N.S. Macklon, M.D., Ph.D.; B.C.J.M. Fauser, M.D., Ph.D.

Disclosures

Semin Reprod Med. 2005;23(3):248-256. 

In This Article

The Rise and Fall of Ovarian Reserve

Human follicles begin their development during the fourth month of fetal life and by the fifth month of intrauterine life, a maximum of approximately 7 million germ cells are present.[2] Thereafter, the pool of immature follicles begins to diminish so that at birth, each human ovary contains from 266,000 to 472,000 follicles.[3] Each follicle contains an oocyte arrested in prophase of the first meiotic division. Depletion in the number of these primordial follicles, already begun prior to birth, continues throughout childhood so that by the menarche approximately 500,000 remain[4] (Fig. 1). During reproductive life, follicle depletion occurs at a rate of approximately 1000/month either by atresia or entry into the growth phase, and this rate may increase after the age of 35 years[5] until the menopause, when the stock of follicles decreases to less than 100.[6,7] The vast majority of follicles are removed from this stock by an atretic process of programmed cell death termed apoptosis.[6] During fetal life and childhood, follicle development occurs up to the early antral stage.[7] From puberty until the menopause, full maturation and ovulation occurs, but only approximately 400 follicles are destined to achieve full maturation. The rate of loss accelerates from the age of approximately 37 years and precedes the true menopause by 10 to 12 years[5] (Fig. 1).

The increase and decrease in oocyte numbers during fetal and postnatal life. Adapted from Baker TC. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc B 1963;158:417-433.

The long-held concept of continual depletion of the fixed number of oocytes laid down during fetal life has recently been cast into doubt. Female mice have been shown to contain a population of germ line stem cells that maintain follicle numbers during adult life.[8] In this landmark study, a population of germ cells was identified near the surface of the ovary, outside the follicles, and displaying characteristics of germ line stem cells. Treating mice with the toxic drug busulfan, which selectively kills male germ line stem cells, rapidly depleted the pool of young follicles. These findings point to the existence of germ line stem cells and a requirement for them in maintaining follicle numbers throughout the reproductive lifetime of female mice. This study clearly raises several questions relating to the development, maintenance, and depletion of ovarian reserve in humans. Follicles produced before birth may fail to survive to reproductive maturity, and fertility may therefore depend on the development of young follicles produced by germ line stem cells. Moreover, the loss of these stem cells rather than the follicles per se may be the cause of follicle depletion and subsequent menopause. These findings are likely to have a major impact on concepts of ovarian aging and the development of therapeutic interventions designed to maintain ovarian reserve in humans.

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