Advances in human primordial follicle activation and premature ovarian insufficiency

Abstract

In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for primordial follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of primordial follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1–2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of primordial follicle activation in order to diagnose, treat and prevent premature infertility. Research in primordial follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to primordial follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence primordial follicle activation in humans presenting new horizons for female infertility treatment.

Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

“…This is, however, later followed by a dramatic wave of attrition observed around the time of cyst breakdown and primordial follicle formation (Findlay, Hutt, Hickey, & Anderson, 2015), the regulation of which is the subject of this review. While the field lacks a firm understanding of these many points of regulation, it is known that germ cell numbers peak at around 6 million in the human fetus (Baker, 1963; Silber, 2015), with a decline to 1–2 million in a newborn (Baker, 1963; Ford, Beckett, Roman, McLaughlin, & Sutherland, 2020; Silber, 2015) and further reduction to 400,000–500,000 around puberty (Pelosi, Forabosco, & Schlessinger, 2015; Silber, 2015). This loss is well‐documented and physiologically normal in many species, with mice also experiencing a similar peak in germ cell numbers during late gestation, reaching about 15,000 oogonia, with a decline by more than half in the following week of development (Ford et al, 2020; Grive & Freiman, 2015; Jones & Pepling, 2013; Morita et al, 2001; Myers et al, 2014; Pepling & Spradling, 2001).…”

“…Despite the large number of oocytes contained within the ovary at the time of birth, women will only ovulate about 400 fertilizable oocytes during their lifetimes (Ford et al, 2020). The nonovulated oocytes may succumb to atresia, or ovarian cell death, during folliculogenesis for reasons that are still not well understood.…”

“…The implications of too much germ cell depletion seem somewhat evident, with POI resulting from accelerated depletion of the primordial follicle pool. Some evidence posits the existence of a fairly firm threshold in humans of around 1,000 primordial follicles (Faddy et al, 1992; Ford et al, 2020; Hansen et al, 2008; Pelosi et al, 2015), under which the functions of the ovary will begin to fail. While this is characteristic during normal menopause, POI affects at least 1% of women worldwide and is characterized by failed formation or accelerated depletion of the primordial follicle reserve, elevated serum gonadotropins, and reduced steroid hormone production, ultimately resulting in premature ovarian senescence before the age of 40 (Cordts, Christofolini, Dos Santos, Bianco, & Barbosa, 2011; Nelson, 2009).…”

A pilot study of assisting IVF by personalized Endo-Gym®exercises

“…Their condition causing subfertility and compromising conception was often uncharacterized. In category 2 ("Hormonal"), women had conditions related to menopause or sub-fertility, such as POF (also empty ovary or ovarian insufficiency), early menopause, irregular/painful period or PCOS [12,13] and low libido. Their primary aim was to relieve adverse longterm consequences of their condition (e.g.…”

“…Beneficial effects of the method combining personalized physical exercises, fertility-optimizing diet and personal coaching are statistically established by following 251 women who have exercised Endo-Gym® for various periods of time during 2012-2019, with the goal of improving their success in IVF or seeking remedy for a range of other gynecological conditions. Several of them had already undergone unsuccessful IVF cycles or struggled with directly related fertility issues, such as polycystic ovary syndrome (PCOS) [12] or premature ovarian failure (POF, also ovarian insufficiency) [13]. Others had different but not less disturbing gynecological problems, such as incontinence, pelvic organ prolapse (POP), irregular/painful periods and low libido.…”