Hypogonadotropic hypogonadism in nephrotic rats: increased sensitivity to negative feedback effects of testosterone

Pituitary-testicular function was examined in adult male rats with aminonucleoside-induced nephrotic syndrome as a model for similar disease in humans. Nephrotic rats developed androgen deficiency, as manifested by decreased prostate and seminal vesicle weights, lower serum total and free testosterone levels, and reduced testosterone release from testes incubated in vitro. Despite hypoandrogenism, the weight and histologic appearance of the testes (light microscopy) were not affected in nephrotic rats. This androgen deficiency seemed to be a consequence of decreased gonadotropin output rather than primary testicular failure, since both pituitary gonadotropin content and serum gonadotropin levels (basally and after luteinizing hormone releasing factor; LHRH) were reduced in nephrotic rats. In addition, the percentage increase in testosterone release by testes incubated in vitro after addition of exogenous gonadotropin was similar in nephrotic and control groups. However, gonadotropin output in nephrotic rats was not impaired in the absence of testis, since no reduction was seen in either post-castration serum gonadotropin levels in vivo or gonadotropin release from pituitaries incubated in vitro. This presumed inhibitory effect of the testis on gonadotropin output in nephrotic rats was confirmed directly by demonstrating an increased sensitivity to testosterone-mediated suppression of gonadotropins in castrate animals in vivo. The presence or absence of albumin also seemed to modulate the suppressive effect of testosterone on gonadotropin output from normal pituitaries incubated in vitro. We conclude that nephrotic male rats develop hypogonadotropic hypogonadism secondary to an increase in sensitivity of the pituitary to the negative feedback effects of testosterone.     

Influences of photoperiod on nuclear androgen receptor occupancy in neuroendocrine tissues of the golden hamster

Day length regulates the negative feedback potency of gonadal steroids upon luteinizing hormone (LH) in seasonal breeders such as the golden hamster. We have used an exchange assay employing 3H-R1881 to determine whether nuclear androgen plus receptor levels in the preoptic area, medial basal hypothalamus, or anterior pituitary differ between male hamsters maintained in long or short days. Cell nuclear androgen plus receptor levels in brain and anterior pituitary were significantly lower in intact males maintained in short days; these differences reflected significant decreases in testis size and serum testosterone (T levels upon exposure to inhibitory photoperiods. In castrated males in which serum T levels were 'clamped' by the insertion of T-filled Silastic capsules, exposure to short days was not correlated with an increase in preoptic area, medial basal hypothalamus, or anterior pituitary receptor occupancy even though T's negative feedback actions upon LH were clearly enhanced. In contrast, there were instances in which androgen receptor occupation was elevated in males exposed to long days. Our results suggest that in the male golden hamster, the well-documented increase in the ability of T to suppress LH secretion in short photoperiods cannot be attributed to an increase in receptor-mediated uptake and nuclear accumulation of androgen in target cells in the brain and anterior pituitary gland.     

Effects of castration or testosterone implants upon pituitary function in hypogonadal mice bearing normal foetal preoptic area grafts

Grafts of normal mouse preoptic area (POA) tissue into the third ventricle of gonadotrophin-releasing hormone (GnRH)-deficient hypogonadal (hpg) mice resulted in an elevation of pituitary GnRH receptors, an increased synthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland, an elevation of gonadal LH receptors and in the stimulation of steroidogenesis and spermatogenesis in the testis. In normal mice both castration or the subcutaneous implantation of testosterone capsules for 10 days reduced GnRH receptors, pituitary LH and FSH content, and the latter treatment also caused a 50% reduction in testicular LH receptors. In hpg mice bearing POA grafts testosterone implants failed to affect any of the above parameters, and castration failed to affect pituitary gonadotrophin hormone content, although there was a slight reduction in pituitary GnRH receptors after castration. These experiments suggest that neither the pituitary gonadotroph, nor the GnRH neurone represent major sites for the direct negative feedback of testosterone upon gonadotrophic hormone secretion in male mice.     

