Evelyne Drapier-Faure, Michel Faure 16

16

Chapter 16

Antiandrogens

Evelyne Drapier-Faure, Michel Faure 16

Key points

Q The role of androgens in hidradenitis suppurativa (HS) is controversial

Q HS may correspond to an inflamma- tory disease with an increased sensitiv- ity to circulating or in situ androgens, but this view is not supported by those few cases in which there is a positive response to antiandrogens

Q Further studies are needed to investi- gate whether HS responds to antian- drogens and to settle the controversy of whether HS can be considered as a manifestation of cutaneous hyperan- drogenism

#ONTENTS

16.1 Introduction . . . .124

16.2 Antiandrogens and Antiandrogen Therapies . . . .124

16.2.1 Cyproterone Acetate . . . .125

16.2.2 Spironolactone . . . .125

16.2.3 Finasteride . . . .125

16.2.4 Antiandrogenic Progestins . . . .125

16.2.5 Oral Contraceptives . . . .125

16.3 Antiandrogens in HS . . . .126

16.3.1 Cyproterone Acetate . . . .126

16.3.2 Spironolactone . . . .126

16.4 Finasteride . . . .126

References . . . .127

16.1 Introduction

In 1986, two reports suggested that hidradenitis suppurativa (HS) responds to antiandrogen therapy [9, 13]. They supported the hypothesis that HS is an androgen-dependent disease. In fact, no further work exists favouring this hy- pothesis. Furthermore, clinical and biological investigations are really needed to elucidate the possible participation of androgens and the pos- sibility of hyperandrogenism in HS (see Chap.

12, Endocrinology). What a so-called response to antiandrogens in HS means, and the evidence for this is really only poorly suggested, and must be discussed in terms of antiandrogen therapy.

16.2 Antiandrogens

and Antiandrogen Therapies

Antiandrogens are molecules that bind the an- drogen receptor (AR) and act as androgen an- tagonists at the target cell level. Cyproterone acetate (CPA) and spironolactone are the most commonly used androgenic antagonists [3, 12].

Additional hormonal treatment of hyperan-

drogenism includes: (1) inhibition of the con-

version of testosterone (T) into its active me-

tabolite dihydrotestosterone (DHT) through

5_-reductase inhibition; (2) suppression of

ovarian androgen production with oral contra-

ceptives (OC); (3) elevation of sex-hormone-

binding globulin (SHBG) levels through oestro-

gens, either natural oestradiol, (E

, as oestrogen

therapy) or ethinyloestradiol (EE, with OC),

with a further decrease in plasma free androgen

levels (Table 16.1).

Antiandrogens Chapter 16 125

16.2.1 Cyproterone Acetate

CPA is a progestin with several antiandrogenic activities: binding to AR, inhibition of andro- gen metabolism and antigonadotropic activity.

CPA has been used extensively in Europe for 30 years in the treatment of hirsutism. It can be given according to various regimens (usually 50 mg daily on days 1–20 of each menstrual cycle, but other regimens are possible with CPA of 50 or 100 mg) together with natural E

or with an OC pill. Good results may be obtained in hirsutism and also in women with severe and/or persistent acne or with androgenic alo- pecia. Side-effects are uncommon and the anti- androgen is well tolerated [6, 11, 17, 18].

16.2.2 Spironolactone

Spironolactone is the most generally used anti- androgen in countries where CPA has not been approved. Spironolactone binds to AR but is de- void of antigonadotropic activity. Doses needed for antiandrogenic efficacy are 75–200 mg daily depending upon the indication (acne, alopecia or hirsutism). Concomitant use of OC or a non- androgenic progestin can prevent menstruation disorders. Tolerance is good even on long-term therapy [3, 10].

16.2.3 Finasteride

Finasteride is not an antiandrogen. It does not act by blocking AR, but by inhibiting 5_-reduc- tase, which transforms T into DHT. Finasteride inhibits the progressive hair loss in men with androgenic alopecia. It remains to be shown whether finasteride is effective in women with female-pattern hair loss. In fact, due to the pos- sible feminization of a male fetus in the case of pregnancy whilst taking finasteride, the drug has not been approved in women [1].

