Ovary

Development

The ovaries develop in early embryogenesis from the genital ridge, following sexual differentiation. The sex of an organism is determined at the time of fertilization, but differentiation only takes place around six weeks later.

Function

At puberty, the ovary begins to secrete increasing levels of hormones. Secondary sex characteristics begin to develop in response to the hormones. The ovary changes structure and function beginning at puberty. Since the ovaries can regulate hormones, they also play an important role in pregnancy and fertility. Usually, ovulation occurs in one of the two ovaries, releasing an egg cell each menstrual cycle. When an egg cell (mature oocyte) is released from the fallopian tube, a variety of feedback mechanisms stimulate the endocrine system, which causes hormone levels to change. These feedback mechanisms are controlled by the hypothalamus and pituitary glands. Messages or signals from the hypothalamus are sent to the pituitary gland. In turn, the pituitary gland releases hormones to the ovaries. From this signaling, the ovaries release their own hormones.

Gamete production

The ovaries are the site of gametogenesis, oogenesis in the female, producing oocytes and periodically releasing an egg cell, a mature oocyte. The developing oocytes mature to egg cells in ovarian follicles. Each pre-antral follicle contains a single oocyte surrounded by granulosa cells, enclosed in a connective tissue covering called the theca. They typically develop one at a time. As they develop they fill with follicular fluid which marks the secondary oocyte stage. When the fluid fills the antrum they are known as antral follicles, or pre-ovulatory follicles.

On maturing, a surge of luteinizing hormone is secreted by the pituitary gland, which stimulates the release of the oocyte through the rupture of the follicle, a process called ovulation. The follicle remains functional and reorganizes into a corpus luteum, which secretes progesterone to prepare the uterus for an eventual implantation of the embryo.

Hormone secretion

At maturity, ovaries secrete estrogen, androgen, inhibin, and progestogen. In women before menopause, 50% of testosterone is produced by the ovaries and released directly into the blood stream. The other 50% of testosterone in the bloodstream is made from the conversion of the adrenal pre-androgens (DHEA and androstenedione) to testosterone in other parts of the body. Estrogen is responsible for the appearance of secondary sex characteristics for females at puberty and for the maturation and maintenance of the reproductive organs in their mature functional state. Progesterone prepares the uterus for pregnancy and the mammary glands for lactation. Progesterone functions with estrogen by promoting menstrual cycle changes in the endometrium.

Ovarian aging

Aging leads to a constant decline in ovarian follicles marked by menopause at around the age of 52. Although about one million oocytes are present at birth, only about 500 (about 0.05%) of these ovulate. As ovarian reserve and fertility decline with age, there is also a parallel increase in pregnancy failure and meiotic errors resulting in chromosomally abnormal conceptions. The ovarian reserve and fertility perform optimally around 20–30 years of age. Around 45 years of age, the menstrual cycle begins to change and the follicle pool decreases significantly. The events that lead to ovarian aging remain unclear. The variability of aging could include environmental factors, lifestyle habits, or genetic factors.

Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely, suggesting that naturally occurring DNA damages in oocytes are repaired less efficiently in these women, and this inefficiency leads to early reproductive failure. The BRCA1 protein plays a key role in a type of DNA repair termed homologous recombinational repair, which is the only known cellular process that can accurately repair DNA double-strand breaks. Titus et al. showed that DNA double-strand breaks accumulate with age in humans and mice in primordial follicles. Primordial follicles contain oocytes that are at an intermediate (prophase I) stage of meiosis. Meiosis is the general process in eukaryotic organisms by which germ cells are formed, and it is likely an adaptation for removing DNA damage, especially double-strand breaks, from germ line DNA (see Meiosis and Origin and function of meiosis). Homologous recombinational repair is especially promoted during meiosis. Titus et al. also found that expression of 4 key genes necessary for homologous recombinational repair of DNA double-strand breaks (BRCA1, MRE11, RAD51, and ATM) declines with age in the oocytes of humans and mice. They hypothesized that DNA double-strand break repair is vital for the maintenance of oocyte reserve and that a decline in efficiency of repair with age plays a key role in ovarian aging. A study identified 290 genetic determinants of ovarian ageing, also found that DNA damage response processes are implicated, and suggests that possible effects of extending fertility in women would improve bone health, reduce risk of type 2 diabetes, and increase the risk of hormone-sensitive cancers.

A variety of testing methods can be used to determine fertility based on maternal age. Many of these tests measure levels of hormones FSH and GnrH. Methods such as measuring anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) can predict ovarian aging. AMH levels serve as an indicator of ovarian aging since the quality of ovarian follicles can be determined.

