Female fertility over 40
Modern lifestyles have led couples, and especially women, to have children relatively late in life. According to statistics (most of them are Americans, but experience shows that statistics are similar in western societies, including Greece), women over 40 are the only age group where birth rates are rising. Today, about 3% of births are performed by women over the age of 40, and of course, there are many medical challenges regarding fertility in this age group. The percentage of genetically normal ova decreases to less than 10% in women over 40 years while there is a high rate of miscarriages (33%) which is even higher in women over 45 years (> 50%). While infertility issues are more frequent over the age of 40, there are some benefits. Women who give birth after the age of 40 have higher rates of education and research shows that it is more likely to take care of their children than younger mothers.
In addition to fertility issues, there are higher risks for children born to older mothers. The incidence of Down syndrome, for example, in women over 45 years old reaches 1 in every 12 births, compared with 1/350 in women under 30 years of age. Autism rates are 50% higher in children whose mothers were over 40 years old. Also, higher rates of developmental delays and food allergies have also been reported in these children.
In women over 40, the total number of ova in the ovaries decreases and there is also a reduction in the percentage of genetically normal oocytes. Also, as we age, the environment of the endometrium and cervical mucus changes, and there is an increased incidence of menstrual cycle abnormalities.
When women over the age of 40 try to conceive, the most common problem is the storage (reserve) of oocytes in their ovaries. The term ovarian reserve refers to a woman's reproductive potential and includes factors such as the number and quality of oocytes, their fertility (chance of achieving pregnancy), and their response to ovarian stimulation (both exogenously with drugs and endogenously with hormones). The determination of the ovarian deposit can be complicated, but it is necessary in order to evaluate and provide the kind of support a woman may need.
In order to estimate the ovarian reserve, scientists measure the level of the follicle-stimulating hormone (FSH). FSH is measured on the 2nd, 3rd, or 4th day of the menstrual cycle, and FSH values < 10 IU/L are indicative of optimal ovarian response. Low FSH levels indicate that there may be an ovarian response. As the ovaries become less receptive to the signal from the pituitary gland, the negative feedback of estradiol to the hypothalamus and pituitary gland decreases, and thus FSH levels become increase. This is especially evident in menopause, where complete ovarian failure often results in a high increase in FSH levels. Studies show that when the FSH is > 18 IU/L there is a very high specificity in the prediction of the failure to achieve a normal pregnancy (but the sensitivity of the prediction is much lower). The measurement of FSH level has a high specificity (83-100%) in predicting the poor response during ovarian stimulation, but there is great variability as well as different reference values in the medical literature. Estradiol (E2) levels should be measured along with FSH, as an early increase in serum estradiol concentration constitute a classic feature of reproductive aging and may also lead to a decrease of elevated FSH level within normal limits. If FSH level is within normal limits but estradiol is elevated (> 60-80 pg/mL) in the early follicular phase, this may indicate a poor ovarian response and a low chance of pregnancy. Other tests, such as clomiphene citrate challenge tests and follicle measurement, can also be used in order to assess ovarian response.
A popular laboratory marker in blood serum for the evaluation of ovarian reserves is the Anti-Müllerian hormone (AMH). AMH is produced by primary follicles (follicles in early development) and does not show significant fluctuations during the menstrual cycle. Optimal AMH levels are between 4.0-6.8 ng/mL (28.6-48.5 pmol/L). Low fertility and ovarian reserve are observed when AMH level falls below 2.2 ng/mL (15.7 pmol/L).
There are four main factors, which explain the changes that occur in fertility with age and which also explain the difficulties in achieving pregnancy. These factors refer to the reduction of androgens in the ovaries, to mitochondrial abnormalities, to the shortening of telomeres in the oocytes, and finally to the dysfunction of granulosa cells as a result of their exposure to oxidative stress.
