Testosterone metabolism in rabbits actively immunized with testosterone.

Active immunization of male rabbits results in a marked increase in plasma testosterone (T) and in the fraction of T bound to circulating proteins. In order to identify the cause of the increased T levels, the half-life of T after castration, and the metabolic clearance rate (MCR) and production rate (PR) after a single injection of tritiated T were determined in normal and immunized rabbits. In the immunized animals the half-life of T was significantly longer, the MCR showed a 10-fold decrease (10.2 +/- 3.2 1/day compared to 108 +/- 43 1/day) and the PR was increased from 0.44 +/- 0.34 mg/day to 1.20 +/- 0.36 mg/day compared with the control group. The binding of T to circulating antibodies is considered to be the direct cause of the decreased MCR and, via the diminished negative feedback at the hypothalamic-pituitary levels, the indirect cause of the increased PR in the immunized animals.     

Effects of pulsatile and continuous luteinizing hormone (LH) infusions on testosterone responses to LH in rams actively immunized against gonadotropin-releasing hormone

Yearling rams actively immunized against GnRH were used as a hypogonadotropic model for studies of the significance of the pulsatility of LH secretion in determining the trophic actions of the hormone on testicular steroidogenesis. GnRH-immunized rams, in which testicular regression was complete, were infused iv for 12-20 days with ovine LH (NIDDK oLH 24) in three different regimens, delivering a total daily dose of 60 micrograms/100 kg: 1) 1-min pulses of 5 micrograms/100 kg every 2 h (low amplitude, high frequency), 2) 1-min pulses of 30 micrograms/100 kg every 12 h (high amplitude, low frequency), or 3) continuous infusion of 2.5 micrograms/100 kg.h. Serum testosterone levels and acute responses to LH challenges were monitored at intervals throughout the infusion periods. Acute responses to LH were evaluated in terms of the area under the curve for serum testosterone vs. time after LH and the lag time between the infusion of LH and attainment of maximum serum testosterone levels. At the beginning of the experiments, serum testosterone was at castrate values, and testosterone responses to LH were of low magnitude with a long lag time. LH infusion in the low amplitude, high frequency regimen consistently increased the magnitude and decreased the lag time of acute responses to LH; these effects were significant by the sixth day of treatment and persisted for the duration of the experiments. This regimen also had positive effects on morphological features of testes and Leydig cells. Infusion of the high amplitude, low frequency regimen, however, had neither of the positive effects on responsiveness to LH, but did seem to improve testicular and Leydig cell morphology. Continuous infusion of LH also increased the magnitude and decreased the lag time of responses to low amplitude pulses of LH, at least as well as the high frequency infusion regimen did. These results suggest that the high frequency, low amplitude pattern of LH secretion characteristic of reproductively active animals has trophic actions on the testes, increasing their responsiveness to acute gonadotropic stimulation, but the pulsatility of that pattern of LH secretion is not necessary for its trophic actions. The efficacy of high frequency LH secretion may depend only on the elevation of basal or mean LH concentrations, rather than on the low amplitude peaks or the dynamic changes in LH concentrations to which the testes are exposed.     

Exogenously administered testosterone maintains spermatogenesis quantitatively in adult rats actively immunized against gonadotropin-releasing hormone.

The administration of testosterone via Silastic capsules has been shown previously to maintain advanced spermatid number quantitatively in intact rats in which LH but not FSH was suppressed, but not in hypophysectomized rats, indicating that pituitary factors in addition to LH are required for the quantitative maintenance of spermatogenesis in the rat. The objective of the present study was to examine whether testosterone is capable of maintaining quantitatively normal spermatogenesis in rats in which both LH and FSH are suppressed. Intact adult male rats were actively immunized against GnRH by intradermal injection of GnRH conjugated to human serum globulin; control rats received intradermal injections of saline and adjuvant. Four weeks after the primary immunization, GnRH-immunized rats received the first booster injection and, at the same time, received testosterone-filled polydimethylsiloxane (PDS) implants of 4, 8, 12, or 24 cm or empty implants. Booster injections were repeated every 2 weeks for 8 weeks. At that time, rats were killed, and serum levels of LH, FSH, and testosterone, testicular advanced spermatid number, and seminiferous tubule fluid testosterone concentrations were determined. Four weeks after the initial administration of GnRH immunogen, i.e. before the first booster injection, serum levels of testosterone, LH, and FSH and the number of advanced spermatids per testis were not different from those in controls. Eight weeks after the first booster injection, serum LH and FSH and advanced spermatids were undetectable in all GnRH-immunized rats. The administration of testosterone-filled PDS implants of 4 and 8 cm to GnRH-immunized rats for 8 weeks resulted in the maintenance of 105 +/- 6 and 161 +/- 5 x 10(6) advanced spermatid/testis, respectively, significantly less than the control value (237 +/- 19 x 10(6)). In GnRH-immunized rats that received testosterone-filled PDS implants of 12 or 24 cm, the advanced spermatid numbers per testis (228 +/- 4 and 229 +/- 8 x 10(6), respectively) were not significantly different from those in controls. These results indicate that testosterone is capable of maintaining spermatogenesis quantitatively in the adult rats testis, in the absence of both radioimmunoassayable LH and FSH.     

