Structure. Gonadal differentiation is responsible for ovarian development. The gonads originate from coelomic epithelium of the urogenital ridge with somatic cells arising from the ridge mesoderm. The majority of ovarian malignancies (75-80%) arise from coelomic epithelium or mesothelium. Wolfian ducts will give rise to the epididymis, vas deferens and seminal vesicles under the direction of factors produced by the developing testis, which also produces Mullerian-inhibiting substance which brings about the regression of Mullerian ducts so that accessory structures associated with feminization like the uterus, fallopian tubes and upper vagina cannot develop. Development of structures originating from the Wolfian duct progresses only under the direct effect of testosterone. In the absence of gonadal development in the male direction, gonocytes proliferate mitotically under the stimulation of elevated fetal gonadotropins which peak between week 16-18. Oogonia become primary oocytes as they leave mitosis, begin meiosis and arrest in prophase. Oocytes that are not within a follicle undergo atresia with no more follicular formations after the 6^th week of neonatal life. Primordial follicles containing oocytes are present until after menopause. Normal ovarian development requires: absence of active Y chromosome material, two intact genetically active X chromosomes in the germ cells, germ cells that migrate and are mitotically active, the development of a granulosa cell mantle, transformation of oogonia to oocytes coupled to a controlled arrest in meiotic prophase and a physiological growth response of primary follicles to fetal FSH. Conditions of abnormal development associated with gonadal dysgenesis due to failed gonocyte migration, and sex chromosome aneuploidy present a risk for genital ridge tumors, most commonly gonadoblastomas and dysgerminomas.

The normal adult ovary has a volume of 9-18 cm³. Germinal epithelium make up the surface and becomes continuous with the peritoneum at the mesovarium. Ovulation enlarges the ovary, as do follicular cysts. Advancing age decreases the number of follicles and increases the amount of scarring from healed ovulation sites so that in advanced postmenopause the ovary is often less than 2 cm³. Accessory ovaries and supernumerary ovaries are rare, but if not discovered at surgery could account for cases of ovarian cancer arising after oophorectomy.

Function. At birth the human ovary is competent for all steroidogenic and gametogenic functions necessary for female reproduction. Until maturation is completed at puberty so that ovulation and conception can take place, ovarian function is constrained by an extragonadal mechanism involving pulsatile release of gonadotropin-releasing hormone (GnRH) in the hypothalamus, which interacts with GnRH receptors on specific cells of the pituitary (gonadotropes) to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). By midgestation the human fetus demonstrates active hypothalamic GnRH pulses and functioning pituitary gonadotropes that provide elevated FSH and LH sufficient for normal gonadal development. Elevated circulating estrogen is evident, indicating that steroidogenesis is underway. FSH, LH and estrogen levels drop at birth, but FSH and LH begin a rebound that lasts to ~3 months of age with FSH often reaching the high levels seen in postmenopause. Thereafter a slow decline occurs reaching a low at ages 2-3 years that is evident to age seven. This decline results from active inhibition of GnRH secretion in the CNS and does not require feedback from ovarian hormones because it also occurs in agonadal children. Normal children in this age range have follicles in varying stages of differentiation and atresia but experience ovulatory quiescence. Between 8-11 years of age, amplification of GnRH pulsing occurs via a maturation in the CNS so that many girls experience enhanced secretion of LH with an increased pulse frequency during sleep that is still independent of ovarian sex steroids. Finally, maturation of the hypothalamic-pituitary-ovarian unit is manifest in the final stage of puberty when the capacity for LH surges in response to high circulating estradiol is acquired as a positive feedback response which permits ovulation and consequent reproduction. This capacity remains intact until death.

