Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

Cells from fetal or neonatal skeleton can synthesize bone-like tissue in vitro In contrast, formation of bone-like tissue in vitro by cells derived from adult animals has rarely been reported and has not been achieved using cells from bone marrow We have explored development of bone-like tissue in vitro by bone marrow stromal cells Marrow stromal cells obtained from 40-43-day-old Wistar rats were grown in primary culture for 7 days and then subcultured for 20-30 days Cells were cultured in either alpha-minimal essential medium containing 15% fetal bovine serum, antibiotics, and 50 micrograms/ml ascorbic acid, or the above medium supplemented with either 10 mM Na-beta-glycerophosphate, 10(-8) M dexamethasone, or a combination of both Cultures were examined using phase-contrast microscopy, undemineralized and demineralized tissue histology, histochemistry (for alkaline phosphatase activity), immunohistochemistry (for collagen type, osteonectin, and bone Gla-protein), scanning and transmission electron microscopy, energy dispersive X-ray microanalysis, and X-ray diffraction Collagenous, mineralized nodules exhibiting morphological and ultrastructural characteristics similar to bone were formed in the cultures, but only in the presence of both beta-glycerophosphate and dexamethasone Cells associated with the nodules exhibited alkaline phosphatase activity The matrix of the nodules was composed predominantly of type-I collagen and both osteonectin and Gla-protein were present X-ray microanalysis showed the presence of Ca and P, and X-ray diffraction indicated the mineral to be hydroxyapatite The nodules were also examined for bone morphogenetic protein-like activity Paired diffusion chambers containing partly demineralized nodules and fetal muscle were implanted intraperitonealy in rats Induction of cartilage in relation to muscle was observed histologically after 40 days in the chambers This finding provided further support for the bone-like nature of the nodules The observations show that bone-like tissue can be synthesized in vitro by cells cultured from young-adult bone marrow, provided that the medium contains both beta-glycerophosphate and, particularly, dexamethasone

Bone formation in vitro by stromal cells obtained from bone marrow of young adult rats.

Dopamine is a small and relatively simple molecule that fulfills diverse functions. Within the brain, it acts as a classical neurotransmitter whose attenuation or overactivity can result in disorders such as Parkinson’s disease and schizophrenia. Major advances in the cloning and characterization of biosynthetic enzymes, transporters, and receptors have increased our knowledge regarding the metabolism, release, reuptake, and mechanism of action of dopamine. Dopamine reaches the pituitary via hypophysial portal blood from several hypothalamic nerve tracts that are regulated by PRL itself, estrogens, and several neuropeptides and neurotransmitters. Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation. Thus, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators, none of which has yet emerged as a primary PRL releasing factor. The generation of transgenic animals with overexpressed or mutated genes expanded our understanding of dopamine-PRL interactions and the physiological consequences of their perturbations. PRL release in humans, which differs in many respects from that in laboratory animals, is affected by several drugs used in clinical practice. Hyperprolactinemia is a major neuroendocrine-related cause of reproductive disturbances in both men and women. The treatment of hyperprolactinemia has greatly benefited from the generation of progressively more effective and selective dopaminergic drugs. (Endocrine Reviews 22: 724–763, 2001)

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Dopamine as a prolactin (PRL) inhibitor.

PRL and GH are hormones with a wide spectrum of actions. Specific receptors are widely distributed in a number of classical target organs, but other tissues that are not known targets also contain measurable binding sites or receptor mRNA. The most likely explanation is that PRL and GH cause effects that have not yet been characterized in certain tissues. Cloning of the cDNAs encoding PRL and GH receptors has led to the discovery that the receptors, like the hormones themselves, form a gene family. Multiple receptor forms have been identified, including a short form, which for PRL is a membrane-bound receptor or for GH is a soluble BP, and a long form, which for both PRL and GH is a membrane-bound receptor. PRL and GH receptors, and the mRNAs encoding them, can be up- and down-regulated. GH induces an up-regulation of both GH and PRL receptors, whereas PRL stimulates an increase of only its own receptor. High concentrations of either hormone induce a homologous down-regulation of receptor expression. An assay has been developed to measure the functional activity of different forms of PRL receptor by cotransfecting a milk protein fusion gene specific to PRL coupled to a reporter-gene along with the cDNA of the PRL receptor. Although the short form represents the major form present in rat mammary gland, only the long form of receptor is able to stimulate milk protein gene transcription. For GH, increased expression of the receptor in some target cells is accompanied by a modest enhancement of the response to GH. No single second messenger mediating the action of either PRL or GH has been identified. Several potential components of the signal transduction pathways have been identified, but as yet none has clearly been shown to be able to mimic the effect of PRL or GH. Because of the wide range of biological actions associated with PRL, and the existence of various forms of PRL receptors, it is doubtful that one unifying mechanism of action will be found for this hormone. No human or animal model of a genetic defect of the PRL receptor has thus far been published. Mutations in the GH receptor gene have been demonstrated in Laron type dwarfism. Different exon deletions or point or nonsense mutations resulting in modifications in the extracellular, GH binding region of the GH receptor have been reported.(ABSTRACT TRUNCATED AT 400 WORDS)

The prolactin/growth hormone receptor family.

Leptin regulation of neuroendocrine systems.

