Idiopathic Hirsutism Hengameh Abdi Endocrine Research Center Research

Idiopathic Hirsutism Hengameh Abdi Endocrine Research Center Research Institute for Endocrine sciences Shahid Beheshti University of Medical Sciences 1396. 10. 14 04 Jan 2018

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 2

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 3

Hair types § Three types of hair: § Lanugo: Soft hair densely covering the skin of the fetus; disappears within the first months of post-partum life. § Vellus hairs: Soft but larger than lanugo hairs, usually non-pigmented, and generally < 2 mm in length and < 0. 03 mm in diameter. § § Terminal hairs: Longer, pigmented and coarser in texture. Eyebrows, eyelashes, scalp hair and pubic and axillary hair in both sexes, and much of the body and facial hair in men, are composed of terminal hairs. Uno H. Semin Reprod Endocrinol 1986; 4: 131– 141 Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 4

Hair follicle growth cycle Active growing phase Involutional (regression) phase Rest and shed phase Escobar-Morreale, et al. Hum Reprod Update 2012; 18(2): 146 -170 5

Regulation of hair growth § § Local and systemic factors § Growth factors and cytokines § Thyroid hormones § Growth hormone Sex steroids § Androgens § Estrogens Although estrogens modulate the hair cycle, they appear to have no direct effects on hair growth. Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 Escobar-Morreale, et al. Hum Reprod Update 2012; 18(2): 146 -170 6

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 7

Androgens and hair growth § Terminalization of vellus hairs in androgen-sensitive areas. § Prolongation of the anagen phase of body hairs and shortening of the anagen phase of scalp hairs. § Increase of sebum secretion and the oiliness of skin and hair. § Systemic androgens § Local androgens § Human skin is a steroidogenic tissue. Therefore, circulating androgen levels may not reflect local androgen concentrations at the pilosebaceous unit. Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 Thiboutot D, et al. J Invest Dermatol 2003; 120: 905 -914 8

Androgen biosynthesis in women 1 3 4 2 5 A: Androstenedione, T: Testosterone, DHT: Dihydrotestosterone; Numbers are indicative of descending order of serum concentrations of androgens. Bulun SE. Williams textbook of Endocrinology 2016 9

Skin 5α-reductase activity A 4: Androstenedione T: Testosterone DHT: Dihydrotestosterone Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 10

Androgens and hair growth Yildiz BO, et al. Human Reproduction Update 2010; 16(1): 51– 64 11

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 12

Hirsutism § The presence of excessive terminal (coarse) hair in androgendependent areas of the female body. § Overall prevalence: 4. 3 -10. 8% § Quantification of hirsutism: Modified Ferriman-Gallwey (m. FG) score (scoring of 9 body areas): § Mild hirsutism: 8 -15 § Moderate hirsutism: 16 -25 § Severe hirsutism: 26 -36 Escobar-Morreale, et al. Hum Reprod Update 2012; 18(2): 146 -170 13

Yildiz BO, et al. Human Reproduction Update 2010; 16(1): 51– 64 14

Yildiz BO, et al. Human Reproduction Update 2010; 16(1): 51– 64 15

Hirsutism § Hirsutism reflects the interaction between circulating androgen concentrations, local androgen concentrations and the sensitivity of the hair follicle to androgens. § The severity of hirsutism does not correlate well with circulating androgen concentrations. Escobar-Morreale, et al. Hum Reprod Update 2012; 18(2): 146 -170 16

Etiology of hirsutism § Polycystic ovary syndrome (PCOS) § Idiopathic hyperandrogenism § Idiopathic hirsutism § Non-classic congenital adrenal hyperplasia (NCCAH) § Androgen-secreting tumors 17

Prevalence of different androgen excess disorders among 950 Italian women with clinical hyperandrogenism IHA 15. 8% IH 7. 6%NCCAH Ovulatory PCOS 15. 5% PCOS 56. 6% PCOS: Polycystic ovary syndrome IHA: Idiopathic hyperandrogenism IH: Idiopathic hirsutism NCCAH: Non-classic CAH Carmina E, et al. J Clin Endocrinol Metab 2006; 91: 2 -6 Carmina E. Fertil Steril 2006; 85: 1582 -85 18

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 19

Diagnostic criteria § Hirsutism § Normal androgen concentrations § Normal ovulatory cycles § Normal ovarian morphology ü Idiopathic hirsutism is a one of exclusion diagnosis. Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 Carmina E. Best Pract Res Clin Endocrinol Metab 2006; 20(2): 207 -220 20

