Differential sensitivity of estrogen target tissues: Implications for estrogen regulation of serum luteinizing hormone

Abstract

In the rat, it is generally accepted that the primary site of estrogen's stimulatory (positive) effects on serum LH is the preoptic area-anterior hypothalamus (POA/AH). In contrast, the primary site of estrogen's inhibitory (negative) effects on serum LH levels has not been conclusively identified. There is evidence to suggest both a medial basal hypothalamic (MBH) and an anterior pituitary site of action. The present studies utilized a unique characteristic of these estrogen effects to investigate their putative loci. Extensive dose-response curves of estrogen's induction of positive and negative feedback indicated that the negative feedback response was activated at a lower concentration of serum estradiol than the positive feedback response. The differential sensitivities of these two responses suggested that the tissues mediating them might also be differentially sensitive to estradiol. In a previous paper, we showed that receptor translocation is an index of estrogen sensitivity. We measured receptor translocation in response to a series of estradiol doses in the POA/AH, the MBH, and the pituitary. Dose-response curves for estrogen's effect on receptor translocation showed that the pituitary receptor translocation mechanism is activated at significantly lower levels of serum estradiol than that of either the POA/AH or the MBH. These results are consistent with the POA/AH as a site of estrogen's positive feedback effects. In addition, they suggest that negative feedback in the rat may be mediated via estrogen's action at the anterior pituitary. Estrogen's negative feedback effect on serum LH occurs at a serum level of estrogen at which no receptor is translocated in the MBH. Therefore, the pituitary, which does possess nuclear receptors at these estradiol dose levels, is more likely to be the primary mediator of estrogen's negative feedback effects. In another experiment, pituitary, but not hypothalamic, receptor was translocated to the nuclear fraction with an injection of 100 micrograms clomiphere (Clomid). Under these conditions serum LH is depressed, thus strengthening the hypothesis that, in the rat, estrogen action on the pituitary can cause suppression of serum LH independently of the hormone's action in the hypothalamus.

Ovarian feedback, mechanism of action and possible clinical implications

“…These two studies provide evidence that the suppressing factor of LH levels during treatment with FSH is endogenous E 2 , which in the case of clomiphene was unable to act due to the occupation of estrogen receptors. The site of action of estrogen is primarily the pituitary; however, an effect on the hypothalamus cannot be excluded (Nakai et al, 1978;Plant et al, 1978;Kelner and Peck, 1984;Richardson et al, 1992).…”

Ovarian and Steroidal Influences on Neuroendocrine Aging Processes in Female Rodents*

“…reproductive aging, major impairments are observed in the regulation of LH . In rats, control of the E2 -induced LH surge and the pulse frequency of LH release resides in the hypothalamus and preoptic regions (3), whereas, the negative feedback of E2 on LH also may involve the pituitary (79,80). Thus, age changes in the LH surge of rodents have particular bearing on the possibility of neural age changes.…”

“…Information on how the effects of E2 vary with stimulus strength (blood concentrations) may be useful in identifying mechanisms of the ovary-dependent neuroendocrine syndrome . In view of the more than 10-fold greater E2 concentration required to occupy nuclear receptors in the hypothalamus vs. pituitary (80), it may be possible to determine if the minimum circulating concentrations of E2 required for irreversible neuroendocrine damage involves only the pituitary E2 receptors, or if hypothalamic E2 receptors must also be occupied. At the other extreme, if the E2-induced damage continues to increase progressively with increases in circulating E2 above that required for occupancy of both hypothalamic and pituitary receptors, then other nonclassical sites of E2 action can be considered such as those involving the very rapid effects of E2 on electrical activities in the basal ganglia (227).…”