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Further evidence on the role of the hypothalamic afferents on the estrogen-induced prolactin release.

Serum prolactin (Prl) concentrations in ovariectomized rats were low without significant differences between morning and afternoon values. These levels were not affected by either frontal or caudal hypothalamic deafferentation. However, they increased after lesioning the hypothalamic median eminence (ME). Three days after the injection of 20 microgram estradiol benzoate (EB) into ovariectomized non-lesioned rats, a rise in serum Prl occurred in the afternoon but not in the morning. In animals with ME lesions estrogen enhanced both morning and afternoon values. The animals with caudal hypothalamic deafferentation and those which had undergone sham operation showed the same pattern as the normal animals. On the contrary, after estrogen treatment of rats with frontal hypothalamic deafferentation high serum Prl concentration during the morning and low levels in the afternoon were observed. It is concluded that estrogen effects on Prl secretion are in part mediated by frontal neural afferents to the hypothalamus. They would facilitate Prl inhibiting factor (PIF) secretion in the morning and inhibit PIF secretion in the afternoon.

Afferent Pathways↗

Prolactin inhibiting activity of dopamine-free subcellular fractions from rat mediobasal hypothalamus.

In order to check the hypothesis of an identity of dopamine (DA) and prolactin inhibiting activity (PIF), their subcellular distribution was studied in the mediobasal hypothalamus (MBH) and the striatum, which served as a control structure. PIF was tested both in vivo and on pituitary incubates. Fractions were also assayed after adsorption of their catecholamine content on alumina, as well as in presence of haloperidol or alpha-flupentixol, potent DA receptor inhibitors. In the MBH, PIF was evenly distributed in the 17,000 g supernatant (S2) and in the crude mitochondrial fraction (P2) which contains synaptosomes. PIF activity was completely removed by alumina adsorption of S2, but not of P2 in spite of an over 99.9% elimination of DA. In contrast, striatal PIF activity was detected only in P2, and disappeared completely upon alumina adsorption, thus indicating that, in this structure, it is entirely due to DA. Addition of haloperidol (10--5M) or alpha-flupentixol (10--6M) reduced PIF activity of crude MBH homogenates, but no longer affected it after alumina adsorption. Quantitative studies suggest that only half of the total MBH PIF activity is accounted for by DA. It is concluded that the MBH contains dopamine-free PIF, which, as already shown for several other neurohormones, is exclusively distributed in nerve-endings.

Animals↗

Prolactin stimulation test with perphenazine: an evaluation of plasma prolactin levels and pituitary secretory activity in the rat.

Many investigations of the regulation of prolactin synthesis and release are based on single plasma prolactin determinations. The purpose of the present experiment was to ascertain whether groups of rats (i.e. young or adult, male or female animals, being either intact, gonadectomized or gonadectomized and treated with oestrone), differing in age and/or endocrine status, will react to a single dose of perphenazine by an acute release of pituitary prolactin in proportion to their initial plasma prolactin levels. No consistent relation existed between the classification of the twelve groups of rats into three categories of basal plasma prolactin levels (i.e. less than 20, 25-50, greater than 125 ng/ml) and their response to perphenazine. Even though all groups showed a highly significant increase of plasma prolactin levels the magnitude of the maximum prolactin response at 30 min varied greatly within the groups of one category and thus was not related to the initial prolactin levels. The effect of 14 days of oestrone treatment in increasing plasma prolactin levels in gonadectomized animals was greatest in young and adult male rats, less in young females and not significant in adult females. The results obtained after perphenazine treatment in the latter group made it clear that the effect of oestrogen treatment on prolactin release can be completely blocked by increasing synthesis and/or release of the prolactin-release inhibiting factor (PIF). Since perphenazine induces decrease of pituitary prolactin and a concomitant increase of plasma prolactin levels through lowered PIF-action, the positive effect of oestrogens on prolactin release (as observed in gonadectomized male and young female rats) apparently is caused by a different mode of action. The implications of these findings for the regulation of prolactin release, as affected by the endocrine status of the rat, is discussed. Moreover, comparison of prolactin lost from the pituitary and gained in the circulation of the experimental animals, with amounts of prolactin that were observed to disappear from plasma during the experiment, provided suggestive evidence that the capacity to synthesize and/or eliminate prolactin, after a sudden provoked release of the hormone, differed among the groups. The rates of synthesis by the pituitary, of release from the pituitary into the circulation as well as of elimination of the hormone from the circulation (equally involved in determing actual plasma levels) are thought, therefore, to be far more important for the elucidation of prolactin regulation than single plasma prolactin determinations.