Alterations in spermatogenic activity and hormonal status in a seasonally breeding rat,Rattus fuscipes

The changes in the levels of serum FSH, LH, and testosterone have been studied during the seasonal reproductive cycle in males of the species Rattus fuscipes. In males captured in winter the seminiferous tubules were small, spermatogenesis was arrested at the primary spermatocyte stage, and the Sertoli cells contained increased numbers of lipid inclusions. The Leydig cells were atrophic and contained large crystalloids. The aspermatic state was accompanied by low levels of serum FSH, LH, and androgen. Reactivation of spermatogenesis occurred in spring and was accompanied by a rise in the levels of FSH, LH, and androgen. These hormonal changes were associated with a depletion of lipid inclusions from the Sertoli cells which paralleled the activation of spermatogenesis. The rising androgen levels were accompanied by the enlargement of Leydig cells and the disappearance of the crystalloids. In summer the fully active testes were associated with further increments of serum FSH and androgen levels above those seen during spring. It is concluded that the environmental cues controlling the seasonal reproductive cycle exert their influence on the testis through changes in gonadotrophin secretion by the pituitary gland.     

Gonadal regulation of pituitary hormone mRNA levels in male rats

The control of anterior pituitary hormone gene expression by testosterone in male rat pituitaries in vivo was investigated using dot-blot mRNA-cDNA hybridization assays. Common alpha subunit mRNA levels doubled by 2 days after orchidectomy and rose progressively to reach plateau levels three to four times intact control values by 2 weeks. LH-beta mRNA increased significantly (congruent to 50%) within 12 h, and thereafter progressively to seven times intact control values by 3 weeks after orchidectomy. The changes in alpha mRNA were likely to have occurred in gonadotrophs and not thyrotrophs, since TSH-beta mRNA levels were unaltered by orchidectomy. LH subunit mRNA changes were accompanied by an initial (1-4 days) decrease in pituitary LH content; thereafter, pituitary LH increased in parallel with and by a similar magnitude to the LH-beta mRNA. Serum LH rises occurred before significant increases in LH subunit mRNA after orchidectomy. The lack of temporal correlation between mRNA levels and serum and pituitary LH in the early stages after removal of testosterone feedback contrasts with the good correlation when a new steady state was achieved after 3-4 weeks, and indicates differing kinetics for changes in these aspects of gonadotroph function. An inhibitory effect of testosterone on LH subunit gene expression was confirmed by prevention of the rise in alpha and LH-beta mRNAs when treatment commenced immediately after castration. However, pituitary LH content and serum LH levels were reduced relative to control values, suggesting additional inhibitory actions of testosterone on translational and post-translational events in gonadotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early effects of pinealectomy on LH and testosterone secretion in white-tailed deer

The early effects of pinealectomy on LH and testosterone secretion were studied in 11 white-tailed bucks. Six bucks were pinealectomized and three were sham-operated in early march at 9 months of age. Two unoperated bucks of the same age were also followed. The response of the pituitary gland and testis to LH releasing hormone (LHRH) was monitored for 2h each month for 1 year by radioimmunoassay of serum LH and testosterone. Prestimulation levels of LH (expressed as microgram NIH-oLH-S7) exhibited a cosinor curve pattern over the year (P less than 0.002) with levels ranging between 0.1 and 3.9 micrograms/l. Highest levels in pinealectomized males occurred in May 2 months after surgery and in control (sham-operated and unoperated) males in August. Maximal LH response to LHRH was characterized by a double-peaked curve in serum LH with the early peak around 20 min and a later peak at about 2h after injection. Maximal response to LHRH occurred in May in pinealectomized bucks and in August in control bucks. Baseline testosterone concentrations and testosterone response to LHRH varied in a seasonal fashion throughout the 12-month period in control bucks (P less than 0.001) but not in pinealectomized bucks. Baseline testosterone concentration and testosterone response to LHRH rose within 2 months after surgery in pinealectomized bucks and remained relatively constant for the next 10 months. These data demonstrate an early effect of pinealectomy on LH and testosterone secretion in 9-month-old animals kept under conditions of natural photoperiod and suggest differences in the response to pinealectomy by the pituitary gland and testes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prepubertal treatment of rats with clomiphene citrate affects postpubertal testicular development

