Stimulatory therapy with either GnRH or gonadotropins is an effective treatment to induce spermatogenesis and achieve paternity in men with secondary hypogonadism. However, there is still uncertainty about the optimal treatment modality and schedule, the duration of treatment necessary and the influence of interfering factors such as maldescended testes. We have extended our previous series of men treated for secondary hypogonadism and now present our therapeutic experience with 42 cases. Twenty-one patients with hypothalamic disorders (11 with idiopathic hypogonadotropic hypogonadism (IHH) and 10 with Kallmann syndrome (KalS)) were treated with GnRH (group Ia) or human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) (group Ib), and 21 patients with hypopituitarism (group II) were treated with hCG/hMG. A total of 57 treatment courses were initiated for induction of spermatogenesis, 36 of these for the purpose of induction of pregnancy in the female partner. Bilateral testicular volumes doubled within 5-12 months of therapy. Spermatogenesis as evidenced by the appearance of sperm in the ejaculate was induced in 54/57 courses. Pregnancies occurred in 26/36 courses. Unilaterally maldescended testes did not preclude patients with IHH or KalS from gaining fertility under therapy and spermatogenesis could be successfully initiated even in some individuals with bilateral maldescended testes. In general there was a tendency for a longer duration of therapy until induction of spermatogenesis in patients with a history of bilateral cryptorchidism. However, this did not reach statistical significance. In patients with IHH or KalS treated with either hCG/hMG or GnRH there were no statistically significant differences in terms of duration to appearance of sperm or pregnancy rates. Even in KalS patients as old as 43 years spermatogenesis could be induced. In repeatedly treated patients stimulation of spermatogenesis tended to be faster while time until induction of pregnancy was significantly shorter in the second treatment course. In conclusion, GnRH or hCG/hMG are effective therapeutic modalities for patients with IHH or KalS. It remains to be determined whether highly purified urinary gonadotropin preparations or recombinant LH and FSH will provide therapeutic advantages.

Testosterone undecanoate is well tolerated by the patients. The injection intervals can be extended even beyond the 6-week periods chosen in the present study. Altogether, intramuscular testosterone undecanoate appears to be well suited for long-term substitution therapy in hypogonadism and hormonal male contraception.

We investigated in a pilot study the effect of testosterone suppression on lipoprotein metabolism, insulin, and leptin in 10 men who were treated either with cetrorelix, an antagonist of gonadotropin releasing hormone, or with placebo (P). Group C + C (n = 4) was treated with 10 mg cetrorelix as daily subcutaneous injections for five days and with a subsequent injection of 60 mg cetrorelix depot. Group C + P (n = 3) received 10 mg cetrorelix as daily intramuscular injections for five days and a subsequent injection of placebo depot. Group P + P (n = 3) received placebo both as daily and depot injections. Treatment with cetrorelix reversibly suppressed testosterone to castrate levels for three weeks in group C + C and for one week in group C + P. Compared to baseline, treatment with cetrorelix increased serum levels of apolipoprotein (apo) A-I, HDL subclass LpA-I, insulin, and leptin. In the group P + P, treatment with placebo was not associated with any change of these parameters. Compared to baseline and group P + P, treatment with cetrorelix in groups C + C and C + P did not lead to considerable or consistent changes in the plasma activities of lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), lipoprotein lipase, and hepatic lipase (HL). Only the pooled data of groups C + C and C + P unraveled small but statistically significant decreases of HL and CETP activities in response to cetrorelix. In conclusion, the small or absent effects of cetrorelix on LCAT, CETP, PLTP, LPL, and HL indicate that testosterone regulates HDL levels by other metabolic pathways. The increases of insulin and leptin in response to cetrorelix suggest that testosterone influences HDL metabolism also via obesity and insulin resistance. These effects, however, are rather in contrast to the HDL raising effect of suppressed testosterone.

Approaches to hormonal male contraception are predominantly based on injectable testosterone (T) application. As most users would prefer an injection-independent modality, this study was designed to develop a self-applicable hormonal male contraceptive regimen by combining transdermal T with an oral gestagen. Eleven healthy men (23-40 yr old) were treated with oral levonorgestrel and transdermal T for 24 weeks. T was applied daily as a transdermal patch to be worn on the trunk. Levonorgestrel was taken orally at a dose of 250 microg daily up to week 12, followed by 500 microg to week 24 in those volunteers who had not become azoospermic by that time. Within 24 weeks, 2 of 11 volunteers had become azoospermic, and 3 of 11 showed sperm concentrations below 3 million/mL. The sperm concentrations of the remaining volunteers declined, but failed to reach the limit considered compatible with contraception by WHO. Treatment resulted in suppression of LH, FSH, and sex hormone-binding globulin, whereby the volunteers with lower sperm concentrations showed more pronounced suppression than the others. Mean T concentrations remained within the lower limit of normal and on occasions were below this level. There were no complaints of hypoandrogenism. Although mean levels of low density lipoprotein cholesterol, apolipoprotein B, as well as basal and postprandial insulin increased, high density lipoprotein cholesterol and apolipoprotein A-I decreased during the treatment phase. Changes in lipid parameters were normalized within 3 weeks after cessation of medication. Although only 5 of 11 volunteers reached the target sperm counts (<3 million/mL), the study shows that a self-applicable hormonal male contraceptive could be developed.

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