P-593 developmental programming by maternal androgen excess is mediated by androgen receptor pathways
Authors: Lu H , Jiang H , Li C , Pui H P , Lindgren E , Risal S , Torstensson S , Eriksson G , Ohlsson C , Benrick A , Stener-Victorin E , Deng Q 
Published: June 2023

Abstract

Study question
How does maternal hyperandrogenism featured PCOS-pregnancy affects the placental and embryo development and further contributes to the development of PCOS-like phenotypes in adult offsping?

Summary answer
Maternal hyperandrogenism compromises PCOS-pregnancy and embryo development due to placenta dysfunction, leading to the subsequent development of anxiety-like behavior and/or impaired metabolism in adult offspring

What is known already
Women with PCOS suffer an increased risk of having miscarriage, preterm delivery, and perinatal mortality. The hostile in utero environment because of maternal hyperandrogenism likely play a detrimental role in embryo development as well as the disease susceptibility later in life. As according to previous findings, daughters of women with PCOS have 5 fold increased risk of getting PCOS diagnosis, while sons of women with PCOS suffer from metabolic diseases.

Study design, size, duration
We used a PCOS-like mouse model induced by continuous exposure to dihydrotestosterone (DHT) from prepuberty, which developed obesity, anovulation, and abnormal ovarian morphology to study the effects of maternal hyperandrogenism during pregnancy. In comparison, we also simultaneously treated PCOS-like females with flutamide, an androgen-receptor blocker. We examined embryos at E10.5 and E13.5 focusing on placentas in relation to embryo development. Their male and female offspring is also phenotyped until 6 months of age.

Participants/materials, setting, methods
To explore molecular mechanisms contributing to the developmental defects, whole genome bisulfite and bulk RNA sequencing of placenta were performed. Human Trophoblast organoid culture under different conditions was applied to further evaluate the detrimental effects of maternal hyperandrogetism in placental development. With the help of trophoblast organoid culture system, possible treatment options are also going to be explored.

Main results and the role of chance
We found a lower pregnancy rate and impaired placentas together with defective embryonic development, which was partially prevented when co-treated with the androgen receptor blocker, flutamide. RNA sequencing of the placenta revealed that DHT severely interferes with placental and fetal development, which are prevented by the treatment with flutamide. In addition, the placenta from DHT-exposed dams showed impaired differentiation capacity of cell types located in the labyrinth. The hyperandrogenic maternal environment led to the development of anxiety-like behavior and impaired metabolism in adult male offspring and partial disturbance in the metabolism of female offspring later in life. The effect of hyperandrogenism on trophoblast differentiation and metabolic capacity is still under investigation.

Limitations, reasons for caution
Although androgen receptor pathway was found to be responsible for placental and fetal abnormalities and the development of adult phenotypes, and the treatment with flutamide prevented most of the unfavorable effects, the use of flutamide in clinic is tightly regulated and not suggested for women with PCOS.

Wider implications of the findings
Maternal hyperandrogenism greatly compromises PCOS-pregnancy and embryo development due to placenta dysfunction, leading to the subsequent development of unfavorable phenotypes in adult offspring. Such effects are mainly mediated by the androgen receptor pathway as the administration of flutamide partially prevents the compromised placenta and fetal development.

Trial registration number
not applicable