Predictors of Chronic LH-Testosterone Axis Suppression in Male Macroprolactinomas With Normoprolactinemia on Cabergoline

Abstract

Context Data regarding prevalence, predictors, and mechanisms of persistent hypogonadotropic hypogonadism (HH) in males with a macroprolactinoma who achieve normoprolactinemia on dopamine-agonist therapy is limited. None of the previous studies provide cut-offs to predict the achievement of eugonadism. Objective To evaluate the prevalence of persistent HH and its determinants in males with a macroprolactinoma who achieve normoprolactinemia on cabergoline monotherapy Design Retrospective study with prospective cross-sectional evaluation. Setting Tertiary health care center. Patients Males with a macroprolactinoma and baseline HH who achieve normoprolactinemia on cabergoline monotherapy Intervention None. Main outcome measures Prevalence of persistent HH and its predictors. Results Thirty subjects (age: 38.3±10.1 years) with baseline tumor size of 4.08±1.48 cm and median (IQR) prolactin of 2871 (1665-8425) ng/ml were included. Eight of 30 participants achieved eugonadism after a median follow-up of three years. Patients with persistent HH had suppression of LH-testosterone axis with sparing of other anterior pituitary hormonal axes including FSH-Inhibin B. Baseline prolactin (1674 vs. 4120 ng/ml; p=0.008) and maximal tumor diameter (2.55±0.36 vs. 4.64±1.32 cm; p=0.003) were lower in patients who achieved eugonadism. Baseline maximal tumor diameter ≤ 3.2 cm (sensitivity: 75%, specificity: 63.6%) and serum prolactin ≤ 2098 ng/ml (sensitivity: 87.5%, specificity: 77.3%) best predicted reversal of HH. Conclusion Recovery of LH-testosterone axis occurred in 26.7% of males with a macroprolactinoma who achieved normoprolactinemia on cabergoline monotherapy. Higher baseline tumor size and serum prolactin predict persistent HH. Our data favors chronic functional modification of hypothalamic-pituitary-gonadal axis over gonadotroph damage as the cause of persistent HH.

Hypogonadism in Male Patients with Pituitary Adenoma and Its Related Mechanism: A Review of Literature

“…Some studies have reported different results. In 2020, Sehemby et al [ 66 ] studied a group of hypogonadal patients in which the PRL levels were restored to the normal range after treatment with cabergoline; the LH–testosterone axis remained suppressed in these men. This phenomenon was also described in a 2014 study by Shimon and Benbassat [ 67 ]; after 3 years of follow-up, only 26.7% of patients were found to have recovered.…”

Predicting hypogonadotropic hypogonadism persistence in male macroprolactinoma

“…In their study, Sehemby et al [11] demonstrated selective suppression of the LH-testosterone axis (without suppression of the FSH-inhibin B axis) and thus they suggest that "chronic functional modi cation" of the hypothalamus, and not gonadotroph cell damage, is the biological mechanism of persistent HH.…”

“…In 2020, Sehemby et al [11] studied a cohort of 30 men, and found high rate of baseline central hypogonadism of 100%. All men included achieved normoprolactinemia with cabergoline therapy, and yet 73% of men had HH persistence at the end of the study period (median follow-up of 2 years).…”

“…De rosa et al (2006, Italy) [10] prospectively evaluated 38 medically treated male patients with macroprolactinoma and identi ed high baseline serum prolactin, low baseline testosterone and large tumor size as predictors of short-term HH persistence (up to 6 months after prolactin normalization). In 2020, Sehemby et al [11] investigated a cohort of 30 men from Mumbai, India, that achieved normoprolactinemia with cabergoline therapy and found that baseline serum prolactin and tumor size predicted HH persistence after a median follow-up of two years (from prolactin normalization to the end of follow-up).…”

Italian Association of Clinical Endocrinologists (AME) and International Chapter of Clinical Endocrinology (ICCE). Position statement for clinical practice: prolactin-secreting tumors

“…There are not enough data regarding predictors of long-lasting/persisting hypogonadism. In a recent retrospective study with a follow-up of only 2 years, hypogonadism persisted in 74% of patients after PRL normalization with Cab; the higher PRL levels and tumor size, the lower the chance of normalizing testosterone levels ( 154 ). In another study, long-term treatment (median: 3 years) was necessary to obtain normalization of hyperprolactinemia and reversal of hypogonadism ( 155 ).…”