Definitions § Normal ovulatory cycles § The regularity of menses does not exclude the presence of anovulation. (In one study from Canada, 3. 7% of eumenorrheic women had anovulation. ) § § The occurrence of ovulation should be documented using either basal body temperature charts, luteal phase serum progesterone or both. Normal ovarian morphology § Ovarian volume and follicle number. Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 Malcolm CE, et al. Obstet Gynecol 2003 Aug; 102(2): 317 -8 Escobar-Morreale, et al. Hum Reprod Update 2012; 18(2): 146 -170 21

Prevalence in the Tehran Lipid and Glucose Study § Idiopathic hirsutism as hirsutism without clinical or subclinical menstrual dysfunction and biochemical hyperandrogenemia: 13% (95% CI: 10. 9%-15. 1%) ü Ovarian morphology was not considered. Ramezani Tehrani F, et al. Reprod Biol Endocrinol 2011; 9: 144 22

Pathogenesis ü Unclear ü Proposed hypotheses: § Exaggerated skin 5α-reductase activity § Androgen receptor polymorphisms § § Sequence variations in the androgen receptor gene would result in receptors with higher affinity for androgens. Altered androgen metabolism Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 Carmina E. Best Pract Res Clin Endocrinol Metab 2006; 20(2): 207 -220 23

Distribution of body weight in patients with PCOS and idiopathic hirsutism Ov-PCOS: Ovulatory PCOS Carmina E, et al. J Clin Endocrinol Metab 2006; 91: 2 -6 Carmina E. Best Pract Res Clin Endocrinol Metab 2006; 20(2): 207 -220 24

Clinical evaluation, follow-up and treatment § It is important to differentiate idiopathic hirsutism from other mild androgen disorders, because patients with idiopathic hirsutism do not need to be screened for metabolic alterations. § Treatment of idiopathic hirsutism is generally similar to that of the other forms of hirsutism. However, non-pharmacological hair removal (laser, electrolysis) has an important role and may in some patients represent the best choice. Azziz R, et al. Endocrine Reviews 2000; 21: 347 -362 25

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 26

Idiopathic hyperandrogenism § Diagnostic criteria: § Clinical hyperandrogenism § § Some patients with idiopathic hyperandrogenism may present with acne or alopecia alone. § Biochemical hyperandrogenism § Regular ovulatory cycles of normal length § Normal ovarian morphology Other features: § Slightly increased body weight § Mild insulin resistance Carmina E. Best Pract Res Clin Endocrinol Metab 2006; 20(2): 207 -220 Escobar-Morreale, et al. Hum Reprod Update 2012; 18(2): 146 -170 27

Patients with idiopathic hyperandrogenism do not show any increased marker of cardiovascular risk. (lipids, CRP, homocysteine) Carmina E. J Clin Endocrinol Metab 2005; 90: 2545– 2549 Carmina E. Best Pract Res Clin Endocrinol Metab 2006; 20(2): 207 -220 28

Outlines n n n Biology of hair growth Androgens and hair growth Introduction to hirsutism Idiopathic hyperandrogenism Conclusions 29

Concluding remarks § Hirsutism is among the most frequent medical complaints involving different subspecialties in medicine. § Idiopathic hirsutism (IH) is one of the mild androgen phenotypes with unresolved pathogenetic issues. § IH is a diagnosis of exclusion. § Its diagnostic criteria include: § § Hirsutism § Normal androgen concentrations § Normal ovulatory cycles § Normal ovarian morphology IH has a benign metabolic profile. 30

Case Presentation § A 28 -year-old single woman with complaint of hirsutism is referred to you. She admits regular monthly menstruation. She denies any other symptoms related to hyperandrogenism, such as acne or hair loss. She takes no medications. Family history is unremarkable. § Physical examination: § § BMI: 24. 5 kg/m²; Waist circumference: 83 cm § Ferriman-Gallwey score (FGS): 14 § 31

Case Presentation § Laboratory tests: § FBS: 82 mg/dl § TG: 102 mg/dl, HDL-C: 50 mg/dl § TSH: 2. 4 m. IU/l § Testosterone: 0. 35 ng/ml § Ovarian US: Normal volume and follicle numbers. § Which is the most likely diagnosis in this patient? A) Idiopathic hyperandrogenism B) Idiopathic hirsutism C) Ovulatory PCOS D) Non-classic congenital adrenal hyperplasia 32