Pegvisomant (somavert) is a GH receptor antagonist that is FDA-approved for the treatment of acromegaly. Pegvisomant binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1 secretion (Figure 55—2). It is administered subcutaneously as a 40-mg loading dose under medical supervision, followed by self-administration of 10 mg/day. Based on serum IGF-1 levels, the dose is titrated at 4- to 6-week intervals to a maximum of 40 mg/day. Liver function should be monitored in all patients, and pegvisomant should not be used in patients with elevated levels of liver transaminases. Because there are concerns that loss of negative feedback by GH and IGF-1 may increase the growth of GH-secreting adenomas, careful follow-up of the pituitary by MRI is mandatory.
Prolactin is related structurally to GH. Whereas serum prolactin levels remain low throughout life in normal males, they are elevated somewhat in normal cycling females. Prolactin levels rise markedly during pregnancy, reach a maximum at term, and decline thereafter unless the mother breast-feeds the infant. suckling or breast manipulation in nursing mothers stimulates circulating prolactin levels, which can rise 10-100-fold within 30 minutes of stimulation. This response is neu-rally transmitted from the breast to the hypothalamus and is distinct from milk letdown, which is mediated by oxytocin release from the posterior pituitary gland. The precise mechanism for suckling-induced prolactin secretion is not known but involves both decreased secretion of dopamine by tuberoinfundibular neurons and possibly increased release of factors that stimulate prolactin secretion (see below). The suckling response becomes less pronounced after several months of breastfeeding, and prolactin concentrations eventually decline to prepregnancy levels.
Prolactin detected in maternal and fetal blood originates from maternal and fetal pituitaries, respectively. Prolactin also is synthesized by decidual cells near the end of the luteal phase of the menstrual cycle and early in pregnancy; the latter source is responsible for the very high levels of prolactin in amniotic fluid during the first trimester.
Many of the factors that influence prolactin secretion are similar to those that affect GH secretion. Thus, sleep, stress, hypoglycemia, exercise, and estrogen increase the secretion of both hormones.
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 D2 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.
The effects of prolactin result from interactions with specific receptors that are widely distributed among a variety of cell types within many tissues. The prolactin receptor is encoded by a single gene, alternative splicing of which gives rise to multiple forms of the receptor, including soluble forms found in the circulation that correspond to the extracellular domain of the receptor. The membrane-bound prolactin receptor is related structurally to receptors for GH and several cytokines and uses similar signaling mechanisms. Like the GH receptor, the prolactin receptor lacks intrinsic tyrosine kinase activity; prolactin induces a conformational change leading to recruitment and activation of JAK kinases (Figure 55-2). The activated JAK2 kinase, in turn, induces phosphorylation, dimerization, and nuclear translocation of the transcription factor STAT5. Unlike human GH and placental lactogen, which bind to the prolactin receptor and are lactogenic, prolactin binds specifically to the prolactin receptor and has no somatotropic (GH-like) activity.
Prolactin plays an important role in inducing growth and differentiation of the ductal and lobu-loalveolar epithelium, which is essential for lactation. Prolactin receptors are present in many other sites; however, the physiological effects of prolactin at these sites remain poorly characterized.
Prolactin has no therapeutic uses. Hyperprolactinemia is a relatively common endocrine abnormality that most often is caused by prolactin-secreting pituitary adenomas. Hyperprolactinemia also can result from: hypothalamic or pituitary diseases that interfere with the delivery of inhibitory dopaminergic signals; primary hypothyroidism associated with increased TRH levels; renal failure; treatment with dopamine receptor antagonists. Manifestations of prolactin excess in women include galactorrhea, amenorrhea, and infertility. In men, hyperprolactinemia causes loss of libido, impotence, and infertility.
The therapeutic options for patients with prolactinomas include transsphenoidal surgery, radiation, and treatment with dopamine-receptor agonists that suppress prolactin production via activation of D2 dopamine receptors. Inasmuch as initial surgical cure rates are only 50-70% with microadenomas and 30% with macroadenomas, most patients with prolactinomas ultimately require drug therapy. Thus, dopamine-receptor agonists have become the initial treatment of choice for many patients. These agents generally decrease both prolactin secretion and the size of the adenoma, thereby improving the endocrine abnormalities, as well as the neurological symptoms caused directly by the adenoma (including visual field deficits). It is worth noting, however, that they typically are not curative.
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