Effects of human growth hormone on reproductive and neuroendocrine functions in transgenic mice.
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Animals↗
Biomedical subjects
R W Steger
Publications and source records attributed to R W Steger.
Alterations in hypothalamic serotonin metabolism in male hamsters with photoperiod-induced testicular regression.
Transfer of adult male golden hamsters to a short photoperiod (SD; 8L:16D) resulted in a significant decrease in testicular weight and plasma luteinizing hormone (LH) and prolactin (Prl) levels as compared to animals maintained in a long photoperiod (LD; 16L:8D). These changes were accompanied by significant increases in serotonin (5-HT) synthesis in the medial basal hypothalamus (MBH) as determined by measuring 5-hydroxytryptophan accumulation after inhibition of aromatic amino acid decarboxylase with NSD-1015. Serotonin synthesis in the median eminence, anterior hypothalamus and olfactory bulbs was not different in SD vs LD animals. Transfer of SD gonadally regressed hamsters to LD restored MBH 5-HT synthesis to control levels.
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Diurnal variations in brain serotonin are driven by the photic cycle and are not circadian in nature.
In an effort to determine the driving force of the diurnal variation of serotonin (5-HT) in the brain, over 500 Syrian hamsters were exposed to long photoperiods (LD17:7; LD), short photoperiods (LD8:16; SD), constant dark (DD) or constant light (LL) for 12 weeks. Hamsters exposed to LD or SD were sacrificed at 3 h intervals; those in constant conditions were sacrificed around the clock. The circadian time (CT) of tissue collection, in the animals in constant conditions, was determined from the onset of locomotor activity (defined as CT12; the beginning of the subjective night). Serotonin content was determined by HPLC with electrochemical detection in the medial basal hypothalamus (MBH); anterior hypothalamus (AH) and olfactory bulbs (OB). In LD and SD, 5-HT levels displayed significant diurnal variation in the MBH, AH and OB (ANOVA; P less than 0.001). The sine waves of the 5-HT rhythm in these conditions were similar in amplitude and phase with relation to lights on (i.e. high 5-HT content during the day and low content at night, with a sharp rise occurring just after lights on). This variation, however, was not apparent in animals exposed to DD or LL; 5-HT content did not display a significant diurnal oscillation. Since 5-HT failed to oscillate in the absence of environmental time cues, the rhythm is likely driven by the environment and not an internal circadian clock.
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Testosterone replacement fails to reverse the adverse effects of streptozotocin-induced diabetes on sexual behavior in the male rat.
The ability of testosterone to reverse the adverse effects of streptozotocin-induced (STZ) diabetes on male sexual function was tested in adult male rats. Treatment with STZ (50 mg/kg) led to a significant reduction of plasma testosterone (T) levels and in the number of rats exhibiting ejaculatory behavior in a 30-minute test period. A similar reduction in T levels and ejaculatory behavior was seen in rats subjected to caloric restriction to mimic the weight loss seen in the STZ-treated rats. T-replacement (200 micrograms/day) restored T levels to those seen in control animals, but did not reverse the adverse effects of STZ on copulatory behavior. STZ-induced changes in copulatory behavior were associated with changes in hypothalamic LHRH levels and catecholamine turnover. Caloric restriction also caused endocrine and neuroendocrine changes, but they were not similar to those seen in STZ rats suggesting that these two treatments affect copulatory behavior by different mechanisms.
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Effects of psychoactive and nonpsychoactive cannabinoids on the hypothalamic-pituitary axis of the adult male rat.
The acute dose-response effects of delta-9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) on gonadotropin and testosterone (T) secretion and on hypothalamic norepinephrine (NE) metabolism were tested in adult male rats. THC and CBN both produced an acute suppression of plasma-luteinizing hormone (LH) and T levels and median eminence NE turnover although a dose-response relationship could not be demonstrated. CBD had no significant effect on any of these parameters and none of these cannabinoids had any effect on plasma follicle-stimulating hormone levels or median eminence LH-releasing hormone (LHRH) content. Except for the highest dose of CBN, none of the in vivo cannabinoid treatments significantly altered in vitro LH secretion although there was a trend towards decreased LH secretion. These results suggest that the decrease in LH secretion in THC- or CBN-treated rats is due to reductions in NE stimulation of LHRH release rather than to changes in LHRH synthesis or pituitary LHRH response.