Animals↗

Inhibition of pituitary prolactin secretion by human placental lactogen in rats.

Intact female rats given twice daily injections of 1 mg human placental lactogen (HPL) showed continued dioestrous vaginal smears and their ovarian corpora lutea were found to be hypertrophied and functiona. The serum prolactin level was significantly lower in these rats than in the controls at dioestrus as well as at pro-oestrus. Twice-daily injections of 0.5 or 2 mg HPL to ovariectomized rats decreased serum and pituitary levels of prolactin and increased hypothalamic activity of prolactin inhibiting hormone, although the effect was less at the lower dose. Human placental lactogen had no direct effect on pituitary prolactin secretion in vitro. These findings have demonstrated that HPL, like prolactin itself, inhibits prolactin secretion by actin

Animals↗

[Prolactin in male reproduction].

Prolactin (PRL), a peptide hormon from the hypophysis, becomes more interesting, since it can be determined by radioimmunassays. The release of prolactin is controlled by two not yet identified factors, the prolactin-releasing-factor and the prolactin-inhibiting-factor. The latter predominantes. Many pharmacological substances can alter the release. The normal serum levels in the man are 6-13 ng/ml. Prolactin affects many organs, f.e. kidney, mamma, ovary, testis, hepar and skin. For clinical tests the raise in the serum levels after TSH or chlorpromacin and the drop after application of 2-brom-alpha-ergocryptin is used. Increased serum levels are found in patients with prolactin-producing tumors. In the male this is followed by disturbances of the sexual potency. Relations between prolactin and male infertility of gynecomastia are not yet known.

Animals↗

[New findings on human prolactin].

Since prolactin (HPRL) occurs as a separate pituitary hormone in man the paper will discuss results about the mechanisms involved regulation of HPRL secretion. A number of factors which lead to an increase in HPRL secretion are named. The clinical relevance of HPRL inhibiting substances as L-DOPA and 2-Br-alpha-ergocryptine is mentioned. The influence of HPRL in pregnancy and lactation period is described also the regulative effect of HPRL on hormone-dependent breast tumors.

Amenorrhea↗

Control of prolactin secretion by the hypothalamic catecholamines.

The neuroendocrine control of prolactin secretion is very complex. Even though the hypothalamus exerts a profound inhibitory influence upon the secretion of this hormone, the mechanism(s) involved is poorly understood. The cerebrospinal fluid seems to be becoming increasingly important as regards neuroendocrine regulatory mechanisms involving prolactin. Pharmacological agents such as apomorphine and many of the ergot alkaloids are very effective inhibitors of the secretion of prolactin. Still other pharmacological agents such as DMPEA, alpha-methyldopa, reserpine, and certain of the phenothiazines are very effective in causing a stimulation of prolactin secretion.

Animals↗

Hormonal control of zinc uptake and binding in the rat dorsolateral prostate.

The zinc uptake in the dorsolateral prostate of rats was studied after different hormonal manipulations. Orchiectomy reduced the uptake of 65Zn. Administration of estradiol benzoate to orchiectomized rats doubled the 65Zn uptake, a phenomenon which was not observed in orchiectomized-adrenalectomized rats. Adrenalectomy in orchiectomized rats had no effect on the concentration of radioactivity beyond the castration-induced decrease. A prolactin release inhibitor, 6-methyl-8-erogelenylacetamide, reduced the radioactivity concentration without changing the weight of the gland. Cyproterone acetate reduced the weight but not the radioactivity concentration. The concentration of 65Zn in the ventral prostate was not changed by orchiectomy, adrenalectomy, or the administration of estradiol benzoate, prolactin release inhibiors, or cyproterone acetate. The results suggest an important role for prolactin in the zinc uptake in the dorsolateral prostate but not in the ventral prostate.

