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Biomedical subjects

S Bhasin

Publications and source records attributed to S Bhasin.

At least 109 records · Page 6Linked to original sources
PubMed1986

Hormonal effects of ketoconazole in vivo in the male rat: mechanism of action.

Ketoconazole, an antifungal agent, has been shown to lower serum testosterone (T) in man. Measurements of circulating precursors of T suggest that ketoconazole may inhibit 17,20-desmolase activity in the testis. To further elucidate its mechanism of action in vivo, we studied its effects on the pituitary-gonadal axis in the male rate. Two groups of normal male Sprague-Dawley rats were treated with either oil or 25 mg ketoconazole in oil by im injection every 8 h for 21 days. Serum ketoconazole concentrations in the rat 2 h after the 25-mg dose were similar to those after oral administration of a much lower (1/33rd) dose to man. Ketoconazole treatment led to 50% suppression of serum T and prostate and seminal vesicle weights. Testis weights were not significantly affected. Intratesticular T concentrations showed a 50% decrease below the control level. Testicular 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase activities in the ketoconazole-treated animals were significantly decreased in proportion to the decreases in serum and intratesticular T concentrations. Elevations of serum LH and FSH concentrations in the ketoconazole-treated rats were not proportionate to the decline in serum T concentration. Therefore, to exclude an additional inhibitory effect of ketoconazole at the pituitary level, we treated two groups of castrated male Sprague-Dawley rats with the same dose of ketoconazole or oil for 3 days. Serum LH and FSH concentrations were not significantly different in the two groups. In separate experiments, combined treatment of intact rats with GnRH agonist and ketoconazole for 21 days led to lower mean serum T concentrations and accessory organ weights than those achieved with either agent alone. We conclude that ketoconazole inhibits T synthesis, primarily by inhibiting the activity of multiple enzymes in the T biosynthetic pathway and has no direct effect at the pituitary level; ketoconazole metabolism in the rat is considerably different from that in man; and ketoconazole enhances the inhibitory effects of GnRH agonist.

Aldehyde-Lyases↗
PubMed1986

Gonadotropin releasing hormone (GnRH) agonists in male contraception.

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.

Contraceptive Agents, Male↗
PubMed1985

Does constant infusion of gonadotropin-releasing hormone agonist lead to greater suppression of gonadal function in man than its intermittent administration?

Constant infusion of gonadotropin-releasing hormone agonist (GnRH-A) in the rhesus monkey leads to far greater suppression of spermatogenesis than its intermittent administration. To assess whether administration of GnRH-A by constant subcutaneous infusion will also lead to greater inhibition of gonadal function, we administered either 20 or 200 micrograms of D(Nal2)6GnRH (GnRH-A) to two groups of normal male volunteers, either by a single daily injection or constant subcutaneous infusion through a portable infusion pump, for 28 days. Basal and integrated luteinizing hormone (LH), follicle-stimulating hormone, and testosterone (T) responses were not significantly different between the two methods of GnRH-A administration at either the 20- or 200-microgram dose, even though subjects in the constant infusion group showed more consistent inhibition of basal and 24-hour integrated T concentrations. Significant decline in serum T in both groups occurred in the face of little or no decline in serum LH. It is concluded that the effects of constant infusion of GnRH-A in man are not as striking as those reported in the rhesus monkey and that the antigonadal effects of GnRH-A in man are complex and cannot be explained on the basis of down-regulation of pituitary gonadotropin secretion alone--additional mechanisms may be operative.

Dose-Response Relationship, Drug↗
PubMed1985

Hormonal effects of GnRH agonist in the human male: an approach to male contraception using combined androgen and GnRH agonist treatment.

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.

Animals↗
PubMed1985

Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III. Effects of long term combined treatment with GnRH agonist and androgen.

