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

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 X 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 X HDE (NEA + EE) and at 10 and 25 X 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 X HDE group and two cases of increased anogenital distance with reduced vaginal opening in the 1,000 X 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 X HDE) also exhibited masculinized external genitalia.(ABSTRACT TRUNCATED AT 250 WORDS)

Development in the cynomolgus macaque following administration of ustekinumab, a human anti‐il‐12/23p40 monoclonal antibody, during pregnancy and lactation

“…Repeat studies with ABT-874 in cynomolgus monkeys showed that the clitoral protrusion represented an insignificant developmental delay, rather than a frank malformation because this was not evident at term. Clitoral enlargement in cynomolgus monkeys had previously been reported for sex steroid hormone combinations (Hendrickx et al, 1987). Therefore, for the second embryofetal development study in which ustekinumab was administered by subcutaneous injection, sex steroids were included as part of the evaluation.…”

Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption

“…Boys with Tanner stage 2 development or higher, buried penis, chordee without hypospadias, imperforate anus, exposure to corticosteroids or growth hormone, or known syndromes were excluded. Collected data Hendrickx et al [29] Cynomolgus monkey included aggregate size distribution (AASD) and potential aggregate size distribution (PASD) [4], age, height, weight, race, and urologic diagnoses. To account for prematurity, age at measurement was adjusted based on gestational age at birth.…”

Prematurity prevention: the role of progesterone

“…Epidemiologic and animal studies have found no significant relationship between clinically administered progestational drugs and congenital malformations [33,34]. However, in one study, embryonic deaths occurred in pregnant rhesus monkeys treated with intramuscular injections of 17P [35].…”