Acetamides↗

[Prolactin].

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Animals↗

Localization of hypophysiotropic neurohormones by assay of sections from various brain areas.

The results of studies of the localization of the hypothalamic hypophysiotropic factors based on their direct determination in sections or nuclear punches are described. Luteinizing hormone-releasing hormone was found in high concentrations in the median eminence-arcuate nucleus complex, in lower concentrations in the mediobasal zone of the preoptic area. In addition to these hypothalamic sites, it is present in all four periventricular organs, especially in the organum vasculosum laminae terminalis. Thyrotropin releasing hormone has a widespread distribution. High concentrations are in the median eminence, arcuate nucleus, dorsomedial nucleus, and anterior part of the ventromedial nucleus. Lower concentrations are in several other structures of the hypothalamus, preoptic area and septum, and low but measurable quantities are found in most of the structures of the brain. Somatostatin is also present in most structures of the central nervous system, with highest concentrations in the median eminence, arcuate nucleus, ventromedial nucleus and periventricular nucleus. There are indications that the ventromedial nucleus or its immediate vicinity contains growth hormone releasing factor. Prolactin releasing activity was present in the median eminence and mediobasal parts of the anterior hypothalamus, whereas prolactin inhibitory activity was in the dorsolateral parts of the anterior hypothalamus and/or preoptic area.

Animals↗

Some new approaches to potential test systems for drugs against prostatic cancer.

We have previously reported on test systems, based on 5alpha-reductase (5alpha-RA) and arginase activities and steroid deposition in animal prostates, potentially useful in screening drugs possibly effective in cancer of the prostate. Recently, we have concentrated on the development of other in vivo and in vitro systems which may prove of further value in testing such drugs. These systems include the following: (a) The effects of drugs on 5alpha-RA activity in human and animal non-malignant and human cancerous prostatic tissues in organ culture. The parameters necessary for the maintenance of optimal 5alpha-RA in such explants have been determined, and it has been shown that certain agents (estramustine phosphate, progesterone, estradiol-17beta) can inhibit 5alpha-RA under in vitro conditions, pointing to the potential use of such an approach in screening various cytostatic agents. In addition, 65Zn deposition, the histology, and the androgen metabolism in such tissues in organ culture are being determined as additional parameters. (b) The deposition of 65Zn in the rat dorsolateral gland, particularly as affected by prolactin and testosterone, and the effects of chemotherapeutic agents on such deposition. Methotrexate and CCNU have been shown to be potent inhibitors of 65Zn deposition in the dorsolateral gland. The parameters related to zinc metabolism in the prostate are being further investigated. (c) The demonstration of receptors for estrogens (estradiol-17beta, diethylstilbestrol) in the prostate of the baboon. The various parameters related to the specificity of such receptors have been established. The development and standardization of these approaches, some facets of which are reported in the present publication, may prove them to be more sensitive, specific, and optimal than other systems and should afford an opportunity to test various combinations of drugs potentially useful in cancer of the prostate with relative speed, efficacy, and ease of manipulation.

Adrenalectomy↗

Dissociation of growth hormone and prolactin response to levodopa during pyridoxine administration.

500 mg of levodopa was administered orally to 8 normal subjects and induced an increase of growth hormone (GH) and a decrease of prolactin (PRL) secretion. The levodopa-induced GH release was inhibited by an intravenous infusion of pyridoxine; on the contrary, the PRL response to levodopa was enhanced by pyridoxine infusion. This dissociation of GH and PRL responses to levodopa during pyridoxine infusion appears to be mediated by peripheral acceleration of the conversion of levodopa to dopamine. Since dopamine does not penetrate the blood-brain barrier, the enhanced PRL decrease observed during pyridoxine infusion might be explained only on the basis of a mechanism of action exerted by dopamine on extra blood-brain barrier sites.

Adult↗