In pituitary stalk section from surgery or head trauma, stalk compression due to a sellar mass, or rare cases of hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of dopamine (prolactin-inhibiting hormone) to the pituitary. Much more commonly, prolactin is elevated as a result of prolactin-secreting adenomas. In addition, a number of drugs elevate prolactin levels. These include antipsychotic and gastrointestinal motility drugs that are known dopamine receptor antagonists, estrogens, and opiates. Hyperprolactinemia causes hypogonadism, which manifests with infertility, oligomenorrhea or amenorrhea, and galactorrhea in premenopausal women, and with loss of libido, erectile dysfunction, and infertility in men. In the case of large tumors (macroadenomas), it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. The hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release. For patients with symptomatic hyperprolactinemia, inhibition of prolactin secretion can be achieved with dopamine agonists, which act in the pituitary to inhibit prolactin release.
Adenomas that secrete excess prolactin usually retain the sensitivity to inhibition by dopamine exhibited by normal pituitary lactotrophs, prolactin secreting cells. Bromocriptine and cabergoline are ergot derivatives (see Chapters 16 and 28) with a high affinity for dopamine D2 receptors. Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D2 receptor affinity. The chemical structure and pharmacokinetic features of ergot alkaloids are presented in Chapter 16.
Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia and GH release is reduced in patients with acromegaly, although not as effectively. Bromocriptine has also been used in Parkinson’s disease to improve motor function and reduce levodopa requirements (see Chapter 28). Newer, nonergot D2 agonists used in Parkinson’s disease (pramipexole and ropinirole; see Chapter 28) have been reported to interfere with lactation, but they are not approved for use in hyperprolactinemia.
All available dopamine agonists are active as oral preparations, and all are eliminated by metabolism. They can also be absorbed systemically after vaginal insertion of tablets to avoid nausea due to oral administration. Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action. Quinagolide has a half-life of about 20 hours, whereas the half-life of bromocriptine is about 7 hours. After vaginal administration, serum levels peak more slowly.
A. Hyperprolactinemia
A dopamine agonist is the standard first-line treatment for hyperprolactinemia. These drugs shrink pituitary prolactin-secreting tumors, lower circulating prolactin levels, and restore ovulation in approximately 70% of women with microadenomas and 30% of women with macroadenomas (Figure 37–4). Cabergoline is initiated at 0.25 mg twice weekly orally or vaginally. It can be increased gradually, according to serum prolactin determinations, up to a maximum of 1 mg twice weekly. Bromocriptine is generally taken daily after the evening meal at the initial dose of 1.25 mg; the dose is then increased as tolerated. Most patients require 2.5–7.5 mg daily. Long-acting oral bromocriptine formulations (Parlodel SRO) and intramuscular formulations (Parlodel LAR) are available outside the United States.
B. Physiologic Lactation