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

Abstract

Context: A sex difference in the progression of prolactin (PRL) tumors has been disputed for years. Objective: To compare tumor characteristics and postoperative clinical course between men and women, and correlate data with estrogen receptor alpha (ERa (ESR1)) expression status. Design, patients, and methods: Eighty-nine patients (59 women and 30 men) operated on for a prolactinoma and followed for at least 5 years were selected. Tumors were classified into five grades according to their size, invasion, and proliferation characteristics. The ERa expression was detected by immunohistochemistry and a score (0-12) calculated as the product of the percentage of positive nuclei and the staining intensity. Results: We found a significant preponderance of high-grade tumors among men and a lower surgical cure rate in men (23%) than in women (71%). Patients resistant to medical treatment were mainly men (7/8), six of whom showed tumor progression despite postoperative medical treatment, which led to multiple therapies and eventually death in three. The median score for ERa expression was 1 in men (range, 0-8) and 8 in women (range, 0-12) (P!0.0001). The expression of ERa was inversely correlated with tumor size (rZK0.59; P!0.0001) and proliferative activity. All dopamine agonist-resistant tumors and all grade 2b (invasive and proliferative) tumors (from ten men and four women) were characterized by low ERa expression. Conclusions: PRL tumors in men are characterized by lower ERa expression, which is related to higher tumor grades, resistance to treatment, and an overall worse prognosis. IntroductionPhenotypically, prolactin (PRL)-secreting pituitary tumors vary greatly, ranging from small indolent tumors to large invasive ones. Sex is a widely accepted factor influencing tumor size (1). The larger size of PRL tumors (prolactinoma) in men is often attributed to differences in detection, with diagnostic delays being the cause of more advanced PRL tumors in men (2). Nevertheless, young men usually present with large PRL tumors and most women of childbearing age with intrasellar tumors, even after a long duration of symptoms (3). When considering giant PRL tumors, the median age at diagnosis is almost 10 years lower in men than in women (4). PRL tumors in men are also less sensitive to dopamine agonists (DAs) (3) and often highly vascularized, whereas in women,

Comparison of Male and Female Prolactinoma Patients Requiring Surgical Intervention

“…Other studies have presented evidence that differential expression of estrogen receptor α and transforming growth factor β 1 may play a role in the difference seen in tumor pathogenesis between the genders, though the results of these studies are yet to be confirmed. 13,26 Previous studies have also shown differences in disease history between men and women with prolactinomas. Specifically, men have been previously shown to have shorter duration of symptoms prior to surgery, higher levels of preoperative serum prolactin levels, and more medically refractory disease.…”

“…Some attribute it to the later onset of vague symptoms resulting in delayed diagnosis, while others to the tumor biology. [12][13][14][15] Men typically present with decreased libido and impotence, whereas women tend to have more clear-cut symptoms including menstrual dysfunction and galactorrhea. 15,16 Thus far, there have also been conflicting results determining if there is a difference in response to medical treatment in males and females.…”

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…It is also recognised that lactotroph tumours in men (37,38) and silent corticotroph (ACTH positive) tumours demonstrate a more aggressive course, and may recur earlier than silent gonadotroph tumours (39,40,41). Rarely, initially silent corticotroph tumours may evolve to secrete ACTH after many years of follow-up, and this transformation may also herald more aggressive tumour behaviour (42,43,44,45).…”

“…Dopamine-resistant lactotroph tumours often are invasive macroadenomas, and according to some studies are more angiogenic and more proliferative (84). The resistant tumours often express a lower number of dopamine D 2 receptors and ER receptors (38); other mechanisms have been proposed (85). Furthermore, high doses, up to 11 mg/week, have been shown to result in prolactin normalisation in most patients (86) (Supplementary Table 5).…”

Pituitary lactotroph adenomas resistant to dopamine agonist treatment: histological and immunohistochemical characteristics

“…E. Delgrange и соавт. [19], показали, что низкая экспрессия ЭРα ассоциируется с инвазивным ростом ЛАГ и резистентностью к лечению агонистами дофамина, и предлагают рассматривать отсутствие экспрессии ЭРα как вероятный показатель неблагоприятного прогноза.…”