Properties of a potent LHRH antagonist (Org 30850) in female and male rats.

Org 30850 (Ac-D-pClPhe1,2,D-Bal3,D-Lys6,D-Ala10-LHRH) is a novel LHRH antagonist, which is being developed for the treatment of hormone-dependent disorders. The activities of this compound with respect to its endocrinological properties and side-effects were tested in rats and the results were compared with one of the first LHRH antagonists: Ac-D-pClPhe1,2,D-Trp3,D-Arg6,D-Ala10-LHRH (Org 30276). A single subcutaneous (s.c.) dose of 0.3 micrograms/kg Org 30850 administered to rats in pro-estrus gave inhibition of ovulation in approx. 50% of the rats, whereas Org 30276 was approx. 4 times less potent. The effect of a single s.c. injection of Org 30850 on testosterone levels in young adult male rats was also studied. The administration of 250 micrograms/kg or higher of Org 30850 induced a significant decrease in testosterone levels after 3 h, this effect lasted for at least 48 h. Treatment of female rats for 14 days with a daily dose of 12 micrograms/kg Org 30850 decreased statistically significantly uterine and ovarian weights. At a daily dose of 50 micrograms/kg Org 30850 completely suppressed estrous cycles and significantly decreased estradiol and FSH serum levels. The LH levels were below the detection level in both control and treated animals on the (expected) second day of di-estrus. Treatment of male rats for 14 days (25-200 micrograms/kg) resulted in a dose-dependent reduction of the gonads, accessory sex organs, testosterone levels and gonadotrophins. The decrease in gonadal function in both sexes was reversible since the females proved to be as fertile as the controls 6 weeks after the last treatment and an almost complete recovery of the weight of testes, seminal vesicles and ventral prostate was observed in the males 4 weeks after cessation of treatment. In contrast to Org 30276, Org 30850 exerted very slight irritation at the site of injection and no edematous reactions in the extremities at a daily dose of up to 8 mg/kg in male rats. It is concluded that Org 30850 is a very potent LHRH antagonist without edematous reactions and with a more favourable therapeutic index than Org 30276.     

The effects of neonatal androgenization of male rats on testosterone metabolism by the hypothalamus-pituitary-gonadal axis

Male rats were androgenized on the third postnatal day by a single injection of 1 mg testosterone propionate. The in vitro metabolism of [4-14C]testosterone by pituitary and hypothalamus homogenates was investigated at the age of 90 days. The pituitary and hypothalamus homogenates from control and neonatally androgenized animals converted [4-14C]testosterone to the same metabolites, mainly 5 alpha-reduced derivatives; the quantitative yield of 5 alpha-reduced metabolites was much higher in the pituitary homogenates of androgenized rats. The hypothalamic homogenates showed no differences. In the androgenized rats a very significant increase of the plasma FSH levels was measured while the LH levels were also augmented. The plasma levels of testosterone were not different from the values in control rats, notwithstanding a 25% reduction in testes weight. The present experiments appear to indicate that the neonatal androgenization results in an accentuation of the sexual dimorphism which normally exists in the pituitary of adult rats for the 5 alpha-reductase activity.     

Inhibition of pituitary-gonadal function in male rats by a potent GnRH antagonist

The inhibitory effects of the potent GnRH antagonist, [Ac-D-pCl-Phe1,2,D-Trp3,D-Arg6,DAla10]GnRH (GnRHant) upon pituitary-gonadal function were investigated in normal and castrated male rats. The antagonist was given a single subcutaneous (s.c.) injections of 1-500 micrograms to 40-60 day old rats which were killed from 1 to 7 days later for assay of pituitary GnRH receptors, gonadal receptors for LH, FSH, and PRL, and plasma gonadotropins, PRL, and testosterone (T). In intact rats treated with low doses of the antagonist (1, 5 or 10 micrograms), available pituitary GnRH receptors were reduced to 40, 30 and 15% of the control values, respectively, with no change in serum gonadotropin, PRL, and T levels. Higher antagonist doses (50, 100 or 500 micrograms) caused more marked decreases in free GnRH receptors, to 8, 4 and 1% of the control values, which were accompanied by dose-related reductions in serum LH and T concentrations. After the highest dose of GnRHant (500 micrograms), serum LH and T levels were completely suppressed at 24 h, and serum levels of the GnRH antagonist were detectable for up to 3 days by radioimmunoassay. The 500 micrograms dose of GnRHant also reduced testicular LH and PRL receptors by 30 and 50% respectively, at 24 h; by 72 h, PRL receptors and LH receptors were still slightly below control values. In castrate rats, treatment with GnRHant reduced pituitary GnRH receptors by 90% and suppressed serum LH and FSH to hypophysectomized levels. Such responses in castrate animals were observed following injection of relatively low doses of GnRHant (100 micrograms), after which the antagonist was detectable in serum for up to 24 h. These data suggest that extensive or complete occupancy of the pituitary receptor population by a GnRH antagonist is necessary to reduce plasma gonadotropin and testosterone levels in intact rats. In castrate animals, partial occupancy of the available GnRH receptor sites appears to be sufficient to inhibit the elevated rate of gonadotropin secretion.     

