Diminished Ovarian Reserve. How Do You Diagnosis It? What Does It Mean?

 

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Menopause, regardless of age, represents the most overt marker of the end of reproduction and a potential health transition for women. Although the STRAW criteria have characterized ovarian aging utilizing primarily changes in menstrual cyclicity, only recently the reliable biomarkers of the remaining ovarian pool (antral follicle count [AFC] and anti-Mullerian hormone [AMH]) have been available for use in normally cycling women. This availability gives us a unique opportunity to characterize the current “ovarian reserve” (ovarian age) and the rate of decline in ovarian follicles/oocytes. However, the implications of these quantitative markers remain to be fully characterized and validated. Despite this continued lack of knowledge, increasingly these markers are being used to counsel women.

The objectives of this issue are to present the current state of knowledge with respect to ovarian follicular development, growth and loss, and how clinical markers of this process have developed and are being used. The issue starts with an article by Dr. Roger Gosden, a pioneer in this field. Here, he describes the basis for germ cell development in the female and the balance between development and loss—the key process responsible for reproductive aging. Dr. Rajkovic, a physician scientist with a focus on human genetics, then characterizes what is known regarding the genetic and epigenetic determinants of the follicular pool. In addition, he discusses the potential role for genes involved in inflammation/immunology and DNA repair and their potential relation to follicular development and loss. Finally, he recognizes the importance of the interaction between the germ cells and the somatic cell niche.

The next section of the issue focuses on the available biomarkers and how normative data are established. With the increasing application of these markers in clinical practice, the excellent contributions by Drs. Hansen and Gracia are critical. Dr. Hansen's classic studies have for the first time objectively determined the correlation between the clinical markers (AMH/AFC) and the nongrowing oocyte pool. This is critical piece of the puzzle then naturally leads to the contribution of Dr. Gracia, who shares with us the available information regarding population normal and what the implication of setting such normal ranges may be.

The next section of the issue focuses on the implications of utilizing the biomarkers and what they really tell us about fertility potential, somatic health, and aging. Knowing that menopause represents the obvious end of reproduction, regardless of age, and also a time when health risks, particularly cardiovascular disease risk begins to increase, understanding the potential implications of ovarian reserve for any given age may hold great potential for proactive health management for clinicians and patients. Since most information about ovarian reserve markers has been derived in the fertility clinic, and specifically regarding impact on ART outcome, it is not clear that these data should affect counseling of otherwise healthy women. Dr. Steiner discusses the implication of applying these biomarkers in the general population and where her studies are taking us regarding the implication of universally applying these markers. The article on reproductive and somatic aging takes a look at the potential health implications of “advanced” reproductive aging as evidenced by lower in AMH and AFC, and whether identification of women with low ovarian reserve may represent a unique, at-risk, group.

In the final section, Drs. Rosen and Huddleston discuss how these markers are being applied in the study of “disease”—particularly patients with a cancer diagnosis, pre/posttreatment, and to aide in the diagnosis of polycystic ovary syndrome. These tools developed for accessing ovarian stimulation response in ART are now being used to look at individuals with risk for both low and high counts in other scenarios. Do they tell us the same thing in these populations as in the infertility population—as in the general population? These authors discuss how and when these markers should be applied in these situations and what new information they may tell us.

The goal of this issue has been to improve understanding of the biological basis of oocyte aging, improve the understanding of the clinical markers available to assess patients with respect to the remaining oocyte pool, and begin to understand the implications of these biomarkers when used outside the ART environment. The scientists and clinicians brought together in this issue have done an excellent job of describing the available literature and the need for further investigation. The already widespread application of these clinical tools must be addressed in this context.