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D J Handelsman

Publications and source records attributed to D J Handelsman.

At least 127 records · Page 7Linked to original sources
PubMed1986

Mechanism of action of dopamine on the in vitro release of gonadotropin-releasing hormone.

Controversy exists on whether dopamine (DA) stimulates or inhibits GnRH secretion and whether its effects are mediated via alpha-adrenergic receptors or dopaminergic receptors. As a means to examine this conflict, we have utilized an in vitro superfusion system to study the effects of DA, norepinephrine (NE), phentolamine (alpha-antagonist), pimozide (DA antagonist), and two DA agonists (apomorphine and bromocryptine) on GnRH release from isolated mediobasal hypothalami from adult male rats. In this dynamic system, graded concentrations of both NE and DA (2.0 nM to 2.0 microM) led to a dose-dependent increase in GnRH output during the 10 min interval that followed each pulse dose of NE (P less than 0.02) or DA (P less than 0.05). The DA-induced GnRH release was reproducible, consistent, and significant over five successive pulses (20 microM) at 30-min intervals (P less than 0.02). Coinfusion of phentolamine (20 microM) prevented the DA (20 microM) induced release of GnRH (P less than 0.03), but pimozide (20 microM) had no significant effect on DA-induced GnRH release (P greater than 0.3). The two DA agonists, apomorphine and bromocryptine, at doses up to 2.0 microM and 200 nM, respectively, had no significant effect on GnRH release. To determine whether DA was causing a direct stimulation of alpha-adrenergic receptors or being enzymatically converted to NE which could then stimulate alpha-receptors to induce GnRH release, rats were injected with sodium diethyldithiocarbamate (DDC) (550 mg/kg BW) ip, 1 h before death. DDC blocks the enzymatic conversion of DA to NE, and this was reflected by a 37% decrease in hypothalamic NE efflux during the superfusion. However, pulses of DA, even in the presence of DDC, were associated with a marked dose-dependent increase in hypothalamic NE efflux, and DDC failed to prevent the subsequent stimulation of GnRH release. We conclude that the apparent DA-induced release of GnRH is most probably attributable to DA-induced release of hypothalamic NE which, in turn, acts through alpha-adrenergic receptors on peptidergic neurons to stimulate GnRH release.

Animals↗
PubMed1986

Mechanism of inhibition of human testicular steroidogenesis by oral ketoconazole.

To determine the antisteroidogenic effect of ketoconazole (KTZ) in the human testis, we measured the plasma delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, dehydroepiandrosterone (DHEA), progesterone, 17 alpha-hydroxyprogesterone, androstenedione (A), and testosterone (T) concentrations in three men with previously untreated metastatic prostate cancer at various time intervals for 24 h before and 48 h after the administration of 200 mg oral KTZ every 8 h. The adrenal glands of these three patients were suppressed (as measured by the plasma cortisol levels) by the administration of 1.0 mg dexamethasone daily for 7 days before and during the study. After six doses of KTZ, bilateral orchiectomy was performed, and the intratesticular concentration of the aforementioned seven steroids and the intratesticular activities of the 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase enzymes in the delta 4-steroidogenic pathway were determined. These seven intratesticular steroids and three intratesticular enzyme activities were compared to those in five men with previously untreated prostate cancer who underwent orchiectomy as primary treatment for their disease. Plasma A, DHEA, and T all significantly decreased during KTZ therapy. There was no significant change in the other four steroids in the plasma. In the testis, delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, and delta 4-17 alpha-hydroxyprogesterone were all significantly elevated, whereas intratesticular DHEA, A, and T were significantly decreased in the three KTZ-treated patients compared to levels in the five non-KTZ-treated patients. Measurement of the enzyme activities demonstrated a significant reduction in both 17 alpha-hydroxylase and 17,20-desmolase, but no change in 17 beta-hydroxysteroid dehydrogenase, in the KTZ-treated patients compared to the levels in the non-KTZ-treated patients. We conclude that oral KTZ decreases testicular T production by inhibiting the 17,20-desmolase and also the 17 alpha-hydroxylase steps in both the delta 4- and delta 5-T biosynthetic pathways.

Administration, Oral↗
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

Testicular function in experimental uremia.

