EFFECT OF ORAL CYPROTERONE ACETATE ON URINARY AND SERUM FSH AND LH LEVELS IN ADULT MALES BEING TREATED FOR HYPERSEXUALITY JANET BROTHERTON Schering Chemicals Ltd, Burgess Hill, Sussex, and School of Biological Sciences, University of Sussex (Received 12th February 1973) Summary. A group of eighteen male hypersexual patients received 50 mg cyproterone acetate orally twice a day. Radioimmunoassays of LH and FSH were carried out at intervals on serum and 24-hr urine speci- mens. All the six `pretreatment' and twenty-eight `during-treatment' levels of urinary FSH fell within the normal range of 2 to 17 i.u. 2nd IRP-HMG/24 hr. One of the six `pretreatment' and three of the twenty\x=req-\ eight `during-treatment' levels of urinary LH were higher than the normal range of 4 to 50 i.u. 2nd IRP-HMG/24 hr. Treated as a whole, the LH levels could be regarded as showing no difference due to treat- ment with cyproterone acetate but if the patient with the high pre- treatment level, who was also suffering from schizophrenia, was removed from the group then the LH levels during treatment showed a significant rise. The mean serum LH was 6\m=.\3mU MRC 69/104 standard/ml with an upper limit of 14\m=.\4mU and the mean serum FSH was 13\m=.\3mi.u. 2nd IRP-HMG/ml with a range of 6 to 33 mi.u. All these results were within the quoted normal ranges. The mechanism of action of cypro- terone acetate is discussed, taking into consideration the normal LH and FSH levels, low testosterone levels and inhibition of spermatogenesis and is compared with the actions of oestrogens, androgens, `pure' pro- gestagens and `pure' anti-androgens on these parameters. INTRODUCTION Initial studies on the treatment of male hypersexuality with anti-androgens were with cyproterone rather than its acetate. It was discovered that cypro¬ terone was a 'pure' anti-androgen, lacking the feedback suppression of gonado¬ trophin levels possessed by most compounds with progestational activity. The net effect was an increase in plasma testosterone and in FSH and LH levels (Rausch-Strooman, Petry, Hocevar, Mauss & Senge, 1970; Vosbeck & Keller, 1971 ; Brotherton, 1972). This is believed to be due to the direct prevention of androgenic feedback to the hypothalamus, so that more gonadotrophins are produced and hence more testosterone. * Present address: Department of Chemotherapy, Schering A.G., 1 Berlin 65, Germany. 177 Downloaded from Bioscientifica.com at 09/26/2021 09:38:42PM via free access 178 Janet Brotherton Current investigations are being carried out exclusively with cyproterone acetate which has strong progestational and antigonadotrophic properties in addition to its anti-androgenic action. This compound has been used experimentally since 1967 for the treatment of hypersexuality in adult males (Laschet & Laschet, 1967). Its use is known to be associated with a gradual reduction in libido and potency while spermatogenesis is also inhibited. By about 6 weeks of treatment, there is absence of ejaculate though there are no pathological changes in the testes. This contrasts with the testicular changes produced by pituitary suppression with androgens or oestrogens (Laschet & Laschet, 1971; Cooper, Ismail, Phanjoo & Love, 1972). The reduction in libido and potency takes place before the failure of spermatogenesis and returns more quickly after the cessation of treatment. This may be a reflection of the long delay of about 64 days for the complete cycle of spermatogenesis in man. Hormone assays have consistently shown that plasma testosterone levels are significantly reduced (Schoonees, Schalch & Murphy, 1971; Sorcini, Sciarra, di Silverio & Fraioli, 1971). The reduction in plasma testosterone may be as much as 50% in the first 5 days of therapy. A simultaneous rise in plasma an¬ drostenedione has been detected by Sorcini et al. (1971) which may be a mani¬ festation of the local anti-androgenic action of cyproterone acetate. The effects of cyproterone acetate on gonadotrophins is less clear and the present study was specifically designed to measure the effects on LH and FSH levels. METHODS A group of eighteen male hypersexual patients from three clinical centres received 50 mg cyproterone acetate orally twice a day. All the patients had normal sexual characteristics and were adults aged 22 to 54 years, except for patients B.6 and B. 10 who were 14 years old and suffering from Down's syndrome. Patients A.l, A.2 and A.3 were classed as manic-depressive, patients C.l, C.2 and