To further investigate how sex steroids regulate galanin (GAL) in the rat pituitary and hypothalamus, we examined the effects of prepubertal gonadectomy (Gx) and long-term (9 weeks) replacement with ...estradiol (E2) or testosterone (T) on pituitary and hypothalamic GAL concentrations in Wistar rats (5-6/group). Sham-operated animals served as controls (CTR). Pituitary GAL concentration was markedly higher in random-cycling CTR-females than in CTR-males (1391 +/- 247 vs 39 +/- 5 pg/mg protein, P < 0.01) and decreased after Gx only in females (20 +/- 3 pg/mg protein, P < 0.01). E2 strongly increased pituitary GAL in Gx-females and Gx-males (4470 +/- 365 and 3853 +/- 347 pg/mg protein, P < 0.01), whereas T had no effect. Inversely, hypothalamic GAL was higher in CTR males than in CTR females (5.4 +/- 0.3 vs 4.0 +/- 0.5 ng/mg protein, P < 0.05), and decreased significantly after gonadectomy in males (3.7 +/- 0.2 ng/mg protein, P < 0.01). The only steroid treatment that significantly modified hypothalamic GAL in Gx animals was administration of E2 to females (5.7 +/- 0.4 ng/mg protein, P < 0.01 vs non-treated Gx). We also studied in hypophysectomized (Hx) rats (8/group) the effects of sex steroids on hypothalamic GAL concentration and distribution. The low hypothalamic GAL concentration observed in male and female Hx rats (1.0 +/- 0.1 ng/mg protein) was significantly increased by T in males and in females (respectively, by 40% and by 50%, P < 0.02) and by E2 in males (by 60%, P < 0.02).
The combination of hypertension, hypokaliemia, and male pseudohermaphroditism or amenorrhea must prompt a search for a rare adrenal enzymatic defect, 17 alpha-hydroxylase/17,20-lyase deficiency. This ...is a report of the observation of a male patient in whom this rare deficit was diagnosed in adulthood on the basis of lifelong ambiguous external genitalia, hypogonadism, severe hypertension, bilateral adrenal hyperplasia, and biological markers evoking an excess of mineralocorticoids without hyperaldosteronism.
To investigate possible sex differences in the feedback regulation of growth hormone (GH) secretion, concentrations of immunoreactive GH-releasing hormone (GRF) and somatostatin (SS) were measured in ...the median eminence (ME) and the hypothalamus of male and female rats bearing the MtTW15 tumor, which secretes high amounts of GH and prolactin (PRL). Four weeks after tumor implantation in male rats, the GRF concentration in the whole hypothalamus, including the ME, was decreased by 37% (0.29 +/- 0.02 vs. 0.46 +/- 0.02 ng/mg protein in intact male controls; p less than 0.001) and the concentration of SS was increased by 40% (11.5 +/- 0.7 vs. 8.1 +/- 0.3 ng/mg protein in male controls; p less than 0.01). In female rats, the presence of tumor for 4 weeks caused a smaller (18%) reduction in GRF concentrations (0.27 +/- 0.02 vs. 0.33 +/- 0.03 ng/mg protein in intact female controls; p less than 0.05) and no significant change in SS concentrations (10.2 +/- 0.08 vs. 9.7 +/- 0.8 ng/mg protein in female controls). Tumor-related changes in GRF and SS concentrations were also more pronounced in male rats than in females, when determined separately in the microdissected ME and in the remaining hypothalamus. These differences occurred despite similar increases in serum GH, PRL and insulin-like growth factor I concentrations in male and female tumor-bearing rats. To assess which hormone (GH or PRL) was responsible for these changes, intact male rats were treated for 10 days with 2 daily s.c. injections of rat GH (rGH; 100 and 250 micrograms/day), rat PRL (100 and 250 micrograms/day) or vehicle.
