Functioning Gonadotroph Adenomas Research Articles

Diagnosis and treatment of functioning gonadotroph adenomas

Functioning gonadotroph adenomas(FGA) are pituitary tumors secreting biologically active gonadotropins. Because of its low incidence, it can be diagnosed only in evident clinical manifestations, and clinicians are often not able to make right diagnosis. The published literature includes only small case series or individual case reports. In this review, we will focus on the main presenting manifestations, the reported management options, and the long-term outcome of the FGA. (Chin J Endocrinol Metab, 2015, 31: 921-924) Key words: Functioning gonadotroph adenomas; FSH-secreting adenomas; LH-secreting adenomas; Ovarian hyperstimulation; Testicular enlargement; Precocious puberty

Clinical review: Functioning gonadotroph adenomas.

Functioning gonadotroph adenomas (FGAs) are pituitary tumors secreting biologically active gonadotropins. The published literature includes only small case series or individual case reports. This review summarizes the published data on this rare entity and, based on them, suggests guidance on the follow-up of these patients. A review of articles in English retrieved from the PubMed up to December 2013 was conducted. The following terms were used for the search: "functioning gonadotroph adenomas," "FSH secreting adenomas," "LH secreting adenomas," "gonadotroph adenomas," "ovarian hyperstimulation," "macroorchidism," "testicular enlargement," and "precocious puberty." All reported cases of FGA were assessed, and information on presenting manifestations, management approaches, and long-term outcome was reviewed. FGAs cause distinct manifestations and, based on the limited published literature, they are mostly macroadenomas. Their pathogenesis remains enigmatic. Systematic series on their optimal management are lacking, but the primary therapy remains surgical excision of the adenoma. Given the risk of recurrence, long-term clinical and imaging follow-up is needed, and radiotherapy may be required. There is little evidence that medical therapies are particularly helpful, certainly in terms of tumor control. Central registration would enhance our insight regarding their pathology and optimal management.

The GnRH receptor gene is preferentially expressed in functioning gonadotroph adenomas and displays a Mae III polymorphism site.

Given the central role of the GnRH receptor (GnRHR) in the regulation of the gonadotrophin secretion, it might be implicated directly or indirectly in the pathogenesis of gonadotroph tumours. We determined if GnRHR mRNA was expressed in gonadotroph tumours using RT-PCR and analysed the GnRHR gene for the presence of mutations in its coding region, using direct sequencing of PCR products. Results were analysed according to the pattern of expression of alpha, beta-FSH and beta-LH subunit (SU) genes. RNA was extracted from 20 gonadotroph tumours identified by immunohistochemistry (> 10% of stained cells): 9 adenomas were functioning (high serum gonadotrophin levels), 3 were associated with high alpha-SU levels and 8 were nonfunctioning. Genomic DNA was extracted from 64 normal subjects. We found GnRHR mRNA in 12 tumours (60%): 8/9 functioning (88%), 1/3 alpha-secreting (33%) and 3/8 nonfunctioning (37.5%) gonadotroph adenomas. There was a significant association between GnRHR expression and immunostaining for beta-FSH (P = 0.014). The nucleotide sequence of the amplified products was identical to that of human pituitary except for the presence, in 3 functioning adenomas, of a silent C to T transition at nucleotide 453 encoding for the serine residue situated in the second intracellular loop at position 151. Heterozygosity provided evidence that both alleles were transcribed in these tumours. This substitution creates a Mae III restriction site. Genomic DNA from normal subjects were then tested for the presence of this new polymorphism. The frequency of the heterozygosity (18.7%) was not significantly different from that found in gonadotroph tumours (25%) and this new Mae III polymorphism site cannot be used as a tumoural marker. The GnRHR gene is preferentially expressed in functioning rather than in nonfunctioning gonadotroph adenomas, but no mutations altering the coding region of the gene were found to further substantiate its role in the pathogenesis of gonadotroph tumours.