Sex at the interface: the origin and impact of sex differences in the developing human placenta

Abstract

The fetal placenta is a source of hormones and immune factors that play a vital role in maintaining pregnancy and facilitating fetal growth. Cells in this extraembryonic compartment match the chromosomal sex of the embryo itself. Sex differences have been observed in common gestational pathologies, highlighting the importance of maternal immune tolerance to the fetal compartment. Over the past decade, several studies examining placentas from term pregnancies have revealed widespread sex differences in hormone signaling, immune signaling, and metabolic functions. Given the rapid and dynamic development of the human placenta, sex differences that exist at term (37–42 weeks gestation) are unlikely to align precisely with those present at earlier stages when the fetal–maternal interface is being formed and the foundations of a healthy or diseased pregnancy are established. While fetal sex as a variable is often left unreported in studies performing transcriptomic profiling of the first-trimester human placenta, four recent studies have specifically examined fetal sex in early human placental development. In this review, we discuss the findings from these publications and consider the evidence for the genetic, hormonal, and immune mechanisms that are theorized to account for sex differences in early human placenta. We also highlight the cellular and molecular processes that are most likely to be impacted by fetal sex and the evolutionary pressures that may have given rise to these differences. With growing recognition of the fetal origins of health and disease, it is important to shed light on sex differences in early prenatal development, as these observations may unlock insight into the foundations of sex-biased pathologies that emerge later in life.

Sexing of Embryos at the Time of Twin Reduction: A Clinical Approach

“…In humans, pregnancy failure is more likely if the baby is a boy [ 59 , 60 , 61 , 62 ]. Boys grow faster than girls before implantation, and this makes them more vulnerable to compromised nutrition [ 63 , 64 , 65 ]. Probably, in all mammals, life in the maternal uterus is more dangerous for male embryos than for female embryos.…”

Sex differences in innate and adaptive immunity impact fetal, placental, and maternal health

“…PARs are often enriched with genes that code for immune signaling. CD99 is found on a PAR and is significantly higher in the undifferentiated, multipotent progenitor cells of the placenta, the cytotrophoblast (CTB) cells, of males at all points in gestation [68, 72, 73]. An additional study observed clusters of X-linked genes biased toward male overexpression on placental PARs [74].…”

“…The fetal testes begin synthesizing and secreting testosterone between 8 and 10 weeks of gestation [103]. Fetal circulating testosterone peaks at approximately week 16 and reaches concentrations analogous to circulating androgens in postpubertal males [72]. During this peak period, the testosterone concentrations of amniotic fluid are 2–5-fold higher in male compared with female amniotic fluid [104, 105].…”

“…While fetal hormones are critical for the masculinization of male fetuses, most sex steroids come from the placenta. Hormone production in pregnancy is tightly regulated and each compartment (maternal, fetal, and placental) has specific rate-limiting enzymes that tightly control the synthesis of each hormone [72]. All forms of estrogen (estriol, estrone, and estradiol) and progesterone are primarily synthesized by the placenta and are critical for the maintenance of pregnancy and prevention of parturition [118, 119].…”

Rhesus macaque fetal and placental growth demographics: A resource for laboratory animal researchers

“…Factors that determine the number of cotyledons are unknown but There is extensive evidence within the literature that demonstrates the impact of sexual dimorphism on fetal growth, development, and organ function (including the placenta) (reviewed in Braun et al, 2022;Kalisch-Smith et al, 2017;Rosenfeld, 2015;Yu et al, 2021). This provided rationale for our presentation of some data parameters stratified as male and female fetuses separately.…”