A previous study showed that clomiphene citrate (clomiphene) reduced serum and pituitary gonadotropins and impaired testis growth and steroidogenesis in 10-day-old rats treated for up to two weeks. The present study was conducted to assess the effect of prepubertal clomiphene treatment on postpubertal pituitary-testicular function. Rats were implanted with pellets that released 0, 0.05, 0.5 or 5.0 mg clomiphene.kg-1.day-1 between 10-31 days of age and were killed at 90 days of age. Testis and prostate weights in treated rats were reduced (P less than 0.05), whereas serum LH, FSH and testosterone, and pituitary gonadotropin and GnRH receptor concentrations had recovered to levels observed in control rats. Testicular FSH receptor concentrations were not altered; however, FSH receptor content was decreased (P less than 0.05) in clomiphene-treated rats proportional to the reduction in testicular weight. In contrast, testicular LH and GnRH receptor concentrations were increased (P less than 0.05) in treated animals, resulting in similar receptor contents. Daily sperm production per gram of parenchyma was unaffected, while daily sperm production per testis was decreased in treated rats (P less than 0.05). These data show early postnatal treatment with clomiphene does not permanently impair pituitary function. Despite reduced testicular mass, normal serum testosterone concentrations and testis LH receptor content of treated rats suggest recovered Leydig cell function. The decreased content of testicular FSH receptors and reduced sperm production suggest seminiferous tubule function was compromised in the adult rat.     

Ionic and endocrine factors influencing the secretion of luteinizing hormone by chicken anterior pituitary cells in vitro

A dispersed cell incubation technique has been used to study the effects of various factors associated with calcium deficiency and steroid hormones on LH release by the chicken anterior pituitary gland. In vitro LH secretion was reduced in the presence of low medium calcium concentration and also by bovine parathyroid hormone. The inclusion of 1,25-dihydroxycholecalciferol in the incubation medium prevented the stimulation of LH release by LH releasing hormone (LHRH). These results may be of significance in relation to the loss of reproductive activity in the calcium-deficient hen. Progesterone had no effect on LH production by the incubated cells, whereas testosterone enhanced LH output and its effect could be prevented by the androgen antagonist cyproterone acetate. Oestradiol reduced LH release and prevented stimulation by LHRH.     

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)     

Changes in pituitary LHRH receptor levels in situations of increased or decreased gonadotrophin secretion in the male rat

Anterior pituitary LHRH receptor numbers were studied by measuring binding of ¹²⁵I-labelled (d-Ser-Bu^t)⁶-des-Gly¹⁰ LHRH ethylamide in male rats in which gonadotrophin output is markedly altered. Rats made hyperprolactinaemic by transplantation of 2 pituitary glands under the kidney capsule 98 days previously had significantly lower pituitary contents and serum levels of LH and FSH than controls, although serum concentrations of testosterone remained within the normal range. Pituitary LHRH receptor numbers in these animals were significantly reduced. A condition of further suppression of pituitary contents and serum levels of LH and FSH was achieved by active immunization against LHRH for one year, which also reduced serum concentrations of testosterone to non-detectable levels. This was associated with a marked reduction in LHRH receptor numbers. In contrast, rats castrated 49 days previously demonstrated the expected marked rise in pituitary content and serum levels of LH and FSH and had a marked rise in the number of pituitary LHRH receptors. Castration of animals with pituitary transplants resulted in a similar response. Rats in which testosterone was neutralized by active immunization also showed an increase in pituitary contents and serum levels of LH and FSH, but these changes were lower than in castrated rats, probably owing to the presence of small amounts of non-antibody-bound testosterone. These animals had only a marginal rise in pituitary LHRH receptor numbers.Our results, showing a lowering in LHRH receptors when hypothalamic LHRH stimulation of the pituitary is thought to be reduced (hyperprolactinaemia and LHRH immunization) and an elevation in receptors when LHRH output is thought to be increased (castration and testosterone immunization), add further support to the view that LHRH regulates its own receptors.     

Effect of chronic administration of estrogen, androgen, or both on serum levels of gonadotropins in adult men.

