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Biomedical subjects

W J Bremner

Publications and source records attributed to W J Bremner.

At least 73 records · Page 4Linked to original sources
PubMed1991

The physiological significance of pulsatile LHRH secretion in man: gonadotrophin responses to physiological doses of pulsatile versus continuous LHRH administration.

This study tested whether pulsatile LHRH stimulation of the pituitary is required for normal gonadotrophin secretion in man. Four men with idiopathic hypogonadotrophic hypogonadism (IHH) and presumed endogenous LHRH deficiency were taken off all hormonal replacement for 5-6 weeks, then 5 micrograms LHRH was administered every 2 h for 1 week in order to prime pituitary gonadotrophin responsiveness. A physiological dose of LHRH (10 micrograms every 2 h) was then administered in both pulsatile and continuous regimens, in varying order, to each man. Pulsatile LHRH was capable of stimulating LH (as measured by bioassay) and FSH secretion, while continuous administration of LHRH was not. Serum LH, measured by RIA and bioassay, and FSH and free alpha-subunit levels, measured by RIA, increased significantly (P less than 0.05) over pretreatment levels during pulsatile LHRH administration. In contrast, bioactive LH and immunoactive FSH did not change significantly compared to pretreatment values during continuous infusion of the same total LHRH dose, although immunoactive LH and free alpha-subunit levels did increase significantly (P less than 0.05). The ratio of LH bioactivity to immunoactivity was significantly lower during the continuous compared to pulsatile LHRH regimen (P less than 0.001). Similar serum LHRH levels were achieved during pulsatile and continuous infusions. Serum testosterone and oestradiol levels did not increase significantly from pretreatment levels during either regimen of LHRH administration. It is concluded that a pulsatile LHRH signal pattern is essential for normal pituitary gonadotrophin secretion in men with IHH. Continuous infusion of a physiological dose of LHRH, which produced serum LHRH levels which were indistinguishable from those found during pulsatile administration, failed to stimulate FSH or bioactive LH secretion.

Clinical Protocols↗
PubMed1991

Prolactin secretion and corpus luteum function in women with luteal phase deficiency.

Luteal phase deficiency (LPD) as a clinical infertility problem is considered to have a heterogeneous etiology. Hyperprolactinemia has long been considered a causative factor of LPD. In this context we investigated PRL secretion in 18 women with LPD. All of the subjects were infertile with 2 out of phase (greater than 2 days) endometrial biopsies; 10 of the women also had daily blood samples, this latter subgroup had significantly decreased integrated luteal phase progesterone (P) levels compared to normal women with in-phase biopsies. PRL secretion was investigated as follows: 1) daily blood levels; 2) pulsatile secretion patterns in 3 cycle phase [early follicular (12 h); late follicular (12 h); midluteal (24 h)], 3) LH-PRL coupling, and 4) nocturnal patterns. Results were compared to findings in 36 normal women. The mean daily levels of PRL over the menstrual cycle were not different between the two groups (LPD, 12.1 +/- 1.5; normal, 13.8 +/- 0.8 microgram/L; P = 0.3). There was no correlation between luteal phase integrated P and PRL levels for either group. There was a small difference in the PRL pulse amplitude in the early follicular phase between the LPD and normal women (2.6 +/- 0.3 vs. 5.5 +/- 1.3 micrograms/L; P less than 0.05). There were no significant differences between groups in PRL pulse frequency or mean level during the 12 or 24 h in any cycle phase. There was an equivalent amount of LH-PRL pulse coupling in both groups in all three cycle phases. Diurnal and nocturnal PRL secretion was studied by breaking the 24 h data (midluteal) into day (0700-2300 h) and night (2300-0700) segments. Mean PRL levels were higher at night in both groups (LPD, 15.9 vs. 12.6; normal, 15.4 vs. 9.3 micrograms/L; P less than 0.05), as expected. There were no differences in nocturnal PRL secretory patterns between the two groups. In summary, we have serious reservations whether abnormalities in PRL secretion are a common or integral part of the pathophysiology of LPD. From previous work we know these subtle abnormalities in PRL secretion in LPD are associated with definite abnormalities in gonadotropin secretion. We believe these gonadotropin abnormalities are probably more significant in terms of decreased P secretion.

Adult↗
PubMed1991

The importance of signal pattern in the transmission of endocrine information: pituitary gonadotropin responses to continuous and pulsatile gonadotropin-releasing hormone.