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Effects of melatonin injections on the ability of golden hamster pituitaries to secrete prolactin and luteinizing hormone.
Chronic afternoon (PM) but not morning injections of melatonin (MEL) induced significant reductions in testicular and seminal vesicle weights as well as attenuating serum prolactin (PRL) and luteinizing hormone (LH) levels. Although there were no treatment-induced effects on hemipituitary weights, PM-Mel injections led to significant reductions in in vitro PRL secretion and tended to increase the ability of dopamine to inhibit PRL release. It was also shown that LH-releasing hormone (LHRH) could inhibit in vitro PRL release from hamster pituitaries. Basal or LHRH-stimulated LH secretion from incubated pituitaries was not affected by Mel in vivo. From these results we conclude that properly timed Mel injections do not reduce pituitary's ability to secrete LH but severely attenuate PRL secretion. These findings are similar to those observed in pituitaries from hamsters housed in short-photoperiod conditions.
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Neuroendocrine function in transgenic male mice with human growth hormone expression.
The neuroendocrine effects of human growth hormone (hGH) secretion were studied in adult male mice into which an hGH gene fused with mouse metallothionein 1 (mMT-1) promoter had been introduced. Intact transgenic mice had significantly greater plasma luteinizing hormone (LH) levels than did normal littermate controls. Castration increased LH levels in normal mice but was without effect on plasma LH levels in the transgenic mice. In vitro LH secretion and pituitary LH content were higher in the intact transgenic mice than in intact controls, while there was no significant difference in pituitary LH levels and in vitro LH secretion between the 2 groups of castrate animals. Intact transgenic mice exhibited a greater median eminence (ME) norepinephrine (NE) turnover than control animals, but ME NE turnover did not increase after castration in the transgenic animals as was the case in control mice. Castrate mice expressing the hGH gene had plasma levels of prolactin (PRL) similar to those seen in castrate controls, which was unexpected based on a previous study showing greatly attenuated PRL levels in intact hGH mice when compared to intact controls from the same line. Dopamine (DA) turnover in the ME was not significantly affected by the presence of the hGH gene, suggesting that the difference in plasma PRL levels between normal and transgenic mice is mediated through changes in PRL-regulating factors other than DA. In conclusion, the expression of the mMT-1/hGH hybrid gene in male mice leads to major alterations in LH secretion and lesser changes in PRL secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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Tryptophan administration inhibits nocturnal N-acetyltransferase activity and melatonin content in the rat pineal gland. Evidence that serotonin modulates melatonin production via a receptor-mediated mechanism.
In the rat pineal gland, the activity of serotonin N-acetyltransferase (NAT) and the concentration of melatonin are normally high at night; conversely, the concentration of serotonin (5-HT), the precursor of melatonin, is low. Since tryptophan administration increases the concentration of pineal 5-HT at night, we examined its effect of melatonin production. Nighttime tryptophan loading led to substantial increases in pineal 5-hydroxytryptophan, 5-hydroxyindole acetic acid (5-HIAA), and 5-HT but a highly significant reduction in NAT activity in comparison to saline-injected controls. In contrast to other measured indoles, melatonin levels also were significantly diminished by tryptophan loading. Nocturnally high pineal norepinephrine levels were unaltered by tryptophan administration. The idea that high concentrations of 5-HT could lead to substrate inhibition of NAT activity was not supported by kinetic analysis of control NAT levels versus tryptophan-inhibited NAT activity under varied substrate concentrations. Hypotheses to explain these results include the possibility that tryptophan inhibition of melatonin synthesis is mediated by the release of 5-HT from the pinealocyte and its subsequent autocrine action on melatonin production.
5-Hydroxytryptophan↗
Effects of delta-9-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combinations, on luteinizing hormone and prolactin release and on hypothalamic neurotransmitters in the male rat.
