lhrh--n-ac-2-nal(1)-4-cl-phe(2)-trp(3)-hci(6)-alanh2(10)- and testosterone-enanthate

To test the hypothesis that over a 4-week treatment period, Nal-Glu GnRH antagonist ([AcD2Nal1, D4ClPhe2, D3Pal3, Arg5, DGlu6 [AA], DAla10] GnRH) at a dose of 200 micrograms/kg per day SC would suppress levels of immunologically active and biologically active LH and FSH more completely than a dose of 100 micrograms/kg per day.. Placebo controlled clinical study.. A university community.. Thirty normal male volunteers.. We administered Nal-Glu at doses of 0, 100, and 200 micrograms/kg body weight per day in combination with T enanthate, 50 mg IM weekly, to separate groups of men (9 or 10 men per group) for 4 weeks.. Serum levels of immunologically active and biologically active gonadotropins were suppressed similarly in both groups of men who received Nal-Glu; this suppression was significantly greater than in the men who received placebo + T. Local side effects were more severe in the Nal-Glu 200 micrograms/kg per day group.. Administration of Nal-Glu in combination with T suppresses gonadotropins more completely than does T alone, but at doses > 100 micrograms/kg, gonadotropins are not suppressed additionally with larger doses of Nal-Glu. Subjects experienced greater local discomfort and side effects with the higher dosage. These findings suggest that dosages of Nal-Glu of > 100 micrograms/kg per day may have no advantage over the 100-micrograms/kg dose in a male contraceptive regimen.

Topics: Adult; Biological Assay; Dose-Response Relationship, Drug; Drug Synergism; Fluoroimmunoassay; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Luteinizing Hormone; Male; Radioimmunoassay; Testosterone

Efforts to develop a hormonal contraceptive regimen for men have focused on administration of testosterone (T), alone or together with other agents. Previous regimens have successfully induced azoospermia in only 50-70% of subjects, however. GnRH antagonists, alone or in combination with T, have been shown to induce azoospermia in a very high percentage of nonhuman primates. We tested the hypothesis that the addition of a GnRH antagonist to a high-dose T regimen would lead to a higher percentage of men developing azoospermia than would T alone. We administered the GnRH antagonist, Nal-Glu (100 micrograms/kg.day sc), plus T enanthate, 200 mg im weekly or placebo sc injections daily plus T enanthate, 200 mg im weekly, to separate groups of healthy men for 16-20 weeks. Seven of 10 men who received Nal-Glu plus T and 6 of 9 men who received T alone became azoospermic; gonadotropin levels were suppressed and T levels were increased similarly in both groups. There was a trend toward higher pretreatment gonadotropin levels and lower sperm counts in men who became azoospermic. Weight gain, development of acne, and increases in hematocrit and hemoglobin were similar in the two groups. In the majority of the men, sperm counts returned to the baseline levels within 4-5 months after treatment ended. We conclude that with the dosages of Nal-Glu and T we used in this study, the addition of GnRH antagonist to a high-dose T regimen does not increase the ability of T to suppress spermatogenesis in healthy men. Use of a higher dose of Nal-Glu, a lower dose of T, delaying the start of T replacement until several weeks after Nal-Glu injections are initiated, or prolonged hormonal administration might lead to a combination regimen that will suppress spermatogenesis more fully than does T alone.

Topics: Adult; Analysis of Variance; Contraceptive Agents, Male; Drug Combinations; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Luteinizing Hormone; Male; Oligospermia; Sperm Count; Spermatogenesis; Testosterone; Time Factors; Weight Gain

