Effect of vitamin A deficiency upon gonadotropin response to gonadotropin-releasing hormone.

There is a monotypic change in basal serum gonadotropin levels following retinol treatment of chronically vitamin A-deficient (VAD) male rats. The present study was undertaken to investigate the hypothesis that the specific increase in serum follicle-stimulating hormone (FSH) represents a change in gonadotrope responsiveness to gonadotropin-releasing hormone (GnRH). To this end, a test dose of GnRH was given to VAD rats pre-, 5 days post-, and 10 days postreplacement of vitamin A (PVA). In VAD rats, basal serum FSH and luteinizing hormone (LH) levels were higher than those of controls. Increased LH/testosterone ratios, both in basal levels and in the secretory response to GnRH, suggested Leydig cell hyporesponsiveness in VAD animals. Both the FSH and LH responses to GnRH were maximal at 1 h, declining thereafter. Although the absolute increments in FSH and LH 1 h after GnRH in VAD rats were greater than in controls, the percent increase in FSH tended to be lower in VAD rats and to increase after vitamin A replacement. The specific enhancement of FSH release PVA became evident only when assessing total secretion of FSH and LH after GnRH. Luteinizing hormone response to GnRH increased PVA, but not significantly, while FSH secretion after GnRH increased both 5 and 10 days PVA, times during which basal FSH levels were also increasing. These changes in FSH secretion could not be attributed either to increases in endogenous GnRH or to changes in testosterone or estradiol levels. Basal serum androgen binding protein levels, elevated in VAD animals, did not respond to the acute increases in FSH after GnRH and remained high PVA, suggesting no acute change in Sertoli cell function. Thus, the PVA increase in FSH secretion unmasks a partial inhibition of the gonadotrope present in the retinol-deficient, retinoic acid-fed male rat.

Effects of an antiprogesterone agent, RU-486, on the menstrual cycle of the rhesus monkey.

RU-486 (RU), a synthetic steroid with antiprogesterone receptor activity, was used to study the role of progesterone in the normal menstrual cycle of rhesus monkeys. The drug, at dosages of 2, 4, or 12 mg/kg, was administered as a single im injection during the luteal phase (days 5-8) in 16 experiments in 8 monkeys. RU had acute effects on the endometrium, as it induced menstruation within 3 days in spite of persistant progesterone elevations, thereby shortening the cycle length by about 5 days. Long term effects on menstrual cyclicity were also found with the higher RU doses. The intermenstrual interval after RU treatment increased from 31.8 +/- 2.4 (+/- SE) days after a 2 mg/kg dose of RU to 82.4 +/- 6.8 days after a 12 mg/kg dose of RU, with a control cycle length of 29.4 +/- 0.7 days. This prolonged interval was related to a delay in the completion of the follicular maturation process and, therefore, a delay in ovulation, as judged by estrogen and progesterone concentrations. Subsequent menstrual cycles were regular and ovulatory. Our results suggest that RU binds to the endometrial progesterone receptor, thereby inducing premature menstruation in the presence of elevated progesterone levels. RU also exerts long term effects on the hypothalamo-hypophyseal axis, since it significantly alters menstrual cyclicity.

The effect of delta 1-testolactone on serum testosterone and estradiol in the adult male rat.

delta 1-Testolactone, an androgen derivative without intrinsic hormonal action, is known to block the aromatization of androgens to estrogens. This study was designed to assess its effect upon serum testosterone (T) and estradiol (E2) in the adult male rat. By itself, testolactone (TL) did not affect T/E2 levels in the dosages utilized. Daily injections of human chorionic gonadotropin (hCG) for 15 days caused a tenfold rise in serum T, although there was no increase in serum E2. When given along with hCG, TL did not alter the Leydig cell response. However, pretreatment of animals with TL increased the testicular response to hCG over that of saline-treated animals. Studies were also carried out to delineate the sources of estrogen in the adult male rat. These experiments demonstrate that (1) the majority of E2 is not testicular in origin but is derived from the adrenal; (2) the conversion of androgen precursors to E2 in the rat is not affected by TL; and (3) in spite of no demonstrable inhibition of E2 production, TL causes an increased Leydig cell responsiveness to hCG.

Naloxone stimulation of luteinizing hormone secretion in the female monkey: influence of endocrine and experimental conditions.

It is known that opiate administration results in the inhibition of LH release. In this paper, we examine the role of endogenous opiates in the regulation of gonadotropin secretion during the menstrual cycle of the monkey. The objectives of these experiments were to determine the experimental and endocrine conditions that are conducive to increased gonadotropin secretion in response to endogenous opiate antagonism. In Exp 1, naloxone was administered during the luteal phase to three groups of monkeys under three different experimental conditions. When naloxone (2 mg, iv) was injected into conscious unrestrained or sedated animals, LH secretion increased 2- to 3-fold. In contrast, the same dose of naloxone failed to stimulate LH secretion in monkeys restrained in primate chairs. In Exp 2, the gonadotropin response to acute naloxone administration on each day of the menstrual cycle was determined. A significant increase in the serum LH concentration (greater than or equal to 20% within 40 min of injection) was observed after naloxone administration in 60% of the trials conducted during the luteal phase. Significant increases occurred in only 13% of the saline-treated control trials during this stage of the menstrual cycle. Mean LH levels increased from 14.4 +/- 1.3 to 31.2 +/- 4.3 ng/ml after naloxone injection. In contrast, naloxone had no effect on LH secretion during the follicular phase. Although small LH increments were noted after naloxone injection in 40 +/- 8% of the trials, neither the frequency nor the amplitude of these increases was different from that in follicular phase controls. We conclude from these results that the ability of naloxone to stimulate LH secretion is limited to the luteal phase. Previous findings from our laboratory indicate that hypothalamic beta-endorphin activity, as reflected by its concentration in hypophyseal portal blood, is increased by ovarian steroids and that its greatest activity occurs during the luteal phase. Since the response of LH to naloxone administration was limited to the luteal phase, we believe that these results support the conclusion that hypothalamic beta-endorphin is a physiological modulator of LH secretion in the monkey.

