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Stein-Leventhal (polycystic ovary) syndrome

Hyperandrogenism with chronic anovulation & polycystic ovaries. Primarily a clinical diagnosis. [3] Epidemiology: 1) most common cause of hyperandrogenicity in women 2) by transvaginal ultrasonography, 20-25% of all women have > 8-10 subcapsular cysts in both ovaries 3) prevalence 6.6% [7a]; 10% of reproductive age women [8] Pathology: 1) enlarged polycystic ovaries with increased stroma & thickened capsule 2) anovulation secondary to increased androgen which is converted to estrogen in adipose tissue 3) hyperestrogen state stimulates pituitary resulting in increased LH:FSH ratio propagating anovulatory state 4) loss of LH surge 5) risk of endometrial hyperplasia is increased 6) insulin-resistance - defects in phosphorylation pattern of insulin receptor Clinical manifestations: 1) amenorrhea or oligomenorrhea since menarche - may manifest several years later [3] - anovulatory infertility, irregular or missed menstrual periods 2) hyperandrogenism a) hirsutism (70%) - terminal hairs on the abdominal midline below the umbilicus b) acne (may be inflammatory) c) male balding patterm d) onset at puberty e) gradual onset, slow progression 3) truncal obesity (50%), insulin resistance - body weight may be normal to obese 4) ancanthosis nigricans Diagnostic criteria: - 2 of 3 criteria + diagnosis of exclusion (see Differential diagnosis) - anovulation (or oligo-ovulation) - evidence of hyperandrogenism (hirsutism, acne) - ultrasound findings of polycystic ovaries [3] - imaging of adrenal glands & pelvis (NEJM) [25] Laboratory: 1) serum FSH is normal 2) serum LH is normal or increased - increased plasma LH resulting in increased urine LH may be mistaken for ovulation using home urinary LH kits [3] 3) progesterone challenge test induces withdrawal bleeding 4) serum testosterone is normal or modestly (< 2-fold) increased 5) increased serum prolactin (20-25%) 6) serum DHEA-sulfate is mildly increased in 25% of patients 7) serum estradiol levels are normal 6) serum estrone levels are increased 8) very high free testosterone & serum androstenedione suggest androgen-producing neoplasm 9) increased serum insulin 10) screen for dyslipidemia a) increased serum triglycerides [5] b) increased total serum cholesterol & LDL cholesterol [5] 11) screen for diabetes mellitus: serum glucose, HgbA1c 12) see ARUP consult [13] Special laboratory: - screening for obstructive sleep apnea Radiology: - pelvic &/or abdominal ultrasound a) symptom onset after menarche b) suspicion of ovarian or adrenal mass [3] - serum testosterone > 150 ng/mL - serum DHEA-sulfate > 7.0 ug/mL [3] Complications: 1) increased risk of endometrial hyperplasia & carcinoma 2) hypertension is common 3) type 2 diabetes is common 4) increased risk of metabolic syndrome - insulin resistance [3] 5) obstructive sleep apnea 6) increased risk for depression [10] 7) excess risk for adverse pregnancy outcomes [12] Differential diagnosis: - thyroid dysfunction - adrenal hyperplasia - hyperprolactinemia - androgen-secreting neoplasm (rapidly progressive hirsutism or virilization) [3] Management: 1) weight reduction through diet & exercise (1st line) 2) oral contraceptives after ruling out pregnancy a) with or without spironolactone b) regulation of menses, improvement of acne [21] c) combined oral contraceptives (estrogen+progestin) suppresses androgen production [3] d) not better than metformin for treatment of hirsutism [21] 3) spironolactone 50 mg daily reduces androgen levels [7] 4) monitor for diabetes mellitus type-2 a) metformin is the drug of choice b) metformin 500 mg TID may restore ovulation & fertility [4,6,25] - inferior to letrozole for treatment of infertility in anovulatory women [25] c) delay pregnancy until diabetes mellitus is controlled [25] d) metformin reduces BMI & LDL cholesterol e) pioglitazone may also be useful [11] 5) artemisinin degrades LONP1-CYP11A,1 an enzyme essential for ovarian production of androgens (investigational) [26] 6) 1st line treatment of fertility in anovulatory women is letrozole [25] - use letrozole or clomiphene for conception [3] 7) long-acting GnRH analogues 8) androgen inhibitors a) flutamide b) cyproterone 9) letrozole may be more effective than clomiphene in stimulating ovulation & facilitating pregnancy [15] 10) clomiphene previously used to stimulate ovaulation in women trying to become pregnant [3,25] 11) for women who do become pregnant (not already diabetic) - screen for gestational diabetes at the time of pregnancy diagnosis & at 24-28 weeks of pregnancy 12) monitor blood pressure 13) screen for obstructive sleep apnea & depression [10] Comparative biology: - transplantation of brown adipose tissue reverses anovulation, hyperandrogenism, & polycystic ovaries in a DHEA-induced rat model of polycystic ovarian disease [20] - administration of adiponectin rescues DHEA-induced polycystic ovarian disease phenotype in this rat model [20]

