Hyperprolactinemia

Prl

Lactotropes and somatotropes are derived from a common precursor cell that may give rise to a tumor secreting both PRL and GH. Marked lactotrope cell hyperplasia develops during the last two trimesters of pregnancy and the first few months of lactation. These transient functional changes in the lactotrope population are induced by estrogen

Normal adult serum PRL levels are about 10–25 g/L in women and 10–20 g/L in men. PRL secretion is pulsatile, with the highest secretory peaks occurring during rapid eye movement sleep. Peak serum PRL levels (up to 30 g/L) occur between 4:00 and 6:00 A.M. The circulating half-life of PRL is about 50 min

PRL is unique among the pituitary hormones in that the predominant central control mechanism is inhibitory, reflecting dopamine-mediated suppression of PRL release. This regulatory pathway accounts for the spontaneous PRL hypersecretion that occurs after pituitary stalk section, often a consequence of compressive mass lesions at the skull base. Pituitary, dopamine type 2 (D₂) receptors mediate PRL inhibition.

Thyrotropin-releasing hormone (TRH) (pyro Glu-His-Pro-NH2) is a hypothalamic tripeptide that releases prolactin within 15–30 min after intravenous injection. The physiologic relevance of TRH for PRL regulation is unclear, and it appears primarily to regulate TSH (Chap. 335). Vasoactive intestinal peptide (VIP) also induces PRL release, whereas glucocorticoids and thyroid hormone weakly suppress PRL secretion.

PRL levels increase significantly (about tenfold) during pregnancy and decline rapidly within 2 weeks of parturition. If breastfeeding is initiated, basal PRL levels remain elevated; suckling stimulates reflex increases in PRL levels that last for about 30–45 min. Breast suckling activates neural afferent pathways in the hypothalamus that induce PRL release. With time, the suckling-induced responses diminish and interfeeding PRL levels return to normal

In the breast, the lobuloalveolar epithelium proliferates in response to PRL, placental lactogens, estrogen, progesterone, and local paracrine growth factors, including IGF-I.

PRL acts to induce and maintain lactation, decrease reproductive function, and suppress sexual drive. These functions are geared toward ensuring that maternal lactation is sustained and not interrupted by pregnancy. PRL inhibits reproductive function by suppressing hypothalamic GnRH and pituitary gonadotropin secretion and by impairing gonadal steroidogenesis in both women and men. In the ovary, PRL blocks folliculogenesis and inhibits granulosa cell aromatase activity, leading to hypoestrogenism and anovulation. PRL also has a luteolytic effect, generating a shortened, or inadequate, luteal phase of the menstrual cycle. In men, attenuated LH secretion leads to low testosterone levels and decreased spermatogenesis. These hormonal changes decrease libido and reduce fertility in patients with hyperprolactinemia.

Hyperprolactinemia

Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. PRL-secreting pituitary adenomas (prolactinomas) are the most common cause of PRL levels >100 g/L (see below). Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly caused by drugs, pituitary stalk compression, hypothyroidism, or renal failure

Pregnancy and lactation are the important physiologic causes of hyperprolactinemia. Sleep-associated hyperprolactinemia reverts to normal within an hour of awakening. Nipple stimulation and sexual orgasm may also increase PRL. Chest wall stimulation or trauma (including chest surgery and herpes zoster) invoke the reflex suckling arc with resultant hyperprolactinemia. Chronic renal failure elevates PRL by decreasing peripheral clearance. Primary hypothyroidism is associated with mild hyperprolactinemia, probably because of compensatory TRH secretion

Drug-induced inhibition or disruption of dopaminergic receptor function is a common cause of hyperprolactinemia (Table 333-8). Thus, antipsychotics and antidepressants are a relatively common cause of mild hyperprolactinemia. Methyldopa inhibits dopamine synthesis and verapamil blocks dopamine release, also leading to hyperprolactinemia. Hormonal agents that induce PRL include estrogens, antiandrogens, and TRH

Amenorrhea, galactorrhea, and infertility are the hallmarks of hyperprolactinemia in women. If hyperprolactinemia develops prior to menarche, primary amenorrhea results. More commonly, hyperprolactinemia develops later in life and leads to oligomenorrhea and, ultimately, to amenorrhea. If hyperprolactinemia is sustained, vertebral bone mineral density can be reduced compared with age-matched controls, particularly when associated with pronounced hypoestrogenemia. Galactorrhea is present in up to 80% of hyperprolactinemic women. Although usually bilateral and spontaneous, it may be unilateral or only expressed manually. Patients may also complain of decreased libido, weight gain, and mild hirsutism.

