Constitutive expression of Steroidogenic factor‐1 (NR5A1) disrupts ovarian functions, fertility, and metabolic homeostasis in female mice

Abstract

Steroid hormones regulate various aspects of physiology, from reproductive functions to metabolic homeostasis. Steroidogenic factor-1 (NR5A1) plays a central role in the development of steroidogenic tissues and their ability to produce steroid hormones. Inactivation of Nr5a1 in the mouse results in a complete gonadal and adrenal agenesis, absence of gonadotropes in the pituitary and impaired development of ventromedial hypothalamus, which controls glucose and energy metabolism. In this study, we set out to examine the consequences of NR5A1 overexpression (NR5A1+) in the NR5A1-positive cell populations in female mice. Ovaries of NR5A1+ females presented defects such as multi-oocyte follicles and an accumulation of corpora lutea. These females were hyperandrogenic, had irregular estrous cycles with persistent metestrus and became prematurely infertile. Furthermore, the decline in fertility coincided with weight gain, increased adiposity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance, indicating defects in metabolic functions. In summary, excess NR5A1 expression causes hyperandrogenism, disruption of ovarian functions, premature infertility, and disorders of metabolic homeostasis. This NR5A1 overexpression mouse provides a novel model for studying not only the molecular actions of NR5A1, but also the crosstalk between endocrine, reproductive, and metabolic systems.

Deficiency of Wnt10a causes female infertility via the β-catenin/Cyp19a1 pathway in mice

“…Ovarian follicular granulosa cells are key cells in steroid hormone production and secretion. β-Catenin is an essential transcriptional regulator of Cyp19a1, activating the expression of Cyp19a1 in the granulosa cells through the functional interactions with Sf1 31 . The transcription factor Sf1, encoded by nuclear receptor family 5 group A member 1 (NR5A1), plays a crucial role in the development and function of the adrenal glands and reproductive tissues at multiple levels 32 .…”

An extra-genital cell population contributes to urethra closure during mouse penis development

“…Despite its critical functions in penis development, how 5α-reductase expression is activated in the fetal external genitalia has yet to be defined. The expression of many steroidogenic enzymes in gonads and adrenals are induced by the orphan nuclear receptor Steroidogenic factor 1 or NR5A1, the master regulator of steroidogenesis (16, 17). We therefore hypothesized that NR5A1 could be responsible for 5α-reductase expression in fetal external genitalia.…”

Steroidogenic factor 1 (SF-1; Nr5a1 ) regulates the formation of the ovarian reserve

“…In contrast, depletion from the periovulatory follicle, after the ovulatory signal ( Pgr -Cre), results in a phenotype of subfertility, accompanied by defects in ovulation, cumulus expansion, and luteinization ( 25 ). Overexpression of SF-1 in the mouse ovary results in polyovular follicles and accumulation of corpora lutea ( 17 , 51 ). Taken together, these results suggest that the disrupted ovarian phenotype observed in SF-1 cKO mice at later ages is due primarily to the effects of depletion of SF-1 during the process of follicular formation.…”

“…Similarly, mice with knockout of LFNG, a Notch regulator, display multiple polyovular follicles ( 55 ). Strikingly, ovarian overexpression of SF-1 results in a similar phenotype of polyovular follicles, driven at least partially by dysregulation of Notch signaling ( 51 , 56 ). These data suggest that inhibition of the Notch pathway results in reduction in oocyte attrition during cyst breakdown, indicating that an increase in Notch in the SF-1 cKO model may be another driver of the increased oocyte attrition.…”

“…Previous work suggested that fine-tuning SF-1 expression during and after ovarian differentiation is required for normal ovarian development, with prenatal overexpression and underexpression resulting in disrupted ovarian function ( 51 , 56 , 66 ). Given that SF-1 germline knockout results in gonadal agenesis, Combes et al ( 66 ) generated a model of hypomorphic SF-1 expression prior to gonadal differentiation using Cited2 −/− mice.…”