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Spatiotemporal expression, endocrine regulation, and activation of epidermal growth factor receptor (EGFR) in the hamster ovary were evaluated by immunofluorescence and in situ hybridization localization. Whereas granulosa cells (GC) of primordial through large preantral (stage 6, 7-8 layers GC) follicles had low immunoreactivity, granulosa cells of antral follicles, theca, and interstitial cells had intense EGFR immunoreactivity. EGFR expression in GC of primordial and small preantral follicles increased progressively from estrous through proestrous, but a significant increase occurred in mural GC of antral follicles following the gonadotropin surge. Interstitial cells around small preantral follicles had strong immunofluorescence, and the intensity increased significantly in fully differentiated thecal cells. Distinct EGFR protein was localized in the nucleus of the oocytes and granulosa cells. FSH significantly stimulated EGFR expression in the GC, especially the mural GC, theca, and interstitial cells in hypophysectomized hamster. Estrogen stimulated EGFR expression in preantral GC as well as in interstitial cells. Progesterone and hCG effect was limited to theca and interstitial cells. EGFR expression correlated well with EGFR activation following endogenous or exogenous gonadotropin exposure. Receptor mRNA expression closely followed the protein expression, with increased mRNA expression in mural GC of antral follicles. These results suggest that low levels of EGF signal as a consequence of low levels of receptors in preantral GC may be critical for cell proliferation, but higher receptor density may evoke increased signal intensity due to activation of other intracellular signal pathways, which activate cellular processes related to granulosa, theca, and interstitial cell differentiation. The spatiotemporal cell type and follicle stage-specific expression of receptor mRNA and protein and EGFR activation is critically regulated by gonadotropins and ovarian steroids, primarily estradiol.
Adult male Sprague-Dawley rats averaging 300 g each were subjected to complete food removal for 7 days (acutely starved), 7 days complete food removal followed by 2 weeks of 1/4 ad libitum food intake (chronically strved), 7 days complete food removal and 2 weeks of 1/4 ad libitum intake followed by ad libitum feeding for 7 days (refed), or fed ad libitum throughout (controls). Serum LH, FSH, TSH, PRL, and GH levels were measured by radioimmunoassays for each group of rats. The in vivo response to the combination of synthetic LHRH and TRH also was tested in each group of rats. Circulating LH, TSH, GH, and PRL were significantly depressed in acutely and chronically starved rats, and FSH was lowered only in acutely starved rats. After 7 days of refeeding, serum levels of LH and FSH were significantly greater than in ad libitum fed controls, PRL returned to control levels, and TSH and GH increased but were still below control levels. After LHRH + TRH injection serum LH and TSH were increased significantly in all groups of rats, FSH and PRL rose in acutely but not in chronically starved rats, and GH was not elevated in any group. The increases in serum LH, FSH, TSH and prolactin in response to LHRH + TRH injection in acutely or chronically starved rats were equal to or greater than in the ad libitum fed controls. These data indicate that severe reductions in food intake result in decreased release of at least 5 anterior pituitary hormones, and this is due primarily to reduced hypothalamic stimulation rather than to inability of the pituitary to secrete hormones.
Follicles were dissected by hand or enzymatically from the ovary of the proestrous hamster at 0900 h and classified into 10 stages: stages 1-4, follicles with 1-4 layers of granulosa cells and no theca; stages 5-8, preantral follicles with 5 or more layers of granulosa cells and theca to small antral follicles; stage 9, intermediate-sized atretic antral follicles; and stage 10, healthy preovulatory antral follicles. Follicles were then incubated for 2 h with [3H]thymidine [( 3H]Tdr) in the absence or presence of gonadotropins and with incorporation of radionuclide into DNA as the end point. FSH (25 ng) significantly stimulated [3H]Tdr incorporation in all stages of follicular development with a latency of 2 h, and this effect was inhibited by 2 micrograms unlabeled Tdr. While FSH and PRL (25 and 100 ng) stimulated [3H]Tdr incorporation in all stages, LH (0.2-5 ng) action began from stage 5 onward, when definitive thecal cells and LH receptors started appearing. LH (5 ng) also suppressed 25 ng FSH-induced DNA synthesis in stages 5-10; however, stages 1-4 were unaffected. Significant increases in both intra- and extracellular cAMP levels occurred in follicles at stages 2-10 after FSH administration. In contrast, LH was active in stages 5-10, whereas PRL was ineffective. Follicular DNA synthesis increased markedly when stimulated by 8-bromo-cAMP (0.01-2 mM). These results show that gonadotropins act directly as a primary stimulus at the level of small primary and secondary follicles to regulate DNA synthesis and, thus, perhaps the growth and differentiation of granulosa and thecal cells; cAMP functions as one of the possible intracellular mediators of gonadotropin action in initiating DNA replication.
