Endocrinology 12 Michel Faure, Evelyne Drapier-Faure

Home , Hidradenitis suppurativa, Hirsutism

Chapter 12 Endocrinology 12 Michel Faure, Evelyne Drapier-Faure

Key points 12.1 Introduction

Q HS does not generally appear to be In 1986 Mortimer et al. [14] reported that hi- associated with signs of hyperan- dradenitis suppurativa (HS) responded to treat- drogenism ment with the potent antiandrogen cyproterone acetate. They suggested that the disease could Q Sex hormones may affect the course of be androgen-dependent [8]. This hypothesis HS indirectly through, for example, was also upheld by occasional reports of women their effects on inflammation with HS under antiandrogen therapy [18]. Actu- ally, the androgen dependence of HS (similarly Q The role of end-organ sensitivity to acne) is only poorly substantiated. cannot be excluded at the time of writing 12.2 Hyperandrogenism and the Skin Q The prevalence of polycystic ovary syndrome in HS has not been system- Androgen-dependent disorders encompass a atically investigated broad spectrum of overlapping entities that may be related in women to the clinical consequenc- es of the effects of androgens on target tissues and of associated endocrine and metabolic dys- functions, when present. #ONTENTS

12.1 Introduction ...... 95 12.2.1 Androgenization 12.2 Hyperandrogenism and the Skin ...... 95 12.2.1 Androgenization ...... 95 One of the less sex-specific effects of androgens 12.2.2 Androgen Metabolism ...... 96 12.2.3 Causes of Hyperandrogenism ...... 96 is that on the skin and its appendages, and in particular their action on the pilosebaceous 12.3 Lack of Association between HS unit. Hirsutism is the major symptom of hyper- and Endocrinopathies ...... 97 androgenism in women. Other dermatological 12.4 HS and Biological Hyperandrogenism ...97 conditions include acne and the chronic hair 12.5 End-Organ Androgen Sensitivity? ...... 98 loss usually termed androgenic alopecia (AGA). References ...... 98 Whereas acne, hirsutism and chronic hair loss may coexist in the same patient, it is not unusu- al to find only one of these androgenic manifestations [16]. Depending on the presence of ovarian dysfunction, extracutaneous manifestations may include abnormalities of menstruation with 96 Michel Faure, Evelyne Drapier-Faure

