Pathologic Effect of Estradiol on the Hypothalamus

Abstract

Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component.

Differential effects of cysteamine on heat shock protein induction and cytoplasmic granulation in astrocytes and glioma cells

“…Steroids also provide signals to the hypothalamus and pituitary that are crucial for the regulation of the ovulatory cycle (Brawer et al, 1993). However, under certain conditions, steroids can mediate changes whieh alter the ability of the CNS to regulate the ovulatory cycle;…”

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

“…Also, it has not been appreciated before that E2 may have little to do directly with IPAH prevalence in women. In animal models, typically in male rodents, E2 would be protective by targeting the hypothalamus directly (49)(50)(51)(52)(53)(54). Thus, as has been shown in the liver literature, E2 would "feminize" GH patterns, changing the male pattern of expression in rodents to a female pattern (Figure 1).…”

“…The targets of E2 and testosterone include neuronal cells in the arcuate nucleus and other ventromedial hypothalamic nuclei (49)(50)(51)(52)(53)(54) (Figure 4). The downstream elements of this sex-bias mechanism are male versus female patterned secretion of GHRH from the hypothalamus into the hypophyseal portal circulation and then corresponding patterned secretion of GH by the pituitary into the general circulation.…”

“…As mentioned earlier, it has been shown extensively that effects of exogenously injected E2 depend on generating the "feminine plasma growth hormone pattern" through central hypothalamic/pituitary mechanisms (27,(32)(33)(34)(35)(36)(37)(38)(39)(40) (Figure 1). Specifically, a single injection of E2 into a rodent affects the function of cells in the arcuate and ventromedial nucleus in the hypothalamus and additional nuclei therein (27,(49)(50)(51)(52)(53)(54). These are the very cells that secrete GHRH in male and female patterns (27).…”

“…BMPR1, BMPR2 and caveolin-1 (cav-1) and various BMPs (-2, -4, -6, -7) are also expressed and function in arcuate neurons of the hypothalamus (74)(75)(76)(77)(78) (Figures 1, 4). Moreover, these are the very neurons that are the target of exogenously administered E2 converting the GHRH secretion pattern into a feminine continuous pattern (49)(50)(51)(52)(53)(54). Thus, it is necessary to consider the possibility that pathogenesis of hereditary PAH might involve contributions of BMPR2 and cav-1 mutations to changes in signaling and altered intracellular trafficking at the level of neuronal cell bodies in the arcuate nucleus of the hypothalamus (Figure 4).…”