Biomedical subjects

S J Winters

Publications and source records attributed to S J Winters.

101 records · Page 6Linked to original sources

PubMed1979

Cimetidine is an antiandrogen in the rat.

Cimetidine has been associated with gynecomastia as a side effect. Because other antiandrogens have been linked to the development of breast enlargement in men, the suggestion by earlier workers that cimetidine possessed antiandrogenic properties prompted us to study the endocrine effects of cimetidine in rats. Cimetidine directly antagonized the effects of exogenously administered testosterone on androgen target tissues. Ventral prostate and seminal vesicle weights were less in cimetidine-treated castrate adult male rats androgenized with testosterone-filled subcutaneous silastic capsules than in vehicle-injected controls. Cimetidine possessed no intrinsic androgen-like bioactivity in prepubertal male rats when given in doses of 50 mg/kg/day for 1 wk. Cimetidine competitively inhibited DHT binding to its cytoplasmic receptor and decreased specific nuclear uptake of [3H]dihydrotestosterone in rat ventral prostate slices. No effects on plasma gonadotropin or testosterone concentrations were observed. We conclude that cimetidine is a nonsteroidal-antiandrogen and that this property may contribute to the production of gynecomastia in cimetidine-treated men.

Androgen Antagonists↗

PubMed1978

Hypothalamic function in men with hypogonadotrophic hypogonadism.

To determine whether hypothalamic function is normal in patients with idiopathic gonadotrophin deficiency, nine men with this syndrome were studied. Water conservation after overnight dehydration, thermoregulatory response to a cold (10 degrees C) environmental stress and prolactin secretion following chlorpromazine stimulation were investigated. In response to dehydration, maximal urinary osmolality was 1058 +/- 135 mOsm/kg (mean +/- SD) and no patient showed further increase after exogenous vasopressin administration. The patients responded to the cold stimulus by vigorous shivering and maintained their core body temperatures. Basal concentrations of prolactin which were 12.7 +/- 4.6 ng/ml increased by 15 ng/ml following Thyrotrophin-releasing hormone in six of seven men tested, indicating normal pituitary reserve. Prolactin concentrations doubled in seven of eight men who received chlorpromazine. All responses were indistinguishable from those of normal men. While a diminished secretion of gonadotrophin releasing hormone by the hypothalamus remains the most plausible cause of idiopathic gonadotrophin deficiency, our data indicate that the associated functions tested are intact in men with this syndrome.

Adult↗

PubMed1978

Suppression of plasma luteinizing hormone by prolactin in the male rat.

Although a direct effect of PRL on gonadotropins has been previously suggested, it has not been convincingly demonstrated. The secretion of LH and FSH was studied in response to the stimuli of castration and LH releasing hormone administration in adult male rats made hyperprolactinemic with ectopic pituitary glands. Although plasma LH and FSH levels were similar in non-castrate hyperprolactinemic rats vs. controls, LH concentrations 24 h postcastration were less in hyperprolactinemic animals as compared to controls (P less than 0.001). The level of LH achieved was inversely correlated with the PRL concentration generated (r = -0.71; P less than 0.01). LH suppression was evident in hyperprolactinemic rats at 1 and 3 days postcastration but was no longer observable at 7 days postcastration. After LH releasing hormone administration to non-castrate rats the rise in plasma LH was significantly less in the hyperprolactinemic animals (P less than 0.05). These experiments support the hypothesis that PRL directly inhibits LH secretion, presumably at the pituitary level.

Animals↗

PubMed1977

The effect of osmotic stimuli on prolactin secretion and renal water excretion in normal man and in chronic hyperprolactinemia.

An osmoregulatory role for prolactin (PRL) in man has been postulated, and PRL secretion has been reported to be influenced by osmotic stimuli. Clinical observation, however, does not support this notion. The effects of water loading, hypertonic saline infusion and nicotine on serum PRL and on renal water metabolism were investigated in 6 normal subjects and in 8 patients with chronic hyperprolactinemia (four with and four without demonstrable pituitary tumors). None of the patients had thyroid, adrenal or vasopressin deficiency. Renal walter handling in these patients was indistinguishable from normal. Likewise, serum PRL was not affected by the stimuli employed in either the normal subjects or the patients. No correlation between degree or duration of hyperprolactinemia and renal water metabolism was found. It is concluded that PRL is not an important osmoregulatory hormone in man.

Adult↗

PubMed1976

Familial mitral valve prolapse and myotonic dystrophy.

