<b>REDUCED HYPOTHALAMIC SEROTONIN SYNTHESIS AND SERUM LUTEINIZING HORMONE LEVELS IN STREPTOZOTOCIN-DIABETIC MALE </b><b>RATS </b>

Abstract

Infertility is a common sequela to experimentally-induced diabetes mellitus in the male rat as well as to diabetes in the human male. This has been attributed both to alterations in hypothalamo-pituitary and pituitary-testicular activity. In view of the role of serotonin in the hypothalamic regulation of luteinizing hormone secretion, we determined the effects of streptozotocin-induced diabetes on hypothalamic serotonin synthesis relative to circulating levels of luteinizing hormone, folliclestimulating hormone and prolactin in these animals._,Half of a group of adult male Sprague-Dawley rats were injected intraperitoneally with 16 mg-kg" of streptozotocin. The other half were injected with vehicle only. The diabetic group was hyperglycemic throughout the study period (488.7 i21.2 mg-d1""1 in diabetic rats vs. 125.1i39.3 mg-dl""' in control rats). A third group of rats served as semi-starved controls, weight-matched by total calorie restriction diet to diabetic rats. All of the rats were injected intraperitoneally with 200 mg-kg" of NSD-1015 30 min prior to sacrifice. Accumulation of 5-hydroxytryptophan in various hypothalamic areas was then assayed by liquid chromatography with electrochemical detection as a relative index for the rate of serotonin synthesis. Serum radioimmunoassayable luteinizing hormone, follicle-stimulating hormone and prolactin were also assayed in these animals. Our results show a 50% decrease in serotonin synthesis in the preoptic area-anterior hypothalamus and mediobasal hypothalamus-median eminence 16 weeks after streptozotocin treatment. We also found that serotonin synthesis was inhibited 4 weeks after streptozotocin treatment in the preoptic area-anterior hypothalamus, but not in the mediobasal hypothalamus-median eminence, indicating region-specificity in the early hypothalamic response to streptozotocin-induced diabetes. Serum luteinizing hormone levels were decreased both 4 and 16 weeks after streptozotocin treatment. No changes either in hypothalamic serotonin synthesis or in serum luteinizing hormone levels were observed 1 week after streptozotocin treatment. Serum follicle-stimulating hormone and prolactin levels remained unaffected by streptozotocin treatment throughout the study period. The differential effect of diabetes on the gonadotropins may represent further evidence for the hypothesis of differential regulatory mechanisms governing the secretion of these two hormones and further emphasizes the pathophysiologicalspecif1city(i.e., not a generalized metabolic disturbance effect) of diabetes-induced male reproductive neuroendocrinopathy. Our study suggests, at least in part, an explanation for such pathological interaction, namely, diabetic inhibition of a region-specific neurotransmitter system integral to hypothalamic regulation of luteinizing hormone secretion.

Cocaine Disrupts Estrous Cyclicity and Alters the Reproductive Neuroendocrine Axis in the Rat

“…Reduced weight gain comparable to that seen in our study does not appear to alter circulating or pituitary go nadotropin levels [17], hypothalamic GnRH levels [1], LH re sponses to GnRH challenge [1], hypothalamic GnRH re sponses to catecholaminergic stimulation [Steger, pers. commun.…”

“…commun. ] or hypothalamic aminergic turnover rates [17]. Thus, it is unlikely that the observed reproductive cycle disruption seen in animals treated with cocaine was due to the reduced weight gain in these animals.…”

Reduced aminergic synthesis in the hypothalamus of the infertile, genetically diabetic (C57BL/KsJ-db/db) male mouse

“…group 5HT and catecholamine activities in hypothalamic areas integral to regulation of reproductive function are diminished in the genetically diabetic male mouse. Earlier reports describe as much as a 50 % decrease in the rate of 5HT synthesis in the hypothalamus of streptozotocindiabetic male rats (Crandall et al 1981 ;King et al 1987). …”

“…Previously, we have shown that diabetes-related reproductive failure in the streptozotocin-diabetic rat model is related to inhibition of region-specific neurotransmitter activities integral to hypothalamic regulation of LH secretion (King et al 1987). We have further shown that stimulated in vitro GnRH release from the hypothalami of chronically (streptozotocin-) diabetic animals is inhibited (King and Kang 1989).…”

“…These animals exhibit impaired spermatogenesis, reduced circulating levels of testosterone, LH and FSH and altered aminergic activity within the hypothalamus controlling pituitary gonadotropin output (Singhal et al 1969;Murray et al 1981 ;Murray et al 1985;King et al 1987). While many such animal models for diabetes are drug-induced, several genetic animal models for this disease exist.…”