Control of Ovulation and the Corpus Luteum



Control of Ovulation and the Corpus Luteum



Key Points


Ovulation


1. Ovulatory follicles are selected at the onset of luteolysis (in large domestic animals).


2. Ovulation is caused by an estrogen-induced preovulatory surge of gonadotropins.


Corpus luteum


1. The corpus luteum secretes progesterone, which is essential for pregnancy.


2. Luteinizing hormone is important for the maintenance of the corpus luteum.


3. Regression of the corpus luteum in nonpregnant large domestic animals is controlled by uterine secretion of prostaglandin F2α.


4. Changes in luteal life span in large domestic animals occur because of changes in prostaglandin F2α synthesis by the uterus.


Ovarian cycles


1. In spontaneously ovulating animals, ovarian cycles have two phases: follicular and luteal; animals that require copulation for ovulation can have only a follicular phase.


2. The luteal phase is modified by copulation in some species.



Ovulation


Ovulatory Follicles Are Selected at the Onset of Luteolysis (in Large Domestic Animals)


Until the advent of ultrasonography, it was difficult to identify growth patterns of follicles in domestic animals, especially those of follicles that develop during the luteal phase of the cycle. The concept that follicles do develop during the luteal phase was emphasized by the earlier work of Rajakowski, who described the midcycle follicle in the cow. With ultrasonography, it has been possible to define follicular growth and regression during the luteal phase of the cycle in the cow and mare. In cattle the predominant pattern is for several dominant (large) antral follicles to develop sequentially during the cycle (Figure 36-1). The follicular cycles are distinct to the extent that follicle regression usually begins (as indicated by follicle size) before the onset of the growth of the next follicle. The first dominant follicle regresses about midluteal phase, with a second dominant follicle beginning growth immediately. Whether the second dominant follicle is the ovulatory follicle, or whether a third develops, depends on the stage of the follicle at the time of regression of the corpus luteum (CL). If the second dominant follicle has begun to regress at the time of CL regression, a third follicle develops. Thus the selected ovulatory follicle is, by chance, the dominant follicle that is still in a developmental stage at the time that regression of the CL is initiated. The duration required for the development of the antral follicle to the point of ovulation has been estimated by various techniques to be about 10 days in domestic animals, perhaps slightly longer in some primates.


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FIGURE 36-1 Mean (± standard error of the mean) profiles of diameters of dominant follicles and the largest subordinate follicle and the cross-sectional luteinized area of the corpus luteum (CL) for the interovulatory intervals with three and two follicular waves in cattle. Regression (P <0.05) of the CL began between days 18 and 20 for three-wave intervals and between days 15 and 16 for two-wave intervals. OV, Ovulation. (From Ginther OJ, Knopf L, Kastelic JP: Temporal associations among ovarian events in cattle during oestrous cycles with two and three follicular waves, J Reprod Fertil 87(1):223–30, 1989.)

From ultrasonographical and endocrinological studies, two different phases in final antral follicle development apparently occur in large domestic animals: a relatively slow phase that lasts 4 to 5 days, followed by a second phase of accelerated growth, again lasting 4 to 5 days, that terminates in ovulation (Figure 36-2). Because the final growth phase of follicle development can be initiated during the luteal phase, the initiation of this phase can occur under the influence of a relatively slow pulse rate of gonadotropin release that occurs during the luteal phase. The rapidly growing follicle requires exposure to a faster gonadotropin pulse rate by the third, or fourth, day in order for the follicle(s) to complete the normal growth pattern through ovulation. This situation usually occurs in conjunction with the onset of CL regression, which passively allows an increase in pulsatile rate of gonadotropin secretion (see Figure 35-4).


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FIGURE 36-2 Development of the dominant and second-largest follicle during the estrous cycle of the mare. Note the divergence in diameter between the largest and second-largest follicles 1 day after ovulation. (From Pierson RA, Ginther OJ: Follicular population dynamics during the estrous cycle of the mare, Anim Reprod Sci 14:219, 1987.)

One of the ways the dominant follicle maintains its status is to produce substances that inhibit the development of other antral follicles. One of the substances is inhibin, a peptide hormone produced by the granulosa, which inhibits the secretion of follicle-stimulating hormone (FSH). The dominant follicle is able to compensate for the lower FSH concentrations and continue to grow because of the numbers of FSH receptors it has compared with competitor follicles. Follicle development is dynamic once the rapid growth phase is achieved; the follicle(s) must be acted on through proper gonadotropin stimulation within a few days, or the result is death of the follicle. If the rapidly growing antral follicle is not exposed to the proper gonadotropin environment, atresia (regression) of the follicle begins almost immediately. Follicles that regress are invaded by inflammatory cells, and the area previously occupied by the antral follicle is eventually filled by connective tissue; that is, the follicle is replaced by an ovarian scar.



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.


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FIGURE 36-3 Preovulatory surge of luteinizing hormone (LH) on day 19 of the estrous cycle in a cow. (From Rahe CH, Owens RE, Fleeger JL, et al: Pattern of plasma luteinizing hormone in the cyclic cow: dependence upon the period of the cycle, Endocrinology 107(2):498–503, 1980.)

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 F2α (PGF2α), 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.



Corpus Luteum


The Corpus Luteum Secretes Progesterone, Which Is Essential for Pregnancy


The main function of the CL is the secretion of progesterone, which prepares the uterus for the initiation and maintenance of pregnancy. The CL forms from the wall of the follicle, which is collapsed and folded after ovulation. With rupture of the follicle, there is a breakdown of the tissues that surround the granulosa, particularly the membrana propria, and hemorrhage into the cavity can occur from vessels in the theca. The folds of tissue that protrude inward into the cavity contain granulosa and theca cells and, importantly, the vascular system that will support cell growth and differentiation. Although the granulosa cell is the dominant cell of the CL, theca cells also contribute significantly to the composition of the structure. The process that granulosa cells undergo during the change from estrogen to progesterone secretion, luteinization, begins with the onset of the preovulatory LH surge and accelerates with ovulation.


In most domestic species, significant production of progesterone by the CL begins within 24 hours of ovulation. In some species, including the dog and primates, small amounts of progesterone are produced during the preovulatory LH surge; in the dog, this is important for the expression of sexual receptivity, which occurs as estrogen levels decline while progesterone levels increase.




Regression of the Corpus Luteum in Nonpregnant Large Domestic Animals Is Controlled by Uterine Secretion of Prostaglandin F2α


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 PGF2α, 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; PGF2α has no known natural role in CL regression in cats and dogs or in primates. Prostaglandin (PGF2α 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 PGF2α (likely of endometrial origin) at about 14 days postovulation. The mode of transfer of PGF2α 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), PGF2α synthesis from a uterine horn only influences the life span of the CL in the ipsilateral ovary. In other species (sow and perhaps mare), PGF2α synthesis from one horn is sufficient to cause regression of CL in both ovaries. This effect likely occurs because of greater production of PGF2α by uterine tissue, as well as a difference in the rate of metabolism of PGF2α. PGF2α is rapidly metabolized systemically, with more than 90% changed by one passage through the lungs. Thus the system involving the use of PGF2α as the luteolytic agent in large domestic species requires that PGF2α be conserved through a special transfer system, or that it be produced in relatively large amounts.


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FIGURE 36-4 Postulated route by which prostaglandin secreted by the progesterone-primed uterus is able to enter the ovarian artery and destroy the corpus luteum in sheep. (From Baird DT: The ovary. In Austin CR, Short RV, editors: Reproduction in mammals, vol 3, Cambridge, UK, 1986, Cambridge University Press.)
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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Control of Ovulation and the Corpus Luteum
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