Testosterone plus GnRH analogues

23.5.1 Testosterone plus GnRH agonists

In contrast to naturally occurring GnRH, GnRH agonists - after producing an initial stimulation of gonadotropin release for approximately two weeks - lead to GnRH receptor down-regulation and thereby to suppression of LH and FSH synthesis and secretion.

Between 1979 and 1992,12 trials for hormonal male contraception using GnRH agonists, mostly in combination with testosterone were published (for review Nieschlag et al. 1992). Altogether 106 volunteers participated in these trials. The GnRH agonists decapeptyl, buserelin and nafarelin were administered at daily doses of 5-500 |xg/volunteer for periods of 10-30 weeks. In about 30% of men, sperm production could be suppressed below 5 x 106/ml and azoospermia occurred in 21 men, while in the remaining volunteers, sperm numbers were only slightly reduced or remained unaffected. One explanation for the ineffectiveness of GnRH

agonist plus androgen is the escape of FSH suppression after several weeks of GnRH agonist treatment (Behre etal. 1992; Bhasin etal. 1994).

Altogether, GnRH agonists in combination with testosterone did not prove useful in male contraception. At times it has been suggested that higher doses of the GnRH agonists should be used, but currently no further clinical studies appear to be under way.

23.5.2 Testosterone plus GnRH antagonists

In contrast to GnRH agonists, GnRH antagonists produce a precipitous and prolonged fall of LH and FSH serum levels in men (e.g. Behre etal. 1994; Pavlou etal. 1989). It took much longer to develop GnRH antagonists that were suitable for clinical application than it did for GnRH agonists, and clinical trials using GnRH antagonists for male contraception started some 12 years later than those using agonists. To date, results have become available from five clinical trials using GnRH antagonists for male contraception (for review Nieschlagand Behre 1996; Swerdloff etal. 1998; Behre etal. 2001).

Overall, 35 of the 40 volunteers (88%) who took part in these studies became azoospermic, most within three months. This is a much better rate of complete suppression than that produced by the administration of testosterone enanthate alone. Although studies in monkeys had suggested that delayed testosterone administration would increase the effectiveness of GnRH antagonists (Weinbauer et al. 1987; 1989) - in men GnRH administration followed by delayed testosterone administration (azoospermia in 20/22 men) offered little advantage over concomitant GnRH and testosterone administration (azoospermia in 15/18 men). It should also be noted that, in the later studies with concomitant administration, all 14 volunteers became azoospermic (Behre et al. 2001; Pavlou et al. 1994). The major advantage of using GnRH antagonists is the short time required to achieve azoospermia, i.e., within 6-8 weeks, which is considerably shorter than the mean of 17 weeks that is required in Caucasian men when testosterone alone was used (WHO 1995).

These results are promising. However, the antagonists and regimen tested to date require daily injections which makes them unacceptable for contraceptive purposes. The development of depot formulations is therefore anticipated with great interest, but such development appears to be much more difficult than it had been for GnRH agonists. Furthermore, it could be argued that the high price of GnRH antagonists may preclude their development as male contraceptives which need to be affordable and in the same price range as comparable female methods. In order to shorten the period of use of GnRH antagonists, two studies have investigated the possibility of applying GnRH antagonists only in an initial suppression phase, and then continuing with the androgen alone (Swerdloff et al. 1998; Behre et al.

2001). Although successful in the monkey model (Weinbauer et al. 1994) studies in men produced contradicting results so that this approach requires further experimentation.

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