Ovarian Hormones · Progesterone
Bartholomeusz RK et al., 1976 · Biol Reprod
Progesterone, at five times normal 24 h endogenous production rates, was administered daily to 37 rats over Days 2 to 10, 11 to 17 or 2 to 21 of gestation: term is Day 23. Peanut oil, the vehicle, was administered alone to 18 control rats over Days 2 to 21. The effect of treatment on fetal, placental and corpus luteal weights was examined on Day 22 of gestation. The administration of progesterone had no apparent effect on the maternal weight gain with pregnancy, myometrial, fetal or placental weights. No external malformations or abnormalities of the internal genitalia were detected in any of the fetuses examined. The mean number of dead fetuses per litter, 0.72 ± 0.19 (SEM) in the control rats, was significantly increased to 1.57 ± 0.34 and 2.25 ± 0.54 in rats treated with progesterone over Days 11 to 17 and 2 to 21 respectively. Male fetuses were about 7.4 percent heavier than female fetuses in the control rats but this difference was significantly less in rats treated with progesterone over Days 11 to 17(3.4 percent). Progesterone treatment had no apparent effect on the mean corpus luteal weight per rat. Over all groups combined, the mean corpus luteal weight was negatively related to the number of corpora lutea per rat. This relationship was unlikely to have been due to local nutritional or overcrowding factors since there was no apparent relationship between corpus luteal weight and the number of corpora lutea in the one ovary.
Ovarian Hormones · Androgens
Schardein JL, 1980 · Teratology
A review of the extensive literature on the subject indicates that sex hormones have been associated with a wide variety of adverse clinical conditions following usage during pregnancy. About 230 cases of female pseudohermaphroditism have been reported following use of hormones with androgenic potency, but masculinization observed with estrogens in a few females may represent only adrenal-stimulated pseudohermaphroditism. Feminization of males, mostly by progestogens in some 45 cases, is unproven at present. Realizing the limitations of the published studies when all present data are considered, there seems no justification for undue concern over the induction of nongenital congenital malformations through hormone use in pregnancy. The available data on the association to cardiac, limb, and CNS defects, and to several malformative syndromes, are not convincing: the effects appear to be remarkably nonspecific, the studies are contradicted by a large number of negative reports, and an increased incidence of defects with increased usage has not materialized. A possible exception are the CNS malformations associated with the use of the antifertility agent clomiphene, and careful surveillance is warranted at present. While a reasonable interpretation from this review would be that hormones present no major teratogenic hazard, elimination of hormonal exposure whenever possible during pregnancy is suggested.
Fetal Medicine · Congenital Anomalies
Wilkins L et al., 1958 · J Clin Endocrinol Metab
There are relatively few reports of female pseudohermaphrodism not associated with congenital adrenal hyperplasia. The writers report 21 cases of females born with partial masculinization of the external gcnitalia, consisting of an enlarged phallus, with or without varying degrees of fusion of the labioscrotal folds. The diagnosis was established by finding female chromatin patterns, low excretion of urinary 17-kctosteroids and absence of progressive virilization. Exploratory laparotomy revealed normal ovaries and a normal female genital tract, although in some cases the vagina and urethra opened into a common urogenital sinus. In 15 of the cases, the mother had been treated because of threatened or habitual abortion with an oral progestin, 17-cthinyltestosterone (anhydrohydroxyprogesterone or ethisterone), marketed undersuch trade names as Pranone, Progestoral and Lutocjlol. In 2 cases the mother had received intramuscular injections of progesterone. In 1 case both intramuscular progesterone and oral methyltcstosterone had been given. In 3 cases no steroids were administered during pregnancy. The progestinic medication was usually begun before the tenth week of gestation and in most instances between the fourth and sixth weeks. Reasons are discussed for believing that the oral and intramuscular administration of progestins induced the partial masculinization of the female fetus. It is believed that the female fetus is affected in only occasional mothers who receive these steroids, and that in such mothers there may be an abnormality of cither the metabolism of progestins or their transmission across the placenta. It is most important to diagnose the condition correctly at birth, and to rear the infant as a female. No treatment is required except surgical correction of the abnormalities of the external genitalia. Normal female development is certain.
Fetal Medicine · Congenital Anomalies
Prahalada S et al., 1985 · Teratology
A single dose of MPA (Depo-Provera; Upjohn Co., Kalamazoo, Michigan) was administered intramuscularly to 12 time-mated pregnant cynomolgus monkeys on day 27 (+/- 2) of gestation at 25 mg/kg or at 100 mg/kg. Maternal blood samples were collected immediately prior to MPA injection and then at regular intervals until cesarean section at term (day 152 +/- 3). Infants in both dose groups had external genital abnormalities. Female infants in the low-dose groups had partial or complete labial fusion, prominent median raphe, and clitoral hypertrophy; at high doses (100 mg/kg), the female infants had complete labial fusion and a distinct penile urethra. MPA had an opposite effect on external genitalia of male infants. The penis was short and the scrotal swelling was absent or less conspicuous, and two males had hypospadias. The adrenal glands were significantly smaller (P less than 0.05) in infants of both sexes treated with 100 mg/kg. One of the infants treated with 25 mg/kg of MPA had a muscular ventricular septal defect. Serum concentrations of MPA were determined by radioimmunoassay in eight pregnant monkeys. In the 25 mg/kg group the patterns of MPA profiles in the serum were similar in all four animals. An initial peak occurred at 24-48 hr postinjection (2.7-9.6 ng/ml), followed by a slight decrease at 3 days postinjection (gestational day 30), and then a steady increase to maximum levels of 10-14 ng/ml occurring between gestational days 37 and 50. Serum levels gradually declined to concentrations below 5 ng/ml by midgestation in three of four monkeys. By comparison, both the patterns and magnitude of MPA concentration showed great interanimal variation in the 100 mg/kg group. MPA was present in cord blood at measurable concentrations in infants at both dose groups; the levels ranged from 0.6 to 8.3 ng/ml, corresponding to 40-72% of the maternal concentrations. These results demonstrate that a single injection of MPA during early pregnancy causes selective embryotoxicity in both male and female fetuses. Presence of high levels of MPA in maternal sera during the critical period of genital development can cause specific genital defects; however, the exact mechanism by which MPA causes these paradoxical genital abnormalities is unknown.