Causes of Infertility: AGE/BIOLOGICAL CLOCK
Causes of Infertility: AGE/BIOLOGICAL CLOCK
A woman is born with all the eggs she will ever have. After menstruation starts, a monthly process of using up numerous eggs continues until the menopause, when most of her eggs have been used up, and both ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function begins to wane rapidly over a 5 to 10-year period, referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) levels begin to rise, Inhibin B concentrations fall (both as measured on the third day of a spontaneous menstrual cycle), and growing ovarian resistance to gonadotropins (stimulation medications) develops. Simultaneously, symptoms such as hot flashes, vaginal dryness and emotional instability emerge and then progressively worsen, the closer the woman gets to the menopause.
While the age of onset of both the climacteric and the menopause is largely genetically determined (and may vary from woman to woman) other factors, such as exposure to environmental toxins, radiation, systemic and pelvic pathology or surgery that compromises ovarian blood flow, can influence the timing of both events. Most American women will enter the climacteric in their early to mid forties and enter the menopause around age 45 to 55.
Egg quality progressively declines after age 35 as a normal consequence of progressive aging, such that an ever increasing number of a woman’s egg quota will, upon fertilization, have an abnormal chromosome number and/or structure (i.e., aneuploidy). It is important to note that even in young women, over 60% of eggs are aneuploid. The incidence increases with advancing age, so that by age 40-42 years, the incidence is probably around 80% – rising to over 90% by age 44-45.
Many aneuploid embryos develop into blastocysts (embryos). Some of these even implant into the uterine lining. While most aneuploid embryos will usually miscarry early in the first trimester of pregnancy, a few continue to develop into viable fetuses, some of which proceed to a live birth and manifest as a birth defect such as Trisomy-21 (Down’s syndrome).
The increased prevalence of embryo aneuploidy with advancing age also serves to clarify why the incidence of “infertility,” miscarriage, and chromosomal birth defects increases as women get older, and why infertility treatment becomes less effective.
The misconception that a raised FSH level is a cause of “poor embryo quality” stems from the observation that both commonly occur together during the climacteric. The young women who prematurely enter the climacteric commonly produce “good quality eggs and embryos” at IVF, (albeit that the number of both is likely to be low). Conversely, older women (e.g., in their mid-40s) with normal FSH and inhibin B levels routinely yield surprisingly large number of eggs/embryos, however these remain highly susceptible to quality-related deficiencies. Simply stated, it is age and not ovarian reserve that influences “egg/embryo quality.”
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