Many hyperprolactinemic patients do not tolerate bromocriptine or other dopamine agonists and, even if they do, often must take them two or three times each day. Cabergoline is a long-lasting ...dopamine agonist whose action lasts up to 2 weeks after a single dose so that it may be taken once or twice a week. This study evaluated cabergoline in 353 women and 102 men with pathologic hyperprolactinemia. Roughly 40 percent of the group had a microadenoma, and the same proportion had a macroadenoma. No cause was evident in 16 percent of cases. Of 292 patients who previously had received bromocriptine, 140 were intolerant and 58 were resistant to the drug. The median baseline serum prolactin was 124 μg/liter. Cabergoline therapy usually began at a dose of 0.25 or 0.5 mg twice weekly, and the dose was adjusted at 2- to 3-month intervals as needed to consistently reduce the prolactin level. Patients then were followed up every 4 to 6 months.Menstrual function became normal during cabergoline therapy in 89 percent of the women evaluated, several of whom became pregnant and delivered healthy children. The visual fields became normal in 70 percent of 47 patients. Migraine symptoms lessened significantly in 72 percent of 71 patients. Prolactin levels became normal in 86 percent of all patients and decreased by 75 percent or more in more than half of the others. The median lowest serum prolactin level, achieved in 8 months on average, was 5.6 μg/liter. The tumor shrank to some degree in two thirds of patients. At the end of follow-up, the median dose of cabergoline was 0.5 mg/week. Minor side effects were reported by 8.5 percent of patients, and major or persistent symptoms were reported by 4 percent. Headache and postural hypotension were the most common adverse effects. Of the 14 patients who withdrew because of intolerance, 12 had also failed to tolerate bromocriptine. Only 9 percent of bromocriptine-intolerant patients were also intolerant of cabergoline. Patients harboring a microprolactinoma required lower doses and were more likely than those with macroadenomas to achieve a normal serum prolactin level. The baseline and lowest serum prolactin levels correlated weakly but significantly. In more than two thirds of patients who had been resistant to bromocriptine, control was achieved with cabergoline. This large-scale study affirms the effectiveness and tolerance of cabergoline when used to treat pathologic hyperprolactinemia.J Clin Endocrinol Metab 1999;84:2518–2522
Sex differences in the hypothalamic control of growth hormone (GH) secretion were investigated by measuring rat GH-releasing factor (rGRF) and somatostatin in male and female rats. Rat GRF-like ...immunoreactivity (rGRF-IR) was higher in the median eminence and hypothalamic tissue outside of the median eminence of adult (90-day-old) male compared to female rats. A similar pattern of rGRF-IR content was found in the median eminence of 35-day-old rats. This sex difference developed between days 25 and 35 of age, during which time serum concentrations of insulin-like growth factor (IGF-1) and body weight increased in both sexes. To a lesser extent, the content of somatostatin-like immunoreactivity (SLI) was higher in the median eminence of adult female rats compared to male rats. Whole hypothalamic rGRF-IR and SLI contents were influenced only moderately by adult gonadectomy or gonadal steroid treatments. For example, estrogen increased rGRF-IR content in castrated rats, but orchidectomy alone or orchidectomy followed by testosterone did not influence rGRF-IR content. Additionally, whole hypothalamic SLI content was unaffected by orchidectomy or orchidectomy followed by testosterone or estrogen. One month after ovariectomy, rGRF-IR and SLI in whole hypothalamic fragments were similar to their respective contents in gonad-intact males. However, ovariectomy followed by estrogen or testosterone did not restore rGRF-IR content and partially restored SLI content to levels seen in gonad-intact females.
To investigate whether pituitary-dependent hormones may regulate galanin (GAL) content, synthesis and distribution in the hypothalamus, female hypophysectomized Wistar rats were treated for 2 weeks ...with subcutaneous injections of thyroxine (T4, 2 x 1 microgram), bovine growth hormone (GH, 2 x 125 micrograms), cortisol (C, 50 micrograms), subcutaneous implants of beta-estradiol (E2, 5-mm implant, dilution 1:1), or with the combinations T4+GH, T4+GH+C+E2 or T4+GH+C+E2 + rat PRL, 2 x 125 micrograms (doses/100 g BW/day). Concentrations of GAL in the hypothalamus were measured by radioimmunoassay (RIA) and GAL mRNA abundance was quantified by Northern blot (6 rats/group); 2 rats/group were used for immunohistochemistry. Hypophysectomy caused decreases of hypothalamic GAL peptide and mRNA concentrations (by 70 and 50%, respectively; p < 0.05 vs. intact rats). GAL immunoreactivity disappeared in the median eminence (ME), but increased in the neurohypophyseal magnocellular neurons of hypophysectomized rats. Substitution with T4, GH, T4+GH, C or E2 had no significant effect on total hypothalamic GAL peptide and GAL mRNA concentrations. A treatment combining T4+GH+C+E2 increased hypothalamic GAL (1.9 +/- 0.1 vs. 1.2 +/- 0.1 ng/mg protein in untreated hypophysectomized rats; p < 0.01) and GAL mRNA concentrations (127 +/- 19 vs. 59 +/- 2 densitometric units in untreated rats, p < 0.001). Addition of PRL to this combined treatment had no further effect. Treatment with T4, GH, T4+GH or E2 enhanced GAL labeling in the ME of hypophysectomized rats. The effect of estrogens was restricted to the GnRH-rich lateral regions of the ME. The combined treatment with T4+GH+C+E2 restored the ME GAL immunoreactivity to levels observed in intact rats. In contrast, the increased GAL labeling observed in magnocellular neurons after hypophysectomy was not influenced by any hormonal treatment. In conclusion, hypophysectomy leads to marked reductions of hypothalamic GAL and GAL mRNA concentrations, and of GAL immunoreactivity in the ME. These reductions are prevented in part by a combined hormonal treatment associating T4, GH, C and E2, but not by any hormone given alone. This suggests specific pituitary hormone-dependent regulation of the hypophysiotropic GAL neurons. In contrast, the increased GAL labeling in magnocellular neurons of hypophysectomized rats persists despite hormonal treatment and likely represents a lesional effect on the neurohypophyseal GAL system.
