Drug-Induced Gynecomastia - Diagnosis and Treatment

What Is Gynecomastia?

Gynecomastia is the growth in the breast of males due to hormonal imbalance. It causes tenderness or pain and discharges in the nipples in one or both breasts. It is a common male breast disorder. Hormonal disparity, medications, testicular growths, or tumors are some of the notable causes of gynecomastia. Studies have shown that medications contribute to almost 20 percent of the total reported cases of gynecomastia and such cases are specifically categorized under drug-induced gynecomastia. Drug-induced gynecomastia is common (1 to 2.5 %), especially with antipsychotics. Typically Phenothiazines and Butyrophenones cause gynecomastia. Sometimes, Risperidone also causes it.

How Prevalent Is Gynecomastia?

The prevalence of gynecomastia can be 50 to 60 percent in adolescents, 60 to 90 percent in neonates, and up to 70 percent in elderly males.

What Are the Symptoms of Gynecomastia?

The symptoms of gynecomastia can be:

• Swollen breast tissues.

• Pain along with swelling.

• Breast tenderness.

• Nipple discharge.

What Are the Causes of Gynecomastia?

Gynecomastia can occur from medications taken to treat conditions like:

• Enlarged prostate.

• Anxiety and depression.

• Heartburn and peptic ulcers.

• Bacterial and fungal infections.

• Heart failure and high blood pressure.

• Male infertility by taking human chorionic gonadotropin (HCG).

• Substance abuse by taking Methadone.

Even the following drugs can cause breast swelling:

• Amphetamines.

• Marijuana.

• Opioids.

• Anabolic steroids are used for muscle building.

• Lavender oils are found in supplements.

• Tea tree oils are found in herbal supplements.

What Can Be the Mechanism of Action of Antipsychotic Drugs?

Antipsychotics act by blocking the dopamine receptor D2. There are four major dopaminergic pathways, which are mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular. D2 receptors are found in all four pathways. Typical antipsychotics like Haloperidol block D2 receptors in a non-limbic-specific fashion. This results in different effects on the four dopaminergic pathways.

1. Limbic: Decreases positive psychotic symptoms.

2. Nigrostriatal: Causes extrapyramidal symptoms.

3. Mesocortical: The mechanism is less precise and maybe a combination of therapeutic benefits and drug-induced negative symptoms.

4. Tuberoinfundibular: Drug-induced hyperprolactinemia.

Atypical antipsychotics act mainly on the 5-HT2A receptor and block D2 receptors only in a limbic specific fashion. Hence, they treat psychosis along with negative symptoms without causing many extrapyramidal side effects and hyperprolactinemia. In contrast to other atypicals, Risperidone can cause sustained hyperprolactinemia. It causes a rapid, dose-related increase in prolactin levels. Risperidone has an almost equal affinity to D2 and 5-HT2A receptors, and it is not limbic specific compared to other atypicals. Although Olanzapine can cause an early dose-related increase in prolactin levels, this effect is not sustained as with Haloperidol or Risperidone.

Blockage of D2 in the tuberoinfundibular system causes sustained hyperprolactinemia, which causes inhibition of GnRH (gonadotropin-releasing hormone) released by the hypothalamus. This decreases LH (luteinizing hormone) and FSH (follicle-stimulating hormone), which decreases testosterone levels. But the peripheral conversion of androgens to estrogens continues and thus resulting in an imbalance in androgen and estrogen levels. This imbalance results in the growth of breast tissue in males, causing gynecomastia.

Hyperprolactinemia is not believed to play a direct role in gynecomastia, although prolactin receptors have been recently demonstrated in gynecomastia tissue. Most patients with gynecomastia have normal serum prolactin levels, but not all patients with elevated prolactin levels develop gynecomastia. The suppression of GnRH release by high prolactin resulting in secondary hypogonadism leads to gynecomastia.

Screening for Gynecomastia:

Since hyperprolactinemia does not directly cause gynecomastia, screening with serum prolactin and testosterone levels is better than testing for prolactin levels alone. An elevated prolactin level alone will not predict the risk for developing gynecomastia since the prolactin levels can be influenced by multiple factors like stress, time of day, chest wall stimulation, sleep, trauma, cocaine, and opioid use. The blood should be drawn in the morning after overnight fasting for evaluating the prolactin levels.

How to Evaluate a Patient With Gynecomastia?

Any patient with gynecomastia (drug-induced or not) will require mammography if any sign of malignancy is present like a hard mass, bloody nipple discharge, nipple retraction, skin dimpling, axillary lymphadenopathy, etc. If the mammography is positive, a biopsy should be done. In cases of drug-induced hyperprolactinemia, the prolactin levels usually will be ten times the normal range. Whereas in the case of a prolactinoma, the prolactin levels will be raised 100 times the normal level. Normal prolactin level in males is 2 to 18 ng/mL.

In symptomatic patients with suspected medication-induced hyperprolactinemia, the drug should be discontinued for three days, or an alternate drug should be substituted, and serum prolactin level should then be repeated. Suppose the drug cannot be discontinued or the discontinuation of the drug for three days does not result in the resolution of hyperprolactinemia. In that case, a more detailed evaluation is required for identifying the underlying cause so the following tests can be done:

1. Thyroid function test.

2. Liver enzymes.

3. Serum creatinine.

4. Serum beta hCG.

5. Serum DHEA (dehydroepiandrosterone) or urinary 17-ketosteroids.

6. Serum total and free or bioavailable testosterone, LH, FSH.

7. MRI of sella turcica, especially if prolactin levels are markedly elevated, the patient has bitemporal hemianopia or any signs of an intracranial space-occupying lesion.

How to Treat Gynecomastia?

Patients with asymptomatic medication-induced hyperprolactinemia need not be treated. In the case of symptomatic medication-induced hyperprolactinemia, gynecomastia decreased libido, infertility, and osteoporosis, it warrants discontinuation or changing to a medication with weaker dopamine blockers. If the medication cannot be discontinued, then careful administration of dopamine agonists like Cabergoline and Pergolide can be tried along with the medication.

In cases where the discontinuation of medication does not resolve gynecomastia, the following medications can be tried even though they are not FDA-approved. Medical therapy should be initiated in the early stages (before 12 months), as long-standing gynecomastia can result in tissue fibrosis.

1. Antiestrogens (Clomiphene citrate), studies have shown complete resolution in six months.

2. SERM-Selective estrogen receptor modulator (Tamoxifen 20 mg) a complete resolution in four months, it is most effective.

3. Aromatase inhibitor (Anastrozole), studies are yet to be done. Evidence shows disappointing results after treatment for seven months.

4. Synthetic testosterone (Danazol).

5. Aripiprazole.

Conclusion:

Most of the drug-induced gynecomastia resolves with either discontinuation of the offending drug or medical therapy. If the medical therapy fails, surgery like breast reduction surgery or radiation therapy can be tried. During this surgical procedure, a plastic surgeon removes breast tissue to make breasts smaller. Persistent gynecomastia is usually very rare and is due to long-standing gynecomastia for more than 12 months resulting in fibrosis of breast tissue.