Serum FSH, LH and the Ovarian Response to Exogenous Gonadotropins in Alloxan Diabetic Immature Female Rats1

Liu, Frank T.Y.; Lin, Hsien S.; Johnson, Donald C.

doi:10.1210/endo-91-5-1172

Cited by 37 publications

(17 citation statements)

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“…The findings of the present experiment demonstrate that insulin deficiency in female rats results in decreased repro ductive organ weight, low serum estradiol and elevated glucose and glycosolated hemoglobin levels. The reduced uterine to body weight ratios were consistent with the impaired ovarian steroidogenesis reported here and by Liu et al [14]. Another reported abnormality in diabetic rats is decreased estrogen and/or estrogen receptor translocation in the hypothalamus and pituitaiy [38,39], The proestrus LH surge was observed in our control and insulin-treated animals, but was absent in our diabetics as has been well documented in previous studies |4 , 6,7], One explanation for the absent LH surge in the diabetic female is insufficient estradiol levels or estrogen effect to trigger this pituitary response.…”

Section: Discussionsupporting

confidence: 92%

“…Similar disparate data have been reported for basal pituitary and serum gonadotropin levels in insulin-deficient rats [4,[7][8][9][10][11][12]. These al tered parameters have been largely corrected with insulin ther apy [ 13], Other studies have indicated that reduced ovarian sen sitivity to hormones is the defect responsible for the repro ductive dysfunction in untreated diabetic rats [5,14]. The ovaries of diabetic rats have displayed diminished responsive ness to exogenously administered gonadotropins despite nor mal circulating endogenous LH and follicle-stimulating hor mone (FSH) (14].…”

supporting

confidence: 58%

“…These al tered parameters have been largely corrected with insulin ther apy [ 13], Other studies have indicated that reduced ovarian sen sitivity to hormones is the defect responsible for the repro ductive dysfunction in untreated diabetic rats [5,14]. The ovaries of diabetic rats have displayed diminished responsive ness to exogenously administered gonadotropins despite nor mal circulating endogenous LH and follicle-stimulating hor mone (FSH) (14]. However, most of these prior investigations did not control for the stage of the estrous cycle making results difficult to interpret given the dramatic cyclic changes in basal and GnRH-stimulated gonadotropins in normally cycling rats [15][16][17][18],…”

mentioning

confidence: 99%

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

Valdés¹,

Elkind‐Hirsch²,

Rogers³

1990

Neuroendocrinology

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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.

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Section: Discussionsupporting

confidence: 92%

supporting

confidence: 58%

mentioning

confidence: 99%

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

Valdés¹,

Elkind‐Hirsch²,

Rogers³

1990

Neuroendocrinology

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“…Our in vitro studies may also shed light upon clinical observations in certain hyperinsulinemic states, in which high circulating concentrations of insulin are achieved chronically in association with a marked increase in ovarian steroid-hormone production (53,54). In addition, the potent trophic actions of insulin on steroidogenesis permit us to suggest that profound insulinopenia may be linked plausibly to deficient ovarian function reported in poorly controlled diabetes mellitus (55)(56)(57).…”

Section: Methodsmentioning

confidence: 68%

Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells

Veldhuis¹,

Kolp²,

Toaff³

et al. 1983

J. Clin. Invest.

108

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A B S T R A C T Direct actions of insulin on gonadal tissues have been difficult to demonstrate in vivo. We have developed an in vitro system in which swine ovarian cells remain highly responsive to trophic actions of insulin. Purified porcine insulin significantly augmented the biosynthesis and secretion of progesterone by cultured granulosa cells. These stimulatory actions of insulin were dose-and time-dependent and saturable. Under serum-restricted conditions, insulin also significantly amplified the capacity of estradiol and 8-bromo cyclic AMP to stimulate progesterone production. Inhibitors of protein and RNA synthesis (cycloheximide, actinomycin D, and alpha-amanatin) inhibited insulin action. The stimulation of progesterone production by insulin was attributable to increased biosynthesis of pregnenolone, rather than diminished catabolism of progesterone to its principal metabolite, 20a-hydroxypregn-4-en-3-one. Insulin also enhanced progesterone production in the presence of a soluble sterol substrate, 5-cholesten-3j3,25-diol, which readily gains access to the mitochondrial cholesterol side-chain cleavage system. Moreover, exposure of granulosa cells to insulin produced a three-to sevenfold increase in mitochondrial content of cytochrome P-450 measured by difference spectroscopy, with a corresponding increase in mitochondrial cholesterol side-chain cleavage activity.The capacity of insulin to facilitate progesterone biosynthesis by ovarian cells was mimicked by the insulinlike somatomedin, multiplication stimulating activity, but not by epidermal growth factor, fibroblast growth factor, or porcine relaxin. Insulin's augmentation of progesterone production reflected a selective action on progestin biosynthesis, since insulin significantly suppressed estrogen biosynthesis by granulosa cells.Thus, our investigations indicate that insulin acts on ovarian cells selectively to stimulate pregnenolone (but not estrogen) biosynthesis. The actions of insulin are exerted by processes that require protein and RNA synthesis, and by mechanisms that augment mitochondrial cytochrome P-450 content and facilitate the utilization of cholesterol in the side-chain cleavage 1046 J. Clin. Invest.

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“…In rats, this impairment in cludes disruption of normal estrous cycles [5,9,14,15] de layed sexual maturity [14], decreased numbers of ova shed when ovulation does occur [4], high rates of fetal resorption [5,14], diminished lactational performance [14] and reduc tions in ovarian and uterine weights [8,9,14], Reduced uter ine weights in diabetics are consistent with impaired ovari an steroidogenesis. The ovaries of alloxan-diabetic rats dis play a diminished responsiveness to exogenously adminis tered gonadotropins, but endogenous gonadotropin levels seem to be normal [8,13,16]. These deficits can be largely corrected by insulin treatment.…”

mentioning

confidence: 99%

Deficits in Pituitary and Brain Cell Nuclear Retention of (<sup>3</sup>H)Estradiol in Diabetic Rats Deprived of Insulin: Time Course and Metabolic Correlates

Dudley¹,

Ramírez²,

Wade³

1981

Neuroendocrinology

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Withdrawal of exogenous insulin for 24 h in ovariectomized, streptozotocin-diabetic rats significantly impairs estradiol uptake in whole homogenate fractions of hypothalamus-preoptic area and pituitary gland. Significant reductions in cell nuclear fractions from the same tissues are seen after 36 h of insulin deprivation. Subsequent reinstatement of insulin treatment does not yield full recovery of estradiol uptake after 24 h of insulin replacement. Fat content of the diet has no effect on brain or pituitary estradiol uptake in diabetic animals deprived of insulin for 36 h. Circulating levels of triglycerides, ketones, glucose, glycerol and free fatty acids were found to predict uptake levels to a significant extent, but no single metabolite is reliably predictive across tissues. These data demonstrate that insulin-dependent changes in brain and pituitary uptake of estradiol in rats are slow to develop, and they support the hypothesis that at least some of the reproductive dysfunctions observed in diabetic rats may be the result of impaired cell nuclear estradiol binding in hypothalamus and pituitary.

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Serum FSH, LH and the Ovarian Response to Exogenous Gonadotropins in Alloxan Diabetic Immature Female Rats1

Cited by 37 publications

References 0 publications

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

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

Mechanisms subserving the trophic actions of insulin on ovarian cells. In vitro studies using swine granulosa cells

Deficits in Pituitary and Brain Cell Nuclear Retention of (<sup>3</sup>H)Estradiol in Diabetic Rats Deprived of Insulin: Time Course and Metabolic Correlates

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