Prolactin is an important hormone that functions during pregnancy and breastfeeding to promote milk production. However, elevated levels of prolactin can disrupt normal menstrual function and cause other problems, such as oligomenorrhea, ejaculation suppression, and galactorrhea.

The most common cause of hyperprolactinemia is a benign tumor on the pituitary gland called a prolactinoma. Prescription medicines can reduce the level of prolactin in the blood and improve symptoms.

Dopamine Agonists

For most patients with hyperprolactinemia due to pituitary microadenomas or idiopathic hyperprolactinemia, drug therapy is the preferred first line approach to treatment. Medications that bind to the dopamine D2 receptors in the pituitary gland cause a reduction in prolactin levels, normalisation of gonadal function and in many cases tumor reduction. A large body of non-comparative longitudinal studies supports these outcomes for bromocriptine, cabergoline or quinagolide (CV 205-502).

In addition, the dopamine D1 receptors in the hypothalamus block the release of prolactin. This action inhibits the production of kisspeptin which in turn inhibits the release of gonadotropin-releasing hormone from the pituitary gland. The decrease in kisspeptin results in decreased follicle stimulating hormone and luteinizing hormone pulsatility causing infertility.

A small number of patients will be resistant to these drugs. A subgroup of these patients have a tumor with a specific molecular biology that does not respond to dopamine agonists. A further group of patients do not respond to the medications because of adverse reactions such as nausea and headache. Despite the adverse effects, the long-term follow up of these studies supports a substantial improvement in patient important outcomes such as infertility, galactorrhea and amenorrhea.

Cabergoline medication to reduce the risk of persistent hyperprolactinemia, amenorrhea/oligomenorrhea and galactorrhea is cabergoline. This medication has a lower risk of developing valvular heart disease compared to bromocriptine and it is administered twice weekly rather than daily.

Serotonin Agonists

Serotonin (also called 5-HT) is a neurotransmitter that helps send messages between nerve cells in the brain. It is also involved in many bodily functions, including mood, sleep, digestion, and wound healing. When you don’t have enough serotonin in your body, it can lead to depression, anxiety, and digestive problems. Serotonin receptor agonists are medications that bind to and activate serotonin receptors in the central nervous system, which increases the amount of serotonin in your brain. There are different types of serotonin receptor agonists, including direct, indirect, selective, and non-selective.

Selective serotonin reuptake inhibitors are indirect agonists that doctors often prescribe for depression. They block nerve cells from absorbing serotonin, which allows more to pass between the nerve cells. Indirect agonists may also help improve symptoms of migraine headaches and other conditions.

Nonselective serotonin antagonists bind to and block serotonin receptors in the central and peripheral nervous systems. These medications can be used to treat nausea and vomiting that occurs after surgery or after anesthesia. They are also used to treat a certain type of migraine headache called a cluster headache. Common examples include ondansetron (Zofran) and dolasetron (Anzemet). In addition, some researchers believe that nonselective serotonin antagonists can decrease prolactin levels in some people with hyperprolactinemia. However, more research is needed.

Serotonin Reuptake Inhibitors

A large number of psychotropic drugs can induce drug-related pharmacologic hyperprolactinemia. While the prolactin-elevating action of antipsychotics is well known, a similar phenomenon has been observed with selective serotonin reuptake inhibitors (SSRIs). The extent of the increase in prolactin concentration and symptoms depends on the drug and patient characteristics, such as sex and age. Women tend to be more susceptible to the prolactin-raising effect of antipsychotics. Chronic hyperprolactinemia caused by antipsychotics can cause overt galactorrhea, but also affects menstrual function and fertility, and has been associated with ovarian dysfunction and breast pathology.

The majority of medications that cause pharmacologic hyperprolactinemia stimulate prolactin release either by inhibiting dopamine activity, removing its inhibitor pathways or directly stimulating production of the hormone. The resulting increase in prolactin concentration is a physiological response that results in a number of clinical effects, including overt galactorrhea, impaired fertility, decreased libido and orgasmic dysfunction, diminished bone density (see Table 1).

The author wishes to acknowledge the assistance of Mr. James L. Navy, Pharmacy Specialist, PFC Floyd K Lindstrom Outpatient Clinic, VA Eastern Colorado Health Care System, in preparing this monograph. Mr. Navy is a Clinical Pharmacy Specialist and Mr. Gardner is a Clinical Pharmacy Specialist, Highline Behavioral Health Clinic, Kaiser Permanente Colorado, Denver, CO. This monograph was reviewed and approved by the Pharmacy and Therapeutics Committee of the American Psychiatric Association.

Estrogen Agonists

The primary ovarian hormone, estrogen, influences prolactin secretion through various mechanisms. Estrogen regulates gene expression, inhibits dopamine receptors and stimulates lactotroph cell proliferation. Therefore, low estrogen levels can contribute to hyperprolactinemia. Estrogen levels can be affected by menopause, pregnancy and medications that affect estrogen production. Consequently, treatment of hyperprolactinemia is dependent on the etiology of the condition.

The most common cause of hyperprolactinemia is a prolactinoma, a tumor in the pituitary gland that causes excess production of the hormone prolactin. Medications such as progestins, aromatase inhibitors and cyproterone acetate, or radiation therapy for tumors on or near the pituitary gland can also trigger hyperprolactinemia.

These medicines work by binding to and activating estrogen receptors, which are located in the cell's nucleus and regulate gene expression and non-genomic signaling pathways. Selective estrogen receptor modulators, which act as agonists or antagonists depending on tissue type, are useful in the management of some types of cancer and in preventing post-menopausal osteoporosis.

In experimental cerebral ischemia, high physiological levels of estrogen significantly reduce the overall size of infarcts (McCullough et al, 2001). Therefore, low endogenous estrogen levels may be associated with increased risk and severity of stroke. Cabergoline, a dopamine agonist, is used to treat hyperprolactinemia. It does not increase the risk of valvular heart disease at recommended doses. A recent study of 29 postmenopausal women with microadenomas or macroadenomas found that 95% of the women who received dopamine agonists in conjunction with surgery and biopsy had remission of hyperprolactinemia and reduction of tumor size, while the rest had no change in their prolactin levels (38). These results indicate that a combination of surgical procedures can have a powerful effect on the outcome of patients with these benign pituitary adenomas.