C.3 showed a variety of aggressive sexual deviations and patient A.4 was suffering from schizophrenia. All the remaining patients were mentally subnormal. All the patients had either drawn the attention of the police to their abnormal hypersexual behaviour or were causing a sexual nuisance in a residential home for the mentally retarded. At the start of this study, the precise nature of the episodic and diurnal fluctuations in plasma LH and FSH were not known and it was decided to estimate these gonadotrophins in 24-hr urine specimens after storage at —20° C until a batch had been accumulated. Radioimmunoassays of FSH and LH were carried out on extracts prepared by the method of Butt & Lynch (1971). Some published normal values with ranges for these assays are shown in Table 1 : the results obtained by the present methods are believed to fall within these ranges. Later, serum gonadotrophin levels were estimated. Human pituitary FSH (preparation CPDS/3) containing approximately 5000 i.u./mg by bioassay (W. R. Butt, personal communication) and human pituitary LH were iodinated by the method of Butt (1972). The antisera were prepared in rabbits and the free and bound fractions were separated by the double antibody method. The Downloaded from Bioscientifica.com at 09/26/2021 09:38:42PM via free access Cyproterone acetate effect on male FSH and LH 179 standard for the urinary assays was the 2nd IRP-HMG: the same standard and MRC 69/104 were used for assays on blood. The MRC 69/104 standard was assumed to have a potency of 10 i.u. FSH and 25 i.u. LH/ampoule, each ampoule being equivalent to the immunoreactive FSH and LH in 0-5 mg of the NIH standard LER-907 from which it is derived (Bangham & Borth, 1972). At first, the inhibition curves for preparation MRC 69/104 were not strictly parallel to those of serum samples in the FSH immunoassay and results are therefore quoted in terms of mi.u. 2nd IRP-HMG. Latterly, the slopes approached parallelism and each mU MRC 69/104 was found to be equivalent Table 1. Normal male urinary gonadotrophin levels by radioimmuno- assay Standard Mean deviation Range Reference FSH 19 8-5 3-6 3 to 17 Raiti«ia/. (1969) LH 10 31-3 10-3 17 to 50 Baghdassarian et al. (1970) 220 23-9 15-5 4 to 45 Wikramanayake et al. (1972) After hypophysectomy FSH = 1-0 to (n 7) 2-2 Mancini et al. LH (n m 7) 1-4 to 2-8 (1971) Urinary gonadotrophin levels expressed in terms of i.u. 2nd IRP-HMG/24 hr. Table 2. Normal serum FSH and LH levels in males by radioimmunoassay Units Mean + S.D. Range Reference FSH mi.u. 2nd IRP-HMG/ml 27 17 4 to 42 Saxena et al. (1969) 230 11-00 ±0-34 Lee et al. (1970) 19 7-4+1-9 2 to 13 Baghdassarian et al. (1970) LH mi.u. 2nd IRP-HMG/ml 234 11-11 + 0-25 Lee et al. (1970) 27 2 to 32 Saxena et al. (1969) 10 10-9 + 4-0 6 to 23 Baghdassarian et al. (1970) mi.u. LER 907/ml 40 12-0±4-0 4 to 20 Kolodny et al. (1972) ßg LER 907/100 mi 48 4-3 + 0-4 1 to 13 Rosen & Weintraub (1971) 8 4-5 + 3-0 3 to 7 Faiman & Winter (1971) to 5 mi.u. 2nd IRP-HMG. In the LH assay, 1 mU MRC 69/104 standard was equivalent to about 4 mi.u. 2nd IRP-HMG. Cross-reaction by FSH in the LH radioimmunoassay was insignificant and cross-reaction by LH in the FSH estimation was not more than 5 °/0. Normal quoted values, with ranges, for these assays are shown in Table 2. Normal results for the present methods are 8-1 + 3-4 mi.u. 2nd IRP-HMG/ml (mean + S.D.) with a range of 4 to 15 for FSH (sixteen samples) and 6-0 + 4-7 mU MRC 69/104 standard/ml with a range of 2-5 to 19-0 for LH (twenty-six samples). RESULTS Urinary levels Tables 3 and 4 show the LH and FSH levels respectively in 24-hr urine Downloaded from Bioscientifica.com at 09/26/2021 09:38:42PM via free access 180 Janet Brotherton specimens. Some pretreatment values were not available as the clinical trial had already started before hormone assays were arranged. The normal range of urinary FSH may be taken as 2 to 17 i.u. 2nd IRP-HMG/24 hr (Table 1). All the 'pretreatment' and all but two of the 'during-treatment' values fell within this range. Two of the 'during-treatment' values were slightly above the Table 3. Urinary LH levels in hypersexual males Weeks (w) or months (m) of treatment Case Before no. treatment 1 w 2w 1 m 2 m 3 m <6 m 6 m 12 A.l 5-7 12-0 8-0 6-8 4-8 5-5 A.2 52-6 71-5 A3 11-3 33-9 9-9 A.4* 104-0 33-6 54-6 60-2 23-4 46-8 B.l 11-4 B.2 7-0 B.3 22-0 4-3 B.4 C.l 4-7 13-1 5-5 99-8 15-9 8-9 C.2 16-5 10-6 11-0 C.3 6-1 16-5 Urinary LH levels expressed in terms of i.u.