Clinical significance

Ovarian diseases can be classified as endocrine disorders or as a disorders of the reproductive system. Ovarian diseases include ovarian tumors such as ovarian germ cell tumors, ovarian cancers, and different types of ovarian cyst. Other ovarian disorders include inflammation (oophoritis), diminished functional activity (hypogonadism), failure to ovulate (annovulation), and twisting (ovarian torsion), or rupture (apoplexy) of the ovary. The ovaries may be affected by the growth of endometrial-like tissue on them (endometriosis).

If the egg fails to release from the follicle in the ovary, an ovarian cyst may form. Small ovarian cysts are common in healthy women. Some women have more follicles than usual caused by a hormonal disorder (polyendocrine metabolic ovarian syndrome), which inhibits the follicles from growing normally, and this will cause cycle irregularities.

The surgical removal or one or both ovaries is called an oophorectomy.

Some types of cancer therapy can negatively impact fertility. An option to preserve this is ovarian tissue cryopreservation where some of the tissue of the ovary cortex is removed and frozen to be replaced near to the remaining tissue after therapy completion. Tissue cryopreservation is also carried out in those who wish to postpone pregnancy, or to delay menopause. Another option to safeguard the ovaries during treatment is ovarian transposition which repositions the ovaries to a safer more shielded nearby location. Both options can be performed by laparoscopy.

History

Aristotle referred to ovarectomy in Historia Animalium, in sows to stimulate growth and fatness, and in female war camels to sterilize them. However, he believed that embryos are formed when the seed of a male (produced by the sperm ducts, rather than the testicles) plants into the soil of a female (probably referring to menstrual blood), and did not subscribe to the significance of gonads in heredity. He also observed that spayed females cease to go into estrus.

Herophilus was the first to describe the ovaries and the oviducts. He called the ovaries the "female testes" and gave the female equal credit with the male for producing the fetus. He thought the ovaries produced female seeds, and the testicles produced male seeds. The female seeds travel through the fallopian tubes and combine with the male seed in the uterus (not the fallopian tubes), thus producing an embryo. Soranus of Ephesus gave a detailed description of the ovaries. Galen in On Semen argued that both the testicles and the ovaries contribute to the embryo, but the testicles contribute more since they are larger.

Vesalius, by dissecting women of reproductive age, discovered the follicles with fluid within "white and like a milky serum", as well as a yellow substance likely to be the corpus luteum. He also noted the ovaries are bumpy with ovarian stigmas. Fabricius observed that in the hen, yolk is formed in the ovary, while the white and the shell are formed during the transit through the oviduct. He also made the first illustration of the corpus luteum in De Formato Foetu (1604) and called it "numerous conjoined little glands". Carlo Ruini noted that the ovaries of the fetal mare are up to 4 times as large as the mother's.

Nicolas Steno in 1667 hypothesized that the ovaries of mammals are analogous to the ovaries of birds, and thus they too contain eggs (rather than the "female semen"). In 1675, he described the ovaries of various animals and hypothesized that she-mules are infertile because their ovaries do not produce eggs. De Graaf made a full-length study of the female reproductive system. He thought the whole follicle was an egg, and proved it by cooking and eating the liquid inside follicles and noting that it had the same color, taste, and consistency as cooked egg-white. He stated that the number of corpus luteum is the same as the number of fetuses, and it only occurs after coitus (he was observing rabbits, who have induced ovulation). He also thought the corpus luteum is the scar tissue left behind after the egg is shed from the ovary. He observed that the corpus luteum is yellow in cows, red in sheep, and ashen in others. Drelincourt in 1685 suggested that the follicle is not the egg, and that the true egg is much smaller, and within the follicle. Malpighi speculated that the follicle never leaves the ovary, but remains within. The true egg is much smaller and within the follicle, and leaves the ovary. He also coined the word "corpus luteum" [Latin for "yellow body"] because he worked with the cow's ovaries, in which the corpus luteum is yellow. Boerhaave clearly stated the currently accepted theory that the ovum escapes from the ovary, leaving scar tissue of the corpus luteum, and passes down the fallopian tube, is fertilized by a sperm within the tube, then enters the uterus.