We tested the hypothesis that pulsatile GnRH stimulation of the pituitary is required for normal gonadotropin secretion in humans. We administered GnRH in pulsatile and continuous regimens in varying order to each of five women with hypothalamic amenorrhea and presumed endogenous GnRH deficiency. Mean serum levels of GnRH were similar during the pulsatile and continuous regimens. All women ovulated during the pulsatile regimen (progesterone, greater than 31.8 nmol/L (10 ng/mL); none ovulated during the continuous regimen. Compared to pretreatment levels, FSH and estradiol, as measured by RIA, and LH, as measured by bioassay, increased significantly during the pulsatile GnRH regimen, but not during the continuous regimen. However, LH and alpha-subunit, as measured by RIA, increased significantly during both continuous and pulsatile GnRH administration. We conclude that a pulsatile pattern of GnRH is essential to normal functioning of the human female reproductive axis. Continuous administration of GnRH, producing mean serum levels of the peptide indistinguishable from those found during pulsatile administration, stimulates some rise in a nonbioactive form of radioimmunoassayable LH-like material and alpha-subunit, but does not stimulate bioactive LH, FSH, estradiol, or progesterone and does not lead to ovulation.

Adult↗
PubMed1991

Gonadotropin-releasing hormone antagonist plus testosterone: a potential male contraceptive.

No effective hormonal contraceptive has yet been devised for men. Through their suppressive effect on gonadotropin secretion, GnRH antagonists inhibit both testosterone (T) production and spermatogenesis in animals. Long term administration of an antagonist alone would result in androgen deficiency; this would cause unacceptable physiological and behavioral sequellae in men. Therefore, androgen replacement must be included in any GnRH antagonist regimen used in human male contraception. We tested the hypothesis that the combination of a GnRH antagonist plus T would suppress spermatogenesis in the male primate to azoospermic levels while maintaining normal serum T levels. We examined the effects of the GnRH antagonist Deterelix [N-Ac-DNal(2)1-DpCl-Phe2-DTrp3-DhArg(Et2)6 -DAla10-GnRH], alone and with simultaneous T replacement, on sperm production and serum T levels in adult male monkeys (n = 22). After 12 weeks of daily sc antagonist injection, all animals that received antagonist alone (n = 5) and those that 750 micrograms/kg.day antagonist plus T (n = 5) were azoospermic. After 16 weeks, four of five animals that received 250 micrograms/kg.day antagonist plus T became azoospermic. Control animals (n = 7) received daily injections of vehicle; sperm counts increased somewhat during the study period in that group. Castrate range T levels were achieved in animals receiving antagonist alone. T levels in the groups that received T supplementation and in the control group were in the normal male range throughout the treatment period. Sperm counts returned to the pretreatment range in all animals during the recovery period. We conclude that the combination of a GnRH antagonist plus T can induce azoospermia reversibly in this nonhuman primates species, and that a similar combination may be an effective contraceptive regimen in men. The GnRH antagonist alone may be an effective treatment for androgen-dependent neoplasia.

Animals↗
PubMed1990

The luteinizing hormone-releasing hormone pulse generator in men: abnormalities and clinical management.

Most men with hypogonadotropic eunuchoidism have absent luteinizing hormone and presumably absent luteinizing hormone-releasing hormone pulses. Pulsatile luteinizing hormone-releasing hormone therapy is effective in restoring normal gonadotropin secretion and testicular function and inducing fertility in men with hypogonadotropic eunuchoidism. Furthermore, pulsatile (versus continuous) luteinizing hormone-releasing stimulation of the pituitary gland is an absolute requirement for normal gonadotropin secretion. Men with idiopathic oligoazoospermia and selective elevation of follicle-stimulating hormone levels have slow luteinizing hormone and presumably luteinizing hormone-releasing pulse frequency. In these men, pulsatile luteinizing hormone--releasing treatment is effective in decreasing serum follicle-stimulating hormone levels, but it is unclear whether spermatogenesis and fertility are improved.

Eunuchism↗
PubMed1990

Sperm counts and reproductive hormones in male marathoners and lean controls.

In women, chronic and intense endurance exercise is frequently associated with menstrual cycle alterations. In men, the effects of similar amounts of exercise are less well-studied. We tested the hypothesis that endurance exercise in men is also associated with alterations in reproductive function. We studied 12 marathon runners and 12 age-matched, lean controls; serum and semen samples were collected every 2 weeks for 12 weeks. Sperm counts, sperm morphologies, and mean levels of testosterone (T), free T, sex hormone binding globulin, cortisol, follicle-stimulating hormone, and biologically active luteinizing hormone (LH) were similar in the two groups. Mean levels of immunologically active LH were somewhat higher in the marathoners. We conclude that this level of strenuous, long-term endurance exercise does not have major adverse effects on reproductive function in men.

