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PCOS and HIRSUTISM

PCOS and HIRSUTISM. G. I. Serour, FRCOG, FRCS, FACOG, FSOGC, FJSOG, FIFFS, FISOG,FEBCOG, (Hon.) Professor of Obstetrics and Gynaecology , Director, International Islamic Center for Population Studies and Research, Al-Azhar University Clinical Director, The Egyptian IVF-ET Center,

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PCOS and HIRSUTISM

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  1. PCOS and HIRSUTISM G. I. Serour, FRCOG, FRCS, FACOG, FSOGC, FJSOG, FIFFS, FISOG,FEBCOG,(Hon.) Professor of Obstetrics and Gynaecology, Director, International Islamic Center for Population Studies and Research, Al-Azhar University Clinical Director, The Egyptian IVF-ET Center, Maadi, Cairo, Egypt FIGO Past President EBCOG/TSOG Joint Congress,   Antalya, Turkey 17th – 21st May 2017

  2. Conflict of interest I declare I have no conflict of interest in this presentation.

  3. Items Addressed • Androgens production in women. • Hyperandrogenism in PCOS. • Hirsutism. • Evaluation of Hirsutism. • Management of Hirsutism.

  4. PCOS PCOS is a heterogeneous syndrome, not a disease. Patients with PCOS have a set of phenotypic characteristics but lack a single defining element or “gold standard” on which the diagnosis could be anchored.

  5. PCOS Phenotypes Dewailly D, et al 2006 J Clin Endocrinol Metab 91(10): 3922-7.

  6. Some authors questioned whether it is appropriate to apply the definition of PCOS in the absence of overt hyperandrogenism and called for a need for a rethink of diagnostic criteria for PCOS Dewailly D 2016 Best practice and Research clinical Obst&Gynec. 37,5-11, 2016

  7. Androgen Production in women Androgens are produced primarily from dietary cholesterol that circulates in the form of low-density Lipoproteins (LDL) in the plasma. Gwynne JT, Strauss JF. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr Rev. 1982:3:299-329.

  8. Testosterone In the circulation testosterone is present as the free or conjugated testosterone. The free portion of testosterone is biologically active and is very small in amount. -Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development [review]. Endocr Rev 2000; 21:363-392. -Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000; 21:347-362.

  9. Conjugated Testosterone Almost 98-99% of plasma testosterone is bound to steroid hormone-binding globulin (SHBG), to cortisol-binding globulin or nonspecifically to albumin and other proteins and is biologically inactive. -Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development [review]. Endocr Rev 2000; 21:363-392. -Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000; 21:347-362.

  10. Sources of Androgen in women Ovaries & Adrenals In women, androgens are secreted in almost equal quantities by the ovaries 35-40% and adrenal glands 40%* and the enzymes involved in the steroidgenesis pathway are similar**. * Carmina E (2006). Ovarian and adrenal hyperandrogenism Ann NY Acad Soc. 2006: 1092:130-7. **Miller WL, Aushus RJ. (2011). The molecular biology, biochemistry and physiology of human steriodogenesis and its disorders. End. Rev 2011; 32:81-151.

  11. Liver/ Skin/ Adipose Tissue Peripheral conversion of androgenic prohormones to testosterone occurs in the liver, genital skin, hair follicles, and adipose tissue. -Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development [review]. Endocr Rev 2000; 21:363-392. -Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000; 21:347-362. - Papadopoulos V et al . Steroid biosynthesis in adipose tissue steroids. 2015; 103:89-104

  12. Androgenic Prohormones and Hormones In women, the major circulating androgens or pro-androgens in a descending order of serum concentration are: 1- Dehydroepiandrosterone sulphate (DHEAS), 2- Dehydroepiandrosterone (DHEA), 3- Androstenedione (AT), 4-Testosterone (T) / 5- Dihydrotestosterone (DHT)/ /has strong affinity to AR

  13. Androstenedione(AT), derived from the ovaries and adrenals, is the most important precursor of T while DHEAS and DHEA, derived almost exclusively from the adrenals, account for only 5% and 13% of circulating T among women of reproductive age respectively. Longcape C. Adrenal and Gonadol androgen secretion in normal females. Clin. EndocrinolMetab. (1986):15 (2) 213-228.

  14. Estrogen/ Androgens/ SHBG Estrogens increase and androgens decrease the production of SHBG in the liver. In hyperandrogenic condition, the SHBG is decreased thus allowing higher levels of free testosterone.

  15. Insulin/ SHBG Insulin decreases the production of SHBG. In condition of insulin resistance and compensatory hyperinsulinemia, the production of SHBG is decreased and this leads to higher levels of free testosterone.