There was a controversy during the period about how reproduction works. Some like Harvey agreed with Aristotle that the ovaries are unimportant. Some like Wharton, Descartes, and Le Grand, agreed with Galen that the ovaries produced female semen that mixes with male semen to produce an embryo. The new "ovism" school, like Steno and de Graaf, thought the ovaries in mammals worked like the ovaries in birds: The entire follicle is an egg. The egg is fertilized in the ovary. Only fertilized eggs can leave the ovary. The new "animalculism" school believed only the sperm contained the generative principle.

John Huner experimentally removed one ovary from a sow and compared her with a sow with two ovaries. He noted that the half-spayed sow became infertile after producing 76 piglets, but continued to go into estrus. The other sow produced 162 piglets; thus, he proposed that each ovary could produce a fixed number of offspring. Percival Pott reported in 1775 that he removed two herniated ovaries from a woman, after which she became thinner, lost her large breasts, and ceased menstruation. This was the first accurate description of the effect of ovariectomy in humans. In 1827, von Baer first described and illustrated the mammalian egg within the follicle.

Albert Peuch in 1873 stated that spaying young sows prevented subsequent growth in the uterus. Emil Knauer showed that transplanting ovaries into the abdominal cavity in spayed dogs, rabbits, and guinea pigs prevented this uterine atrophy, similar to the testicle transplant experiment of Berthold in 1849. Prenant in 1898 concluded by histology that the corpus luteum was an endocrine gland. Ludwig Fraenkel Vilhelm Magnus both showed independently in 1901 that spaying pregnant rabbits or removing their corpora lutea by thermocautery resulted in abortion or resorption of the embryos. Leo Loeb noted in 1906 that traumatizing the endometrium of a nonpregnant guinea pig or rabbit resulted in formation of placenta or deciduoma, but this did not happen if corpora lutea were removed. In 1915, Edmund Herrmann, an Austrian obstetrician, showed that a lipid extract of pig's corpora lutea produced a fully progestational endometrium when injected into immature rabbits. This line of work was continued by Corner and Allen, resulting in the discovery of progesterone. Leo Loeb also showed in 1911 that removing the corpora lutea hastened the next ovulation. (Makepeace et al, 1937) showed specifically that injecting progesterone inhibited ovulation in rabbits. This eventually resulted in hormonal contraception.

Other animals

The ovaries of Old World primates such as macaques and great apes share many structural and functional features with those of humans. In rhesus monkeys (Macaca mulatta), the number of ovarian follicles declines with advancing age, and the monkeys reach menopause by the age of 25–30 years. Ovarian follicles are depleted with age also in chimpanzees (Pan troglodytes), which reach menopause at around the age of 50 years. New World primates for which information is available include tamarins (Saguinus spp.) marmosets (Callithrix jacchus) and squirrel monkeys (Saimiri sciureus). In aging squirrel monkeys, the loss of follicles is accompanied by the (apparently benign) proliferation in both ovaries of granulosa cells that resemble granulosa cell tumors in humans.

Birds have only one functional ovary (the left), while the other remains vestigial. In mammals, including humans, the female ovary is homologous to the male testicle, in that they are both gonads and endocrine glands. Ovaries of some kind are found in the female reproductive system of many invertebrates that employ sexual reproduction. However, they develop in a very different way in most invertebrates than they do in vertebrates, and are not truly homologous.

Many of the features found in human ovaries are common to all vertebrates, including the presence of follicular cells, tunica albuginea, and so on. However, many species produce a far greater number of eggs during their lifetime than do humans, so that, in fish and amphibians, there may be hundreds, or even millions of fertile eggs present in the ovary at any given time. In these species, fresh eggs may be developing from the germinal epithelium throughout life. Corpora lutea are found only in mammals, and in some elasmobranch fish; in other species, the remnants of the follicle are quickly resorbed by the ovary. In birds, reptiles, and monotremes, the egg is relatively large, filling the follicle and distorting the shape of the ovary at maturity.

Amphibians and reptiles have no ovarian medulla; the central part of the ovary is a hollow, lymph-filled space.

The ovary of teleosts is also often hollow, but in this case, the eggs are shed into the cavity, which opens into the oviduct. Certain nematodes of the genus Philometra are parasitic in the ovary of marine fishes and can be spectacular, with females as long as 40 cm (16 in), coiled in the ovary of a fish half this length. Although most female vertebrates have two ovaries, this is not the case in all species. In most birds and in platypuses, the right ovary never matures, so that only the left is functional. (Exceptions include the kiwi and some, but not all raptors, in which both ovaries persist.) In some elasmobranchs, only the right ovary develops fully. In the primitive jawless fish, and some teleosts, there is only one ovary, formed by the fusion of the paired organs in the embryo.

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