Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

Oxytocin produces uterine contractions and milk ejection, functions related to parturition and nuturing. Studies were conducted to determine if this peptide, native to the brain and the posterior pituitary gland, plays a role in the induction of maternal behavior. Intact virgin female rats were given 0.4 μg of oxytocin, 0.4 μg of [Arg8]vasopressin, or saline through lateral ventricular cannulae. Forty-two percent of intact rats receiving oxytocin displayed full maternal behavior towards foster pups. None of the saline- or vasopressin-treated animals displayed full maternal behavior. Criteria in five behavioral categories had to be fulfilled by an animal within 2 hr of injection for its behavior to be considered fully maternal. When partial maternal responses were considered, oxytocin was significantly more effective than saline and marginally more effective than vasopressin. Five animals responding fully maternally after oxytocin injection were allowed to stay with pups for 10 days. All five continued to display full maternal behavior during this time. Nearly all animals that responded fully maternally to oxytocin injection were in the last day of diestrus or in proestrus or estrus. This suggested that elevated or recently elevated levels of estrogen may be necessary for the induction of full maternal behavior by oxytocin. Twenty-seven virgin female rats were ovariectomized and given either 100 μg of estradiol benzoate per kg in oil subcutaneously or oil alone immediately after operation. Forty-eight hours later, all animals received 0.4 μg of oxytocin intracerebroventricularly. Eleven of 13 estrogen-primed animals became fully maternal; none of 14 nonprimed animals became fully maternal.

https://www.pnas.org/content/pnas/76/12/6661.full.pdf

Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin

The corpus luteum (CL) is one of the few endocrine glands that forms from the remains of another organ and whose function and survival are limited in scope and time. The CL is the site of rapid remodeling, growth, differentiation, and death of cells originating from granulosa, theca, capillaries, and fibroblasts. The apparent raison d'etre of the CL is the production of progesterone, and all the structural and functional features of this gland are geared toward this end. Because of its unique importance for successful pregnancies, the mammals have evolved a complex series of checks and balances that maintains progesterone at appropriate levels throughout gestation. The formation, maintenance, regression, and steroidogenesis of the CL are among the most significant and closely regulated events in mammalian reproduction. During pregnancy, the fate of the CL depends on the interplay of ovarian, pituitary, and placental regulators. At the end of its life span, the CL undergoes a process of regression leading to its disappearance from the ovary and allowing the initiation of a new cycle. The generation of transgenic, knockout and knockin mice and the development of innovative technologies have revealed a novel role of several molecules in the reprogramming of granulosa cells into luteal cells and in the hormonal and molecular control of the function and demise of the CL. The current review highlights our knowledge on these key molecular events in rodents.

The Molecular Control of Corpus Luteum Formation, Function, and Regression

Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.

Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms

Introduction * Hormonal and Nonhormonal Basis of Maternal Behavior * Experiential Factors Influencing Maternal Behavior * Motivational Models of the Onset and Maintenance of Maternal Behavior and Maternal Agression * Neuroanatomy of Maternal Behavior * Neurochemistry and Molecular Biology of Maternal Behavior * Paternal Behavior * Neural Basis of Parental Behavior Revisited * Human Implications

The Neurobiology of Parental Behavior

Serum levels of luteinizing hormone (LH) and prolactin were measured twice daily, and those of progesterone once daily, throughout gestation in rats with confirmed pregnancies, and in which parturition was seen to have occurred on day 23. Serum LH concentration during the first 11 days of pregnancy was distinctly higher than during the period between days 13–19, with a conspicuous pivot—point occurring at about day 12; beginning on day 20 and continuing to term, a progressive increase occurred, which was not contiguous with the acute, post—partum, ovulation inducing surge of LH. Serum prolactin level did not show as distinct a pattern of change, although highly erratic levels during the initial 10 days, and consistently low levels during most of the second half of pregnancy were noted. When related to the pattern of changes in the levels of serum LH and prolactin, the changes in serum progesterone level were seen to be inversely related to those in serum LH during the period from day 11 to term (r = -0.97...

Serum luteinizing hormone, prolactin and progesterone levels during pregnancy in the rat.