anovulatory patterns, oligomenorrhoea, fertili- Sebaceous glands, but also keratinocytes ty problems, android obesity and risks for from the acroinfundibulum and dermal papilla metabolic complications, such as hyperinsulin- cells, can synthesize androgens de novo from ism, insulin resistance, diabetes mellitus, and cholesterol or by locally converting weaker an- dyslipidaemia, and for cardiovascular diseases drogens (64A and DHEA) to testosterone and [6, 16]. DHT. As in other classic steroidogenic organs, the pilosebaceous unit expresses the major enzymes involved in androgen metabolism, name- 12.2.2 Androgen Metabolism ly steroid sulfatase, 3`-, 3_- and 17`-hydroxysteroid dehydrogenases, and 5_-reductase, which The causes of hyperandrogenism are multiple converts testosterone into DHT. Furthermore (Table 12.1). Skin androgenization in women aromatase, which converts testosterone into may be due to abnormal production of andro- oestradiol, is localized to sebaceous glands and gens by the ovaries and/or the adrenal glands, to both outer and inner root sheath cells of ana- and/or to an excessive response of target cells gen terminal hair follicles. This hormone may in the pilosebaceous unit (peripheral androgen- play a “detoxifying” role by removing excess an- ism) [6]. drogens [5]. Androgens [testosterone and the less potent androgens in women 64-androstenedione (64A) and dehydroepiandrosterone (DHEA)] 12.2.3 Causes of Hyperandrogenism are synthesized by the adrenals (mostly DHEA and its sulfate – SDHEA) and the ovaries (most- As far as hyperandrogenisms due to an excess of ly 64A) and may be subsequently transformed androgen production are concerned, tumoral into oestrogens through the aromatization of causes and Cushing’s syndrome are rare. The the molecules. Sex hormone binding globulin most common endocrine disorders are polycys- (SHBG) synthesized in the liver is the major tic ovary syndrome (PCOS) and non-classic ad- carrier protein for androgens and oestradiol. renal hyperplasia (NCAH) with 21-hydroxylase Only free androgens, unbound to SHBG, are di- deficiency. Hyperandrogenism is associated rectly active on target cells. In tissues, andro- with high levels of circulating androgens and 12 gens are first metabolically transformed into decreased SHBG levels. PCOS also requires mor- the active form dihydrotestosterone (DHT), phological and ultrasound criteria: an increased which then binds to androgen receptors (AR) number of subcapsular follicles and stromal [16]. hyperplasia. Plasma levels of 17-hydroxyproges- terone (17-HP) are increased in NCAH. If NCAH is only suspected with moderately increased Table 12.1. Causes of hyperandrogenism 17-HP, an adrenocorticotropic hormone (ACTH) test must be performed [1, 6, 7]. 1. Polycystic ovary syndrome (PCOS) On the other hand, hyperandrogenic skin 2. Non-classic adrenal hyperplasia changes (“idiopathic” hirsutism, hypertrichosis with 21-hydroxylase deficiency in men, most cases of acne, AGA in women but 3. Skin hypersensitivity = also in men) mostly occur in fact in patients peripheral hyperandrogenism: with normal androgen levels. Increased enzyme – with hirsutism (idiopathic) activities in the peripheral metabolism of ste- – and/or acne or androgenic alopecia roids, and/or increased sensitivity of AR, both 4. Drugs presumed to be subjected to genetic polymor- – androgenic progestins phisms, might account for abnormal responses – OP contraception with androgenic progestins to androgens. The first possibility in patients 5. Others (rare): with androgen-dependent skin manifestations – adrenal and ovarian tumours corresponds to increased metabolic pathways – Cushing’s syndrome that lead to the transformation of weaker an- Endocrinology Chapter 12 97 drogens to testosterone, increased 5_ reduction lapse after pregnancy, as well as premenstrual to DHT and lower aromatase activity [16]. and menstrual exacerbations are usually noted, The second possibility (the