In a 27‑year‑old male with elevated estradiol (~200 pg/mL), elevated prolactin (initially 27.2 ng/mL then 15.1 ng/mL), elevated free testosterone (~874–939 pmol/L) and mildly elevated morning cortisol (~558 nmol/L), what is the most likely etiology and how should this be evaluated and managed?

Evaluation and Management of Elevated Estradiol, Prolactin, and Testosterone in a Young Male

This 27-year-old male requires immediate endocrinology referral and pituitary MRI to evaluate for a prolactin-secreting adenoma or mixed pituitary tumor, given persistently elevated estradiol and initially elevated prolactin that normalized on repeat testing. 1, 2

Most Likely Etiology

The constellation of findings suggests three possible diagnoses that must be systematically excluded:

• Prolactinoma (most concerning): The initial prolactin of 27.2 ng/mL (nearly double the upper limit) followed by normalization to 15.1 ng/mL raises concern for either a small prolactinoma with fluctuating secretion or stress-induced hyperprolactinemia that has resolved. 2

• Mixed GH/prolactin-secreting adenoma: Persistently elevated estradiol (~200 pg/mL) combined with supraphysiologic free testosterone (874-939 pmol/L, well above the 700 pmol/L upper limit) and mildly elevated cortisol (558 nmol/L) could indicate a mixed pituitary tumor. 3

• Exogenous androgen use: The markedly elevated free testosterone levels are suspicious for undisclosed anabolic steroid use, which can cause secondary hyperprolactinemia and elevated estradiol through aromatization. 4

Immediate Diagnostic Workup

Essential Laboratory Tests

• Measure LH and FSH levels immediately: These will differentiate between primary testicular pathology versus pituitary-driven hormone excess. Low or low-normal LH/FSH with elevated testosterone strongly suggests exogenous androgen use. 1, 2

• Obtain IGF-1 level: This screens for acromegaly/mixed GH-prolactin tumors, which can present with marginally elevated prolactin and must not be missed. 2, 3

• Repeat morning prolactin measurement: Confirm the normalized prolactin level with a fasting morning sample, ideally using an indwelling cannula with samples 20-60 minutes apart to exclude stress-related elevation. 2

• Check for macroprolactinemia: Given the initial modest elevation, assess for macroprolactin to exclude this benign variant that requires no treatment. 2

• Consider prolactin dilution studies: If pituitary imaging reveals a large mass but prolactin remains only modestly elevated, perform serial dilutions to rule out the "hook effect" (falsely low prolactin due to assay saturation). 2, 5

Critical Imaging

• Pituitary MRI with gadolinium is mandatory: Even though prolactin normalized, the persistently elevated estradiol and supraphysiologic testosterone warrant imaging to exclude a pituitary adenoma. 1, 2, 3

• Do not delay imaging based on normalized prolactin: Non-secreting adenomas, mixed tumors, or small prolactinomas can present with fluctuating hormone levels. 1, 2

Key Diagnostic Pitfalls to Avoid

• Do not miss exogenous androgen use: Directly question the patient about anabolic steroid, testosterone, or "supplement" use. The free testosterone levels (874-939 pmol/L) are 25-35% above the upper limit and highly suspicious for exogenous administration. 4

• Do not overlook the hook effect: If imaging shows a large pituitary mass but prolactin is only modestly elevated, the assay may be saturated. Request serial dilutions. 2, 5

• Do not dismiss normalized prolactin: The initial elevation (27.2 ng/mL) combined with persistently elevated estradiol still warrants full evaluation. 2

• Do not forget to screen for acromegaly: Marginal prolactin elevations with pituitary masses require IGF-1 measurement to exclude mixed GH/prolactin tumors. 3

• Rule out assay interference: Given the unusual hormone pattern, consider heterophile antibodies or biotin interference if results remain discordant with clinical picture. 6

Management Algorithm

If Prolactinoma is Confirmed

• Initiate cabergoline as first-line therapy: Start at 0.25 mg twice weekly, increasing by 0.25 mg twice weekly every 4 weeks based on prolactin levels, up to a maximum of 1 mg twice weekly. 5, 7, 8

• Cabergoline is superior to bromocriptine: It offers better efficacy, tolerability, and convenient once or twice-weekly dosing. 7, 8

• Obtain baseline echocardiogram before treatment: Assess for valvular disease, as cabergoline carries a risk of cardiac valvulopathy, particularly at higher doses. 5

• Monitor with echocardiography every 6-12 months: Watch for new valvular regurgitation, restriction, or leaflet thickening. Discontinue cabergoline if these develop. 5

• Repeat pituitary MRI at 3-6 months: Assess tumor response to dopamine agonist therapy. 2

If Exogenous Androgen Use is Confirmed

• Discontinue all exogenous testosterone/anabolic steroids immediately: These suppress the hypothalamic-pituitary-gonadal axis and can cause secondary hyperprolactinemia and elevated estradiol through aromatization. 4

• Reassess hormones 3-6 months after cessation: Allow time for endogenous axis recovery before determining if underlying pathology exists. 2

If Fertility is a Concern

• Perform reproductive health evaluation before any treatment: Measure FSH, perform testicular examination, and obtain semen analysis to assess baseline fertility potential. 1

• Do not initiate testosterone therapy if fertility is desired: This will suppress spermatogenesis. If hypogonadism persists after prolactin normalization, use gonadotropin therapy (hCG ± FSH) instead. 2

Monitoring Strategy

• Recheck prolactin, estradiol, free testosterone, LH, FSH, and IGF-1 in 4-6 weeks: Establish trend and confirm initial findings. 2

• If prolactin remains elevated after repeat testing, refer to endocrinology immediately: Persistently elevated prolactin of unknown etiology requires specialist evaluation. 1, 2

• Monitor for symptoms of mass effect: Assess for headaches, visual field defects, or other neurological symptoms that would indicate tumor growth. 9, 8

• If dopamine agonist therapy is initiated, monitor prolactin levels to assess response: Adjust dosing every 4 weeks based on biochemical response. 5

• After 6 months of normalized prolactin, consider discontinuing cabergoline: Monitor prolactin periodically to determine if treatment needs to be reinstituted. 5