Adult↗
PubMed1990

Serum inhibin levels during the periovulatory interval in normal women: relationships with sex steroid and gonadotrophin levels.

Inhibin is a gonadal glycoprotein believed to be important in the regulation of pituitary FSH secretion and/or to function as a paracrine factor within the ovary and testis. We studied serum levels of inhibin, oestradiol (E2), progesterone (P), FSH and LH during the periovulatory interval in order to determine whether there is differential control of sex steroid and inhibin secretion by the mature follicle and the emerging corpus luteum. Seven normal cyclic women were admitted 3-4 days prior to midcycle and blood samples drawn every 3 h for 5-7 days. Serum E2, P, FSH, LH and inhibin were measured by radioimmunoassay. Data were normalized around the peak LH value (0 h). Serum E2 and inhibin rose in parallel (r = 0.92, P less than 0.001) between -69 and -18 h, E2 reached a peak of 1296 +/- 154 (mean +/- SEM) pmol/l at -18 h, then fell to 1050 +/- 139 pmol/l at 0 h. Serum inhibin, on the other hand, continued to rise to a peak of 837 +/- 95 U/l at -6 h, fell to 455 +/- 48 U/l at +45 h, then rose again. On average, the peak inhibin level occurred 10.4 +/- 5.1 h after the peak E2 (P less than 0.05). Inhibin levels were positively correlated with both serum LH and FSH between -24 and +24 h (P less than 0.01). Serum E2 was negatively correlated with LH, FSH and inhibin between -24 and 0 h (P less than 0.01). Serum P levels increased from 1.8 +/- 0.3 nmol/l at -24 h to 14.3 +/- 1.0 nmol/l at +60 h. Serum inhibin was positively correlated with serum P from -24 to 0 h (P less than 0.01) and +45 to +60 h (P less than 0.01), but was inversely correlated from 0 to +45 h (P less than 0.01). We conclude that the maturing follicle secretes both E2 and inhibin in parallel until -18 h, at which time the process of luteinization is initiated by the onset of the midcycle LH surge, as evidenced by the rise in P. E2 secretion then falls while inhibin secretion rises, indicating different regulation of secretion of these two hormones by the maturing follicle. Furthermore, the close positive correlation between inhibin and gonadotrophin levels around midcycle suggests that FSH and/or LH stimulate inhibin secretion and that the presumed negative feedback effect of inhibin on FSH secretion is overcome at this time. After midcycle, inhibin secretion initially falls, then rises, while P rises progressively.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

The immunoreactive inhibin secretion pattern in the midluteal phase: relationships with luteinizing hormone and progesterone.

With the development of a sensitive radioimmunoassay for inhibin, luteal phase inhibin levels have been noted to parallel progesterone levels and be acutely dependent upon luteinizing hormone (LH) stimulation. To define the midluteal secretory pattern of immunoreactive inhibin and its relationships with LH and progesterone, blood samples were obtained from five normal women every 20 min for a period of 24 h. Individual data series of LH, progesterone and inhibin were analysed for pulsatile secretion using an adaptive-threshold method. Inhibin levels exhibited a relatively frequent, low-amplitude pulsatile secretory pattern (14.6 +/- 6.9 pulses/24 h (mean +/- SE), amplitude = 17% of the mean inhibin level). In contrast, LH levels demonstrated an infrequent high amplitude secretory pattern (6.2 +/- 0.7 pulses/24 h, amplitude = 139% of the mean LH level). The average progesterone pulse frequency and amplitude were intermediate to LH and inhibin (9.2 +/- 1.2 pulses/24 h, amplitude = 36% of the mean progesterone level). In addition, each individual's hormone data were analysed for coincident pulsatile secretion and cross-correlations were performed on the data, with one hormone pattern shifted relative to another by 20-min time intervals. None of the individual inhibin data series showed significant pulse coincidence when compared to the LH or progesterone data series. The cross-correlation analysis, however, revealed a significant (P less than 0.05) relationship in general trends between the inhibin and LH data series, and the inhibin and progesterone data series in three subjects.

Adult↗
PubMed1990

Serum inhibin concentrations before and during gonadotropin treatment in men with hypogonadotropic hypogonadism: physiological and clinical implications.

