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Biomedical subjects

E Knobil

Publications and source records attributed to E Knobil.

At least 73 records · Page 4Linked to original sources
PubMed1980

Monkey pituitary oestrogen receptors and the biphasic action of oestradiol on gonadotropin secretion.

Evidence has been advanced in favour of the hypothesis that, in the rhesus monkey, the negative feedback as well as the stimulatory or so-called "positive feedback" action of oestrogen on gonadotropin secretion is at the level of the pituitary gland. The cellular basis for this biphasic action of oestrogen on the gonadotroph is not understood. In oestrogen target tissues the elicitation of physiological responses is generally associated with the binding of oestrogen to cytoplasmic receptor proteins which are subsequently translocated to the nucleus. Such receptors have been characterized in the anterior pituitary of the rat. In the ovariectomized rhesus monkey refused with 3H-oestradiol, autoradiography and parallel cell fractionation have demonstrated the accumulation of 3H-oestradiol by the nuclei of a significant number of pituitary cells. We describe here some of the properties of these putative oestrogen receptors in the anterior pituitary of the monkey and observe that their distribution between cytoplasmic and nuclear compartments is constant in response to sustained elevations in serum oestrogen concentration which produce a biphasic pattern of circulating gonadotropins.

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PubMed1980

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.

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PubMed1980

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.

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PubMed1979

Further studies on the effects of lesions in the rostral hypothalamus on gonadotropin secretion in the female rhesus monkey (Macaca mulatta).

Bilateral radiofrequency lesions were stereotaxically placed in the rostral hypothalamus of four adult female rhesus monkeys. These lesions resulted in extensive destruction of the ventromedial preoptic-anterior hypothalamic area (POA-AHA) and included the suprachiasmatic nucleus as well as, with the exception of one animal, the organum vasculosum of the lamina terminalis. In three of these four animals, gonadotropin surges similar to those observed before surgery were elicited in response to either a spontaneous increment in serum estrogen concentration or an estradiol benzoate injection. This stimulatory action of estradiol on LH and FSH release was not demonstratable in the remaining lesioned animal, but estradiol benzoate injections also failed to elicit a gonadotropin discharge in one of a series of five normal control animals. These findings fail to support the view that destruction of the ventromedial POA-AHA in this species compromises the ability of the hypothalamicohypophysial apparatus to respond to the positive feedback action of estradiol. The diurnal variation in serum cortisol concentration was not interrupted by placement of the lesions in the ventromedial POA-AHA.

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PubMed1979

[Electrophysiological study of hypothalamic neurons and gonadotropin regulation in rhesus monkey (author's transl)].

The electrical activity of various hypothalamic areas was recorded in anesthetized (sodium pentobartital) (n = 3) and unanesthetized (n = 3) ovariectomized rhesus monkeys. The plasma gonadotropin levels of the animals during the recording sessions were obtained by a chronic cardiac catheter. 1. Sodium pentobarbital greatly affected the electrical activity of most hypothalamic neurons (84%). The mean spontaneous electrical unit activity of neurons in the unanesthetized animals (n = 30) was 1.5 spike/sec. This value decreased to 0.1 spike/sec in the anesthetized group (n = 30). However, a small number of hypothalamic neurons were insensitive to the anaesthetic. 2. The multiunit electrical activity recorded in the median eminence showed marked periodic increases, about 200 sec before LH was observed to rise in the plasma (10/12). This increased firing lasted about 10 min (Fig. 1A). 3. In a few cases (2/12), however, increased firing was not associated with LH release. Since, in this area, multiunit activity represents the summation of a large number of axon terminals, the release of a hypothalamic hormone other than Gn-RH is put foreward as a possible hypothesis. 4. Of 51 neurons recorded in various hypothalamic areas, 3 showed periodic increases of electrical unit activity which corresponded to a rise in plasma LH levels (Fig. 1 B). These neurons are located in the arcuate area. 5. These results are consistent with the hypothesis of a relation between the electrical activity of some hypothalamic neurons and the periodical LH discharges observed in the ovariectomized rhesus monkey.

