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PubMed1999

Biphasic effect of nitric oxide on testosterone and cyclic GMP production by purified rat Leydig cells cultured in vitro.

Nitric oxide (NO) biphasically modulates osteoclast function and sperm motility by exerting a positive effect at low concentrations and a negative effect at high concentrations. We therefore tested whether NO exerts a comparable effect on testosterone secretion by cultured rat Leydig cells. Three NO-donors, S-nitroso-N-acetylpenicillamine (SNAP), diethylamine/nitric oxide complex sodium salt (DEA/NO) and diethylenetriamine nitric oxide adduct (DETA/NO) were administered in a wide range of concentrations (10(-8)-10(-3) M for 3 h) to Percoll-purified Leydig cells from adult rats. These drugs raised testosterone and cGMP secretion when used at low concentrations (10(-8)-10(-5) M); however, they inhibited testosterone, but did not affect cGMP, secretion at concentrations higher than 10(-5) M. Administration of the NO scavenger haemoglobin (160 micrograms/mL) prevented both the stimulatory and the inhibitory effect of these drugs. Nitrite accumulation was measured as a marker of NO released by the drugs in our in vitro system; it fell within the range of control media in the presence of NO-donor concentrations lower than 10(-5) M, but was several-fold higher in the media of cells treated with concentrations of the NO-donors greater than 10(-5) M. These data show that (1) NO exerts a biphasic effect on testosterone secretion, which is stimulatory at low and inhibitory at high concentrations; (2) the stimulatory effect of NO is mediated by cGMP, the classic second messenger for NO action.

Adult↗
PubMed2000

Localization of 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase isoform expression in the developing mouse testis--androstenedione is the major androgen secreted by fetal/neonatal leydig cells.

The final step in the biosynthesis of testosterone is reduction of androstenedione by the enzyme 17beta-hydroxysteroid dehydrogenase/ 17-ketosteroid reductase (17betaHSD/17KSR). In this study, we have examined expression of the four known reductive isoforms of 17betaHSD/ 17KSR (types 1, 3, 5, and 7) in the developing mouse testis and have determined changes in the localization of isoform expression and testosterone secretion during development. Using RT-PCR isoforms 1, 3, and 7 were shown to be expressed in the seminiferous tubules of neonatal testis, whereas isoforms 3 and 7 were expressed in the interstitial tissue of the adult testis. The type 7 isoform is unlikely to be involved in androgen synthesis and further study concentrated on the type 3 isoform. Developmentally, isoform type 3 was expressed in the seminiferous tubules up to day 10, showed little or no expression on day 20 and from day 30 was confined to the interstitial tissue. In situ hybridization confirmed that the type 3 isoform was expressed only in the seminiferous tubules in fetal testes and in the interstitial tissue in adult testes. In accordance with the localization of enzyme messenger RNA expression 17-ketosteroid reductase enzyme activity was very low in isolated interstitial tissue from neonatal testes while interstitial tissue from adult testes showed high activity. Seminiferous tubules from both neonatal and adult testes showed high levels of enzyme activity. The major androgen secreted by the interstitial tissue of prepubertal animals was androstenedione up to day 20 while 5alpha-androstanediol and/or testosterone were the major androgens secreted from day 30 onwards. These results show that fetal Leydig cells do not express significant levels of a reductive isoform of 17betaHSD/ 17KSR and that androstenedione is the major androgen secreted by these cells. Production of testosterone up until puberty is dependent upon 17betaHSD/17KSR activity in the seminiferous tubules--a "two cell" requirement for testosterone synthesis. Expression of the 17betaHSD/17KSR type 3 isoform (the main reductive isoform in the testis) declines in the seminiferous tubules before puberty but then reappears in the developing adult Leydig cell population.

17-Hydroxysteroid Dehydrogenases↗
PubMed1992

Development of cytoplasmic digitations between Leydig cells and testicular macrophages of the rat.