Chronic treatment with agonist analogs of GnRH results in reversible oligospermia in man, but leads to impotence and decreased libido due to a concomitant fall in serum testosterone (T) concentrations. We, therefore, assessed the effects of combined treatment with a potent GnRH agonist and T on gonadotropins and spermatogenesis in normal men, anticipating that addition of androgen would prevent agonist-induced changes in libido. Seven normal men were treated with 200 micrograms of the GnRH agonist D-(Nal2)6GnRH (GnRH-A), sc, daily for 16 weeks. In addition, 200 mg T enanthate were administered every 2 weeks for the entire 16-week treatment period. Basal LH, FSH, and T concentrations were measured every week during a 5-week control period, daily on treatment days 0, 1-10, 14, 18, 22, 26, and 28, every week thereafter until day 56, and every 2 weeks thereafter for the remainder of the treatment and recovery phases. Detailed analysis of LH and FSH over the 24-h period was performed by multiple blood sampling on days 0, 1, 10, 28, 56, 84, and 112. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. The mean sperm count declined by 83%, to a nadir of 16.6 +/- 6.2 (+/- SEM) million/ml. One subject had no significant decrease in sperm count. Azoospermia was not achieved in any subject. Basal serum LH concentrations, after an early phase of stimulation, declined to near baseline by day 14. However, basal, 24-h integrated serum LH concentrations, and 24-h urinary LH excretion were not significantly lowered by combined treatment. Bioassayable serum LH concentrations, however, declined significantly from 20.4 +/- 6.3 to 4.5 +/- 0.5 mIU/ml, and the bioassayable to immunoassayable LH ratio decreased from 2.1 +/- 1.0 to 0.7 +/- 0.1 after 16 weeks of GnRH-A treatment. Basal and 24-h integrated FSH concentrations, after an initial period of stimulation, declined progressively to baseline by days 5-6 and were significantly below baseline by day 112. Serum T concentrations did not fall into the hypogonadal (less than 250 ng/dl) range in any subject at any time during the treatment period. After discontinuation of treatment, LH, FSH, and sperm counts returned to normal in all subjects. Thus, single daily injection of GnRH-A and T failed to predictably induce azoospermia in normal men over the 16-week treatment period.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1985

Hypothalamic hypogonadism.

The reproductive system consists of a series of feedback loops involving the higher centers, the hypothalamus, the pituitary, and the gonads. The factors involved in physiologic restraint of the hypothalamic pituitary gonadal axis until the time of puberty are complex. The pattern (frequency and amplitude) of GnRH signal is important in regulating pituitary LH and FSH secretion. This signal can be amplified and modulated at the pituitary level at least in part by the sex steroids. Hypothalamic hypogonadism can be considered a disorder of the hypothalamic GnRH pulse generator that results in deficient or dysrhythmic GnRH release. The mechanisms underlying the abnormal GnRH release in acquired, functional disorders such as anorexia nervosa and amenorrhea of joggers remain controversial. Evaluation of patients with hypothalamic hypogonadism involves exclusion of hyperprolactinemia, space-occupying lesions, and other systemic disorders. The pulsatile administration of GnRH for induction of fertility represents a major advance in the treatment of these patients.

Adipose Tissue↗
PubMed1984

Testicular GnRH-like factors: characterization of biologic activity.

Observations that gonadotropin releasing hormone and its agonists directly inhibit gonadal function by binding to receptors on the Leydig cells had led to search for testicular GnRH-like peptide(s). This communication presents evidence that GnRH-like factors isolated from rat testis by immunoaffinity chromatography and previously characterized by radioimmunoassay and radioreceptor assay possess biologic activity. The partially purified material led to dose dependent inhibition of oLH stimulated testosterone production in a mixed Sertoli-Leydig cell monolayer culture. Pre-incubation of the cells with a potent GnRH antagonist prevented the inhibitory effects of the partially purified material suggesting that inhibition of oLH stimulated testosterone production may be receptor mediated.

Animals↗
PubMed1984

Somatostatin-14 and -28 in the male rat reproductive system.

Somatostatin-14 (SRIF-14) has been shown to occur throughout the male rat reproductive system by SRIF radioimmunoassay, Sephadex G-50 exclusion chromatography, and parallel line analysis. SRIF-28 was found only in the epididymis. The highest concentrations of total SRIF-like immunoreactivity (SLI), representing the combined concentrations of SRIF-14 and SRIF-28, were measured in the prostates of 1 1/2- and 3-month-old Sprague-Dawley rats. The levels of SLI in prostates from 9-month-old males were about 10% that of the younger animals. Dilution curves for extracts of all reproductive tissues were parallel with synthetic SRIF-14.

