In humans the female reproductive system consists of paired ovaries and the reproductive tract comprising paired uterine tubes, a uterus and a vagina (Fig. 16.1). Prior to puberty, as in males, the reproductive system in females is quiescent. At puberty, hormones from the pituitary gland initiate developmental changes which are prerequisites for reproduction. In contrast to the male reproductive system, the female system after puberty in humans is regulated by hormones secreted by the anterior pituitary gland on a monthly, cyclical basis. The cycle of activity begins at puberty and is manifested by the onset of menstruation (the loss of blood, cells and secretions from the uterus which drain through the vagina). The time when menstruation begins is known as the menarche and it occurs between 9 and 15 years of age. During each monthly menstrual cycle female oocytes differentiate and usually a single, mature oocyte is shed from an ovary each month, a process described as ovulation. The ability to produce a haploid gamete (an ovum), ovulate, conceive, support one or more developing fetuses and give birth continues from puberty until the menopause. During the menopause, which may begin between 45 and 50 years of age, the menstrual cycles and ovulation become irregular and then cease. During and beyond the menopause the hormonal signals required to stimulate the cyclical activity of the ovaries and the uterus also cease but the factor(s) that cause this cessation are not understood.

Fig. 16.1 The components of the female (human) reproductive system.

Ovaries

The ovaries are located in the pelvic cavity and are small (approximately 3 × 2 × 1.5 cm) and roughly ovoid in shape. Each ovary is attached by a stalk of double-layered membrane to the posterior surface of each side of the broad ligament (the peritoneal membrane surrounding the uterus) (Fig. 16.1). Blood (and lymphatic) vessels and nerves pass to each ovary within this membrane. The ovary is divided into two main regions, an outer cortex and inner medulla, though the demarcation between the two is not well defined. A simple cuboidal epithelium, known as the germinal epithelium, covers the cortex of each ovary and is continuous with the peritoneal epithelium. This name arises from the erroneous supposition that ‘germ’ cells capable of becoming ova (the female gametes) developed from this layer. It is now known that the ‘germ’ cells which are the stem cells (oogonia) for female gametes develop in the embryonic yolk sac and migrate to the ovaries during fetal development in utero (see Mitchell B, Sharma R. Embryology: An Illustrated Colour Text. Elsevier: 2004).

Cortex of the ovary

Immediately below the germinal epithelium is a thin layer of dense irregular connective tissue, the tunica albuginea. A connective tissue stroma containing some fibroblast-like cells supports structures in the cortex known as ovarian follicles (Fig. 16.2). Ovarian follicles comprise an oogonium, or a developing oocyte, surrounded by epithelial cells. In human females, between puberty and the menopause, ovarian follicles vary widely in appearance and size as they are in various stages of development. Some stromal cells are irregularly distributed in whorls in the cortex and others lie around developing follicles as layers known as theca (Fig. 16.2). Some of the fibroblast-like cells differentiate and are able to secrete steroid hormones.

Fig. 16.2 Ovary. A primary follicle and several small, primordial follicles are present in the cortex surrounded by connective tissue cells and fibres. Connective tissue is stained red. Special stain. Medium magnification.

Oogenesis and ovarian follicle development

In utero and prepubertal stages

In a developing female embryo from about the sixth week in utero, primordial, diploid oogonia migrate from the yolk sac and enter the developing ovary. From this time oogonia undergo mitosis and produce more oogonia. By about the fifth month of fetal life each ovary contains 5–7 million oogonia and migration of oogonia from the yolk sac stops. In contrast to spermatogonia, which continue to act as stem cells for spermatozoa production throughout life in males, mitosis of oogonia stops before birth and no new oogonia are formed thereafter. Indeed, the majority of oogonia die before birth.

All surviving oogonia become primary oocytes before birth as they replicate their DNA and then enter the prophase of the first (reduction) division of meiosis. This is the phase in which homologous chromosomes pair and exchange short regions of DNA, thus introducing genetic variation to the chromosomes derived originally from the mother and the father. Primary oocytes remain in the first prophase of meiosis unless they become atretic and die in the ovary or, after puberty, are shed at ovulation.

At birth there are 1–2 million primary oocytes remaining and each is surrounded by a layer of flattened epithelial cells known as follicular cells. Each primary oocyte and the surrounding follicular cells form a spherical, primordial follicle. Such follicles are predominant in the outer regions of the cortex (Fig. 16.2). Many primordial follicles die during childhood, leaving only about 400 000 at puberty.

Ovarian follicles in menstrual cycles

During each menstrual cycle several primordial follicles begin to develop but many become atretic (see below) and the oocyte dies. Usually, only one oocyte is released from a developed follicle every 28 days at ovulation, so that the lifetime total of female gametes shed is only around 400. In adults, ovarian follicles may be defined by the stage of their development and are categorised into four types: primordial, primary, secondary (antral) and Graafian (mature) follicles.