The acute effects of low oral doses of delta 9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) administered alone or in combinations on LH and prolactin (PRL) secretion and on hypothalamic norepinephrine (NE), dopamine (DA) and serotonin (5-HT) dynamics were examined in adult male rats. Plasma LH levels were significantly reduced 60 min after administration of 0.5 mg THC/kg body weight and 30, 60 and 120 min after administration of THC + CBN or THC + CBD. There were no changes in plasma PRL in response to cannabinoid treatments. The turnover of NE in both the median eminence (ME) and medial basal hypothalamus (MBH) was dramatically affected by all the cannabinoid treatments. Complete suppression of NE turnover occurred 30 min post-THC and 120 min post-THC + CBN in the ME and 120 min post-THC + CBD in the MBH. Cannabinoids did not significantly affect DA turnover in the MBH or the content of NE, DA, 5-HT or 5-hydroxyindole-3-acetic acid in either the ME or MBH. These data demonstrate that treatment of adult male rats with a low dose of THC suppresses LH secretion and that CBN and CBD potentiate this action of THC. Although the mechanisms responsible for the inhibition of LH release by cannabinoids cannot be positively identified from these experiments, the results suggest that alterations in hypothalamic noradrenergic activity may be involved in this effect.
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Influence of photoinhibition, photostimulation and prolactin on pituitary and hypothalamic nuclear androgen receptors in the male hamster.
Testosterone (T) feedback sensitivity is markedly altered in adult male golden hamsters following exposure to short photoperiods (SD). Using a technique which measures total androgen receptors within the cell nucleus, the present study examined pituitary and hypothalamic nuclear androgen receptor levels in animals exposed to (1) long days (LD) or SD in the presence and absence of a constant T level supplied via a Silastic implant, (2) photostimulation following SD-induced testicular regression and (3) short-term prolactin injections following SD-induced testicular regression. Short photoperiods were associated with a drop in nuclear androgen receptor levels which was correlated with a decline in circulating T. When constant T was supplied to gonadectomized hamsters, those exposed to SD possessed higher pituitary and similar hypothalamic nuclear androgen receptor levels than those exposed to LD. As expected, plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were greatly reduced in SD-exposed, castrated, T-treated hamsters as compared to LD-exposed, castrated, T-treated animals. Photostimulation of intact SD-exposed hamsters for 5 or 10 days was associated with a decline in pituitary nuclear androgen receptors. Prolactin treatment caused no noticeable change in pituitary or hypothalamic androgen receptors even though plasma LH and FSH levels were significantly increased. These results support the hypothesis that altered T feedback mechanisms controlling LH and FSH release following chronic exposure to SD may be related to an alteration in the amount of androgen receptors present in the anterior pituitary.
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Effect of continuous versus delayed insulin replacement on sex behavior and neuroendocrine function in diabetic male rats.
The ability of insulin replacement to reverse the adverse effects of streptozocin-induced diabetes (STZ-D) on neuroendocrine and sexual function was tested in adult male rats. Rats were injected with STZ (50 mg/kg) or vehicle and then either started immediately on insulin (continuous) or allowed to remain untreated for 4 wk before insulin replacement was started (delayed). Replacement consisted of 5 IU/kg of insulin injected just before the lights were turned off and 2 IU/kg of insulin injected within 1 h of the lights being turned on. Copulatory behavior was tested 2, 4, 5, and 6 wk after induction of diabetes. Forty-five days after STZ administration, rats were killed for measurement of plasma hormone levels and hypothalamic catecholamine turnover and serotonin content. The STZ-D rats showed significant deficits in mount, intromission, and ejaculatory behaviors that were prevented by continuous insulin replacement. Delayed insulin replacement reversed the deficits in mount and intromission behaviors but not ejaculatory behavior. Plasma luteinizing hormone levels were unaffected by STZ or insulin treatment, but plasma testosterone and prolactin levels were both reduced in the diabetic animals. Continuous or delayed insulin replacement normalized both testosterone and prolactin levels. Median eminence, medial basal hypothalamus, anterior hypothalamus, and olfactory bulb rates of norepinephrine turnover were all reduced after STZ administration. Delayed insulin replacement restored norepinephrine turnover in all brain regions, whereas continuous insulin replacement enhanced norepinephrine turnover in the anterior hypothalamus and olfactory bulb but only partially blocked the effects of STZ in the median eminence and medial basal hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)
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Regulation of GH and TSH release from hyperplastic and ectopic pituitaries: effects of dopamine in vitro.
