Prolactin: It’s not all about milk

Mark P. Trolice, M.D., FACOG, FACS, FACE

Normal menstrual function involves an exquisitely synchronized coordination of hormonal signals involving the hypothalamus, pituitary, and ovary (HPO). During a woman’s reproductive years, the most dramatic indication of a disruption in the HPO axis is amenorrhea (absence of menses for six months, excluding pregnancy). Approximately one-third of patients presenting with amenorrhea will have an elevated serum prolactin (ESP). Of those patients with elevated prolactin levels, one-third present with galactorrhea (inappropriate milky nipple discharge). Most importantly, one third of patients presenting with amenorrhea combined with galactorrhea will be diagnosed with an adenoma, a hyperplasia of cells in the pituitary. While 10-15% of all women may have an adenoma, this condition may have serious consequences so the appropriate thorough evaluation and management of ESP is essential.

Prolactin is the only anterior pituitary hormone under tonic inhibition by dopamine. The remaining hormones are all stimulated by releasing hormones from the hypothalamus: FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone), TSH (Thyroid-stimulating Hormone), GH (Growth Hormone), and ACTH (Adrenocorticotrophic Hormone). Any interruption of the signal by dopamine, either by mass effect, hormonal, or iatrogenic, will elevate prolactin. Prolactin stimulates the breast to produce milk during pregnancy. Although prolactin is a ubiquitous hormone, its role outside of the pregnant state is largely unknown. Nevertheless, ESP can disrubt menstrual function from effecting the luteal phase to amenorrhea. In men, the most common symptoms of prolactinoma are impotence, decreased libido, erectile dysfunction, and infertility. A thorough discussion of ESP in men is beyone the scope of this article.

The following will discuss evaluation and management of various clinical presentations.

Galactorrhea

There are three essential steps to evaluate galactorrhea: a) a thorough breast examination; b) serum prolactin; and c) nipple microscopy for fat droplets. If all these are normal, then the patient may be reassured a pathologic cause of galactorrhea is excluded. A dopamine agonist, such as bromocriptine, may be offered to suppress the nipple discharge if the patient desires.

Infertility with Ovulation Dysfunction

In addition to the basic infertility evaluation, serum prolactin should be included in patients with ovulatory dysfunction. However, ESP should not be acted upon until the myriad causes of false elevations have been excluded. These causes have been categorized into Physiologic, Pharmacologic, and Pathologic (please see table for a partial list). Any persistent ESP should be evaluated further with a pituitary MRI then managed appropriately.

Table 1

Common Causes of Elevations in Serum Prolactin

PHYSIOLOGIC

Pregnancy, Ectopic pregnancy, Lactation

Late follicular and luteal phase of menstrual cycle

Nipple stimulation, Stress, Sleep disorder

PHARMACOLGIC

Dopamine receptor antagonists: phenothiazines, butyrophenones, thioxanthene, risperidone, metoclopramide, sulpiride, pimozide

Dopamine-depleting agents: α-methyldopa, reserpine

Hormones: estrogens, antiandrogens

Others: danazol, isoniazid, verapamil, cyproheptadine, opiates, H2-blockers (cimetidine), cocaine and marijuana, tricyclic antidepressants

PATHOLOGIC

Acromegaly, Alcoholic cirrhosis, Herpes zoster

Pituitary tumors: prolactinomas, adenomas

Chest wall trauma or tumor, Uterine leiomyomas

Hypothalamic and pituitary stalk disease

Polycystic ovarian syndrome, Hypothyroidism

Renal failure, Sarcoidosis, Empty sella syndrome

Once a pituitary adenoma is excluded, the standard treatment is a dopamine agonist (DA), typically bromocriptine due to its longer safety profile. DA should be started in the evening with low dosage and slowly titrated to the desired amount since hypotension is a common side effect. Once prolactin is normalized, ovulation should resume (unless another cause exists) and bromocriptine is continued until pregnancy.

Hypothyroidism has an interesting association with hyperprolactinemia. While Thyrotropin-releasing hormone (TRH) is well established as the stimulus to Thyroid-stimulating hormone (TSH), it is also the putative suspect for Prolactin-releasing factor. Consequently, primary hypothyroidism (end organ dysfunction) raises TRH and TSH through decreased feedback inhibition and may concurrently increase serum prolactin levels. Therefore, as part of the evaluation of hyperprolactinemia, obtaining TSH and treating, if applicable, primary hypothyroidism should be performed before offering a dopamine agonist.

Pituitary Adenoma

Based on size, a pituitary adenoma can be classified as a microadenoma (<10 mm diameter) or macroadenoma (>10 mm diameter). Expansion of the adenoma may result in a mass effect, cause headaches and distort vision. When ESP is associated with a pituitary adenoma, it is essential to measure all anterior pituitary hormones since an adenoma may be any tropic hyperplasia or even non-functioning (usually a macroadenoma and ESP < 150).Although not all adenomas are prolactin producing, DA can often be used as a first line irrespective of the adenoma origin. Surgery is reserved for patients who cannot tolerate medications, have rapid visual loss or have adenomas resistant to medication.&

In conclusion, the management of ESP depends on the patient’s desire for pregnancy. If fertility is the goal, then a dopamine agonist may be needed to induce ovulation. Otherwise, restoration of ovulation is essential to maintain bone mineral density and avoid osteoporosis from hypogonadism. Combined hormonal contraception (CHC) may be used in patients with microadenomas but close monitoring is necessary. Pregnancy and macroadenomas require careful surveillance and CHC is contraindicated in the latter.

REFERENCES

• Biller BM, Luciano A, Crosignani PG, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1075–1084.