Stress- as well as suckling-induced prolactin release is blocked by a structural analogue of the putative hypophysiotrophic prolactin-releasing factor, salsolinol.

Prolactin is secreted from the anterior lobe of the pituitary gland in response both to suckling and to stress. We recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), produced in the neurointermediate lobe of the pituitary gland, as well as in the medial basal hypothalamus, can selectively release prolactin from the anterior pituitary. Therefore, it has been proposed that salsolinol is a putative endogenous prolactin-releasing factor (PRF). Here, we report that one structural analogue of salsolinol, 1-methyl-3,4-dihydroisoquinoline (1MeDIQ), can block salsolinol-induced release of prolactin, but does not affect prolactin release in response to thyrotropin releasing hormone (TRH), alpha-methyl-p-tyrosine (alpha MpT) (an inhibitor of tyrosine hydroxylase), domperidone (a D(2) dopamine receptor antagonist), or 5-hydroxytryptophan (5-HTP), a precursor of serotonin). 1MeDIQ profoundly inhibited suckling-, immobilization-, as well as formalin-stress induced prolactin release without any influence on corticosterone secretion. The 1MeDIQ-induced reduction in prolactin response to immobilization stress was dose-dependent. These results suggest that salsolinol can play a pivotal role in the regulation of prolactin release induced by either physiological (suckling) or environmental (stress) stimuli.

Inhibición de la lactancia con lis rida: evaluación clínica / Lactation inhibition with lisuride clinical evaluation

El fenómeno de lactancia en la especie humana obedece a un complicado mecanismo neuro-endocrino. Durante el embarazo, el papel de los estrógenos y la progesterona es determinante y en el posparto inmediato, la presencia de insulina, cortisol, tiroxina, hormona del crecimiento y lactógeno placentario son indispensables para la completa expresión de la acción lactogénica de la prolactina. En un estudio lineal, prospectivo, simple y abierto, 50 mujeres primigestas o multigestas, entre 19 y 30 años de edad, con parto vaginal o cesárea y con gestaciones entre 34 y 41 semanas, se les administró lisurida como inhibidor de la lactancia, a dosis de 0.2 mg cada 8 horas, por vía oral, durante 14 días. Todas las pacientes tenían indicación médica para inhibir la lactancia y la medicación se inició en el posparto inmediato, con supresión de la succión mamaria, con restricción líquida durante 24 horas y con vendaje mamario compresivo. La evaluación de los efectos se hizo a la 24 horas y a los 14 días del parto o la cesárea anotando los datos mamarios de forma, volumen, simetría, coloración, estado de la superficie, temperatura, turgencia, consistencia, presencia de red venosa, estado de los pezones, presencia de calostro y crecimiento de los ganglios vecinos. La inhibición de la lactancia que ya se había iniciado a las 24 horas en el 87 por ciento de las pacientes, fue excelente. Los fenómenos inflamatorios y el dolor fueron mínimos y a las 2 semanas la involución fue muy evidente. En ninguna hubo lactancia de rebote. 5 pacientes tuvieron náusea leve y pasajera al inicio del tratamiento y en 6 hubo adenomegalia dolorosa. Creemos que la lisurida constituye una opción recomendable para inhibir la lactancia suprimiendo los molestos síntomas del dolor y la ingurgitación mamaria-y sin los efectos indeseables de la hormonoterapia

Purification of a non-dopaminergic and non-GABAergic prolactin release-inhibiting factor (PIF) in sheep stalk-median eminence.

Prolactin release-inhibiting factor (PIF) extracted from 1200 sheep stalk-median eminences was purified by gel filtration on a Sephadex G-25 column (4.5 X 150 cm). PIF activity was determined by measuring the inhibition of prolactin release from dispersed anterior pituitary cells of adult male or estrogen-primed, ovariectomized rats. Using this system, PIF was detected in tube fractions 122-127 (volume = 20 ml/tube). These fractions also contained LHRH and somatostatin; however, these peptides had no prolactin-inhibiting activity in the quantities present. No dopamine or gamma-aminobutyric acid (GABA) was detected in the active fractions by radioenzymatic assay and fluorophotoenzymatic assay, respectively. Furthermore, receptor blockers for dopamine or GABA did not interfere with the PIF activity. These findings indicate that the PIF activity cannot be attributed to either dopamine or GABA, both of which are known to inhibit prolactin release, and provide evidence for the presence of a non-dopaminergic and non-GABAergic PIF within the hypothalamus.

Steroid receptor levels in intact and ovariectomized estrogen-treated rats: an examination of quantitative, temporal and endocrine factors influencing the efficacy of an estradiol stimulus.

Cell nuclear estrogen receptors and cytosol progestin receptors were measured in the pituitary gland, preoptic area and hypothalamus throughout the estrous cycle of the rat. Cell nuclear estrogen receptor levels paralleled changes in serum estradiol concentrations with highest values on proestrus and lowest on diestrus. Proestrous values were 50-60% of capacity for each tissue. Cytosol progestin receptor number in these tissues was also highest on proestrus and lowest on diestrus. With these data as a guide, Silastic capsules filled with estradiol-cholesterol mixtures were used to generate physiologic levels of estrogen receptor occupation within the brain-pituitary complex of ovariectomized rats and to examine the kinetics of estradiol stimulation of lordosis behavior and cyclic gonadotropin release. Our results indicate that the effectiveness of an estradiol stimulus to elicit lordosis or luteinizing hormone release depends on at least three factors: the magnitude of the increment in serum estradiol and brain and pituitary cell nuclear estradiol receptor levels; the duration over which these increments area maintained; and the interval from previous exposure to estrogen.

Dopamine, PIF, and other regulators of prolactin secretion.

Considerable evidence now exists that dopamine is a physiological prolactin inhibiting factor (PIF); however, it may not represent the only PIF. Amphetamine, which releases newly synthesized dopamine and blocks prolactin release, caused an increased in dopamine levels in the pituitaryb gloand. Prolactin release appears to be regulated also by a prolactin releasing factor (PRF). A wide variety of hypothalamic peptides stimulate prolactin release, but only two of these (thyrotropin releasing hormone and vasoactive intestinal polypeptide) can act directly on the pituitary and thus are candidates for PRF.

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.

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.

Evaluation of research on control of prolactin secretion.

At least three substances have been reported to be present in the hypothalamus that can inhibit prolactin release, namely a PIF, catecholamines and acetylcholine. At least four substances have been reported to be present in the hypothalamus that can stimulate prolactin release, namely PRF, TRH, serotonin and prostaglandins. Neither the existence of a distinctive PIF or PRF in the hypothalamus can be considered as definitely established. The predominant action of the mammalian hypothalamus on prolactin release is inhibitory under most conditions, and is stimulatory in avian species. In addition to control by the hypothalamus, several hormones and drugs can act directly on the pituitary to alter prolactin release. The interrelationships of these agents within and without the hypothalamus on prolactin secretion are complex, and there are many questions about their mode of action. Studies on the regulation of prolactin secretion have resulted in development of many methods for either increasing or decreasing release of this important hormone, and thereby have provided opportunities for influencing lactation, growth of mammary and pituitary tumors and other tissues responsive to prolactin.