The intrauterine environment induces developmental adaptations that impact health and disease risk later in life. Reproductive abnormalities are now included in the long list of health complications seen in offspring exposed to early life adversity including poor prenatal nutrition. Previous work has shown using a rat model, that offspring born to mothers that were nutrient restricted (UN) during pregnancy are growth restricted, enter puberty early, and as adults, display characteristics of early ovarian aging with reduced follicle number. This present study aimed to investigate whether key proteins involved in ovarian follicle recruitment and growth, including the PI3K/Akt pathway, may be impaired as a result of early life nutritional adversity. Maternal UN resulted in irregular estrous cyclicity due to persistent estrus, a significant decrease in young adult ovarian antral follicles, corpora lutea, and a significant increase in atretic follicles. A decrease in growing follicles in UN offspring appears to be due to lowered expression of granulosa-cell secreted growth factor IGF-1 in antral follicles, and increased expression of pro-apoptotic factor Casp3 in secondary follicles of young adult offspring born to UN dams. Changes in follicle signalling pathways were apparent before observing altered ovarian function. In UN prepubertal offspring, expression levels of IGF1-R and FSHR were lowered in secondary and antral follicles respectively. These growth factors may contribute to a decrease in PI3K/Akt activation as immunohistochemical staining revealed a decrease in pAkt immunolocalization in prepubertal antral follicles. Moreover, neonatal ovaries of UN offspring show decreased levels of immunopositive staining for AMHRII, a regulatory receptor of the ovarian reserve. This study demonstrates that maternal UN during pregnancy impacts ovarian function in female offspring as early as P65. Findings from this study provides a model of understanding mechanisms of follicle loss and reproductive dysfunction as a result of nutrient restriction during fetal life. / Thesis / Master of Science (MSc)

Abstract The number of ovarian follicles declines with age resulting in a significant decrease of fertility by the age of 40. However, the age when follicle loss starts to affect ovarian endocrine function is not well recognized. The purpose of the present study was to investigate age-related ovarian/adrenal androgen secretion, which is crucial for estrogen biosynthesis in healthy women and in women with polycystic ovarian syndrome (PCOS). Another aim of the study was to compare the usefulness of different serum markers in assessing ovarian aging and in diagnosing polycystic ovaries (PCOs) and PCOS. The human chorionic gonadotropin (hCG) test was used to study the endocrine potential of ovaries/adrenals. The ovarian capacity to secrete and synthesize androgens was found to be decreased as early as at the age of 30 in regularly menstruating women. In women with PCOS, both basal and hCG-stimulated androgen levels were about 50% higher than in healthy women and they remained high until late reproductive age. Similarly to regularly menstruating women, the androgen secretion capacity in PCOS subjects decreased with age, and estradiol concentrations remained unchanged until the age of 44 years. Adrenal androgen synthesis was not changed during hCG-tests. Since serum antimüllerian hormone (AMH) and follicle stimulating hormone (FSH) levels were changed significantly after the age of 25 years in regularly menstruating women, they may be considered as useful serum markers reflecting the ovarian aging process. In women with PCOS, AMH levels were continuously 2- to 3-fold higher than in healthy women possibly reflecting high follicle number in these women. A decline in ovarian endocrine function before the age of 30 is one of the first signs of ovarian aging. However, in women with PCOS ovarian androgen secretion capacity is markedly increased and remain high throughout the reproductive years. The results of the present studies also indicate that LH/hCG does not play a role in adrenal androgen synthesis, since LH/hCG did not stimulate adrenal androgen synthesis. The measurement of AMH is a useful tool to estimate ovarian aging process as well as to diagnose PCOs/PCOS.

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