A model for the study of testicular function in experimental uremia induced by subtotal nephrectomy in mature male rats is described. Glomerular filtration rate was reduced by 87%, resulting in stable uremia for up to 13 weeks with characteristic biochemical changes and reduction in weight of testes, prostate, seminal vesicles, and epididymis but not of heart, liver, spleen, or epididymal fat-pads in comparison with pair-fed and sham-operated, ad libitum-fed littermate controls. Basal serum LH, FSH, and testosterone were reduced and PRL levels increased in chronic uremic rats compared with pair-fed and sham-operated controls. Intratesticular and peripheral venous testosterone levels were reduced by 73-85%, whereas spermatic vein testosterone levels were reduced by 47% suggesting a reduction in blood flow to the uremic rat testis. Sensitivity of uremic Leydig cells to human CG stimulation was normal to increased both in vivo and in vitro without changes in LH receptor affinity or numbers. Fertility was markedly impaired in uremic rats but was restored to normal by either human CG or testosterone treatment. Spermatogenesis was minimally depressed after up to 3 months of uremia. These studies suggest that this experimental paradigm is a suitable model for studying the pathogenesis of early changes in uremic hypogonadism. The predominant early changes of uremic hypogonadism are due to central defects in regulation of pituitary LH secretion with consequent testicular and peripheral hypoandrogenism but initial preservation of spermatogenesis.

Animals↗
PubMed1985

Hypothalamic-pituitary function in experimental uremic hypogonadism.

In companion studies we have shown that chronic uremic male rats are infertile and hypoandrogenic and have lowered basal LH levels. Fertility was restored by either human CG (hCG) or testosterone treatment. Testicular steroidogenic responses to hCG in vivo and in vitro were normal or excessive, indicating that hypothalamic-pituitary dysfunction was the predominant early lesion in uremic hypogonadism. Further studies were undertaken to characterize the nature of the central defects in regulation of pituitary LH secretion. Uremic rats have reduced MCRs for rat LH (rLH) (61%), rat FSH (rFSH) (47%), and LHRH (41%). Pituitary gonadotropin and hypothalamic LHRH content were unchanged in uremic rats. Pituitary rLH and rFSH responses to LHRH stimulation in vivo and in vitro were quantitatively normal or excessive, with delayed peaks suggesting that uremic pituitary gonadotrope secretion is deficient due to lack of appropriate hypothalamic LHRH drive rather than intrinsic pituitary defects. Despite reduced pituitary gonadotropin secretion in intact uremic rats, castration induced paradoxical excessive increases in pituitary LHRH binding, serum rLH, and rFSH beyond those of nonuremic controls. Paradoxical postcastration hyperresponses of serum rLH and rFSH were not due to circulating immunoreactive fragments of gonadotropins or undernutrition. Dysfunction of the uremic hypothalamus was further characterized in vivo by lack of rLH responsiveness to naloxone and hypersensitivity to negative testicular feedback in castrate-steroid-replaced and intact rats. These data demonstrate that uremic hypogonadism is principally due to aberrant hypothalamic regulation of pituitary LH secretion resembling those of the immature rat or seasonally regressed animal. This recrudescence of the inactive regulatory state in a disease model suggests that common mechanisms are operative in orderly gonadal withdrawal under hostile or inappropriate environments and may underly the reversibility of human uremic hypogonadism with successful renal transplantation.

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

Identification of insulin-like growth factor-I and its receptors in the rat testis.

As part of a study of the testicular production and action of insulin-like growth factor-I (IGF-I), adult rat testes were extracted with acidified methanol, yielding an immunoreactive IGF-I fraction corresponding in size to human IGF-I. The mean IGF-I content (+/- SEM) of testes weighing approximately 1.1 g was 51.5 +/- 5.6 ng/testis, and was not due to serum contamination. After a 3-day fast testicular IGF-I decreased by 80%, whereas serum IGF-I levels declined by 90%. Testicular homogenates and isolated Leydig cells were shown to contain specific IGF-I receptors, Ka = 2 X 10(9) M-1, with 10% IGF-II cross-reactivity. The concentration of these receptors was 2 pmol binding sites per testis, or 3.3 fmol per 10(6) Leydig cells. However IGF-I at 250 ng/ml had no effect on basal or hCG-stimulated testosterone production by isolated Leydig cells, measured over 3 h. Although an effect of IGF-I over longer incubation periods cannot be excluded, it is also possible that testicular IGF-I has a mitogenic role, rather than acting on differentiated testicular functions.

Animals↗
PubMed1985

The effects of cyclooxygenase and lipoxygenase inhibitors on the collagen abnormalities of diabetic rats.

The importance of cyclooxygenase and lipoxygenase pathways in the determination of collagen abnormalities in diabetes was investigated. Pharmacological agents with antiprostaglandin activity, such as indomethacin, naproxen, and aspirin, were able to prevent the rise in thermal rupture time of tail collagen in diabetic rats. Paracetamol was without effect. The action of indomethacin on diabetic collagen was abolished by concurrent administration of sodium benoxaprofen, an inhibitor of lipoxygenase, to the diabetic rats. Collagen abnormalities in diabetes may be regulated by a balance of the cyclooxygenase and lipoxygenase pathways. Antiprostaglandin agents may have a role in the prevention of some diabetic complications.

Acetaminophen↗
PubMed1985

Psychological and attitudinal profiles in donors for artificial insemination.