Erectile function and bulbospongiosus EMG activity in estrogen-maintained castrated rats vary with behavioral context.

Electromyographic (EMG) activity in the bulbospongiosus muscles (BS) was recorded to monitor potential castration-induced alterations in muscle activity during copulation and reflexive erections. EMG recordings were made from intact male rats and from castrated rats maintained from 7 to 50 days on estradiol benzoate (300 micrograms/day) or testosterone (200 micrograms/day). Despite a 40-50% postcastration reduction in the weight of the BS and accessory sexual glands in estrogen-treated rats, the pattern of EMG activity during copulation was similar across groups. In estradiol-treated males, the EMG burst frequency during mounts and burst duration during intromissions exceeded the parameters of intact males and of castrated males maintained on testosterone. Between intromissions, and following ejaculatory patterns, estrogen-treated males displayed spontaneous muscle bursts accompanied by visually confirmed erection of the glans penis, but these males quickly lost the capacity for reflexive erections. These data demonstrate that despite castration-induced atrophy of the penile muscles and, presumably, their spinal motor nuclei, the motor output to these muscles is maintained following androgen removal. The capacity for substantial penile erection is retained during copulation long after reflexive erections have diminished.     

Adrenal microsomal C19-steroid 5α-reductase activity in the Snell transplantable rat adrenocortical tumour 494 and the effect of oestradiol, testosterone propionate and adrenocorticotrophin in intact and gonadectomized rats

The C(19)-steroid 5alpha-reductase activity in the microsomal fraction of rat adrenal tissue under various hormonal treatments was examined. In intact control rats the activity is similar in both males and females, and after gonadectomy it is markedly increased. Treatment with oestradiol (150mug/day per animal for 7 days) or testosterone propionate (2mg/day per animal for 7 days) lowered the activity of 5alpha-reductase in castrated animals to approximately the values for intact animals in both sexes, and in intact animals the activity was also decreased by these treatments. The enzyme activity was also decreased by adrenocorticotrophin treatment but to a lesser extent than by the steroid hormones. The activity of the 5alpha-reductase enzyme in the Snell adrenocortical tumour 494 is very low when incubated as a whole homogenate, but the activity in microsomal material of the tumour was measured and unexpectedly found to be similar to that in intact controls.     

Increase in testosterone sensitivity induced by constant light in relation to melatonin injections in rats.

In this experiment we investigated whether the lack of the nocturnal melatonin peak under constant light would cause an increase in testosterone sensitivity. Castrated rats were kept under periodic or constant light for one week. They received a daily injection of vehicle, testosterone propionate (125 micrograms), melatonin (50 micrograms) or testosterone plus melatonin (125 micrograms + 50 micrograms). Serum and pituitary gonadotrophins and pineal melatonin were measured at the end of the experiment. Under constant light, testosterone injections reduced the serum luteinizing hormone concentration in castrated rats to that in intact rats, but, under periodic light, the decrease was smaller. Melatonin did not reverse the stronger effect of testosterone under constant light. The serum melatonin peak produced by the exogenous melatonin injection had a higher amplitude, shorter duration and earlier appearance than the physiological melatonin peak. Exogenous melatonin did not modify the physiological melatonin secretion, measured either as serum melatonin concentration or pineal melatonin content on the consecutive day. We conclude that the increase in testosterone negative feedback sensitivity of castrated rats under constant light was not due to the absence of the nocturnal melatonin pulse.     

Effect of neonatal testosterone and oestradiol treatment on the development of the hypothalamo-hypophysial axis in the female rat.

