Elevated Prolactin / Hyperprolactinemia and Male Infertility
Introduction to the Relationship Between Elevated Prolactin / Hyperprolactinemia and Male Fertility Potential
Prolactin is a peptide hormone made by the pituitary gland. It has multiple functions throughout the body, including stimulation of lactation in women. Elevated levels of prolactin (hyperprolactinemia) can inhibit GnRH release from the hypothalamus. Decreased GnRH can disrupt FSH and LH secretion by the pituitary gland, which can result in low testosterone levels and impair sperm production and quality.
Causes of Elevated Prolactin in Men With Male Infertility
1) Medications (the number one cause)
a) Phenothiazines
b) Tricyclic antidepressants
b) CNS-active drugs: antipsychotics, opiates, cocaine, sedative hypnotics, antidepressants
c) Anti-hypertensives: alpha-methyldopa, reserpine, verapamil, labetolol
d) Other medications: cimetidine, ranitidine, anesthetics, anticonvulsants, antihistamines, estrogens, opiate antagonists
2) Prolactinoma (functional tumor of the pituitary gland; can cause headaches and changes in vision)
a) Macroadenomas (tumors larger than 10 mm)
b) Microadenomas (tumors smaller than 10 mm; this is the most common type of pituitary tumor)
3) Hypothyroidism
4) Stress
5) Strenuous exercise
6) Nipple stimulation
7) Liver disease
8) High-protein diet
9) Kidney failure (dialysis does not improve prolactin levels, but prolactin levels can normalize with a kidney transplant)
10) Growth-hormone-secreting tumors
11) Seizures
12) Idiopathic (unknown cause; 30 percent of cases resolve on their own without treatment)
Diagnosis of Hyperprolactinemia in Male Infertility
The diagnosis of hyperprolactinemia is made by blood testing. A typical hormone profile for a man with clinical hyperprolactinemia is elevated prolactin levels with low LH levels and low testosterone.
Technically, a prolactin level of over 25 mcg/L is defined as hyperprolactinemia. However, mildly elevated levels of prolactin are generally considered not to be clinically significant or cause male fertility problems. Pituitary imaging to check for a pituitary tumor should be considered when prolactin levels are ³30 mcg/L. An MRI of the pituitary with gadolinium is the imaging test of choice for diagnosing pituitary tumors.
A prolactin level of between 25 and 100 mcg/L may be drug-related, caused by a microadenoma, or the result of pituitary stalk compression by non-prolactin secreting tumor. A prolactin level over 250 mcg/L is usually consistent with prolactinoma, though some medications (such as reserpine or metoclopramide) can increase prolactin levels to over 200 mcg/L. A prolactin level over 500 mcg/L is diagnostic for macroadenoma (mean level 1,415 mcg/L).
Hyperprolactinemia can have no symptoms at all. When symptoms do occur, they may include:
1) Symptoms of hypogonadism (decreased energy, libido, erections, decreased body hair, delayed or absent orgasm)
2) Galactorrhea (release of fluid from the nipples, which can occur in men)
3) Bilateral temporal visual field defects (due to compression of the optic nerve by the pituitary tumor)
4) Gynecomastia (breast enlargement in men)
Management of Hyperprolactinemia in male infertility
When elevations of prolactin are found, any potentially reversible causes should be addressed, including:
1) Hypothyroidism (check TSH level; see the “Thyroid Abnormalities” section for more information)
2) Strenuous exercise
3) High-protein meals
4) Nipple stimulation
5) Medications (see above list)
Mild Elevations of Prolactin
Mild elevations of prolactin generally do not have clinically significant effect on fertility. As described above, pituitary imaging with MRI should be performed for prolactin levels over 30 mcg/L. An assessment of the hormonal impact of elevated prolactin should be undertaken in men with prolactin levels over 30 mcg/L; possible findings including low testosterone, low FSH, or low LH. If the elevated prolactin levels appear to be having a negative clinical effect, then medical treatment can be initiated (see below).
Tumors of the Pituitary Gland
If any tumors of the pituitary gland are found, see a neurosurgeon for evaluation. Most pituitary tumors are benign and do not require surgical treatment, but a neurosurgeon is best qualified to make that determination.
Management of Drug-Related Elevated Prolactin Levels
Psychoactive medications are a relatively common cause of elevated prolactin levels because they are dopamine antagonists (that is, they block dopamine receptors). Stopping these medications can be difficult in some patients, and therefore one strategy is to bypass the problem by treating the hypogonadism with medications such as SERMs (see “Management of Low Testosterone,” earlier in this chapter). If that does not have the desired effect, then a man can work with his psychiatrist or primary care physician to switch to psychoactive medications with a lower dopamine antagonist potency. If changing medications does not work, one possibility is cautious administration of a dopamine agonist (see below) under close supervision by the primary care physician or psychiatrist. It must be noted, however, that not all patients will normalize their prolactin with this strategy, and the use of the dopamine agonist can exacerbate the patient’s underlying medical or psychological problems.