Testicular macrophages and Leydig cells from adult animals are known to be functionally coupled. For example, secreted products from macrophages stimulate testosterone secretion by Leydig cells. In adult rat testes, structural coupling also exists between these cells. This coupling consists of cytoplasmic projections from Leydig cells located within cytoplasmic invaginations of macrophages. Although macrophages are known to exist in the testis in immature animals, it is not known when these digitations develop. The purpose of the present study was to determine whether the time of their development coincides with known maturational events that occur in Leydig cells, particularly during the peripubertal period. Testes from rats at 20, 30 and 40-days-of-age as well as testes from mature rats weighing more than 500 gm were prepared for ultrastructural analysis. It was found that digitations form between 20 and 30-days-of-age. These structures varied from simple tubular projections to complicated branched structures, suggesting that digitations are more than simple invaginations of microvilli into coated vesicles as previously described. Subplasmalemmal linear densities were also observed within macrophages juxtaposed to Leydig cells. Collagen was commonly observed between macrophages and Leydig cells in animals 20 days old. These studies demonstrate that although macrophages are present in the testis in maximal numbers at 20 days-of-age, they do not form junctions with Leydig cells until day 30. This is just prior to the major increase in secretory activity of rat Leydig cells that occurs during puberty.

Animals↗
PubMed1997

Growth and reproductive development from weaning through 20 months of age among breeds of bulls in subtropical Florida.

To determine the effect of breed on growth and reproductive development, weaned bulls in each of 2 yr were managed as a single group for approximately a year. In Year 1, the study group consisted of 24 Angus, 24 Brahman, 20 Hereford and 14 Senepol bulls, while in Year 2, it contained 25 Angus, 17 Brahman. 13 Romosinuano and 9 Nellore x Brahman bulls. Body and testicular growth measurements were recorded at 6-wk intervals. At approximately 1 yr of age and quarterly thereafter (4 periods), bulls were evaluated for libido, pubertal status, and GnRH-induced LH and testosterone secretion. Significant breed-by-age interactions occurred for most growth measurements. Brahman bulls (Bos indicus ) were (P < 0.05) older and heavier at puberty than Angus, Hereford, Senepol and Romosinuano bulls (Bos taurus ). Libido scores were lowest for Brahman and Nell ore x Brahman bulls (Bos indicus ). highest for Angus and Hereford bulls (temperate Bos taurus breeds) and intermediate for Senepol and Romosinuano bulls (tropical Bos taurus breeds; P < 0.05). Differences were not consistent among breeds or between years for GnRH-induced LH secretion. In both years, basal testosterone concentrations and areas under the GnRH-induced testosterone curve were higher (P < 0.05) for Angus and Hereford bulls (temperate breeds) than for Brahman, Senepol, Romosinuano and Nellore x Brahman bulls (tropical breeds). In conclusion, reproductive development of Senepol and Romosinuano bulls (tropical Bos taurus breeds) was more similar to Angus and Hereford bulls (temperate Bos taurus breeds) than to Brahman and Nellore x Brahman bulls (Bos indicus ).

Journal Article↗
PubMedDate not supplied

Effect of intratesticular administration of oxytocin on testicular steroidogenesis in immature rats.

The possible physiological role of testicular oxytocin in testicular steroidogenesis was studied in immature rats. In 5-, 9-, and 25-day-old animals one of the testes was injected with 20, 50, and 200 ng of oxytocin, respectively, then the contralateral gonad was removed. Rats were killed 1 h, 1 day, or 7 days post-surgery. In each age group studied intratesticular injection of oxytocin resulted in a significant increase in basal testosterone secretion in vitro and/or serum testosterone concentration. Data indicate that in immature rats oxytocin of testicular origin might act as a local stimulator of steroidogenesis.

Animals↗
PubMed2005

Interleukin 1-beta injected into the testis acutely stimulates and later attenuates testicular steroidogenesis of the immature rat.

