The female reproductive system (see Graphic 17-1) is composed of the ovaries, genital ducts, external genitalia, and the mammary glands, although, in a

strict sense, the mammary glands are not considered to be genital organs. The reproductive system functions in the propagation of the species and is under the control of a complex interplay of hormonal, neural, and, at least in the human, psychologic factors.

OVARY

Each ovary is a small, almond-shaped structure whose thick connective tissue capsule, the tunica albuginea, is covered by a simple squamous to cuboidal mesothelium known as the germinal epithelium (a modified mesothelium). The ovary is divisible into the cortex, rich in ovarian follicles and the medulla, a highly vascular connective tissue stroma.

•The cortex, located just deep to the tunica albuginea, houses the female germ cells, oogonia, which have undergone a series of cell divisions to form numerous primary oocytes.

Each primary oocyte is surrounded by a layer of epithelial cells known as follicular cells (whose origin is controversial), and these two structures together constitute an ovarian follicle.

Follicular cells secrete meiosis-preventing substance that prevents the continuation of meiosis and maintains the primary oocyte in the prophase of meiosis I.

Under the influence initially of local factors and later of follicle-stimulating hormone (FSH), follicles enlarge, are modified, become encapsulated by the ovarian stroma (connective tissue), and mature.

•The medulla is a highly vascularized loose connective tissue stroma rich in fibroblasts and estrogen-secreting interstitial cells.

Additionally, occasional hilar cells are present in the medulla; these cells resemble interstitial cells of the testis, and they manufacture a small amount of androgens.

Ovarian Follicles

Each ovarian follicle passes through various maturational stages, from the primordial follicle (or non-growing follicle), through the growing follicles which have four stages, namely, unilaminar primary, multilaminar primary, secondary, and, finally, the Graafian (mature) follicle (see Table 17-1).

•The primordial follicle is composed of a primary oocyte surrounded by a single layer of flattened follicular cells.

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•As maturation progresses, the follicular cells become cuboidal in shape, and the follicle is referred to as a unilaminar primary follicle.

•Multilaminar primary follicles display a primary oocyte surrounded by several layers of follicular cells (at this stage also referred to as granulosa cells).

The zona pellucida, manufactured by the primary

oocyte is composed of three glycoproteins, ZP1, ZP2, and ZP3, begins to be evident as it is interposed between the follicular cells and the primary oocyte.

Filopodia of the follicular cells adjacent to the zona pellucida and the microvilli of the primary oocyte contact and form gap junctions with each other in the zona pellucida.

The connective tissue stroma coalesces around the follicular cells but is separated from them by a basement membrane. This connective tissue layer is the theca folliculi and has two layers, a cellular theca interna adjacent to the basement membrane and a fibromuscular theca externa, surrounding the theca interna.

•With further growth of the follicle, accumulations of follicular fluid form in the extracellular spaces of the follicular cells. At this point, the entire structure is known as a secondary follicle, and it presents a welldeveloped zona pellucida,

as well as a clearly distinguishable basement membrane that is interposed between the follicular cells and the highly cellular theca interna

the theca interna is surrounded by a more fibrous theca externa.

•As maturation progresses, the Graafian follicle (also referred to as the mature follicle) stage is reached.

This large structure is characterized by a follicular fluid containing the central antrum, whose wall is composed of the membrana granulosa (follicular cells are also known as granulosa cells).

Jutting into the antrum is the cumulus oophorus, housing the primary oocyte and its attendant zona pellucida and corona radiata.

The membrana granulosa is separated from the theca interna by the basement membrane.

The theca externa merges imperceptibly with the surrounding ovarian stroma.

Several Graafian follicles develop during an ovulatory cycle, but (usually) only one will release its oocyte and that is known as the dominant (Graafian) follicle.

The dominant follicle, mostly because of the activity of luteinizing hormone (LH), ruptures, thus releasing the oocyte with its attendant follicular cells.

Regulation of Follicle Maturation and Ovulation

Early development of the follicle from the primordial through the secondary follicle stage is dependent on local factors. Later development depends on gonadotropinreleasing hormones (GnRHs) from the hypothalamus, which activate gonadotrophs of the adenohypophysis to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

•FSH not only induces secondary follicles to mature into Graafian follicles but also causes cells of the theca interna to secrete androgens.

•Additionally, FSH prompts granulosa cells to develop LH receptors, to convert androgens to estrogens, and to secrete inhibin, activin, and folliculostatin.

These hormones assist in the feedback regulation of FSH release. Moreover, as estrogen reaches a threshold level, it causes a surge of LH release.

•The LH surge results not only in resumption of meiosis I in the primary oocyte and initiation of meiosis II in the (now) secondary oocyte, but also in ovulation.

Additionally, LH induces the development of the corpus luteum from the theca interna and membrana granulosa, and this can occur only when the granulosa cells respond to FSH to produce LH receptors.

Locally produced prostaglandins stimulate smooth muscle cells of the theca externa to undergo contraction thus assisting in ovulation.

Corpus Luteum and Corpus Albicans

Once the Graafian follicle loses its oocyte, it becomes transformed into the corpus hemorrhagicum. Within a couple of days, the corpus hemorrhagicum is transformed

into the corpus luteum. The transformation into the corpus luteum involves

•the breakdown of the basement membrane between the theca interna and the granulosa cells

•collapse and folding of the former Graafian follicle upon itself

•resorption of the blood from the corpus hemorrhagicus and its replacement by fibrous connective tissue.

•transformation of the theca interna cells into theca lutein cells

•transformation of the granulosa cells into granulosa lutein cells

The transformation into the corpus luteum is due to both local factors such as IGF-I (insulin-like growth fac- tor-I), IGF-II, as well as the following hormones LH and prolactin.

•The corpus luteum, a yellow glandular structure, secretes progesterone, a hormone that suppresses LH release by inhibiting GnRH and facilitates the thickening of the uterine endometrium.

•Additionally, estrogen (inhibitor of FSH) and relaxin (which causes the fibrocartilage of the pubic symphysis to become more pliable) are also released by the corpus luteum.

In case pregnancy does not occur, the corpus luteum atrophies, a process known as luteolysis, and the absence of estrogen and progesterone will once again permit the release of FSH and LH from the adenohypophysis. In this case, the corpus luteum is known as the corpus luteum of menstruation and will degenerate into the corpus albicans.

In case pregnancy does occur, the syncytiotrophoblasts of the forming placenta