FSH secretion predominates in vivo and in vitro in patients with non-functioning pituitary adenomas

Abstract

Objective: Non-functioning pituitary adenomas (NFPAs) are characterised by the lack of symptoms of hormone hypersecretory syndromes but in vitro studies have demonstrated that tumour cells may stain for gonadotrophins and/or their a-or b-subunits. In this study, we aimed to examine the pattern of secretion of LH and FSH from a series of pituitary adenomas cultured in vitro and where data were available to relate the results to pre-operative serum gonadotrophin levels. Methods: The in vitro secretion of LH and FSH was measured from 46 cultured NFPAs and compared with pre-operative serum gonadotrophin levels in 38 patients. Peri-tumorous 'normal' pituitary cell cultures from 20 additional pituitary tumour patients were used for comparison with the NFPA group. Results: A median pre-operative LH:FSH ratio of 0.33:1 was found in 38 patients with NFPAs. Preferential secretion of FSH was also documented from media of 46 NFPAs cultured in vitro with a median LH:FSH ratio of 0.32:1. A significant correlation (r ¼ 0.43, P , 0.01) was observed between serum and media levels of FSH but not LH. Peri-tumorous 'normal' pituitary cells released LH and FSH in a reversed ratio (median LH:FSH ratio ¼ 3.6:1, P , 0.01 compared with NFPAs). Conclusions: This study has evaluated pre-operative serum gonadotrophin levels and in vitro release of hormones in cultures of surgically removed tissue from patients with NFPAs. The data suggest preferential secretion of FSH occurs both in vitro and in vivo. By demonstrating that NFPAs cultured in vitro reflect the in vivo situation of preferential secretion of FSH, it may be possible in future to perform functional studies using this system to elucidate the cellular and molecular mechanisms involved in the development of an imbalance in gonadotroph cells preferentially overproducing FSH in NFPAs.

Fetal gonadotrope cell origin of FSH‐secreting pituitary adenoma – insight into human pituitary tumour pathogenesis

“…6,7,[17][18][19][20][21] It has been recently reported that many nonfunctioning pituitary adenomas display predominant FSH secretion compared to LH, but this has not been explained. 22 In our case, detailed analysis of the tumour tissue afforded an unusual insight into the nature of the pituitary disease, and may have implications for understanding the origins of pituitary adenomas.…”

Macroorchidism and Panhypopituitarism: Two Different Forms of Presentation of FSH-Secreting Pituitary Adenomas in Adolescence

“…In our second case, FSH levels were higher than in case 1, however, interestingly, the biological effects of FSH were not clinically evident, testicular volume was not enlarged and inhibin B values were proportionally lower, suggesting defective peripheral FSH activity. These two different forms of presentation (presence or absence of macroorchidism) could be explained either by secretion of less biologically active FSH [5,17] or by different FSH sensitivity due to loss or gain of function mutations in the hFSHR gene or its regulatory regions [20]. Unfortunately, in our second case, FSH bioactivity was not studied either in vivo or in vitro.…”

“…Prolactin- and ACTH-secreting adenomas are the most frequent subtypes, however gonadotrophin-secreting adenomas are extremely rare, accounting for less than 3–6% of all pituitary adenomas in children [1,3,4]. The use of immunohistochemistry in surgically-removed specimens in adults has revealed that these tumors represent 15–20% of pituitary adenomas and that most clinically non-functioning adenomas have positive immunohistochemistry for gonadotrophins [5]. While FSH secretion is the most common, clinical manifestations of FSH hypersecretion, such as macroorchidism or ovarian cysts, are not always present owing to inefficient and/or insufficient secretion.…”

Recent Clinical and Pathophysiological Advances in Non-Functioning Pituitary Adenomas

“…There are, however, indications that the majority – probably all – of these tumours are of gonadotropic cell origin [11]. Interestingly, there is a correlation between pre-operative serum gonadotropin levels and the in vitro release of hormones in cultures of surgically removed tissue from patients with NFPA, suggesting that, although they may not be clinically relevant, biochemically detectable release is present in some cases [12], similar to other ‘whispering adenomas’ (see below). In addition, there is a preferential secretion of follicle-stimulating hormone over luteinizing hormone both in vitro and in vivo.…”