandrogenism lab workup (Testosterone, DHEA-S, Anti-Mullerian Hormone, utility of LH and FSH); Quick word on US
• 37:15 Recap of how to diagnose PCOS
• 38:15 Insulin resistance, body habitus in PCOS
• 40:04 Pathophysiology in PCOS (two schools of thought: Hypothalamus vs Insulin)
• 43:27 Dr. Sherif’s spiel to patients newly diagnosed with PCOS
• 46:40 Long term risks in PCOS
• 50:35 Approach to treatment of PCOS (OCPs, metformin, spironolactone, hair removal)
• 60:35 Treatment of alopecia; Lifestyle factors
• 63:55 Take home points and Outro

PCOS Pearls

1. To diagnose PCOS, patients need any 2 of the following 3: oligomenorrhea, hyperandrogenism, and/or polycystic ovaries seen on imaging
2. The underlying cause of PCOS is controversial, but may be related to abnormal hypothalamic-pitutitary-ovarian signaling or primary insulin resistance.
3. PCOS can manifest with many dermatologic complaints including hirsutism, alopecia, and acne related to hyperandrogenism and acanthosis nigricans, skin tags, and hidradenitis suppurativa related to insulin resistance 
4. Treatment for PCOS can include oral contraceptive pills, androgen blockers, and/or insulin sensitizing medications.

Polycystic Ovary Syndrome (PCOS) Defined:

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)

Pathophysiology of PCOS:

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. 

Common presenting complaints:

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.

Hyperandrogenism:

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)

Insulin resistance:

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.

Lab testing:

Evaluate causes of oligo/amenorrhea by checking a pregnancy test, prolactin, and thyroid stimulating hormone. (Williams 2016) 

CAH

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.

Androgen Testing

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.  

AMH

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)

LH/FSH

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). 

Long term risks of PCOS:

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)

Treatment of PCOS:

OCPs

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)

Insulin resistance

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).  

Anovulation and fertility

Clomiphene or letrozole are used to treat anovulation/infertility, though these are most often prescribed by a fertility specialist.  (Williams 2016)

Acne, hirsutism, alopecia

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)

Alopecia

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.

Take home points:

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.  

Goal

Listeners will explain the basic pathophysiology, diagnosis, and management of PCOS.

Learning objectives

After listening to this episode listeners will…  

1. List the criteria for diagnosis of PCOS.
2. Explain the relationship between PCOS and metabolic risks.
3. Determine first line treatments for PCOS symptoms including oligomenorrhea, hirsutism, acne and alopecia.
4.  Counsel patients on long term risks associated with PCOS and how to mitigate these.

Links*

1. The Beginner’s Guide to the End: Practical Advice for Living Life and Facing Death, by Dr BJ Miller and Shoshana Berger
2. Overdrive App to download audio books and other media from libraries
3. More from @KatherineSherif on Twitter

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

References

1. Williams T, Mortada R, Porter S. Diagnosis and Treatment of Polycystic Ovary Syndrome. Am Fam Physician. 2016 Jul 15;94(2):106-13. PubMed PMID: 27419327.  
2. Abbara A, et al. Anti-Müllerian hormone (AMH) in the Diagnosis of Menstrual Disturbance Due to Polycystic Ovarian Syndrome. Front Endocrinol (Lausanne). 2019 Sep 26;10:656. eCollection 2019. PubMed PMID: 31616381.
3. Witchel SF, Oberfield SE, Peña AS. Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment. J Endocr Soc. 2019 Jun 14;3(8):1545-1573. eCollection 2019 Aug 1. Review. PubMed PMID: 31384717.
4. Martin KA, Anderson RR, Chang RJ, Ehrmann DA, Lobo RA, Murad MH, Pugeat MM, Rosenfield RL. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1233-1257. doi: 10.1210/jc.2018-00241. PubMed PMID: 29522147.
5. Goodman NF, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review: Guide to the best practices in the evaluation and treatment of Polysytic Ocary Syndromes–PART 1. Endocr Pract. 2015 Nov;21(11):1291-300. PubMed PMID: 26509855.
6. Misitzis A, Cunha PR, Kroumpouzos G. Skin disease related to metabolic syndrome in women. Int J Womens Dermatol. 2019 Jul 4;5(4):205-212. eCollection 2019 Sep. Review. PubMed PMID: 31700973.
7. Trakakis E et al. The presence of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with hirsutism and PCOS. Endocrine Journal, 2008. PMID18187875
8. Choi JH, Kim GH, Yoo HW. Recent advances in biochemical and molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Pediatr Endocrinol Metab. 2016 Mar;21(1):1-6. Epub 2016 Mar 31. Review. PubMed PMID: 27104172.
9. Xu Y, Wu Y, Huang Q. Comparison of the effect between pioglitazone and metformin in treating patients with PCOS:a meta-analysis. Arch Gynecol Obstet. 2017 Oct;296(4):661-677. Epub 2017 Aug 2. Review. PubMed PMID: 28770353
10. Devin JK et al. Sitagliptin decreases visceral fat and blood glucose in women with PCOS. J Clin Endocrinol Metab. 2020. PMID 31529097
11. Moretti C, et al. Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial. J Clin Endocrinol Metab. 2018 Mar 1;103(3):824-838. PubMed PMID: 29211888.
12. Ramos PM, et al. Minoxidil 1 mg oral versus minoxidil 5% topical solution for the treatment of female-pattern hair loss: A randomized clinical trial. J Am Acad Dermatol. 2020 Jan;82(1):252-253. Epub 2019 Aug 29. PubMed PMID: 31473295.

Disclosures

Dr Sherif reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

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.