It has been observed an age-related decrease in testosterone production by theca cells in women. Testosterone increases the activity of the FSH receptor in the ovaries, stimulates IGF-1 (Somatomedin C or Insulin 1-like Growth Factor) which can enhance the metabolism of oocytes and their maturation and improve the health of granulosa cells. There is a positive correlation between free androgen index (FAI) and insulin sensitivity with the number of follicles after stimulation in women without polycystic ovary syndrome (PCOS) and in non-obese women with polycystic ovary syndrome. Also, there is a correlation between high testosterone level and the number of oocytes collected (after correction for age, BMI, smoking, and time). Interestingly, women with polycystic ovaries tend to be better candidates for IVF as they age, possibly due to higher testosterone than women without PCOS, and women with PCOS tend to retain the ability to have children at a more advanced age.
Testosterone-targeting therapies, including testosterone, DHEA, aromatase inhibitors such as letrozole, the administration of low doses of LH, growth hormone, and IGF-1, have significant success rates in improving female fertility. For example, DHEA (in women over 35) has been shown to improve ovarian storage, promote the growth of primary follicles, increase pregnancy rates, and reduce miscarriage rates. AMH level also responds to DHEA administration. In addition, aromatase inhibitors can be given even though the diet (green tea, green vegetables - kale, broccoli, etc - and grape seed extract).
Mitochondrial changes constitute both the cause and the result of increased production of reactive oxygen species (ROS) and other toxic metabolic by-products. Inside the ovary, oxygen-free radicals play an important role and are essential for ovulation. ROS is also involved in apoptosis (cell destruction) of tertiary follicles. Older granulosa cells present a reduced ability to neutralize ROS, as is indicated by the reduced level of peroxide dismutase and glutathione. This reduced ability to neutralize free radicals due to the process of aging can lead to increased damage to lipids, proteins, and DNA in the ovaries. But in addition to oxidative stress, carbonyl stress also plays a role in age-related ovarian damage. Glycolysis produces endogenous active metabolites called reactive carbonyl radicals (RCs) that can interact with proteins, lipids, and DNA. These reactive carbonyl radicals can glycosylate proteins, causing the formation of stable end-products called advanced glycosylation end products (AGEs), which destroy proteins and impair the function of enzymes. AGEs have been linked to several chronic conditions and can also be developed in ovarian tissue, leading to vascular damage, cellular hypoxia, decreased cellular nutrient uptake and increased oxidative stress. All of these conditions can pose a threat to follicular maturation and the integrity of chromosomes.
Carbonyl and oxidative stress can be treated through a healthy Mediterranean diet with an emphasis on blood sugar balance, exercise, and a targeted diet such as green tea and polyphenols. In addition, special antioxidant supplements can mitigate the effects of oxidative and carbonyl stress on fertility. Several studies have demonstrated the positive effect of melatonin on fertility, including improved ovum maturation, increased fertility rates, and pregnancy rates in women undergoing IVF.
Mitochondrial damage is another factor that contributes to the aging of the ovaries. The oocyte has the largest number of mitochondria and the largest mitochondrial DNA copy number per cell in the body (200.000 copies per cell, a number 1 to 2 times above the mitochondrial DNA copy number of the most energy-intensive somatic cells, such as neurons and muscle cells). Nutrients that support mitochondrial function, such as coenzyme Q10 (CoQ10), provide benefits in supporting fertility in both men and women. The deficiency of CoQ10 in the ovaries can lead to decreased energy production, increased production of oxygen free radicals, increased lipid oxidation, and cell death. Animal studies have shown that the intake of CoQ10 supplements can increase follicular maturation. In addition to CoQ10, α-lipoic acid can also help in neutralizing oxidative stress.
Less research has been done on the fourth factor of oocyte aging, which is telomere shortening. It is known that telomere shortening occurs in every cell division, it depends on the genetic predisposition and also increases after exposure to ROS and other toxins that can damage our DNA. Some cells, such as stem cells, cancer cells, and spermatozoa, express compensatorily the enzyme telomerase (an enzyme that inhibits telomere shortening). The follicles cannot compensate for the shortening of telomeres, possibly in the context of evolutionary adaptation in order to be ensured that only the healthiest women will have children.
Additional nutrients that may be administered therapeutically to support oocyte health and fertility in women of advanced reproductive age include myoinositol or d-chiro inositol as well as N-acetyl cysteine. In addition, all women trying to conceive should take multivitamins, fish oil (omega-3 fatty acids), and vitamin D.