We measured by RIA the inhibin concentrations in the sera of 20 men with hypogonadotropic hypogonadism before and during treatment with gonadotropins in order to determine the role of gonadotropins in the control of inhibin secretion and the utility of the serum inhibin concentration in assessing the spermatogenic response to gonadotropin treatment in these patients. Before treatment the mean serum inhibin concentration in the 20 hypogonadotropic men as a group (391 +/- 49 U/L) was significantly lower (P less than 0.001) than that in 27 normal men (741 +/- 52 U/L). In the 7 men whose hypogonadism was of postpubertal onset, the mean serum inhibin concentration (559 +/- 69 U/L) was not significantly lower than that in normal men. In the 13 men whose hypogonadism was of prepubertal onset, the serum inhibin level was significantly lower [381 +/- 74 U/L (P less than 0.01) in the 7 without a history of cryptorchidism and 207 +/- 46 U/L (P less than 0.01) in the 6 with a history of cryptorchidism]. All 20 patients were azoospermic or severely oligospermic and had distinctly subnormal serum testosterone concentrations, even those whose serum inhibin values were normal. In the 7 patients with postpubertal hypogonadism, treatment with hCG alone for 6 months increased the serum testosterone concentration and maximum sperm count to normal, even though the previously normal inhibin concentration was not increased further. In the 13 patients with prepubertal hypogonadism, treatment with hCG alone increased the serum inhibin concentration, and combined treatment with hCG and human menopausal gonadotropin (hMG) increased inhibin further, to well within the normal range (742 +/- 143 U/L) in the patients without a history of cryptorchidism and to just within the normal range (487 +/- 96 U/L) in those with such a history. In the 7 patients with prepubertal hypogonadism but no history of cryptorchidism, treatment with hCG and hMG increased the maximum sperm count to normal in 5. In the 6 patients with prepubertal hypogonadism who did have a history of cryptorchidism, hCG and hMG treatment produced a normal sperm count in only 1. Of 12 patients whose serum inhibin level was more than 300 U/L before treatment, 11 developed a normal maximum sperm count in response to treatment, but of 8 patients whose inhibin concentration was less than 300 U/L before treatment, only 2 developed a normal sperm count in response to treatment (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

Hormonal responses to a potent gonadotropin hormone-releasing hormone antagonist in normal elderly men.

GnRH analogs, both agonists and antagonists, have potential use in androgen-dependent diseases of older men, such as prostatic cancer and benign prostatic hyperplasia. Previous experience with agonists of GnRH has suggested that GnRH analogs may be more effective in aged men than in young men, but little is known about GnRH antagonists in older men. Therefore, we evaluated the hormonal effects of a single dose and a short course of a GnRH antagonist (Nal-Glu) in normal elderly men. Six young men (25-34 yr old) and six older men (66-76 yr) each received single morning injections of Nal-Glu (25, 75, and 250 micrograms/kg), separated by 2 weeks. Serum levels of testosterone (T), immunoreactive LH (LH RIA) and FSH (FSH RIA), and bioactive LH (LH BIO) were evaluated periodically for 7 days after each injection. In addition, six elderly men received 25 and 75 micrograms/kg.day Nal-Glu for 10 consecutive mornings each, and serum levels of T, inhibin, LH RIA, LH BIO, FSH RIA, and bioactive FSH were evaluated. Nal-Glu in all three single doses caused a significant (P less than 0.01) decline in serum levels of T and gonadotropins that was similar in extent in the elderly and young men. For example, T declined to a level of 19% of baseline after the 250 micrograms/kg dose of Nal-Glu in both age groups. For both the young and elderly men, the major effect of increasing the Nal-Glu dose was a prolongation of the period of suppression. Multiple Nal-Glu injections in the elderly men also resulted in a rapid decline in T, inhibin, and bioactive and immunoreactive gonadotropins. For both LH and FSH, bioactivity decreased to a greater extent than immunoreactivity. Local side-effects of Nal-Glu tended to be fewer and of less intensity in the elderly men compared to those in the young men. These results demonstrate that the response to Nal-Glu in healthy elderly men is similar to that in younger men, and extended administration of Nal-Glu in elderly men effectively suppresses gonadal and pituitary function. These results suggest that the role of GnRH antagonists in the effective treatment of androgen-dependent disease in the aging male needs to be explored further.

Adult↗
PubMed1989

Endocrine control of human spermatogenesis.

