An investigation of the effectiveness of testosterone implants in combination with the prolactin inhibitor quinagolide in the suppression of spermatogenesis in men

Human Reproduction Vol.18, No.4 pp. 749±755, 2003 DOI: 10.1093/humrep/deg173 An investigation of the effectiveness of testosterone implants in combination with the prolactin inhibitor quinagolide in the suppression of spermatogenesis in men W.Morton Hair1, Frederick C.W.Wu2 and Gerald A.Lincoln1,3 1 MRC Human Reproductive Sciences Unit, The University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB and 2University Department of Endocrinology, Manchester Royal In®rmary, Oxford Road, Manchester M13 9WL, UK 3 To whom correspondence should be addressed. E-mail: BACKGROUND: Administration of testosterone inhibits gonadotrophin secretion and spermatogenesis in men but the degree of response is highly variable. This treatment also stimulates prolactin, itself a progonadal hormone in animals. This study investigated whether concomitant suppression of prolactin (PRL) with the non-ergot, dopamine receptor agonist quinagolide (Q), would enhance the ef®cacy of testosterone in its inhibition of spermatogenesis in healthy eugonadal men. METHODS: A total of 46 men were randomized to three treatment groups: Group 1, T1200: 1200 mg testosterone implant plus daily oral placebo; Group 2, T1200 + Q: 1200 mg testosterone plus oral Q 75 mg/day; Group 3, T800 + Q: testosterone 800 mg plus oral Q 75 mg/day. After an initial pre-treatment period of 4 weeks, subjects were treated for 24 weeks followed by an 8-week recovery period. RESULTS: The total numbers of subjects that achieved severe oligospermia (<106/ml including azoospermia) from weeks 8±16 were 11/13 (85%), 11/ 12 (92%), 8/13 (61.5%) in the three groups respectively. CONCLUSIONS: The results show that inhibition of PRL does not to confer additional ef®cacy in spermatogenic suppression in men. However, Q did not totally block PRL secretion in the subjects, possibly because testosterone replacement itself stimulated PRL by a direct action on the lactotroph, thus the effectiveness of dual inhibition of gonadotrophin and PRL could not be fully investigated. Key words: prolactin inhibition/quinagolide/spermatogenesis/testosterone Introduction Androgen administration aimed at producing a reversible contraceptive for men acts by inhibition of FSH and LH secretion to suppress spermatogenesis. It does not however suppress PRL secretion, which, at least in animal models, is a weak gonadotrophin (Bartke et al., 1975; Ouhtit et al., 1993; Lincoln et al., 1996; Jabbour and Lincoln, 1999). Initial studies showed that long-term treatments with testosterone esters, even at high doses, induce azoospermia in only a proportion (~65%) of subjects with notable differences between ethnic groups (World Health Organization Task Force, 1990; Handelsman et al., 1992; Sundaram et al., 1993; Behre et al., 1995). More recently, steroid treatments involving testosterone combined with progestins, have been shown to be more effective in the suppression of spermatogenesis (Bebb et al., 1996; Handelsman et al., 1996; Meriggiola et al., 1996; Wu et al., 1999; Martin et al., 2000). Treatments with anti-androgenic progestins (e.g. cyproterone acetate) however, produce undesirable changes in the haemopoeitic system (Meriggiola et al., 1996), and progestins may produce effects on mood, as is well demonstrated in women (Pearlstein, 1995). In addition these treatments have not been shown to produce universal ã European Society of Human Reproduction and Embryology azoospermia (Bebb et al., 1996; Handelsman et al., 1996; Meriggiola et al., 1996; Wu et al., 1999; Martin et al., 2000). A number of suggestions have been proposed to explain the heterogeneity in the contraceptive response to steroid treatments. These include differing sex hormone-binding globulin (SHBG) levels and responsiveness to gonadotrophin suppression (Behre et al., 1995; Wang et al., 1998), differing 5-alpha reductase activity in the testis and its impact on intra-testicular androgen levels (Anderson et al., 1996), structural differences in testicular morphology between ethnic groups (Zhengwei et al., 1998) and possible differences in sex steroid metabolism and/or diet (Santner et al., 1998). An additional explanation for the failure to induce complete azoospermia is that it may be necessary to inhibit PRL, in addition to the classical gonadotrophins, to fully block spermatogenesis. This is because PRL potentially acts in the testis to stimulate both androgenic and spermatogenic functions, based on studies in rodents (Hondo et al., 1995). In man the progonadal role of PRL is less clear. Early studies using I125-PRL failed to demonstrate PRL binding in the human testis, in contrast to the situation in the rat (Wahlstrom et al., 1983). More recently, mRNA for the PRL receptor has been 749 W.M.Hair, F.C.W.Wu and G.A.Lincoln characterized in the human testis (Kline et al., 1999), and immunocytochemistry has revealed that PRL receptors are weakly expressed in the Leydig cells in the interstitial tissue and more strongly expressed in germ cells undergoing spermatogenesis in the seminiferous tubules (Hair et al., 2002). Functional activation of these receptors and their secondary messenger systems JAK-STAT and the extracellular signal-regulated kinase (ERK) by PRL has also been demonstrated in human testis and vas deferens. Furthermore, there is clinical data indicating that PRL may promote spermatogenesis. In one study, treatment with exogenous PRL, or a dopamine antagonist to increase circulating PRL concentrations was shown to restore testicular function and fertility in hypoprolactinaemic infertile men (Ufearo and Orisakwe, 1995), and in another study, combined suppression of gonadotrophins and PRL in eugonadal men treated for prostatic carcinoma produced a more marked reduction in testicular weight than gonadotrophin suppression alone (Huhtaniemi et al., 1991). Based on these observations, and the demonstration that the administration of testosterone and oral progestin stimulates PRL secretion (Bellis and Wu, 1998), we infer that suppression of PRL may enhance the effectiveness of sex steroid in inducing spermatogenic suppression in man. The purpose of the present study was to test this hypothesis. Healthy male volunteers were treated orally with the non-ergot dopamine receptor agonist quinagolide (Q), to chronically suppress PRL secretion. This drug has been shown to inhibit PRL production with minimal effects on the gastrointestinal tract and on nausea, mood and sleep behaviours (Brownell et al., 1996). At the start of the treatment, the volunteers also received s.c. implants of testosterone to suppress gonadotrophin secretion. Implants were used rather than intermittent injections to provide a smooth androgen pro®le with less inconvenience to the subjects. A high and an intermediate dose of testosterone was selected to establish whether PRL inhibition would act in synergy with the degree of gonadotrophin suppression and perhaps allow use of a lower dose of (...truncated)