Oogenesis

In the fetus, primordial germ cells migrate from the yolk sac to the developing ovaries, where a single layer of follicular cells surrounds a germ cell destined to become an ovum.

Figure 27-1. Sagittal section of an ovary showing the origin, growth, and ovulation of a follicle and a corpus luteum developing at the site of a follicle that has ovulated. A, Primary follicle; B, growing follicle; C, Graafian or tertiary follicle; D, ovulation; E, corpus luteum. (Reprinted with permission of Wiley-Blackwell from Reece W.O. Physiology of Domestic Animals. 2nd ed. Baltimore: Williams & Wilkins, 1997.)

prophase before the first division. At this stage, the developing ovum is a primary oocyte, and the combination of a primary oocyte and its surrounding cuboidal follicular cell (granulosa cell) layer is a primary follicle (Fig. 27-1). At birth, the ovaries of most domestic species contain hundreds of thousands of primary fol­licles waiting to continue their development. What determines which of the thousands of primary follicles is selected to develop further during a specific estrous cycle is unknown.

in contrast to spermatogenesis, which pro­duces four spermatozoa from each primary germ cell, the maturation of the primary oocyte results in only one mature ovum and three rudimentary cells, called polar bodies. In most animals, the first of the two meiotic divisions is complete, resulting in the formation of the first polar body, before or immediately after ovulation (the discharge of an oocyte from a follicle).

Secondary Follicles

in all animals, multiple primary follicles typi­cally begin further development during a single estrous cycle. in monotocous animals (animals not bearing litters and normally having only one offspring per gestation, such as the mare and cow), one follicle usually develops more rapidly than others, and only one ovum is released at ovulation. The rest of the developing follicles regress and form atretic follicles. Polytocous animals, such as carnivores and swine, which normally produce two or more offspring per gestation, usually have several fol­licles that develop and ovulate at approximately the same time. The ova may all come from one ovary, or some may come from each ovary.

The further development of primary follicles includes enlargement of the oocyte and replica­tion of the surrounding follicular cells. The replicating follicular cells become several layers thick, and this surrounding group of cells is a granulosa. The granulosa cells secrete glyco­proteins that cross-link to form a protective shell, the zona pellucida, around the oocyte (Fig. 27-1). Cytoplasmic processes of granulosa cells penetrate the zona to permit communica­tion and exchange between them and the oocyte. The initial development to this point is independent of hormonal stimulation by gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]).

The developing follicle is termed a second­ary follicle when the oocyte has enlarged and is surrounded by a developing granulosa. A theca, consisting of layers of cells immediately surrounding the granulosa, also first develops late during the secondary follicle stage.

Hormones and Follicular Development

Gonadotrophin-releasing hormone (GnRH) is released from the hypothalamus to promote the release of both FsH and LH from the adenohy­pophysis. The release of GnRH can be modu­lated by steroid (estradiol and progesterone) and peptide (inhibin) hormones from the ovary, but its basal release is determined by neural inputs to the hypothalamus.

The granulosa and theca of secondary folli­cles develop cellular receptors for FsH and LH, respectively, and become responsive to these hormones. From this point, the coordinated effects of FsH and LH are both needed for normal follicular development. Under the influ­ence of LH, thecal cells proliferate and produce androgens (androstenedione and testosterone) that diffuse into the granulosa. FsH promotes further granulosa cell proliferation, the devel­opment of cellular enzymes necessary for the conversion of androgens to estrogens (estradiol), and the secretion of several other paracrine agents necessary for follicular development.

The cellular secretions accumulate among the granulosa cells, and ultimately a fluid-fllled cavity (antrum) can be identified. The develop­ing follicles are tertiary follicles (also known as vesicular or Graafian follicles) when an antrum can be identified among the granulose cells (Fig. 27-1). Theca surrounding tertiary follicles have two layers, the theca externa and theca interna (Fig. 27-1). The internal layer is highly vascular and contains thecal cells with cellular characteristics of steroid-producing cells. The theca externa primary consists of connective tissue.

The estrogen produced by the granulosa cells acts as a paracrine agent on the developing follicle and also enters the systemic circulation to affect other sites throughout the body (Fig. 27-2). Locally, the estrogen acts on granulosa cells to increase FsH and LH receptors, and, together with these gonadotrophins, it pro­motes further granulosa cell replication, growth, and secretion. The overall effect is that locally produced estrogens promote the development of the follicle from which they are being pro­duced.

Estrogens from developing follicles are also necessary to prepare the follicles and the hypo- thalamic-adenohypophyseal axis for ovulation. Within the ovary, estrogens promote an increase in LH receptors in thecal cells so that these cells increase their production of androgens and appropriately respond to LH at the time of ovulation. Circulating estrogens promote an increase in LH within the adenohypophysis and condition the hypothalamic-adenohypophyseal axis so that the short-term large LH release (termed LH surge) necessary for ovulation can be delivered (Fig. 27-2).

Figure 27-2. Ovarian, uterine, and hormonal changes during the estrous cycle of the cow. The scale indicates days 1 to 21 of the cycle. Relative blood levels of progesterone (***), estrogen(-), FSH(^A^∣∩), and LH (—)are shown. (Reprinted with permission of Wiley-Blackwell from Dellmann H.D. and Eurell J. Textbook of Veterinary Histology. 5th ed. Baltimore: Lippincott Williams & Wilkins, 1998.)

Non-litter-bearing animals typically have one or two follicles per estrous cycle that develop faster and grow larger than the rest. These are dominant follicles. In primates there is typically only one dominant follicle per estrous cycle, and it provides the ovum. The development of the dominant follicle is acceler­ated after the corpus luteum (discussed later) from the previous estrous cycle has regressed (Iuteolysis).

in domestic animals that typically have only one or two offspring per pregnancy, large domi­nant follicles may develop while a corpus luteum remains intact. These dominant follicles may or may not ovulate. Mature follicles that do not ovulate undergo atresia if a corpus luteum remains intact. At that point, another dominant follicle begins to develop rapidly so that ovula­tion can occur soon after luteolysis. Because dominant follicles may develop while a corpus luteum remains intact, the estrous cycles of large domestic animals are considered to have over­lapping follicular and luteal phases.

Inhibins are peptide hormones secreted by granulosa cells of developing follicles. Circulat­ing levels of inhibins increase with follicular development, and inhibins have a negative feedback effect on FSH release from the adeno­hypophysis. By this means, a developing domi­nant follicle can suppress the development of competing follicles in non-litter-bearing animals. in litter-bearing animals, the com­bined negative feedback effect of inhibins from multiple follicles can suppress other follicles to prevent litter sizes from becoming inappropri­ately large. inhibins from developing follicles apparently do not suppress LH secretion neces­sary for ovulation.