Control of the corpus luteum, Exercises of Toxicology

Download Control of the corpus luteum and more Exercises Toxicology in PDF only on Docsity! Environmental Health Perspectives Vol. 38, pp. 51-54, 1981 Control of the Corpus Luteum: A Model System for Toxicology Research by Marc E. Freeman* The rodent corpus luteum is an ephemeral structure releasing progesterone for only a few hours rather than several days. However, in response to the mating stimulus, sufficient prolactin is released from the pituitary gland in a unique pattern to activate the corpus luteum and maintain it in a secretory state for several days. Progesterone, secreted from the corpus luteum, prolongs the secretion of prolactin, while the uterus may secrete a substance which terminates the functional life of the corpus luteum directly and also acts upon the prolactin secretory apparatus within the hypothalamopituitary axis to terminate prolactin secretion. In order to gain insight into the loci at which a toxic agent might intervene, one must have an appreciation for the normal function of the organ- ism. When studying effects on female reproductive processes, one can focus on the primary organ of reproduction, the ovary, or the endocrine organ which provides support for the ovary, the pituitary gland. This gland controls two aspects of ovarian function: release of the egg from the ovarian follicle or ovulation and the initiation and maintenance of corpus luteum function. The corpus luteum forms on the ovary immediately after release of the egg and begins to secrete progesterone. In most non- pregnant mammals, the corpus luteum persists for 12-14 days. If the recently shed ovum is fertilized, pregnancy ensues and progesterone secretion is maintained due to the hormonal stimuli provided by the newly formed placenta. In the absence of a fertile mating the corpus luteum wanes after the 12-14 day "luteal phase," progesterone secretion ceases and a new estrous or menstrual cycle begins. The corpus luteum of the nonfertile cycle is main- tained in most mammals by the basal levels of luteinizing hormone (LH) secreted from the pitu- itary gland after ovulation. On the other hand, rats, mice, and hamsters are unique in that their estrous cycles are short, usually 4-5 days, and are charac- terized by a "luteal phase" lasting only a day or * Department of Biological Science, Florida State University, Tallahassee, Florida 32306. April 1981 two. However, prolactin, secreted from the pitu- itary gland is capable of initiating a functionally prolonged luteal phase. The following sections will describe the initiation and maintenance of luteal progesterone secretion by pituitary prolactin and show that one function of luteal progesterone in turn, is to modify pituitary prolactin secretion. The possible sites at which toxic agents may intervene to modify these processes will be summarized. Activation of the Corpus Luteum in the Rat Ovulation occurs on the morning of estrus in response to the release of LH on the previous day. Over the next two days, the newly formed corpus luteum begins to function as reflected by the gradually rising blood levels of progesterone (1). In the absence of mating, the corpus luteum begins to fail within two days of its formation and progester- one secretion wanes (1). During the ensuing days a new crop of ovarian follicles grow which rupture on the morning of estrus and a new set of corpora lutea are formed. In rodents the corpus luteum can be induced to function for a prolonged interval by the mating stimulus. That is, a fertile mating results in a pregnancy characterized by heightened secretion of progesterone for 20-22 days (2). On the other hand, a sterile mating or artificial mechanical or electrical stimulation of the uterine cervix on proes- trus results in a "pseudopregnancy" characterized 51 by enhanced secretion of progesterone and a dis- tinctive persistent leukocytic vaginal smear pattern lasting 10-13 days (2, 3). Thus, in response to the mating stimulus the corpus luteum of the estrous cycle is "rescued" and transformed into a functional state during which it secretes progesterone for a prolonged interval. Control of the Corpus Luteum of Pseudopregnancy and Pregnancy In order to evaluate the control of this period of enhanced and extended secretion of progesterone brought on by mating, one can compare the circu- lating levels of the pituitary hormone follicle stimu- lating hormone (FSH), LH, and prolactin as well as the ovarian hormone