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PubMed1978

Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone.

In rhesus monkeys with hypothalamic lesions that abolish gonadotropic hormone release by the pituitary gland, the constant infusion of exogenous gonadotropin-releasing hormone (GnRH) fails to restore sustained gonadotropin secretion. In marked contrast, intermittent administration of the synthetic decapeptide once per hour, the physiological frequency of gonadotropin release in the monkeys, reestablishes pituitary gonadotropin secretion. This phenomenon is attributable to the pattern of GnRH delivery rather than to the amounts of this hormone to which the cells of the pituitary are exposed. Moreover, the initiation of continuous GnRH administration in animals with lesions and in which gonadotropin secretion is reestablished by intermittent GnRH replacement can result in a "desensitization" or "down regulation" of the processes responsible for gonadotropin release.

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PubMed1978

Identification of inhibitory and stimulatory control of prolactin secretion in the rhesus monkey.

In the unanesthetized, ovariectomized rhesus monkey, gonadotropin secretion is episodic while prolactin (Prl) release is relatively constant. Under pentobarbital anesthesia, however, Prl secretion also becomes pulsatile in synchrony with the discharges of LH. This finding suggests that the anesthesia has unmasked normally inhibited Prl releasing stimuli which are driven by the circhoral 'clock' that also times the discharges of GnRH.

Animals↗
PubMed1978

The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta).

Attempts were made to destroy selectively the arcuate nucleus with radiofrequency current in adult female rhesus monkeys as a first step in identifying the areas of the mediobasal hypothalamus (MBH) that are responsible for the neural control of gonadotropin secretion in this species. Extensive or complete destruction of the arcuate region was produced in three animals and in two of these the lesion was confined primarily to the arcuate region and the dorsal aspect of the posterior median eminence. These lesions resulted in the cessation of LH and FSH secretion and blocked the positive feedback action of estradiol on gonadotropin release but did not appear to influence grossly basal thyroid and adrenocortical function, or to abolish GH discharge in response to insulin hypoglycemia. Adenohypophysial infarcts were not observed and exogenous LHRH and TRH induced marked discharges of the appropriate anterior pituitary hormones. In two additional animals with large hypothalamic lesions, destruction of the arcuate region was incomplete. In this group only partial inhibition of gonadotropin secretion was observed. LH and FSH secretion did not appear to be influenced in one animal bearing a large MBH lesion that entirely spared the arcuate region. Although serum prolactin remained at pre-lesion control levels after placement of the two relatively discrete lesions confined to the arcuate region, unambiguous increases in the secretion of this hormone were observed when the area of destruction encompassed tissue anterior and/or dorsal to the arcuate region. These observations suggest that the arcuate region is the primary structure mediating the hypothalamic control of gonadotropin secretion in the rhesus monkey. They also suggest that, in this species, the regions of the MBH involved with the regulation of gonadotropin release and those which control prolactin secretion are anatomically distinct.

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PubMed1978

On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey.

Ovariectomized rhesus monkeys bearing hypothalamic lesions which had abolished endogenous LHRH production, as evidenced by a profound reduction in gonadotropin secretion, but in which LH and FSH secretion was reestablished by a chronic intermittent iv infusion of synthetic LHRH (1 microgram/min for 6 min every hour) were used to investigate the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion. The administration of estradiol to such animals, while continuing the LHRH replacement regimen, resulted in a decline in circulating LH and FSH levels, followed by an unambiguous discharge of these hormones. The time course of this biphasic pattern of gonadotropin secretion was remarkably similar to that observed in response to estradiol administration in otherwise intact ovariectomized animals. These results suggest that, in the rhesus monkey, estradiol can exert both its negative and positive feedback actions on gonadotropin secretion at the level of the pituitary gland.