When a patient with mitral valve prolapse was found to have myotonic dystrophy, his family was studied to ascertain the occurrence of these abnormalities. Of 25 relatives screened, 8 had evidence of both myotonic dystrophy and mitral valve prolapse and 2 had evidence of myotonic dystrophy alone. Thirteen patients had evidence of neither condition and 1 had mitral valve prolapse alone. The association of these two conditions within a family has not previously been observed and valvular heart disease has not been recognized in myotonic dystrophy. This association should be looked for in other patients.

Adolescent↗

PubMedDate not supplied

Current status of testosterone replacement therapy in men.

Testosterone plays an essential role in the development of the normal male and in the maintenance of many male characteristics, including muscle mass and strength, bone mass, libido, potency, and spermatogenesis. Androgen deficiency occurs with disorders that damage the testes, including traumatic or surgical castration (primary testicular failure) or disorders in which the gonadotropin stimulation of the testes is reduced (hypogonadotropic hypogonadism). The clinical manifestations of androgen deficiency depend on the age at onset and the severity and duration of the deficiency. In adult males, these manifestations may include reduced body hair, decreased muscle mass and strength, increased fat mass, decreased hematocrit, decreased libido, erectile dysfunction, infertility, osteoporosis, and depressed mood. The forms of androgen replacement currently available in the United States are intramuscular depot injections of testosterone esters, oral tablets of testosterone derivatives, and transdermal patches. For most patients, androgen replacement therapy with testosterone is a safe, effective treatment for testosterone deficiency.

Adult↗

PubMedDate not supplied

Estrogens and cytosolic estrogen receptors in aged male rats.

To determine whether estrogens may play a role in the decline in Leydig cell function in aged rats, plasma levels of testosterone, estradiol, and estrone; intratesticular concentrations of testosterone and estradiol; as well as cytosolic estrogen receptors were studied. Plasma and intratesticular testosterone levels were reduced in aged Sprague-Dawley rats, but circulating levels of estrone and estradiol, as well as intratesticular estradiol concentrations, were similar in aged and young-adult animals. Furthermore, in both testicular and kidney cytosol, the dissociation constants for estradiol and the concentrations of estradiol binding sites remained unchanged during aging. These data suggest that estrogens are unlikely to be important mediators of the reduced Leydig cell function in old rats.

Aging↗

PubMedDate not supplied

Seasonal changes in steroidogenesis in the testis of the rhesus monkey (Macaca mulatta).

To investigate the influence of seasonal changes from breeding to nonbreeding season on testicular steroidogenesis in the adult rhesus monkey, two animals were hemiorchidectomized in November and the second testis of each was removed the following April. Intratesticular steroid concentrations related to the formation of testosterone from pregnenolone were measured by radioimmunoassay. Related steroidogenic enzyme activities were also assayed and dynamic studies of the bioconversion of radiolabeled precursor steroids by testicular microsomes were performed. Testosterone was synthesized from pregnenolone through both dehydroepiandrosterone and 17 alpha-hydroxyprogesterone. No distinct differences were found in the testosterone biosynthetic pathway between testes in breeding and nonbreeding seasons. In the breeding season, intratesticular testosterone concentrations, the sum of intratesticular steroids measured, and the ratio of testosterone to the steroid sum were increased when compared to those in the nonbreeding season. No major seasonal changes in microsome enzyme activities were found, although enzyme activities, except for delta 5-3 beta-hydroxysteroid dehydrogenase for C21-steroids, were slightly higher in the breeding season. We conclude that increased testosterone production in the testis during the breeding season is due primarily to increased pregnenolone supply from Leydig cell mitochondria and, to a lesser extent, to an enhanced pregnenolone bioconversion to testosterone in the microsomes.

3-Hydroxysteroid Dehydrogenases↗

PubMedDate not supplied

Nature of alpha subunit secretion in men: circadian rhythms, pulsatile release and secretory profiles.

