Embryotoxicity of sex steroidal hormone combinations in nonhuman primates: I. Norethisterone acetate + ethinylestradiol and progesterone + estradiol benzoate (Macaca mulatta, Macaca fascicularis, and Papio cynocephalus)

Andrew G Hendrickx, R. Korte, F. Leuschner, B. W. Neumann, S. Prahalada, A. Poggel, P. E. Binkerd, P. Günzel

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Two sex steroid hormone combinations which have been used clinically as tests for detection of early pregnancy were examined for embryotoxic effects in macaques and baboons. Norethisterone acetate and ethinyl estradiol (NEA + EE) were orally administered to rhesus and cynomolgus monkeys and baboons at dosages ranging from one to 1,000 times the human dose equivalent (HDE) during days 20–50 of pregnancy. Progesterone and estradiol benzoate (P + EB) were delivered by two to six intramuscular injections to rhesus and cynomolgus monkeys between gestational days 20 and 35 at 0.1–25 × HDE. Fetuses were examined following cesarean section at 100 ± 2 days (NEA + EE) or at term (P + EB). The results showed increased embryolethality over controls at 100–1,000 × HDE (NEA + EE) and at 10 and 25 × HDE (P + EB). Besides growth retardation, isolated cases of minor nongenital malformations were observed only in cynomolgus monkeys following treatment with both hormone combinations mainly at embryolethal dose levels and were considered spontaneous in nature. Virilization of female cynomolgus fetuses following NEA + EE treatment was manifested as two cases of clitoral enlargement in the 300 × HDE group and two cases of increased anogenital distance with reduced vaginal opening in the 1,000 × HDE group. The highest dose of NEA + EE was also maternally toxic, as two maternal deaths occurred at the end of the treatment period. One dead female cynomolgus fetus exposed to P + EB (10 × HDE) also exhibited masculinized external genitalia. The results support epidemiologic and laboratory data which indicate that sex steroid exposure during early pregnancy does not induce nongenital teratogenicity.

Original languageEnglish (US)
Pages (from-to)119-127
Number of pages9
JournalTeratology
Volume35
Issue number1
DOIs
StatePublished - 1987

ASJC Scopus subject areas

  • Embryology
  • Toxicology
  • Developmental Biology
  • Health, Toxicology and Mutagenesis

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