The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropins and spermatogenesis were examined to assess its potential as a male contraceptive regimen. The potent Nal-Glu GnRH antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5, D4-p-methoxybenzoyl-2-amino butyric acid6,D-Ala10]GnRH) was administered daily (7.5 mg, sc) to eight normal men for 16 weeks. T enanthate was given im starting at week 2 and every 2 weeks thereafter through week 14 of the treatment phase. Serum LH, FSH, T, and estradiol concentrations were measured frequently during the 5-week control period, the 16-week treatment phase, and the 14-week recovery phase. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. Seven of eight subjects became azoospermic by 6-10 weeks of treatment; the eighth subject, who failed to achieve azoospermia, suppressed his sperm count to 7 million/mL by week 14 (from a mean baseline of 42 million/mL) before treatment was prematurely terminated because of localized swelling at each of his injection sites. Sperm counts returned to baseline 10-14 weeks after the end of Nal-Glu administration. Seven of the eight subjects showed suppression of LH to the limit of assay detection (less than 0.2 U/L), whereas the eighth subject showed incomplete suppression. Serum bioactive and immunoreactive LH concentrations showed concordant responses. Mean serum FSH concentrations were also markedly suppressed. Serum T and estradiol concentrations declined dramatically during the first 2 weeks of Nal-Glu GnRH treatment, but returned to the normal physiological range after T enanthate replacement was initiated. Libido and sexual potency were maintained. No systemic side-effects, other than erythema and induration at injection sites, were observed. These data demonstrate that combined GnRH antagonist plus T treatment can predictably and reversibly induce azoospermia in most men and has potential as a male contraceptive regimen.. This study examined the hypothesis that a gonadotropin-releasing hormone (GnRH) antagonist, given at a dose that will suppress gonadotropin secretion and combined with a replacement dose of androgen, will induce reversible azoospermia in normal men while maintaining sexual function. About 8 normal men aged 24-48 years participated in the study. Sperm concentration in all 8 subjects decreased during the treatment; 7 became azoospermic by 6-10 weeks of treatment. In the 8th subject, who failed to achieve azoospermia, the sperm count declined to 7 million/ml by week 14, when treatment was prematurely terminated because of localized inflammation and induration at each of the injection sites. Sperm count returned to baseline following the end of Nal-Glu administration. No statistically significant change was observed in the sperm function during the oligospermic phase of treatment from baseline. 7 subjects showed suppression of luteinizing hormone, while the 8th experienced edema and discomfort at the injection sites. Mean serum follicle stimulating hormone concentrations were suppressed. Serum testosterone and estradiol concentrations declined during the treatment but returned to normal following T enanthate replacement initiation. Main side effects of Nal-Glu GnRh treatment were local erythema and induration at the injection sites due to local histamine release. In conclusion, the combined GnHR antagonist and T treatment can induce azoospermia in most men and has potential as a male contraceptive regimen.

Topics: Adult; Contraceptive Agents, Male; Gonadotropin-Releasing Hormone; Hormones; Humans; Male; Middle Aged; Oligospermia; Reference Values; Sexual Behavior; Sperm Count; Spermatozoa; Testosterone

GnRH antagonists have been developed in large part because of their potential use as contraceptive agents, particularly in men. Specifically, it was hoped that GnRH antagonists combined with testosterone (T) would be a more effective contraceptive regimen than T alone. We compared the suppressive effects of a potent GnRH antagonist, Na1-Glu [AcD2NaL1,D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),+ ++DAla10-GnRH], and of T together and separately on serum and urinary gonadotropin and serum inhibin levels in normal men. Ten-day courses of Nal-Glu (75 micrograms/kg; Nal-Glu alone), 200 mg testosterone enanthate, im, on days 0 and 7 (T alone), and the combination (Na1-Glu + T) were given to nine men. Serum gonadotropin and inhibin concentrations decreased after 1-2 days of Na1-Glu administration, while gonadotropin suppression occurred more slowly after T alone. Serum T fell to 30% of baseline values during Na1-Glu administration. The combination of Na1-Glu + T was more effective in suppressing serum LH, FSH, and inhibin than was either Na1-Glu alone or T alone. All hormone levels returned to baseline levels within 2.5 weeks after the end of the three regimens. We conclude that the Na1-Glu GnRH antagonist effectively inhibits gonadotropin, inhibin, and sex steroid secretion when given daily for 10 days and that the administration of Nal-Glu + T results in more complete gonadotropin and gonadal suppression than that produced by either agent given alone. These results encourage further investigation of the combination of a GnRH antagonist and T as a male contraceptive regimen and of the antagonist alone as a treatment for hormone-dependent neoplasia.

Topics: Adult; Contraceptive Agents, Male; Drug Administration Schedule; Estradiol; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Humans; Inhibins; Luteinizing Hormone; Male; Radioimmunoassay; Testosterone