Prolactinomas

Michael Scally MD

Doctor of Medicine
10+ Year Member
A 42-year-old man presents with decreased libido, erectile dysfunction, and headaches. He reports no weight change, gynecomastia, fatigue, or other symptoms. He takes no medications. Testicular size is decreased on examination. His prolactin level is 648 µg per liter (normal value, <15). Magnetic resonance imaging (MRI) reveals a sellar mass (2.5 by 1.5 by 2.0 cm) that is 5 mm below the optic chiasm and that extends bilaterally into the cavernous sinuses.

What are the diagnostic and therapeutic considerations?

The Clinical Problem

Prolactinomas are the most common type of secretory pituitary tumor. Typically benign, they are classified according to size; microadenomas are less than 10 mm and macroadenomas 10 mm or more. Serum levels of prolactin in patients with prolactinomas are usually proportional to the tumor mass, and prolactin levels above 250 µg per liter are common in patients with macroprolactinomas; levels can exceed 10,000 µg per liter. Pituitary microadenomas are found in 10.9% of autopsies, and 44% of these microadenomas are prolactinomas.1 Although they are rarely hereditary, prolactinomas can occur as part of the multiple endocrine neoplasia type 1 syndrome. No risk factors have been identified for sporadicprolactinomas. Although it has been hypothesized that oral contraceptives might increase the risk, their use has not been associated with an increased likelihood of prolactinoma development.2

Clinical symptoms and signs of hyperprolactinemia in women include oligoamenorrhea, infertility, and galactorrhea. Restoration of ovulatory menstrual periods when pulsatile gonadotropin-releasing hormone (GnRH) is administered in women with hyperprolactinemia confirms the presence of abnormalities in GnRH secretion in these patients.3 In women with hyperprolactinemia who continue to have menses, luteal-phase abnormalities can lead to infertility. Estrogen deficiency in amenorrheic women with untreated prolactinomas causes low bone mass and is associated with an increased risk of fracture, whereas bone density is preserved in women with hyperprolactinemia who have regular menses.4,5 Large prolactinomas can also cause gonadotropin insufficiency because of mass effect(compression of normal gonadotrophs). In men, hyperprolactinemia may lead to hypogonadism, decreased libido, erectile dysfunction, infertility, gynecomastia, and, in rare instances, galactorrhea. Decreased bone mass6 and anemia can result from testosterone deficiency. In contrast with women, who usually present with microadenomas, most men present with macroadenomas, often with headache, visual symptoms, or both, in addition to hypogonadism.7 The larger tumor size in men presumably reflects diagnostic delay, although there may be sex-specific differences in biologic features of the tumors. Although rare, prolactinomas may occur in children, typically with mass effect, pubertal delay, or both.8

Continue Reading - See Attached Article
Klibanski A. Prolactinomas. N Engl J Med;362(13):1219-26.
 

Attachments

The Epidemiology, Diagnosis and Treatment of Prolactinomas

Prevalence and incidence of prolactinomas are approximately 50 per 100,000 and 3-5 new cases/100,000/year. The pathophysiological mechanism of hyperprolactinemia-induced gonadotropic failure involves kisspeptin neurons.

Prolactinomas in males are larger, more invasive and less sensitive to dopamine agonists (DAs). Macroprolactin, responsible for pseudohyperprolactinemia is a frequent pitfall of prolactin assay.

DAs still represent the primary therapy for most prolactinomas, but neurosurgery has regained interest, due to progress in surgical techniques and a high success rate in microprolactinoma, as well as to some underestimated side effects of long-term DA treatment, such as impulse control disorders or impaired quality of life.

Recent data show that the suspected effects of DAs on cardiac valves in patients with prolactinomas are reassuring. Finally, temozolomide has emerged as a valuable treatment for rare cases of aggressive and malignant prolactinomas that do not respond to all other conventional treatments.

Chanson P, Maiter D. The epidemiology, diagnosis and treatment of Prolactinomas: The old and the new. Best practice & research Clinical endocrinology & metabolism 2019:101290. https://www.sciencedirect.com/science/article/abs/pii/S1521690X19300417
 

Attachments

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

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.

Sehemby DMK, Lila DAR, Sarathi DV, et al. Predictors of chronic LH-testosterone axis suppression in male macroprolactinomas with normoprolactinemia on cabergoline. The Journal of Clinical Endocrinology & Metabolism 2020. Predictors of chronic LH-testosterone axis suppression in male macroprolactinomas with normoprolactinemia on cabergoline
 
True Hyperprolactinemia in Men Without Visible Pituitary Adenoma

Purpose: Men with mild to moderate hyperprolactinemia rarely present with normal pituitary on MRI with no visible adenoma, a condition entitled also "idiopathic hyperprolactinemia" or "non-tumoral hyperprolactinemia". We have characterized a cohort of hyperprolactinemic men with normal pituitary imaging.

Design: We have identified 13 men with true hyperprolactinemia and normal pituitary MRI. Baseline clinical and hormonal characteristics and response to medical treatment were retrospectively retrieved from medical records.

Results: Mean age at diagnosis was 51 ± 16 years (range, 20-77); mean serum prolactin level at presentation was 91 ng/ml (range, 28-264), eight men presented with low baseline testosterone. Initial complaints leading to diagnosis included sexual dysfunction in ten men and gynecomastia in five.

All patients were treated with cabergoline, except for one who was given bromocriptine; none required pituitary surgery. All patients normalized prolactin and testosterone with subsequent clinical improvement reported by most men. Currently, after a mean follow-up of 72 months, ten patients continue treatment with caborgoline (median weekly dose, 0.25 mg), whereas three men discontinued treatment.

Conclusions: Men with symptomatic hyperprolactinemia may rarely present with normal pituitary imaging. Medical treatment can lead to hormonal improvement with clinical benefit.

Shimon I, Rudman Y, Manisterski Y, Gorshtein A, Masri H, Duskin-Bitan H. True hyperprolactinemia in men without visible pituitary adenoma. Endocrine. 2021 Feb 10. doi: 10.1007/s12020-021-02624-1. Epub ahead of print. PMID: 33566310. True hyperprolactinemia in men without visible pituitary adenoma
 
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