Plasma bioactive LH and testosterone profiles in male New Zealand rabbits experimentally infected with Schistosoma mansoni

The effects of Schistosoma mansoni (S. mansoni) infection on plasma levels of bioactive luteinising hormone (LH) and testosterone in the New Zealand rabbit model were studied. S. mansoni infection significantly decreased the pulse frequency (P < 0.05), amplitude (P < 0.05), area under LH curve (P < 0.05) and mean plasma LH concentrations (P < 0.05) on days 42 and 70 post-infection, as compared to values for day 14 pre-infection. Areas under the response curves for plasma testosterone levels decreased significantly (P < 0.05) on days 42 and 70 post-infection in infected animals compared to day 14 pre-infection. In the praziquantel-treated group, the levels of LH and testosterone remained unchanged throughout the experimental period. The pulsatile secretion of LH was completely inhibited in S. mansoni-infected animals 70 days post-infection. These results suggest that the effects on reproductive gonadal hormones caused by S. mansoni in the rabbit model may partly be induced by alteration in pituitary synthesis or release of LH.     

Effects of sodium depletion in rats actively immunized against renin

The influence of active immunization against renin on systolic blood pressure in response to a dietary sodium restriction was assessed in normotensive rats (WKY) and spontaneously hypertensive rats (SHR). Immunization was obtained by multiple injections of pure submaxillary murine renin. Animals received a normosalt diet (NS diet) for 6 days. Then sodium was abruptly removed from the diet (LS diet), and rats were maintained for an additional 6 day-period on this salt-free diet. In rats maintained on NS diet, immunization induced a decrease in systolic blood pressure (SBP) about 11 p. 100 and 27 p. 100 respectively in WKY immune and SHR immune groups. SBP was not affected by abrupt dietary sodium removal in non-immunized rats from both strains. However, in immunized rats sodium restriction was accompanied by a significant SBP decrease compared to the value observed during NS period in the same group. The relative variation in SBP was about 10 p. 100 and 14 p. 100 respectively in WKY immune and SHR immune groups. The present study shows that active immunization against renin leads to a reduction in systolic blood pressure regardless to the initial pressure level. When sodium is removed from the diet, systolic blood pressure level is maintained in non-immunized rats, whereas it decreases in immunized rats of both strains. These results confirm the importance of an efficient renin-angiotensin system in the adaptative response to sodium restriction.     

Plasma concentrations of luteinizing hormone and follicle-stimulating hormone during anoestrus in ewes actively immunized against oestradiol-17 beta, oestrone or testosterone

The concentrations of LH and FSH in jugular venous plasma were measured during anoestrus in control ewes and ewes actively immunized against 17 beta-oestradiol-6-(O-carboxymethyl)oxime--bovine serum albumin, oestrone-6-(O-carboxymethyl)oxime--bovine serum albumin or testosterone-3-(O-carboxymethyl)oxime--bovine serum albumin. During a 12 h sampling period, the basal level of LH and the frequency of LH pulses were significantly increased in all the immunized animals. The plasma FSH concentration was increased in two out of five oestradiol-immunized ewes and two out of three oestrone-immunized animals. The plasma FSH concentration in the testosterone-immunized animals was similar to the control values. Significant titres of antibodies to oestradiol-17 beta were found in all the immunized animals. It is suggested that binding of oestradiol-17 beta in the circulation by antibodies reduced the negative feedback action normally eserted by this steroid on LH secretion and, to a lesser extent, on FSH escretion. However, since the oestradiol antibody titres in the testosterone-immunized and oestrone-immunized ewes were considerably lower than those found in the oestradiol-immunized animals, it is possible that testosterone and oestrone, perhaps by acting as prehormones, could influence the negative feedback control by oestradiol-17 beta of gonadotrophin secretion in the anoestrous ewe.     

