Gender Differences in Macroprolactinomas: Study of Clinical Features, Outcome of Patients and Ki-67 Expression in Tumor Tissue

Abstract

Prolactinomas in men are usually macroprolactinomas and other investigators have attributed bigger size of tumors in men to delay in diagnosis. A retrospective study of 71 macroadenomas (42 men) was carried out. Parameters studied were age, signs and symptoms at presentation, time of onset of symptoms, basal prolactin, estradiol, and total testosterone levels, tumor size and Ki 67 expression in tumor tissue. Male patients were older. Visual defects were significantly more prevalent in men. Hardy 4 stage tumors were found only in men. We found no significant correlation between tumor size and the patients age nor between tumor size and the onset of symptoms. Whereas basal E2 levels (21.2+/-12.9 vs. 33.3+/-43.3 pg/ml, p=n.s.) were very similar in male and female patients, testosterone levels were significantly higher in men (0.6+/-0.5 vs. 1.8+/-1.2 ng/ml, p=0.02). The rate of cell proliferation represented by Ki 67 was significantly higher in tumors in men (3.5+/-1.2 vs. 1.5+/-0.5%, p=0.0001). This is the first study focused in macroprolactinomas that shows that they are clinically and biologically more aggressive in men. Hypogonadism in men could appear later in the progression of prolactinomas and this might explain why men were older at the time of diagnosis. Furthermore, testosterone could be a source for E2 in situ aromatization giving male tumors an advantage in cell proliferation.

Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth

“…Owing to surgical recruitment, between 1988 and 2005, this series also included nine patients (all men) admitted for large tumors with rapidly progressive loss of vision (19), which is no more regarded as an indication for primary surgery, surgical cure being unlikely (0/9 in the present series) and improvement of visual impairment occurring promptly after initiation of DA therapy (20). Mitosis and MKI67 expression were higher in men, as has been reported in smaller series (3,21,22,23). Moreover, according to the new prognostic clinicopathological classification (16), men have higher grade tumors than women.…”

“…Estrogen appears therefore to differentially effect cell proliferation and PRL secretion (30). Two case reports of male patients with macroprolactinomas treated with cabergoline demonstrated an increase in the PRL level following testosterone supplementation, which was reversed by the aromatase inhibitor anastrozole (23,31). This was considered a demonstration of the negative impact of estrogens on PRL tumors, and yet there was no mention of any tumor growth.…”

Anastrozole as add-on therapy for cabergoline-resistant prolactin-secreting pituitary adenomas: real-life experience in male patients

“…In humans, similar findings were confirmed by the PRLoma growth during estrogen therapy in a transgender male-to-female patient [19]. Furthermore, testosterone could be aromatized to estradiol, giving male tumors an advantage on cell proliferation [20]. In men, a lower estrogen-receptor expression has been reported in aggressive PRLomas with DA-resistance [21].…”

Is receptor profiling useful for predicting pituitary therapy?

“…Some authors have proposed that these differences in presentation could be in part explained by the fact that hypogonadism in males is usually neglected and medical attention is sought later, possibly allowing the development of a DA-resistant phenotype (i.e. due to decreased DR2 expression) (67,68). On the contrary, other authors provide evidence for the lack of a gender prevalence in D-resistant prolactinomas (66).…”