A 31-year-old woman is referred by her Ob-Gyn for elevated prolactin. She initially presented with a three-month history of amenorrhea, a negative home pregnancy test, and 100% compliance with condom use. She denies hirsutism and acne but admits to thin milky nipple discharge upon squeezing (but not spontaneous).

Two weeks ago, her Ob-Gyn ordered labs; results were negative for serum beta human chorionic gonadotropin and within normal ranges for thyroid-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone, estradiol, free and total testosterone, dehydroepiandrosterone sulfate (DHEAs), complete chemistry panel, and complete blood count. Her serum prolactin level was 110 ng/mL (normal, 3 to 27 ng/mL).

Q: How is prolactin physiologically regulated?

The primary role of prolactin, which is produced by lactotroph cells in the anterior pituitary gland, is to stimulate lactation and breast development. Prolactin is regulated by dopamine (also known as prolactin inhibitory hormone), which is secreted from the hypothalamus via an inhibitory pathway unique to the hypothalamus-pituitary hormone system. Dopamine essentially suppresses prolactin.

Other hormones can have a stimulatory effect on the anterior pituitary gland and thus increase prolactin levels. Estrogen can induce lactotroph hyperplasia and elevated prolactin; however, this is only clinically relevant in the context of estrogen surge during pregnancy. (Estrogen therapy, such as oral contraception or hormone replacement therapy, on the other hand, is targeted to “normal” estrogen levels.) Thyrotropin-releasing hormone (TRH) from the hypothalamus also stimulates the anterior pituitary gland, so patients with inadequately treated or untreated primary hypothyroidism will have mildly elevated prolactin.

Neurogenic stimuli of the chest wall, through nipple suckling or varicella zoster infection (shingles), can also increase prolactin secretion. And since prolactin is eliminated by the liver (75%) and the kidney (25%), significant liver disease and/or renal insufficiency can raise prolactin levels, due to decreased clearance.

What are the possible etiologies for elevated prolactin? See answer on the next page...

Q: What are the possible etiologies for elevated prolactin?

The causes of hyperprolactinemia fall into three categories: physiologic, pharmacologic, and pathologic.² The table provides examples from each category.

A nonsecretory pituitary adenoma or any lesion in the brain that would disrupt the hypophyseal stalk may interfere with dopamine’s inhibitory control and thereby increase prolactin. This is called the stalk effect. It is important to note that not all MRI-proven pituitary adenomas are prolactin secreting, even in the presence of hyperprolactinemia. According to an autopsy series, about 12% of the general population had pituitary microadenoma.³

There is rough correlation between prolactinoma size and level of prolactin. Large nonsecretory pituitary adenomas have prolactin levels less than 150 ng/mL. Microprolactinomas (< 1 cm) are usually in the range of 100 to 250 ng/mL, while macroprolactinomas (> 1 cm) are generally
≥ 250 ng/mL. If the tumor is very large and invades the cavernous sinus, prolactin can measure in the 1,000s.³

Polycystic ovarian syndrome (PCOS) is a common disorder affecting women of reproductive age and the most common cause of underlying ovulatory problems. Patients with PCOS can have mildly elevated prolactin; the exact mechanism of hyperprolactinemia in PCOS is unknown. One theory is that constant high levels of estrogen experienced in PCOS would stimulate prolactin production. It is important to rule out other causes of hyperprolactinemia before making the diagnosis of PCOS.

What is the clinical significance of elevated prolactin? Why do we have to work up and treat it? See answer on the next page...

Q: What is the clinical significance of elevated prolactin? Why do we have to work up and treat it?

By physiologic mechanisms not completely understood, hyperprolactinemia can interrupt the gonadal axis, leading to hypogonadism. In women, it can cause irregular menstrual cycles, oligomenorrhea, amenorrhea, and infertility. In men, it can lower testosterone levels. Long-term effects include declining bone mineral density due to insufficient estrogen in women or testosterone in men.

With macroadenoma, the size of the tumor can have a mass effect such as headache and visual defect by compressing the optic chiasm (bitemporal hemianopsia), which may lead to permanent vision loss if left untreated. Referral to an ophthalmologist may be necessary for formal visual field examination.

How is hyperprolactinemia treated? See answer on the next page...

Q: How is hyperprolactinemia treated?

There are three options for treatment: medication, surgery, and radiation.

Dopamine agonists (bromocriptine, cabergoline) are effective in normalizing prolactin and reducing the size of the tumor in the majority of cases. However, some patients may require long-term treatment. Bromocriptine has been used since the late 1970s, but, due to better tolerance and less frequent dosing, cabergoline is the preferred agent.³

Transsphenoidal surgery is indicated for patients who are intolerant to medication, who have a medication-resistant tumor or significant mass effect, or who prefer definitive treatment. Women of childbearing age with a macroadenoma might consider surgery due to the risk for tumor expansion during pregnancy (estrogen effect) and risk for pituitary apoplexy (hemorrhage or infarct of the pituitary gland). Surgical risk is usually low with a neurosurgeon who has extensive experience.

Radiation can be considered for large tumors that are resistant to medication. It can be used as adjunctive therapy to surgery, since reducing the size of the tumor can make the surgical field smaller. In some medication-resistant tumors, radiation can raise sensitivity to medication.

What does follow-up entail? See next page for answer...

Q: What does follow-up entail?

Once medication is initiated or dosage is adjusted, have the patient follow up in one month and recheck the prolactin level to assess responsiveness to medication (as well as medication adherence). When a therapeutic prolactin level is achieved, recheck the prolactin and have the patient follow up at three and six months and then every six months thereafter.³

MRI of the pituitary gland should be performed at baseline, then in six months to assess tumor response to medication, and then at 12 and 24 months.³ If tumor regression has stabilized or if the tumor has shrunk to a nondetectable size, consider discontinuing the dopamine agonist. If medication is discontinued, recheck prolactin every three months for the first year; if it remains in normal reference range, simply check serum prolactin annually.³

See next page for summary.

See next page for references.

REFERENCES

1. Jameson JL. Harrison’s Endocrinology. 18th ed. China: McGraw-Hill; 2010.

2. Gardner D, Shoback D. Greenspan’s Basic & Clinical Endocrinology. 9th ed. China: McGraw-Hill; 2011.

3. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(2):273-288.

Hyperprolactinemia: Causes and Treatments