How Is the Number of Primordial Follicles in the Ovarian Reserve Established?1

Abstract

The number of primordial follicles in the ovarian reserve is an important determinant of the length of the ovarian lifespan, and therefore the fertility of an individual. This reserve contains all of the oocytes potentially available for fertilization throughout the fertile lifespan. The maximum number is set during pregnancy or just after birth in most mammalian species; current evidence does not support neofolliculogenesis after the ovarian reserve is established, although this is increasingly being reexamined. Under physiological circumstances, this number will be influenced by the number of primordial germ cells initially specified in the epiblast of the developing embryo, their proliferation during and after migration to the developing gonads, and their death during oogenesis and formation of primordial follicles at nest breakdown. Death of germ cells during the establishment of the ovarian reserve occurs principally by autophagy or apoptosis, although the triggers that initiate these remain elusive. This review outlines the regulatory steps that determine the number of primordial follicles and thus the number of oocytes in the ovarian reserve at birth, using the mouse as the model, interspersed with human data where available. This information has application for understanding the variability in duration of fertility that occurs between normal individuals and with age, in premature ovarian insufficiency, and after chemotherapy or radiotherapy.

BMP signalling in human fetal ovary somatic cells is modulated in a gene-specific fashion by GREM1 and GREM2

“…This occurs during fetal life in humans, and around the time of birth in mice. The size of the primordial follicle pool is determined by a mixture of germ cell proliferation and apoptosis, and interactions with surrounding somatic cells (Findlay et al ., 2015), mediated by juxtacrine, paracrine and endocrine factors within the ovary. In mice, follicle formation occurs in two distinct waves (Mork et al ., 2012, Zheng et al ., 2014), with an early population of follicles assembled in the medulla which support puberty and the early phases of fertility, and second cohort formed in the cortex, which supports long-term female fertility.…”

When few survive to tell the tale: thymus and gonad as auditioning organs: historical overview

“…At her birth, a human female has an 'ovarian reserve' of around one million oocytes, which is itself a considerable decline from the five million at 20 weeks gestation. During her lifetime, oocyte number further declines and, from a wave of some 30 ovarian follicles that develop prior to each ovulation, only one is given the opportunity of contributing to a new life (Findlay et al, 2015). A further, less extreme, opportunity for quality control arises when this one egg emerges victorious over other products of meiotic divisions (two polar bodies; Mira, 1998).…”

Moderate episodic prenatal alcohol does not impact female offspring fertility in rats

“…However, the number initially established varies widely between individuals, with a 70-fold range predicted at birth corresponding with a predicted age range at menopause of ∼38-60 years (Wallace and Kelsey 2010). The putative molecular factors involved in the establishment and maintenance of the ovarian reserve are just beginning to be elucidated (Findlay, et al 2015a, Kelsey, et al 2012, Pangas 2012), with a balance between factors involved in follicle quiescence, activation or apoptosis integral to ensuring the longevity of the reproductive lifespan (Reddy, et al 2010).…”