two not being suggesting that hormones, at least oestrogens, mutually exclusive) is directly linked to AR sen- may influence the course of the disease. Oestro- sitivity. AR is a structurally conserved member gens in fact are known to interfere with inflam- of the nuclear receptor superfamily. The amino- matory processes, independently of a direct ge- terminal domain is required for transcriptional nomic action of the steroids. This could account activation and contains a region of polygluta- for their influence on the natural course of in- mine encoded by CAG trinucleotide repeats. In flammatory diseases, such as acne, but also HS. humans the number of CAG repeats is polymor- Other observations in HS in terms of premen- phic. Longer repeat lengths are associated with strual and/or menstrual exacerbations may be androgen-insensitivity syndromes. It has been unrelated to the oestrogen or androgen depen- suggested that AR polymorphisms (CAG-repeat dency of the disease. lengths) account for AGA, hirsutism and acne, Although HS may be associated in some since shorter repeat lengths may be associated women with classic signs of skin androgeniza- with the development of androgen-mediated tion such as acne and/or hirsutism, no real as- skin disorders in men and women [17]. sociation of HS with hirsutism (the major symptom of hyperandrogenism) has ever been reported. In a series of 70 women with HS, acne 12.3 Lack of Association between HS was not more frequent than in controls [10]. The and Endocrinopathies incidence of patients with signs of androgenization did not differ significantly between the two Although HS has been reported in two men groups. Only a shorter menstrual cycle and a with acromegaly [4], which is very likely due to longer duration of menses in patients with HS a direct effect not of androgens but of growth were noted. Although there was no evidence in hormone on apocrine glands, HS was not found favour of or against an association with PCOS to be associated with endocrine disorders. or with NCAH, these data indicate that HS is In women HS has not been reported in asso- not accompanied by the usual clinical signs of ciation with ovarian or adrenal tumours, Cush- androgenization. ing’ syndrome, PCOS or NCAH, all known causes of hyperandrogenism with increased or abnormal androgen production. In fact, a pos- 12.4 HS and Biological sible association of HS with functional hyperan- Hyperandrogenism drogenism (ovarian or adrenal dysfunction) merits investigation with modern biological and Furthermore, as far as serum levels of andro- ultrasound markers [7]. gens and SHBG are concerned, there is no clear HS usually begins after puberty when the evidence for biochemical hyperandrogenism. apocrine glands are fully developed. A few cases On average, androgen levels (total plasma tes- have been reported in children, as clinical man- tosterone and free testosterone index due to a ifestations of premature adrenarche or early pu- low SHBG) were increased, but were normal in berty [11, 12, 15]. This represents in fact the many individual patients, and no significant de- strongest evidence for an influence of andro- crease of SHBG could be detected [13]. In fact, gens on HS. However, HS is more common in SHBG is known to be regulated by factors that women and usually affects premenopausal influence body weight and this study was not women, although it may appear after meno- controlled for body weight, and neither was a pause [3]. The rare incidence of HS in post- second one which found hyperandrogenism in a menopausal women does not stand in favour of subgroup of women who did not experience a a role for androgens, since hyperandrogenism premenstrual flare in their disease [9]. In a fur- after the menopause has yet to be demonstrated. ther group of 66 women with HS, among which On the other hand, improvement during and re- 23 had acne, 23 were significantly obese and 19 98 Michel Faure, Evelyne Drapier-Faure