In the present study two recently developed techniques have been combined to enable the simultaneous in vivo determination of pulsatile release of GnRH, LH, and FSH in the orchidectomized rat. The first of these techniques involves the implantation of two vascular catheters and collecting serial blood samples through one while simultaneously infusing a replacement blood mixture through the other; consequently, blood samples can be collected for an extended period of time, and detailed plasma LH and FSH release profiles can be established for individual animals. The second technique involves push-pull perfusion of the pituitary gland to determine changes in GnRH concentration as might be perceived by the gonadotropes. For each animal (n = 6), blood (150 microliters) and push-pull perfusate (200 microliters) samples were collected at 5- and 10-min intervals, respectively, for approximately 6 h, and the hormone release profiles were determined by RIA. All of the rats showed a clear pulsatile release pattern for GnRH, LH, and FSH. Moreover, the interpulse interval was remarkably similar for each of these hormones (36.9, 41.5, and 43.5 min, respectively, as determined by PULSAR). The percentage of GnRH pulses associated with a gonadotropin pulse was 72% for LH and 76% for FSH; only 14% of the pulses were silent for both gonadotropins. These results demonstrate that in the orchidectomized rat the pulsatile pattern of GnRH release is reflected in the pulsatile pattern of not only LH but also FSH. They may, therefore, be construed to support the concept that the pulsatile secretion of both gonadotropins is primarily orchestrated by a single hypothalamic releasing hormone. Alternatively, if two separate hypothalamic releasing hormones do indeed exist (LHRH and FSH-releasing hormone), it would appear that in the orchidectomized rat their episodic release is tightly coupled to the same hypothalamic pulse generator.
Puberty may be induced rapidly in young female mice by exposing them to adult males. The relevant male stimuli include a urinary pheromone and tactile cues, the latter acting in a potentiating capacity. The specific action of the urinary pheromone on pituitary gonadotropins was the subject of the present research. Immature females of a standard size were either paired with adult males, isolated and their bedding sprayed with male urine, or maintained as isolated controls. Exposure to male urine resulted in a rapid and significant release of LH (30 min) which was maintained at an average of 50% higher than levels in isolated controls throughout the 48 h experiment; no immediate changes were observed in either serum FSH or prolactin, but FSH was depressed and prolactin rose progressively during later sampling periods. Cohabitation with an adult male yielded parallel but decidedly stronger reponses in the concentrations of all three hormones. Exogenous estrogen, administered in a second experiment at a dosage previously found to mimic the puberty-inducing action of a male, suppressed serum FSH and LH while elevating serum prolactin. Thus, the present results suggest a) that the male's urinary stimulus exerts its action on immature females via LH release with no immediate and/or direct effects on the other two tropic hormones, and b) that the delayed alterations in serum FSH and prolactin concentrations accompanying male- and/or urine-exposure are secondary consequences of an LH-induced release of estradiol. Attempts to induce the entire pubertal cycle in intact females with subovulating doses of LH, nevertheless, were unsuccessful.
Six adult Soay rams were housed under artificial lighting conditions of long days (16 h light:8 h darkness) for 4 months and this caused the animals to lapse into a state of reproductive quiescence with low levels of gonadotrophins in the circulation and regressed testes secreting very low amounts of testosterone. The photoperiod was changed abruptly to short days (8 h light:16 h darkness) to induce a resurgence of sexual activity, and a detailed study was made of the pituitary and testicular responses over the first 100 days. Plasma levels of LH and FSH first began to increase between days 6 and 12 of short days, and rose progressively until days 33-54 before declining again. Testicular growth of the rams began on days 19-26 and continued for most of the remaining period of study. Plasma testosterone levels rose in parallel with the growth of the testes, and were greatly increased by day 100 when gonadotrophin levels were reduced. At most stages there were short-term fluctuations in the plasma levels of FSH, LH and testosterone indicative of episodic secretion. Peaks in plasma levels of LH were especially conspicuous and from the changes in frequency and amplitude of these peaks it was possible to predict the way in which photoperiod influenced gonadotrophin secretion by its effect on hypothalamic LH-RH secretion. A slight 24 h rhythm in the plasma levels of all three hormones was observed, and the significance of this in relation to the photoperiodic response is discussed.