Intact rats were injected once, subcutaneously, with either 1.0 mg of ergocornine, free base (ECO), to prevent prolactin release, or an equine antiserum to bovine LH (LH-AS), to neutralize endogenous LH, on one of the days between days 6 and 12 of pregnancy. ECO treatment was uniformly abortifacient on day 6, only slightly less so on day 7, and was ineffective at 0400 hr or later on day 8. LH-AS treatment on day 6 or 7 induced abortion in very few rats; at 0400 hr on day 8, it induced abortion in 92%, and at 1200 or 1600 hr on day 8 or at 1200 hr on day 10, in 100% of the rats; when given on day 12, it was again ineffective. ECO did not depress serum LH or FSH levels, but abolished the nocturnal surge of prolactin; ECOinduced abortions could be prevented by treatment with prolactin but not with LH. Absorption of the LH-AS with LH, but not with either FSH or bovine serum abolished its abortifacient effect. A severe fall in the serum progesterone level occurred within 12 to 48 hr after treatment with either...

Temporal aspects of the regulation of corpus luteum function by luteinizing hormone, prolactin and placental luteotrophin during the first half of pregnancy in the rat.

The ability of decidual tissue (DT) to maintain progesterone secretion was tested by oberving the effect of ergocornine (ECO) on the serum progesterone level 24 hr after treatment, and on the duration of the post-treatment diestrus in pseudopregnant rats bearing decidualized uteri. ECO, which was used to suppress prolactin release, was given as a single subcutaneous injection of 1.0mg of the free base in 0.25 ml of 70% ethanol, on either day 6, 7, 8, or 9 of pseudopregnancy (PSP)(day 1 = day of ovulation). Controls, which were otherwise treated in exactly the same way, included:normal (ordinary) PSP rats; rats hysterectomizedon either day 5 of PSP or several cycles before induction of PSP; PSP rats whose uteri were slit lengthwise on day 8 or 9; and DT-bearing rats in which the DT was removed immediately before the ECO injection. There was-no significant differenceamong any of the control rats in either criterion ofprogesterone secretion; their mean (‡SEM) post treatmentdiestrus was 2.2 ‡ 0.1 days (N = 81...

Luteotrophic action of decidual tissue in the rat.

The relation between the number of live conceptuses in the uterus in pregnant rats bearing a full complement of corpora lutea (CL) and the growth of the CL and their rate of progesterone secretion after day 12 was determined by aspirating all but the desired number of conceptuses on day 7 of pregnancy (day 1 = insemination). In one series of rats, bearing 0, 1, 2, 3, 4, 5–7, or 10 or more conceptuses, the weights of the CL and the serum progesterone levels were measured on days 12 and 15; in another, consisting of rats with 0, 1, or 10 or more conceptuses, the serum progesterone level was measured on days 12, 15, 17, 19, and 21. There was a direct relation between the number of conceptuses, the size of the CL, and the serum progesterone level on day 15. The maximum normal values for both parameters of CL activity were found in rats with 4 or 5 or more conceptuses. In the rats bearing 10 live conceptuses, the serum progesterone levels rose and fell between days 12–21, very much as has been described for no...

A Quantitative Relation between the Experimentally Determined Number of Conceptuses and Corpus Luteum Activity in the Pregnant Rat

To determine whether the secretion of progesterone by the corpora lutea (CL) of pseudopregnant (PSP) rats is (or becomes) dependent on LH, 0.5 ml of a specific equine antiserum tobovine LH (LH-AS) was injected subcutaneously once on one of the days between day 7 and day 11 of PSP; the peripheral serum progesterone level 24 and 72 hr after treatment was determined, together with atleast one biological indication of progesterone secretion. In decidual tissue-bearing rats (DT-PSP) LH-AS on day 7 had no effect on the progesterone level, PSP duration or DT weight. LH-AS on day 8 caused a fall in the progesterone level 72 hr later, a moderate shortening of PSP and a profound regressionof the DT. LH-AS on day 9 also caused a profound regression of the DT, but also drastically reduced the progesterone level within 24 hr, and markedly shortened the PSP. In PSP rats hysterectomized on day 5 (acute Hect-PSP) LH-AS on either day 7 or day 8 had no effect; treatment on day 9 reduced the progesterone level and shortened...

Walter K. Morishige

Papers

Serum luteinizing hormone, prolactin and progesterone levels during pregnancy in the rat.

Temporal aspects of the regulation of corpus luteum function by luteinizing hormone, prolactin and placental luteotrophin during the first half of pregnancy in the rat.

Luteotrophic action of decidual tissue in the rat.

A Quantitative Relation between the Experimentally Determined Number of Conceptuses and Corpus Luteum Activity in the Pregnant Rat

Factors Affecting the Dependency on LH in the Regulation of Corpus Luteum Progesterone Secretion in the Rat1