Ethinyl estradiol (50 micrograms/day) or fluoxymesterone (10 or 20 mg/day), chosen because each is orally active and because fluoxymesterone is probably not converted to an estrogen, were given alone and in combination to adult men over several weeks. Measurements were made of serum FSH, LH, testosterone, and estradiol. The estrogen given alone suppressed serum FSH while the androgen given alone did not; however, the androgen may have enhanced the suppressive effect of the estrogen on the serum FSH. Neither steroid alone changed the serum LH but both together suppressed it. The estrogen alone decreased the serum testosterone, an effect probably mediated by the concomitant fall in serum FSH and a resulting decrease in sensitivity to the constant level of LH; a direct effect of estrogen on the testis seems less likely. The doses of estrogen and androgen used probably had a biologic effect equal to or somewhat above that of endogenously produced estrogen and androgen and thus reflected the maximum physiological effects of the endogenous steroids. Thus, in the chronic physiological control of FSH and LH in adult men, these data indicate that (1) testosterone alone, as an androgen, has little effect on FSH or LH, (2) estradiol (or total estrogen) has a greater suppressive effect on FSH than on LH and by its effect on FSH may indirectly regulate the secretion of testosterone, and (3) testosterone and estradiol together may be involved in the regulation of both FSH and LH.     

LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis.

The demonstration of an inhibitory effect of gonadotropin-releasing hormone (GnRH) agonists upon steroidogenesis in hypophysectomized rats and the presence of mRNA coding for GnRH and GnRH receptors (GnRH-R) in rat gonads suggests that GnRH can act locally in the gonads. To assess this hypothesis, we investigated the effects of GnRH analogs, gonadotropins and testosterone on the levels of both GnRH and GnRH-R mRNA in the rat testis. Using dot blot hybridization, we measured the mRNA levels 2 to 120 h after the administration of the GnRH agonist, triptorelin. We observed an acute reduction of both GnRH and GnRH-R mRNAs 24 h after the injection (about 38% of control). However, the kinetics for testis GnRH-R mRNA were different from those previously found for pituitary GnRH-R mRNA under the same conditions. Initially, the concentrations of serum LH and FSH peaked, then declined, probably due to the desensitization of the gonadotrope cells. In contrast, the GnRH antagonist, antarelix, after 8 h induced a 2.5-fold increase in GnRH-R mRNA, but not in GnRH mRNA, while gonadotropins levels were reduced. Human recombinant FSH had no significant effect on either GnRH or GnRH-R mRNA levels. Inversely, GnRH-R mRNA levels markedly decreased by 21% of that of control 24 h after hCG injection. Finally, 24 h after testosterone injection, a significant increase in GnRH-R mRNA levels (2.3 fold vs control) was found, but a reduction in the concentration of serum LH, probably by negative feedback on the pituitary, was observed. In contrast, GnRH mRNA levels were not significantly altered following testosterone treatment. Since LH receptors, GnRH-R and testosterone synthesis are colocalized in Leydig cells, our data suggest that LH could inhibit the GnRH-R gene expression or decrease the GnRH-R mRNA stability in the testis. However, this does not exclude the possibility that GnRH analogs could also affect the GnRH-R mRNA levels via direct binding to testicular GnRH-R. In contrast, the regulation of GnRH mRNA levels appeared to be independent of gonadotropins. Taken together, our results suggest a regulation of GnRH and GnRH-R mRNA specific for the testis.     

Effect of intratesticular administration of gonadotropins on testicular and plasma androgen concentration in the lizard, Uromastix hardwicki

An acute effect of intratesticular injections of varying doses of ovine FSH (NIH-FSH-S12), ovine LH (NIH-LH-S20), and a lizard hypophyseal extract was observed on testicular and plasma androgen concentrations in Uromastix hardwicki. FSH and LH were used in a dose range of 0.25–4.00 ng and the hypophyseal extract was administered at concentrations representing 10–160 μg of fresh pituitary tissue obtained from adult male Uromastix. The test material was injected directly into one testis while the contralateral testis was likewise treated with an equal volume of saline. The control lizards received intratesticular injections of saline on both sides. Testicular and plasma androgen concentrations were measured 3 hr following the injections, using a specific RIA for testosterone. A significant increase in androgen concentration both in the testis and the plasma was obtained with 0.25 ng of FSH and 4.00 ng of LH. Both FSH and LH induced a significant rise in plasma androgen at 1.00 ng, but the increase was markedly greater in the FSH treated lizards. The homologous hypophyseal extract was shown to be active at the minimum dose level used (10 μg). The testosterone content of the uninjected testis in treated lizards was not significantly different from that of the control lizards. It is concluded that the intratesticular route of administration can be used as a sensitive and rapid method for studying in vivo responsiveness of the testis to mammalian and nonmammalian gonadotropins.     

The effect of induced hyperprolactinaemia on Leydig cell function and LH-induced loss of LH-receptors in the rat testis.