The effect of intratesticular administration of interleukin-1beta (IL-1beta) on steroidogenesis was studied in immature and adult rats. In 21-d-old animals local bilateral injection or unilateral administration of 0.1 microg/testis of IL-1beta to hemicastrates resulted in a significant increase in basal testosterone secretion in vitro and serum testosterone concentration one day posttreatment. Six days after treatment the cytokine induced opposite effect in animals with two testes in situ, i.e., it suppressed steroidogenesis. When IL-1beta was combined with hemi-castration, IL-1beta failed to alter the parameters studied. In adult animals subjected to bilateral treatment or to unilateral injection followed by hemicastration, IL-1beta in doses of 1.5 microg/testis or 15 microg/testis did not influence steroidogenesis and serum testosterone concentration. No change in serum LH and FSH concentration could be observed in any experimental group. The data suggest that the proinflammatory cytokine IL-1beta exerts a local action on testicular steroidogenesis, and the effect is age-dependent.

Age Factors↗
PubMed2005

Androgens and fertility.

Androgens play a pivotal role in the development of the male reproductive tract. The spermatogenesis requires high levels of intratesticular testosterone secreted by the Leydig cells. Testosterone exerts its action through the androgen receptor (AR), which is located both in the cytoplasm and in the nucleus of cells in the target tissue. Severe defects of the AR may result in abnormal male sexual development, while more subtle modifications can be a potential cause of male infertility. Low circulating levels of testosterone can be found in 20-30% of infertile men, but administration of testosterone or gonadotropins does not result in improved sperm production. Abuse of anabolic steroids is a frequent cause of male infertility, and substances such as endocrine disruptors can alter male fertility through an anti androgenic action.

Aged↗
PubMed1977

[Effect of light on variations in blood testosterone in the ram: demonstration of a photosensitive phase in diurnal rhythm].

6 groups each of 5 adult rams were subjected in light controlled pens to a pretreatment of normal variations in daylength during May and June. Then one group followed the normal daylength and the other five different "skeleton photoperiods" of 8 hrs of light per day consisting of: 7 hrs continuous light (7 L) + 1 hr light (1 L) situated at different times of the dark period (D) according to groups. Blood samples were taken once each week and hourly during one 24 hr period in June, July and September. Peripheral plasma testosterone measured by radio-immunoassay was used as an index of testicular activity. There was increase in the level of testosterone resuting from a rise in the number of peak release during the 24 hrs. In the different light treatments tested, only the treatment (7L+9D+1L)+7D) stimulated testosterone secretion with the pattern of testosterone of this group being similar to that of the control group. This indicates that there exists a photosensitive phase at 16 to 17 hrs after the beginning of the principal light (the subjective dawn).

Animals↗
PubMed1999

Testosterone and depression in aging men.

In men, testosterone secretion affects neurobehavioral functions such as sexual arousal, aggression, emotional tone, and cognition. Beginning at approximately age 50, men secrete progressively lower amounts of testosterone; about 20% of men over age 60 have lower-than-normal levels. The psychiatric sequelae are poorly understood, yet there is evidence of an association with depressive symptoms. The authors reviewed 1) the physiology of the hypothalamic-pituitary-gonadal axis and its changes with age in men; and 2) the evidence linking testosterone level and major depression in men. Data on this relationship are derived from two types of studies: observational studies comparing testosterone levels and secretory patterns in depressed and non-depressed men, and treatment studies using exogenous androgens for male depression. The data suggest that some depressed older men may have state-dependent low testosterone levels and that some depressed men may improve with androgen treatment.

Adult↗
PubMed1991

Gonadotropin-releasing hormone pulses: regulators of gonadotropin synthesis and ovulatory cycles.

