Hyperprolactinemia in a male pituitary androgen receptor knockout mouse model is associated with a female-like pattern of lactotroph development

2020 ◽  
Author(s):  
Laura O’Hara ◽  
Helen C. Christian ◽  
Paul Le Tissier ◽  
Lee B. Smith
Keyword(s):  
Androgen Receptor ◽  
Anterior Pituitary ◽  
Sexually Dimorphic ◽  
Cell Type ◽  
Prolactin Release ◽  
Knockout Mouse Model ◽  
Receptor Knockout Mouse ◽  
Pituitary Prolactin ◽  
Knockout Line ◽  
Stimulation Of

AbstractCirculating prolactin concentration in rodents and humans is sexually dimorphic. Estrogens are a well-characterised stimulator of prolactin release. Circulating prolactin fluctuates throughout the menstrual/estrous cycle of females in response to estrogen levels, but remains continually low in males. We have previously identified androgens as an inhibitor of prolactin release through characterisation of males of a mouse line with a conditional pituitary androgen receptor knockout (PARKO) which have an increase in circulating prolactin, but unchanged lactotroph number. In the present study we aimed to specify the cell type that androgens act on to repress prolactin release. We examined lactotroph-specific, Pit1 lineage-specific and neural-specific conditional AR knockouts, however they did not duplicate the high circulating prolactin seen in the pituitary androgen receptor knockout line, suggesting that the site of androgen repression of prolactin production was another cell type. Using electron microscopy to examine ultrastructure we showed that pituitary androgen receptor knockout male mice develop lactotrophs that resemble those seen in female mice, and that this is likely to contribute to the increase in circulating prolactin. When castrated, pituitary androgen receptor knockout males have significantly reduced circulating prolactin compared to intact males, which suggests that removal of circulating estrogens as well as androgens reduces the stimulation of pituitary prolactin release. However, when expression of selected estrogen-regulated anterior pituitary genes were examined there were no differences in expression level between controls and knockouts. Further investigation is needed into prolactin regulation by changes in androgen-estrogen balance, which has implications not only in the normal sexual dimorphism of physiology but also in diseases such as hyperprolactinemia.

scholarly journals Nonmyocytic Androgen Receptor Regulates the Sexually Dimorphic Development of the Embryonic Bulbocavernosus Muscle

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2467-2479 ◽  
Author(s):  
Lerrie Ann Ipulan ◽  
Kentaro Suzuki ◽  
Yuki Sakamoto ◽  
Aki Murashima ◽  
Yuuki Imai ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Androgen Receptor ◽  
Cell Activation ◽  
Kinase Inhibitors ◽  
Myogenic Differentiation ◽  
Vital Role ◽  
Sexually Dimorphic ◽  
Receptor Knockout Mouse ◽  
Wild Type Female ◽  
Morphological Differences

The bulbocavernosus (BC) is a sexually dimorphic muscle observed only in males. Androgen receptor knockout mouse studies show the loss of BC formation. This suggests that androgen signaling plays a vital role in its development. Androgen has been known to induce muscle hypertrophy through satellite cell activation and myonuclei accretion during muscle regeneration and growth. Whether the same mechanism is present during embryonic development is not yet elucidated. To identify the mechanism of sexual dimorphism during BC development, the timing of morphological differences was first established. It was revealed that the BC was morphologically different between male and female mice at embryonic day (E) 16.5. Differences in the myogenic process were detected at E15.5. The male BC possesses a higher number of proliferating undifferentiated myoblasts. To identify the role of androgen signaling in this process, muscle-specific androgen receptor (AR) mutation was introduced, which resulted in no observable phenotypes. Hence, the expression of AR in the BC was examined and found that the AR did not colocalize with any muscle markers such as Myogenic differentiation 1, Myogenin, and paired box transcription factor 7. It was revealed that the mesenchyme surrounding the BC expressed AR and the BC started to express AR at E15.5. AR mutation on the nonmyocytic cells using spalt-like transcription factor 1 (Sall1) Cre driver mouse was performed, which resulted in defective BC formation. It was revealed that the number of proliferating undifferentiated myoblasts was reduced in the Sall1 Cre:ARL−/Y mutant embryos, and the adult mutants were devoid of BC. The transition of myoblasts from proliferation to differentiation is mediated by cyclin-dependent kinase inhibitors. An increased expression of p21 was observed in the BC myoblast of the Sall1 Cre:ARL−/Y mutant and wild-type female. Altogether this study suggests that the nonmyocytic AR may paracrinely regulate the proliferation of myoblast possibly through inhibiting p21 expression in myoblasts of the BC.