■ Primordial follicles (Figs 16.2 and 16.3). These consist of a primary oocyte, in the prophase of the first meiotic division, surrounded by a single layer of flattened epithelial cells which is surrounded by a basement membrane.

Fig. 16.3 Ovary. Two primary and several primordial follicles. The nucleus of the primary oocyte in one primary follicle and the nuclei in the primordial follicles have the clumped chromatin typical of cells in prophase of the first meiotic division. Special stain. High magnification.

■ Primary follicles. Each month, several primordial follicles begin to develop and form primary follicles. This development is stimulated by follicle-stimulating hormone from the anterior pituitary gland. In each developing primary follicle the primary oocyte increases in volume and the surrounding flattened follicle cells become cuboidal or columnar in shape and are then known as granulosa cells. At this stage, the follicles are described as unilaminar primary follicles (Fig. 16.3), and they are deeper in the ovary than primordial follicles.

Unilaminar follicles become multilaminar follicles as mitotic activity is high in granulosa cells and the new cells form layers around each developing primary oocyte (Fig. 16.2, Fig. 16.3 and Fig. 16.4). During this time, the primary oocyte enlarges considerably and a prominent deposit of condensed material known as the zona pellucida appears between the oocyte and the granulosa cells (Fig. 16.2, Fig. 16.3 and Fig. 16.4). Primary oocytes, which may grow to 120 μm in diameter, may appear to lack a nucleus (Figs 16.2 and 16.3) in routine histological sections which, at only 5–10 μm thick, can fail to include the nucleus. As primary follicles grow the basement membrane which separates the (epithelial) granulosa cells from surrounding connective tissue (Fig. 16.2) becomes more apparent.

Fig. 16.4 Ovary. Multilaminar follicle. Connective tissue is stained red. Special stain. High magnification.

Stromal cells around each primary follicle form two layers during this phase: the theca interna and theca externa. The inner theca is well vascularised whereas the outer theca is composed of fibrous connective tissue, although the layers are not always distinct (Fig. 16.2). Luteinising hormone from the anterior pituitary gland binds to cells of the theca interna and this stimulates them to produce steroids. These steroids are converted by granulosa cells into oestrogens (female steroid hormones). Oestrogens are involved in stimulating the uterus each month (see below) and in the development and maintenance of the secondary sexual characteristics and of the mammary glands.

■ Secondary follicles. Some multilaminar primary follicles develop and enlarge further, under the influence of follicle-stimulating hormone. The granulosa cells produce fluid, liquor folliculi, which appears in spaces between the granulosa cells (Fig. 16.5). These follicles are described as secondary (antral) follicles. Gradually, the fluid-filled spaces coalesce into a single large space, the antrum, and development proceeds with the formation of a Graafian (mature) follicle.

Fig. 16.5 Ovary. Secondary (antral) follicle. Special stain. Low magnification.

■ Graafian (mature) follicles. As the single antrum enlarges the granulosa cells appear as layers around the fluid and the layers become thinner as the follicle enlarges further. The oocyte, surrounded by granulosa cells, bulges into the fluid in the antrum and the whole bulge is known as the cumulus oophorus (Fig. 16.6).

Fig. 16.6 Ovary, Graafian follicle. Special stain. Low magnification.

Graafian follicles may become very large (2.5 cm in diameter) and bulge from the surface of the ovary prior to ovulation. The primary oocyte (which was arrested in utero in prophase of the first reduction meiotic division) completes the first meiotic division just prior to ovulation. The result is one large secondary oocyte with half the original number of chromosomes (23 in humans) and a small cell, known as the first polar body (also with 23 chromosomes), which degenerates.

Atresia of follicles

Most developing follicles fail to become mature Graafian follicles. Atresia may occur at any stage of follicle development and it involves the death of granulosa cells (Fig. 16.7) and the oocyte. Atretic follicles are gradually replaced by scar tissue containing fibroblasts and collagen (Fig. 16.2).

Fig. 16.7 Ovary. Atretic follicle. Densely stained fragments of DNA and disruption of the layers of granulosa cells characterise atretic follicles. This follicle is large and had developed into a secondary follicle. The developing primary oocyte is not in the plane of section but it too will be undergoing degeneration. Connective tissue is stained red. Special stain. Low magnification.

Ovulation

Ovulation usually happens once at the mid-point (day 14) of every menstrual cycle. It is the process whereby a secondary oocyte and the surrounding cluster of granulosa cells (the corona radiata) are expelled from a Graafian follicle and away from the surface of the ovary. Ovulation is brought about as the increasing volume of the Graafian follicle puts pressure onto the tunica albuginea and surface epithelium of the ovary and also compresses blood vessels in the region. This is coincidental with a breakdown of the wall of the follicle in the same region. The oocyte, granulosa cells forming the corona radiata and fluid burst from the antrum of the follicle and enter the peritoneal cavity. Further development of the oocyte normally occurs only if it passes from the peritoneal cavity into the lumen of the uterine tube (see below).

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