James A. Clemens

Hypothalamic Control of Prolactin Secretion

Publisher Summary This chapter emphasizes the current concepts and observations hypothalamic control of prolactin secretion. The regulation of prolactin secretion is exerted by the hypothalamus, and involves the action of a prolactin-inhibiting factor (PIF), a possible prolactin-releasing factor (PRF), catecholamines, serotonin, and other biogenic amines—all produced in the hypothalamus. Some other agents that stimulate or inhibit prolactin secretion including estrogen, the suckling stimulus, stresses, several drugs, and prolactin, act through hypothalamic mechanism. However, there are some hormones and drugs that can directly influence the anterior pituitary to increase or decrease prolactin secretion, although several of these also can act through the hypothalamus. The interference with hypothalamic pathways to the anterior pituitary by appropriate hypothalamic lesions, stalk section, pituitary transplantation or by administration of certain drugs, results in augmented prolactin release. PIF release from the median eminence is at least partially under the regulation of biogenic amines. The physiological importance of circulating prolactin in controlling secretion of pituitary prolactin remains to be elucidated. The ability of many drugs to either increase or depress prolactin release suggests a useful approach for controlling the secretion and functions of prolactin in the organism.

Effects of Hypothalamic Stimulation, Hormones, and Drugs on Ovarian Function in Old Female Rats

Summary Old female rats in constant estrus were given different treatments in an attempt to induce ovulation. Subcutaneous injections of progesterone for 3 days or epinephrine for 10 days, induced ovulation in 6 out of 10 and 11 out of 22 rats respectively, with normal appearing estrous cycles observed in many epinephrine-treated rats. Electrical stimulation of the preoptic area of the hypothalamus produced ovulation in 3 out of 5 old rats. Injections of reserpine, thyroxine or cyproterone acetate, and cervical stimulation, failed to induce ovulation, whereas ovariectomy resulted in anestrus. These observations suggest that changes in hypothalamic function account for constant estrus in old female rats.

Neuroendocrine Status of Old Constant-Estrous Rats

Hypothalamic and pituitary functions of 21-month-old rats in constant estrus were compared with those of 3-month-old cycling rats on the day of estrus. FSH-RF in the hypothalamus and pituitary FSH were significantly higher in the old than in the young rats. Pituitary LH was significantly lower in the old than in the young rats. Hypothalamic PIF was similar in both groups, but pituitary prolactin concentration was significantly greater in the old rats. The old constant-estrous rats showed well-developed ovarian follicles but no corpora lutea, increased uterine weight, hyperplastic mammary glands, and increased pituitary weight. It is suggested that the constant estrus observed in many old female rats is the result of a fundamental change in hypothalamic control of pituitary FSH, LH, and prolactin secretion.

Effects of Hypothalamic Lesions on Incidence and Growth of Mammary Tumors in Carcinogen-Treated Rats

Summary Intact and ovariectomized Sprague-Dawley rats with ME lesions placed prior to treatment with DMBA, showed a 30 and 0% mammary tumor incidence, respectively, in contrast to a 95 and 54% mammary tumor incidence in the respective nonlesioned control groups. Intact and ovariectomized rats lesioned 75 days after DMBA treatment showed a 120 and 80% increase, respectively, in number of palpable mammary tumors 10 days after treatment. In contrast the non-lesioned intact and ovariectomized control groups showed a 19% increase and a 27% decrease in number of palpable mammary tumors, respectively. After 25 days, stimulation of mammary tumor growth was still marked in the intact-lesioned group but regression occurred in the ovariectomized-lesioned group. These results indicate that ME lesions placed before DMBA treatment inhibit mammary tumorigenesis, presumably by increasing prolactin secretion and stimulating mammary growth, thereby leaving the mammary glands refractory to DMBA; ME lesions placed 75 days after DMBA treatment are believed to promote growth and development of mammary tumors by increasing prolactin secretion.

Termination of Pregnancy in Rats by a Prolactin Implant in Median Eminence

Summary A prolactin-cocoa butter mixture was implanted once in the median eminence of rats on each of days 1–8 of pregnancy. Control pregnant rats were given similar implants of cocoa butter alone. When laparotomies were performed on day 15, all of the control rats were still pregnant. None of the rats implanted with prolactin-cocoa butter on days 1–6 remained pregnant, but almost all rats remained pregnant when implanted on days 7 or 8 of pregnancy. These results indicate that a prolactin implant in the median eminence, by reducing pituitary prolactin secretion, terminates pregnancy if given during the first 6 days of gestation. When prolactin was implanted in the median eminence of rats on the fourth day of gestation and 2 mg of progesterone were injected daily until day 11, pregnancy was maintained. When progesterone was withdrawn after day 11, and the rats were killed on day 15, it was evident that resorption of the fetuses had occurred. This indicates that the decrease in pituitary prolactin secretion produced by the implant of prolactin into the median eminence, resulted in luteal regression and reduced progesterone secretion.

Effects of Estrogen on Pituitary Prolactin Levels of Female Rats Bearing Median Eminence Implants of Prolactin

Summary A median eminence implant of prolactin significantly lowered anterior pituitary prolactin content and concentration in female rats. Injection of 1.0 μg of estradiol benzoate daily for 5 days was unable to counteract this action of the ME implant of prolactin, whereas 5 μg was only partially effective. However, injection of 10.0 μg of estradiol benzoate daily was as effective in increasing anterior pituitary prolactin levels in the presence as in the absence of an ME implant of prolactin. These results suggest that circulating levels of prolactin, by acting on the hypothalamus, may be able to modify the action of estrogen in promoting prolactin secretion.

Relation of Local Circulation between Ovaries and Uterus to Lifespan of Corpora Lutea in Rats

Summary The effects of sham operation, bilateral ligature of blood vessels joining the uterus to the ovary, and hysterectomy were determined on the length of pseudopregnancy in rats. Hysterectomy or bilateral ligature of blood vessels joining the uterus to the ovary significantly increased the length of pseudo-pregnancy when compared to sham-operated controls. These results indicate that the circulation between the uterus and ovaries is important in local control of luteal lifespan in the rat.

6-methyl-8-β-ergoline-acetonitrile (MEA)-induced suppression of mammary tumorigenesis in C3H/HeJ female mice

Abstract Daily treatment for 14 months of 2 -month-old nulliparous C3H/HeJ mice with 6-methyl-8-β-ergoline-acetonitrile (MEA), an effective inhibitor of pituitary prolactin secretion, markedly suppressed development of mammary hyperplastic alveolar nodules and sharply reduced mammary tumor incidence. Mature 8 -month-old multiparous C3H/HeJ mice, treated daily for 30 -day periods, at bimonthly intervals for a period of 1 year, also had reduced numbers of mammary hyperplastic alveolar nodules and decreased mammary tumor incidence. Treatment with the ergoline derivative had no significant effect on pituitary, ovarian, uterine, adrenal or body weight nor did it alter the estrous cycles. Thus, significant inhibition of spontaneous mammary tumorigenesis by drug-induced hormone (prolactin) suppression has been demonstrated in this study.