Interactions

disease interactions

Related

amenorrhea (oligomenorrhea) flutamide (Eulexin, Niftholide) oral contraceptive (OC) progesterone challenge test

General

chronic endocrine disease ovarian disease

Properties

PATHOLOGY: Stein-Leventhal syndrome

Database Correlations

OMIM 184700

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 389
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 245
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Journal Watch 21(6):51, 2001 Vandermolen DT et al Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 75:310, 2001 PMID: 11172832
  5. Journal Watch 22(3):22, 2002 Legro RS et al Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 111:607, 2001 PMID: 11755503
  6. Journal Watch 24(1):10, 2004 Lord JM et al Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327:951, 2003 http://bmj.bmjjournals.com/cgi/content/full/327/7421/951 PMID: 14576245
  7. Journal Watch 24(14):115, 2004 - Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004 Jun;89(6):2745-9. PMID: 15181052 - Ganie MA, Khurana ML, Eunice M, Gulati M, Dwivedi SN, Ammini AC. Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. J Clin Endocrinol Metab. 2004 Jun;89(6):2756-62. PMID: 15181054
  8. Prescriber's Letter 11(10): 2004 Pharmacologic Treatment of Polycystic Ovary Syndrome Detail-Document#: 201006 (subscription needed) http://www.prescribersletter.com
  9. The American Association of Clinical Endocrinologists (AACE) Position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome http://www.aace.com/clin/guidelines/PCOSpositionstatement.pdf
  10. Dokras AS et al. Increased risk for abnormal depression scores in women with polycystic ovary syndrome: A systematic review and meta-analysis. Obstet Gynecol 2011 Jan; 117:145. PMID: 21173657
  11. Prescriber's Letter 18(5): 2011 Metformin vs Pioglitazone for Polycystic Ovary Syndrome Detail-Document#: 270506 (subscription needed) http://www.prescribersletter.com
  12. Roos N et al. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: Population based cohort study. BMJ 2011 Oct 13; 343:d6309 PMID: 21998337 - Macklon NS. Polycystic ovary syndrome: Independently increases the risk of adverse pregnancy and birth outcomes. BMJ 2011 Oct 13; 343:d6407 PMID: 21998338
  13. ARUP Consult: Polycystic Ovarian Syndrome - PCOS The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/polycystic-ovarian-syndrome
  14. Prescriber's Letter 21(5): 2014 CHART: Drug Treatment for Polycystic Ovary Syndrome. Detail-Document#: 300524 (subscription needed) http://www.prescribersletter.com
  15. Legro RS et al Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome. N Engl J Med 2014; 371:119-129July 10, 2014 PMID: 25006718 http://www.nejm.org/doi/full/10.1056/NEJMoa1313517
  16. Legro RS, Arslanian SA, Ehrmann DA et al Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013 Dec;98(12):4565-92. PMID: 24151290 https://www.nejm.org/doi/pdf/10.1056/NEJMoa1313517
  17. Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). Hum Reprod. 2012 Jan;27(1):14-24 PMID: 22147920
  18. Legro RS, Barnhart HX, Schlaff WD et al Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66. PMID: 17287476 Free Article
  19. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. PMID: 14711538
  20. Komaroff AL Understanding the Pathogenesis of Polycystic Ovary Syndrome NEJM Journal Watch. March 10, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Yuan X et al. Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Proc Natl Acad Sci U S A 2016 Mar 8; 113:2708 PMID: 26903641 http://www.pnas.org/content/113/10/2708
  21. Al Khalifah RA, Suppere C, Haidar A et al. Metformin or oral contraceptives for adolescents with polycystic ovarian syndrome: A meta-analysis. Pediatrics 2016 May; 137:e20154089. PMID: 26773719 http://pediatrics.aappublications.org/content/137/5/e20154089
  22. Rothaus C Polycystic Ovary Syndrome Now@NEJM. July 7, 2016 http://blogs.nejm.org/now/index.php/polycystic-ovary-syndrome/2016/07/07/
  23. McCartney CR, Marshall JC. CLINICAL PRACTICE. Polycystic Ovary Syndrome. N Engl J Med. 2016 Jul 7;375(1):54-64. Review. PMID: 27406348 PMCID: PMC5301909 Free PMC Article https://www.nejm.org/doi/pdf/10.1056/NEJMcp1514916
  24. Rosenfield RL The Diagnosis of Polycystic Ovary Syndrome in Adolescents. Pediatrics 2015 Dec;136(6):1154-65. PMID: 26598450 Free article
  25. NEJM Knowledge+ Endocrinology - American College of Obstetricians and Gynecologists' Committee on Practice Bulletins - Gynecology ACOG Practice Bulletin No. 194: Polycystic Ovary Syndrome. Obstet Gynecol. 2018 Jun;131(6):e157-e171. PMID: 29794677 - Teede HJ, Tay CT, Laven J et al Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Hum Reprod. 2023 Sep 5;38(9):1655-1679. PMID: 37580037 PMCID: PMC10477934 Free PMC article.
  26. Liu Y, Jiang JJ, Du SY et al. Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction. Science 2024 Jun 14; 384:eadk5382. PMID: 38870290 https://www.science.org/doi/10.1126/science.adk5382