Effects of Estradiol-Induced Lesions of the Arcuate Nucleus on Gonadotropin Release in Response to Preoptic Stimulation in the Rat

Brawer, James R.; Ruf, K. B.; Naftolin, Frederick

doi:10.1159/000122990

Cited by 33 publications

(12 citation statements)

References 14 publications

(27 reference statements)

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“…This dysfunction may be due to refractoriness of the hypothalamic-pituitary axis to hormonal stimulation, as suggested by the impaired preovulatory surge of LH in aging rodents with regular cycles (3-6) or after stimulation with exogenous steroids (7,8). The reactive gliosis in the hypothalamic arcuate nucleus of spontaneously acyclic aging rodents (18) has been offered as evidence for a lesion deafferentating the medial basal hypothalamus from the medial preoptic area and, thereby, impairing the induction of a preovulatory LH surge (19). It is noteworthy that these glial changes can also be delayed by long-term ovariectomy (18) and that their age of onset can be accelerated by chronic treatment with physiological levels of estradiol (10).…”

Section: Discussionmentioning

confidence: 99%

Restoration of ovulatory cycles by young ovarian grafts in aging mice: potentiation by long-term ovariectomy decreases with age.

Felicio¹,

Nelson²,

Gosden³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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The relative contributions of ovarian and hy--iuk ha,..|>itt~->; Cetors to the anovulatorv status of aging mice were evaluated by measuring the capacity of mice to resume ovulatory cyclicity after receiving young ovaries under the renal capsule. Young grafts partially restored cyclicity if old hosts were acutelv ovariectomized but almost fully restored cyclic ovulatory function if the old hosts had been ovariectomized early in adulthood. With advancing age, however, the efficacy of the grafts declined progressively in both acute and long-term ovariectomized groups. These data show that both ovarian and hypothalamic-pituitary aging contribute to the etiology of anovulation. Although chronic withdrawal from ovarian secretions retards the age of onset of hypothalamic-pituitary aging, the duration of this ameliorative effect is limited by progressive ovary-independent neuroendocrine dysfunction.The acyclic anovulatorv status of aging mammals is well-docunmented (1), yet the relative importance of ovarian versus hypothalamic-pituitary factors has not been established. Although steadily declining oocvte reserves clearly place an upper limit on the ovulatory life span (2), the reduced capacity of the aging hypothalamic-pituitary axis to release preovulatory surges of luteinizing hormone is also implicated in some rodent species (3-8). The possibility that this hypothalamic-pituitary dysfunction is a consequence of long-term exposure to ovarian steroids was first indicated by Aschheim's observation in a small group of old rats that young ovarian grafts restored vaginal cyclicity only if these rats had been ovariectomized at an early age (9). Subsequent studies showed that chronic treatment of young rodents with estradiol (10) led to a premature onset of degenerative changes in the hypothalamic arcuate nucleus, a region involved in the regulation of gonadotropin secretion. However, crucial questions bearing on the etiology of ovulatory failure in rodents remain unanswered. Namely, is hvpothalamic-pituitary dysfunction solely responsible for the anovulatory condition, or does primary ovarian failure contribute as well? What is the duration of the ameliorative effect of long-term ovariectomy on reproductive function? Do factors other than exposure to ovarian secretions contribute to the aging of the reproductive hypothalamic-pituitary axis?To answer these questions, we examined the ability of young ovarian grafts to restore ovulatory cyclicity in a longitudinal study of mice at ages spanning the adult life span. WVe report that the anovulatory condition is a consequence of both ovarian and hypothalamic-pituitary insufficiency. Although long-term withdrawal from endogenous ovarian secretions dramatically potentiates the restoration of ovulatory cyclicity in aging animals with young ovarian grafts, this effect is transitory. Progressive neuroendocrine dysfunction, independent of ovarian secretions, sets an upper limit on the ameliorative influence of longterm ovariectomy. MATERIALS AND METHODSAnimals and Vaginal Cyc...

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Section: Discussionmentioning

confidence: 99%

Restoration of ovulatory cycles by young ovarian grafts in aging mice: potentiation by long-term ovariectomy decreases with age.

Felicio¹,

Nelson²,

Gosden³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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“…Some years ago, ultrastructural examination of arcuate nucleus tissue from aging SD female rats revealed the presence of dendritic and axonal degeneration, and astrocytic and microglial reaction (39). This picture of neuropathological change had actually been observed earlier in estrogen-treated young female rats, which also had developed a persistent vaginal estrus (40) and inability to generate preovulatory LH Volume 102, Supplement 11, December 1994 surges (41). It was suggested that continual estrogen exposure advances the aging process by inducing pathologic change in the hypothalamus.…”

Section: Ultrastructural Changes In Arcuate Nucleus With Chlorotriazimentioning

confidence: 96%

Factors affecting mammary tumor incidence in chlorotriazine-treated female rats: hormonal properties, dosage, and animal strain.

