Prolactin-inhibiting hormone Dopamine

BIO. Ben-Jonathan, N Dopamine A prolactin-inhibiting hormone. Endocr. Rev. 6,564-589 (1985). 

The release of prolactin from the adenohypophysis is normally inhibited by prolactin-inhibiting hormone (PIH, dopamine) from the hypothalamus. Prolactin secretion is also controlled by prolactin-releasing factor (PRF). The release of PRF from the hypothalamus is mediated by reflexes elicited by suckling and breast stimulation. 

Prolactin secretion is under the inhibitory control of hypothalamus through prolactin inhibiting hormone (PRIH) which is a dopamine and acts on pituitary lactotrope receptor. 

Prolactin-inhibiting hormone (PIH), also known as dopamine, is not a peptide (Chapter 17). It functions as a neurotransmitter in the CNS and as a precursor of norepinephrine and epinephrine in the adrenal medulla. In the hypothalamus, it originates in the TIDA and is released at the median eminence. Dopamine is a potent inhibitor of PRL release by the lactotropes (and mammosomatotropes) of the anterior pituitary, and this effect is mediated by D2 receptors that are coupled to Gj inhibition of adenylate cyclase. The lactotropes are unique in that they do not require stimulation by the hypothalamus to secrete PRL in fact, blockage of the blood flow from the hypothalamus to the anterior pituitary results in elevated serum levels of PRL, due to withdrawal of dopamine. Thus, unlike somatostatin, the effectiveness of dopamine does not depend on the presence of a stimulating hormone (Chapter 34). 

Definition of abbreviations ACTH, adrenocorticotropin hormone DA, dopamine FSH, follicle-stimulating hormone GH, growth hormone GnRH, gonadotropin-releasing hormone LH, luteinizing hormone PIH, prolactin-inhibiting hormone. 

F. Prolactin-Inhibiting Hormone (PIH, Dopamine) Dopamine is the physiologic inhibitor of prolactin release. Because of its peripheral effects and the need for parenteral administration, dopamine is not useful in the control of hyperprolactinemia, but bromocriptine and other orally active ergot derivatives (eg, cabergoline. pergolide) are effective in reducing prolactin secretion from the normal gland as well as from pituitary tumors. 

Receptor Class Mu (pi) Primary Therapeutic Effect(s) Spinal and supraspinal analgesia Other Effects Sedation respiratory depression constipation inhibits neurotransmitter release (acetylcholine, dopamine) increases hormonal release (prolactin growth hormone)... 

Prolactin has been shown to increase LH receptor numbers in dwarf mice, seasonally repressed hamsters and hypophysectomized rats (see Ref. 6 for other references). In the hypophysectomized rats the combined effects of prolactin, growth hormone and LH were necessary to maintain the LH receptors [46]. The induction of hyperprolactinemia leads to increased LH receptors. Decreases in serum prolactin levels caused by treatment with compounds that inhibit the release of prolactin (dopamine analogues) decrease LH receptors (see Ref. 6 for other references). 

Bromocriptine was the first D2-receptor agonist to be used in the treatment of hyperprolactinemia and has been the mainstay of therapy for over 20 years. It inhibits the release of prolactin by directly stimulating postsynaptic dopamine receptors in the hypothalamus. Hypothalamic release of dopamine (prolactin-inhibitory hormone) inhibits the release of prolactin. Decreases in serum prolactin concentrations occur within 2 hours of oral administration with maximal suppression occurring after 8 hours, and suppressive effects persisting for up to 24 hours. Medical therapy with bromocriptine normalizes prolactin serum concentrations, restores gonadotropin production, and shrinks tumor size in approximately 90% of patients with prolactinomas. ... 

Like other anterior pituitary hormones, prolactin is secreted in a pulsatile manner. Prolactin is unique among the anterior pituitary hormones in that hypothalamic regulation of its secretion is predominantly inhibitory. The major regulator of prolactin secretion is dopamine, which is released by tuberoinfundibular neurons and interacts with the Dj receptor on lactotropes to inhibit prolactin secretion. A number of putative prolactin-releasing factors have been described, but their physiological roles are unclear. Under certain pathophysiological conditions, such as severe primary hypothyroidism, persistently elevated levels of TRH can induce hyperprolactinemia and consequent galactorrhea. 

Prolactin Prolactin is an anterior pituitary hormone which induces milk secretion from the breasts of lactating women. Nipple stimulation promotes prolactin release and dopamine inhibits prolactin release. 

Prolactin is peptide hormone secreted by the pituitary gland. It acts on prolactin receptors in breast tissue where it stimulates production of casein and lactalbu-min. It also acts on the testes and ovaries to inhibit the effects of gonadotrophins. Since the secretion of prolactin is under tonic dopaminergic inhibition by the hypothalamus, dopamine D2-receptor antagonists... 

The dopamine D2 agonists bromocriptine and cabergoline (pp. 114, 188) inhibit prolactin-releasing AH cells (indications suppression of lactation, prolactin-producing tumors). Excessive, but not normal, growth hormone release can also be inhibited (indication acromegaly) (3). 

All antipsychotics except clozapine and perhaps olanzapine produce hyperprolactinemia by removing the inhibitory actions of dopamine on prolactin secretion. This results in amenorrhea, galactorrhea, and infertility in women and in loss of libido and impotence in men. Inhibition of the release of follicle-stimulating and luteinizing hormones may also play a role. In addition, weight gain is common, and food intake must be monitored. 

The secretion of anterior pituitary hormones is controlled in part by hypothalamic regulatory factors that are stored in the hypothalamus and are released into the adenohypophyseal portal vasculature. Hypothalamic regulatory factors so far identified are peptides with the exception of dopamine. Secretion of anterior pituitary hormones is also controlled by factors produced more distally that circulate in the blood. Predominant control of hormone production may be relatively simple, as with thyroid-stimulating hormone (TSH), the production of which is primarily stimulated by thyrotropin-releasing hormone (TRH) and inhibited by thyroid hormones, or it may be complex, as with prolactin, the production of which is affected by many neurotransmitters and hormones. 

Mechanism of Action A dopamine agonist that directly stimulates dopamine receptors in the corpus striatum and inhibits prolactin secretion. Also suppresses secretion of growth hormone. Therapeutic Effect Improves symptoms of parkinsonism, suppresses galactorrhea, and reduces serum growth hormone concentrations in acromegaly. 

Endocrine system Dopamine inhibits prolactin release in human being. It also acts on somatotrophs to increase growth hormone release. 

The G protein-GTP complexes related to receptors for these hormones activate adenylyl cyclase, which synthesizes the second messenger cAMP. Cyclic AMP activates protein kinases, which phosphorylate certain intracellular proteins (eg, enzymes), thus producing the hormonal effect. Conversely, dopamine binding to lactotroph receptors causes conformational changes in its G protein that reduce the activity of adenylyl cyclase and inhibit the secretion of prolactin. 

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

Prolactin (PRL) Protein, MW 20,000 Prolactin release factor (PRF) may or may not be identical to thyrotropin-releasing hormone Prolactin release-inhibiting factor (PIF) most likely dopamine Supports lactation... 

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