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.

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 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.

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

Clinical and biochemical features of depression in Parkinson's disease.

Among 49 consecutive patients with Parkinson's disease, 40% were depressed according to DSM-III; they had major depression or dysthymic disorder accompanied by sleep disturbance, fatigue, psychomotor retardation, loss of self-esteem, and excessive guilt. During a 10-day dopamine-free period, lumbar puncture was performed to measure the metabolites of dopamine, serotonin, and norepinephrine. Patients were given an overnight dexamethasone suppression test, and the effects of thyrotropin-releasing hormone and L-dopa on plasma growth hormone and prolactin were examined. Level of CSF 5-hydroxyindoleacetic acid was lowest in parkinsonian patients with major depression and was related to psychomotor retardation and loss of self-esteem.

Hypothalamic-pituitary-adrenal-cortical activity in anorexia nervosa and bulimia.

We studied hypothalamic-pituitary-adrenal-cortical (HPA) activity in nine underweight women with anorexia nervosa, 12 women of normal body weight with bulimia, and nine control subjects. The measures of HPA activity were the pattern of plasma cortisol secretion over 24 hr and the responses of plasma cortisol to dexamethasone suppression and to low dose ACTH stimulation. The patients with anorexia nervosa had significantly elevated 24 hr concentrations of plasma cortisol compared to the controls and showed significantly less cortisol suppression following dexamethasone. There was no difference between patients with anorexia nervosa and controls in the rise in plasma cortisol following ACTH. On most measures of HPA activity, the normal weight patients with bulimia were indistinguishable from the controls. These results suggest that HPA activity is normal in most patients of normal body weight with bulimia and that the psychological and behavioral disturbances common to both anorexia nervosa and bulimia are, in the absence of significant weight loss, insufficient to produce major alterations in HPA activity.

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.

Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes.

Thermoregulatory, cardiovascular and endocrine changes were simultaneously monitored in 11 post-menopausal women with frequent hot flashes (catecholamine and LH levels were measured in 5 and 6 subjects respectively). Plasma samples were obtained at 1- and 5-min intervals. Hot flashes were accompanied by abrupt increases in plasma epinephrine (about 150%) and concomitant decreases in norepinephrine (about 40%). Increased luteinizing hormone was associated with most hot flashes. A detailed sequence of hot flash-associated changes was established. An aura preceded the onset of the hot flash by several seconds. HR and FBF increased just before the onset of the flash and reached peak levels of 10-20 beats/min and 30-fold respectively. Coincident with vasodilation and sweating, finger temperature increased an average of 3.9 degrees C and esophageal temperature fell 0.2-0.6 degrees C. Flashes of both discrete and prolonged intervals were observed. Sensation was a reliable index of flash occurrence and intensity as measured physiologically. Our observations are consistent with the hypothesis that hot flashes are due to a change in the thermoregulatory set point. Furthermore, the changes in catecholamine levels are consistent with the cardiovascular changes accompanying hot flashes.