The hypothalamic LH-RH content and the concentrations of pituitary and plasma LH were measured at various ages in female rats treated daily with 10 micrograms testosterone propionate or 10 micrograms oestradiol-17beta from birth to Day 15. Persistent vaginal oestrus was induced in all the treated rats. Both hormones significantly reduced the hypothalamic LH-RH content and pituitary and plasma LH concentrations. Hypothalamic LH-RH increased after cessation of treatment but pituitary LH did not return to normal levels. Plasma LH levels were significantly lower than those in control rats. It is concluded that testosterone propionate and oestradiol-17beta (1) have a direct negative feed-back influence on the hypothalamus in the neonatal female rat; (2) alter the normal pattern of plasma and pituitary LH in developing female rats; (3) prevent the cyclic secretion of plasma LH after maturity; and (4) probably cause a chronic impairment in the release of LH-RH.     

Effects of alcohol feeding on androgen receptors in the rat pituitary gland

Specific binding of testosterone-1 beta, 2 beta-3H by cytosol from anterior pituitary gland of alcohol-fed, isocaloric control, and castrated control and alcohol-fed rats with or without testosterone treatment has been investigated by charcoal assay. The number of androgen binding sites was significantly reduced in alcohol-fed rats (8 +/- 1.0 fmoles/mg cytosol protein), when compared to the isocaloric control value (13.2 +/- 2.1 fmoles/mg protein), with no significant change in Kd (0.7 +/- 0.14 nM). Castration significantly increased the number of receptor sites in control rats and when castrated control animals were treated with testosterone the binding sites were decreased to the intact control level. In contrast, castration or testosterone given to castrated alcohol-fed rats did not alter alcohol-induced reduction of the receptor sites. The binding affinity (Kd) is identical in all groups. The concentration of serum luteinizing hormone (LH) was significantly lower in alcohol-fed rats when compared to that of normal controls. An increased serum LH level with a decreased testosterone level was noted in castrated control rats. However, castration of alcohol-fed rats had little or no effects on the concentrations of LH and testosterone. Administration of testosterone suppressed castration-induced high LH in control rats but alcohol-induced reduction of LH level was not altered by this treatment. These findings indicate that alcohol exerts a suppressive effect on the content of androgen receptors and secretory functions of gonadotropins in the pituitary gland.     

Hormonal regulation of 5 alpha-reductase activity in anterior pituitary gland microsomes of the male rat]

It was previously shown that the microsomal 5 alpha-reductase activity in the male rat pituitary was increased by castration. Subcutaneous administration of androgens to castrated rats prevented the rise in 5 alpha-reductase activity. Their relative efficiency was as follows: 5 alpha-dihydrotestosterone greater than 5 alpha-androstane-3 alpha, 17 beta-diol greater than testosterone. Under our experimental conditions 5 alpha-androstane-3 beta, 17 beta-diol and estrogens were inefficient. The rise in 5 alpha-reductase activity following castration is exclusively located in hypophysis and it is probably due to an increased of the enzyme biosynthesis.     

Testosterone-dependent effects of galanin on pituitary luteinizing hormone secretion in male rats

Galanin is a 29-amino-acid peptide that colocalizes with GnRH in hypothalamic neurons. High concentrations of galanin are present in portal vessel blood of both male and female rats, and galanin receptors are present on gonadotropes in both sexes. Results from studies of female rats indicate that galanin acts at the level of the pituitary to directly stimulate LH secretion and also to enhance GnRH-stimulated LH secretion. The effects of galanin on pituitary LH secretion in male rats are relatively uncharacterized; thus, the present in vivo study was conducted 1). to examine the ability of galanin to affect basal or GnRH-stimulated LH secretion in male rats and 2). to determine whether the effects of galanin on LH secretion in male rats are testosterone-dependent. All three doses of galanin used (1, 5, and 10 micro g/pulse) significantly enhanced GnRH-stimulated LH secretion in intact male rats. Only the highest dose of galanin directly stimulated LH secretion (without GnRH coadministration) in intact males. Galanin did not directly stimulate LH secretion or enhance GnRH-stimulated LH secretion in castrated male rats. In fact, the highest dose of galanin inhibited GnRH-stimulated LH secretion in castrated males. Upon testosterone replacement, the ability of galanin to directly stimulate LH secretion and to enhance GnRH-stimulated LH secretion was restored in castrated males. These results suggest a role for galanin in the regulation of LH release in male rats and demonstrate that testosterone upregulates the ability of the pituitary to respond to the stimulatory effects of galanin.     