This study was undertaken to examine the consequences of prolonged removal of the pituitary from hypothalamic control and of estrogen-induced pituitary tumors on the susceptibility of GH and TSH release to regulatory influences of dopamine (DA). Adult male Fischer 344 rats were treated with transplants of female anterior pituitaries under the renal capsule or with Silastic capsules containing diethylstilbestrol (DES). Capsules with DES remained in place until the animals were killed (DES-IN) or were removed 7 weeks prior to sacrificing the rats (DES-OUT). Both pituitary grafts and DES caused the expected elevation in plasma prolactin and suppression of plasma GH and TSH levels. Basal GH release in vitro was not affected by exposure to DES in vivo but was reduced by transplantation of the pituitary to an ectopic site. Treatment with DA in vitro suppressed GH release from the in situ pituitaries of control, DES treated and grafted rats but increased GH release from the ectopic pituitaries. Basal release of TSH in vitro was reduced in the pituitaries of DES-IN and DES-OUT animals but was not affected by the presence of pituitary transplants. No detectable TSH was released from the ectopic pituitaries in the absence of DA. DA decreased TSH release from the pituitaries of control, DES-OUT and DES-IN rats but not from the in situ pituitaries of grafted rats. In contrast, DA produced an increase in TSH release from ectopic pituitaries. These results demonstrate that somatotrophs and thyrotrophs removed from the hypothalamic influences on subjected to direct and indirect effects of DES exhibit abnormal responses to DA. We suspect that prolonged absence of normal pituitary control leads to the development of regulatory mechanism of pituitary hormone release which are different from those operating under physiological conditions.
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Effects of elevated gonadotropin levels on thyroid function in the male rat.
In order to determine if thyroid disease in hypogonadal men is the result of chronic elevation of serum gonadotropins, thyroid histology and serum thyroid hormone levels were evaluated in male rats that had been castrated either 2 weeks or 15 months previously. Despite significantly elevating serum LH levels, castration did not affect thyroid structure or function. Serum total T4 levels were reduced with age in both short and long-term castrate animals but returned to the levels seen in young rats when testosterone was replaced. Testosterone replacement also increased free T4 levels in both the young and old castrate rats. Neither age nor testosterone replacement affected serum T3 or TSH levels.
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Changes in the catecholamine metabolism in the adrenal medulla of male hamsters with experimental hyperprolactinemia.
1. Prolactin (PRL) can play a role as a physiological modulator of adrenal medulla function in several rodents. 2. We have examined the effects of hyperprolactinemia induced by ectopic pituitary grafts in Syrian hamsters on the adrenal medulla contents of catecholamines (CA) and their metabolites, as well as on the activities of several enzymes involved in the metabolism of these amines. 3. Increases in the peripheral levels of PRL in these animals were associated with decreases in adrenal medulla weight and increases in adrenal medulla contents of norepinephrine, epinephrine and vanilmandelic acid, the main degradative metabolite of CA, while adrenal medulla contents of the O-methylated derivatives of CA, normetanephrine and metanephrine, were unaltered. 4. These changes were correlated with increases in the adrenal medulla activity of monoamine oxidase, while the activities of tyrosine hydroxylase, phenylethanolamine-N-methyl transferase and catechol-O-methyl transferase were unaltered. 5. These results indicate that PRL is able to act on the adrenal medulla of hamsters by increasing the ability of these cells to metabolize CA via oxidative deamination.
Adrenal Medulla↗
Effects of diethylstilboestrol on testicular function and luteinizing hormone receptors.
Adult male Fisher-344 rats were implanted with DES-filled or empty Silastic capsules. After 14 weeks, capsules were removed and a second group of rats received DES capsules. Seven weeks later, all the rats were sacrificed. DES treatment decreased body, testes and seminal vesicle weights, and removal of the capsules partially restored the weight of these organs. The concentration of testicular LH receptors was increased by DES treatment. Circulating PRL levels were increased and gonadotropin levels were reduced in all animals having received DES at anytime. Plasma testosterone (T) levels were similar in all groups, but testicular T levels were reversibly decreased by DES. Similarly, whereas basal incubation media T levels were unchanged by DES treatment, the steroidogenic response in vitro to hCG was abolished by the presence of DES, and removal of the capsules restored this response. It appears that in this animal model DES and PRL exert opposing effects on testicular LH receptor.
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Catecholamine effects on testicular testosterone production in the gonadally active and the gonadally regressed adult golden hamster.