estradiol during pseudopreg- nancy and the estrous cycles (1). Of the hormones known to play a role in reproductive function, blood levels of FSH, LH and estradiol do not differ in mated and unmated animals (1). However, mating institutes a unique pattern of pituitary prolactin secretion in rodents (1, 4-6). Though the unmated animal presents low unchanging blood levels of prolactin for all but a brief period on the afternoon of proestrus, the mated animal begins to secrete two daily "surges" of prolactin. The early morning surge begins by 1 AM, peaks by 5 AM and returns to basal levels by noon. This has been called the nocturnal surge (5, 6). The other surge, called diurnal (6), begins by 3PM, reaches peak levels by 7PM and returns to basal levels by midnight. These surges occur daily through the tenth day after cervical stimulation in both pregnant and pseudop- regnant rats (6, 7). During pregnancy, the last surge, a nocturnal surge, is secreted on day 10. Basal levels of prolactin are secreted thereafter (7). Since implantation of the blastocyst within the uterus is complete by this time, it has been sugges- ted that substances secreted by the placenta may be responsible for termination of the surges (8, 9). On the other hand, during the luteal phase induced by a sterile mating, a nocturnal and diurnal surge are found on day 10. The last nocturnal surge is secreted on day 11 with no diurnal surge on this day. During the afternoon of day 12 a proestrous- like surge of prolactin occurs, the corpus luteum fails, the pseudopregnancy is terminated and the animal returns to short estrous cycles (7). Since the only pituitary hormone which is se- creted in this unique pattern in response to mating is prolactin, this suggests that prolactin is the so-called luteotrophic hormone which prevents the corpus luteum from waning on day 2. This concept can be tested with the use of an ergot alkaloid, 52 2-Br-a-ergocryptine or CB-154, known to block only prolactin secretion by acting at the specific cell within the pituitary gland (10). Indeed, administra- tion of 1 mg of this drug at 11 AM and 11 PM on the first day of pseudopregnancy blocks both the diur- nal surge of prolactin on this day as well as the nocturnal surge of prolactin the following morning (10). As a result of this, the "rescue of the corpus luteum" which would have occurred on day 2 is prevented as reflected by the waning levels of progesterone in ergocryptine-treated rats (10). That the death of the corpus luteum is attributed to inhibition of prolactin secretion by CB-154 is sug- gested by the fact that prolactin is the only hor- mone whose administration will prevent luteal death when administered simultaneously with the drug (10). Moreover, neutralization of circulating levels of LH by administration of an antiserum to the hormone failed to prevent "rescue" of the corpus luteum in cervically stimulated rats. These data, together with the unique pattern of its secretion in response to the mating stimulus, sug- gests that only prolactin secretion initiated by this stimulus serves as the initial luteotrophic hormone activating a prolonged luteal phase. However, it is now well established that corpora lutea become dependent upon LH for maintenance of progester- one secretion during midpregnancy (11). Though prolactin satisfies the luteotrophic requirement dur- ing the early part of pregnancy which corresponds to pseudopregnancy, beyond this time the corpus luteum requires LH and ultimately placental lac- togen for functional maintenance (11). Prolactin additionally induces luteal cell LH receptors in preparation for the changing luteotrophic require- ments of the cell (12). Control of Prolactin Secretion by the Ovaries Given that the gonads regulate their own trophic support with positive and negative controls over the secretion of the pituitary gonadotrophins FSH and LH, it is not surprising that the prolactin surges induced by cervical stimulation may be regulated by ovarian steriods as well (Fig. 1A). However, the presence of ovarian steroids is not obligatory for surges to be secreted. Indeed, if one stimulates the cervix of animals which had been without their ovaries for at least two weeks, both the nocturnal and diurnal surges of prolactin occur at the usual time of day. But, both surges occur in an attenuated form in ovariectomized rats (13). Ovarian steroids have a profound influence on the magnitude and recurrence of prolactin surges initi- Environmental Health Perspectives