Relationship of changing delta 4-steroid 5 alpha-reductase activity to [125I]iododeoxyuridine uptake during regeneration of involuted rat prostates

To elucidate the phenotypic expression of proliferating prostatic cells, rats were castrated, and the regenerating process of involuted ventral prostates during testosterone propionate (TP) administration was investigated by examining morphology, [5-125I]iododeoxyuridine (125I-UdR) uptake, DNA content, weight, acid phosphatase, and delta 4-steroid 5 alpha-reductase (5 alpha-reductase) activities. Morphologically, TP treatment initially increased the number of epithelial cells lining glandular lobules and subsequently restored the shape of epithelial cells. 125I-UdR uptake peaked on Day 3 of TP treatment and stayed at higher levels than for uncastrated controls until Day 14 of treatment. Prostatic weight, protein content, acid phosphatase, and DNA content returned to uncastrated control levels by Day 14 of TP treatment. TP administration markedly stimulated prostatic 5 alpha-reductase activity, which peaked on the Day 5 of treatment and decreased to uncastrated control levels by Day 14 of treatment. It is concluded that TP administration to castrated rats initially induced active mitotic division of the remaining stem cells, followed by formation of differentiated functional epithelial cells. Prostatic 5 alpha-reductase was highly active at the initial phase of active mitotic cell division. The major portion of the increased enzyme activity can be regarded as a phenotypic expression of stem or transient cells of prostatic epithelium.     

The action of 5 alpha-dihydrotestosterone and antiandrogens on the activities of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase in the pituitary gland of gonadectomized rats

In gonadectomized rats of either sex s.c. administration of 5 alpha-dihydrotestosterone (DHT) reversed, in a dose dependent manner, effects brought about by gonadectomy: it decreased pituitary wet weight and serum levels of LH and FSH and suppressed microsomal enzyme activities involved in testosterone and progesterone metabolism in the pituitary gland, NADPH-linked 5 alpha-reductase and NADH-linked 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH). Concomitantly administered nonsteroidal antiandrogen, flutamide (5 mg/day), antagonized some of the suppressive effects induced by a 14-day treatment of gonadectomized rats with high dose (1 mg/day) of DHT. It completely blocked DHT action on pituitary 5 alpha-reductase activity in the female rat and, in the male, inhibition was found to be 30-35%. In male, but not female rats, it completely blocked DHT suppression of serum FSH level whereas it slightly, but significantly inhibited DHT suppression of serum LH in rats of either sex. However, flutamide did not prevent DHT suppression of pituitary wet weight or NADH-linked 3 alpha-HSDH activity. Concomitantly administered progestational antiandrogen, cyproterone acetate (5 mg/day), inhibited DHT-induced weight increase of seminal vesicles by 50-55% and completely blocked the weight decrease of pituitary gland but did not antagonize DHT suppression of serum gonadotropins or pituitary enzyme activities. The results obtained with flutamide suggest that DHT-induced suppression of pituitary NADPH-linked 5 alpha-reductase, but not NADH-linked 3 alpha-HSDH activity, might involve an androgen receptor mechanism.     

Testosterone 5 alpha-reductase in discrete hypothalamic nuclear areas in the rat: effect of castration

The conversion of testosterone into 5 alpha-dihydrotestosterone (DHT) has been studied in different hypothalamic nuclear areas and in the superficial layers of the cerebral cortex of normal and castrated male rats. The tissue fragments utilized in each incubation have been punched from frozen brain sections utilizing calibrated needles. Castration has been performed 12 (short term) and 180 (long term) days before sacrifice. The nuclear areas studied include: the medial preoptic nucleus (MPN), the lateral preoptic nucleus (LPN), the anterior hypothalamic nucleus (AHN), the lateral hypothalamic nucleus (LHN), the posterior hypothalamic nucleus (PHN), the nucleus ventromedialis (HVM), the arcuate nucleus (AR), the median eminence (ME), the nucleus paraventricularis (HPV), the supraoptic nucleus (SO) and the suprachiasmatic nucleus (SC). The possible effect of castration on the 5 alpha-reductase, were assessed in the MPN,LPN,AHN,LHN,PHN and in the cerebral cortex. The results indicate that, in the male rat: 1) the lateral preoptic(LPN) and the lateral hypothalamic nuclei(LHN) possess a 5 alpha-reductase activity higher than that present in the cerebral cortex and in the other hypothalamic nuclei considered; 2)the suprachiasmatic nucleus (SC) apparently possesses a testosterone metabolizing activity lower than that found in any other nervous structures studied so far; 3) castration does not seem to influence the 5 alpha-reductase activity either in the hypothalamic nuclear structures considered or in the cerebral cortex.     

