Developing anti-Müllerian hormone as an ovarian reserve biomarker.

In conclusion, the possibility of measuring AMH serum concentrations, which arose in the beginning of this millennium, has allowed for a true breakthrough in female reproductive health assessment ( Fig. 5 ). AMH has been demonstrated to be the most robust currently available biomarker for ovarian reserve. Its potential clinical implications have been demonstrated in assessing ovarian function and dysfunction, especially related to fertility and infertility treatment ( Broer et al. , 2014 ). Beyond doubt, the AMH story is still a ‘work in progress’ and deserves continued high-quality investigation. Most importantly, more robust AMH assays with improved standardization and less variation ( Fauser and Nelson, 2020 ) will be key to further progression in understanding human ovarian function and dysfunction. Summary representation of the potential clinical roles of anti-Müllerian hormone as a human ovarian reserve biomarker . PCOS, polycystic ovary syndrome; POI, premature ovarian insufficiency. The most promising areas include: With advances in developing bioengineering tools for the study of female reproduction (for a review, see Francés-Herrero et al. , 2022 ), three-dimensional artificial ovaries may be generated which could prove a useful tool for the more detailed study of the role of AMH in regulating primordial follicle arrest or growth, its potential interaction with other factors, and the presumed inhibitory roles of AMH in later stages of gonadotropin-dependent follicle development. AMH levels as an additional tool for (early) diagnosis and follow-up over time regarding the type and extent of the disease for women presenting with various forms of ovarian dysfunction (especially PCOS and POI). AMH levels as an additional tool to fine-tune safe and effective patient-tailored ovarian stimulation for various forms of infertility treatment. AMH levels should be explored in greater detail as a potential predictor of pregnancy chances without medical intervention, and the chances of success of various infertility treatments such as ovulation induction, IVF, endometriosis, or ovarian surgery. A role for AMH measurements in oncofertility should be further advanced. AMH levels may help to identify women at risk for irreversible loss of ovarian function due to gonadotoxic cancer treatment, to identify the least damaging cancer treatment, to follow recovery of ovarian function after cessation of treatment, and predict future fertility potential. More information is needed regarding the capacity of AMH levels, assessed at a young age, to reliably predict the age of menopause. It is possible that the combined use of measured serum AMH concentrations along with contemporary genomic data related to the age of menopause may significantly improve the predictive potential. More individualized knowledge regarding the age of menopause may be crucial not only in relation to infertility that precedes menopause (hence, early menopause means a decrease in natural fertility at an earlier age), but also for long-term quality of life and cardiometabolic health. The preclinical development of both AMH agonists and antagonists is still ongoing, and unfortunately, these are not yet ready for studies in humans. The availability of such compounds could, in the future, allow the modification of the age of menopause, with distinct implications for both the fertility decrease preceding menopause and later-life health. The ability to extend female reproductive life would represent a true revolution.

Our initial preliminary study, which took place in 41 young healthy normo-ovulatory volunteers, demonstrated for the first time that serum AMH concentrations decrease with increasing female age, and that AMH levels correlate well with the number of antral follicles (antral follicle count; AFC), as assessed by transvaginal ultrasound scanning ( de Vet et al. , 2002 ) ( Fig. 3 ). More recently, this work was recognized as one of the most influential papers so far published in Fertility and Sterility ( Niederberger et al. , 2018 ). Using immunohistochemistry, we also investigated AMH expression patterns in human ovarian tissue sections obtained from 12 healthy, regularly cycling women who underwent surgery for benign gynecological reasons. This showed high AMH staining in the granulosa cells of secondary, preantral, and small antral follicles, along with absent AMH expression in primordial and large pre-ovulatory follicles. These preliminary findings were published in Molecular Human Reproduction ( Weenen et al. , 2004 ) ( Fig. 4 ). Such initial observations underline a critical role of AMH in early human follicle development, especially the recruitment of resting primordial follicles. Later on, others provided additional pivotal evidence that confirmed serum AMH levels indeed directly correlate with the size of the ovarian primordial follicle pool—in human ovarian tissue obtained from 42 healthy women between 26 and 52 years of age undergoing oophorectomy for benign gynecological reasons ( Hansen et al. , 2011 ). Anti-Müllerian hormone immunohistochemically stained human ovarian tissues . Left: ( A, D, G ) controls, ( B, E, H ) stained using AMH antibody. (A, B) section at 100× magnification with primordial follicles. (D, E) adjacent section (40×) with small antral follicles. (G, H) adjacent section (100×) with two large antral follicles. Right: Graphical depiction of the percentage of follicles with strong and total AMH staining in relation to stages of follicle development. Staining increased rapidly with the stage of follicle development and decreased beyond 4–6 mm diameter. Reproduced with permission from Weenen et al . (2004) . AMH, anti-Müllerian hormone; GC, granulosa cell; MIS, Müllerian inhibiting substance (AMH). Over subsequent years, evidence rapidly accumulated that serum AMH represents the best available biomarker for diminished ovarian reserve—associated with reduced female reproductive potential—as compared to chronological age, AFC, or FSH levels. However, various endpoints used in initial studies concerning AMH and ovarian reserve all represent surrogate markers of diminished ovarian reserve. Ovarian follicle pool depletion eventually ends in exhaustion of the stock of primordial follicles, resulting in menopause, representing the end of female reproductive life. Hence, the key question remained whether serum AMH levels assessed at a younger age indeed correlate over time with the real-life endpoint—i.e. the age of menopause. Our initial study addressing this vital question involved an 11-year follow-up of a cohort of 257 normo-ovulatory women between 21 and 46 years of age ( Broer et al. , 2011a ). Nineteen percent of women in the initial cohort had reached postmenopause, and age, AFC, and AMH were all significantly correlated with the age of menopause. Numerous well-designed studies have followed since then (for a review, see Nelson et al. , 2023 ). The robust assessment of individual variation in ovarian aging (for a review, see Broekmans et al. , 2009 ) and its associated varying extent of diminished fertility with increasing female age still represents the most crucial challenge in fertility care today.