In vitro inhibition of pituitary prolactin synthesis and release by hypothalamic extract

1963 ◽  
Vol 205 (2) ◽  
pp. 213-218 ◽  
Author(s):  
P. K. Talwalker ◽  
A. Ratner ◽  
J. Meites
Keyword(s):  
Cerebral Cortex ◽  
Anterior Pituitary ◽  
Acid Extract ◽  
Prolactin Release ◽  
Lysine Vasopressin ◽  
In Vitro Inhibition ◽  
Hormone Inactivation ◽  
Prolactin Synthesis ◽  
Pituitary Prolactin

When rat anterior pituitary (AP) was incubated at 37.5 C in a Dubnoff metabolic shaker for 2 hr, 169% more prolactin was found in the combined medium and AP than in nonincubated AP. When AP was incubated together with homogenate or acid extract of rat hypothalamus, prolactin levels in the medium and AP were markedly decreased (36–75%), indicating inhibition of synthesis and release. Acid extract of rat cerebral cortex had no effect on prolactin synthesis or release. Incubation of ovine or rat prolactin, with or without hypothalamus, did not decrease prolactin activity, demonstrating that hypothalamic inhibition of AP prolactin production was not due to hormone inactivation. Acetylcholine, epinephrine, norepinephrine, serotonin, histamine, substance P, oxytocin, and arginine or lysine vasopressin had no effect on AP prolactin release. These results indicate that the hypothalamus contains a factor(s) which inhibits synthesis and release of prolactin by the rat AP in vitro, and this factor(s) is not any of the recognized neurohumors in the hypothalamus.

Kallidin-induced stimulation of inositol phosphate production and prolactin release in rat anterior pituitary cells

1990 ◽  
Vol 123 (1) ◽  
pp. 37-42 ◽  
Author(s):  
T. Hugh Jones ◽  
Barry L. Brown ◽  
Pauline R. M. Dobson
Keyword(s):  
Anterior Pituitary ◽  
Inositol Phosphate ◽  
Prolactin Secretion ◽  
Male Rat ◽  
Pituitary Cells ◽  
Phosphoinositide Metabolism ◽  
Prolactin Release ◽  
Anterior Pituitary Cells ◽  
Inositol Phosphate Production ◽  
Stimulation Of

Abstract. The effect of the kinin, kallidin (lysyl-brady-kinin) on phosphoinositide metabolism and prolactin secretion was examined in male rat anterior pituitary cells in primary culture. Kallidin was found to stimulate both total inositol phosphate production and prolactin release. The stimulation of inositol phosphate was biphasic in nature, similar to that previously reported for bradykinin, although kallidin was approximately 10-fold more potent. Kallidin also stimulated prolactin secretion provoking a maximal stimulation of 193.0±11.1 (sem)% at 1 μmol/l. These findings suggest that kallidin-induced prolactin secretion may be mediated intracellularly by activation of phosphoinositide metabolism. The B2 receptor antagonists had no significant inhibitory effects on kallidin-stimulated phosphoinositide metabolism or prolactin release. The B1 agonist des-Arg9-bradykinin has previously been shown to have no effect on either parameter. As the effects of kinins on anterior pituitary cells do not appear to be mediated by either of the known kinin receptors, they may, therefore, act via a hitherto unrecognised kinin receptor.