Testosterone selectively increases serum follicle-stimulating hormonal (FSH) but not luteinizing hormone (LH) in gonadotropin-releasing hormone antagonist-treated male rats: evidence for differential regulation of LH and FSH secretion

Both testosterone (T) and gonadotropin-releasing hormone (GnRH)-antagonist (GnRH-A) when given alone lower serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in intact and castrated rats. However, when graded doses of testosterone enanthate (T.E.) were given to GnRH-A-treated intact male rats, a paradoxical dose-dependent increase in serum FSH occurred; whereas serum LH remained suppressed. This surprising finding led us to ask whether the paradoxical increase in serum FSH in GnRH-A-suppressed animals was a direct stimulatory effect of T on the hypothalamic-pituitary axis or the result of a T effect on a testicular regulator of FSH. To test these hypotheses, we treated adult male castrated rats with GnRH-A and graded doses of T.E. In both intact and castrated rats, serum LH remained undetectable in GnRH-A-treated rats with or without T.E. However, addition of T.E. to GnRH-A led to a dose-dependent increase in serum FSH in castrated animals as well, thus pointing against mediation by a selective testicular regulator of FSH. These data provide evidence that pituitary LH and FSH responses may be differentially regulated under certain conditions. When the action of GnRH is blocked (such as in GnRH-A-treated animals), T directly and selectively increases pituitary FSH secretion.     

Localization of a 5alpha-reductase activity in the nuclear membranes of the anterior hypophysis of normal and castrated adult male rats]

A 5alpha-reductase activity may be found in purified nuclei from anterior pituitary of intact or castrated male rats. When nuclear membranes are separated from nucleoplams this enzymic activity is recovered in nuclear membranes. Following 7 days of castration, the 5alpha-reductase activity in nuclear membranes is increased by 105 % with regard to the activity in nuclear membranes from intact animals.     

Influence of the degree of stimulation of the pituitary by gonadotropin-releasing hormone on the action of inhibin and testosterone to suppress the secretion of the gonadotropins in rams

This experiment determined if the degree of stimulation of the pituitary gland by GnRH affects the suppressive actions of inhibin and testosterone on gonadotropin secretion in rams. Two groups (n = 5) of castrated adult rams underwent hypothalamopituitary disconnection and were given two i.v. injections of vehicle or 0.64 microg/kg of recombinant human inhibin A (rh-inhibin) 6 h apart when treated with i.m. injections of oil and testosterone propionate every 12 h for at least 7 days. Each treatment was administered when the rams were infused i.v. with 125 ng of GnRH every 4 h (i.e., slow-pulse frequency) and 125 ng of GnRH every hour (i.e., fast-pulse frequency). The FSH concentrations and LH pulse amplitude were lower and the LH concentrations higher during the fast GnRH pulse frequency. The GnRH pulse frequency did not influence the ability of rh-inhibin and testosterone to suppress FSH secretion. Testosterone did not affect LH secretion. Following rh-inhibin treatment, LH pulse amplitude decreased at the slow, but not at the fast, GnRH pulse frequency, and LH concentrations decreased at both GnRH pulse frequencies. We conclude that the degree of stimulation of the pituitary by GnRH does not influence the ability of inhibin or testosterone to suppress FSH secretion in rams. Inhibin may be capable of suppressing LH secretion under conditions of low GnRH.     

Gonadotropin-releasing hormone binding sites in ovaries of normal cycling and persistent-estrus rats

The gonadotropin-releasing hormone (GnRH) binding capacity in ovaries and pituitaries of normal cycling rats at different stages of the estrous cycle and in ovaries of persistent-estrus rats was measured using radioligand-receptor assay (RRA). Persistent estrus was induced either by neonatal administration of testosterone propionate (1.25 mg s.c.) on the second day of life or by a hypothalamic suprachiasmatic frontal cut made with Halász' knife. All animals were killed during the critical period (1400-1600 h), and GnRH receptor was assayed. GnRH receptor levels in both ovaries and pituitaries changed during the estrous cycle. The total number of ovarian GnRH binding sites was significantly higher in proestrus than in diestrus 1, the stage in which the lowest level was found. When binding sites were expressed in fmol/mg ovary, the highest level was observed in diestrus 2; however, no changes were observed during the estrous cycle when GnRH binding sites were expressed as fmol/mg protein. Changes noted were very similar to those demonstrated in pituitary GnRH receptors in our present and previous experiments. Higher levels of pituitary binding sites were found in diestrus 2 and proestrus than in estrus and diestrus 1. The changes in the GnRH receptor levels were more striking in the pituitary than in the ovaries. It appears that the total number of ovarian GnRH binding sites was not altered in either of the two persistent-estrus groups, but that their concentration was significantly higher (expressed in fmol/mg ovary or fmol/mg protein) than on any day during the estrous cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex hormones metabolism in the brain: influence of central acting drugs on 5 alpha-reduction in rat diencephalon.