Animals↗
PubMed1984

Hormonal effects of GnRH agonist in the human male: II. Testosterone enhances gonadotrophin suppression induced by GnRH agonist.

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)

Adolescent↗
PubMed1984

Hormonal control of prostatic thyrotropin-releasing hormone (TRH) testosterone modulates prostatic TRH concentrations.

The presence of extremely high concentrations of authentic TRH in the rat prostate prompted us to examine whether prostatic TRH concentrations were under hormonal control. Both the immunoreactive TRH content per prostate and TRH immunoreactivity expressed per 100 mg prostatic protein were lower in animals 2 weeks after hypophysectomy than in sham-operated and calorically restricted weight-matched controls. Since many of the prostatic functions are testosterone dependent, we assessed the possibility that testosterone modulated prostatic TRH concentrations. We measured prostatic TRH concentrations in the following four groups of sexually mature male Sprague-Dawley rats: group I, sham operated; group II, castrated; group III, castrated animals with 5-mm Silastic testosterone implants; and group IV, castrated animals with 20-mm testosterone implants. Prostatic TRH concentrations in these four groups 2 weeks after surgery were 600.5 +/- 33.3, 65.1 +/- 22.6, 169.4 +/- 55.3, and 609.5 +/- 144.3 (+/-SE) ng/100 mg protein. There was good linear correlation between prostatic TRH concentrations and serum testosterone concentrations (r = 0.65; P less than 0.01). By subjecting the pooled prostatic extracts from each group to ion exchange chromatography on a SP-Sephadex C-25 column and measuring the proportion of immunoreactivity coeluting with authentic TRH, it was shown that the fall in prostatic TRH immunoreactivity after castration and hypophysectomy was indeed due to a loss of authentic TRH. We conclude that the prostatic TRH concentrations are under hormonal control and appear to be modulated by serum testosterone concentrations. This is the first demonstration of hormonal regulation of a neuropeptide in a mammalian extrahypothalamic site and suggests a physiological role for this neuropeptide at this site.

Animals↗
PubMed1984

The stimulatory and down-regulatory effects of a gonadotropin-releasing hormone agonist in man.

Synthetic long-acting agonistic analogs of GnRH both stimulate and paradoxically inhibit gonadotropin secretion in male animals and humans. To characterize the stimulatory and down-regulatory effects of such a superactive GnRH analog in man, either 10 or 100 micrograms D-( Nal2 ) 6GnRH were administered sc to two groups of seven normal men for 10 days. Serum LH, FSH, and testosterone were determined daily before analog injection and 1, 2, 4, 6, 8, 12, 16, and 24 h after analog injection on days 1 and 10. Both doses of analog led to initial increases in LH, FSH (peak, days 2-3), and testosterone (peak, days 3-4), but by day 10 of analog administration, serum levels of LH, FSH, and testosterone returned to pretreatment levels. The integrated 24-h responses above baseline of serum LH and FSH to both doses of GnRH analog were significantly decreased on day 10 compared to day 1 (P less than 0.05). The integrated 24-h responses of serum testosterone to both doses of agonist were not significantly decreased on day 10 of agonist treatment compared to those on day 1 (P greater than 0.2). Integrated serum testosterone responses above baseline in response to 3000 IU hCG administered 2 weeks before analog treatment and 24 h after the last analog injection were not different (P greater than 0.2). GnRH agonist treatment resulted in proportionate stimulation of LH, FSH, and testosterone consistent with a predominant pituitary effect of the analog at these doses given for 10 days. The stimulatory effects of daily GnRH agonist treatment in men are transient with some down-regulatory effects evident after 10 days of treatment.

Adult↗
PubMed1983

Effect of GnRH superactive analogs (alone and combined with androgen) on testicular function in man and experimental animals.

