Effect of Natural Progesterone Treatment during Pregnancy on Fetal Testosterone and Sexual Behavior of the Male Offspring in the Mouse

Abstract

The effect of maternal exposure to progesterone upon the fetal pituitarygonadal axis and the sexual behavior of the male offspring of mice were studied. Daily injection of progesterone from days 14 to 16 of pregnancy reduced testosterone production in the fetus but caused a significant increase in circulating LH levels. Progesteroneexposed males showed no alteration in anogenital distance or in body weight at any time from birth to adulthood. At 80-90 days of age males from control and progesteroneexposed groups did not differ from each other in testis and seminal vesicle weights. However, in the latter group, there was a marked reduction in the percentage of males that displayed mount, intromission and ejaculation patterns. These findings indicate that in utero exposure to pharmacological doses of progesterone that do not cause abnormalities of male internal and external genitalia may interfere with masculine behavior in adulthood. This alteration could partially be due to diminished peripheral testosterone levels during the prenatal period.

NTP Research Report on the Scoping Review of Prenatal Exposure to Progestogens and Adverse Health Outcomes

“…Significant results were reported in 20 of the 28 studies evaluating nervous system effects; however, assessing the evidence for any potential pattern of effects for most outcomes was difficult due to too few studies per exposure and outcome pair, heterogeneity in the endpoints assessed within a domain, and/or heterogeneity in the results ( Figure 6). The most consistent results were reported for studies evaluating sexually dimorphic behavior, with 10 of 12 studies reporting significant findings of alteration in mating behavior with apparent feminization of males and masculinization of females following exposure to progesterone (3 studies) (Hull et al 1980;Pointis et al 1987;Regestein et al 1975), cyproterone acetate (4 studies) (Etzel et al 1974;Perakis and Stylianopoulou 1986;Vega Matuszczyk and Larsson 1995;Ward 1972;Ward and Renz 1972), or allylestrenol (3 studies) (Csaba et al 1993;Karabelyos et al 1994a;Karabelyos et al 1994b) in various animal models (e.g., rats, mice, guinea pig) [see Nervous System, Filter -Effect Significance in Tableau (NTP 2020)]. An additional study that did not conduct statistical analyses reported that 11 of 14 male guinea pigs prenatally exposed to cyproterone acetate did not display mating behavior toward females in estrus (Etzel et al 1974).…”

“…No congenital malformations were observed following prenatal exposure to 17OHPC (five studies) (Carbone and Brent 1993;Hendrickx et al 1987;Johnstone and Franklin 1964;Schardein et al 2012;Seegmiller et al 1983), similar to its absence of effect in human studies. In contrast to the bird and fish models, no congenital malformations were reported in the studies evaluating progesterone in nonhuman mammalian models (Foote et al 1968;Harini et al 2009;Pointis et al 1987;Wharton and Scott 1964) or in an amphibian model (Thomson and Langlois 2018).…”

“Natural” progesterone: information on fetal effects

“…In an additional study not included in Table 3 (because female newborns were not included), Pointis et al (1987) reported no effect on anogenital distances in newborn male mice after maternal progesterone administration (2 mg/kg) on gd 14-16.…”

“…Only one study was found that examined reproductive function of males after gestational exposure to exogenous progesterone. Pointis et al (1987) administered 2 mg/day progesterone to pregnant mice on gd 14, 15, and 16 via subcutaneous injections. Plasma obtained from fetuses on gd 17 showed significantly lower testosterone, and higher LH with no change in FSH.…”

Comparative Study of Doses of Exogenous Progesterone Administration Needed to Delay Parturition in Jcl:MCH(ICR) Mice

“…In repeated administration of P4 to mothers in the perinatal period in studies of delayed parturition models and in production using reproductive engineering with P4, we assume that one of the factors in the low survival rates of pups, in reproductive engineering in particular, is the 2 mg dose which the results of this study demonstrate is an overdose. In addition, it was reported that P4 injection of pregnant mice induces testosterone production in the fetus [11] and decreases masculine sexual behavior after birth and maturity [12]. Therefore, overdosing pregnant mice with P4 may not be the only reason for the decrease of the survival rate after Caesarean section in reproductive engineering, as sexual dysfunction after maturity in next generation is also a possible cause.…”