Oogenesis

What is oogenesis?

Oogenesis is a type of gametogenesis. It is the process of producing female gametes, once sex determination of the embryo has occurred. The presence of the SRY gene on the Y chromosome leads to male gonad formation and spermatogenesis, while female gonad development is the ‘default state’. The process of oogenesis creates egg cells, known as ova, and is completed throughout a woman’s lifetime. Like spermatogenesis, oogenesis involves the creation of haploid sex cells through the process of meiosis.

Oogenesis takes place in the female ovaries and differs from spermatogenesis in several ways:

  • Sex-specific timing of entry into meiosis: During spermatogenesis, meiosis begins at puberty to produce sperm in the sexually mature male, whereas meiosis occurs before birth in females. Research suggests that this difference occurs due to differential regulation of retinoic acid induced expression of the Stra8 gene in the ovaries and testes.
  • Oogenesis is not a continuous process throughout the life of a female, unlike spermatogenesis in the male. It begins in utero when the primordial oocytes, known as oogonia (Figure 1), enter meiosis but are subsequently prevented from entering prophase I until ovulation. The oogonia enter meiosis again before their release, then arrest in metaphase II. Meiosis will only be completed if the egg is fertilised.
  • Females are born with all the eggs they will ever produce. This is why all women go through the menopause eventually.
  • Meiotic divisions in the female are not symmetrical: cell division is asymmetrical and leads to the production of two polar bodies (genetic material discarded by the egg) by the time meiosis is completed.
  • Oogenesis will produce one mature egg cell from one germ cell which contains nutrients and other substances for early development. Spermatogenesis can generate four sperm cells from every germ cell and these will essentially be a motile nucleus.

The process of oogenesis

Following sex determination, oogenesis begins with the formation of primary oocytes in a process known as oocytogenesis. This occurs before birth. The primordial oocytes, known as oogonia, migrate through the embryo from the germinal epithelium, to the genital ridges and undergo mitosis to produce the primary oocytes (Figure 1). The first meiotic division of these cells also occurs before birth, while the foetus is still developing. However, the first meiotic block will be met here and this process will arrest in the prophase of meiosis I, until puberty begins.  These oocytes reside within structures made up of granulosa and theca cells derived from the germinal epithelium, known as follicles (Figure 2), in the ovaries.



At puberty, each oocyte enters meiosis again, just before it is ready to be ovulated. This means some oocytes can remain dormant for up to 50 years. Proceeding ovulation, a reproductive hormone, gonadotrophin releasing hormone (GnRH), is released from the hypothalamus of the brain. This stimulates the release of two other reproductive hormones; follicle stimulating hormone (FSH) and luteinising hormone (LH) from the anterior lobe of the pituitary gland in the brain. FSH and LH act on a primary follicle in the ovaries, promoting its development into a secondary follicle (Figure 2).

 

The granulosa cells proliferate to form a thick layer. Theca cells are recruited to the oocyte and form 2 distinct layers; theca interna and theca externa. Oestrogen will then start to rise as the stoma-like theca cells begin to secrete androgens. Oestrogen is converted by the granulosa cells into oestrodiol to serve two purposes; preparing the female for the possibility of an embryo by thickening the endometrium and thinning cervical mucus. Secondly, oestrogen acts on the hypothalamus and pituitary gland to ‘switch off’ GnRH, FSH and LH secretion through negative feedback (Figure 3). Meiosis I is now complete and we have a secondary oocyte, with the first polar body, inside a secondary follicle (Figure 2). The polar body will eventually go through atresis and degrade. Meiosis will continue, but again meets a meiotic block, this time at the metaphase II stage of meiosis II (Figure 1).

 

The secondary follicle will continue to develop, and eventually forms a mature ovarian follicle called a tertiary, or Graafian, follicle (Figure 1). The granulosa cells closest to the oocyte differentiate to form a protective outer layer called the zona pellucida. Layers of follicular cells attach to the zona pellucida to form the corona radiata. The granulosa cells secrete follicular fluid to produce a fluid filled cavity, adjacent to the oocyte, called the antrum. More oestrogen is released as the theca has also thickened. The whole follicle will be attached to the ovary by the newly formed cumulus oophorus; a stalk produced by the granulosa. Once this mature follicle has developed, the further rise in oestrogen leads to a surge in LH (and some FSH), which stimulates ovulation. The oocyte (surrounded by its zona pellucida and cumulus of granulosa cells) will burst out of the follicle, remaining attached to the ovary on a loosened cumulus oophorus, through a wall weakened by the hormone surge. The mature oocyte is then ovulated and free to travel towards the uterus, hoping to meet a sperm cell on the way.

 

The cycle now reaches the luteal (secretory) phase, and ruptured follicle will develop into the corpus luteum, due to the continued LH stimulation. The remaining granulosa cells form large lutein cells that secrete progesterone and some oestrogen, while theca cells from small lutein cells and secrete progesterone as well as some aromatised androgens. This, once again, leads to negative feedback on GnRH/FSH/LH. The increased progesterone levels will stimulate glandular activity and maintain the endometrium in case a pregnancy occurs. Now, it depends whether the oocyte is fertilised or not as to what happens next.





Post-ovulation events

If the oocyte is fertilised, it can finally complete meiosis and will also produce the second polar body (Figure 1). This embryo will then produce a hormone stimulus, human chorionic gonadotrophin (hCG), to maintain progesterone production from the corpus luteum, which is needed to support pregnancy. The raised progesterone and oestrogen levels will also act to suppress further ovulation so that there is no multi-release of oocytes. After 6 weeks or so, the placenta will take over this role and the corpus luteum can finally degenerate to form the corpus albicans which is then lost.

If the oocyte isn’t fertilised, and there no hCG is detected by 12-14 days post-ovulation, the corpus luteum will rapidly degenerate to the corpus albicans. As it degenerates, progesterone and oestrogen levels fall (as the corpus luteum is no longer producing them), removing the inhibition from GnRH, LH and FSH, allowing the cycle to recommence with the development of a new follicle in the ovary.

References

 

  • Bukovsky et al, Oogenesis in Adult Mammals, including Humans, 2005, Endocrine, volume 26, pages 301-316
  • Bukovsky et al, Oogenesis in cultures derived from adult human ovaries, 2005, Reproductive Biology and Endocrinology, volume 3.
  • Eggan et al, Ovulated oocytes in adult mice derive from non-circulating germ cells, 2006, Nature, volume 441, pages 1109-1114
  • Koubova et al, Retinoic Acid regulates sex-specific timing of meiotic initiation in mice, 2006, PNAS, volume 103, pages 2474-2479
  • Liu et al, Germline stem cells and neo-oogenesis in the adult human ovary, 2007, Developmental Biology, volume 306, pages 112-120
  • Zuckerman, The number of oocytes in the mature ovary, 1951, Recent Prog Horm Res, volume 6, pages 63-109
  • Zuckerman and Mandl, The relation of age to numbers of oocytes, 1951, J. Endocrinology, volume 7, pages 190-193
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