From the Guidelines
The ovary becomes less sensitive to gonadotropin stimulation with age primarily due to a decline in both the quantity and quality of remaining follicles, as evidenced by the reduction in retrieved oocytes with increasing age, from 15.4 ± 8.8 in women <26 years to 9.9 ± 8.0 in women 36-40 years old 1. This decline in ovarian sensitivity is closely related to the depletion of the ovarian reserve, which includes a decrease in the number of primordial follicles available for recruitment and development. As women age, the remaining follicles undergo cellular aging processes, including increased oxidative stress, mitochondrial dysfunction, and DNA damage in both oocytes and surrounding granulosa cells.
- The number of retrieved oocytes is reduced in women with poor ovarian reserve, which is often indicated by low Anti-Müllerian Hormone (AMH) levels due to ovarian surgery or age 1.
- Recent data have shown that the cumulative live birth rate is significantly affected by the number of cryopreserved oocytes and the age of the woman, with a cumulative live birth rate of 61.9% if 12 oocytes were cryopreserved in women 35 years of age and 43.4% if 10 oocytes were cryopreserved in women >35 years of age 1. The follicles that do remain often have reduced expression of follicle-stimulating hormone (FSH) receptors on granulosa cells, impairing their ability to respond to gonadotropin signals. Additionally, age-related changes in the ovarian microenvironment, including altered paracrine signaling, reduced blood flow, and changes in the extracellular matrix, further compromise follicular response.
- The efficacy of oocyte and embryo cryopreservation to generate a subsequent pregnancy is tightly connected to the number of mature oocytes retrieved after ovarian stimulation, which is age-dependent 1. Hormonal feedback mechanisms also become dysregulated with age, with decreased inhibin B production leading to elevated FSH levels that may cause receptor desensitization. These combined factors result in follicles that require higher doses of gonadotropins to achieve adequate stimulation, explaining why older women often need increased medication during fertility treatments to achieve ovarian response.
From the Research
Ovarian Sensitivity to Gonadotropin Stimulation with Age
- The ovary becomes less sensitive to gonadotropin stimulation with age due to various factors, including the decrease in primordial follicle numbers 2.
- As women age, the average number of primordial follicles per ovary decreases, leading to a decrease in inhibin B, which in turn leads to an increase in follicle-stimulating hormone (FSH) 2.
- The age-related decrease in ovarian primordial follicle numbers also leads to a decrease in the numbers of small antral follicles, making the ovary less responsive to gonadotropin stimulation 2.
Gonadotropin Regulation of Ovarian Follicle Growth and Development
- Gonadotropins, such as FSH and luteinizing hormone (LH), play a crucial role in regulating ovarian follicle growth and development 3, 4.
- The dose of gonadotropins used in ovarian stimulation may affect cycle success, with optimal dosing depending on individual factors such as age and ovarian reserve 4.
- Estrogen receptors, particularly estrogen receptor β (ERβ), regulate gonadotropin responses during folliculogenesis, with ERβ playing a vital role in regulating gonadotropin-induced gene expression in granulosa cells 5.
Age-Related Changes in Ovarian Function
- As women approach menopause, they experience a gradual increase in follicular phase FSH and a decrease in inhibin B, leading to erratic and unpredictable cycle characteristics 2.
- Anovulatory cycles become more frequent with age, characterized by low levels of inhibin B, markedly increased levels of FSH, and low levels of estradiol (E2) 2.
- The marked decrease in follicle numbers during late reproductive age predisposes to erratic and unpredictable cycle characteristics, with normal ovulatory cycles continuing to occur episodically 2.