Photoperiod and ovulatory menstrual cycles in female macaque monkeys.

Macaques (Macaca mulatta and M. assamensis) which had been maintained on a 12L :12D light cycle for the previous 4 years and had 25-35-day menstrual cycles were randomly assigned to two groups. Those in Group 1 were kept in 12L :12D for 13 months. Those in Group 2 were subjected to three successive 5-month periods of 20L :4D, 4L :20D and 20L :4D. There were no significant differences between the two groups in the frequency, duration and percentage of ovulatory menstrual cycles, suggesting that photoperiod is not the sole regulator of seasonal breeding in these animals.

The use of human menopausal and chorionic gonadotropins for induction of ovulation. Sixteen years' experience at the Sloane Hospital for Women.

Gonadotropin therapy for anovulation is highly successful: 58.6% of treated patients conceive. Better results are achieved in patients with galactorrhea-amenorrhea (77.1%) and hypogonadotropic hypogonadism (63.3%) than in patients with normal gonadotropin levels (45.4%). The spontaneous abortion rate (27.5%) is somewhat higher than that in spontaneous pregnancies. The multiple pregnancy rate is 31% and was slightly lower in cycles with preovulatory estrogen levels in the physiologic range. In patients treated with human menopausal and chorionic gonadotropins for 7 to 9 days per cycle, the multiple pregnancy rate is considerably less (12.9%) than in patients with longer treatment. The efficacy of treatment does not diminish with repeat-treatment cycles.

Section of the pituitary stalk in the rhesus monkey. I. Endocrine studies.

The effects of pituitary stalk section on anterior pituitary secretion were studied in 20 female rhesus monkeys. Vascular connections between the hypothalamus and the pituitary gland were permanently interrupted in all but 4 animals. Prolactin levels rose rapidly and remained significantly elevated in all effectively stalk-sectioned animals for as long as the observation period (up to 3 years). Only smaller and transient elevations of prolactin were seen in the animals in which revascularization of the anterior pituitary gland had occurred. Growth hormone and cortisol were significantly decreased after stalk section, and were not released by insulin. Radioimmunoassayable luteinizing hormone (LH) levels decreased following surgery and, by bioassay, LH became undetectable within 5 weeks after stalk section, indicating that gonadotropin-releasing hormone is essential for the viability of the gonadotrope. The results indicate that plasma prolactin concentrations can be used to monitor completeness of pituitary gland isolation from direct hypothalamic influence. Stalk-sectioned monkeys provide good models to study direct pituitary effects of various hormones or drugs.

Gonadotropin, estrogen and progesterone response to long term gonadotropin-releasing hormone infusion at various stages of the menstrual cycle.

PIP: 6 normally menstruating women, aged 22-27, were given constant infusions of 12.5-25 mcg/hour gonadotropin releasing hormone (GnRH) for 24 hours during 10 cycles. 4 were infused in the early follicular, 3 in the late follicular, and 3 in the luteal phase. Frequent blood samples were assayed for luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, progesterone, and GnRH. The increase in gonadotropin and patterns of response varied in the different stages of the cycle. Quantitatively the response was minimal in the early follicular phase, maximal at midcycle, and moderate in midluteal phase. In the latter 2 phases most of the gonadotropins were released during the first 8 hours of infusion. The ratio of the LH-FSH areas under the curves favored FSH in the early follicular phase and LH at midcycle and luteal phase. In all the cycles there was an initial increase in both gonadotropins which lasted 6-8 hours after which the levels declined but nevertheless remained above baseline as long as the infusion was continued. Plasma GnRH measured during 6 infusions was undetectable prior to the starting and after discontinuation of the infusion, but during infusion fluctuations were considerable ranging from 150 to 500 pg/ml. These studies bring additional evidence to the possible existence of 2 gonadotropin pools in the human pituitary and point to the complexity of the response mechanism to GnRH stimulation and its relation to ovarian secretion.^ieng

The significance of weight loss in the evaluation of pituitary response to LH-RH in women with secondary amenorrhea.

Sixteen women with amenorrhea occurring in the setting of severe self-imposed weight loss and 18 women with secondary amenorrhea due to other causes were given LH-RH (luteinizing hormone-releasing hormone). Women with weight loss were found to be unresponsive to LH-RH when severely underweight. FSH responsiveness returned in a linear fashion as weight gain occurred and was not related to estrogen levels. LH responsiveness also returned with weight gain although the relationship was not linear but exponential and a sudden increase in responsiveness occurred at 15% below ideal weight. No relationship to estrogen levels could be found. Women who experienced amenorrhea in a setting other than weight loss did not demonstrate responsiveness to LH-RH which could be correlated with body mass, even when underweight. Women who experienced amenorrhea with weight loss had a consistently lower LH response to LH-RH than the second group and their LH response was always lower than the FSH response. On the other hand, a variety of patterns was found in women with amenorrhea due to other causes.