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The role of estrogen in the maintenance of primate pregnancy

      Abstract

      Objective: The aim of this study was to determine the role of estrogen in pregnancy maintenance in baboons by suppressing estrogen synthesis through administration of a highly specific nonsteroidal aromatase inhibitor, CGS 20267. Study Design: CGS 20267 was administered subcutaneously at maximal dosages of 2.0 mg/d to pregnant baboons (n = 24) daily beginning on either day 30 (n = 8), day 60 (n = 8), or day 100 (n = 8) of gestation (normal length of gestation is 184 days) until animals miscarried or were delivered abdominally on days 160 through 168 of gestation. CGS 20267 and estradiol (n = 9), each at maximal dosages of 2 mg/d, were administered at the same intervals of gestation. Twenty baboons served as untreated control animals. Serum estradiol and progesterone levels were determined by radioimmunoassay from serum samples obtained at 1- to 3-day intervals from a maternal peripheral vein. Results: Within 1 to 3 days of the initiation of CGS 20267 administration, maternal serum estradiol concentration decreased to and remained at a level that was substantially lower (mean ± SE, 0.096 ± 0.003 ng/mL) than in the untreated control animals throughout gestation (0.35-4.0 ng/mL; P < .001). Although pregnancy was maintained in 19 of the 20 untreated control baboons (95%), only 12 of the 24 animals that received CGS 20267 (50%) maintained pregnancy. In contrast, all the baboons treated concomitantly with estradiol and CGS 20267 (9/9) maintained pregnancy. Thus estradiol alone prevented the high rate of miscarriage induced by the antiestrogenic agent CGS 20267. Serum progesterone concentrations were not significantly different throughout the experimental period between the CGS 20267–treated baboons that maintained pregnancy (12.9 ± 1.4 ng/mL) and those that miscarried (13.6 ± 1.6 ng/mL) and were not lower in antiestrogen-treated baboons than in untreated control baboons (10.6 ± 0.8 ng/mL). Conclusion: Estrogen, acting directly, indirectly, or both through a factor or factors other than the level of progesterone, plays a critically important physiologic role in the maintenance of primate pregnancy. (Am J Obstet Gynecol 2000;182:432-8.)

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      References

        • Albrecht ED
        • Pepe GJ
        Placental steroid hormone biosynthesis in primate pregnancy.
        Endocr Rev. 1990; 11: 124-150
        • Pepe GJ
        • Albrecht ED
        Actions of placental and fetal adrenal steroid hormones in primate pregnancy.
        Endocr Rev. 1995; 16: 608-648
        • Albrecht ED
        • Pepe GJ
        Central integrative role of estrogen in modulating the communication between the placenta and fetus that results in primate fetal-placental development.
        Placenta. 1999; 20: 129-139
        • Albrecht ED
        • Henson MC
        • Pepe GJ
        Regulation of placental low density lipoprotein uptake in baboons by estrogen.
        Endocrinology. 1991; 128: 450-458
        • Henson MC
        • Pepe GJ
        • Albrecht ED
        Regulation of placental low-density lipoprotein uptake in baboons by estrogen: dose-dependent effects of the anti-estrogen ethamoxytriphetol (MER-25).
        Biol Reprod. 1991; 45: 43-48
        • Henson MC
        • Pepe GJ
        • Albrecht ED
        Developmental increase in placental low density lipoprotein uptake during baboon pregnancy.
        Endocrinology. 1992; 130: 1698-1706
        • Babischkin JS
        • Pepe GJ
        • Albrecht ED
        Estrogen regulation of placental P-450 cholesterol side-chain cleavage enzyme messenger ribonucleic acid levels and activity during baboon pregnancy.
        Endocrinology. 1997; 138: 452-459
        • Pepe GJ
        • Waddell BJ
        • Albrecht ED
        Activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis at midgestation by estrogen-induced changes in placental corticosteroid metabolism.
        Endocrinology. 1990; 127: 3117-3123
        • Smith OW
        Diethylstilbestrol in the prevention and treatment of complications of pregnancy.
        Am J Obstet Gynecol. 1948; 56: 821-834
        • Lehrer S
        • Sanchez M
        • Song HK
        • Dalton J
        • Levine E
        • Savoretti P
        • et al.
        Oestrogen receptor B-region polymorphism and spontaneous abortion in women with breast cancer.
        Lancet. 1990; 335: 622-624
        • Shetty G
        • Krishnamurthy H
        • Krishnamurthy HN
        • Bhatnagar S
        • Moudgal RN
        Effect of estrogen deprivation on the reproductive physiology of male and female primates.
        J Steroid Biochem Mol Biol. 1997; 61: 157-166
        • Morishima A
        • Grumbach MM
        • Simpson ER
        • Fisher C
        • Qin K
        Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.
        J Clin Endocrinol Metab. 1995; 80: 3689-3698
        • France JT
        Steroid sulfatase deficiency.
        J Steroid Biochem. 1979; 11: 647-651
        • Shozu M
        • Akasofu K
        • Harada T
        • Kubota Y
        A new cause of female pseudohermaphroditism: placental aromatase deficiency.
        J Clin Endocrinol Metab. 1991; 72: 560-566
        • Novy MJ
        • Walsh SW
        Regulation of fetoplacental steroidogenesis in rhesus macaques.
        in: Fetal endocrinology. Academic Press, New York1981: 66-94
        • Challis JR
        • Lye SJ
        Parturition.
        in: The physiology of reproduction. Raven Press, New York1994: 985-1031
        • Nathanielsz PW
        • Jenkins SL
        • Tame JD
        • Winter JA
        • Guller S
        • Giussani DA
        Local paracrine effects of estradiol are central to parturition in the rhesus monkey.
        Nat Med. 1998; 4: 456-459
        • Bhatnager AS
        • Hausler A
        • Schieweck K
        • Lang M
        • Bowman R
        Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new nonsteroidal aromatase inhibitor.
        J Steroid Biochem Mol Biol. 1990; 37: 1021-1027
        • Csapo AI
        • Pulkkinen MO
        • Ruttner B
        • Sauvage JP
        • Wiest WG
        The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary Studies.
        Am J Obstet Gynecol. 1972; 112: 1061-1067
        • Okulicz WC
        • Savasta AM
        • Hoberg LM
        • Longcope C
        Immunofluorescent analysis of estrogen induction of progesterone receptor in the rhesus uterus.
        Endocrinology. 1989; 125: 930-934
        • Magness RR
        • Rosenfeld CR
        Local and systemic estradiol-17β: effects on uterine and systemic vasodilation.
        Am J Physiol. 1989; 256: E536-E542
        • Stock MK
        • Metcalfe JM
        Maternal physiology during gestation.
        in: The physiology of reproduction. Raven Press, New York1994: 947-983
        • Younes MA
        • Besch NF
        • Besch PK
        Estradiol and progesterone binding in human term placental cytosol.
        Am J Obstet Gynecol. 1981; 141: 170-174
        • Iveson TJ
        • Smith IE
        • Ahern J
        • Smithers DA
        • Trunet PF
        • Dowsett M
        Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women.
        J Clin Endocrinol Metab. 1993; 77: 324-331
        • Lanman JT
        • Thau R
        • Sundaram K
        • Brinson A
        • Bonk R.
        Ovarian and placental origins of plasma progesterone following fetectomy in monkeys (Macaca mulatta ).
        Endocrinology. 1975; 96: 591-597