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PubMed1978

The sites of action of estradiol and phentolamine in the inhibition of the pulsatile, circhoral discharges of LH in the rhesus monkey (Macaca mulatta).

Pulsatile LH secretion was re-established in ovariectomized monkeys bearing hypothalamic lesions by an intermittent infusion of LHRH. The administration of estradiol to such animals resulted in a prompt cessation of these pulsatile discharges of LH and a resultant decline in the mean plasma concentration of the gonadotropin. The time course of this inhibition of LH secretion was indistinguishable from that observed after estrogen administration to ovariectomized animals with intact nervous systems. In contrast, phentolamine did not interrupt the pulsatile LH discharges occasioned by the hourly administration of exogenous LHRH to the lesioned animals. These results are consistent with the conclusion that the acute negative feedback action of estradiol on circhoral LH release in the monkey is at the level of the pituitary gland, whereas the inhibitory action of phentolamine on this mode of LH secretion is at a neural site.

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PubMed1977

The effect of luteinizing hormone releasing hormone (LHRH) antiserum administration on gonadotropin secretion in the rhesus monkey.

Single iv injections of a rabbit antiserum to synthetic LHRH promptly suppressed serum LH and FSH concentrations in ovariectomized rhesus monkeys. Gonadotropin levels remained depressed for 10-21 days, the approximate duration of enhanced LHRH binding activity in the circulation. Doses of LHRH antiserum sufficient to reduce tonic gonadotropin secretion did not modify the time course or magnitude of estrogen-induced gonadotropin surges. These negative findings, however, cannot be interpreted to signify that such surges are not caused by a release of LHRH.

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PubMed1977

A new substance resembling luteinizing hormone in the blood of rhesus monkeys.

Sera from a number of rhesus monkeys showed low or undetectable levels of LH according to radioimmunoassays which employ radioiodinated rhesus LH and antisera against rhesus LH or hCG. These same sera, when assayed by a system utilizing radioiodinated ovine LH and a unique anti-ovine LH serum which cross-reacts with LH from a variety of species, appeared to contain large and variable quantities of LH. The chromatographic behavior on Sephadex G-100 of the LH-like material in these sera was indistinguishable from that of authentic rhesus LH. Chromatographic fractions containing this LH-like material, as well as the sera from which they were derived, generated dose-response curves in the ovine:anti-ovine radioimmunoassay with steeper slopes than those produced by rhesus LH. These same chromatographic fractions had negligible activity in an alpha subunit radioimmunoassay which detects not only free rhesus alpha subunit but also the alpha component of undissociated rhesus glycoprotein hormones including LH. Treatment of these fractions with 4M guanidine-HCl produced a substance of smaller molecular size which, like rhLH beta, was active in the ovine:anti-ovine assay. A substance closely resembling the serum LH-like material but having a somewhat greater molecular size is also present in the rhesus adenohypophysis, but its relationship to the serum substance remains uncertain.

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PubMed1977

Estrogen-induced gonadotropin surges in decerebrated female rhesus monkeys with medial basal hypothalamic peninsulae.

Hypothalamic peninsulae, posteriorly continuous with the brain stem, were produced in ovariectomized rhesus monkeys by aspiration of the cerebral hemispheres and all brain structures anterior and dorsal to the optic chiasm. These preparations were sustained for 52 to 60 h postoperatively by maintaining blood gases and pH within physiological limits and by supporting arterial blood pressure, when necessary, with infusions of rhesus monkey blood and norepinephrine. The sc injection of estradiol benzoate (EB) to such animals upon completion of the ablation procedure was followed 18-24 h later by unambiguous surges of serum LH and FSH with durations in the excess of 24 h. These findings are consonant with the view that the central components of the control system that initiates the preovulatory gonadotropin surge in the rhesus monkey are resident within the medial basal hypothalamic-hypophysial apparatus.

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