During the years when women are active reproductively, ovarian function is related to cyclic alterations in circulating gonadotropins, estradiol and progesterone. The gonadotropins stimulate growth, development and maturation of follicles, oocytes and stroma, where steroidogenesis occurs. Ovarian stromal and thecal interstitial cells primarily produce androgens, in particular androstenedione. Usually a cohort of follicles is readied for development, out of which a single follicle becomes dominant by the 5^th day of the menstrual cycle, growing ahead of the rest and reactivating meiosis, dormant since fetal development, in the oocyte. When the oocyte is ovulated, the follicular wall involutes, internalizing granulosa cells and thecal interstitial cells, which incorporate lutein a yellow pigment and abundantly produce progesterone.

As a woman ages, an accelerated atresia of the remaining follicles leaves fewer available for gonadotropin promoted growth and differentiation. Symptoms of estrogen deprivation will occur as follicular steroidogenesis declines and circulating estradiol wanes. Eventually, follicular and gametogenic functions disappear. However, the senescent ovary is not inactive, maintaining extensive gonadotropin-dependent androgen production, with androstenedione and testosterone the most abundant. Estrogen production is entirely extragonadal aromatization of androstenedione to estrone. As age advances, the cortex of the shrinking ovary becomes thin and devoid of follicles with the medulla assuming prominence. Old corpora albicantia act as stromal cells and hilar cells become prominent, retaining responsiveness to high circulating gonadotropins with androgen production. As a consequence, it is not uncommon for postmenopausal women to develop stroma hyperthecosis and signs of virilization. Peripheral conversion of androgen to estrogen can lead to endometrial hyperplasia and risk of endometrial carcinoma. As a result of high circulating postmenopausal LH, hilar cell hyperplasia may occur producing testosterone that present signs of virilization and endometrial hyperplasia.

Ovarian Tumors and Malignancy. Ovarian neoplasms originate largely from coelomic epithelium, including 50-65% of benign neoplasms in the premenopause and 80% of those in the postmenopause. Malignant epithelial tumors of the ovary account for 85% of all ovarian carcinomas. Nulliparous women are at higher risk with lower risk associated with multiple pregnancies and oral contraceptive use, both factors that interrupt ovarian cycling. This disease is infrequent before puberty and elevated after menopause suggesting a hormonal link. It has been suggested that ovulation and the associated ovarian trauma may be causative. Under conditions of incessant ovulation, germinal inclusion cysts are predisposed to form as coelomic epithelium extends into the ruptured follicle, being sealed inside and proliferating under local estrogenic influence. As follicular healing continues, the bud of epithelium is burrowed into ovarian tissue and undergoes extensive squamous metaplasia that can be the focus of a benign or malignant differentiation. It seems possible that this process involves estrogen because the coelomic epithelium proliferates when estrogen levels are high and because estrogen receptors occur in many ovarian carcinomas.

Related to ovulation and the potential for inclusion of surface epithelium is the use of pharmaceuticals used to treat infertility by increasing ovulation. Central to this consideration is clomiphene, a nonsteroidal agent used to induce ovulation that has both the properties of a weak estrogen and of an antiestrogen. Clomiphene competitively binds to estrogen receptors in the hypothalamus and pituitary, and acting like an antagonist interferes with receptor replenishment so that an insensitivity to estrogen results which stimulates GnRH release and thereby induces FSH and LH secretion leading to ovulation. Clomiphene and tamoxifen are similar chemically and demonstrate equivalence for inducing ovulation. Moreover, the risk of ovarian cancer is raised by fertility treatments that include clomiphene. The use of antiestrogens and the risk of ovarian cancer may be unified as follows. Use of clomiphene in premenopausal women may increase inclusion cysts due to increased ovulation. Late In the postmenopause, circulating levels of gonadotropins may be further elevated above the high levels of the postmenopause, accounting for increased ovarian androgen production, which could be peripherally converted to estrogen capable of stimulating greater proliferation within inclusion cysts. Finally, although it has generally been accepted that estrogens are primarily tumor promoters, recent evidence indicates that estrogens may be initiators of carcinogenesis through oxidations to catechol 3,4 quinones which form depurinating adducts which generate mutations. It is entirely possible that estrogens serve this role within inclusion cyst foci.