The Effects of Age on Fertility

Aging is a normal, inescapable process. As we age, various components of our bodies develop limited function or cease to function altogether.

Changes in our reproductive processes are some of the more subtle changes that take place. However, as societal changes have resulted in many women delaying childbearing, these nearly silent changes can have a huge impact on a woman’s life and her chances at conception. The scientific community had recognized for quite some time that a woman’s reproductive potential declines with age. Unfortunately, there are few, if any, outward signs of decline in reproductive potential for most women. A woman may continue to have regular cycles until she nearly reaches menopause, but her chance of conception starts to decline at a much younger age (Figure 1), generally around 30 years old. This results in a situation where nearly 1/3 of the couples with the woman 35 or older will have problems with fertility. It has been estimated that only 10-30% of women over 40 are able to become pregnant on their own. In addition, a woman’s chance of miscarriage also significantly increases with age.

(Read about DHEA's use in poor responders and IVF; and women with premature ovarian failure [POF] below [under DHEA studies at VCRM])

The probable reason for the decrease in chance of conception and the increase in miscarriage with age is the increased number of abnormal eggs that are present (Figure 3).

Evaluation of Ovarian Reserve

This topic is covered in more detail in another segment on our website entitled “What is ovarian reserve and how does it impact my fertility”.

Ovarian reserve is the term that we use to describe where a woman’s ovaries are in the aging process. Age is an important determinant of ovarian reserve. As previously discussed, the chances of conception clearly decrease with age. However, it is critical to understand that since no two women are alike, not all women of the same age have the same reproductive potential. The further evaluation of ovarian reserve is accomplished by tests that measure important components of the reproductive system.

The standard screening test is the measurement of the hormones FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone) and Estradiol on cycle day 2, 3, 4, or 5. (Day one of your cycle is the first full day of full menstrual flow). The FSH level is the most important of the three tests, with the measurement of LH and estradiol modifying how we look at the FSH level. It has been clearly demonstrated that there are subtle rises in the FSH level as a woman ages, and that women with abnormal FSH levels can have considerable difficulty conceiving using their own oocyte.

Another test that can be incorporated into the evaluation of ovarian reserve is the Clomiphene Citrate Challenge Test (CCCT). In this test, the cycle day 3 labs are followed by 5 days of the ovulation induction agent clomiphene citrate (Clomid, Serophene). On cycle day 10, the FSH and estradiol are re-drawn. We expect the FSH level to be in a certain range, due to the feedback from the follicle (s) developing under the stimulation by the clomiphene citrate. If the FSH is not in the correct range, the test is abnormal and the live birth rate for these patients is extremely poor. This test picks up another 30% of the patients with abnormal ovarian reserve.

A simple test of ovarian reserve that can be employed is the Antral Follicle Count (AFC). Early in the cycle, the small follicles that can be seen with ultrasound are counted (patients frequently ask “what are you counting?” at the time of the ultrasound examination). A low number of follicles can predict the increased likelihood of a poor response to therapy and decreased chance of live birth. Very high numbers of small follicles suggests a tendency to over respond to hormonal stimulation, and this is a common finding in women with polycystic ovaries (PCOS). The AFC count is very important in tailoring the stimulation regimen and the amount of ovulation induction medications used.

It is important to understand that none of these tests individually are absolute when test results are normal or equivocal, meaning having a normal test does not guarantee a pregnancy. (A markedly elevated FSH level, indicating a loss of reproductive potential, is as close to certainty as we get.) However, they can be part of a picture, combined with the patient’s age and response to previous treatment that gives the physician a pretty good idea where the patient’s ovarian function stands.

Treatment

There are a variety of treatments for infertility, but the options become more limited as ovarian function wanes. Surgical solutions can be appropriate for certain problems in some patients, but require recovery time as well as time to conceive after that. Conservative hormonal therapies (such as clomiphene citrate or gonadotropins combined with intrauterine insemination) can be effective for appropriately selected patients under 40, but are much less effective in women over 40 years old. In vitro fertilization (IVF) remains the most effective therapy for women using their own eggs at any time in the reproductive age-group, but the live birth rate drops off considerably in women in their 40’s. Unfortunately, there is currently no treatment that can restore eggs or improve their quality. Thus, it is critical to make sure that women have access to good treatment modalities early on so that their own eggs can still be used.

Figure 4. The chance of pregnancy declines with age, regardless of choice of therapy. In vitro fertilization is the most effective therapy for women using their own eggs at any age. Key: CC/IUI=clomiphene citrate and intrauterine insemination; Gnd/IUI=Gonadotropins and intrauterine insemination; IVF= in vitro fertilization (2001-pregnancy per embryo transfer)

Studies of women with abnormal ovarian reserve testing show a dramatic decrease in fertility regardless of age. In a study publish in the October, 2001 issue of Fertility and Sterility, the basal FSH measurements of nearly 10, 000 patients was evaluated. About 10% of the patients had abnormal ovarian reserve on the basis of the basal FSH measurement. In this group, there were only 28 pregnancies (2.7% of the patients) with 20 of them (71%) ending up as a miscarriage. The 8 patients with a child represent 0.7% of the patients with abnormal ovarian reserve.