The data reviewed present evidence that the pattern of GnRH secretion is an important factor in the regulation of gonadotropin subunit gene expression, gonadotropin synthesis, and secretion. The information on regulation of mRNA expression by GnRH pulses should be considered with some caution, as the experiments were performed in male rats and may not accurately reflect events in female primates or humans. However, an overall pattern emerges which suggests that common factors may be involved in all mammalian species. If current evidence is correct, and only a single gonadotropin-releasing hormone exists, then mechanisms to differentially regulate the three gonadotropin genes may involve changes in GnRH secretion. Alterations in GnRH pulse frequency and amplitude are recognized by the pituitary gonadotrope cell and could be the mechanism used to effect differential expression of the gonadotropin subunit genes. Differential regulation of subunit gene expression would be expected to be critically important in the establishment of pubertal maturation, and subsequently in the maintenance of ovulatory cycles in women. Our hypotheses, proposing a major role of pulsatile GnRH secretion in the regulation of human reproduction, are summarized in schematic form in Fig. 14 for men and Fig. 15 for women. In utero and during the first few months of life, GnRH is secreted at a relatively fast frequency (approximately 1 pulse/hour). During the first year, GnRH secretion is inhibited and both the amplitude and apparent frequency of pulsatile release is markedly reduced. The mechanisms involved in inhibiting GnRH release remain unclear in humans. Similarly, the mechanisms involved in the disinhibition of GnRH secretion, which first occurs during sleep at the initiation of puberty, are unclear, but in humans do not appear to involve opiates. In males, the increased frequency and amplitude of GnRH secretion favor LH synthesis and release, which in turn stimulates testosterone secretion (Fig. 14). Testosterone acts at the hypothalamus, perhaps through opioid mechanisms, to inhibit GnRH pulse frequency and to maintain a regular pattern of pulses occurring approximately every 90-110 min in adult males. In females, the mechanisms involving alterations in the patterns of GnRH secretion to regulate reproduction appear more complex. This may reflect the need to differentially synthesize and secrete FSH and LH at different times during reproductive cycles to allow orderly follicular maturation and ovulation. As shown in Fig. 15, we hypothesize that the events during the first decade of life and through the initiation of nocturnal GnRH secretion at puberty are similar in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

d24-hour changes in circulating prolactin, follicle-stimulating hormone, luteinizing hormone and testosterone in male rats subjected to social isolation.

BACKGROUND: This work analyzes the effect of social isolation (a mild stressor) on the 24-h variation of pituitary-testicular function in young Wistar rats, assessed by measuring circulating levels of prolactin, FSH, LH and testosterone. METHODS: Animals were either individually caged or kept in groups (4-5 animals per cage) under a 12:12 h light-dark cycle (lights on at 0800 h) for 30 days starting on day 35 of life. Rats were killed at 4-h intervals during a 24-h cycle, beginning at 0900 h. RESULTS: Isolation brought about a decrease in prolactin, LH and testosterone secretion and an increase of FSH secretion. In isolated rats the 24-h secretory pattern of prolactin and testosterone became modified, i.e., the maximum in prolactin seen in control animals at the beginning of the activity span was no longer detected, whereas the maximum in circulating testosterone taking place at 1700 h in controls was phase-delayed to 2100 h in isolated rats. CONCLUSION: Social isolation affects the 24-h variation of pituitary-testicular function in young rats. Secretion of prolactin, LH and testosterone decreases, and secretion of FSH increases, in isolated rats. The maximum in prolactin seen in group-caged rats at the beginning of the activity span is not observed in isolated rats. The maximum in circulating testosterone taking place at the second part of the rest span in controls is phase-delayed to the light-dark transition in isolated rats.

Journal Article↗
PubMed2000

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey.

We investigated a possible modulation of growth hormone (GH) secretion by testosterone by measuring the growth hormone releasing hormone (GHRH)-stimulated and N-methyl-d,l-aspartic acid (NMA)-induced GH secretion in adult rhesus monkeys. Intact, orchidectomized and testosterone-substituted (testosterone enanthate 125 mg/week, i.m. for 5 weeks) orchidectomized monkeys (n=5) were used in the study. GHRH (25 microg/kg body weight) or NMA (15 mg/kg body weight) was infused through a Teflon cannula implanted in the saphenous vein. Sequential blood samples were collected 30-60 min before and 60 min after the injection of the neurohormone or the drug at 10-20-min intervals. All bleedings were carried out under ketamine hydrochloride anaesthesia (initial dose 5 mg/kg body weight i.m., followed by 2.5 mg/kg at 30-min intervals). The plasma concentrations of GH, testosterone and oestradiol (E(2)) were determined by using specific assay systems. Administration of GHRH elicited a significant increase in GH secretion in all three groups of animals. There was no significant difference in the responsiveness of pituitary somatotrophs to exogenous GHRH challenges between intact and orchidectomized monkeys and testosterone replacement in orchidectomized animals did not significantly alter the GHRH-induced GH response. The responsiveness of hypothalamic GHRH neurones apparently did undergo a qualitative change after orchidectomy, as GH response to NMA was less in orchidectomized animals than in intact monkeys. The responsiveness of GHRH neurones to exogenous NMA was restored and even potentiated when orchidectomized monkeys were treated with testosterone. Taken together, these findings suggest that testosterone does not affect the sensitivity of the pituitary somatotrophs to GHRH but stimulates the secretion of GH by modulation of the NMDA drive to GHRH neurones.