16.2.4 Antiandrogenic Progestins

Other progestins with antiandrogen properties [11, 14] (antagonists at the AR levels) include chlormadinone acetate (CMA), drospirenone and dienogest. They may be used either in com- bination with EE [5, 8, 16] as a contraceptive OC (similarly the combination of CPA 2mg + 30 +g EE) or as antiandrogenic progestin alone (CMA for instance) according to countries where the drugs have been approved. In fact no evaluation of the effects of these progestins exists in wom- en with hirsutism, severe acne or chronic alope- cia.

16.2.5 Oral Contraceptives

Androgenic symptoms in patients with hyper- androgenism may also be minimized with OC combinations. OC may be indirectly antiandro- genic through the suppression of ovarian an- drogen production (antigonadotropic activity) and the oestrogen-induced elevation of SHBG.

In fact, all synthetic progestins are either pro- gesterone or testosterone derivatives. They not only bind the progesterone receptor but may also bind AR, with either agonistic or antago- nistic activity. Therefore, most progestins have androgenic properties, balancing, when com- bined with EE, the antiandrogenic activity of EE. Therefore, OC in women with a hyperan- drogenic disorder should comprise oestrogen–

progestin combinations containing antiandro- genic or non-androgenic progestins. However, these OC cannot be considered as effective anti-

Table 16.1. Treatments for androgenic disorders Antiandrogens = androgenic antagonists Cyproterone acetate

Spironolactone Others

5α-Reductase inhibition Finasteride

Ovarian suppression Combination OC

Progestogens (non-androgenic) Oestrogens

Increase of SHBG Oestrogens

Combination OC (non-androgenic) Weight loss

Non-hormonal Depilation, epilation

Anti-acne (retinoids, antibiotics)

126 Evelyne Drapier-Faure, Michel Faure

16

androgens in women with hirsutism, severe acne or chronic diffuse hair loss. Their antian- drogenic action is limited to moderate or mild acne, in association with other anti-acne thera- pies [3, 14, 15].

16.3 Antiandrogens in HS

There are only three reports suggesting a possi- ble role for antiandrogens in the management of HS.

16.3.1 Cyproterone Acetate

In 1986 Mortimer et al. [9] published the first and only study of the effects of CPA in women with HS. This was a double-blind controlled cross-over trial of EE 50 +g /CPA 50 mg compared to an ordinary OC in combination with EE 50 +g/norgestrel 500 +g, in 24 female patients for 12 cycles. They reported substantial improvement in disease activity with both treat- ments. In fact, only 18 patients out of 24 com- pleted the trial and only 12 patients improved, while 4 deteriorated. No clinically significant differences between the two regimens were not- ed. Indeed, objective assessments provided insufficient evidence for improvement. “Accu- rate” assessments could only be made with knowledge of the frequency and severity of at- tacks of the disease, as judged by the patients themselves [9].

The fact that no difference was noted be- tween the two groups does not favour a role for CPA as an antiandrogen in HS. The combina- tion used in the control group was an OC with an androgenic progestin. In hirsutism, which is a major skin hyperandrogenic condition, and in severe acne, this kind of combination with ei- ther 50 +g or 35 +g EE is not effective, while 50 mg CPA daily is. If some improvement in HS could be noted in 12 patients out of the initial 24, whichever combination was used, this can- not be related to the antiandrogenicity of CPA.

Rather, it may reflect the indirect antiandrogen- icity of EE, decreased ovarian androgen produc- tion and increased SHBG synthesis, as evi- denced by the variations in plasma testosterone,

SHBG and T/SHBG ratio (free androgen index) that were noted.

Also in 1986, Sawers et al. [13] reported the analysis of four women with HS who received CPA in combination with EE according to the then classic reversed sequential regimen of Hammerstein, namely 100 mg CPA per day for 10 days and 50 +g EE per day for 21 days. This was a classic antiandrogenic regimen used to treat hirsutism. All four patients were reported to exhibit objective clinical improvement and to report a subjective impression of improvement after only one to two cycles of treatment. Three patients experienced a worsening of the symp- toms when CPA was reduced. In fact, it is ques- tionable whether these women, or at least two of them, were really suffering from HS and not from acne. Furthermore this was merely an uncontrolled study, an open report of only four cases of “mild” HS under antiandrogen and oestrogen therapy.

In fact there are presently no studies to sug- gest a role for CPA as an antiandrogen in the management of HS.