Presently, women with abnormal ovarian reserve are best served by therapies that do not utilize their own eggs. Fortunately, women with diminished ovarian reserve still have good options for becoming parents, which include egg donation and adoption. In egg donation, a young woman with normal ovarian reserve donates her eggs to the couple (usually donors are between 21-33). The egg donation allows the patient the opportunity to become pregnant and deliver the child regardless of her ovarian function. Recent studies, albeit very few and with small numbers, suggest however that some women, even those with elevated FSH who are now being told to pursue donor egg or adoption, may have still a chance at conceiving using their own eggs after using DHEA (see below). This may represent a quantum shift in the field of reproductive medicine, and would overturn some established dogma. At VCRM, we are undergoing clinical studies to investigate this novel concept further, and try to identify the groups that are likley to benefit from DHEA.

DHEA Studies at VCRM

At VCRM, we are currently evaluating the use of DHEA in women with poor ovarian reserve and high FSH, and women with premature ovarian failure (POF). DHEA is a weak androgen (male hormone) that is available as a supplement in most Vitamin stores. There are currently only a very small number of papers, mostly from one group, detailing their experience with DHEA. It seems that DHEA, when taken for at least 2-3 months, may increase fertility potential in some patients. The literature is indeed very scant, and we do not know currently whether DHEA provides ANY benefits. One recent paper (evaluating ONLY 5 women) showed an improvement in women with POF, with even some spontaneous pregnancies. We believe DHEA MAY hold some promise for SOME patients with diminished ovarian reserve and high FSH. If DHEA indeed shows promise in these groups, many women now relegated to donor egg or adoption may still have a chance at conceiving using their own eggs, with very significant implications for many women who cannot (or will not) proceed with donor egg or adoption. 

We are currently performing 2 clinical trials on women with diminished ovarian reserve and high FSH, and women with POF. For more information about those studies, and whether you qualify to take part in these studies, please schedule a consultation with Dr Sharara by calling our office at 703-437-7722.

Conclusions

Aging has a profound effect on all of us. The signs of aging on a woman’s reproductive capabilities may be subtle or hidden all together. Women should understand that this normal process exists and take it into account as they plan their futures.

Although egg donation is a highly effective therapy, earlier discovery of problems will often allow couples to have more options for therapy to choose from. If couples are having trouble building a family, they should seek medical attention promptly, especially if they are above 35. A discussion of your concerns with your gynecologist is a good place to start, and a prompt referral to a Fertility Specialist can make all the difference in your chances at having a child.

Glossary of Terms

Clomiphene Citrate: an oral anti-estrogen drug used to induce ovulation in women. It works by causing the pituitary gland to release the hormones FSH and LH, which, in turn, stimulate the ovaries to develop follicles and release eggs.

Estradiol: a steroid hormone produced by the follicle. It helps regulate the pituitary gland secretion of the hormones FSH and LH, as well as cause the lining of the uterus to grow.

Follicle: cystic structures in the ovary that contain the egg. They develop under the stimulation of the hormones FSH and LH.

FSH: Follicle Stimulation Hormone is a hormone secreted by the pituitary gland in the brain that causes the follicles in the ovary to grow.

Gonadotropins: hormones that stimulate the ovary, FSH and LH. They are normally secreted by the pituitary gland in the brain. They may be also contained in drugs that are injected in women as part of infertility therapy.

Infertility: one year of attempting conception without success (6 months for women > 35).

Intrauterine Insemination: The male partner produces sperm; it is then processed, concentrated and injected into the inside of the uterus via a flexible catheter. When combined with fertility drugs (gonadotropins or clomiphene), it can be an effective therapy.

In Vitro Fertilization: a process in which eggs are retrieved from the woman and are combined with the partner’s sperm in the laboratory. Embryos subsequently develop and an appropriate number are replaced in the woman’s uterus.

LH: Luteinizing hormone is a hormone secreted by the pituitary gland that causes ovulation to occur.

Oocyte: the egg, contained within the follicles in the ovary.

Ovarian Reserve: the term used to describe where a woman’s ovaries are in the aging process. Age, testing and response to therapy are taken into account as part of the determination.

Ovulation: the process by which the follicle releases the egg from the ovary

Disclaimer: The intent of this information is to inform patients regarding the effects of aging on a woman’s reproductive capabilities. A comparison of clinic success rates may not be meaningful because patient medical characteristics and treatment approaches may vary form clinic to clinic.