Further Studies on the Maturation of the Estrogen Negative Feedback on Gonadotropin Release in the Female Rat

Abstract

To evaluate estrogen negative feedback in infantile female rats, 9-day-old rats were ovariectomized (OVX) and treated with different doses of estradiol benzoate (Eb, s.c. once daily for 2 days); plasma LH, FSH and estradiol (E₂) levels were then determined by RIA. The responses of these rats were compared with those of 25-day-old rats subjected to the same experimental procedures. In intact sham-operated controls, plasma FSH was elevated on days 9–13 and low on days 25–29, whereas LH did not change significantly throughout the period studied. OVX at day 9 or 25 increased the levels of both hormones, with the response faster and larger in the older rats. Treatment with Eb was more effective in suppressing the post-castration rise in gonadotropin levels in 27-day-old than in 11-day-old rats. At day 27 plasma E₂ was elevated to pre-castration values by as little as 10 ng of Eb, whereas at day 11 this dose produced plasma E₂ titers even higher than pre-castration values. Plasma E₂ titers were high at 9–13 days of age and low at days 25–29. OVX on day 9 decreased E₂ 2–4 days later to about ½ the initial concentration, whereas adrenalectomy (ADRX) or ADRX-OVX was followed by an almost complete disappearance of the steroid. When E₂ was injected at day 10 in intact rats to elevate plasma E₂, E₂ remained elevated when measured 3 to 120 min after its injection, but on day 25, 50% of the injected E₂ had disappeared from plasma in 90 min. These results provide additional support for the view that estrogen negative feedback, even though present in infantile rats, is less effective than later in life and hence indicate that high gonadotropin titers observed at days 9–13 in the presence of high E₂ may be caused by the relative ineffectiveness of the feedback at these early ages. The high E₂ titers appear to be caused by an enhanced rate of production of E₂ by the adrenals and ovaries and by a reduced metabolic clearance of the steroid.

Ovarian Control of Gonadotropin Secretion during Induced Precocious Sexual Maturation in the Rat

“…First, ovarian steroids pro duced within the first 24 or 48 h appear to be sufficient to keep FSH secretion in check and to prevent the rapid post-castration rise observed in nonlesioned OVX rats, but they exert no clear-cut inhibitory effect on the secre tion of LH. These findings are in keeping with observations made by others [Ojeda et al, 1975] on differences in the negative feedback control of LH and FSH secretion in rats of comparable age. The preferential negative feedback effect on FSH release probably accounts for the striking increase in the LH/FSH ratio observed in immature rats subjected to this type of brain lesion [Yo u n g L ai et al, 1976] or given injections of a small amount (0.25 /ig) of estradiol benzoate [R u f et al, 1976].…”

“…These delays are of the same order as those observed after the administration of exogenous estrogen; immature rats of the age used in this study rapidly reduce FSH release in response to small amounts of the steroid [Ojeda et al, 1975;R u f et al, 1975], but they require the injection of a pharmacological dose [Br o w n -G r a n t , 1976] or a prolonged infusion [Steele and W e isz , 1975] if positive feedback effects are to be induced. These parallels reinforce our view [R uf et al, 1974] that brain lesions advance sexual maturation by in ducing precocious ovarian steroidogenesis, particularly increased synthesis of estrogen, rather than by removing hypothetical neural restraints upon the pituitary-ovarian axis [D a v idson, 1974].…”

Effects of estradiol and progesterone on food intake, body weight, and carcass adiposity in weanling rats

“…For example, it has been proposed that declining levels of alphafetoprotein account for the age-related increases in sensitivity to negative feedback effects of estrogen and for increases in the sensitivity of the reproductive tract to estrogen (Ojeda, Kalra and McCann, 1975;Germain et^. , 1978 The extreme leanness of immature rats may be an important factor in the inability of estradiol to affect feeding behavior.…”

“…The metabolic clearance rate of estradiol is lower in 28-day-old rats as compared with adult rats (De Hertogh, Ekka, Vanderheyden and Hoct, 1970), so that even 5 days after OVX, significant circulating levels of estrogen may still be present. Furthermore, the adrenal also may produce significant amounts of estiogen in the young animal (Ojeda, Kalra and McCann, 1975;Weisz and Gunsalus, 1973 There are several lines of evidence which rule out this possibility.…”

The Neuroendocrinology of Reproduction: An Overview1

“…Since removal of the ovary is without apparent consequence to sexual differentiation, it was logical to assume that the ovaries were relatively quiescent during this perinatal period of differentiation. However, when radioimmunoassay for estrogens became available, it became apparent that during the lifetime of the female rat, the period when estrogen levels in the blood are probably the highest is actually this perinatal period (Ojeda et al, 1975;Weisz and Gunsalus, 1973). Although the source and nature of this immuneassayable estrogen is still controversial, it would appear that plasma levels of true estradiol are very high in the perinatal female rat.…”