May C. Robertson

Endocrine Communication between Conceptus and Mother: Placental Lactogen Stimulation of Maternal Behavior

The possible role of the conceptus in stimulating the onset of maternal behavior through its secretion of placental lactogens and their passage into the brain was investigated in female rats. In the first study, significant mitogenic activity in the Nb2 lymphoma cell bioassay was detected in cerebrospinal fluid (CSF) samples collected by push-pull perfusion from rats on days 12-21 of pregnancy, coincident with the establishment of placental function. In contrast, mitogenic activity was absent from CSF in lactating and gonadectomized, virgin females. In a second study the mitogenic activity in day 12 pregnant samples was neutralized 71% with antibodies to rat placental lactogen-I (rPL-I) and > 90% with a combination of antibodies to rPL-I plus rPL-II. In contrast, activity on day 21 of pregnancy, 1 day prepartum, was reduced by antibodies to rPL-II (> 85%), but not by antibodies to rPL-I, indicating that the predominant lactogen in the CSF prepartum is rPL-II. The behavioral actions of placental secretions were assessed in the third experiment by infusing recombinant rPL-I and purified rPL-II directly into the medial preoptic area of the brain of steroid-primed, nulliparous rats. Latencies to respond maternally to foster young were significantly reduced in rPL-I- and rPL-II-treated rats (2- to 3-day latencies) when compared with latencies in control females (5- to 6-day latencies). Thus, the conceptus through its secretion of rPLs which apparently gain access to the CSF helps to prime the pregnant females brain to respond maternally at the end of gestation. This endocrine communication between the developing conceptus and pregnant female appears to be an important part of the biological system which helps to establish successful maternal care.

Rat placental lactogen-I abolishes nocturnal prolactin surges in the pregnant rat.

The twice-daily surges of prolactin (PRL) present during the first half of pregnancy abruptly terminate at midpregnancy concurrent with the appearance of high levels of placental lactogen-I (PL-I) in the blood. This study addressed the role PL-I and other pituitary or placental hormones have in terminating PRL surges in pregnant rats. Implantation of rat PL-I (rPL-I) or ovine PRL into the arcuate-median eminence area of the hypothalamus of day 7 pregnant rats totally eliminated nocturnal PRL surges on days 8 and 9. To assess the specificity of the inhibitory effects of hormones from the PRL-growth hormone (GH) family, rat growth hormone (rGH), human growth hormone (hGH), and rat prolactin-like protein-A (PLP-A) were tested. Only the lactogenic hormone, hGH, had any effect. Since lactogenic hormones may inhibit PRL by stimulation of dopamine synthesis and release into the hypophysial portal blood vessels leading to the anterior pituitary, the effect of these hormones on tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine activity, was determined. In pregnant rats, both ovine prolactin (oPRL) and hGH significantly increased (64%) TH activity, whereas rPL-I was less effective. In ovariectomized, bromocriptine-treated rats, both rPL-I and oPRL increased TH activity 207 and 151%, respectively. This supports the concept that termination of PRL surges at midpregnancy are owing to secretion of placental lactogens (PLs) from the placenta. However, the mechanism for the inhibition cannot be entirely attributed to an increase in tuberoinfundibular dopaminergic neuronal activity.

Molecular Genetics and Biology of the Rat Placental Prolactin Family

The prolactin (PRL) family of hormones plays a key role in the establishment and maintenance of pregnancy in the rat. Astwood and Greep (1) demonstrated that the hypophysectomy of a pregnant rat before day 12 of gestation resulted in abortion. After midterm the outcome of pregnancy was unaffected, suggesting that pituitary hormones were essential in the earlier stages, but that placental proteins were able to take over their roles after that time. Early in pregnancy, PRL is the hormone that is responsible for transforming the corpus luteum of the cycle to the corpus luteum of pregnancy (2, 3). Beginning by day 2 after mating, PRL is secreted as diurnal and nocturnal surges (4, 5). These surges decline at midpregnancy: first the diurnal surge at day 8, then the nocturnal surge by day 10. It has been speculated that not only might placental proteins replace the functions of PRL in the pregnant rat, but that they also could have a role in regulating the decline in these surges (7–9). This switch, from the mother to the developing fetuses, in the synthesis of proteins important to the successful outcome of pregnancy means that their times and locations of synthesis, as well as their quantities, are directly related to the presence of the fetuses. This may allow more precise control of the expression of these proteins during the specific times in pregnancy when they are needed.

Regulation of PKC δ expression by estrogen and rat placental lactogen-1 in luteinized rat ovarian granulosa cells.

Protein kinase C (PKC) delta is dramatically upregulated in the corpus luteum in the second half of pregnancy in the rat. To gain insight into the hormonal regulation of PKC delta expression, studies were undertaken to analyze the regulation of PKC delta expression in a luteinized rat granulosa cell model. PKC delta protein expression was evaluated in luteinized granulosa cells, isolated from human (h)CG-treated immature female rats 7 h after the injection of an ovulatory dose of hCG and cultured up to 12 days. Cytochrome P450 cholesterol side chain cleavage enzyme expression was observed throughout the culture period, and a majority of the cells expressed steroidogenic acute regulatory protein and responded to rat placental lactogen (rPL)-1 by exhibiting hypertrophy, consistent with maintenance of the luteal phenotype. Both PKC delta protein and mRNA expression increased 3.5-4-fold with time of culture, and PKC delta mRNA expression could be eliminated by treatment of cells with the PKC inhibitor GF109203X. E(2) caused a specific dose- and time-dependent increase in expression of PKC delta protein of twofold, whereas PKC delta mRNA was unaffected by E(2) over a 12-day culture period. Treatment of cells with 500 ng/ml rPL-1 for the final 4 days of a 12-day culture in the absence of E(2) had no effect on PKC delta protein or mRNA expression, while treatment with 500 or 3000 ng/ml rPL-1 in the presence of E(2) significantly enhanced both PKC delta protein and mRNA expression (up to threefold). These results show that two of the major regulators of luteal function in the second half of pregnancy in the rat, E(2) and rPL-1, cooperate to regulate PKC delta expression in luteinized granulosa cells.

The Placental Lactogen Gene Family: Structure and Regulation

The placenta has been recognized as a major endocrine gland for well over half a century. Its repertoire of secretory products includes both steroids, proteins, and peptides, several of which are secreted in large amounts. Another notable feature of placental endocrinology is the great species variation of specific hormones and pattern of hormones secreted. This feature makes studies of placental endocrinology more fascinating as well as more complex and challenging. Excellent reviews on placental endocrinology should be consulted for a more detailed account of the subject (Forsyth, 1974; Blank et al., 1977; Talamantes et al., 1980).

Placental Lactogen/Growth Hormone Gene Family

Before focusing on selective aspects of current research on placental lactogens (PLs), it is useful to look at advances in this area from a historical perspective. Several landmark studies can be recognized that were instrumental in providing new directions to the field (Table 11.1). Four major periods, each ushered in by the applications of new technologies or methods, can readily be identified, underscoring the importance of technology to scientific advance.