Radioimmunoassay of inhibin in the serum of male monkeys

A heterologous inhibin radioimmunoassay method to measure inhibin in serum of male cynomolgus (Macaca fascicularis) and rhesus (Macaca mulatta) monkeys has been validated using a specific antibody against bovine 31 kDa inhibin and 125I-labelled 31 kDa inhibin as tracer. A serum pool from male monkeys was used as standard. Serial dilutions of normal monkey serum showed parallel logit-log dose-response curves to purified porcine and bovine inhibin as well as to a female human serum pool. The intra-assay coefficient of variation was 4.2% (n = 10) and the interassay coefficient of variation 5.1% (n = 10). No loss of inhibin immunoactivity was noted after storage at 23 degrees C for 5 days or repeated thawing and freezing of the serum samples. Serum from castrated monkeys showed undetectable levels of inhibin. Treatment with a gonadotrophin-releasing hormone agonist for 15 weeks led to a marked suppression of peripheral serum inhibin to concentrations similar to those after hypophysectomy or pituitary stalk section.     

Low serum testosterone and mortality in male veterans

BACKGROUND: Low serum testosterone is a common condition in aging associated with decreased muscle mass and insulin resistance. This study evaluated whether low testosterone levels are a risk factor for mortality in male veterans. METHODS: We used a clinical database to identify men older than 40 years with repeated testosterone levels obtained from October 1, 1994, to December 31, 1999, and without diagnosed prostate cancer. A low testosterone level was a total testosterone level of less than 250 ng/dL (<8.7 nmol/L) or a free testosterone level of less than 0.75 ng/dL (<0.03 nmol/L). Men were classified as having a low testosterone level (166 [19.3%]), an equivocal testosterone level (equal number of low and normal levels) (240 [28.0%]), or a normal testosterone level (452 [52.7%]). The risk for all-cause mortality was estimated using Cox proportional hazards regression models, adjusting for demographic and clinical covariates over a follow-up of up to 8 years. RESULTS: Mortality in men with normal testosterone levels was 20.1% (95% confidence interval [CI], 16.2%-24.1%) vs 24.6% (95% CI, 19.2%-30.0%) in men with equivocal testosterone levels and 34.9% (95% CI, 28.5%-41.4%) in men with low testosterone levels. After adjusting for age, medical morbidity, and other clinical covariates, low testosterone levels continued to be associated with increased mortality (hazard ratio, 1.88; 95% CI, 1.34-2.63; P<.001) while equivocal testosterone levels were not significantly different from normal testosterone levels (hazard ratio, 1.38; 95% CI, 0.99%-1.92%; P=.06). In a sensitivity analysis, men who died within the first year (50 [5.8%]) were excluded to minimize the effect of acute illness, and low testosterone levels continued to be associated with elevated mortality. CONCLUSIONS: Low testosterone levels were associated with increased mortality in male veterans. Further prospective studies are needed to examine the association between low testosterone levels and mortality.     

Plasma testosterone and LH levels in male quail bearing hypothalamic lesions or radioluminous implants.

Radioluminous material (RLM) was implanted in either the infundibular complex or the preoptic area of sexually immature quail exposed to short days. Direct selective photic stimulation of the infundibular complex resulted in testicular growth (3,300 mg) and increase in levels of plasma testosterone (T, 23 ng/10 ml) and luteinizing hormone (LH, 4 ng/ml). Direct selective photic stimulation of the preoptic area did not induce any testis enlargement (84 mg) and plasma T and LH levels remained low (1.4 ng/10 ml and 0.9 ng/ml). However, preoptic as well as infundibular lesioning completely suppressed any gonadotropic and testicular responses to environmental photic stimulation. The respective and possibly differential roles played by these 2 structures in the photosexual reflex are discussed.     

The contribution of corticosterone and testosterone to the suppression of serum LH in hyperprolactinaemic adult male rats with pituitary transplants

The effects of hyperprolactinaemia on serum levels of LH were investigated in adult male rats of the R X U strain. Hyperprolactinaemia was induced by three pituitary grafts under the kidney capsule, transplanted on day 0 of each experiment. Special attention was paid to the contribution of prolactin-stimulated testes, adrenals and corticosterone. In experiment 1, hyperprolactinaemia significantly reduced the serum concentrations of LH in intact rats. In spite of a significant increase in the serum levels of corticosterone, serum testosterone was not significantly affected by hyperprolactinaemia. The weights of both the adrenals and accessory sex glands were significantly increased at autopsy. In experiment 2, treatment with 10 mg corticosterone s.c. daily from day 14 to day 28 after pituitary grafting significantly reduced serum levels of both LH and testosterone. The suppression of testosterone in the hyperprolactinaemic corticosterone-treated animals was significantly less than in the corticosterone-treated control animals. The weights of the accessory sex glands were significantly increased in the hyperprolactinaemic animals. In experiment 3, rats were adrenalectomized and half of them were substituted with corticosterone. Serum testosterone levels significantly increased in both hyperprolactinaemic adrenalectomized rats and in adrenalectomized corticosterone-treated animals without any significant effect on serum LH. Again the weights of the accessory sex glands were significantly increased in the hyperprolactinaemic animals. In experiment 4, rats were adrenalectomized, gonadectomized and corticosterone treated on day 0 and then implanted with a 2, 1.5 or 1 cm silicone elastomer capsule containing testosterone.(ABSTRACT TRUNCATED AT 250 WORDS)     

