Basic Research Advances on Pituitary Stem Cell Function and Regulation

As a central regulator of major physiological processes, the pituitary gland is a highly dynamic organ, capable of responding to hormonal demand and hypothalamic influence, through adapting secretion as well as remodelling cell numbers among its seven populations of differentiated cells. Stem cells of the pituitary have been shown to actively generate new cells during postnatal development but remain mostly quiescent during adulthood, where they persist as a long-lived population. Despite a significant body of research characterising attributes of anterior pituitary stem cells, the regulation of this population is poorly understood. A better grasp on the signalling mechanisms influencing stem proliferation and cell fate decisions can impact on our future treatments of pituitary gland disorders such as organ failure and pituitary tumours, which can disrupt endocrine homeostasis with life-long consequences. This minireview addresses the current methodologies aiming to understand better the attributes of pituitary stem cells and the normal regulation of this population in the organ, and discusses putative future avenues to manipulate pituitary stem cells during disease states or regenerative medicine approaches.

Effects of TRH on thyrotroph function and number in rat pituitaries transplanted to renal capsule

We investigated the function of thyrotrophs in rat pituitaries that were transplanted under the renal capsule of 3-wk-old male Sprague-Dawley rats, which were either intact or hypophysectomized. Groups of 12 animals were implanted with osmotic minipumps that delivered a constant infusion of either thyrotropin-releasing hormone (TRH; 1 mg X kg-1 X day-1) or normal saline for 1 wk. In hypophysectomized rats, TRH infusion led to the appearance of substantial amounts of biologically active serum TSH and prevented the hypothyroidism that occurred in the control group. However, TRH did not change the transplant contents of DNA, immunoactive TSH, and mRNA levels for TSH subunits. Comparison of sellar and renal pituitary tissues, obtained from intact rats after 1 wk of either saline or TRH infusion, showed that removal of the pituitary from hypothalamic influence resulted in a 90% depletion of the thyrotroph TSH content. TRH infusion depleted only 63% of the TSH content of sellar thyrotrophs. The mRNA levels for TSH beta-subunit were similar in sellar and transplanted pituitaries and did not significantly change after TRH infusion. When immunocytochemically stained using rat TSH antiserum, the thyrotrophs in pituitary transplants were morphologically and numerically indistinguishable from the thyrotrophs in sellar pituitaries, in the presence or absence of TRH. These data indicate that in transplanted pituitary, for up to 1 wk of a constant infusion, TRH does not significantly affect either the number of thyrotrophs or their ability to synthesize TSH subunit mRNA. However, it is required to maintain released TSH in circulation, since TSH levels were low in the absence of TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of thyrotrophin-releasing hormone in the development of pituitary-thyroid axis in four anencephalic infants

Anencephaly provides a unique model for studying endocrine functions in absence of hypothalamic influence. We previously reported that in anencephalic newborns both pituitary TSH-secreting cells and the thyroid were normal and were able to function if adequately stimulated. In order to verify if the normal development of the pituitary-thyroid axis in these infants depends on TRH of extrahypothalamic origin, we measured endogenous TRH levels in the clear fluid of a cyst of the cerebro-vasculosa in 4 anencephalic newborns. In these cysts we also injected 200 μg of synthetic TRH and evaluated TSH response in peripheral blood samples. Endogenous TRH was detectable in the cysts of the cerebro-vasculosa in 3 of the 4 infants. In all 4 cases serum TSH sharply increased after TRH administration. Our data suggest that the normal development of the pituitary-thyroid axis in anencephalic infants either requires no TRH or depends on extrahypothalamic TRH. In this latter case TRH produced by other areas of the central nervous system might be secreted into the cysts of the cerebro-vasculosa, actively transported to the hypophyseal vessels, and might thus reach the pituitary to stimulate TSH-cells growth and function.

DIFFERENTIAL SENSITIVITY OF PROLACTIN RELEASE TO DOPAMINE AND THYROTROPHIN-RELEASING HORMONE IN INTACT AND PITUITARY STALK-SECTIONED RHESUS MONKEYS

The effects of dopamine and thyrotrophin-releasing hormone (TRH) on prolactin release was studied in 14 intact and six pituitary stalk-sectioned (SS) female rhesus monkeys (Macaca mulatta). Baseline prolactin values were ninefold higher in SS animals (149 ± 16 ng/ml) than in intact animals (16 ± 1 ng/ml). Prolactin release after intravenous administration of TRH in doses of 0,125,250, 500 and 1000 ng revealed that SS monkeys were more sensitive to the prolactin-releasing activity of this tripeptide than were intact animals. A significant (P < 0·05) increment in serum prolactin was observed in SS animals after injection of 125 ng TRH whereas 250 ng was required to raise prolactin levels in the circulation of intact animals significantly (P <0·05). Furthermore, at each comparable dose level of TRH, the increment in serum prolactin was distinctly greater in SS animals than in intact monkeys. Infusion of dopamine at the rate of 10 μg/kg body weight per min significantly (P <0·05) lowered prolactin levels within 60 min in intact animals and no further decline was observed with 20 or 40 μg dopamine. Serum prolactin concentrations were not affected by saline infusion or by 5 μg dopamine. Infusion of dopamine at the rate of 10 μg/kg body wt per min also resulted in significant (P <0·01) suppression of serum prolactin in SS animals. This prolactin decrease was apparent within 40 min. Prolactin release after 500 ng TRH was less in these dopamine-treated SS monkeys than after an infusion of saline. Higher doses of dopamine (20 and 40 μg) did not cause a further decrease in basal serum prolactin concentrations, but these two dopamine treatments blocked the increase in prolactin elicited by 500 ng TRH. The results suggest that the removal of hypothalamic influence, possibly related to the effects of dopamine, renders the pituitary gland more sensitive to the prolactin-releasing action of TRH.

Hypothalamic influence on insulin and glucagon release in the rat.

Blood glucose, plasma insulin, and glucagon levels were measured in undisturbed and free-moving rats. The insulin and glucagon levels rise in the 1st min after the beginning of food ingestion, whereas the glucose level begins to increase only in the 3rd min if carbohydrate-rich food is eaten. This early rise in insulin and glucagon level is also observed under conditions in which carbohydrate-free food is eaten. A similar release of insulin and glucagon can be obtained by injection of 0.1 microgram of norepinephrine into the ventromedial hypothalamus, but the same injection made into the lateral hypothalamus causes release of insulin only, whereas injections in other hypothalamic areas are nearly without effect. Similar injections of isoproterenol did not cause changes in insulin, glucagon, and glucose levels. It is suggested that the early insulin and glucagon responses are of reflex origin and that the ventromedial and lateral hypothalamic areas are relay stations in the reflex pathways. The lack of effect of atropine to block the insulin and glucagon responses to noradrenergic stimulation of the ventromedial hypothalamus indicates that the efferent pathway is not cholinergic.