Anti-Müllerian Hormone and Ovarian Reserve: Update on Assessing Ovarian Function

Introduction

Anti-müllerian hormone (AMH) is a member of the transforming growth factor beta family that has derived its name from its role during male sex differentiation by inducing the regression of the müllerian ducts. To date, AMH is best known as a serum marker for ovarian function, with assessment of AMH levels at both ends of the spectrum, that is, ovarian reserve and polycystic ovarian syndrome. In the ovary, AMH is expressed by granulosa cells of growing follicles from the primary up to the small antral stage. After follicle-stimulating hormone (FSH)-dependent selection, AMH expression disappears, although some expression remains in cumulus cells of preovulatory follicles. Also, in atretic follicles and corpora lutea, AMH expression is lost. This window of expression is largely preserved among species and in the adult human ovary. Increasing expression levels of AMH are detected in follicles up to 8 mm, and expression is absent in follicles >8 mm. This expression pattern is positively matched by AMH concentrations in follicular fluid, showing highest levels in follicles up to 8 mm and a sharp drop thereafter (Fig. 1A) (1).

Since AMH is expressed by growing follicles prior to FSH-dependent selection and has been shown to be detectable in circulation, serum AMH has taken momentum as a marker for ovarian function, in particular in the assessment of the quantitative aspect of the ovarian reserve, which is the focus of this review. By definition, the ovarian reserve is constituted by the quality and quantity of the primordial follicles, which both decline with increasing age (2). The number of growing follicles recruited from the primordial follicle pool reflect the number of primordial follicles. Since there is no serum marker that directly can measure the number of primordial follicles, a marker that reflects the number of growing follicles is currently the best proxy for the quantitative aspect of the ovarian reserve. Initial studies, performed nearly 2 decades ago, showed that serum AMH levels indeed strongly correlate with the number of growing follicles and that both decline with increasing age (3). Based on these initial studies, serum AMH was rapidly put forward as an indirect marker for the ovarian reserve despite limited knowledge of factors that regulate ovarian AMH expression and lack of standardized AMH assays.

Since serum AMH is only an indirect marker, this has led to confusion or even misinterpretation of the term ovarian reserve. To make a clear distinction between the pool of resting primordial follicles and the pool of growing follicles, the term functional ovarian reserve (FOR) has been suggested (4). FOR constitutes the pool of follicles 2 to 5 mm in diameter from which 1 follicle is destined to be selected by FSH and to ovulate (4, 5). This pool of growing follicles is known as the AMH-producing follicles, and thus serum AMH levels directly reflect FOR (Fig. 1B). In the clinical application of serum AMH to assess the ovarian reserve, it is therefore more accurate to use the term FOR. The importance to distinguish between ovarian reserve and FOR in the interpretation of AMH levels is illustrated by mouse studies and the scarce human studies in which the number of primordial follicles were determined. In mice, AMH levels remained constant at younger ages despite declining primordial follicle numbers. Only at older ages did AMH levels reflect the number of primordial follicles, while at all ages, serum AMH levels correlated with the number of growing follicles (6). Similar findings were observed in human studies in which the density of primordial and primary follicles was directly determined in ovaries removed because of benign gynecologic indications or prior to gonadotoxic therapies. In younger women AMH levels did not correlate, while in women of late reproductive age, a significant correlation was observed with the primordial follicle density (7-10). These studies suggest that at all ages serum AMH levels reflect FOR, and only at older reproductive ages, AMH levels may also reflect the ovarian reserve. Therefore, in this review, we will use the term FOR in order to discuss recent insights and limitations in the use of serum AMH to predict age of menopause in healthy women and in disease conditions.

Published online 2020 Aug 8.