lhrh--n-ac-2-nal(1)-4-cl-phe(2)-trp(3)-hci(6)-alanh2(10)- and Adenoma

As they are clinically silent, gonadotroph cell pituitary adenomas are usually diagnosed only when pituitary enlargement causes visual impairment or hypopituitarism. In postmenopausal women presenting with pituitary tumors it can be difficult to determine whether gonadotropin hypersecretion is due to adenomatous or normal gonadotrophs prior to surgery. The usual GnRH dependency of gonadotropin secretion may be of diagnostic and therapeutic value. We therefore evaluated responses to the GnRH antagonist Nal-Glu-GnRH and to the long-acting GnRH agonist D-Trp6 (3.75 mg IM) in 9 and 4 patients with FSH- and/or alpha-subunit-secreting adenomas, respectively. Six of the 7 patients with FSH-secreting adenomas and one of the 2 patients with pure alpha subunit-secreting adenomas were studied postoperatively. In these patients postoperative FSH and/or alpha-subunit levels remained elevated and pituitary imaging by CT-scan and/or MRI disclosed tumoral residues. In the 2 remaining patients testing was performed preoperatively. A single administration of 5 mg Nal-Glu to the 7 patients with FSH-secreting adenomas produced a slight but significant fall in above-normal FSH levels from 24.4 +/- 15.4 IU/l to a nadir of 20.3 +/- 11.9 IU/l (-17%, p < 0.05) 20 h following the injection. LH levels fell markedly in the 6 patients with normal basal serum LH concentrations to those observed in hypophysectomized patients, while mean alpha-subunit levels were not modified. Alpha-subunit levels were not modified by Nal-Glu administration in the 2 patients with alpha-subunit-secreting adenomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenoma; Adult; Aged; Capsules; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Immunohistochemistry; Injections, Subcutaneous; Luteinizing Hormone; Male; Middle Aged; Pituitary Neoplasms; Testosterone; Time Factors; Tomography, X-Ray Computed

The clinical manifestations of gonadotroph adenomas are almost always neurological, consequences of their large size, and are rarely endocrinological. We report an exception, a 39-yr-old woman whose gonadotroph adenoma caused supranormal serum concentrations of FSH, which resulted in the development of multiple ovarian cysts, persistent elevation of her serum estradiol concentration, and endometrial hyperplasia. She initially presented because of amenorrhea at age 30 yr and was treated for an intrasellar mass by transsphenoidal surgery at age 31 yr and again at age 36 yr. Before and after the second operation she had persistently supranormal plasma estradiol concentrations (> 1840 pmol/L) and endometrial hyperplasia. When she was evaluated at age 39 yr, transvaginal ultrasound showed multiple ovarian cysts and endometrial thickening. Her plasma estradiol level was markedly supranormal (2160 pmol/L), FSH was mildly supranormal (17.8 IU/L), and alpha-subunit was markedly supranormal (23.3 micrograms/L). Characteristic of gonadotroph adenomas, her LH beta level increased by 69% in response to TRH. Neither FSH nor alpha-subunit decreased in response to administration of the GnRH antagonist, Nal-Glu-GnRH (5 mg/12 h for 4 weeks). Excised adenoma tissue exhibited morphological features of a gonadotroph adenoma. This patient appears to be unique, in that her gonadotroph adenoma caused slightly, but persistently, supranormal concentrations of FSH, which caused ovarian stimulation, including supranormal plasma estradiol concentrations, multiple ovarian cysts, and endometrial hyperplasia. We propose that gonadotroph adenomas be considered in the differential diagnosis of patients who have this constellation of abnormalities.

Topics: Adenoma; Adult; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Ovarian Hyperstimulation Syndrome; Pituitary Neoplasms; Thyrotropin-Releasing Hormone; Ultrasonography

Because administration for 1 week of the GnRH antagonist Nal-Glu GnRH had been shown to decrease FSH secretion from supranormal to normal in men with gonadotroph adenomas, we investigated the effect of prolonged administration of Nal-Glu on the size of gonadotroph adenomas. To quantitate the effect of Nal-Glu GnRH on gonadotroph adenoma size, we first developed a technique for calculating adenoma volume. The technique involved collecting magnetic resonance (MR) imaging data from each adenoma at 1-mm slice intervals in the coronal, axial, and sagittal views and using the Softvu computer program to calculate adenoma volume from the MR data. The precision of this technique, as judged by the coefficients of variation of the calculations of the same view of the same study three times, was 1.7%, 1.0%, and 1.0% for each of three studies. When Nal-Glu GnRH (5 mg, sc, every 12 h) was self-administered for 3-12 months to five men with gonadotroph adenomas and supra-normal serum FSH concentrations, the serum FSH concentrations decreased to normal or below normal for the entire treatment period. Adenoma size, however, did not change during treatment in any of the five men. We conclude that calculating pituitary adenoma volume from MR data using the Softvu computer program is a highly reproducible technique, but that Nal-Glu GnRH is not an effective treatment for reducing gonadotroph adenoma size. The failure of Nal-Glu to reduce adenoma size despite its success in reducing FSH secretion suggests that FSH secretion from gonadotroph adenomas is dependent on endogenous GnRH, but growth of gonadotroph adenomas is not.

Topics: Adenoma; Adult; Aged; Basophils; Endocrinology; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Pituitary Gland; Pituitary Neoplasms; Vision, Ocular

As a preliminary step in searching for a pharmacological treatment for gonadotroph adenomas, we administered the GnRH antagonist analog Nal-Glu GnRH to five patients, four men and a woman, with FSH-secreting gonadotroph adenomas in order to determine its effect on FSH secretion. Administration of a single 10-mg dose of Nal-Glu GnRH to four of the patients produced a significant decrease in the serum FSH concentration in two patients and returned the FSH level to normal in only one. Administration of 5 mg Nal-Glu every 12 h for 7 days, however, produced a significant (P less than 0.001) decrease, and to within the normal range, in four of the five patients (mean +/- SEM, 32.7 +/- 5.6 IU/L during the 3 days before treatment and 9.8 +/- 1.4 IU/L during the last 3 days of treatment). Also, in response to the 7-day treatment, LH fell significantly in all five patients, alpha-subunit fell in three, and testosterone fell in all four men. Administration for 6 weeks of the GnRH agonist analog leuprolide did not decrease the serum FSH concentration of one of the patients whose serum FSH did decrease in response to Nal-Glu GnRH. We conclude that repetitive administration of Nal-Glu GnRH may often inhibit FSH secretion by gonadotroph adenomas and that FSH secretion by gonadotroph adenomas may be dependent on endogenous GnRH secretion.

Topics: Adenoma; Adult; Aged; Amino Acid Sequence; Dose-Response Relationship, Drug; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Molecular Sequence Data; Paraneoplastic Endocrine Syndromes; Pituitary Neoplasms; Testosterone; Time Factors; Tumor Cells, Cultured