Regulation of Baboon Fetal Pituitary Prolactin Expression by Estrogen1

Abstract

We previously showed that fetal adrenal fetal zone growth was increased and the number of follicles in the fetal ovary reduced in baboons in which estradiol was suppressed by treatment with the aromatase inhibitor letrozole between mid and late gestation periods. Because adrenal/ovarian development was restored in animals treated with letrozole and estradiol, and both tissues express estrogen receptor, we proposed that estrogen regulates fetal adrenal/ovary development via a direct action. However, because prolactin can modulate fetal adrenal and adult pituitary/ovarian function, the current study determined whether estrogen action involved estradiol-regulated changes in fetal prolactin/luteinizing hormone (LH) expression. Fetal prolactin levels and the number of prolactin-positive fetal pituitary cells (per 0.37 mm(2)) were increased (P < 0.01) between mid (6 +/- 1 ng/ml; 15.8 +/- 2.4) and late (257 +/- 28 ng/ml; 57.3 +/- 5.1) gestation, reduced (P < 0.01) in late-gestation fetuses in which estradiol was suppressed (>95%) by letrozole (61 +/- 11 ng/ml; 19.3 +/- 2.0), and minimally but not significantly increased by letrozole and estradiol (99 +/- 11 ng/ml; 32.7 +/- 5.2). In contrast, the number of LH-positive fetal pituitary cells decreased (P < 0.01) between mid (48.8 +/- 9.5) and late (17.4 +/- 3.2) gestation, remained elevated (P < 0.01) in estrogen-suppressed animals (56.6 +/- 5.1), and was partially but not significantly decreased by letrozole-estradiol (28.8 +/- 5.2). We conclude that estrogen regulates fetal pituitary prolactin and LH expression and fetal prolactin levels. However, because prolactin and LH expressions in estrogen-suppressed fetuses were inversely related to previously demonstrated changes in adrenal/ovarian development, we propose that estrogen regulates the fetal ovary and adrenal gland directly and not via action on the fetal pituitary gland.

Regulation of Baboon Fetal Ovarian Development by Placental Estrogen: Onset of Puberty Is Delayed in Offspring Deprived of Estrogen In Utero1

“…Thus, fetal testosterone levels were equally elevated in utero in both letrozole-and letrozole plus estradiol-treated baboons, but only the animals concomitantly treated with letrozole plus estrogen achieved puberty onset comparable to that in untreated estrogen-replete offspring. Although the level of estradiol in letrozole and estradiol-treated baboons was not restored to normal, this level of estradiol was sufficient to overcome the adverse effects of estrogen deprivation on the timely onset of puberty, as well as on fetal ovarian follicle development [6] and pituitary FSH secretion/expression [10,11]. It is unlikely, but remains to be established, that the adverse effect of estrogen suppression on puberty onset are due to an alteration in estrogen-dependent events in the mother that could affect the fetus.…”

“…Thus, in baboons in which estrogen was suppressed by treatment with the aromatase inhibitor letrozole during the second half of gestation, the number of primordial follicles formed in the fetal ovary was reduced by more than 50% [6], and the majority of follicles that developed contained unhealthy oocytes [7]. Additional studies showed that this critical action of estrogen most likely is elicited directly on the fetal ovary, which expresses estrogen receptor (ER) a/b [8,9], and not indirectly via fetal pituitary gonadotrophin support, fetal ovarian follicle-stimulating hormone (FSH) receptor expression [10], or fetal pituitary prolactin secretion [11]. Collectively, these observations, plus the fact that fetal ovarian folliculogenesis and oocyte integrity were normal in baboons treated with letrozole and estradiol, support our hypothesis that placental estrogen programs fetal ovarian development and regulates formation of the stockpile of healthy follicles critical for long-term survival [5,6] and presumably reproductive function in adulthood.…”

Pituitary Aromatase P450 May Be Involved in Maintenance of the Population of Luteinizing Hormone-Positive Pituitary Cells in Mice

“…The role that aromatization of testosterone to estradiol might play in pituitary function remains to be fully elucidated, but there is evidence suggesting a physiological [Belle et al, 2005;Pitteloud et al, 2008;Pepe et al, 2009;Caglar et al, 2015] and pathophysiological [Sodi et al, 2005;Heidari et al, 2010] role for pituitary aromatase. Indeed, aromatase is responsible for the production of estrogen from androgen, and significant coexpression of the enzyme in prolactin-, growth hormone-, and thyroidstimulating-hormone-secreting cells of the human anterior hypophysis has been reported, which could indicate that aromatase may also regulate the synthesis and secretion of these hormones [Caglar et al, 2015].…”

Estrogen Regulation of Fetal Adrenal Cortical Zone-Specific Development in the Nonhuman Primate Impacts Adrenal Production of Androgen and Cortisol and Response to ACTH in Females in Adulthood

“…Samples of blood were also obtained at 46 -70 months of age from representative offspring delivered to baboons untreated (n ϭ 3) or treated with letrozole (n ϭ 4) or letrozole plus estradiol (n ϭ 4) for determination of plasma ACTH and prolactin levels using chemiluminescent immunoassay procedures (Siemens) and highly specific antibodies that exhibited minimal (Ͻ0.5%) cross-reactivity with other pituitary or placental hormones as described previously (28). Animals were examined for timing of the onset of puberty defined as a change in perineal sex skin appearance, color, and tumescence (swelling) indicative of increase and/or response to estradiol, as well as determination of serum estradiol levels at 36 -58 months of age or immediately preceding puberty onset and these findings including assessment of growth have been reported (27).…”