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Neonatal androgenization-induced early endocrine-metabolic and ovary misprogramming in the female rat
Luisina Ongaro1, Natalia R Salvetti2, Andrés Giovambattista1
1Neuroendocrine Unit (IMBICE, CONICET-CICPBA), La Plata, Argentina.
Insights
Neonatal exposure to excess androgens in rats caused metabolic and reproductive issues, mimicking Polycystic Ovary Syndrome (PCOS). Ovarian function was impaired, but granulosa cell function remained intact, highlighting risks for assisted reproduction.
Area of Science:
- Endocrinology
- Reproductive Biology
- Developmental Programming
Background:
- Androgen excess is linked to metabolic and reproductive disorders, including Polycystic Ovary Syndrome (PCOS).
- Neonatal exposure to androgens can disrupt normal development and lead to long-term health consequences.
Purpose of the Study:
- To investigate the effects of a single neonatal testosterone propionate (TP) dose on metabolic-endocrine and ovarian functions in rats.
- To assess the impact on steroidogenesis, granulosa cell (GC) function, and follicular dynamics.
Main Methods:
- Administered a single neonatal dose of testosterone propionate (TP) to female rat pups.
- Analyzed metabolic-endocrine parameters, ovarian steroidogenesis, GC function, and ovarian histology in juvenile and adult rats.
- Compared TP-exposed rats with control (CT) rats.
Main Results:
- TP rats exhibited accelerated growth, hyperadiposity, hyperleptinemia, and hyperinsulinemia.
- Early vaginal opening and estrous cycles arrested at estrus were observed in TP rats.
- Ovarian histology showed altered follicle frequencies and large cystic structures, indicative of PCOS-like changes, though GC function was preserved.
Conclusions:
- Transient neonatal hyperandrogenemia misprograms metabolic-endocrine and ovarian functions, leading to a PCOS-like phenotype.
- Ovarian granulosa cell endocrine function was preserved despite developmental programming disruptions.
- These findings suggest an increased risk of ovarian hyperstimulation syndrome in women with hyperandrogenemia undergoing assisted reproductive technologies.
Aim:
Androgen excess predisposes the organism to develop metabolic-endocrine and reproductive dysfunctions, among them the development of a phenotype resembling that of human Polycystic Ovary Syndrome (PCOS).
Methods:
We analyzed the impact of a single neonatal (5day-old) testosterone propionate (TP; s.c. 1.25mg/female pup) dose on: a) several metabolic-endocrine activities and b) ovarian steroidogenic and granulosa cell (GC) functions and also follicular population in juvenile and adult TP and control (CT) rats.
Key Findings:
Compared to CT rats, TP animals were characterized by: a) accelerated growth, hyperadiposity and hyperleptinemia, b) very early (pre-weaning age) vaginal opening, c) hyperinsulinemia in adult life, d) dysfunctional ovarian steroidogenesis, e) conserved GC functionality in both juveniles (in vitro) and adults (in vivo), and f) estrous cycles arrested at estrus. Finally, histological studies of the ovaries indicated that in TP (vs. CT) rats: i) primary and antral follicle frequencies were 3- and 15-fold higher and lower, respectively, in juveniles and ii) secondary and atretic follicle frequencies were 3- and 5-fold lower and higher, respectively, in adults. Large cystic images without corpus luteum were observed in the ovaries from adult TP rats only.
Significance:
Our results strongly suggest that transient neonatal hyperandrogenemia induced early misprogramming of metabolic-endocrine and ovarian (steroidogenesis/folliculogenesis) functions. Conversely, TP rats preserved their ovary GC endocrine function. Our results further support the high risk of developing ovarian hyperstimulation syndrome for infertile women with transient/chronic hyperandrogenemia (PCOS) subjected to assisted reproductive technologies.
