Fetal programming of sexual development and reproductive function

Abnormal concentrations of steroid hormones in critical windows of hypothalamus–pituitary–gonadal axis development adversely impact sexual maturation and reproductive function

Abstract

The recent growth of interest in developmental programming of physiological systems has generally focused on the cardiovascular system (especially hypertension) and predisposition to metabolic dysfunction (mainly obesity and diabetes). However, it is now clear that the full range of altered offspring phenotypes includes impaired reproductive function. In rats, sheep and nonhuman primates, reproductive capacity is altered by challenges experienced during critical periods of development. This review will examine available experimental evidence across commonly studied experimental species for developmental programming of female and male reproductive function throughout an individual’s life-course. It is necessary to consider events that occur during fetal development, early neonatal life and prior to and during puberty, during active reproductive life and aging as reproductive performance declines.

Sex steroid exposure

Fetal programming of sexual development and reproductive function, US National Library of Medicine National Institutes of Health, Molecular and Cellular Endocrinology, NCBI PubMed PMID: 24045010, 2014 Jan.

Image credit Newman University.

Prenatal estrogen exposure significantly affects reproductive tract development, clearly shown by the teratogenic effects of diethylstilbestrol (DES), a drug used in the 1950s and 1960s in the attempt to prevent spontaneous abortion and other pregnancy complications.

Daughters of women treated with DES showed higher rates of cervical dysplasia , vaginal hypoplasia, vaginal and cervical clear cell adenocarcinoma, uterine malformations,  menstrual irregularities, lower fertility, ectopic pregnancy and premature delivery.

Sons of women treated with DES exhibited symptoms of testicular dysgenesis including epididimal cysts, hypospadias, cryptochidism and low semen quality.

DES effects have been shown to cross generations, the sons of DES daughters exhibit a higher proportion of hypospadias compared to sons of non-exposed mothers.

DES administration to pregnant and lactating ewes and mice produces similar effects to those seen in humans. Experimental studies have revealed DES effects at the hypothalamic and pituitary levels. Female rats exhibit hypothalamic masculinization and increased FSH and LH levels. DES developmental effects include epigenetic alterations in the mammary gland that may increase the incidence of breast cancer in later life.

Exposure of prepubertal female rats to estradiol disrupts ovarian dynamics, causes anovulation and advances fertility. In males, neonatal estrogen exposure increases germ cell apoptosis, reduces testosterone levels and compromises sperm morphology, sperm motility patterns, and sperm numbers in the adult epididymis without alterations in LH. Estrogen administration to male pups during the postnatal period decreases gonocyte proliferation and migration towards the basal lamina causing their degeneration and decreasing the final population of germ cells and their testicular function. Goyal et al., have reported that exposure of male rats to DES from postnatal day 2 to 12 induces penile abnormalities evident by postnatal day 18 and associated with reduced plasma testosterone and overexpression of estrogen receptor (ER)a, without androgen receptor (AR) alterations. Similar results and decreased fertility occur due to exposure to estradiol.

Other endocrine disrupting compounds, either estrogenic, antiestrogenic or antiandrogenic (bisphenol A, organochlorine pesticides, phthalates, dioxins, and flutamide) have been associated with urogenital malformations, altered fertility  and reproductive cancers in humans and rats. No data exist on developmental exposure to progesterone, a critically important issue in the light of the current extensive use of progestagenic compounds as potential treatments for premature labor and progestin contraceptives during lactation. The extensive demonstration of developmental programming by steroids given above provides a compelling argument for studies on progestagens.

In summary, abnormal (both decreased and elevated) concentrations of steroid hormones in critical windows of hypothalamus–pituitary–gonadal axis development adversely impact sexual maturation and reproductive function.

DES DIETHYLSTILBESTROL RESOURCES

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