Exogenous Testosterone and Prolactin Levels
Exogenous testosterone can paradoxically increase prolactin levels through aromatization to estradiol, though this is not a typical or common effect and the mechanism involves peripheral conversion rather than direct testosterone action.
Mechanism of Testosterone-Induced Hyperprolactinemia
The relationship between exogenous testosterone and prolactin is complex and bidirectional:
Exogenous testosterone undergoes aromatization to estradiol in peripheral tissues, and this estradiol can stimulate prolactin release from the anterior pituitary 1. This represents an indirect mechanism where testosterone itself is not the culprit, but rather its metabolite.
Endogenous estrogens increase prolactin secretion, while androgens typically decrease prolactin secretion 2. This creates a paradox where testosterone replacement can sometimes elevate prolactin despite androgens normally suppressing it.
A documented case report demonstrated a direct correlation (r = 0.6090, P = 0.0095) between testosterone replacement initiation and rising prolactin levels, with prolactin falling when testosterone was discontinued 1. Imaging studies in this case even suggested possible tumor regrowth after testosterone therapy.
Clinical Context and Frequency
This is an under-recognized complication that clinicians should be aware of:
The effect appears most relevant in patients with pre-existing prolactinomas or pituitary pathology 1. In one case, an 18-year-old man with a suprasellar macroadenoma experienced documented rises in prolactin with testosterone replacement and falls when stopped.
Older studies showed that depot testosterone administration (100 mg) caused significant increases in prolactin levels by day 4 after injection 3. This same study found that men with low baseline testosterone had significantly higher baseline prolactin levels.
The typical effect of exogenous testosterone is to suppress gonadotropins (LH and FSH) through negative feedback to the hypothalamus and pituitary 4. This is the dominant and expected hormonal response.
When to Suspect Testosterone-Related Hyperprolactinemia
Men with decreased libido, impotence, and/or testosterone deficiency accompanied by low or low-normal LH levels warrant measurement of serum prolactin to investigate for hyperprolactinemia 4. This guideline recommendation applies regardless of whether the patient is on testosterone replacement.
Key clinical scenarios include:
Patients on testosterone replacement who develop new symptoms of hyperprolactinemia (gynecomastia, galactorrhea, worsening sexual dysfunction) should have prolactin measured 1.
For persistently elevated prolactin levels above normal without an exogenous etiology (such as dopamine antagonist medications), MRI is indicated 4.
Approximately 5% of patients with macroprolactinomas show paradoxically normal or mildly elevated prolactin due to the "high-dose hook effect," requiring manual serial dilutions 5.
Management Considerations
If testosterone-induced hyperprolactinemia is suspected:
Consider using aromatase inhibitors together with testosterone replacement therapy, or switching to non-aromatizable androgens (such as dihydrotestosterone) 1. The AUA guidelines note that aromatase inhibitors may be used in men with testosterone deficiency desiring to maintain fertility 4.
Dopamine agonists apparently do not suppress the hyperprolactinemia induced by testosterone replacement 1. This is a critical pitfall—the usual treatment for hyperprolactinemia may not work in this specific context.
Dihydrotestosterone (a non-aromatizable androgen) has been shown to decrease prolactin levels in both eugonadal and agonadal men 2. This makes it a logical alternative if aromatization is the suspected mechanism.
Important Caveats
The dominant effect of exogenous testosterone is gonadotropin suppression, not prolactin elevation 4. Most patients on testosterone replacement will not experience clinically significant prolactin increases.
Exclude other common causes of hyperprolactinemia first: medications (dopamine antagonists), hypothyroidism, chronic kidney disease, liver disease, and pituitary stalk compression 5.
Stress alone can elevate prolactin up to five times the upper limit of normal 5. Ensure measurements are obtained in appropriate clinical conditions.
Screen for macroprolactinemia (10-40% of hyperprolactinemia cases) when prolactin is mildly or incidentally elevated 5, 6, as this represents biologically inactive prolactin complexes that do not require treatment in most cases.