prolactin-inhibiting factor

**Identity:** PIF is primarily dopamine (DA), made by arcuate nucleus neurons of the hypothalamus (tuberoinfundibular dopaminergic neurons). It travels through the hypophyseal portal vessels to the anterior pituitary.

**Mechanism:** Dopamine binds D2 receptors (Gi-coupled) on lactotrophs. This decreases adenylyl cyclase activity and cAMP, which reduces prolactin synthesis and release. Because inhibition is tonic, prolactin is the only anterior pituitary hormone that rises when the pituitary is disconnected from the hypothalamus.

**Regulation of prolactin:** - Inhibited by: dopamine (PIF), and prolactin itself through short-loop feedback (prolactin stimulates hypothalamic dopamine release). - Stimulated by: TRH, estrogen (pregnancy), serotonin, oxytocin, VIP, and suckling (neural reflex). - Physiologic effects of prolactin: breast development and milk production (lactogenesis). It suppresses GnRH, which inhibits ovulation and causes lactational amenorrhea. Oxytocin, not prolactin, mediates milk letdown.

**Clinical correlations (high-yield):** - **Pituitary stalk lesions/compression** (e.g., a large nonfunctioning adenoma, craniopharyngioma, trauma): this is the "stalk effect." Loss of dopamine delivery causes mild hyperprolactinemia, usually under 100 ng/mL. - **Prolactinoma** (the most common functional pituitary adenoma): causes amenorrhea, galactorrhea, and infertility in women, and decreased libido, erectile dysfunction, and gynecomastia in men. Prolactin levels are often over 200 ng/mL. Treatment is a dopamine agonist, either cabergoline (first line) or bromocriptine. Surgery is for patients who fail or can't tolerate medical therapy. - **Dopamine antagonists** cause hyperprolactinemia. Examples include antipsychotics (risperidone is the classic offender), metoclopramide, and prochlorperazine. Others that raise prolactin include verapamil, methyldopa, and estrogens. - **Primary hypothyroidism:** raised TRH stimulates prolactin release, which can cause galactorrhea. - **Other causes:** pregnancy, nipple stimulation, renal failure (reduced clearance), and cirrhosis. - **Dopamine agonists** (levodopa, bromocriptine, cabergoline) lower prolactin. Levodopa for Parkinson disease can do this. - **Sheehan syndrome** (postpartum pituitary necrosis): the first sign is often failure to lactate because of prolactin deficiency.

**Pearls:** - Always check pregnancy test, TSH, and medication list, and consider renal function, in the workup of hyperprolactinemia before ordering MRI. - A "hook effect" with very large prolactinomas can falsely lower the measured prolactin. Dilute the sample to detect it. - Macroprolactin (prolactin bound to IgG) can cause falsely elevated lab values without clinical symptoms. - Bitemporal hemianopia can occur with large macroadenomas that compress the optic chiasm. - Prolactin is the one anterior pituitary hormone for which a hypothalamic inhibitory factor is the dominant control. Somatostatin (GH-inhibiting hormone) also inhibits GH and TSH, but GHRH and TRH still drive their release.