Analysis of Variance↗
PubMed1984

Endocrine control of mammalian testicular ontogenesis.

The endocrine control of ontogenesis of the male gonad involves the development of the gonad itself and, at the same time, the development of the endocrine system. During the impubertal phase, the seminiferous tubules contain supporting cell and gonocytes, both of which increase in number by mitotic divisions. Over this period, the pituitary secretion of both FSH and LH increases, FSH progressively and LH in pulsatile fashion. In the interstitial tissue, the numbers of Leydig cells also increase. The increase in LH secretion and in leydig cell numbers leads to an increase in testosterone secretion, so that a little before puberty the system of LH-testosterone feedback is fully operational. The testicle then reaches the prepubertal phase, where the supporting cells stop dividing and differentiate to become the highly specialised Sertoli cells. Thereafter, their numbers remain almost constant. the gonocytes now begin rapidly dividing and differentiating, their rate of division resulting in a drastic increase in testicular size. The end result of their division and differentiation is that the testicle begins to produce spermatozoa. Very few are produced at first, but eventually production reaches adult levels and the testis begins to show normal spermatogenic cycle. Also during this phase, the pulsatile secretion of LH and testosterone continue and the secretion of FSH increases. The developments of these two systems are not unrelated. The division of the supporting cells and their maturation into Sertoli cells are under the control of LH in synergy with FSH, while the differentiation of primordial cells into spermatogonia and the subsequent production of spermatozoa are under the control of FSH, LH and testosterone.

Androgens↗
PubMed1996

[The effect of many years of hemodialysis therapy on hypophyseal-gonadal axis function in males with chronic renal insufficiency].

The study aims at evaluating an effect of hemodialyses duration on LH, FSH, and testosterone secretion in males with chronic renal insufficiency. Secretion of these hormones was assessed with LH-RH stimulation test in 41 men with chronic renal insufficiency and 15 healthy controls. Increased LH and FSH and decreased testosterone serum levels were seen in men with chronic renal insufficiency in comparison with healthy controls, independently of hemodialysis therapy duration. Duration of the treatment with hemodialyses has no significant effect on LH levels. Testosterone and FSH levels were significantly higher in patients treated over 50 months than those treated for shorter periods. Reactivity of LH secretion in LH-RH stimulation test was lower in patients dialysed for less than 100 months whereas in patients dialysed for over 100 months it was normal. Reactivity of testosterone secretion was higher in patients dialysed for over 50 months that those dialysed for shorter periods of time.

Adult↗
PubMed1997

Testosterone pharmacokinetics after application of an investigational transdermal system in hypogonadal men.

This open-label, randomized, placebo lead-in, three-treatment crossover study in 19 hypogonadal men (27-82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

Administration, Cutaneous↗
PubMed1993

The sleep EEG and nocturnal hormonal secretion studies on changes during the course of depression and on effects of CNS-active drugs.

