Persistence of hyperprolactinemia after treatment of primary hypothyroidism and withdrawal of long term use of estrogen: are the tuberoinfundibular dopaminergic neurons permanently lesioned?

Long term use of high doses of estrogen and the presence of chronic hyperprolactinemia may, at least in the rat, provoke lesions in the tuberoinfundibular dopaminergic (TIDA) neurons responsible for the control of prolactin (Prl) secretion. This occurrence, which is not yet well documented in humans, may have taken place in a patient on chronic oral hormonal contraceptive (OC) treatment who was seen for primary hypothyroidism, hyperprolactinemia and a pituitary mass. After thyroid hormone replacement, OC withdrawn and bromocriptine treatment, this patient could not maintain normal Prl levels, unless continuously treated with a dopaminergic agonist even when MRI was indicative of a normal situation. Function of TIDA neurons was investigated by TRH test (200 microg IV) performed before and after treatment with 25 mg carbidopa plus 250 mg L-dopa every 4 hours for one day. Basal TSH was normal (3.9 microU/mL) whereas basal Prl was high (67.5 ng/mL); both TSH and Prl levels appropriately increased after TRH: peaks 31.8 microU/mL and 157.8 ng/mL, respectively. After treatment with carbidopa/L-dopa, basal TSH (1.6 microU/mL) and Prl (34 ng/mL) decreased and the response to TRH was partially blocked (10.3 microU/mL and 61 ng/mL, respectively). In spite of a normal response, we discuss the possibility that the persistence of hyperprolactinemia is due to lesion of the TIDA neurons produced by the long term use of high doses of estrogens and by the presence of chronic hyperprolactinemia

A prospective longitudinal study of Pasireotide in Nelson's syndrome

PURPOSE: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome. METHODS: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly. RESULTS: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p < 0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI - 45.2 to - 7.1, p < 0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4 ± 0.9 vs. 1.3 ± 1.0, p = 0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients. CONCLUSIONS: Pasireotide lowers plasma ACTH levels in patients with Nelson's syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume. TRIAL REGISTRATION: Clinical Trials.gov ID, NCT01617733

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

Effect of oestrus cyclicity on the number of brain opioid mu receptors in the rat

The present experiments have been performed in order to analyse whether the binding characteristics of brain opioid receptors of the mu type vary during the different phases of the oestrous cycle in the female rat. To this purpose different groups of females with a regular 4-day oestrous cycle were killed by decapitation in different phases of their oestrous cycle, i.e. at 10.00 and 16.00 h of the first and second day of dioestrus, at 10.00, 12.00, 14.00, 16.00 18.00 and 20.00 of the day of pro-oestrus, and at 10.00, 12.00 14.00, 16.00 and 18.00 of the day of oestrus. The total brains, after discarding the cerebellum, were homogenized and crude membrane preparations were obtained. On these preparations the maximal binding capacity (Bmax, index of the number of receptors) and the constant of affinity (Ka) for dihydromorphine, a typical ligand of mu opioid receptors were evaluated. Serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin were measured by specific radioimmunoassays in order to exactly ascertain the different phases of the oestrous cycle. The results obtained show that the number of mu opioid receptors in the whole brain presents significant changes during the different phases of the oestrous cycle. In particular, an increase in the concentration of these receptors was observed at 12.00 h of the day of pro-oestrus and at 18.00 h of the day of oestrus; these fluctuations of the number of mu receptors were not accompanied by any change of their affinity for the ligand.(ABSTRACT TRUNCATED AT 250 WORDS