Haploinsufficiency of the Follicle-Stimulating Hormone Receptor Accelerates Oocyte Loss Inducing Early Reproductive Senescence and Biological Aging in Mice1

Abstract

Female mice that are null for the FSH-receptor (FSH-R) gene are estrogen deficient, acyclic, and sterile. However, the heterozygous (+/-) mice initially have reduced fertility and stop breeding by 7-9 mo. The purpose of this study was to understand the basis of reduced fertility in mice with haploinsufficiency of the FSH-R. Heterozygous females were compared to +/+ females at 3, 7, and 12 mo of age. By 7 mo most of the +/- females were acyclic and <50% delivered pups. The wild-type females were normal in these respects. None of the 1-yr-old +/- females gave viable offspring (73% in +/+). Many degenerative changes, including atresia and apoptosis, and profound loss of oocytes, were apparent in +/- mice by 7 mo. The 1-yr-old +/- ovary had very few follicles and consisted mostly of fibroid tissue and cysts. Our data support the hypothesis that reproductive deficits in +/- FSH-R mice occur because of accelerated oocyte loss due to increased cell death in the ovary. These events contribute to early reproductive senescence and biological aging in mice. Thus FSH-R status is an important determinant of ovarian aging and all phenomena that arise from subsequent estrogen deficiency and other aberrations.

Methods for quantifying follicular numbers within the mouse ovary

“…In particular if preantral (i.e. secondary) and antral follicles are grouped together (for ease of interpreting previous data) follicular numbers range from 57 between days 50 and 70 (Smith et al 1991) to 6800 at day 53 (Benedict et al 2000), with many variations in between (Pedersen, 1972, Ratts et al 1995, Durlinger et al 2001, Flaws et al 2001, Danilovich & Sairam 2002, Tomic et al 2002, Canning et al 2003. Our estimate for preantral and antral stages together is approximately 135 follicles per ovary based upon exact counts of serial sections where the oocyte nucleus is used as a defining feature, to avoid overestimation.…”

“…Experimentally altered ovaries may show changes of numbers and or dynamics within follicles. Follicles or oocytes may be retarded in their physical growth in size (Wang & Greenwald 1993, Danilovich & Sairam 2002 or show precocious enlargement (Wang & Greenwald 1993, Carabatsos et al 1998, Danilovich & Sairam 2002, Castrillon et al 2003 but these dysmorphic follicles are not necessarily accompanied by a change in their cytological classification. The disector method describes a probe that samples follicles with a uniform probability in a threedimensional space, irrespective of their size and shape (Gundersen et al 1988).…”

Classical Models of Senile Osteoporosis

“…3 Female mice do not appear to experience menopause but show age-related retardation of estrous cycles. 5 Age-related bone loss in trabecular bones of vertebra and femora is more pronounced in female mice, 2 which show decreases in trabecular bone as early as 2-6 months of age. However, age-related changes in the parameters of bone formation and resorption differ among femoral mid-diaphysis, metaphysis, and lumbar vertebrae, which also differ in composition of trabecular and cortical bones and in mechanical properties.…”

Androgen excess, abnormal ovarian development and associated pathologies in genetically altered FORKO female mice: a paradigm for exploring hyperandrogenism

“…A genetically altered animal, which we have called the FORKO mouse, affords unlimited opportunities to examine issues relevant to women's health. FSH-R gene disruption causes complete loss of estrogen creating steroid hormone imbalance [4,8]. Null mutants lacking mature follicles cannot ovulate and are sterile.…”

“…Null mutants lacking mature follicles cannot ovulate and are sterile. Heterozygous females undergo early ovarian senescence and lose fertility [8] reminiscent of premature ovarian failure. In addition, the appearance of other phenotypes [4] such as obesity, skeletal changes, late onset of ovarian tumors, uterine pathology in (+/ À mice), as well as neuronal deficits prompted us to perform a careful chronological study of ovarian structure and function in the mutants.…”