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Menopause Matters

Fertility Changes During Perimenopause

Robert A. Wild, MD, PhD, MPH

The slight but real persistence of fertility in a woman¡s later reproductive years poses a contraceptive challenge for some and a reproductive opportunity for others, representing a clinical balancing act for patient and physician.

The functional activity of the ovary changes more with age than almost any other organ in the body. This translates into a significant decline in fertility in women starting at age 35 to 38 years, or 10 to 15 years before menopause.

OVARIAN CHANGES

The ovary attains the maximum number of germ cells during fetal development, and follicular loss begins in utero. Women are born with 1 to 2 million follicles. By menopause, there are only several hundred to several thousand remaining. Most follicular loss results from atresia (cell death and degeneration) and not ovulation, which accounts for < 500 follicles lost over a lifetime. The number of follicles declines in a linear progression until approximately age 37 years, when atresia begins to accelerate. However, the rate of atresia varies from woman to woman. Once the oocyte pool decreases to approximately 1,000 follicles, menopause ensues.1

As the number of follicles declines, so do levels of inhibin B, contributing significantly to rising levels of follicle-stimulating hormone (FSH) during perimeno-pause.2 The higher FSH levels recruit relatively more follicles per cycle, and for a time, this feedback loop sustains follicular development and ovulatory function. It may also promote the acceleration in follicular atresia seen at this age. Thus, the increase in FSH values reflects the quality and quantity of aging follicles. However, as the relationships among the monotropic FSH rise, accelerated follicular atresia, shortened follicular phase, and oocyte quality remain to be determined.

In addition to oocyte quality, which is the primary determinant of reproductive potential, age-related uterine changes may contribute to decreased fertility without creating any major shift in the menstrual cycle. Together, the ovarian and uterine changes contribute to the increased risks of spontaneous miscarriage (> 50% by age 45 years), fetal chromosomal abnormalities (approximately one in eight at age 49 years), and other pregnancy complications (eg, premature labor, fetal mortality) in women of advanced maternal age.3

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ASSESSMENT

It is important for women to know that fertility becomes significantly compromised long before overt clinical signs of perimenopause occur. Much of the recent research on ovarian function comes from efforts to assess fertility. The FSH value is used as an indicator of Àovarian reserve,” a term coined to reflect the remaining reproductive capacity of the ovary. Measuring FSH in the early follicular phase is used to predict the likelihood of a successful response to infertility treatment, and correlates better with treatment outcome than does age.

Changes in FSH levels appear to be preceded by a decline in ovarian production of inhibin B. A lower fertility rate has been observed in women who have a normal FSH level on cycle day 3 but a low inhibin B level.4

As inhibin B levels decline, FSH levels rise. It is now thought that the functional ovarian reserve (ie, reproductive potential as it relates to the processes of follicular depletion and oocyte quality), as directly measured by basal serum FSH values on cycle day 3, is the most important indicator of age-related infertility.

Inhibin B levels are very low after menopause, and the average value in premature ovarian failure is only slightly higher. However, inhibin B measurements are not widely used in clinical practice. Production of inhibin A does not decrease until just before menopause.5 Newer markers are currently under assessment to determine whether they may be more predictive.

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CONTRACEPTION

Despite the decline in fertility during perimenopause, women should be aware that pregnancy is still possible until FSH levels are consistently elevated (> 30 mIU/mL) and menopause occurs. Therefore, it is important to consider appropriate contraception if pregnancy is not desired.

A number of effective options are available. Hormonal contraceptives provide nonsmoking perimeno-pausal women with safe, effective pregnancy prevention as well as several noncontraceptive benefits, including regulation of irregular uterine bleeding, reduction of vasomotor symptoms, and retardation of bone mineral loss. However, hormonal contraceptives can mask changes in FSH levels, invalidating the FSH test. Hormonal contraceptive use can also result in regular menstrual periods, eliminating the most predictive marker of menopause (amenorrhea).

For women who want contraception, the choice should be individualized based on medical history, lifestyle, and sexual habits. Because of the difficulty in assessing when menopause actually occurs in hormonal contraceptive users, many clinicians advise women to continue contraceptive use until at least age 51 years.

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ASSISTED REPRODUCTIVE TECHNOLOGIES

Fertility-enhancing technologies provide an option for women of advanced reproductive age who still desire childbearing. Alternatives include in vitro fertilization, intrauterine insemination, oocyte donation, and embryo transfer, as well as using surrogacy/gestational carriers. Hormonal therapies are also available to promote ovulation.

Whether fertility-enhancing technologies will succeed depends on the woman¡s age, general health, reasons for treatment, and the modality used. Many of these options are expensive, involve some risks, and are not always successful—and the chance of success decreases still more with the approach of menopause. Furthermore, a woman of advanced reproductive age has a number of health risks. In general, fertility-enhancing techniques are discouraged for women older than age 43 years, and are not recommended after age 51 years. Any woman contemplating these alternatives should be fully apprised of the risks and benefits of each technique.

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CONCLUSION

Fertility at perimenopause is decreased but not absent, representing a reproductive risk to some women and a prospect to others. As this transition may cover 10 to 15 years, it is important for the physician to discuss each woman¡s desires and goals in the context of her hormone levels, medical profile, and lifestyle.

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Robert A. Wild, MD, PhD, MPH, is professor of reproductive endocrinology, adjunct professor of epidemiology and biostatistics; and adjunct professor of medicine (cardiology) at Oklahoma University Health Sciences Center, Oklahoma City, Okla. He is a member of The North American Menopause Society¡s 2005-2006 Professional Education Committee.

References

1. Bopp BL, Seifer DB. Oocyte loss and the perimenopause. Clin Obstet Gynecol. 1998;41(4):898-911.
2. Klein NA, Houmard BS, Hansen KR, et al. Age-related analysis of inhibin A, inhibin B, and activin A relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab. 2004;89(6):2977-2981.
3. Pal L, Santoro N. Age-related decline in fertility. Endocrinol Metab Clin North Am. 2003;32(3):669-688.
4. Seifer DB, Scott RT Jr, Bergh PA, et al. Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone. Fertil Steril. 1999;72(1):63-65.
5. Klein J, Sauer MV. Assessing fertility in women of advanced reproductive age. Am J Obstet Gynecol. 2001; 185(3): 758-770.

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