Ovulation Is Caused by an Estrogen-Induced Preovulatory Surge of Gonadotropins

The preovulatory surge of luteinizing hormone (LH), which begins about 24 hours before ovulation in most domestic species, including the cow, dog, goat, pig, and sheep, initiates the critical changes in the follicle that affect its endocrine organ status and result in release of the oocyte (Figure 36-3). Two important tissues, the oocyte and the granulosa, have been kept under control by the production of inhibitory substances that are probably of granulosa origin. An oocyte-inhibiting factor prevents the oocyte from resuming meiosis, and a luteinizing-inhibiting factor prevents the granulosa from prematurely being changed into luteal tissue. The impact of the LH surge blocks the production of both these factors. In most animals the resumption of meiosis results in the first division of meiosis (meiosis I), or formation of the first polar body, which is complete before ovulation. In animals with the potential for reasonably long reproductive longevity (e.g., cattle), the initiation of the meiotic process could have begun as many as 10 years or more before its completion.

The effect of the LH surge on the granulosa is to allow initiation of the process of luteinization, which transforms the cells from estrogen to progesterone secretion. This process is underway before ovulation occurs. With the advent of the LH surge, estrogen secretion declines concomitantly with the onset of progesterone secretion.

Another function of the preovulatory surge release of LH is to cause the granulosa to produce substances, such as relaxin and prostaglandin F_2α (PGF_2α), that affect the continuity of the connective tissue of the thecal layers of the follicle. These and other unknown substances disrupt the theca through the development of vesicles (within fibrocytes) that contain hydrolytic enzymes capable of breaking down the collagen matrix of connective tissue. The rupture of the follicle is caused by the disintegration of the connective tissue.

In summary, estrogen is used by the follicle(s) (1) to stimulate the growth and development of the granulosa and (2) to signal the hypothalamus and anterior pituitary as to the readiness of the follicle(s) for ovulation.

Luteinizing Hormone Is Important for the Maintenance of the Corpus Luteum

For most domestic animals, LH is the important luteotropin, with the CL maintained in either nonpregnant or pregnant animals by a relatively slow pulsatile pattern of LH release (one pulse every 2 to 3 hours). In rodents, prolactin is the important luteotropin; daily biphasic release of prolactin is initiated by copulation, which is essential for the maintenance of the CL. Of the domestic species, prolactin has been implicated as a luteotropin in sheep and dogs.

Normal folliculogenesis, a prerequisite for ovulation, sets the stage for the subsequent development of the postovulatory CL. Thus, more clinical attention is paid to factors controlling the regression of the CL than to luteotropic factors.

Regression of the Corpus Luteum in Nonpregnant Large Domestic Animals Is Controlled by Uterine Secretion of Prostaglandin F_2α

Regression of the CL is important in large domestic nonpregnant animals so that animals reenter a potentially fertile state as soon as possible. The CL life span after ovulation must be of sufficient duration to allow a newly developing conceptus to synthesize and release factors that allow the CL to be maintained, but it must be relatively short so that a nonpregnant animal can return to a potentially fertile state. In large domestic animals the duration of the luteal phase is about 14 days in the absence of pregnancy. This allows large domestic animals to recycle at relatively frequent intervals, approximately every 3 weeks.

Leo Loeb first showed (in 1923) the importance of the uterus for the regression of the CL through hysterectomy studies that extended the luteal phase in guinea pigs. He concluded that the uterus must produce a substance that terminated luteal activity. This information lay dormant for many years, until hysterectomy studies in cattle, pigs, and sheep in the 1950s produced similar results, that is, a prolongation of the luteal phase of the estrous cycle. Through these studies the concept developed that the uterus is responsible for control of the duration of the life span of the CL, at least in large domestic species (and guinea pigs).

It is now accepted that PGF_2α, a 20-carbon unsaturated fatty acid, is the uterine substance that causes regression of the CL in large domestic animals, including cattle, goats, horses, pigs, and sheep; PGF_2α has no known natural role in CL regression in cats and dogs or in primates. Prostaglandin (PGF_2α and PGE) therapy has been used clinically to cause luteolysis in the bitch and queen, for the treatment of pyometra, or to induce abortion. In large domestic species, regression of the CL is initiated by uterine synthesis and release of PGF_2α (likely of endometrial origin) at about 14 days postovulation. The mode of transfer of PGF_2α from the uterus to the ovary is thought to occur either by local countercurrent transfer or general systemic transfer. Countercurrent transfer involves the movement of molecules across the blood vascular system from higher concentrations in the venous effluent (utero-ovarian vein) to an area of lower concentration (ovarian artery) (Figure 36-4). Systemic transfer involves passage of the molecules through the general circulatory system. In some species (cow and ewe), PGF_2α synthesis from a uterine horn only influences the life span of the CL in the ipsilateral ovary. In other species (sow and perhaps mare), PGF_2α synthesis from one horn is sufficient to cause regression of CL in both ovaries. This effect likely occurs because of greater production of PGF_2α by uterine tissue, as well as a difference in the rate of metabolism of PGF_2α. PGF_2α is rapidly metabolized systemically, with more than 90% changed by one passage through the lungs. Thus the system involving the use of PGF_2α as the luteolytic agent in large domestic species requires that PGF_2α be conserved through a special transfer system, or that it be produced in relatively large amounts.