Few objective data are available concerning the psychological profiles and attitudes of sperm donors in artificial insemination programs. We studied 30 consecutive new volunteers and 45 established sperm donors using the Cattell 16PF personality profile and an attitudinal survey concerning motives for donation, attitudes toward uses of sperm, desire for knowledge of outcomes, and attitudes toward disclosures of identifying and nonidentifying information between the parties to artificial insemination. Donors differed from the population norms in 7 of 16 first-order and 1 of 4 second-order personality factors, and this difference appeared to reflect their self-selection as donors. The predominant motive for donation was altruism, but secondary motives were also common. Financial motivation was very low in this population with few students. Donors approved of all current and most hypothetical uses of sperm but were not in favor of disclosures of information to other participants in the program. Restriction of disclosures to nonidentifying details was more acceptable. Unmarried donors were more often motivated for nonaltruistic reasons and were more in favor of disclosures. Attitudes of sperm donors were mostly stable over at least 3 years, but an increasing minority with time envisaged circumstances that might lead to their withdrawal from the program.

Attitude↗
PubMed1984

Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections.

We studied 29 men with Young's syndrome, a combination of obstructive azoospermia and chronic sinopulmonary infections. Men with this syndrome have only mildly impaired respiratory function and normal spermatogenesis; the azoospermia is due to obstruction of the epididymis by inspissated secretions. The diagnosis is based on the occurrence of chronic sinopulmonary infections, persistent azoospermia, normal spermatogenesis, and characteristic epididymal findings, as well as exclusion of cystic fibrosis and the immotile-cilia syndrome. The sperm themselves appear to be normal in Young's syndrome. Pregnancies had occurred in five couples; in three paternity was documented by genotyping. Thus, improved microsurgical and medical therapy might restore fertility. We suggest that Young's syndrome has a prevalence comparable to that of Klinefelter's syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia.

Adult↗
PubMed1984

The effects of aldose reductase inhibition on nerve sorbitol and myoinositol concentrations in diabetic and galactosemic rats.

The interrelationship between sorbitol excess and myoinositol deficiency in the peripheral nerve was examined in acutely diabetic rats. Nerve myoinositol concentration was also studied in galactosemic rats. Polyol pathway blockade with Sorbinil (Pfizer, Connecticut) prevented nerve myoinositol reduction in both groups of animals. This conclusion was independent of alteration in the fluid content of the peripheral nerve. It is likely that myoinositol loss from nerves is causally related to the sorbitol and galactitol accumulation.

Aldehyde Reductase↗
PubMed1984

Testicular function in potential sperm donors: normal ranges and the effects of smoking and varicocele.

Testicular exocrine (semen analysis) and endocrine (plasma LH, FSH, prolactin and testosterone) function was assessed in 119 consecutive healthy men presenting for screening as potential sperm donors. Since these volunteers were unbiased with respect to their fertility status, this sample of the general male population was suitable to determine normal ranges and the influence of a variety of physical (height, weight, standardized body weight, varicocele) and demographic (age, marital and fertility status, tobacco and alcohol consumption) factors on normal human testicular endocrine and exocrine function, without the confounding effects of bias in selection of subjects. The statistical distribution of all seminal parameters was non-gaussian, but cube-root transformation of the data normalized the distribution, allowing for parametric statistical analysis. The median (and 95% confidence limits) for the various semen parameters was 73.0 (10.6-235.3) million sperm per ml; 189.0 (12.6-868) million sperm per ejaculate; 50.4 (5.9-181.9) million motile sperm per ml; 133.0 (6.9-661.7) million motile sperm per ejaculate; 54.0 (7.0-172.9) million morphologically normal sperm per ml and 138.5 (7.5-672) million morphologically normal sperm per ejaculate. Testicular volume was correlated positively with measures of physique such as standardized body weight (r = 0.25, P less than 0.01) and body surface area (r = 0.30, P less than 0.002), and negatively with plasma levels of FSH (r = -0.31), P less than 0.002) but not LH. Sperm output was positively correlated with testicular volume (r = 0.28, P less than 0.005) and negatively correlated with plasma FSH (r = -0.31, P less than 0.002) and plasma LH (r = -0.31, P less than 0.002). Smoking was associated with a highly significant reduction in sperm output and motility. Men with varicocele (25%) were significantly taller, had slightly lower haemoglobin levels and moderate left (but not right) testicular atrophy, but neither seminal nor hormonal parameters were different from men without varicocele. There was no difference in any markers of human testicular function between men according to marital or fertility status, grades of moderate alcohol consumption or the presence of low titres of sperm antibodies.

Adult↗
PubMed1984

Obstructive azoospermia after a second renal transplant: an avoidable cause of infertility.