Eldridge

Tennant

Wetzel

et al. 1994

Environ Health Perspect

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Chlorotriazines are widely used in agriculture as broadleaf herbicides. The compounds specifically inhibit photosynthesis, and, as such, display little interaction with animal systems. However, a 24-month feeding study with atrazine (ATR) revealed a significant dose-related increase of mammary tumors in female Sprague-Dawley (SD) rats. Because numerous studies indicated that ATR had a low mutagenic and oncogenic potential, it was decided to test a hypothesis that the herbicide possessed endocrine activity. Among tests for estrogenic action, oral dosing of ATR up to 300 mg/kg did not stimulate uterine weight of ovariectomized rats. However, ATR administration did reduce estrogen-stimulated uterine weight gain. Further evidence of inhibition came from measures of [3H]-thymidine incorporation into uterine DNA of ATR-treated immature rats. Again, no intrinsic estrogenic activity was observed up to a 300-mg/kg dose. In vitro, ATR competed poorly against estradiol binding to cytosolic receptors, with an approximate IC50 of 10-5 M. Atrazine administration to SD and Fischer-344 (F-344) rats for 12 months, up to 400 ppm in food, was correlated with significant alterations of estrous cycling activity; but there was a divergent strain response. SD rats showed an increased number of days in vaginal estrus, increased plasma estradiol, and decreased plasma progesterone by 9 to 12 months of treatment. F-344 rats rdid not demonstrate treatmentrelated affects. A study of ultrastructure in the hypothalamic arcuate nucleus of female SD rats that were fed diaminochlorotriazine (DACT), an ATR metabolite, suggested that age-associated glial pathology was enhanced by treatment. It is proposed that antiestrogenic actions of ATR are able to disrupt critical hormone-mediated functions at very high dose levels. In SD rats, this disruption delays ovulation, maintains estrogen secretion from ovarian follicles, and produces a hormonal milieu more conducive to mammary tumors. Aging in F-344 rats promotes higher progesterone secretion, and it is predicted that mammary tumors would not be increased in ATR-fed F-344 animals. It is also concluded that the risk of ATR-related mammary tumors in humans would be quite low because of the unique response of the SD rat estrous cycle, the nature of stimulated mammary tumors in rats, and the extremely high dose levels and concentrations required for ATR to express activity in vivo and in vitro. -Environ Health Perspect 1 02 (Suppl 11):29-36 (1994)

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“…In other rat strains, 16 weeks of chronic E 2 caused the loss of synapses and degeneration of β-endorphin-containing neurons without indications of increased animal mortality [41, 42, 43]. In humans, there are no indications that sustained estrogen levels, with or without progesterone, cause irreversible neuroendocrine changes.…”

Section: Discussionmentioning

confidence: 99%

Aging and Increased Hypothalamic Glial Fibrillary Acid Protein (GFAP) mRNA in F344 Female Rats

et al. 2002

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During reproductive aging, female rodents show impaired inducibility of the estradiol (E2)-induced (preovulatory) surge of luteinizing hormone (LH), which is associated with hypothalamic neuronal impairments of aging. To evaluate if astrocytes show comparable age changes, we analyzed the regulation of glial fibrillary acidic protein (GFAP) mRNA which is transiently increased in the arcuate nucleus in association with the proestrus LH surge in young rats. In aging (18-month-old) F344 rats in persistent estrus, the loss of the E2-induced LH surge was paralleled by the lack of increased GFAP mRNA in the arcuate nucleus (in situ hybridization with X-ray film). We then tested the hypothesis that restoration of the LH surge by chronic ovariectomy (OVX) in aging rats would restore or block GFAP mRNA induction, respectively. Despite restoration of the inducible LH surge in aging rats by chronic OVX, there was no induction of GFAP mRNA in the arcuate nucleus. Moreover, young rats given chronic E2 implants for 6 weeks as a model for persistent estrus, retained induction of arcuate nucleus GFAP mRNA, despite loss of the induced LH surge. The aging rats were highly sensitive to gross pituitary enlargement from chronic E2 with 50% mortality; thus, the F344 genotype is not optimum for studies of aging-E2 interactions that require prolonged E2 treatments. More detailed cellular level analysis of GFAP mRNA is needed to define the relationship of GFAP expression to synaptic reorganization during the LH surge. The aging rats also showed higher levels of GFAP mRNA in the arcuate nucleus and ventromedial nucleus, consistent with the general trend for elevated GFAP mRNA during aging in other brain regions and in both sexes.

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Effects of Estradiol-Induced Lesions of the Arcuate Nucleus on Gonadotropin Release in Response to Preoptic Stimulation in the Rat

Cited by 33 publications

References 14 publications

Restoration of ovulatory cycles by young ovarian grafts in aging mice: potentiation by long-term ovariectomy decreases with age.

Restoration of ovulatory cycles by young ovarian grafts in aging mice: potentiation by long-term ovariectomy decreases with age.

Factors affecting mammary tumor incidence in chlorotriazine-treated female rats: hormonal properties, dosage, and animal strain.

Aging and Increased Hypothalamic Glial Fibrillary Acid Protein (GFAP) mRNA in F344 Female Rats

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