Several lines of evidence support a role of testicular innervation and peripheral catecholamines in the control of male gonadal function, particularly before puberty. It was therefore of interest to compare the effects of catecholamines on androgen production during the periods of gonadal activity and quiescence in a seasonally breeding species. We have examined direct effects of epinephrine (EPI), norepinephrine (NE), the beta-adrenergic agonist isoproterenol (ISO), and the alpha-adrenergic agonist phenylephrine (PHE) on testicular testosterone (T) production in hamsters with gonadal regression induced by 12 wk exposure to short photoperiod (SD) and in gonadally active hamsters maintained in long photoperiod (LD). Fragments of decapsulated testes were incubated with various combinations of these catecholamines (10(-5)-10(-9) M), human chorionic gonadotropin (hCG; 3.1 mIU/ml), the beta-receptor antagonist propranolol (10(-5) M) and the alpha-l-receptor antagonist prazosin (10(-5) M), for 6 h. In the incubations of testes from LD hamsters, the accumulation of T in the medium was stimulated by hCG but not affected by either catecholamine. However, EPI, NE, and PHE at 10(-5) M, but not ISO, augmented the stimulation of T by hCG. In sharp contrast to these findings, T production by the regressed testes of SD animals was stimulated by EPI (at 10(-8)-10(-5) M), NE (at 10(-6)-10(-5) M), and PHE (at 10(-6)-10(-5) M) in a dose-related manner, but unaffected by ISO. These stimulatory effects were prevented by prazosin, but not by propranolol. Moreover, 10(-5) M of EPI, NE, and PHE augmented the stimulatory effect of hCG on T production. We conclude that the seasonal transition from gonadal activity to quiescence in the adult golden hamster is accompanied by a major increase in the responsiveness of testicular steroidogenesis to catecholamines acting via the alpha-1-adrenoreceptor and that catecholamines can modulate Leydig cell response to gonadotropins in this species. These findings could be related to up-regulation of the alpha-1-receptor in the testis of the SD animal and suggest that catecholamines may be involved in the regulation of the testis during physiological suppression of gonadotropin release and during stress.
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Prolonged neuroendocrine effects of a brief exposure of adult male rats to diethylstilbestrol.
Eleven weeks of exposure to diethylstilbestrol (DES) releasing capsules caused marked changes in neuroendocrine function in male rats sacrificed 22 months later. Plasma prolactin levels were increased and plasma LH levels were decreased in the DES-exposed as compared to the control animals. DES-treated animals had significantly decreased levels of dopamine (DA) in the median eminence and lower rates of DOPA accumulation after blockade of aromatic amino acid decarboxylase than did the control animals. Norepinephrine and serotonin content and 5-hydroxytryptophan content in the ME, the medial basal and the anterior hypothalamus were not significantly affected by DES treatment. Basal prolactin release in vitro was reduced in the DES animals while prolactin responsiveness to inhibitory effects of 10(-7) M DA was enhanced. From these data it appears that a relatively brief exposure to DES in early adulthood causes marked and persistent changes in tuberoinfundibular DA function that are responsible for continued hyperprolactinemia. Associated reductions in LH secretion also appear to be due to hypothalamic as opposed to pituitary factors.
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Streptozotocin-induced deficits in sex behavior and neuroendocrine function in male rats.
The effects of streptozotocin-induced (STZ) diabetes on neuroendocrine and sexual function were evaluated in adult male rats. Adult male rats were injected with STZ (50 mg/kg) or vehicle and tested for copulatory behavior 7, 14, and 21 days later. The rats were killed 1 month after STZ or vehicle treatment for measurement of plasma hormone levels, hypothalamic catecholamine turnover, LHRH content, and in vitro pituitary function. The STZ rats showed significant deficits in mount, intromission, and ejaculatory behaviors. Plasma levels of testosterone, LH, FSH, and PRL were all significantly reduced in the STZ compared to the control rats, but in vitro LH secretion was enhanced after STZ treatment. In vitro PRL secretion and the inhibitory response to dopamine did not differ between the two groups. The levels of LHRH were reduced in the medial basal hypothalamus (MBH), but LHRH levels in the median eminence (ME) and anterior hypothalamus (AH) were unchanged after STZ treatment. Norepinephrine turnover was reduced in the ME, MBH, and AH of the STZ rats, while dopamine turnover was unchanged in the ME, increased in the MBH, and reduced in the AH of the STZ rats compared to those in the vehicle-treated controls. These results suggest that changes in pituitary and testicular function in rats made diabetic by STZ treatment are secondary to changes in hypothalamic catecholamine metabolism. Changes in copulatory behavior could be due to both reductions in plasma testosterone levels as well as changes in central neurotransmitter metabolism.
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