GnRH long acting agonists, when given chronically, are potent inhibitors of testicular function in both man and experimental animals. Administration of these agents to male rats and to men results in suppression of testosterone secretion and diminished sperm counts. Despite the similarity of these observations the mechanisms by which these agents effect the testes appear to be different in the two species. In man GnRH analogs have an early stimulatory effect on LH and FSH secretion with down regulation evident by the 10th day of daily treatment. Longer treatment results in suppressed LH, FSH and testosterone levels. In the rat the stimulatory phase of GnRH analogs on LH and FSH secretion persisted for a much longer period of time (20-60 days). In the rat, direct testicular effects of analogue were the most likely cause of early suppression of testosterone and impaired sperm production. In both species combined testosterone and GnRH analog had additive effects on gonadotropin hormone suppression; combined therapy is being tested as a male contraceptive regimen.

Animals↗
PubMed1983

Partial isolation and characterization of testicular GnRH-like factors.

We report here partial isolation and characterization of at least two GnRH-receptor binding factors from the ethanol: chloroform: acetic acid (ECA) extracts of rat testis. The displacement curve of defatted, steroid-free and desalted ECA extract was parallel to that of D-(leu)6-des (Gly)10-GnRH-EA in a GnRH-radioreceptor assay. Immunoaffinity chromatography on cyanogen bromide-activated Sepharose 4B beads covalently bound to an antibody raised against d-(lys)6-GnRH resulted in more than a hundredfold increase in receptor binding specific activity. Equivalent amounts of kidney extract after affinity chromatography showed no significant activity. Coincubation of the material purified by affinity chromatography with the labeled ligand did not result in significant peptidase degradation of the label, indicating that apparent displacement of the label in the receptor assay was not the result of cleavage of the ligand. HPLC of the material partially purified by affinity chromatography on a reverse phase 5 micron ODS column revealed two peaks of receptor binding activity. Preliminary estimates of molecular weights of these factors based on SDS-PAGE and gel filtration are 68,000 and 6,000 respectively. We conclude that there are at least two factors in rat testis with GnRH-receptor-binding properties that are chemically distinct from the native decapeptide.

Animals↗
PubMed1982

Fetal fuels. V. Ketone bodies inhibit pyrimidine biosynthesis in fetal rat brain.

Ketonemic states complicating late pregnancy are accompanied by lower brain weights in the newborn. Potential mechanisms whereby ketone bodies might inhibit cell proliferation were therefore examined in the fetal rat brain slice by measuring their impact on the de novo pathway for pyrimidine biosynthesis. DL-beta-hydroxybutyrate (10.8 mM) and acetoacetate (5.4 mM) were both found to diminish the incorporation of NaH14CO3 into [14C]UMP by 30%. This effect was similar in fetal tissues from fed and 48-h starved mothers. Graded concentrations of DL-beta-hydroxybutyrate (1.4-43.2 mM) resulted in a progressive inhibition that could not be explained either by isotope dilution consequent to ketone body oxidation or by a generalized inhibition of protein synthesis. The inhibition was not reversed with 10 mM glutamine, the principal nitrogen substrate for de novo biosynthesis of pyrimidines. When the conversion of orotic acid into UMP was blocked with 6-azauridine, DL-beta-hydroxybutyrate (10.8 mM) inhibited the incorporation of NaH14CO3 into orotic acid by 28%. By contrast, maximally inhibitory concentrations of this ketone body (43.2 mM) had no effect on the incorporation of [6-14C]orotic acid into [14C]UMP. Is is concluded that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal brain slices and that they do so at a site proximal to orotic acid formation.

Animals↗
PubMed1981

Sudden death associated with thyroid hormone abuse.

Three patients with hyperthyroidism due to deliberate intake of excessive amounts of L-thyroxine are described wherein death was "instantaneous" and presumably due to ventricular fibrillation. Hyperthyroidism was not recognized on admission in two of these patients because of atypical presentations. Autopsy was performed in two patients. In one patient no coronary disease was present and focal myocarditis with leukocytic infiltration was noted. The second patient had an acute posterior myocardial infarction due to acute coronary thrombosis, but focal areas of leukocytic infiltration and fibrosis were also seen in the anterior wall not involved in the process of infarction. Factitious hyperthyroidism due to L-thyroxine abuse can be associated with sudden death in the absence of coronary artery disease and may be related to a drug induced myocarditis.

Adult↗