We performed a series of studies in normal men to determine the relative roles of FSH and LH in the regulation of human spermatogenesis. Experimental gonadotropin deficiency was induced in normal men by administration of high-dosage testosterone (T) enanthate, resulting in suppression of spermatogenesis to severely oligospermic or azoospermic levels. In these gonadotropin deficient normal men, we found that selective replacement of either LH activity, with human chorionic gonadotropin (hCG) or hLH, or FSH activity with hFSH increased sperm counts into the 20-50 million/ml range, but quantitatively normal spermatogenesis was not achieved. To determine whether both LH and FSH together are required for quantitatively normal spermatogenesis, selective FSH deficiency was induced in normal men by administration of hCG. In the setting of high LH-like activity and markedly suppressed FSH levels induced by hCG, sperm production was partially suppressed again into the 20-50 million/ml range. Replacement of FSH activity, with either hFSH or human menopausal gonadotropin in hCG-treated normal men stimulated sperm production into the control range in all subjects. These studies demonstrate that neither normal serum levels of FSH or LH are required for qualitatively normal spermatogenesis in man, since sperm counts in the range of 20-50 million/ml are found in states of selective FSH or LH deficiency. However, normal levels of both FSH and LH are required to achieve quantitatively normal sperm production in man.

Chorionic Gonadotropin↗
PubMed1989

Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS.

The testicular paracrine factor PModS is produced by peritubular myoid cells under androgen control and modulates Sertoli cell function and differentiation. The observation that luteinizing hormone (LH) stimulates inhibin production in vivo, but has no effect on isolated Sertoli cells in vitro, suggested an indirect mode of LH action, potentially mediated by PModS. The effects of the testicular paracrine factor PModS and hormones on inhibin secretion by Sertoli cells were investigated to provide insight into the endocrine control of inhibin expression. An inhibin radioimmunoassay was utilized which showed essentially parallel displacement curves with purified bovine follicular fluid inhibin, Sertoli cell conditioned medium and concentrated Sertoli cell secreted proteins. An immunoblot analysis of Sertoli cell secreted proteins with the inhibin antisera consistently detected a 32 kDa protein which is the expected size of the mature of inhibin (alpha beta) and periodically detected a 57 kDa protein which is speculated to be an incomplete processed form of the inhibin precursor (alpha 43 beta). Follicle-stimulating hormone (FSH) was found to stimulate inhibin secretion initially between days 2 and 5 of Sertoli cell culture. Insulin and retinol alone had no significant effect on inhibin secretion; however, together they appeared to enhance the ability of FSH to stimulate inhibin secretion. Testosterone had no effect on inhibin production alone or in combination with other regulatory agents. PModS was found to stimulate inhibin secretion approximately 3-fold, but with a delayed time course of stimulation which did not occur until days 5-7 of Sertoli cell culture. Treatment with a combination of PModS and FSH resulted in an apparent maximal stimulation of inhibin secretion. Both forms of PModS, PModS (A) and PModS (B), were found to have equivalent biological activities in their ability to stimulate inhibin production with an apparent half-maximal effective concentration between 10 and 15 ng/ml. The current study provides evidence for the local testicular control of inhibin production and adds to the complexity of the endocrine control of inhibin expression. The cellular interaction is proposed in which LH acts on Leydig cells to stimulate androgen production which in turn acts on peritubular cells to regulate PModS production which subsequently can act on Sertoli cells to control inhibin production. Testicular control of inhibin production provides a potential short feedback loop for the local regulation of androgen production and an additional regulatory element for the pituitary-gonadal axis.

Animals↗
PubMed1989

Recombinant human activin-A stimulates basal FSH and GnRH-stimulated FSH and LH release in the adult male macaque, Macaca fascicularis.

Activin-A is a homodimer of the beta A inhibin subunit that stimulates FSH secretion by pituitary cells in vitro; however, the physiological relevance of this effect is unknown. We have examined whether recombinant human activin-A (activin-A; 80 micrograms/kg/day iv infusion for 50.5 h) has in vivo bioactivity in the adult male macaque (n = 5). Serum FSH and LH bioactivity and serum testosterone (T) levels were measured on 2 control days and after 24 and 48 h of activin-A administration. Basal FSH levels increased significantly (p less than 0.05) by 17% at 24 h and 82% at 48 h during activin-A administration. No changes in basal LH or T levels were seen. The FSH and LH responses to GnRH (5 micrograms/kg, iv bolus) increased significantly (p less than 0.05) by 117% and 55% after 48 h of activin-A, respectively. A small (16%), but statistically significant (p less than 0.05), increase in the T response to the GnRH challenge was also noted. These data are preliminary evidence in support of a physiological role for activin-A in the control of gonadotropin secretion in the male primate.

