OVARIAN AGING AND INFERTILITY

by Jane Frederick, M.D., F.A.C.O.G.
Board Certified, Reproductive Endocrinology and Infertility

The decrease in female fecundity beginning after the age of 30 and exaggerated after 40, is a well documented finding. This age related decline in fertility is the result of several factors that contribute to overall reproductive failure. Women over 35 require a longer period to achieve conception than younger individuals, and a higher percentage of older than younger women will never achieve pregnancy. In addition, the rate of early pregnancy wastage increases substantially during the 30s, and is over 50% after age 40.

With the aging of the baby boom generation and social trends to delay childbearing, the treatment of women ≥40 years of age who desire fertility has become a major challenge of today’s fertility specialists. For many women, the option to exercise other choices while deferring their reproduction, has resulted in the need to use new reproductive technologies while treating their infertility.

These technologies include controlled ovarian hyperstimulation (COH), intrauterine insemination (IUI), and assisted reproductive techniques (ART). Though the age related decline in pregnancy is seen in ART, there are few reports of COH-IUI results with respect to age. I would like to share my report of a large series of COH-IUI in women 40 years and older.

RESULTS OF IUI IN PATIENTS > 40

In the patients who were ≥ 40 years of age, a total of 300 cycles were initiated, of which 30% were cancelled due to poor response. Of the remaining 210 cycles, there was an average of 2.7 cycles per patient. The average number of follicles per cycle with COH was 5.3 + 3.0. The type of COH protocol used, or whether hCG was administered, did not affect cycle outcome. A total of 11 pregnancies were achieved, with 8 spontaneous abortions, giving a live birth rate of 3.8% per patient and 1.4% per cycle.

This is in sharp contrast to the pregnancy rates in patients less than 39 years old receiving IUI and identical protocols of ovarian stimulation. Out of 543 patients, there were 141 pregnancies for a pregnancy rate of 21% per patient and 10% per cycle. Miscarriage rate in this group was 18% (Human Reproduction, 9:2284-86, 1994).

LITERATURE REVIEW

Over the past 15 years, there has been a surge in the assisted reproductive technologies available to treat infertility. Given such a vast array of treatments, clinicians are faced with uncertainty about the optimal technique for an individual patient with functional fallopian tubes. The optimal choice depends on the pregnancy rates per cycle (cycle fecundity) and costs, as well as the degree of invasiveness associated with each of these procedures. Recently, some authors have suggested superovulation with hMG, combined with IUI as an alternative treatment for couples with nontubal causes of infertility. A review of the literature dealing with IUI by Allen et al evaluated the results in 18 studies with a 28% mean pregnancy rate (range 3.4% - 62%) in 714 patients.

Confounding variables included specifics of sperm preparation, reason for IUI, insemination timing, and number of attempts per cycle. Few studies reported on the efficacy of IUI with respect to age of the patient. Further studies by Dodson et al showed that the mean serum estradiol concentration per follicle is inversely proportional to age, and that the woman’s age is inversely proportional to cycle fecundity with IUI. My results show there is a very poor live birth rate (1.4%) per cycle in infertile couples in which the female partner is ≥ 40 years of age and treated with COH/ IUI. This study seriously questions the indication of COH and IUI in women ≥ 40 years old.

SPONTANEOUS ABORTION RATE

The incidence of spontaneous abortion rises markedly with maternal age. Cytogenetic studies have shown that in 40% of all first trimester abortions, there is evidence of chromosomal abnormalities, and the majority of these anomalies are autosomal trisomic defects. Among recognized conceptions there is an exponential rise in the frequency of trisomies of almost every human chromosome with advancing maternal age.

IN VITRO FERTILIZATION

The early use of IVF in the treatment of women over 40 was influenced by the experience of Steptoe and Edwards, who reported a pregnancy rate less than half of that for women under 40 along with a spontaneous abortion rate that was almost 60%, yielding a live birth rate of only 3%.

The most recently published data from the US IVF-ET registry mimics the early Bourne Hall experience. The results of 5,868 IVF cycles from 281 clinics in 1995 where a delivered pregnancy rate for women 40 or older was 8% compared with 19% for all age groups. The older women also suffered a 36% spontaneous abortion rate. Previous data from 5,590 cycles collected from 48 French IVF centers in 1986 demonstrated a marked reduction in both oocyte production and embryo implantation beginning at age 37, that lowered the pregnancy rate from 19.8% in women under 25 to 9% in women over 40. Older women undergoing IVF have high cancellation rates, most often because of insufficient follicular development, but the pregnancy rate declines with increasing age regardless of the number of embryos transferred.

LEADING FACTORS

Biological data suggest at least three factors undergo change: at age 37, the uterus becomes increasingly unreceptive to maintaining pregnancy; oocyte abnormalities, most commonly expressed as chromosomal trisomies, finally become clinically dominant and compose half of all conceptions after 45; and altered patterns of gonadotropin release, marked by rising basal FSH levels, increase incidence of irregular menstrual function, which finally expresses itself as the inability to conceive. It is biologic or ovarian age and not chronologic age that most likely determines the endpoint of fertility. Women who conceive late in life generally have a late menopause— the number of years from the loss of fertility to menopause appears to be about 10 years. As there is no accurate way to predict the onset a decade in advance, perhaps women have been right all along when they say they hear the ticking of their biological clocks.

IMPACT OF OOCYTE DONATION

Oocyte donation dramatically alters the fertility of women over 40. Success rates are independent of age. Most series reports now demonstrate live birth rates above 30% per embryo transfer in patients up to 55. Lifetable analysis indicates that more than half of perimenopausal women will be successful within three attempts of oocyte donation, and more than 85% by the fifth try. Furthermore, miscarriage rates reflect that of the donor, who is usually under 35. Thus, losses are experienced typically in fewer than 15% of conditions (See Figure I below).

Maternal age decreases liveborn rates after assisted reproductive technology (ART). These data are from the 45,906 fresh ART cycles with patients’ own oocytes reported to the Society for Assisted Reproductive Technology and the Centers for Disease Control and Prevention for the year 1995. Advancing maternal age adversely affects live birth rates following ART. When fresh donor ART cycles are plotted, pregnancy rates do not decrease even into the 40s.

Adapted from SART/CDQ report for ART clinics, 1995, December, 1997. Results of oocyte donation suggests that although the uterus is less relative in women over 40, it is the ability of the aging oocyte that is the most important factor in the decreasing fertility of older women. Patients have indicated satisfaction after having made the decision to proceed with oocyte donation. Only time will tell if this trend becomes the accepted norm.