Anterior pituitary glands were transplanted beneath the kidney capsule of intact, adult male rats to induce hyperprolactinaemia. This resulted in reduced serum levels of LH and FSH and increased adrenal weight. In pituitary-transplanted rats, testicular hCG-receptor binding was increased by 55 to 175%, whilst the capacity of the testis to secrete testosterone in vitro was greatly reduced. Injection of ovine LH into control and pituitary-transplanted rats resulted in similar percentage reductions in hCG-receptor binding in the two groups. This treatment impaired the in vitro steroidogenic responsiveness of testes from control rats at 24 h after injection, but had no major effect on the already-impaired, steroidogenic responsiveness of testes from pituitary-transplanted rats. Although induction of hyperprolactinaemia resulted in marked changes in Leydig cell function, these alterations were possibly due to the chronically reduced serum gonadotrophin levels in hyperprolactinaemic rats as well as a direct effect of prolactin on the Leydig cell.     

Influence of pinealectomy on the suppression of gonadotropin secretion induced by hyperprolactinaemia in the adult male rat

To investigate the role of the pineal gland in the long-term suppression of gonadotrophin secretion induced by prolactin, the effects of pinealectomy were studied in adult male rats with hyperprolactinaemia produced by the transplantation of two pituitary glands under the kidney capsule. Pinealectomy had no effect on basal levels of LH, FSH or prolactin. The presence of pituitary transplants induced a significant twofold increase in prolactin levels and a prolonged suppression in both LH and FSH. These changes were not affected by pinealectomy. Castration resulted in a similar rise in plasma levels of LH and FSH in rats with and without pituitary transplants. In control rats this rise in LH and FSH was reduced by testosterone-containing silicone elastomer implants (s.c) of 10 mm in length and delayed by implants of 30 mm. These rises in LH and FSH were significantly delayed (10-mm implant) or abolished (30-mm implant) in rats with pituitary transplants indicating an increase in sensitivity of the hypothalamic-pituitary axis to the negative feedback effects of testosterone in these animals compared to controls. These responses were not affected by pinealectomy. These results suggest that the pineal gland is not involved in the mechanism whereby pituitary grafts, possibly through their secretion of prolactin, cause long-term suppression of gonadotrophin secretion.     

Disruption of the joint synchrony of luteinizing hormone, testosterone, and androstenedione secretion in adolescents with polycystic ovarian syndrome

The present study explores the postulate that the polycystic ovarian syndrome (PCOS) is marked by failure of physiological feedforward and feedback signaling between pituitary LH and ovarian androgens. To this end, we appraised the 3-fold simultaneous overnight release of LH (assayed by high precision immunofluorometry), testosterone (RIA), and androstenedione (RIA) in 12 an- or oligoovulatory adolescents with PCOS (mean +/- SEM age, 16.4 +/- 0.47 yr) and 10 eumenorrheic girls (age, 16.5 +/- 0.45 yr). Gynecological (postmenarchal) ages (years) were also comparable at 4.8 +/- 0.39 (PCOS) and 4.0 +/- 3.6 (control; P = NS). Body mass index and fasting serum insulin and estradiol concentrations were indistinguishable in the two study cohorts. Mean overnight serum concentrations of LH (assayed by both immunofluorometry and Leydig cell bioassay), testosterone, androstenedione, and 17alpha-hydroxyprogesterone were each elevated significantly in patients with PCOS (all P 相似文献   

Antifertility effects of estradiol in adult male rats.

