Vasomotor symptoms (VMS) such as hot flushes and night sweats are frequently encountered during menopause and can greatly reduce the quality of life. These symptoms are causally related to decreasing estradiol concentrations, mainly in the serum and subsequently also in the hypothalamic temperature regulating centre. The lack of estrogens alters neurotransmitter activity, especially in the serotonergic and noradrenergic pathways. Because sex steroids act as potent neuromodulators, the substitution of ovarian sex steroids by hormone replacement therapy is the most effective treatment option for VMS. When contraindications exist for the use of sex steroids, steroid-free drugs are a possible alternative. A better understanding of the physiology of thermoregulation, thermoregulatory dysfunction and adaptive processes of the brain may facilitate the development of new therapeutic approaches. Such drugs could then be used to treat vasomotor disorders even when the use of steroid hormones is contraindicated. This review article summarises our knowledge on the mechanisms of temperature regulation and describes deviations from this regulation during altered sex steroid conditions. Our current knowledge on neuroendocrinology of thermoregulation may serve as a basis for the use of steroid-free pharmacological intervention.

Although chronological aging is known to result in reduced gonadotropin secretion in women, the precise mechanisms to account for this neuroendocrine manifestation are yet obscure. To evaluate the extent to which the pituitary and/or hypothalamus are involved in the process of aging, we aimed at characterizing the unstimulated and GnRH-stimulated gonadotropin secretion in postmenopausal women (PMW) of different ages. Accordingly, 9 younger PMW (mean age: 53.8 years) in their first and 9 older PMW (mean age: 80.3 years) in their 4th decade of life after natural onset of menopause were studied. In both groups, blood was collected at 10-min intervals for 10 h, while GnRH (25 µg i.v.) was administered 8 h after initiation of blood samplings. Compared to younger PMW, basal serum concentrations of dehydroepiandrosterone-sulfate were lower (p < 0.05) in older PMW, while estrogen (estradiol, estrone), androgen (testosterone, androstendione) and sex hormone binding globulin levels were similar. Lower (p < 0.01) mean LH levels composed of attenuated (p < 0.05) LH pulse amplitudes and pulse frequencies (as determined by the cluster pulse algorithm) were found in the 8-hour LH secretory profiles of older PMW. Furthermore, the FSH secretion of older PMW was characterized by lower (p < 0.01) mean FSH levels with lower (p < 0.05) FSH pulse amplitudes, but not pulse frequencies. The absolute peak concentrations attained and the total amount of LH and FSH released in response to GnRH stimulations were blunted (p < 0.001) in older PMW. Similarly, the percentual GnRH-stimulated LH and FSH increases over preceding unstimulated basal concentrations were greater (p < 0.01) in younger than in older PMW. These observations indicate that the gonadotropin secretion is reduced during advanced age in PMW. This attenuated serum gonadotropin pulsatility found in older PMW is presumably the consequence of reduced release of hypothalamic GnRH and of a decreased sensitivity of the pituitary gonadotroph.

Neuropeptides such as gonadotrophin releasing hormone (GnRH) are presumed to play an important role in the regulation of the function and growth of human placenta. Knowledge about the placental site of GnRH expression and the eventual co-localization of its peptide with the GnRH receptor (GnRH-R) is crucial for a better understanding of possible autocrine/paracrine mechanisms. We therefore investigated these questions by use of in-situ reverse transcription-polymerase chain reaction (RT-PCR) alone or in combination with immunocytochemistry in human first and third trimester placentae. Paraffin-embedded placental sections (7 microm thick), or single trophoblasts in monolayer cultures for up to 3 days, were treated with proteinase K. Following RT with GnRH or GnRH-R specific oligoprimers, PCR was performed employing primers with exon-exon overlaps to exclude non-specific DNA amplification. Detection of the amplicons was accomplished by nested PCR which was performed with digoxigenin-labelled dUTP and nitroblue tetrazolium/5-bromo-4-chloro-3-indoyl-phosphate (NBT/BCIP) for substrate visualization. The GnRH peptide was detected using a sandwich-antibody assay. GnRH and GnRH-R gene expression was found in all first and third trimester placentae, with abundant signals for the GnRH and GnRH-R message both in the cyto- and syncytiotrophoblasts. Single trophoblasts of different gestational ages in culture also displayed GnRH expression in individual cytotrophoblasts and in syncytiotrophoblast-like fusionates. Additional immunostaining revealed GnRH peptide to be co-localized with GnRH-R message in trophoblast layers. Since messages for GnRH and GnRH-R were found in virtually all trophoblasts, we infer that GnRH and GnRH-R are co-expressed in identical cells. These data strongly suggest that the trophoblasts are the source of GnRH, and that there is autocrine/ paracrine regulation by GnRH in human placenta.

On the day of proestrus in the rat, rising plasma levels of estradiol (E) act in concert with progesterone (P) to trigger a preovulator y release of gonadotropins. Cellular levels of galanin mRNA in GnRH neurons are increased in association with the proestrous surge of gonadotropin secretion; however, the relative contribution made by E and P to the induction of galanin mRNA expression in GnRH neurons is unknown. We investigated the role of E and P in the induction of galanin gene expression in GnRH neurons by examining the effects of different combinations of E (estradiol benzoate; 50 mg and P (5 mg)) on the LH surge and the concomitant induction of galanin mRNA in GnRH neurons. We sacrificed ovariectomized adult rats after 1 of 4 treatments: Group 1: vehicle control (n=6); Group 2: P alone (n= 7) Group 3: E alone (n=7); Group 4: combined E/P (n=6); the animals were killed at 18.00 h at the time of the LH surge. The brains from these animals were processed by double-label in situ hybridization to allow measurement of galanin mRNA levels in GnRH neurons. GnRH neurons were identified with a digoxigenin-labeled cRNA probe for GnRH mRNA, and galanin mRNA was detected and measured simultaneously with an 35S-labeled cRNA probe coupled with computerized grain counting. Estimation of cellular levels of GnRH mRNA was accomplished with single-label in situ hybridization, an 35S-labeled GnRH cRNA probe and computerized grain counting. We observed a 3-fold induction of galanin mRNA in the GnRH neurons of animals treated with E alone compared with those treated with the vehicle alone (vehicle: 13±2 vs E: 42±4 grains/cell (g/c); P<0.01); LH levels in the E-treated animals were elevated, albeit moderately, with respect to the vehicle controls. Compared with vehicle-treated animals, those treated with the combination of E and P showed a 5-fold induction of galanin mRNA in GnRH neurons (68±9 g/c), which was significantly (P<0.01) greater than that observed in the animals treated with E alone; in addition, the magnitude of the LH surge was much greater (P<0.05) in the E/P-treated group compared with the E alone group. In contrast, compared to the vehicle controls, animals treated with P alone (15±2 g/c) showed no discernable effect on galanin mRNA levels; moreover, no LH surge occurred in the P alone group. Neither the number of identified GnRH cells nor their content of GnRH mRNA differed significantly among the experimental groups (GnRH mRNA signal: vehicle controls: 153±6 vs E: 159±6 vs E/P: 153±3 vs P: 148±8 g/c). We conclude that while E is the primary ovarian signal inducing galanin mRNA expression in GnRH neurons and the LH surge itself, P plays a facilitatory role in both of these processes.In the rat, beginning on the day of diestrus and continuing pin secretion (3, 4 ). While the basic endocrine aspects of this so-called positive feedback event have been carefully defined over through proestrus, a rising tide of estradiol (E ) serves as the proximate signal eliciting the preovulatory surge of LH (see ( 1) the p...