Specific oxytocin agonist stimulates prolactin release but has no effect on inositol phosphate accumulation in isolated rat anterior pituitary cells

1993 ◽  
Vol 10 (2) ◽  
pp. 107-114 ◽  
Author(s):  
S E Chadio ◽  
F A Antoni
Keyword(s):  
Pituitary Gland ◽  
Anterior Pituitary ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Pituitary Cells ◽  
Uterine Tissue ◽  
Prolactin Release ◽  
Anterior Pituitary Cells ◽  
Oxytocin Receptors ◽  
Stimulation Of

ABSTRACT We have previously characterized specific oxytocin receptors in the rat anterior pituitary gland, using a highly selective oxytocin receptor antagonist as radio-ligand. The aim of the present study was to examine whether occupation of these receptors by oxytocin produces a stimulation of prolactin release and a rise in the accumulation of total inositol phosphates in the rat adenohypophysis. Anterior pituitary cells harvested from randomly cycling and diethylstilboestrol (100 μg s.c.)-treated rats were perifused with Dulbecco's minimal essential medium at a rate of 0·3 ml/min. Oxytocin and the specific oxytocin agonist [Thr4-Gly7]-oxytocin (TG-OT) both stimulated a significant prolactin release at concentrations of 10-6 and 10-7 m. Oestrogen treatment did not affect the response to oxytocin, indicating that there is no straightforward correlation between receptor number and prolactin secretory response in the rat pituitary gland. The involvement of phosphoinositide hydrolysis was investigated in dispersed anterior pituitary cells and uterine tissue from randomly cycling rats. Oxytocin and arginine-vasopressin stimulated a significant (P<0·05) and dose-related increase in total inositol phosphates, vasopressin being more potent. The specific oxytocin agonist TG-OT had no effect on total inositol phosphate production in pituitary cells, but when tested in uterine tissue it significantly (P< 0.05) stimulated the accumulation of total inositol phosphate at all concentrations tested (10-5 to 10-9 m). In conclusion, the data show that oxytocin has prolactin-releasing activity, acting on specific receptors in the anterior pituitary gland. Furthermore, although oxytocin receptors in the rat uterus are coupled to the inositol phospholipid cycle, it would appear that this is not a prerequisite for the stimulation of prolactin secretion when specific oxytocin receptors in the rat adenohypophysis are activated.

The dopaminergic regulation of anterior pituitary 45Ca2+ homeostasis and prolactin secretion

1986 ◽  
Vol 108 (3) ◽  
pp. 423-429 ◽  
Author(s):  
M. P. Schrey ◽  
H. J. Clark ◽  
S. Franks
Keyword(s):  
Dopamine Agonist ◽  
Anterior Pituitary ◽  
Prolactin Secretion ◽  
Prolactin Release ◽  
Pituitary Glands ◽  
Dopaminergic Regulation ◽  
Cellular Ca ◽  
Stimulation Of ◽  
Dopaminergic Control

ABSTRACT A role for the regulation of cellular Ca2+ homeostasis in the dopaminergic control of prolactin secretion was investigated in rat anterior pituitary glands. Withdrawal of dopamine stimulated the uptake of 45Ca2+ into hemipituitary tissue by 48% after 3 min. Radioisotope desaturation from tissue prelabelled with 45Ca2+ was significantly retarded in the presence of dopamine. Withdrawal of dopamine rapidly stimulated 45Ca2+ efflux from prelabelled tissue by 79% and was accompanied by a three- to fourfold rise in prolactin secretion. The 45Ca2+ efflux response to dopamine withdrawal was reduced in tissue prelabelled in the presence of dopamine. Agonist displacement with metoclopramide mimicked the effect of dopamine withdrawal on 45Ca2+ efflux and prolactin secretion. These observations demonstrate that the stimulation of prolactin release by dopamine withdrawal is accompanied by a redistribution of cellular Ca2+ and support the hypothesis that dopamine inhibits secretion by decreasing Ca2+ influx in the mammotroph cell. J. Endocr. (1986) 108, 423–429

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