  16. In the hair follicles, testosterone is converted to its biologically active form, dihydrotestosterone, by the enzyme. 5α- reductase. -Depleski D, Rosenfield RL: Role of hormones in pilosebaceous unit development [review]. Endocr Rev 2000; 21:363-392. -Azziz R, Carmina E, Sawaya ME: Idiopathic hirsutism [review]. Endocr Rev 2000; 21:347-362.

  17. Hyperandrogenism in PCOS Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities that produce androgens from cholesterol. Yong EL et al 1992 Clin. Endocrinol:37:51-58

  18. In women the most common cause of hyperandrogenism is PCOS. Ovarian theca cells increased androgen production in response to chronically elevated LH and high insulin levels are the causes of this hyperandrogenism.

  19. Hyperinsulinemia promotes androgen biosynthesis via insulin receptor and to a lesser extent, the insulin-like growth factor-1 (IGF.1) receptor on theca cells and increases levels of circulating free testosterone by suppressing hepatic production of steroid hormone binding globulin SHBG. • Landy M , Huang A, Azziz R. Degree of hyperinsulinemia, independent of androgen levels, is an important determinant of the severity of hirsutism in PCOs. Fertil and Steril, 2009; 92 (2): 643-7. • Ovalle F, Azziz R. Insulin resistance, PCOs and type 2 diabetes mellitus. Fertil&Steril 2002; 77 (6): 1095-105.

  20. Hyperandroginsim - Hirsutism While androgen excess will contribute to the ovulatory and menstrual dysfunction of PCOS patients the most recognizable sign of hyperandrogenaemia includes hirsutism, acne and androgenic alopecia or female pattern hair loss.

  21. Normal Pattern of Hair distribution Vellus Hair Adults have two types of hair, vellus and terminal. Vellus hair is soft, fine, generally colorless, and usually short.

  22. Vellus Hair Vellus hair covers the face, chest, and back and gives the impression of “hairless” skin.

  23. Terminal Hair Terminal hair is long, coarse, dark, and sometimes curly.

  24. Terminal hair grows on the scalp, pubic, and armpit areas in both men and women.

  25. Excessive hair that is due to genetic and ethnic variation rather than hormonal causes is typically located on the arms, hands, legs, and feet.

  26. If excessive hair growth is present only on the lower legs and forearms, it is not considered hirsutism and will not respond to hormonal therapy.

  27. If hair follicles are hormone-sensitive, androgens may cause some vellus hairs to change to terminal hairs and cause the terminal hairs to grow faster and thicker.

  28. Clinical Diagnosis of Hirsutism in PCOS Hirsutism due to hormonal causes is the excessive growth of coarse dark hair on the face, chest, abdomen, back upper arms or upper legs of women* and PCOS is the most common etiology of hirsutism**. *American society of Reproductive Medicines (ASRM) 2016. Hirsutism and PCOS. A guide for patients, 2016. **Spritzer PM et al. 2016. Curr. Pharm 2016; 22 (36):5603-5613.

  29. The prevalence of hirsutism in PCOS ranges from 70 to 80%, vs. 4% to 11% in women in the general population. Spritzer PM et al. 2016. Hirsutims in PCOS. Pathophysiology and Management.

  30. Evaluation of Hirsutism Hirsutism is usually evaluated by scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method. However, the hirsutism score correlates poorly with serum androgens. Haung A et al 2006, Fertil & Steril: 86 S12-S

  31. Biochemical Assessment • Total and free testosterone (High normal) • Serum LH elevated. • LH/FSH higher than 3. • Dehydro-epiandrosteroneSulphate (DHEAS) (marginal elevation). • Prolactin level (mildly elevated in 30% PCOS.

  32. Ultrasound Evaluation Ultrasound evaluation of the ovaries, adrenals or both may be useful for screening if symptoms or biochemical levels suggest the presence of neoplasm.

  33. Differential Diagnosis of hyperandrogenic Patient • Idiopathic hirsutism. • Hyper-androgenic insulin-resistant acanthuses nigrican (HAIRAN) syndrome. • 21-hydroxylase-deficient non-classic congenital adrenal hyperplasia. • Classic congenital adrenal hyperplasia. • Androgen-secreting neoplasm. • Side effects of medication. • Cushing disease. • Hypothyroidism. • Hyper-prolactinaemia. - Azziz R et al 2004 J. Clin EndrocrinolaMetab:89(2) 453-62 - Lergo RS et al 2013. J Clin. Endocrinol Metab:98(12)4565-92.

