Diabetes-Induced Alterations of Reproductive and Adrenal Function in the Female Rat

Abstract

Diabetes interferes with reproductive function in laboratory animals. Previous studies in female diabetic rats have not resolved if the reproductive abnormalities observed are at the hypothalamic, pituitary and/or ovarian level. The interaction of the gonadal and adrenal axes has not been studied in the diabetic female rat. The purpose of this study is twofold: first, to determine the level of dysfunction in the hypothalamic-pituitary axis caused by diabetes in the adult female rat controlling for stage of the estrous cycle, and, second, to evaluate basal coricosterone secretion in female diabetic rats. Sixty cycling 40-day-old female rats were randomly assigned to 3 groups; control (n = 32), diabetic (n = 14), and diabetic insulin-replaced animals (n = 14). The level of hyperglycemia in each group was documented by glycosylated hemoglobin levels and biweekly blood glucoses. Three weeks after induction of diabetes, pituitary luteinizing hormone (LH) responsiveness following an i.v. injection of gonadotropin-releasing hormone (GnRH) was assessed in representative diestrous rats from each group. All animals were sacrificed in either diestrus or proestrus for determination of GnRH concentration in the hypothalamus, LH and follicle-stimulating hormone (FSH) content in pituitary and LH, FSH, estradiol and corticosterone in serum. Uterine weight to body weight ratios (a bioassay for estrogen) were also calculated. Hypothalamic GnRH concentration was significantly lower in diabetic versus control diestrous rats. Basal pituitary and serum gonadotropin levels were not different between any groups. GnRH-stimulated serum LH levels were higher in diabetic vs. control and diabetic insulin-treated animals. LH surges occurred in the control and diabetic insulin-replaced but not the diabetic group. Estradiol levels and uterine weight/body weight ratios were high in control and diabetic insulin-replaced animals in proestrus, and low in untreated diabetic animals. Corticosterone levels were significantly lower in diabetic vs. control proestrous animals. The decreased GnRH concentration with normal basal pituitary function suggests that the abnormality in the hypothalamic-pituitary-ovarian axis in diabetes is at the hypothalamic level. Circulating corticosterone levels, which may impact on reproductive function, were not increased in our female diabetic rats as has been previously reported in diabetic male rats.

Effects of Diabetes and Estradiol on Norepinephrine Release in Female Rat Hypothalamus, Preoptic Area and Cortex

“…These changes in NE turnover correlate with aberrant ovarian hormone regulation of luteinizing hormone release in diabetic female rats [7, 8, 9]. Moreover, ovulatory failure is a common feature of diabetic rats [8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. Hence, these studies are also consistent with the conclusion that diabetes-induced changes in hypothalamic NE metabolism may interfere with the ability of NE to regulate reproductive physiology.…”

“…Diabetes leads to deficits in the neuroendocrine regulation of reproductive physiology [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. For example, diabetes reduces the ability of estrogen to facilitate the display of female reproductive behavior [1, 2, 3, 4, 5, 6] and also leads to aberrant ovarian hormone regulation of luteinizing hormone release [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17].…”

“…For example, diabetes reduces the ability of estrogen to facilitate the display of female reproductive behavior [1, 2, 3, 4, 5, 6] and also leads to aberrant ovarian hormone regulation of luteinizing hormone release [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. Despite these observations, little is presently known about the neurochemical basis underlying these diabetes-induced deficits in reproductive physiology.…”

Effect of Insulin on LHRH Release by Perifused Hypothalamic Fragments

“…Insulin-deficient states (type I diabetes mellitus, ex perimental diabetes) are associated to reproductive fail ure [9,10]; among other abnormalities of the hypotha lamic-pituitary-gonadal axis present in streptozotocin-diabetic rats [11][12][13][14], a reduced LHRH content has been described [ 15], Some of these alterations are corrected by insulin replacement [15,16]; the question arises whether insulin deficiency or elevated glucose levels, or both, are responsible for the impaired function of LHRH neurons. Titus, the following experiments were designed to evalu ate the effect of different glucose concentrations and of the addition of insulin on LHRH release by perifused hy pothalamic fragments.…”

Estrogen and Insulin Replacement Therapy Modulates the Expression of Insulin‐Like Growth Factor‐I Receptors in the Salivary Glands of Diabetic Mice

“…Among these hormones, estrogen is associated with cell function, glucose metabolism, insulin secretion and sensitivity, and an increased risk of diabetes. Diabetes alters hormone levels, compromising their function and intensifying the damage caused by the hyperglycaemia (Valdes et al, 1990;Hawkins et al, 1993;Goldsland et al, 2004;Herrmann et al, 2005). Thus, hormone replacement therapy may reverse this damage, but due to the presence of various complications, doubts still exist regarding the efficacy of this procedure under hyperglycemic conditions (Persson et al, 1999;Miller et al, 2002;Nelson et al, 2002;Ceylan-isik et al, 2009).…”