Medical Treatment of Hyperprolactinemia in Male Infertility
Dopamine agonists are a class of drugs that inhibit prolactin secretion. These medications can normalize blood prolactin levels and cause tumors to regress, typically over the course of several months. Improvements in semen parameters can often be seen within six months. However, a significant percent of men will continue to have low testosterone levels despite therapy and may require other treatments for hypogonadism, such as SERMs.
Bromocriptine was the dopamine agonist of choice before cabergoline was available. The typical dosage of bromocriptine is 5–10 mg by mouth daily. Potential side effects include nausea, dizziness, hypertension, and headaches.
Cabergoline and Male Infertility
Cabergoline is now the number one choice for the treatment of hyperprolactinemia. More effective than bromocriptine in decreasing prolactin levels and causing tumor regression, it has fewer side effects and higher rates of permanent remission of tumors. It needs to be given only once or twice a week. The initial dose of cabergoline is 0.25 mg twice a week with food. The dosage can be increased by 0.25 mg increments every two weeks, slowly titrating up to 4.5 mg per week if needed, limited by medication side effects (especially nausea, headache, and lightheadedness. Some men may need as much as 11 mg/week to respond.
See the "Fertility Medications Cost" section of this website for more information on cabergoline pricing at several regional and fertility-specific pharmacies.
If no tumor is present, prolactin levels should be checked one month after treatment begins, then every three months for one year, and yearly afterward; once normal prolactin levels have been maintained for six months, discontinue the medication and monitor prolactin levels. However, if prolactin has not normalized by six months after beginning treatment, then consider adding a SERM or HCG to increase testosterone levels.
If a pituitary tumor is present, prolactin levels should be checked one month after treatment begins, then every three months for one year, and yearly afterward. For a macroadenoma, repeat the imaging tests in three months if the prolactin levels are not improving or if new symptoms arise; if the prolactin levels are improving, imaging should be repeated in six to twelve months. If there are any visual field changes, repeat the imaging immediately, to see if the tumor is impinging on the optic chiasm. For microadenomas, which rarely progress in size, repeat the imaging in twelve months. If two years of treatment have passed with normal prolactin and no visible tumor, the treatment can be tapered off. However, there is a 25–70 percent recurrence rate.
In general, with cabergoline most patients see a normalization of prolactin levels in two months. For patients with tumors, shrinkage occurs in 80–90 percent of cases (compared to 75 percent with bromocriptine). Return of fertility is seen in about 50 percent of men. About 10 percent of microadenomas and 18 percent of macroadenomas do not respond to therapy.
Resistant Prolactinoma
If symptoms are still present, or if there are persistently elevated prolactin levels despite standard medication, then treatment involves increasing the dosage of medications gradually to the maximum tolerable dose. If there is still no response, consult a neurosurgeon about possible ablative therapy.
Risks and Side Effects of Cabergoline
Dopamine agonists should be used with caution if there is a history of severe liver dysfunction, peptic ulcer disease or GI bleeding, Raynaud’s disease, or valvular heart disease.
Most of the side effects of cabergoline are dose-dependent:
1) Gastrointestinal: nausea (28 percent), constipation, dry mouth, gastric irritation.
2) Central nervous system: headache (26 percent), sleep disturbances, vertigo (15 percent),
depression, dyskinesia, hallucinations.
3) Cardiovascular: hypotension, peripheral edema, arrhythmia, palpitations, angina. Protracted
high dosage use can increase risk of cardiac valve problems (there is no evidence of a
significantly increased risk in men receiving standard doses). In men at higher risk for
cardiovascular disease, a cardiac consultation should be considered prior to starting
therapy with a dopamine agonist.
Ablative Therapy for Pituitary Tumor
As mentioned earlier, a neurosurgical evaluation should be requested for all newly discovered pituitary tumors to make sure that more aggressive therapy is not needed prior to starting medical therapy. However, ablative therapy for prolactin-secreting tumors is generally reserved for patients who have seen no improvement with medical therapy. One of the potential risks of ablative procedures is damage to the other pituitary functions, which can result in pituitary insufficiency. It is therefore important to measure the other pituitary hormones (TSH, FSH, LH, etc.) after ablative treatment.
Types of ablative therapy include surgical resection and radiation therapy. With surgery, 53 percent of patients achieve long-term normalization of prolactin levels without addition of medications. However, 7–50 percent of the tumors recur with time. Risks of surgery include hypopituitarism, cerebrospinal fluid leak, infection, and diabetes insipidus. With radiation therapy, one-third of patients see normalization of their prolactin levels, though it can take years before this happens. Risks with radiation treatment include hypopituitarism, cranial nerve damage, and secondary tumor formation.