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This experiment was conducted to determine the changes in secretion of LH, FSH, estrogen and progesterone during follicle maturation. Ovaries were recovered from 11 non-treated (control) gilts, three on day 13, four on day 16, and four on day 19 of the estrous cycle, and from four altrenogest-treated gilts on day 19. Altrenogest, a progesterone agonist, was fed at a dose of 20 mg once daily from days 13 to 18 to block spontaneous follicle maturation. Gilts were bled daily from day 12 until slaughter. For control gilts, the number of follicles/gilt 1-6 mm in diameter decreased (P less than .05) from 93.5 on day 13 to 21.5 on day 19, and the number of large (greater than 6 mm) follicles increased (P less than .05) from 5.3 to 13.2. Altrenogest treatment blocked loss of small follicles and growth of large follicles between days 13 and 19. Plasma progesterone decreased (P less than .001) between days 12 and 16 in both control and altrenogest-treated gilts. Plasma FSH decreased (P less than .05) between days 12 and 16 only in control gilts. Plasma LH was not significantly affected by day or altrenogest treatment. Plasma estrogen increased (P less than .05) between days 15 and 19 only in control gilts. These results indicate that 1) no increased LH secretion was detected in conjunction with emergence of ovulatory follicles, and 2) atresia of nonovulatory follicles was associated with decreased secretion of FSH. Both atresia and decreasing FSH secretion began before estrogen concentration increased in the systemic circulation.
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Reproductive aging in the Brown Norway rat occurs because of testicular as well as hypothalamic-pituitary dysfunction. Excitatory amino acids (EAA) participate in the regulation of pulsatile secretion of hypothalamic GnRH and pituitary LH. In the present study, we studied the EAA-GnRH-LH axis for possible age-related alterations in prepubertal (35 days), young (3-4 months), middle-aged (12-13 months) and old (21-23 months) rats. In the first experiment, an intra-atrial cannula was implanted in rats of different ages to evaluate the pituitary response to small, physiological intravenous bolus administration of GnRH (0.5 or 1.0 nmol/100 g body weight). The results showed no age-related significant differences in in-vivo serum LH or FSH responsiveness to GnRH. In a second experiment, blood samples for the gonadotropins were withdrawn immediately before and 10 min after an iv injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 5 mg/kg, a dose that induces a physiological LH pulse in young rats). Administration of NMDA induced significant increases in LH and prolactin in all groups of animals (P<0.05) and a significant FSH response in young and middle-aged but not old rats. NMDA-induced LH, FSH and prolactin release was higher (P<0.05) in prepubertal rats than in all other age groups. Compared with young rats, NMDA-induced increase in plasma LH and prolactin was lower (P<0.05) in old rats. In the third experiment, to ascertain whether this reduced LH response to NMDA in old rats was exerted at the hypothalamic level, the effects of NMDA on GnRH release in vitro from preoptic area-medial basal hypothalamus (POA-MBH) fragments were compared among rats of different ages. GnRH efflux in response to NMDA was significantly attenuated with increasing age. GnRH release in vitro was higher in prepubertal and lower in old than in young rats (P<0.05). Lastly, we measured amino acid concentrations in hypothalamic tissue (POA-MBH fragments). Prepubertal rats had higher levels of glutamate and taurine than young rats. Significant reductions in glutamate and gamma-aminobutyric acid (GABA) levels were found in old compared to young rats. In conclusion, these results showed that the hypothalamic NMDA-GnRH-LH axis was altered in old rats. The decreased hypothalamic content of some of the EAA and the reduced responsiveness of GnRH neurons to NMDA (both in vivo and in vitro) may contribute to an altered LH pulsatile secretion observed in old rats.
