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Between weeks 4 and 8 of gestation, undifferentiated germ cells migrate from the yolk sac to the genital ridges where they populate and allow the development of the ovaries by differentiating into oogonia. By week 6 of gestation mitosis of the oogonia begins, resulting in a population of over 3 million germ cells per ovary by 20 weeks.1 From 15 weeks, the oogonia begin to transform into oocytes by entering the first meiotic division which stops at prophase I. No further development occurs until menarche, when the first few go forward to complete meiosis I and proceed toward ovulation as a secondary oocyte. Meiosis II immediately follows meiosis I but is arrested at metaphase II and is only completed if fertilization occurs. Primordial follicles are formed from about 20 weeks gestation as granulosa cells move to surround each germ cell.

From the peak of about 3 million germ cells in each ovary at 20 weeks gestation, there is gradual attrition of numbers so that at birth it is estimated that only one-third remain. Although occasionally disputed,2 it is generally accepted that no further germ cell development occurs after birth. From the one million germ cells per ovary at birth, less than half survive to menarche. This process is often interpreted as a form of quality control, ensuring optimal oocyte quality by time of conception some 30 to 40 years later. There continues to be a log-linear decline in germ cell number to the age of 50, when the average menopause occurs.3 The decline in germ cell number is mediated by apoptosis and is timed with remarkable precision, with the rate of loss slowing from over 150 to less than 20 per day over life.4 As an organ of limited lifespan, the ovary is unique.

The life span of the ovary can be shortened by defects in any part of the process of oogenesis from germ cell migration through mitosis to accelerated apoptosis.

Normal Function of the Hypothalamic-Pituitary-Ovarian Axis

The hypothalamus secretes pulses of the oligopeptide gonadotropin-releasing hormone (GnRH), which is transported through the portal vessels to the pituitary. In childhood, GnRH pulse frequency is irregular and the amplitude is very low. As puberty approaches, there is initially a nocturnal increase in the frequency and amplitude of GnRH pulses, followed gradually by similar pulses during the daytime until an adult frequency of one pulse every 60 to 90 minutes is reached.

GnRH receptors (GNRHR) are G-protein–coupled receptors that are present on the cell membrane of the gonadotrope cells of the pituitary. GnRH acts on the GNRHR, activating adenylate cyclase. This results in an intracellular cascade of events culminating in the release of the stored glycoprotein hormones, follicle-stimulating hormone (FSH) or luteinizing hormone (LH). At the same time, further synthesis of these hormones within the gonadotropes is also activated.


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