FSH and LH response to testosterone and gonadotropin-releasing hormone in aging male rats

Abstract

Gonadotropins were measured in young (3 months) and old (24 months) male Sprague-Dawley rats. Basal levels of LH were lower in old animals, whereas the basal levels of FSH were unchanged. The levels of gonadotropins increased significantly following castration in both age groups. However the old animals secreted less LH than the young. When 50 mg/100 g BW of testosterone propionate (TP) was given, the postcastration levels of FSH and LH were suppressed only in the old rats. When higher doses of TP were given, the levels of FSH and LH were reduced in both groups. However these levels remained suppressed longer in the old rat than in the young. The levels of FSH and LH were elevated after an iv injection of 10 or 100 ng gonadotropin releasing hormone (GnRH)/100 g BW. FSH levels were similar in both groups of animals. LH values were higher in the young rats only after the injection of 100 ng GnRH/100 g BW. These data suggest that age differentially influences the control mechanisms for FSH and LH secretion.     

Effects of an intraventricular injection of synthetic ACTH on plasma testosterone, progesterone and LH levels and on sexual behavior in male and female rabbits.

Sexual behavior and elevation of gonadal steroids were induced in both male and female New Zealand white rabbits following injection of synthetic beta (1-24) ACTH into the lateral cerebral ventricle. In blood assays collected by cardiac puncture, testosterone, progesterone and corticosterone were all increased above both resting levels and samples were taken after a control intraventricular injection of physiological saline. Parallel increases of plasma LH were also demonstrated. The results were interpreted to indicate that intraventricular ACTH, through LH release, influences sex hormone levels and sexual behavior by 'centrally', probably within the hypothalamus.     

FSH and LH response to testosterone and gonadotropin-releasing hormone in aging male rats

Gonadotropins were measured in young (3 months) and old (24 months) male Sprague-Dawley rats. Basal levels of LH were lower in old animals, whereas the basal levels of FSH were unchanged. The levels of gonadotropins increased significantly following castration in both age groups, However the old animals secreted less LH than the young. When 50 mg/100 g BW of testosterone propionate (TP) was given, the postcastration levels of FSH and LH were suppressed only in the old rats. When higher doses of TP were given, the levels of FSH and LH were reduced in both groups. However these levels remained suppressed longer in the old rat than in the young. The levels of FSH and LH were elevated after an iv injection of 10 or 100 ng gonadotropin releasing hormone (GnRH/100 g BW. FSH levels were similar in both groups of animals. LH values were higher in the young rats only after the injection of 100 ng GnRH/100 g BW. These data suggest that age differentially influences the control mechanisms for FSH and LH secretion.     

Effect of long-term testosterone oenanthate administration on male reproductive function: clinical evaluation, serum FSH, LH, testosterone, and seminal fluid analyses in normal men.

The effect of long-term testosterone administration on male reproductive function has been investigated in seven healthy young men age 20 to 27 years. Testosterone oenanthate (TOe) was administered in doses of 250 mg per week for 21 weeks. No toxic side-effects were observed. Libido, sexual potency, frequency of sexual intercourse and body hair development generally remained unaffected, but there was a reversible mean weight gain of 3.6 kg during TOe administration. Seminal fluid parameters and radioimmunoassayable serum FSH, LH, testosterone, and androstenedione levels were monitored before, during, and after TOe administration. The serum testosterone rose approximately by a factor of two, while the serum FSH and LH were rapidly suppressed after the initiation of the TOe therapy. The mean sperm concentration fell to values below three million spermatozoa per ml, and changes in sperm motility, the percentage of normal sperm morphology, and seminal fructose concentrations generally paralleled those of the mean sperm concentrations. In contrast, the mean seminal fluid volume and serum androstenedione levels did not change significantly during TOe administration. The mean sperm concentration showed a marked recovery 13 to 16 weeks after TOe withdrawal, but sperm counts remained below pre-treatment levels in three out of seven subjects 25 to 28 weeks after discontinuation of TOe.