In men with hyperprolactinemia, diminished libido, infertility, or visual loss (from optic nerve compression) are the usual presenting symptoms. Gonadotropin suppression leads to reduced testosterone, impotence, and oligospermia. True galactorrhea is uncommon in men with hyperprolactinemia. If the disorder is longstanding, secondary effects of hypogonadism are evident, including osteopenia, reduced muscle mass, and decreased beard growth.

The diagnosis of idiopathic hyperprolactinemia is made by exclusion of known causes of hyperprolactinemia in the setting of a normal pituitary MRI. Some of these patients may harbor small microadenomas below MRI sensitivity (~2 mm).

Galactorrhea, the inappropriate discharge of milk-containing fluid from the breast, is considered abnormal if it persists for longer than 6 months after childbirth or discontinuation of breastfeeding. Mammography or ultrasound is indicated for bloody discharges (particularly from a single duct), which may be caused by breast cancer.

Prolactinoma

Microadenomas are classified as <1>1 cm in diameter and may be locally invasive and impinge on adjacent structures. The female:male ratio for microprolactinomas is 20:1, whereas the gender ratio is near 1:1 for macroadenomas. Tumor size generally correlates directly with PRL concentrations; values >100 g/L are usually associated with macroadenomas. About 5% of microadenomas progress in the long term to macroadenomas. Hyperprolactinemia resolves spontaneously in about 30% of microadenomas

Women usually present with amenorrhea, infertility, and galactorrhea. If the tumor extends outside of the sella, visual field defects or other mass effects may be seen. Men often present with impotence, loss of libido, infertility, or signs of central CNS compression including headaches and visual defects. Assuming that physiologic and medication-induced causes of hyperprolactinemia are excluded (Table 333-8), the diagnosis of prolactinoma is likely with a PRL level >100 g/L. PRL levels <100>

For symptomatic microadenomas, therapeutic goals include control of hyperprolactinemia, reduction of tumor size, restoration of menses and fertility, and resolution of galactorrhea. Dopamine agonist doses should be titrated to achieve maximal PRL suppression and restoration of reproductive function (Fig. 333-6). A normalized PRL level does not ensure reduced tumor size. However, tumor shrinkage is not usually seen in those who do not respond with lowered PRL levels. For macroadenomas, formal visual field testing should be performed before initiating dopamine agonists. MRI and visual fields should be assessed at 6- to 12-month intervals until the mass shrinks and annually thereafter until maximum size reduction has occurred.

Oral dopamine agonists (cabergoline or bromocriptine) are the mainstay of therapy for patients with micro- or macroprolactinomas. Dopamine agonists suppress PRL secretion and synthesis as well as lactotrope cell proliferation.

Cabergoline

An ergoline derivative, cabergoline is a long-acting dopamine agonist with high D₂ receptor affinity. The drug effectively suppresses PRL for >14 days after a single oral dose and induces prolactinoma shrinkage in most patients. Cabergoline (0.5 to 1.0 mg twice weekly) achieves normoprolactinemia and resumption of normal gonadal function in ~80% of patients with microadenomas; galactorrhea improves or resolves in 90% of patients. Cabergoline normalizes PRL and shrinks ~70% of macroprolactinomas. Mass effect symptoms, including headaches and visual disorders, usually improve dramatically within days after cabergoline initiation; improvement of sexual function requires several weeks of treatment but may occur before complete normalization of prolactin levels. After initial control of PRL levels has been achieved, cabergoline should be reduced to the lowest effective maintenance dose

Bromocriptine

The ergot alkaloid bromocriptine mesylate is a dopamine receptor agonist that suppresses prolactin secretion. Because it is short-acting, the drug is preferred when pregnancy is desired. In microadenomas bromocriptine rapidly lowers serum prolactin levels to normal in up to 70% of patients, decreases tumor size, and restores gonadal function. In patients with macroadenomas, prolactin levels are also normalized in 70% of patients and tumor mass shrinkage (50%) is achieved in up to 40% of patients.

Therapy is initiated by administering a low bromocriptine dose (0.625–1.25 mg) at bedtime with a snack, followed by gradually increasing the dose. Most patients are successfully controlled with a daily dose of 7.5 mg (2.5 mg tid).

The pituitary increases in size during pregnancy, reflecting the stimulatory effects of estrogen and perhaps other growth factors. About 5% of microadenomas significantly increase in size, but 15–30% of macroadenomas grow during pregnancy. Bromocriptine has been used for more than 30 years to restore fertility in women with hyperprolactinemia, without evidence of teratogenic effects. Nonetheless, most authorities recommend strategies to minimize fetal exposure to the drug. For women taking bromocriptine who desire pregnancy, mechanical contraception should be used through three regular menstrual cycles to allow for conception timing. When pregnancy is confirmed, bromocriptine should be discontinued and PRL levels followed serially, especially if headaches or visual symptoms occur. As cabergoline is long-acting with a high D₂-receptor affinity, it is not approved for use in women when fertility is desired.