A case of obstructive azoospermia and infertility after renal transplantation is presented. Vasectomies were performed incidental to insertion of a renal allograft on each side and were not amenable to vasovasostomy owing to retraction of the proximal vasal stump. The desirability of spermatic cord preservation in younger men undergoing renal transplantation is discussed.

Adult↗
PubMed1984

Ovarian function after renal transplantation: comparison of cyclosporin A with azathioprine and prednisone combination regimens.

Ovarian function was assessed in 24 women after renal transplantation who were treated either with cyclosporin A (10 patients) or with a combination of azathioprine and prednisone (14 patients) as immunosuppressive therapy. The different regimens were not associated with any differences in clinical or endocrine indices of ovarian function (LH, FSH, prolactin, testosterone, oestradiol, dehydroepiandrosterone sulphate). Excessive hair growth was common in both treatment groups. Levels of testosterone and dehydroepiandrosterone were higher in cyclosporin-treated women but this was due to prednisone-induced suppression of adrenal androgen output in the azathioprine- and prednisone-treated women. Excessive hair growth was present in postmenopausal women on both treatments suggesting that hypertrichosis is a consequence of renal transplantation and is not a specific side-effect of cyclosporin A therapy.

Adult↗
PubMed1984

Pharmacokinetics of gonadotropin-releasing hormone: comparison of subcutaneous and intravenous routes.

Pulsatile administration of GnRH has been used to stimulate gonadal function in both hypogonadotropic men and women; however, deficient responses were observed with the sc in contrast to the iv route of hormone delivery. To clarify whether this was due to altered bioavailability, we compared the pharmacokinetics of these two routes of GnRH administration by bolus injection and steady state continuous infusion methods. Synthetic GnRH was administered by both sc and iv routes to 14 hypogonadotropic patients (11 women and 3 men) as a bolus (5 micrograms in 25, 100, or 250 microliters, sc, and 250 microliters, iv; n = 6) or by continuous iv or sc infusion (3.17 micrograms/h for 6 h; n = 11). In single dose studies, plasma immunoreactive GnRH (IR-GnRH) peaks were earlier and higher (400 vs. 93.5 pg/ml) and returned to baseline sooner (less than 60 vs. greater than 120 min) after iv than after sc bolus injection. Plasma IR-GnRH levels were lower between 1 and 5 min, but higher between 30-90 min after sc injection compared with iv bolus injection. During the continuous infusions, plateau levels of IR-GnRH between 2 and 6 h were 34% lower with sc delivery (67.5 vs. 102.4 pg/ml), indicating irreversible losses of about one third of GnRH injected sc. In patients undergoing pulsatile GnRH therapy delivered by programmed portable minipumps, plasma IR-GnRH profiles were highly damped after sc administration, but retained an intermittent pulse wave form with the iv route. These data suggest that pharmacokinetic differences in the sc and iv routes of GnRH administration are due to a combination of prolonged and delayed absorption with reduced bioavailability of GnRH via the sc route. The consequent damping of the plasma GnRH profiles with sc administration may contribute to differences in the clinical efficacy of pulsatile GnRH regimens, and specific modifications of pulsatile regimens may be required to adapt the physiological requirements of an intermittent plasma GnRH wave form to the damped and reduced bioavailability of sc GnRH therapy.

Adult↗
PubMed1984

Identification of human semen insulin-like growth factor-I/somatomedin-C immunoreactivity and binding protein.

Human seminal plasma (SP) samples have been tested for insulin-like growth factor-I/somatomedin-C (IGF-I/SM-C) immunoreactivity. Gel chromatography of SP at neutral pH indicated that all immunoreactive IGF-I/SM-C was present at a higher molecular weight than the free peptide from plasma, while in 1 M acetic acid, a major peak of immunoreactivity was seen at an apparently lower molecular weight than the free peptide, together with a peak with molecular weight about 40 000. This latter peak contained a binding protein which, on Scatchard analysis, was shown to have a single class of binding site, Ka = 1.2 X 10(10) L/mol. The low molecular weight peak material was displaced from monoclonal and polyclonal IGF-I/SM-C antibodies parallel to standard preparations. Its elution on gel chromatography later than plasma IGF-I/SM-C was shown by re-chromatography to be due to physical retardation on the column, rather than a lower molecular weight. As acid-ethanol extraction of SP samples failed to remove binding activity, samples from patients were all subjected to acid gel chromatography before assay. The mean IGF-I/SM-C content in 5 normal men was 20.7 +/- 3.7 (SD) ng/ml while that for 4 azoospermic subjects was 9.2 +/- 3.7 ng/ml. A hyposomatotrophic subject with normal sperm density and low serum IGF-I/SM-C had an SP IGF-I/SM-C value in the normal range. This study indicates that human semen contains protein-bound immunoreactive IGF-I/SM-C which is at least in part of testicular origin, and apparently not growth hormone-dependent.

Adult↗