were hirsute; testosterone and DHEAS were cal skin hyperandrogenism in women with HS. normal in all subjects [3]. In obese subjects, On the other hand, a genetic polymorphism in SHBG was reduced, consistent with body-mass- enzyme activities at the epithelial cell level re- index-matched controls. No evidence for bio- mains to be demonstrated. Finally, in the chemical hyperandrogenism could be found in absence of precise investigations, based upon women with HS when compared with controls biological markers (testosterone, 64A, 17-OHP, matched for age, weight, and hirsuteness [3]. SHBG levels, free testosterone index) and ovarian echography [1, 7], the possibility that some women with HS suffer from PCOS or NCAH 12.5 End-Organ Androgen cannot be excluded. Sensitivity?

All the above data suggest that the main mecha- References nism for the possible role of sex hormones in HS lies in end-organ sensitivity rather than in the 1. Azziz R, Hincapie LA, Knochenhauer ES, Dewail- plasma levels. Women can develop HS while ly D, Fox L, Boots LR (1999) Screening for 21-hy- taking oral contraceptives especially when an- droxylase-deficient non-classic adrenal hyperplasia among hyperandrogenic women: a prospective drogenic progestins are used, and this also sug- study. Fertil Steril 72:915–25 gests, as in acne, a possible androgen depen- 2. Barth JH, Kealey T (1991) Androgen metabolism by dence of the disease [19]. In acne, not only isolated human axillary apocrine glands in hidrad- sebocytes but also other epithelial cells are in- enitis suppurativa. Br J Dermatol 125:304–8 volved in the “skin hyperandrogenism” that is 3. Barth JH, Layton AM, Cunliffe WJ (1996) Endocrine responsible for the formation of the comedo. factors in pre- and postmenopausal women with hi- Keratinocytes from the acroinfundibulum ex- dradenitis suppurativa. Br J Dermatol 134:1057–9 press the key enzymes involved in the in situ 4. Chalmers RJ, Ead RD, Beck MH (1983) Acne vul- garis and hidradenitis suppurativa as presenting metabolism of androgens (in situ synthesis of features of acromegaly. Br Med J 287:1346–7 the weaker androgens, their transformation into 5. Chen WC, Thiboutot D, Zouboulis C (2002) Cutane- testosterone and its reduction into DHT) [5]. In- ous androgen metabolism: basic research and clini- vestigation for the activity of these enzymes in cal perspectives. J Invest Dermatol 119:992–1007 12 the epithelial cells that are presumed to be in- 6. Cortet-Rudelli C, Dewailly D (2004) Hyperan- volved in the first stage, i.e. follicular occlusion, drogenism in adolescent girls. In: Sultan C (ed) of HS remains to be conducted. Pediatric and adolescent gynecology. Karger, Basel, pp 148–62 However, androgen metabolism has been in- 7. Dewailly D, Robert Y, Helin I, Ardaens Y, Thom- vestigated in normal human apocrine glands as-Desrousseaux P, Lemaitre L, Fossati P (1994) and in those isolated from age-matched patients Ovarian stromal hypertrophy in hyperandrogenic with HS [2]. No increased activity of 3`-hy- women. Clin Endocrinol 41:557–62 droxysteroid dehydrogenase, 64-5 isomerase, or 8. Ebling FJG (1986) Hidradenitis suppurativa: an 17 `-hydroxysteroid dehydrogenase was found androgen-dependent disorder. Br J Dermatol 115: and 5_-reductase activity was similar. These re- 259–62 9. Harrison BJ, Read GF, Hughes LE (1988) Endocrine sults suggest that HS cannot be attributed to ex- basis for the clinical presentation of hidradenitis aggerated activities of androgen-interconvert- suppurativa. Br J Surg 75:972–5 ing enzymes within apocrine gland cells. 10. Jemec GBE (1988) The symptomatology of hidrade- These data should not be interpreted as re- nitis suppurativa in women. Br J Dermatol 119:345– flecting a lack of apocrine sensitivity to andro- 50 gens, since they relate to the quantity of active 11. Lewis F, Messenger AG, Wales JKF (1993) Hidrad- metabolite (DHT) and not to the androgen re- enitis suppurativa as a presenting feature of premature adrenarche. Br J Dermatol 129-: 447-8 sponse at the receptor level. It cannot be exclud- 12. Mengesha YM, Holcombe TC, Hansen RC (1999) ed that there is increased sensitivity of cellular Prepubertal hidradenitis suppurativa: two case re- AR, due to genetic polymorphism of the recep- ports and review of the literature. Pediatr Dermatol tor, that might account for the as yet hypotheti- 16:292–6 Endocrinology Chapter 12 99

13. Mortimer PS, Dawber RPR, Gales MA, Moore RA 17. Saawaya ME, Shalita AR (1998) Androgen receptor (1986) Mediation of hidradenitis suppurativa by an- polymorphisms (CAG repeat lengths) in andro- drogens. Br Med J 292:245–8 genic alopecia, hirsutism and acne. J Cut Med Surg 14. Mortimer PS, Dawber RPR, Gales MA, Moore RA 3:9–15 (1986) A double-blind controlled cross-over trial 18. Sawers RS, Randall VA, Ebling FJB (1986) Control of cyproterone acetate in females with hidradenitis of hidradenitis suppurativa in women using com- suppurativa. Br J Dermatol 115:263–8 bined anti-androgen (cyproterone acetate) and oes- 15. Palmer RA, Keefe M (2001) Early-onset of hidrad- trogen therapy. Br J Dermatol 115:269–74 enitis suppurativa. Clin Exp Dermatol 26:501–3 19. Stellon AJ, Wakeling M (1989) Hidradenitis suppu- 16. Redmond GP (1995) Androgenic disorders of wom- rativa associated with the use of oral contraceptive. en: diagnostic and therapeutic decision making. Br Med J 298:28–9 Am J Med 98:1A120S–A129S