Evaluation of Female Fertility—AMH and Ovarian Reserve Testing

Abstract

Approximately 1 in 8 couples have trouble conceiving or sustaining a pregnancy according to the Centers for Disease Control 2006 to 2010 National Survey of Family Growth. In the United States, infertility is typically defined as the inability to conceive after 1 year, at which time an evaluation should begin. For women older than 35 years, evaluation is advised at 6 months (1). While the percentage of women with infertility, and no living children, has increased largely because of the increasing age of first pregnancy (2), the overall percentage of women with infertility has been relatively stable over several decades. Although infertility is frequently considered a “women’s disease,” about 35% of couples will have both a male and female etiology of their infertility with another 10% to 20% having a sole male factor as the identifiable cause.

Normal fertility requires a competent oocyte (requiring normal ovulatory function in the woman); a functional sperm (requiring normal endocrinological function and spermatogenic capacity in the man); an anatomic capacity for sperm/egg interaction (functional cervix, uterus, and fallopian tubes in the woman and functional vasa, epididymis, and penis in the man); and the capacity for implantation (endocrinological and anatomic uterine environment). Infertility or reduced fecundity (ability to produce a live born) can result from abnormalities in any of these areas. We are aware today that there are many ways to build a family and many types of families. This manuscript will focus on the role of ovarian reserve in conception success.

Barriers to Optimal Practice

The strongest driver for successful conception is the age of the female partner. Whether spontaneous pregnancy or pregnancy with assisted reproductive technologies (ART), age determines the likely success for any given cycle attempt. This is due largely to the increasing aneuploidy with age as shown by stabilization of success rates with the use of donor eggs (3) (Fig. 1). With increasing aneuploidy, there is less likely for development of a healthy, viable embryo and thus lowered implantation, higher risk of miscarriage, and more pregnancies/children at risk of chromosomal abnormalities. Compounding this intrinsic biology is a societal delay in attempts at pregnancy as women play an increasingly vital role in the workforce, thus increasing the age of the female partner for pregnancy attempts (2).

Figure 1.

Live birth per transfer based on age (Society for Assisted Reproductive Technology) comparing autologous eggs to donor eggs (https://www.sartcorsonline.com/rptCSR_).

This demographic change is compounded by an incomplete understanding of physiology of normal female and male reproductive function and the importance of health, lifestyle, and age. In addition, cost and lack of access to fertility care—particularly due lack of insurance or underinsurance—limits accessibility to effective education and treatment. There remains a perception that infertility is caused by the patient or couple (eg, lifestyle choices such as delay in decision to conceive or exposure to sexually transmitted infections) limiting support for appropriate treatment of this medical disease (4). Further, the press/public focuses on high-tech treatments such as ART, suggesting these expensive treatments are the only appropriate care and/or are so powerful they can overcome all factors, including age. In vitro fertilization (IVF) is a very powerful tool to overcome nearly all male factor infertility, but the effect of female age remains a key factor limiting success even with IVF. While the advent of preimplantation genetic testing for aneuploidy has improved pregnancy rate per transfer (5), the age-related decline in pregnancy rate per stimulation cycle is not overcome by any current techniques of assisted reproduction (Fig. 2).

Figure 2.

Percentage of live birth declines with increasing age (sart.org/patients/history-of-IVF/).

Ovarian reserve is frequently defined both as a quantitative and qualitative aspect of ovarian aging. The qualitative aspect (genetic risk) is most closely tied to a woman’s chronological age (6) (Fig. 3) and seems to be consistent across populations. The quantitative aspect has a wide variation within women of the same age (7, 8) (Fig. 4), with the strongest driver being genetic. It is estimated that more than 50% of the age of menopause is heritable (9-11). Because women are born with a finite number of eggs (as opposed to men who continually make new sperm), this original endowment, and the rate of loss, are critical to the lifespan of the ovary. Menopause represents the complete loss of functional oocytes. Thus, it would be anticipated a woman’s quantitative capacity would likewise have a strong genetic component. We and others have shown the age of the mother’s menopause strongly correlates with the daughter’s antral follicle count (AFC) (12) and antimüllerian hormone (AMH) (13). As noted in the excellent review by Moolhuijsen and Visser (14), AMH best reflects the “functional ovarian reserve” or the pool of growing follicles available in any given month. This may not always correlate with the primordial follicle pool, particularly in prepubertal girls and women of young reproductive age (7). The decline in markers of ovarian reserve parallels the decline in the primordial pool (8, 15). And while AMH is an excellent marker of quantity, it must be interpreted in the context of the endocrinological environment, and does not reflect “quality” (aneuploidy risk) of the oocyte and/or fertility potential, particularly in young women.

Figure 3.