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Home , Cimetidine

J. Appl. Cosmetol. 9. 69-72 (October - December 1991)

TREATMENT OF

Vortra g , Schmidt J.B. Department of Dermatology Il, Medicai School, University of Vienna

Received: October 27, 7989. Presented at the 3'd INTERNATIONAL CONGRESS ON COSMETIC DERMATOLOGY. "PROGRESS IN COSMETIC DERMATOLOGY". Vienna (AUSTRIA) October 27-29, 7989

Key words: Hirsutism; Receptor: Androgen Serum Leve/; Acetate: Cimetidine: : Medroxyprogesterone Acetate: ______Synopsis

The hormonal sources of hirsutism to a great extent go back to increased locai androgen in the skin. Elevateci binding sites in hirsute areas of body hair as well as elevateci peripheral contribute to the overstimulation of the androgen dependent hair follicles. Prior to treatment of hirs utism a careful hormonal investigation should evaluate the origin of hyper­ androgenaemia in order to establish a causative treatment. act by blocking the androgen receptors in skin tissue. Besides, they may suppress serum androgens. Cyproterone acetale (CPA) can be applied in various dosages. Besides a monthly, parenterally applied bolus CPA showed good effects and mini mal . Other antiandrogens - spironolactone and cimetidine - are not convincing as mono-treatment and should be preserved for additional therapy in severe cases. Medroxyprogesterone acetate implantants show good effects by 6 weekly intramuscular application or intracutaneous injection into hairy areas and is mainly apt for menopausa! females.

In linea di massima a livello ormonale l'irsutismo provoca un aumento del metabolismo cutaneo lo­ cale degli androgeni. Nelle aree affette da irsutismo l'elevata presenza degli androgeni periferici e dei relativi siti recettoriali contribuisce alla elevata stimolazione dei follicoli piliferi androgeno di­ pendenti. Prima di iniziare il trattamento dell'irsutismo deve essere condotta un 'attenta disamina ormonale per ben valutare l'origine dell 'iperandrogenia. Gli antiandrogeni agiscono bloccando i recettori ormonali presenti a livello cutaneo. Il ciproterone acetato (CPA) puo' essere applicato a vari dosaggi. L'applicazione parenterale mensi­ le di un bolo di CPA ha mostrato una buona efficacia accompagnata da minimi effetti collaterali. Altri antiandrogeni-spironolattone e cimetidina non convincono nel monotrattamento e dovrebbero essere util izzati soltanto come coadiuvanti terapeutici nei casi piu' gravi. L'impianto dell'acetato di Medrossiprogesterone mostra buoni risultati dopo sei settimane sia se effettuato intramuscolo che sottocutaneo direttamente nelle zone affette, soprattutto nelle donne in menopausa.

69 Treatment of hirsutism

lntroduction Studies and results

The clinica( aspect of facial and body hair dis­ In our s tudies of hirs utism in 36 females tribution shows broad individuai variations due androgen receptors (AR) were determined by to racial, geneti c and hormonal infl uences. hir­ saturation analysis and found to be abnormally sutism is the overgrowth of hair in hig h in 26%. The mean AR level was 68 dependent areas of facial and body hair under /fmol/mg protein and thus almost 8 times higher increased androgenic influence.. In the face the than in normai skin and 3 times hi gher than in chin , the submental region, the cheeks and the (5, Schmidt & Spana, 1985). The e n­ upper lips are mainly involved. On the body of docrine profile s howed elevations of Tes­ sites predilecti o n are the presternal and cir­ tosterone (T) in 63%, Dehydoepiandrosterone - cumareolar regions and the abdomen. The den­ sulfate (DHEA-S) in 50% and sity of pubic hair is nearly always increased in (A) in 37% of the patients. Moreover , the m iss­ hi rsute women and the hair mostl y extends to ing correlation between androgen serum levels the inner parts of thighs. and AR ind icateci an autonomous hormo ne Regulation of hair growth is modulateci by com­ metabolism at the receptor level. plex interactions of multiple - also hormonal - These results show that both elevateci androgens influences on the different structures of the hair and increased AR binding may contribute to hir­ follicle and the derma( papill a. Hamilton ( I) sutism. The most effective treatment thus aimed showed as early as 1942 that hair fo ll icles are at both levels, the hormonal as well as the cel­ active target sites of . Plucked hai r lu lar. follicles were shown to metabolize testosterone. If the androge n constell a ti on indicates an Fazekas and Sandor were the f irst to ovarian source of hyperandrogenaemia, the ex­ demonstrate androgen receptors in pilary roots tent of the androgen elevations (testostero ne, (2). These observati ons confirmed the rote of androstenedione) determines further diagnostic the hair follicles not only as endocrine targets or therapeutic steps. Of course, in severe cases but also as active sites of androgen metabolism. polycystic ovary syndrome has to be excluded Androgens seem to interact with aJJ of the com­ prior to any hormonal treatment. In the other pounds that are responsible for hair growth. By cases antiandrogens can properl y be used to e lo ngation of the growth phase the previous suppress the increased hormone levels and the thin, medulla and pigment less vellus hair is block the AR binding sites. transformed into the medullated, pigmented and Of ali avaible substances, is thick terminal hair in androgen dependent areas, clinically the most promising substance. The which is characteristic of hirsute aspect. low dose cyproterone acetate treatment (Diane: Although the stimulatory effects of androgens on 2 mg CPA + 50 or 35 µg E2/pill) is a successful androgen dependent hair roots are well descri bed, regimen for the treatment of moderate hi r­ the percentage of elevateci androgen serum levels sutism, but has the disadvantage of late onset of in hirsutism varies between 90% elevateci (3, the therapeutic effects. By additive application Kirschner & al) and normai range levels (4, of 50 mg cyproterone acetate (Androcur) from Korernnan & al.). Hirsutism in females with nor­ day 5 to 15 of the menstrual cycle the effects are mai androgen levels is the so-called "idiopathic increased. hirsutism''. Determination of androgen receptors Recently, improved effects had been reported by al lows conclusions about the a ndrogen a once monthly parenteral application of a bolus stimulability of the target organ - the skin tissue. of 300 mg CPA (6, Moltz & al). In o ur study the