16.3.2 Spironolactone

No study exists on the effects of spironolactone as an antiandrogen in women with HS. Howev- er, Cunliffe noted in 1989 that some clinical benefit had been obtained in an uncontrolled study with spironolactone 200 mg daily in about half of patients [2].

16.4 Finasteride

Two patients were reported in 1999 by Farrell

et al. [4] to have a good response to finasteride

(5 mg/day), a dose five times higher than that

used in male alopecia. A 56-year-old man with a

10-year past history of HS reported significant

improvement in his symptoms as early as the

4th week of treatment. A 55-year-old postmeno-

pausal woman with a history of HS since ado-

lescence and a previous absence of response

to CPA received finasteride 5 mg/day. After

3 months she reported an improvement of her

lesions without any significant adverse effects.

Antiandrogens Chapter 16 127

Since then, seven patients of both sexes have been treated with finasteride 5 mg/day in an open study with follow-up periods ranging from 8 months to 2 years [7]. Three patients had com- plete healing of lesions and six patients were said to improve significantly. In fact, double- blind placebo-controlled studies are needed to clarify this situation.

References

1. Brenner S, Matz H (1999) Improvement in andro- genic alopecia in 53-76 year old men using oral finas- teride. Int J Dermatol 38:928–30

2. Cunliffe WJ (1989) Non-acne disorders of the pilose- baceous unit, hidradenitis suppurativa. In: Cunliffe W (ed) Acne. Martin Dunitz, London, pp 87–92 3. Drapier-Faure E (1998) Traitement hormonal des hy-

perandrogenies. Reprod Hum Hormones 11:80–8 4. Farrell AM, Randall VA, Vafaee T, Dawber RPR

(1999) Finasteride as a therapy for hidradenitis sup- purativa. Br J Dermatol 141:1138–9

5. Fuhrmann J, Krattenmacher R, Slater E, Fritzmeier KH (1996) The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Contraception 54:243–51

6. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F (1975) Use of cyproterone acetate in the treatment of acne, hirsutism and virilism. J Ster Bio- chem 6:827–36

7. Joseph MA, Javaseelan E, Ganapathi B, Stephen J (2005) Hidradenitis suppurativa treated with finas- teride. J Dermatol Treat 16:74–8

8. Moore C, Luderschmidt C, Moltz L, Oettel M, Klinger G, Schreiber G (1999) Antiandrogenic prop- erties of the dienogest-containing oral contraceptive Valette

. Drugs Today 35:S69–S78

9. Mortimer PS, Dawber RPR, Gales MA, Moore RA (1986) A double-blind controlled cross-over trial of cyproterone acetate in females with hidradenitis suppurativa. Br J Dermatol 115:263–8

10. O’Brien RC, Cooper ME, Murray RML, Seeman E, Thomas AK, Jerums G (1991) Comparison of sequential cyproterone acetate/estrogen versus spi- ronolactone/oral contraceptive in the treatment of hirsutism. J Clin Endocrinol Metabol 72:1008–13 11. Raudrant D, Rabe T (2003) Progestogens with anti-

androgenic properties. Drugs 63:563–92

12. Rittmaster RS (1995) Medical treatment of andro- gen-dependent hirsutism. J Clin Endocrinol Metab 80:2559–63

13. Sawers RS, Randall VA, Ebling FJB (1986) Control of hidradenitis suppurativa in women using combined anti-androgen (cyproterone acetate) and oestrogen therapy. Br J Dermatol 115:269–74

14. Sitruk-Ware R (2004) Pharmacological profile of progestins. Maturitas 47:277–83

15. Stanczyk FZ (2002) Pharmacokinetics and potency of progestins used for hormone replacement ther- apy and contraception. Rev Endocr Metab Disord 3:211–24

16. Terouane B, Paris F, Servant N, Georget V, Sultan C (2002) Evidence that chlormadinone acetate exhib- its antiandrogenic activity in androgen-dependent cell line. Mol Cell Endocrinol 198:143–7

17. Thorneycroft IH (1999) Update on androgenicity.

Am J Obstet Gynecol 180:S288–S94

18. Vexiau P, Boudou P, Fiet J, Hardy N, Conard J,

Consoli S, Abramovici Y, Cathelineau G (1995)

17` Estradiol: oral or parenteral administration in

hyperandrogenic women? Metabolic tolerance in

association with cyproterone acetate. Fertil Steril

63:508–15