Metergoline, a prolactin (PRL)-lowering drug with an antiserotoninergic activity, is known to restore menstruations and fertility in hyper-PRL patients even when PRL levels are not normalized. This suggests that metergoline might also affect gonadotropins release. In a double-blind cross-over study in 8 normal males, repeated administration of metergoline enhanced the LH response to LHRH and reduced the PRL response to TRH; for females, three different tests were performed on days 5, 8 and 21 of two different menstrual cycles, each test being preceded by metergoline or by placebo administration. Metergoline always reduced the PRL response to TRH; on the 5th day, metergoline reduced the FSH response to LHRH and on the 21st day enhanced the LH response to LHRH. Basal levels of LH, FSH, T3, T4, Testosterone, 17 beta-estradiol and progesterone as well as the FSH response to LHRH (in males) and the TSH response to TRH (in both males and females) were not modified by metergoline. The data suggest that tests with TRH and LHRH can yield different results when performed during metergoline administration and that metergoline, acting through an unknown mechanism, can modify gonadotropins release.
Plasma prolactin levels rise in stimulated cycles. To clarify the effects of gonadotrophin on the lactotrophs, three studies were performed. First, plasma concentrations of prolactin during clomiphene citrate (CC)-human menopausal gonadotrophin (HMG)-human chorionic gonadotrophin (HCG) treatment of women enrolled for in-vitro fertilization (IVF) were compared with those during HMG-HCG administration while under pituitary suppression with a gonadotrophin releasing hormone (GnRH) analogue (buserelin). Women suppressed with buserelin had higher basal levels of PRL in plasma (14.4 +/- 4.3 ng/ml versus 6.9 +/- 1.4 ng/ml, P less than 0.001). Only buserelin-suppressed women showed a significant rise in plasma prolactin before HCG administration, while both patient groups had marked prolactin peaks after HCG injection. This peak was higher in the buserelin group (71.9 +/- 50.7 ng/ml versus 52.6 +/- 29.7 ng/ml). The second study showed that plasma levels of prolactin of 6 post-menopausal women were significantly increased 48 h after an injection of 5000 IU HCG, i.m. (24.9 +/- 17.4 ng/ml versus 12.4 +/- 6.2 ng/ml P less than 0.05). Third, plasma prolactin was studied in 5 women over 30 days after surgical castration. An upward trend was observed similar to that of endogenous gonadotrophin, with the change in prolactin values closely correlating with the change in concentrations of follicle stimulating hormone (P less than 0.005). All these findings suggest that human gonadotrophins stimulate lactotrophs.
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In adult male hamsters, 2 months of exposure to a short photoperiod (5 h of light:19 h of darkness) caused testicular regression and a precipitous decline in plasma PRL, in agreement with earlier reports from other laboratories. Depressed release of PRL cannot be explained by a reduction in testicular steroidogenesis, because castration of males kept in a long photoperiod did not reduce PRL levels and administration of testosterone to males kept in a short photoperiod failed to reverse the decline in plasma PRL concentration. Treatment of such "regressed" animals with PRL, GH, or ectopic pituitary transplants stimulated growth of the testes and the accessory reproductive glands, increased the concentration of LH receptors in the testes, and elevated plasma testosterone levels. A single injection of 250 microgram PRL was sufficient to increase testicular LH binding, and chronic treatment with pituitary grafts completely reversed testicular regression. The effectiveness of exogenous PRL in stimulating testicular growth and LH receptors was significantly influenced by the timing of the injection. In some experiments, gonadotropin levels appeared elevated in animals injected with PRL, but these differences were not statistically significant. In hamsters with gonadal regression induced by exposure to a short photoperiod, daily administration of 20 microgram H and/or 150 microgram FSH had no apparent effect on testicular function. However, treatment with large doses of hCG and/or PMS gonadotropin resulted in significant stimulation of testicular growth and steroidogenesis. Chronic treatment of males maintained in a long photoperiod (14 h of light:10 h of darkness) with an inhibitor of PRL release, 2-Br-alpha-ergocryptine, resulted in a decreased weight of the testes and seminal vesicles. Administration of this inhibitor for a longer period (2 months) produced a significant increase in body weight but had little effect on testicular function. These results indicate that changes in the release of PRL (and possibly also GH) may plan an important role in mediating the effects of the photoperiod on testicular function in the golden hamster.
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