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Long-term use of clomiphene in male macroprolactinomas with persistent hypogonadism

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Men with macroprolactinoma can present persistent hypogonadism despite normoprolactinemia achieved with clinical and/or neurosurgical treatment. Usually, testosterone replacement therapy is indicated. Nevertheless, although off-label, clomiphene citrate (CC), a selective estrogen receptor modulator, has also been used, mainly when fertility is an issue. The aim of this study is to evaluate the effectiveness of CC in recovering the gonadal axis in men with macroprolactinoma, with or without hyperprolactinemia, and evaluate its safety as a long-term therapy.


This is a retrospective study including 10 men with macroprolactinoma on cabergoline treatment and persistent hypogonadism. All patients received initially 50 mg/d of CC.


The median age at diagnosis of prolactinomas was 34 (range, 26–60) years old. All patients were treated with cabergoline at a median maximum dose of 2 (1–7) mg/week, with a median time of treatment of 8.5 (2–15) years. Prolactin was still above the normal range when CC was introduced only in two patients. The mean duration of CC therapy was 3.2 (±2.8) years. Prolactin levels maintained stable (p = 0.252) and testosterone increased (p = 0.027) significantly on CC therapy. Tumor size remained stable. Eight patients (80%) maintained testosterone above 300 ng/dL and were classified as responders. Three responders succeeded in using a lower dose of CC and one of them completed withdrawal CC and maintained eugonadism. There were no side effects or safety concerns reported.


CC should be seen as a safe treatment option for men with macroprolactinoma and persistent hypogonadism.

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In memory of Marcello Delano Bronstein, former head of the Neuroendocrinology Unit at HCFMUSP and a pioneer in prolactin-related research.

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A.G. and M.A.M.S. wrote the main manuscript text, and prepared the figures and tables; S.A.G. and C.B.F.B. collected the data; A.G. reviewed the literature; all authors edited the main article, reviewed and approved the final version of the manuscript.

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Correspondence to Matheo A. M. Stumpf.

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Stumpf, M.A.M., Galliano, S.A., Bueno, C.B.F. et al. Long-term use of clomiphene in male macroprolactinomas with persistent hypogonadism. Endocrine 85, 152–157 (2024).

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