The endocrin control of seasonal reproductive function in the ewe: a marked change in response to the negative feedback action of estradiol on luteinizing hormone secretion.
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Biomedical subjects
Publications and source records attributed to D L Foster.
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The effect of progesterone on the secretion of LH was studied in intact and castrated immature female sheep between 12 and 42 weeks of age. (First spontaneous ovulation occurs between 30 and 50 weeks of age.) Progesterone was administered by means of Silastic capsules inserted SC to achieve circulating progesterone concentrations similar to those found in the adult during the mid-luteal phase of the estrous cycle (3-4 ng/ml). Prior to treatment, concentrations of circulating LH in intact lambs fluctuated widely (2 to 20 ng/ml) over a 24- to 48-h period. These high and variable levels of serum LH, reflecting a pulsatile secretion of LH characteristic of young female sheep, were not altered by the insertion of empty capsules. Implantation of progesterone-containing capsules, however, resulted in a decrease in serum LH to low levels (less than 0.5 ng/ml) within 4 h. Furthermore, the insertion of progesterone capsules into the same lambs after castration produced an immediate and sustained suppression of LH secretion similar to that which was observed when the ovaries were present. These findings led to the conclusion that in the immature female sheep, protesterone can effect a marked inhibition of LH secretion in the presence or absence of the ovaries. Although it has been postulated that progesterone plays an important role in the negative feedback control of LH secretion in adult sheep during the estrous cycle, it remains to be determined whether this steroid normally plays a physiologic role in the regulation of tonic LH secretion prior to the onset of ovarian cyclicity in the lamb.
To determine the basis for the marked daily variability in circulating luteinizing hormone (LH) in the female lamb shortly after birth and to determine whether circulating follicle-stimulating hormone (FSH) exhibits similar variability during this period of life, serum levels of both gonadotropins were monitored frequently (20-min intervals) over a 3- or 6-hr period each week for the first 9 weeks of life. Similar measurements of circulating LH and FSH were made in lambs ovariectomized at 2 weeks of age to assess whether the ovary influences the secretion of these gonadotropins. Pulsatile release of LH, but not FSH, was observed in both groups of lambs. Although mean concentrations of circulating FSH in intact female lambs were similar to basal levels of the cyclic adult, mean concentrations of serum LH were much higher. Because of the discontinuous release of LH in intact lambs after 4-5 weeks of age, patterns of LH were often indistinguishable from those of the long-term ovariectomized adult. At 9 weeks of age the frequency of episodic LH release in intact lambs ranged from 0.33-1.1 pulses/hr. Castration at 2 weeks of age produced a concomitant, but delayed, rise in mean serum LH and FSH beginning 4-5 weeks later. By 9 weeks of age serum LH, but not FSH, had attained levels comparable to those of the castrated adult, and the mean frequency of LH release (about hourly) was similar for both groups. The results indicate that by 9 weeks of age the ovary of the lamb influences the secretion of LH and FSH. Because in the 9-week-old intact female lamb episodic release of LH occurs producing high (castrate) levels of this gonadotropin while circulating concentrations of FSH remain stable and within basal levels of the adult cycling female, it is suggested that acute concomitant release of LH and FSH does not occur at this age and that separate negative feedback loops for the control of LH and FSH secretion may exist during early postnatal life.
Silastic capsules containing estradiol-17beta were implanted subcutaneously into male and female sheep which had been gonadectomized as adults, In both sexes, this treatment resulted in a prompt decrease in serum LH concentrations reflecting a negative feedback suppression of tonic LH secretion. In females but not males, this decrease was followed, within 24 h, by an LH surge after which circulating LH declined to low levels resembling those in intact ewes during the luteal phase of the estrous cycle. In males, only a sustained reduction in circulating LH was observed. Three weeks after placement of the initial estradiol implants, while serum LH levels were low and stable, additional estradiol implants were inserted. This additional treatment effected step-like increments in circulating estradiol to approximately 20 or 55 pg/ml (depending on the number of implants) and elicited single or multiple LH discharges in females but failed to induce LH surges in males. These findings lead to the conclusion that the mechanism which governs the cyclic mode of LH secretion in sheep, as in rats, undergoes sexual differentiation. Further, the presence of multiple LH surges in some females suggests that an increment and sustained elevation in circulating estradiol can induce the occurrence, or permit the expression, of consecutive signals for the LH surge in the ovariectomized ewe.
Patterns of circulating LH and FSH were examined during several 6-h periods in developing female sheep from 3 weeks of age through the first estrous cycles (30--40 weeks of age) and early pregnancy. With the onset of pulsatile LH secretion, beginning 11 weeks after birth, circulating LH increased to levels 2- to 5-fold greater than those observed in the adult. Thereafter, high and variable levels of circulating LH persisted through young adulthood when ovarian cyclicity including ovulation became manifest. Although prior to the initial estrus changes in frequency of LH release (number of LH discharges/6-h period) appeared to occur randomly from week to week, after first estrus, changes in frequency became predictable. During the early (day 1) and late (day 15) luteal phases of the first estrous cycles, when circulating progesterone was low (less than 0.6 ng/ml), the frequency of LH release was increased (5--7 discharges/6 h) while during the mid-luteal phase (day 7--12), when circulating progesterone was high (2--4 ng/ml), the frequency was diminished (0--2 discharges/6 h). Massive and sustained discharges of LH which resembled preovulatory surges were observed only shortly before first estrus. In contrast to the pulsatile release pattern of LH, concentrations of circulating FSH within the 6-h periods were relatively constant and within the range found in the adult. These findings lead to the following conclusions: a) changes in negative feedback control are not directly responsible for the onset of ovarian cyclicity in the sheep as indicated by the lack of differences in mean concentrations of circulating LH and FSH before and after first ovulation; b) the onset of the surge mode of gonadotropin secretion occurs only shortly before first ovulation; and c) progesterone may play an inhibitory role in regulating tonic LH secretion during the first estrous cycles.
Development of the mechanism controlling cyclic LH secretion in the sheep was studied by examining the ability of estradiol to elicit LH surges in lambs at various ages. Silastic capsules containing estradiol were implanted sc for a 96-hour period at 3, 7, 12, 20, and 27 weeks of age. (First spontaneous ovulation occursss between 30 and 50 weeks). Although administration of estradiol failed to elicit a discharge of LH at 3 weeks of age, LH surges of progressively increasing magnitude (36 +/- 15, 73 +/- 28, 107 +/- 19 ng/ml) were elicited by estradiol as the lambs became older (7, 12, 20 weeks). By 27 weeks, the maximal serum LH level attained during the induced surge (123 +/- 29 ng/ml) was similar to that of the estrogen-induced LH surge in anestrous adults (179 +/- 23 ng/ml). Ovulation, however, did not occur in response to the induced LH surges. An additional experiment was performed to determine whether, as in the adult, progesterone can block the estradiol-induced LH discharge in the immature (12-week old) female. A sustained elevation of circulating progesterone to levels characteristic of the mid-luteal phase of the estrous cycle of the adult (3--4 ng/ml), beginning 24 h prior to insertion of the estradiol capsules, blocked the induced LH surge. These results demonstrate that, in immature female sheep, the LH surge mechanism is capable of functioning long before first ovulation occur and, further, suggest that timing of the initial preovulatory LH surge is limited by the ability of the ovary to produce the estradiol stimulus rather than by the ability of the hypothalamo-hypophyseal system to respond to the positive feedback action of estradiol. Additionally, the hypothalamo-hypophyseal mechanism whereby progesterone blocks the LH surge develops long before first ovulation.
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