Rats after adrenalectomy-testectomy showed a gradual increase in diencephalon 3-oxo-5 alpha-steroid: (acceptor) delta4-oxidoreductase (5 alpha-reductase) activity for 3 days. The activity then returned near to the normal range on the 4th postoperative day. When rats were given testosterone propionate (TP) 3 days after adrenalectomy-testectomy, diencephalon 5 alpha-reductase activity returned to the preoperative range 2 hr after TP administration. Diencephalon 5 alpha-reductase activity showed a highly significant increase (p less than 0.01) after a single administration of carbamazepine, reserpine, diazepam, phenytoin, phenobarbital or disulfiram. A significant increase (p less than 0.05) was also found after a single administration of methylphenidate, caffeine or methamphetamine. Plasma testosterone decreased concurrently after administration of all these agents, except diazepam. Diencephalon enzyme activity decreased significantly after repeated disulfiram administrations (p less than 0.01) but increased significantly after methamphetamine administrations (p less than 0.05). Plasma testosterone showed a tendency to decrease after repeated methamphetamine administrations but tended to increase after repeated disulfiram administrations.     

Altered sexual differentiation of hepatic uridine diphosphate glucuronyltransferase by neonatal hormone treatment in rats

The hepatic microsomal enzyme UDP-glucuronyltransferase undergoes a complex developmental pattern in which enzyme activity is first detectable on the 18th day of gestation in rats. Prepubertal activities are similar for males and females. However, postpubertal sexual differentiation of enzyme activity occurs in which male activities are twice those of females. Neonatal administration of testosterone propionate or diethylstilboestrol to intact animals resulted in lowered UDP-glucuronyltransferase activity in liver microsomal fractions of adult male rats, whereas no changes were observed in the adult females and prepubertal male and female animals. Neonatal administration of testosterone propionate and diethylstilboestrol adversely affected male reproductive-tract development as evidenced by decreased weights of testes, seminal vesicles and ventral prostate. Diethylstilboestrol also markedly decreased spermatogenesis. Hypophysectomy of adult male rats resulted in negative modulation of microsomal UDP-glucuronyltransferase and prevented the sexual differentiation of enzyme activity. In contrast hypophysectomy had no effect on female UDP-glucuronyltransferase activity. A pituitary transplant under the kidney capsule was not capable of reversing the enzyme effects of hypophysectomy, therefore suggesting that the male pituitary factor(s) responsible for positive modulation of UDP-glucuronyltransferase might be under hypothalamic control in the form of a releasing factor. Neonatal testosterone propionate and diethylstilboestrol administration apparently interfered with the normal sequence of postpubertal UDP-glucuronyltransferase sexual differentiation.     

The effect of testosterone on serum gonadotropins of castrated rats kept under different lighting conditions.

Testosterone feedback sensitivity was measured as the ability of testosterone propionate to decrease serum LH and FSH of long-term castrated (4 wk) rats under four different lighting conditions: periodic light (12L:12D), constant light (LL), constant darkness (DD), and dim night illumination (1 lx) with a 12L:12D photoperiod. Rats were exposed to the different lighting conditions for 1 wk, during which they received daily testosterone propionate (125 micrograms or 250 micrograms s.c.). At the end of the experiment the rats were decapitated at 1100 h, and serum gonadotropin levels were measured by RIA. Serum LH of the rats kept under LL was reduced to the level of the intact rats with the smaller testosterone dose (125 micrograms/day). Under all other lighting conditions only the large dose (250 micrograms/day) was able to restore the serum LH concentration to the level of the intact rats. Serum FSH was restored only partially, and the effect was the same with both doses and similar under all lighting conditions. We conclude that the increase in testosterone negative feedback sensitivity was not caused by the lack of periodicity of illumination alone, but that sufficient intensity of lighting throughout the 24 h was needed as well.