The dose-related effects of estradiol 17-beta at the doses 0.1 pg, 10 microg, 100 microg, 200 microg, 300 microg, 400 microg, 1,000 microg/kg/day were determined on sperm motility, potency, fertility parameters, serum levels of LH, FSH, PRL and testosterone, weights of testes and accessory sex organs, weights of pituitary and adrenal glands. The drug was administered daily via sc route for a period of 60 days. Dose-related effects on fertility parameters of the estradiol-treated male rats were ascertained by allowing them to mate with normal cycling female rats. Estradiol at 0.1 microg/kg/day dose significantly reduced sperm motility with no effects seen on potency or fecundity, serum LH, FSH, PRL or testosterone, weights of testes and accessory sex organs while pituitary weight increased. Estradiol at 10 microg/kg/day dose significantly reduced motility, serum LH, FSH, weights of testes and accessory sex organs, while pituitary weight increased with no effects seen on potency, fecundity, PRL or testosterone. Estradiol at 100-1,000 microg/kg/day dose significantly reduced motility, potency and fecundity, serum LH, FSH and testosterone, weights of testes and accessory sex organs while serum PRL and the weights of pituitary and adrenal glands increased significantly. Histology of the testes revealed disorganization of the cytoarchitecture in the seminiferous tubules, vacuolation, absence of lumen and compartmentalization of spermatogenesis. Estradiol withdrawal, testosterone propionate at 100 pg/kg/day or antiestrogen (tamoxifen citrate) at 400 microg/kg/day prevented the histological changes. It is conduded that estradiol reduces sperm motility even at a low dose. Low doses (<10 microg/kg/ day) appear to maintain whilst high doses (>10 microg/kg/day) reversibly disrupt spermatogenesis. Prevention of disruption by testosterone or antiestrogen indicates crosstalk between androgen and estrogen receptors in Sertoli cells. Loss of potency and fecundity also suggests effects on crosstalk between these receptors in other male reproductive organs.     

Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis.

Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an alpha beta heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the alpha beta heterodimer, the beta beta homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrating the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, we have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the alpha beta heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the beta beta homodimer suppresses androgen production. Furthermore, similar modulatory actions of inhibin-related proteins were found in cultured ovarian theca-interstitial cells and theca explants treated with LH. In contrast, treatment with the inhibin-related proteins alone did not affect gonadal steroidogenesis. Our data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops.     

Increased sensitivity to the negative feedback effects of testosterone induced by hyperprolactinemia in the adult male rat

High plasma levels of PRL induced by transplants of two donor pituitaries under the kidney capsule of adult male rats resulted in a prolonged suppression of plasma levels of LH and FSH although testosterone levels were maintained within normal limits. Castration of rats with pituitary transplants resulted in a normal though delayed rise in serum levels of both LH and FSH to levels equivalent to those in normal castrated controls. This increase in gonadotropin levels occurred in spite of maintenance of elevated PRL levels. Two experiments were carried out in which testosterone was restored after castration by Silastic testosterone-containing implants of various lengths (Exp 1:60, 30, and 10 mm; Exp 2: 30, 20, 10, 5, and 2 mm). In both experiments 60- and 30-mm testosterone implants prevented the postcastration rise in LH and FSH in both control and hyperprolactinemic rats. However, although the shorter testosterone implants delayed this rise in control rats, levels of LH and FSH increased by 4 days and were not significantly different from castrated rats without testosterone implants by 15 days after castration. In contrast, this rise in gonadotropins was abolished or considerably delayed by the shorter implants in hyperprolactinemic rats, demonstrating an increase in sensitivity of the hypothalamic pituitary axis to the negative feedback effects of testosterone in these animals. These results suggest that 1) to maintain suppression of gonadotropin secretion in hyperprolactinemia high levels of PRL alone are insufficient and gonadal steroids are required, and 2) high levels of PRL appear to sensitize the hypothalamic-pituitary axis to the negative feedback effects of gonadal steroids.     

Effect of testosterone on gonadotrophin-releasing hormone receptors in the castrated rat: preliminary evidence for a stimulatory effect of testosterone on gonadotrophin function in the male rat

In the long-term castrated rat the negative feedback effect of testosterone is markedly reduced and the raised levels of plasma LH seen in the castrated animals are not suppressed by physiological concentrations of plasma testosterone. In this study we have measured pituitary gonadotrophin-releasing hormone (GnRH) receptor content as well as plasma and pituitary LH on days 1, 10 and 40 after castration and noted the effect of testosterone replacement on these parameters. We found that the negative feedback effect of physiological concentrations of testosterone on plasma and pituitary LH, pituitary GnRH receptor content and response to exogenous GnRH was attenuated 10 and 40 days after castration. It is suggested that the lack of effect of testosterone in the long-term castrated rat is due to its inability to reduce the pituitary GnRH receptor content. On increasing testosterone to supraphysiological levels, the negative feedback effect was reinstated. We also found that in rats 40 days after castration, physiological and subphysiological concentrations of testosterone significantly increased pituitary GnRH receptor content and this may explain the previous findings that low concentrations of testosterone can enhance the effect of GnRH and increase plasma LH levels.