70 Vortrag. Schmidt J B.

effects of 100 mg cyproterone acetate ad­ fora mean of 16 weeks: 150 mg MPO was ad­ ministered daily perorally for the first IO days ministered as an intramuscular implant or as in­ of menstrual cycle have been compared with tralesional injections into hairy areas of the face those of a once monthly implant of 300 mg in 6 weekly intervals. A third group of patients cyproterone acetate on the first day of each applied a 0.2% MPO containing ointment on the cycle. IO patients with severe hirsutism were hairy sites of the face. As before, c linica! recruited for each treatment. Additionally, con­ changes were noted and hair measurements traception was mantai ned with Diane in both were made. The comparis on of these groups. parameters revealed that the best results were The clinica! effects, consisting of reduced hair achieved by the intralesional application of growth and thinning of hair, decrease of pig­ MPO into the hairy areas where both the locai mentation and prolongation of the intervals and systemic effects of MPO contributes to the between epilatory measures, were noted in both action. Next best was parenteral application groups from 3 months of treatment onwards. whe re the syste mic effects predominate. Side effects consisted mainly of tension, However, the locai ointment also showed posi­ nausea and menstrual di sturbances. tive effects, thus confirm ing a peripheral action C linicall y, parenteral administration of of MPO at the tissue leve!, as no decrease of cyproterone acetate appeared sli ghtl y more serum androgens was shown. Side effects con­ effective than ora! administration (7, Schmidt, s i sted mainly of me nstrual disturbances (8, Huber, Spona). Schmidt & Spona, 1985). In menopausa! hirsute As well as the classica! a ntiandrogen , women, expecially MPO treatment is of great cyproterone acetate, also antiandrogens such as benefit, as it also displays beneficiai effects on spironolactone and cimetidine have also been menopausa! symptoms. c laimed to provide beneficiai effects in hir­ suti sm. In our experience, spironolactone should be administered only in cases which s how Discussion therapeutic resistance to other substances. Al­ though the effects of treatme nt show rapid A range of substances, broader than in former onset, they a lso diminish after few months. years, allows more specific and individuai treat­ Regular controls of the electrolytes, which often ment of hirsutism than previously. Detailed are responsible for severe side effects are re­ dete rmination of the hormone parameters quested if treatment is performed in adequate s hould he lp to clarify th e source of hyper­ dose (2x 100 mg/d). androgenenia and should precede the decision Cimetidine is the weakest and on hormonal treatment. the refore should only be administered for Adequate treatment may sometimes include a moderate forms of hirsutism or as additional combination of various hormonal substances treatment, in a dosage of at least 3x400 mg/day. adapted to the individuai hormone profile. New Another promising but less well-known sub­ developments of m erely topically active stance is medroxyprogesterone acetate (MPO). androgens could mainly amplify the endocrine The Depot-Gestagen acts by inhibition of the treatment of hirsutism and permit effecti ve 5a-reductase which converts T to DHT therapy without side effects in cases in which and by a decrease of serum androgens. For com­ serum androgens are normai. parison of systemic and locai effects of the sub­ stance 3 forms of application were carried out in a group of 26 females with moderate hirsutism

71 Treatment of h1rsutism

References:

1. Hamilton J .B. (1942): "Male hormon is a prereq uisite incitan t in cornrnon baldness". Am.J.Anat. 71:451-80 2. Fazekas A.G., Sandor D. (1972): "Harrfollikel. In Fourth lnternational Congress of Endocrinol­ ogy" p. 80, Amsterdam: Excerpta Medica. 3) Kirschner M.A., Zucker J .R., Jespersen D. (1976) : "Idiopathic hirsutisrn and ovarian abnor~ mality". N. Engl. J. Med. 294: 637-41 4. Korenman S.B., Kirschner M.A., Lipsetle M.B. (1965): "Testosterone production in normaJ, virili zed wornen with the Stein-Leventhal Syndrorne or idiopathic hirs utisrn." J. Clin. Endocrin. Metab. 25: 798-803 5. Schmidt J.B., Huber J ., Spona J. (1985): " Hormone Levels & Skin receptor Con­ centrations in Hirsutisrn ." Endocrino!. Exp. 19: 147-155 6. Moltz L., Haase F., Schwartz U., Hammerstein J. (1983): "Die Behandlung androgenisierter Frauen mit intramuskular applizierbarem Cyproteronacetat. " Geburtshilfe & Frauenheilk. 43:281 7. Schmidt J.B., Huber J ., Spona J. (1987): "Parenteral and Oral Cyproterone Acetate Treatment in Severe Hirsutism." Gynecologic & Obstetic lnvestigation. 24: 125-130 8. Schmidt J.B., Huber J ., Spona J . (1985): "Medeoxyprogesterone Acetate T herapy in Hirsutism" British J. Derm. 113: 16 1-165.

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