1. The sleep EEG and nocturnal hormone secretion were studied simultaneously in normal male controls and in male patients with major endogenous depression before treatment with tricyclics and after recovery and drug cessation. 2. Several studies were performed in normal male controls to investigate the effect of antidepressants (brofaromine, moclobemide, amitriptyline, clomipramine and trimipramine) and of neuropeptides (CRH and the ACTH (4-9) fragment analog ebiratide) on the sleep EEG and sleep-associated hormone secretion. 3. Elevated cortisol and blunted testosterone secretion are state markers of acute depression, whereas sleep EEG, GH and prolactin variables do not show marked differences between acute depression and recovery. Except for trimipramine, all antidepressants investigated suppress REM sleep. No systematic relationship between the sleep EEG and endocrine effects of antidepressants is detectable. Pulsatile application of CRH in controls mimicks some of the neurobiological symptoms of acute depression. More shallow sleep occurs under ebiratide, whereas hormonal secretion remains unchanged. 4. Our data demonstrate that antidepressants exert distinct effects on sleep. However, these substances do not induce changes in sleep structure which persist after their withdrawal in remitted patients. Pulsatile application of neuropeptides leads to specific effects on CNS activity which are not mediated by changes of peripheral hormone secretion. The view that CRH plays a key role in the pathophysiology of affective disorders is corroborated.

Adult↗
PubMed1976

Endocrine effects of oestrogen treatment in patients with prostatic cancer.

In 36 men with prostatic cancer, the following findings were obtained: intravenous administration of 12.0 g diethylstilboestrol diphosphate (DSDP) induced a relatively slight decrease of the LH plasma level from 22.7 +/- 11.8 to 7.7 +/- 3.6 mIU/ml (34%), whereas the total testosterone plasma level decreased from 435.3 +/- 187.8 to 29.9 +/- 16.4 ng/100 ml (6.7%) suggesting a direct inhibitory effect of the oestrogen on testicular testosterone secretion. The apparently free, biologically active testosterone plasma level even decreased from 6.2 +/- 3.7 to 0.21 +/- 0.16 ng/100 ml (3.4%), due to the oestrogen-induced increase of the concentration of testosterone-binding beta-globulin (from 9.6 +/- 4.4 to 20.6 +/- 10.7-10(-8) M). 3--7 days after additional orchidectomy plus subcutaneous implantation of 100 mg dienoestrol diacetate a further decrease of the apparently free testosterone plasma level from 0.21 +/- 0.16 to 0.14 +/- 0.07 ng/100 ml was found. In contrast, 6 weeks after orchidectomy without oestrogen implantation a significant increase of th- apparently free testosterone plasma level -rom 0.21 %/- 0.16 to 0.34 +/- 0.15 ng/100 ml was observed (p less than 0.01). In view of these findings the biologically active free testosterone plasma level appears to be even more suppressed by intravenous administration of high DSDP than by orchidectomy. The most effective suppression of apparently free testosterone was achieved, however, by oestrogen treatment combined with orchidectomy.

Aged↗
PubMed1981

Ovarian function in the ewe after active immunization against testosterone.

The secretion rates of testosterone measured during the last half of the oestrous cycle in 2 Merino crossbred ewes with utero-ovarian autotransplants were 1.95 +/- 0.34 ng/min and 2.48 +/- 0.63 ng/min. The secretion rate of testosterone was not correlated with the secretion rate of oestradiol or androstenedione in either ewe. Welsh Mountain ewes were actively immunized against testosterone-3-(O-carboxymethyl)-oxime-bovine serum albumin (testosterone-3-BSA) or BSA alone (controls). Immunization against testosterone-3-BSA (5 ewes) resulted in anovulation (2 ewes) and the disruption of oestrous cycles and irregular ovulations (2 ewes). The ovaries showed morphological and endocrinological evidence of over-stimulation. Numerous large non-atretic follicles were present and in those ewes still ovulating the numbers of corpora lutea (ovulation rate) were increased. The concentrations of androstenedione and of oestradiol in the ovarian venous plasma were also markedly increased when compared to those in control ewes. The plasma binding capacity for steroids and the jugular venous concentrations of steroids were higher in immunized ewes. The binding capacity of follicular fluid for testosterone was similar to that of jugular venous plasma from the same ewe. These results show that immunization against testosterone-3-BSA leads to a disruption of ovarian cycles and ovarian over-stimulation.

Androstenedione↗