E. Knobil

The Neuroendocrine Control of the Menstrual Cycle

Publisher Summary This chapter discusses the construction of a model of the neuroendocrine control system that governs the 28-day ovarian cycle of the rhesus monkey. This model has three basic components: the arcuate nucleus of the hypothalamus, the gonadotrophs of the pituitary gland, and the ovary. The arcuate nucleus is the central component of the control system. The gonadotrophs respond to this unvarying pulsatile gonadotropin releasing hormone (GnRH) stimulation by releasing pulses of follicle stimulating hormone (FSH) and luteinizing hormone (LH). Immature follicles respond to this unvarying gonadotropic stimulus by increasing in size and secreting increasing quantities of estradiol, which achieve maxima near mid-cycle. This process occupies approximately 14 days. The magnitude of the response to each GnRH pulse is modulated by estradiol acting directly on the gonadotrophs. The characteristic duration of the rhesus monkey ovarian cycle is thus determined by the duration of follicular development. This can occur in the presence of an absolutely unvarying pattern of hypophysiotropic stimulation.

On the Control of Gonadotropin Secretion in the Rhesus Monkey

Publisher Summary This chapter discusses the regulation of gonadotropin secretion in the rhesus monkey. The time courses of the circulating gonadotropic hormones during the menstrual cycle of the rhesus monkey are ascertained after long and arduous methodological struggles and are essentially identical to those described in the human female. These are perceived as being the resultant of relatively continuous or tonic secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) interrupted once every 28 days, on the average, by an abrupt, massive discharge of these hormones, which is represented as “cyclic” secretion by analogy to the basic schema postulated for the rat. In the rhesus monkey, the peak of this midcycle gonadotropin surge precedes ovulation by 37 hours, on the average. Moreover, the tonic secretion of LH and of FSH, as reflected by their concentrations in peripheral plasma at times other than during the preovulatory surge, appears to be controlled by a classical negative feedback loop involving, among other components, the ovary and the gonadotrophs of the adenohypophysis.

Experimental induction of puberty in the infantile female rhesus monkey

Normal ovulatory menstrual cycles were initiated in prepubertal female rhesus monkeys by the infusion of gonadotropin-releasing hormone for 6 minutes once every hou;. When this regimen was discontinued, the animals promptly reverted to an immature state. These findings permit the conclusion that neither adenohypophysial nor ovarian competence is limiting in the initiation of puberty and suggest that this process depends on the maturation of the neuroendocrine control system that directs the pulsatile secretion of gonadotropin-releasing hormone from the hypothalamus.

Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone

In rhesus monkeys with hypothalamic lesions (which appear to abolish the endogenous production of gonadotropin-releasing hormone), normal ovulatory mestrual cycles were reestablished by an unvarying, long-term replacement regimen consisting of one intravenous pulse of synthetic gonadotropic-releasing hormone per hour. This finding is in accord with the hypothesis that the pattern of pituitary gonadotropin secretion throughout the menstrual cycle (basal secretion interrupted, once every 28 days on the average, by a preovulatory surge) is not directed by alterations in hypothalamic gonadotropin-releasing hormone secretion but by the ebb and flow of ovarian estrogens acting directly on the pituitary gland.

Sexual Differentiation of Pituitary Function: Apparent Difference between Primates and Rodents

Surges in luteinizing hormone secretion resembling those which occur spontaneously during the menstrual cycle were induced by acute elevations in circulating estrogen concentrations in both male and female rhesus monkeys gonadectomized in adulthood. These experiments demonstrate that in primates, in contrast to rodents, exposure of the hypothalamohypophyseal unit to androgens throughout fetal and postnatal development does not prevent the differentiation of the control system that governs cyclic gonadotropin secretion.

Acute effects of N-methyl-DL-aspartate on the release of pituitary gonadotropins and prolactin in the adult female rhesus monkey

The acute effects of an aspartic acid analogue, N-methyl-DL-aspartate (NMA), upon the release of several anterior pituitary hormones were examined in adult female rhesus monkeys. Intravenous injection of NMA (15 mg kg body weight) induced a large and rapid rise in plasma levels of luteinizing hormone, follicle stimulating hormone, and prolactin. Thyroid stimulating hormone concentrations were not altered. Thus, in primates, as in rodents, systemically administered NMA is capable of eliciting pituitary hormone secretion, although the site of its action in the rhesus monkey remains to be established.

Effect of adrenergic blocking agents on fatty acid mobilization during fasting.

Summary Repeated doses of ergotamine and hexamethonium had no effect on increase in plasma non-esterified fatty acid (NEFA) concentration which occurs during fasting. Dibenzyline was similarly without effect on this response. These findings suggest that the stimulus to increased NEFA mobilization during fasting may not be mediated by the adrenergic nervous system.

The Sites of Action of Ovarian Steroids in the Regulation of LH Secretion

In the monkey, estradiol appears to exert both its negative and positive feedback actions on gonadotropin secretion primarily at the hypophysial level. In the rat, inhibitory and stimulatory effects of estradiol on the pituitary are also evident, but additional actions on the medial basal hypothalamus (MBH) and preoptic area must be postulated to fully account for the negative and positive feedback effects of estradiol in this species. The available evidence points to the MBH as a site for the negative feedback action of progesterone in the rat. In both species, progesterone probably acts in the central nervous system to block the positive feedback action of estradiol while the facilitation of luteinizing hormone release by this steroid appears to be at a hypophysial level.

Peripheral plasma progesterone levels during human pregnancy and labor

Abstract Circulating plasma progresterone levels have been measured in 12 hospitalized, obstetrically normal, nulliparous patients during the last 7 weeks of gestation and spontaneous labor. A total of 92 blood samples were collected sequentially and analyzed by 3 independent investigators using the protein-binding method. Plasma progesterone reached peak values at different times during the last 4 weeks of gestation in individual patients but subsequently decreased slightly with the onset of clinical labor. This finding may be significant, in that it indicates a terminal failure in increased placental progesterone genesis, at a time when thecontinued increase in uterine volume promotes myometrial activity through a stretch effect.

Mobilization of Fatty Acids by Epinephrine in Normal and Hypophysectomized Rhesus Monkeys.

Summary Mobilization of NEFA by epinephrine in rhesus monkeys is abolished by hypophysectomy while the hyperglycemic response is retained. Pretreatment of hypophysectomized monkeys with cortisol acetate, ACTH, prolactin and growth hormone fails to restore response to epinephrine in terms of NEFA mobilization. Pretreatment with TSH or triiodothyronine, however, produced a restoration of the response. It is concluded that optimal thyroid function is requisite for the NEFA mobilizing action of epinephrine in vivo.