Impaired estrogen-induced negative feedback on gonadotropin secretion in patients with gonadotropin-secreting and nonfunctioning pituitary adenomas.

BACKGROUND: Several in vitro studies suggest that gonadotropin-secreting pituitary adenomas (Gn-omas) and non functioning pituitary adenomas (NFPA) originate from gonadotroph cells. Patients with Gn-oma and NFPA frequently show abnormal gonadotropin response to TRH. The aim of the study was to investigate whether the estrogen-induced negative feedback is operating in either patients with Gn-oma or NFPA. MATERIALS AND METHODS: Serum gonadotropin levels were evaluated at 24 h after ethinylestradiol administration (1 mg per os; EE2 test) in seven patients with a diagnosis of Gn-oma, based on the presence of high follicle-stimulating hormone (FSH) and/or lutenising hormone (LH) levels with normal or high levels of sex steroids, in 22 patients with NFPA with normal or low levels of gonadotropin and sex steroids, and 30 sex- and age-matched healthy subjects. A normal response to EE2 test was arbitrarily defined as a serum LH and FSH decrease of at least 40 and 30% below basal levels. RESULTS: Among patients with Gn-oma, only one had a normal FSH inhibition and another, a normal LH inhibition. Among the 22 patients with NFPA, the EE2 test caused a normal FSH or LH reduction in 10 and 15, respectively, while a normal reduction of both FSH and LH was observed in nine. CONCLUSIONS: The study demonstrates that estrogen-induced negative feedback of gonadotropin secretion is disrupted in almost all patients with Gn-oma and in half of those with NFPA. This defective feedback is reminiscent of the resistance to thyroid hormones and glucocorticoids observed in patients with thyroid-stimulating hormone- (TSH-) and adrenocorticotropic hormone- (ACTH-)secreting adenomas, respectively.

Comparison between buserelin and dexamethasone testing in the assessment of hirsutism.

Many hirsute women may present a form of functional ovarian hyperandrogenism (FOH), since they show an exaggerated 17-hydroxyprogesterone (17-OHP) response to GnRH agonists administration. As the failure of dexamethasone to reduce testosterone levels may be indicative of an ovarian source of androgen secretion, we evaluated the usefulness of dexamethasone suppression test, in comparison with buserelin challenge, in the assessment of hirsutism. Twenty-seven hirsute women (aged 15-42 yr) underwent ACTH and buserelin tests: 4 patients were heterozygotes for 21-OH deficiency and 8 patients were affected with FOH: 2 of the patients with hyperresponse to buserelin also had 21-hydroxylase deficiency. The results of the dexamethasone suppression test (2 mg/day for 7 days) were compared to those obtained after buserelin test. Basal T and delta4 levels (mean+/-SE) were higher than in controls (4.2+/-0.5 vs 2.2+/-0.2 nmol/l and 10.9+/-0.9 vs 5.9+/-0.6 nmol/l, p<0.02), while no differences were found in 17-OHP and DHEAS levels. A significant reduction (p<0.001) in T (1.8+/-0.4 nmol/l), delta4 (3.2+/-0.5 nmol/l) and DHEAS levels (2.4+/-0.3 micromol/l) was observed at the 3rd day of dexamethasone administration and no differences between sampling at 3rd, 5th and 7th day were found. Serum T was not suppressed in 6 cases, delta4 and DHEAS levels in 3 and 1 of them, respectively. Buserelin injection caused an excessive 17-OHP response in 8 patients, only 4 of them did not reduce T levels during dexamethasone. The sensitivity and specificity of the dexamethasone suppression test, with respect to the buserelin test, were 50% and 89%, respectively. In conclusion, 37% of hirsute patients had an abnormal responsiveness to buserelin and/or ACTH tests, indicating that hormonal investigations are mandatory. An ovarian origin of hirsutism was identified by buserelin test in 30% of patients and by dexamethasone in 22% of cases; only 4 of 8 patients showed concordant results to both tests. Therefore, buserelin challenge seems a more useful, cost-effective and less time consuming tool than dexamethasone administration in order to recognize the possible ovarian origin of hyperandrogenism.

Assessment of cure and recurrence after pituitary surgery for Cushing's disease.