  34. Management of Hirsutism in PCOS Hirsutism is a sign, not a disease of itself and PCOS is the most common etiology and found in 72% to 82% of patients with hyperandrogenism. Azziz R et al 2004 J. Clin EndrocrinolaMetab:89(2) 453-62

  35. The patient needs to be assessed and evaluated. Treatment should be patient centered whether for hirsutism only or hirsutism and anovulation, anovulatory bleeding, desire to get pregnant or metabolic comorbidities.

  36. Initiation of treatment should be based on the patient’s perception of hirsutism rather than the quantitative characteristics of hirsutism. Martin KA et al 2008 J. Clin Endocrinol Metab. 93(4) 1105-20.

  37. Furthermore monitoring of T and other androgens during treatment is generally unnecessary as the hirsutism score correlates poorly with serum androgens. Legro RS et al 2010 J Clin Endocrinol Metab. 95(12) 5305-13.

  38. Modification of life style smoking Smoking cessation is strongly recommended for hirsute patients as many of the undesirable side effects of the medications prescribed to treat hirsutism are exacerbated when patients indulge in smoking. Escobar-Morreale HF et al 2012 Hum. Reprod. Update. 18(2): 146-70.

  39. Weight Loss A systematic review of six small RCTs observed that lifestyle modification was beneficial in the reduction of serum androgens and increased SHBG, along with some improvement in hirsutism as achieved by the mFG Score. Moran LJ et al 2011, Cochrane Database Syst Review (7) CD007506.

  40. Medication The management of hirsutism due to PCOS involves primarily either androgen suppression, with a hormonal combination contraceptive or androgen blockade as with androgen receptor blocker or a 5α reductase inhibitor or a combination of the above. Yong EL 2016 Best Practice and Research Clinical Obstet and Gynecol 37:1-4.

  41. Androgen SuppressionHormonal Combination contraceptives HCCs - Progestins in HCCs cause suppression of LH levels and inhibition of LH-mediated ovarian androgen synthesis* • Ethinylestrodial in HCCs leads to significant increase in SHBG, thereby contributing to a reduction of free T **. • HCCs decrease the synthesis and release of androgens by the adrenal.*** *Archer DF et al 2009 Contraception 80 (3): 245-53. ** Vrbikova J et al 2005, Hum. Reprod Update. 11(3): 277-91. *** Madden JD et al 1978 Am. J Obstet Gynecol. 132(4): 380-4.

  42. 60-100% of women with hirsutism demonstrate improvement on oral HCCs *. • 21 day active 7 day placebo provides better ovarian suppression compared to continuous regimen** * Burkman JR RT 1995, Am. J M Med 98(1A) S 130-5. ** Legro RS et al 2008, J. Clinical Endocrinol Metab 93 (2): 420-9.

  43. HCCs with Antiandrogenic Progestins • Cyproterone acetate (CPA). • Chlormadinone acetate (CMA). • Drospirenone (DRSP). • Dienogest (DNG). Comparative studies of HCCs containing progestin with antiandrogenic properties are limited. Lizneva D et al 2016, Best Practice and Research Clinical Obstet and gynecol 37:98-118.

  44. Antiandrogens MonotherapyAndrogen Receptor Blockers • Spironolactone. • Flutamide. • Cyproterone acetate.\ • 5 αreductase inhibitor. Antiandrogens have not been used with any regularity in women, all are teratogenic and their use is generally discouraged. Lizneva D et al 2016, Best Practice and Research Clinical Obstet and gynecol 37:98-118.

  45. Combined Treatment of Antiandrogens with HCCs Four RCTs demonstrated that antiandrogens in combination with HCCs were more effective than monotherapy with HCCs. Swiglo BA et al 2008 J Clin Endocrinol Metab. 93 (4): 1153-60.

  46. Why antiandrogen+HCCs? - Efficacy is generally higher when using a combination of HCCs and antiandrogens than with either HCCs or antiandrogen monotherapy, - HCCs minimize the risk of teratogenicity. It is advisable to begin therapy with a combination of HCCs and antiandrogens. Lizneva D et al 2016, Best Practice and Research Clinical Obstet and gynecol 37:98-118.

  47. GnRHa and Insulin Sensitizers Several studies have demonstrated the superior efficiency of HCCs monotherapy compared to GnRHa* and insulin sensitizers ** * Heiner JS et al 1995 J Clin Endocrinology Metab. 80(12) 3412-8. ** Costello M et al 2007 Cochrane Database Syst Review (1) CD 005552.

  48. Metformin If HCCs are contraindicated, mainly in the presence of insulin-resistance related comorbidities, a second-line option for reducing androgen secretion may be metformin associated with lifestyle changes.

  49. Combined Treatment of Antiandrogen with Metformin In a small RCT, flutamide in combination with metformin appeared to be superior to monotherapy. Koulouri O et al 2008 Clin Endocrinol (Oxf) 68 (5): 800-5.

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