We examined effects of maternal stress on prenatal serum concentrations of testosterone and estradiol and on postnatal reproductive traits in female mice from different intrauterine positions. On Day 18 of fetal life, control females positioned in utero between two male fetuses (2M females) had higher concentrations of testosterone and lower concentrations of estradiol in serum than control female fetuses located between two females (0M females). Control females positioned between a male and a female fetus (1M females) had intermediate levels of both hormones. Prior intrauterine position in control females accounted for differences in genital morphology (length of the anogenital separation) at birth and length of estrous cycles during adulthood. Maternal stress eliminated these postnatal differences due to prior intrauterine position: all 0M, 1M, and 2M female offspring of stressed mothers exhibited postnatal traits that were indistinguishable from those of control 2M females. Maternal stress resulted in an increase of over 1 ng/ml in serum testosterone in all female fetuses; the magnitude of the increase was similar for 0M, 1M, and 2M females. There was no effect of maternal stress on serum concentrations of estradiol in 0M and 2M female fetuses. Maternal stress resulted in a dramatic change in the postnatal traits of 0M females, whereas 2M females showed no change. Since the effect of maternal stress on sex steroids was similar among fetuses from different intrauterine positions but postnatal response to maternal stress varied by intrauterine position, other components of the endocrine system may mediate effects of maternal stress on these postnatal characteristics.

Steroid hormones, which affect development of reproductive traits, alter immune responses in rodents and appear to control severity of disease in F1 hybrid NZB/W mice, an animal model of systemic lupus erythematosus. We tested the hypothesis that exposure of NZB/W fetuses to altered hormonal environments would influence subsequent expression of autoimmune renal disease and affect longevity. NZB females, pregnant with NZB/W fetuses, were treated from Days 13-18 of gestation with testosterone or the antiandrogen, flutamide. Similar treatments were carried out in C57BL/6 dams mated to DBA/2 males to permit comparison with nonautoimmune hybrid mice. Serum concentrations of testosterone were greater in testosterone-implanted dams of both strains, but concentrations of estradiol were greater only in C57BL/6 dams treated with flutamide. Alpha fetoprotein (AFP), which binds estrogen and modulates immune responsiveness, was greater in serum from both groups of testosterone-treated dams, while flutamide treatment increased serum AFP only in NZB dams. We conclude that factors governing circulating estradiol and AFP differed in pregnant NZB and C57BL/6 females. Morphological analyses confirmed effects of hormonal manipulation on the developing fetuses. Testosterone implants resulted in female offspring with greater anogenital spaces, and treatment of dams with flutamide eliminated the expected difference between anogenital spaces in females and males. Effects of altered prenatal hormonal environments on immune-mediated disease in NZB/W offspring were examined in a longevity study. Early deaths were delayed in NZB/W females produced by flutamide-treated dams. An unexpected result was observed in NZB/W males. Male offspring from both testosterone- and flutamide-treated mothers lived longer than males from control dams. This paradox suggested that a characteristic shared by both groups of treated NZB dams had similar effects on the developing fetuses. It is proposed that elevated concentrations of AFP modulated the course of autoimmune disease and contributed to increased longevity in NZB/W offspring of treated dams.

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To evaluate effects of commonly used progestational estrogenic contraceptive steroids in a hormone-responsive model of lupus, we treated female NZB/W mice before clinical disease (6 wks of age) and after onset of lupus (24 wks of age) with doses of hormones titered to suppress reproduction. We report efficacy of norethindrone (NE) and norgestrel (NG), progestins derived from 19-nor-testosterone, in delaying expression of anti-DNA antibodies. Mice implanted with NG at 24 wks of age had prolonged lifespans. In contrast, the hydroxyprogesterone derivative, medroxyprogesterone acetate (MP), did not affect autoimmune disease. These observations suggest that prolonged administration of 19-nor-testosterone derivatives, in small doses adequate to suppress reproduction, may have ameliorative effects in systemic lupus erythematosus. Mice receiving ethinyl estradiol (EE) plus courses of tetracycline to suppress cystitis had active anti-DNA responses. In 60% of EE-treated mice, however, early deaths resulted from malignant lymphomas and complications of obstructive uropathy. Estrogen toxicity, rather than accelerated lupus, was the major cause of death in NZB/W mice treated with EE.

Summary. Of 19 dioestrous ewes given 50 \ g=m\ g GnRH on Day 10 of the oestrous cycle, 15 (79%) formed corpora haemorrhagica within 2 days after injection of GnRH. After excision of the Day 10 spontaneous CL, the GnRH-induced CL were short lived when compared to spontaneous CL in saline-treated ewes (3\m=.\1\ m=+-\0\m=.\4 vs 17\m=.\3\ m=+-\0\m=.\3days, respectively). Hysterectomy ofewes bearing the GnRH-induced CL prevented regression of the short-lived CL, thus extending functional lifespan > 38 days. Serum concentrations of progesterone produced by the GnRH-induced CL in hysterectomized ewes were less than those observed during a comparable interval (Days 7\p=n-\14) in sal i ne\x=req-\ treated, non-hysterectomized ewes (2\m=.\24\ m=+-\ 0\m=.\1 vs 3\m=.\67\ m=+-\0\m=.\15ng/ml, respectively; P \ m=l e\0\m=.\001).When GnRH was given before (5 h before) or during (5 h after) PGF-2\g=a\-induced regression of the Day 10 spontaneous CL, the GnRH-induced CL which formed were also short-lived. In contrast, when GnRH was given following (36 h after) PGF-2\g=a\\x=req-\ induced regression of the Day 10 spontaneous CL, the CL which formed were not different in lifespan or production of progesterone from spontaneous CL. Efforts to enhance function of the GnRH-induced subnormal CL by treating ewes with the synthetic progestagen, norgestomet, to suppress follicular development after CL formation, were unsuccessful.We suggest that these results provide new evidence to support the hypothesis that subnormal luteal function may be the result of inadequate follicle development (i.e. the follicle needs exposure to some sequence of events characteristic of luteal regression and/or a normal follicular phase) which impairs uterine luteolytic mechanisms. These results also support the hypothesis that periovulatory determinants of normal luteal function are established between 5 and 36 h after PGF-2\g=a\-inducedluteal regression.