Activins↗
PubMed1989

Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary.

Testosterone (T) administration slows LH pulse frequency in man, presumably by an effect on the hypothalamic GnRH pulse generator, but it also may have a direct action on the pituitary. To determine if T does indeed affect gonadotropin secretion by acting directly on the pituitary, we studied the effect of T on GnRH-stimulated gonadotropin secretion. Six men with hypogonadotropic hypogonadism were treated with physiological doses of GnRH (5 micrograms every 2 h, sc by automatic infusion pump) for 6 weeks. Once their gonadotropin levels were normal, the men received a supraphysiological dosage of T enanthate (200 mg, im, weekly for 8 weeks) in addition to GnRH. They then received GnRH alone for a final 8-week period. Blood sampling was performed every 10 min for 8 h at the end of each of the three study periods. T administration suppressed the mean serum LH level to about 50% of the value during GnRH alone [18 +/- 2 (+/- SE) vs. 37 +/- 2 micrograms/L; P less than 0.05] and suppressed the mean serum FSH level to about 30% of the value during GnRH alone (39 +/- 6 vs. 128 +/- 28 micrograms/L; P less than 0.05). Eight weeks after stopping T, while continuing GnRH alone, serum LH and FSH levels were similar to those at the end of the first period of GnRH administration. The mean LH response to GnRH was reduced during T administration (17 +/- 3 micrograms/L) compared to that during the initial period of GnRH alone (31 +/- 4 micrograms/L; P less than 0.05). Serum T and estradiol levels were in the low normal range after GnRH alone before T administration (11 +/- 2 nmol/L and 105 +/- 17 pmol/L, respectively) and increased to just above the normal adult ranges after 8 weeks of T administration (36 +/- 5 nmol/L and 264 +/- 49 pmol/L, respectively). These results demonstrate that T and/or its metabolites inhibit LH and FSH secretion by a GnRH-independent mechanism, probably directly on the pituitary gland, in man.

Adult↗
PubMed1989

The importance of luteinizing hormone in the control of inhibin and progesterone secretion by the human corpus luteum.

Serum inhibin levels rise markedly during the luteal phase of the human menstrual cycle and are closely correlated with serum progesterone (P) levels, suggesting that the corpus luteum (CL) secretes inhibin. While FSH is the major regulator of inhibin secretion by the granulosa cells, the control of CL inhibin secretion is unclear. We hypothesized that, like P, CL inhibin secretion would be LH dependent. To examine this possibility, normal women were given the GnRH antagonist [Ac-D2Nal1, D4CL Phe2, D3Pal3, Arg5, DGlu6 (AA), DAla10]GnRH (Nal-Glu antagonist) for 3 consecutive days commencing on day 6-8 of the luteal phase. The daily doses were 2.5 (n = 3), 10 (n = 4), and 25 micrograms/kg (n = 5), sc. Serum LH levels fell 2 h after injection, and the fall was maximal (70-74%) at 6 h; the degree of suppression was not dose dependent. The duration of suppression was dose related, being less than 12 h, between 12, and 24 h, and more than 24 h for the 2.5, 10, and 25 micrograms/kg doses, respectively. Serum FSH levels declined by 22-43%, but the effect was not dose related. Serum P levels fell by 42-45% 8 h after each dose of antagonist. They returned to baseline 24 h after the 2.5 micrograms/kg dose, but after both the 10 and 25 micrograms/kg doses serum P levels continued to fall, and menstrual bleeding commenced within 48-72 h after the first antagonist injection. Serum inhibin levels were not altered relative to normal cycles by the 2.5 micrograms/kg dose, but fell by 48% and 58%, and 62% and 73% respectively, 48 and 72 h after the 10 and 25 micrograms/kg doses, respectively. Serum P and inhibin levels correlated closely in all women. To examine the relative roles of FSH and LH in the control of CL function, Nal-Glu antagonist (25 micrograms/kg, sc) was administered at 0 and 24 h commencing on day 6-8 of the luteal phase, in combination with either human menopausal gonadotropin (hMG; 150 IU, im, every 12 h) or hCG (1500 IU, im, once), both commencing at 0 h. hMG administration led to a rapid (by 2 h) and marked (3- to 9-fold) rise in serum FSH levels, whereas serum LH remained low, similar to antagonist alone treatment cycless.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

A comparison of the suppressive effects of testosterone and a potent new gonadotropin-releasing hormone antagonist on gonadotropin and inhibin levels in normal men.

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.

Adult↗