BACKGROUND: The treatment of choice in Cushing's disease is transsphenoidal adenomectomy with a recurrence rate ranging 9-23%. We investigated whether abnormal hormonal responses may predict the relapse in "operated" patients followed-up for a long period. METHOD: Sixty-eight surgically treated patients with Cushing's disease were followed-up for 12-252 months. Forty-eight patients underwent selective adenomectomy, 17 enlarged adenomectomy and 3 underwent total hypophysectomy. After surgery ACTH and cortisol levels were measured after stimulatory (desmopressin and CRH) and inhibitory tests (dexamethasone and loperamide). FINDINGS: After operation 46 patients were cured (group A), 15 patients only normalized cortisol levels (group B), 7 patients were surgical failures. During the follow-up, a disease-free condition was maintained in 48 of 61 cases (79%), while a recurrence occurred in 13 patients (21%, 5 of group A and 8 of group B). In 5/13 patients who relapsed an absent inhibition after dexamethasone and an exaggerated response to CRH test preceded the recurrence. In 5 other patients the relapse was suspected by loperamide test. In the 3 remaining cases, positive responses to desmopressin preceded the recurrence. In 7/13 patients who relapsed the pituitary tumour was visualized by MRI/CT imaging. INTERPRETATION: During the follow-up a careful assessment of ACTH dynamics is needed. Although no single test can reliably predict the late outcome, individual patients at risk for relapse may be identified by abnormal responses to desmopressin, CRH and loperamide tests; particularly, the persistent responsiveness to desmopressin may be a criterion of risk for recurrence in patients who only normalized cortisol levels after surgery.

The one microgram adrenocorticotropin test in the assessment of hypothalamic-pituitary-adrenal function.

The possibility of assessing hypothalamic-pituitary-adrenal (HPA) function by the standard ACTH test (250 microg) has been widely discussed in the past years and compared with the role of the insulin tolerance test (ITT). Recently, it was shown that low doses of ACTH, such as 1 microg i.v., induce a maximal adrenal response and, by reducing the discrepancies compared with the ITT also allow one to detect mild forms of secondary hypoadrenalism. In the present study the 1 microg ACTH test was performed in patients with hypothalamic-pituitary disease in order to assess adrenal function, and the results have been compared with those obtained after the insulin test. Fifty-seven patients (31 men and 26 women, aged 19-73 years) with hypothalamic-pituitary diseases were studied: 51 patients were affected with pituitary tumor and 6 patients had hypothalamic disorders. All these patients and 18 healthy volunteers (7 men and 11 women, aged 19-46 years) received 1 microg i.v. ACTH injection. In addition, the ITT (0.1-0.15 U/kg body weight) was performed in all patients. In normal subjects mean cortisol levels significantly (P<0.001) increased from a baseline of 393+/-43 nmol/l to a peak of 770+/-41 nmol/l after 1 microg ACTH. In 44 patients with hypothalamic-pituitary disease 1 microg ACTH caused a cortisol rise similar to that of normal subjects (from 332+/-17 to 769+/-24 nmol/l; P<0.001), while an impaired response (from 124+/-23 to 312+/-46 nmol/l) was observed in 13 cases (23%), 7 of them with low morning cortisol levels (10-127 nmol/l) and 6 with basal values at the lower limit of normality. The cortisol response to ITT was compared with that obtained after the 1 microg ACTH test: 10 patients failed both challenges, 4 patients who passed the ACTH test failed the ITT, while 3 patients who failed the ACTH test passed the ITT. The 23 out of 57 patients (40%) who showed a cortisol peak greater than 750 nmol/l after 1 microg ACTH had a normal response to ITT. A positive correlation between cortisol peaks after ACTH and after insulin was also found (r = 0.68, P<0.001). Assuming a 100% accuracy of ITT, the low dose ACTH test yielded a 71% sensitivity and a 93% specificity. In conclusion, the low-dose ACTH test is a useful, safe and inexpensive tool for the initial assessment of HPA function in patients with hypothalamic-pituitary disease. In fact, the ITT is unnecessary when cortisol peaks are greater than 750 nmol/l after 1 microg ACTH and also when very low cortisol basal levels indicate an overt hypoadrenalism. Within these limits the ITT is mandatory and its important role in the recognition of secondary adrenal failure is further confirmed.

[Assessment of bone resorption/neoformation indexes in obese women before and after weight loss]. / Valutazione degli indici di riassorbimento/neoformazione ossea in donne obese prima e dopo riduzione ponderale.

Serum osteocalcin and alkaline phosphatase levels, as indexes of bone formation, and urinary calcium and hydroxyproline excretions relative to creatinine, as indexes of bone resorption, were measured in 10 obese women before and after two months of hypocaloric diet. In basal condition, serum osteocalcin, but not alkaline phosphatase levels, were higher in obese than in controls (7 +/- 0.4 vs 5.3 +/- 0.2 ng/ml). Urinary calcium/creatinine and hydroxyproline/creatinine ratios were also significantly higher than those in normals (0.37 +/- 0.05 vs 0.2 +/- 0.01 and 0.035 +/- 0.004 vs 0.02 +/- 0.002, respectively). After weight loss, serum osteocalcin significantly increased (9.5 +/- 0.5 ng/ml), while urinary calcium/creatinine and hydroxyproline/creatinine ratios fell to the normal values (0.23 +/- 0.03 and 0.026 +/- 0.001). In conclusion, it appears that obesity, at least in young women, is associated with a high bone turnover, which seems to be reversible with weight loss.