While most healthy older women who become pregnant have uneventful pregnancies and healthy babies, thousands more are unable to achieve pregnancy because of declining ovarian function. A decline in ovarian function is normal with increasing age. A woman's number of eggs steadily decreases from a peak at mid-gestation of 7 million to approximately 400,000 at puberty. Certain tests can reflect gradations in ovarian reserve status and predict a woman's potential fertility. The most important lab test is the day 2/3 follicle-stimulating hormone level.
Women with declining ovarian responsiveness and clinical outcomes consistent with declining ovarian reserve have decreased day 3 serum inhibin B levels despite having non-elevated day 3 serum FSH concentrations. Declining ovarian reserve may be demonstrated by a decrease in day 3 inhibin B levels before a rise in day 3 FSH levels. A constant source of frustration in fertility centers is that patients are referred to the specialty clinic too late, when diminished ovarian reserve is so marked that treatment success is severely limited. Earlier assessment of ovarian function would alter this unfortunate trend.
Reproductive failure in women of older age appears to be directly related to ovarian age. It seems that the age-related decline in fertility may be due more to degenerative oocytes than to aneuploidy. The decline in female fertility occurs primarily as a result of a decline in oocyte quality as well as quantity A decline in the number of oocytes retrieved with age may be of less importance than the decline in oocyte quality. Embryo implanting ability and survival decline gradually after 30 years of age, but by more than two thirds after 40 years and in younger women with reduced ovarian capacity. The frequency of chromosomal anomalies in recognized abortuses increases in parallel with the age-specific rise in the incidence of spontaneous abortions. Recent techniques such as cytoplasmic or germinal vesicle transfer are designed to replace the senescent cellular machinery believed to be responsible for genetic errors that occur during early cell division. PGD can accurately identify embryos with genetic deficiencies prior to implantation.
Research indicates that much of the decline in fecundity can be attributed to an increasing risk of fetal loss with maternal age. Much of this fetal loss is due to chromosomal abnormalities--a result of ageing oocytes. Fecundability, on the other hand, does not begin to decline until the early 40s. This is also a result of ageing at the ovarian level, namely follicular atresia, in the years just prior to menopause. The irregularity of menstrual cycles--longer cycles and increasingly variable hormonal patterns--at these ages may be a direct result of the small and rapidly dwindling remaining pool of follicles. The number of small antral follicles in both ovaries as measured by vaginal ultrasonography is clearly related to reproductive age and could well reflect the size of the remaining primordial follicle pool.
There is a significant decline in human fecundity with advancing age. A significant decrement in success rates is also seen in older women undergoing assisted reproduction, including in-vitro fertilization. We have observed a drop in the ongoing pregnancy rate per patient, from about 32 % in women aged less 30 years to lesss than 28 % in women aged more than 35 years. Embryo implantation rates also decline in a linear fashion, from 5 % in women less than 30 years to approximately 2 % at age over 40 years. We observed that the impaired implantation efficiency seen in older women is apparently independent of the magnitude of their stimulation response. Although no statistically significant relationships were found between serum FSH concentrations as obtained in the early follicular phase and the number of oocytes collected, or the total dose, there was a trend to poorer response as the FSH approached closer to 10 mIU/mL. The decline in number of oocytes retrieved with increasing age can be at times overcome by augmenting the daily dose of gonadotropins to as much as 1050 mIU/mL. Oocyte factors are felt to be primarily responsible; however, some available data suggest that uterine factors, e.g. diminished endometrial receptivity, may also play a role.
Natural fertility rates decline in most animals with age, becoming dramatically apparent in women as they enter the fifth decade of life. By the time of the perimenopause, pregnancy rarely occurs, whether or not assisted reproductive techniques are initiated. However, if oocytes are donated by young women to older women, both embryo implantation and pregnancy rates are restored to normal levels in recipients. These results strongly suggest the pregnancy wastage experienced by older women is largely a result of degenerative changes within the aging oocyte(egg), rather than senescent changes in the uterus. The poor prognosis for fertility in older women can be reversed through oocyte donation from younger individuals.
There are presently no treatment strategies apart from oocyte donation, which have been shown to significantly improve implantation efficiency in older women. Women in the older age group have a higher chance of achieving pregnancy from ovum-donation programs than by persisting in using their own aged eggs, which have a very poor prognosis for success.
However, recent efforts have focused on the continued development of improved stimulation protocols in higher doses, facilitation of embryo implantation by zona pellucida micromanipulation, and the possibility of screening preimplantation embryos for aneuploidy. Elderly women with partners who have suboptimal sperm parameters reflected by low fertilization capacity scores may benefit from micro-manipulation procedures. Egg Donation is the only answer presently until maybe Cytoplasmic Transfer becomes routine- maybe a decade from now.