To understand better the relationship between hypothalamic galaninergic neurons and the pituitary gland, we studied the effects of hypophysectomy on hypothalamic galanin (GAL) content and ...distribution by radioimmunoassay and immunohistochemistry, and on GAL mRNA by Northern blot analysis. Three weeks after hypophysectomy, performed at 5 or 8 weeks of age, the hypothalamic concentrations of GAL and GAL mRNA were reduced by 30-50% in both male and female rats, compared to age- and sex-matched controls. Similar reverse-phase HPLC retention times of hypothalamic GAL were observed in intact and hypophysectomized rats. The reduction of hypothalamic GAL concentration following hypophysectomy was time-dependent, as peptide levels were unaffected one week after surgery. Immunohistochemistry showed regional differences in the effect of hypophysectomy on galaninergic neurons. In the hypophysiotropic hypothalamus, the scarce GAL immunoreactivity normally observed in the arcuate nuclei was no longer detectable in hypophysectomized rats, and the intense GAL immunoreactivity of the external zone of the median eminence progressively decreased and completely disappeared 3 and 6 weeks after hypophysectomy. In contrast, in the neurohypophyseal system, there was an increase of GAL labelling of the perikarya and emerging axons in the supraoptic and lateral-paraventricular nuclei, 1 and 3 weeks after hypophysectomy, that disappeared 6 weeks after hypophysectomy. An increase of GAL immunoreactivity was also observed in the internal zone of the median eminence 1 week but not 3 weeks after hypophysectomy. We conclude that hypophysectomy reduces the content of GAL and GAL mRNA in the rat hypothalamus. These changes are time-dependent and clearly detected after 3 weeks. The neurohypophyseal and hypophysiotropic galaninergic systems respond differently to hypophysectomy.
Galanin (GAL) is a 29-amino acid peptide implicated in neuroendocrine regulation of prolactin, growth hormone and thyrotropin in the rat. GAL-like immunoreactivity and GAL messenger RNA (mRNA) are ...present in the anterior pituitary (AP) and hypothalamus and the expression of GAL mRNA has been shown to be modulated by peripheral gonadal steroid hormones. In view of possible interactions between members of the steroid/thyroid hormone receptor family and recent data suggesting an effect of GAL on thyrotropin secretion, we investigated the possible influence of thyroid status on GAL concentrations in the hypothalamus and AP of the male rat. Three weeks after the surgical removal of the thyroid gland from male rats, the concentrations of GAL in the median eminence (ME) and AP were reduced 54 and 65%, respectively. Similarly, GAL concentrations were decreased 39% in the ME and 69% in the AP of animals rendered hypothyroid by treatment with propylthiouracil (PTU). The effects of PTU treatment in both regions were reversed by daily T4 injections (50 micrograms/kg). The effects of PTU in the ME were reversed after 2 weeks of T4 treatment, whereas 3 weeks of replacement therapy were required to restore GAL concentrations in the AP. However, T4 treatment of intact control animals did not influence GAL concentrations. This study demonstrates that the presence of thyroid hormones is required for the maintenance of physiological concentrations of GAL in the hypothalamus and AP of the rat. These data also suggest that GAL may be involved in the negative feedback regulation of the hypothalamohypophysial-thyroid axis.
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