Alpha subunit complements LH as a marker of the activity of the hypothalamic GnRH pulse generator. To characterize episodes of alpha subunit release and to determine if a circadian pattern of alpha subunit secretion is present in man, spontaneous alpha subunit pulsatility was analyzed in six healthy young men by blood sampling every 5 min for 24 h. The resulting alpha subunit concentration time series were analyzed by two statistically based independent peak detection methods, and subjected to Fourier transformation to assess underlying circadian rhythms. Cross-correlation analyses and multiple parameter deconvolution were used to estimate the concordance of spontaneous and exogenous GnRH-stimulated LH and alpha subunit secretion. These analyses revealed that two independent discrete peak detection algorithms yielded similar estimates of spontaneous alpha subunit pulse frequency, namely, 21 +/- 1.1 (Cluster) and 21 +/- 1.5 (Detect) alpha subunit peaks/24 h. Sampling intensity markedly influenced the estimate of endogenous alpha subunit pulse frequency, inasmuch as estimates from 5-min sampling were significantly greater than those of 10-min or 20-min sampling. Fourier transformation unmasked a significant circadian alpha subunit rhythm in all six men, with maximal concentrations at 0836 h and an average amplitude of 28% of the 24-hr mean hormone concentration. Cross-correlation analysis of spontaneous glycoprotein release revealed that serum LH and alpha subunit concentrations were highly cross-correlated when considered simultaneously, but not at various lags. Finally, deconvolution analysis of exogenous GnRH-stimulated glycoprotein release disclosed distinct half-times of alpha subunit and LH clearance with virtually simultaneous underlying secretory bursts. These data indicate that human alpha subunit is secreted in both a circadian and a discrete pulsatile fashion at a pulse frequency that is significantly underestimated at conventional sampling rates. The approximately hourly alpha subunit interpulse interval (68 +/- 4.6 min) is similar to that reported earlier for LH in peripheral blood and for testosterone in gonadal vein blood in healthy men. Moreover, cross-correlation analysis of endogenous GnRH-driven alpha subunit and deconvolution analysis of exogenous GnRH-stimulated alpha subunit and LH secretion suggest that these glycoproteins are secreted virtually simultaneously, but have significantly different endogenous clearance properties. The remarkably similar in vivo pulse frequencies for alpha subunit, LH, and testosterone in man suggest that the release of these three hormones is coordinately regulated.

Adult↗

PubMedDate not supplied

Diurnal rhythm of testosterone and luteinizing hormone in hypogonadal men.

To determine the relationship between increasing luteinizing hormone (LH) production and the diurnal secretion of LH and testosterone (T) in adult men, studies were performed on five men with gonadotropin insufficiency associated with prolactinoma, five eugonadal men, and five men with primary testicular failure. Blood samples were drawn every 10 to 20 minutes for 24 hours beginning at 8:00 to 8:30 AM to evaluate diurnal periodicity. Mean (+/- SEM) LH levels in the three groups were 7.67 +/- 1.46 mlU/ml, 13.9 +/- 3.2 mlU/ml, and 62.3 +/- 14.4 mlU/ml, respectively, and mean serum T levels were 8.05 +/- 1.49 nmol/L, 13.9 +/- 3.5 nmol/L, and 9.15 +/- 1.3 nmol/L, respectively. Cosinor analysis revealed that each hyperprolactinemic man had a T rhythm with a significant 24-hour periodicity; the mean acrophase was at 5:00 AM. Testosterone levels were 35.0 +/- 10.6% less at 4:00 PM than at 8:00 AM. Eugonadal men also demonstrated a significant diurnal T rhythm with an acrophase at 6:00 AM, and T levels were 15.8 +/- 5.3% less at 4:00 PM than at 8:00 AM. By contrast, there was no significant diurnal rhythm in T secretion among the men with testicular failure, although serum T levels were 11.5 +/- 3.7% less at 4:00 PM than at 8:00 AM. For LH, hyperprolactinemic men demonstrated a significant 24-hour rhythm with an acrophase at 1:30 AM, whereas no significant 24-hour periodicity was identified among either eugonadal men or men with testicular failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

FSH is produced by GnRH-deficient men and is suppressed by testosterone.

Because there is an unexpected action of testosterone (T) to increase follicle-stimulating hormone (FSH) production in the absence of gonadotropin-releasing hormone (GnRH) in the rat, the effects of T treatment on circulating FSH were studied in men with GnRH deficiency. FSH immunoreactivity was identified in serum using a sensitive two-site immunoassay in each of five untreated GnRH-deficient men. Analysis by gel filtration chromatography revealed that circulating immunoreactive FSH coeluted with radiolabeled authentic FSH. T enanthate treatment suppressed serum FSH levels in each subject from (mean +/- standard error of the mean [SEM]) 1.02 +/- 0.94 to 0.26 +/- 0.21 mIU/ml (P = 0.061, Wilcoxon rank sum test). Thus, FSH is produced in GnRH-deficient men, but there is no evidence for the stimulatory effect of T on FSH production in the absence of GnRH, as observed in the rat. These preliminary data provide further evidence that male contraceptive strategies using GnRH antagonists to suppress LH and FSH production in normal men will not be counteracted by T replacement therapy, although the issue deserves further attention in that study population.

Adult↗