nafarelin and testosterone-enanthate

Downregulation of anterior pituitary GnRH-receptors by application of a slow release GnRH-implant offers an effective and reversible alternative to surgical castration of the male dog. Aim of the present study was to test the efficacy and the underlying mechanisms of a new non-biodegradable controlled-release device implant (Gonazon((R)), Intervet, containing 18.5mg of the GnRH-agonist Azagly-Nafarelin). Eight male beagle dogs were implanted s.c. at the para-umbilical region. In four dogs implant removal was after 180 days (group 1), in the other four dogs after 365 days (group 2). Eleven weeks after implantation availability of LH was reduced (p<0.0001) by 70%. After an initial increase lasting for about 4 days, testosterone (T) and estradiol (E2) concentrations decreased (p<0.0001) to basal levels within 17.5+/-8.4 days. Size of testes was decreased by about 82% after 17 weeks, size of prostate by about 46% after 5 weeks (p<0.0001). Five to 7 weeks after implantation all dogs were aspermic. Testosterone and estradiol concentrations, together with testicular and prostatic size remained suppressed in all dogs in group 1 and one dog of group 2 until implant removal. The other three dogs of group 2 escaped from down-regulation between 223 and 324 days. Effects on the availability of LH, T, E2 and on testicular and prostatic size were fully reversible after implant removal or escape from down-regulation. In six dogs semen quality was back to pre-treatment values after about 29 weeks, however, one dog developed oligozoospermia while another one stayed azoospermic, probably due to an obstruction within the epididymal duct.

Topics: Animals; Dogs; Drug Implants; Estradiol; Luteinizing Hormone; Male; Nafarelin; Orchiectomy; Organ Size; Prostate; Semen; Sperm Count; Spermatogenesis; Testis; Testosterone; Time Factors

A potent gonadotropin releasing hormone (GnRH) agonist, D(Nal2)6 GnRH (Nafarelin) has been administered to two groups of normal men for 16 weeks by two routes in order to assess its effectiveness in suppressing spermatogenesis. In this report 400 micrograms of the GnRH agonist was given daily by constant subcutaneous infusion and the results compared to an earlier study in which 200 micrograms of the same agonist was given as a single daily subcutaneous injection. All subjects in both groups received an intramuscular injection of testosterone enanthate (200 mg) every two weeks to prevent symptoms of androgen deficiency. The higher dose infusion regimen was much more effective in suppressing spermatogenesis than the single daily injection. With infusion treatment, 3 of 7 subjects were azoospermic, a fourth subject had less than 1 million sperm per ml of semen and 5 of 7 subjects had sperm counts less than 5 million per ml. Because of the differences in GnRH dose it is unclear if the enhanced effect seen in the infusion group is the result of the route or dose of drug. Data from experimental animals and short term comparative studies with two routes and two doses suggest that both mechanisms may be operative. In either case, the results are the most promising to date and raise the possibility that constant delivery of a higher dosage of agonist could produce azoospermia in most or all subjects.

Topics: Contraceptive Agents, Male; Drug Combinations; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Nafarelin; Pituitary Hormone-Releasing Hormones; Spermatogenesis; Testosterone

Observations that hypophysectomized men demonstrate predictable azoospermia have led to attempts to suppress gonadotropin secretion with drugs for contraceptive purposes. Testosterone enanthate, given on a weekly or bimonthly basis, failed to predictably induce azoospermia in men. Treatment with agonist analogs of GnRH significantly suppressed spermatogenesis, but led to concomitant decline in serum testosterone concentrations. To prevent GnRH agonist induced changes in libido and potency we tested regimens employing daily subcutaneous injections of 200 micrograms of D(Nal2)6GnRH in combination with 200 mg testosterone enanthate every 2 weeks. This regiment led to 86% decline in mean sperm count over the 16-week treatment period, but azoospermia was not achieved in any subject. Basal or 24 h integrated serum LH or 24 h urinary LH concentrations were not significantly suppressed by combined treatment. In order to assess whether constant infusion of GnRH agonist will lead to greater suppression of gonadal function than its intermittent administration, we administered either 20 or 200 micrograms of D(Nal2)6GnRH to 2 groups of normal male volunteers for 28 days either by single daily injection or by constant subcutaneous infusion. Serum testosterone, LH and FSH responses were not significantly different between the two modes of agonist delivery either at 20 or 200 micrograms dose. Marked decrease in serum testosterone and sperm counts in these studies occurred in the face of little or no change in immunoreactive LH, indicating that the antigonadal actions of GnRH agonist in the human male cannot be fully explained on the basis of downregulation of pituitary LH secretion alone. GnRH agonist treatment however, led to marked decrease in bioassayable LH concentrations suggesting secretion of a molecularly altered LH species with diminished biologic activity.

Topics: Animals; Contraceptive Agents, Male; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Nafarelin; Rats; Rats, Inbred Strains; Sperm Count; Testosterone; Time Factors

Superactive analogues of gonadotrophin releasing hormone and testosterone, when administered together, synergistically inhibit gonadotrophin secretion and spermatogenesis in the rat. In order to determine whether testosterone also enhanced gonadotrophin suppression by GnRH agonist in the human male, two groups of four normal male volunteers first received either 10 or 100 micrograms of a GnRH agonist D(Nal2)6GnRH (GnRH-A) daily for 10 d. After at least a 50 d recovery period, the same subjects received a single injection of 200 mg of testosterone oenanthate (TE) on day 1 in addition to the same dose of GnRH-A daily for 10 d. Serum LH, FSH and testosterone (TS) concentrations were measured daily just prior to the next analogue dose, and on days 1 and 10 at 0, 1, 2, 4, 6, 8, 12, 16 and 24 h after the analogue injection. Daily administration of both 10 and 100 micrograms of GnRH-A alone resulted in an early phase of stimulation followed by progressive decline in LH, FSH and testosterone to levels below baseline by day 10 despite continued administration of GnRH-A. Addition of testosterone to 10 micrograms of GnRH-A resulted in hormonal responses identical to those seen with GnRH-A alone. Combined treatment of testosterone with 100 micrograms of GnRH-A did not blunt the peak LH and FSH responses on day 2, but resulted in significantly lower LH (mean integrated responses: 187 +/- 30 vs. 234 +/- 42 mIU-d/ml) and FSH (mean integrated responses: 20.6 +/- 3.3 vs. 32.8 +/- 4.2 mIU-d/ml) responses from days 3 to 11. By day 11, all subjects receiving combined treatment (GnRH-A 100 micrograms + testosterone oenanthate) had undetectable serum FSH levels. In contrast, serum FSH concentrations on day 11 after treatment with GnRH-A alone were 43.6 +/- 8.9% of control and none of the subjects had values below the limit of detection. Serum testosterone levels in the combined treatment group did not fall below baseline by day 10 in either the 10 (161.4 +/- 48%) or the 100 micrograms GnRH-A groups (104.6 +/- 11.2%), while in the group receiving GnRH-A alone, testosterone levels declined to 45.6 +/- 8.3% and 80 +/- 18.8% with the 10 and 100 micrograms dose respectively. We conclude that addition of a suppressive dose of testosterone to an appropriate dose of GnRN-A significantly enhances gonadotrophin suppression by GnRH-A in the human male.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Drug Synergism; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Nafarelin; Testosterone