Adult male Sprague-Dawley rats averaging 300 g each were subjected to complete food removal for 7 days (acutely starved), 7 days complete food removal followed by 2 weeks of ¼ ad libitum food intake (chronically starved), 7 days complete food removal and 2 weeks of ¼ ad libitum intake followed by ad libitum feeding for 7 days (refed), or fed ad libitum throughout (controls). Serum LH, FSH, TSH, PRL, and GH levels were measured by radioimmunoassays for each group of rats. The in vivo response to the combination of synthetic LHRH and TRH also was tested in each group. Circulating LH, TSH, GH, and PRL were significantly depressed in acutely and chronically starved rats, and FSH was lowered only in acutely starved rats. After 7 days of refeeding, serum levels of LH and FSH were significantly greater than in ad libitum fed controls, PRL returned to control levels, and TSH and GH increased but were still below control levels. After LHRH + TRH injection serum LH and TSH were increased significantly in all groups...

Effects of Starvation in Rats on Serum Levels of Follicle Stimulating Hormone, Luteinizing Hormone, Thyrotropin, Growth Hormone and Prolactin; Response to LH-Releasing Hormone and Thyrotropin-Releasing Hormone

The effects of naloxone hydrochloride and morphine sulfate on the proestrous surge of PRL and gonadotropins (LH and FSH) were investigated in normal cycling Sprague-Dawley rats. Blood samples (0.45–0.50 ml) were withdrawn without anesthesia every 20 min from 1400–2000 h through an atrial cannula implanted the same morning. RIA revealed that a single iv injection of naloxone (0.2 mg/kg) at 1400 h completely suppressed the surge of PRL, and this was reversed by a concomitant injection of morphine (10 mg/kg). Morphine itself did not alter the peak of the PRL surge. Morphine suppressed only the early phase of the LH surge, and this was reversed by naloxone. Naloxone alone did not change the peak of the LH Surge but maintained higher levels than controls during the declining phase. The FSH surge was not altered by either morphine or naloxone. These results suggest that endogenous opioid peptides may have a role in regulating the PRL and LH surges during proestrus in the rat. (Endocrinology 106: 1568, 1980)

Effects of Naloxone and Morphine on the Proestrous Surge of Prolactin and Gonadotropins in the Rat

l25I-radiolabeled ovine prolactin (oPRL) binding activity was measured in microsomal membranes of liver tissue from intact, ovariectomized, ovariectomized-thyroidectomized, and ovariectomized-thyroidectomized rats injected with thyroxine (T4) or estradiol benzoate (EB). Thyroidectomy and ovariectomy each reduced PRL binding activity in liver tissue significantly. The combination of ovariectomy and thyroidectomy decreased PRL binding activity more than thyroidectomy or ovariectomy alone. Doses of 2.5 μg or 10 μg T4⁄1OO g BW daily returned PRL binding activity in the thyroidectomized rats to intact control values, and in the ovariectomized-thyroidectomized rats to the ovariectomized values. A dose of 2 μg EB⁄rat increased PRL binding activity significantly in variectomized-thyroidectomized rats, and a combination of 2 μg EB and 2.5 μg T4100 g BW raised binding activity above that of intact controls. Scatchard analysis showed that ovariectomy and thyroidectomy decreased the number of PRL binding sites in the...

Effects of thyroid and ovaries on prolactin binding activity in rat liver.

Lactoperoxidase-catalyzed 125I-labeled ovine prolactin (PRL) was found to bind specificallyto participate membrane fractions of rat ventral prostate. Unlabeled PRL readily displaced thelabeled PRL, whereas ovine GH, LH, FSH, or TSH showed no such competition. Castration reduced the binding of 125I-labeled PRL to about 1⁄6 of that in intact rats, and injections of testosterone propionate (TP) increased PRL binding to values as great or greater than those in intact controls. Injections of TP into intact immature and mature rats also increasedPRL binding. In vitro binding of labeled PRL was inhibited in prostatic tissue removed from intact immature rats 2 h after injecting unlabeled PRL, but not in ventral prostates from rats killed 26 or 74 h after injecting unlabeled prolactin. PRL injected together with TP in castrated rats produced no greater increase in prolactin binding than TP alone, while estrogen appeared to decrease PRL binding beyond that produced by castration alone. (Endocrinology98:373, 1976)

Effects of Castration, Testosterone, Estradiol, and Prolactin on Specific Prolactin-Binding Activity in Ventral Prostate of Male Rats

Binding of PRL to specific binding sites in kidney and adrenal was shown to be time- and temperature- dependent. The binding of [l25I]iodo-PRL to kidney preparations increased with increasing amounts of membrane protein. Adrenalectomy increased concentrations of PRL receptors in the kidneys 49% above control values, whereas dexamethasone treatment reduced PRL receptors to below control levels. The latter effect was not mediated primarily through the pituitary because dexamethasone treatment of hypophysectomized rats also produced a significant decrease in specific receptor-binding from 2.85 ± 0.20%-0.74 ± 0.08%. However, the pituitary was partly responsible for maintaining PRL receptors because kidney membrane preparations from intact control rats specifically bound 9.98 ± 0.32% ovine [125]iodo-PRL after incubation, which is significantly higher than what was found in hypophysectomized rats. In the adrenals, a reduction in specific PRL binding also was observed after hypophysectomy, from 12.72 ± 0.63%-5.7...

G. A. Campbell

Papers

Effects of Starvation in Rats on Serum Levels of Follicle Stimulating Hormone, Luteinizing Hormone, Thyrotropin, Growth Hormone and Prolactin; Response to LH-Releasing Hormone and Thyrotropin-Releasing Hormone

Effects of Naloxone and Morphine on the Proestrous Surge of Prolactin and Gonadotropins in the Rat

Effects of thyroid and ovaries on prolactin binding activity in rat liver.

Effects of Castration, Testosterone, Estradiol, and Prolactin on Specific Prolactin-Binding Activity in Ventral Prostate of Male Rats

Glucocorticoid regulation of prolactin receptors in kidneys and adrenals of male rats.