PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

Endometriosis

A methodical gross examination should be undertaken in all births and the results incorporated in the patient’s record.

The Pathology of the Human Placenta

Pregnancy has commonly been viewed as a cooperative interaction between a mother and her fetus. The effects of natural selection on genes expressed in fetuses, however, may be opposed by the effects of natural selection on genes expressed in mothers. In this sense, a genetic conflict can be said to exist between maternal and fetal genes. Fetal genes will be selected to increase the transfer of nutrients to their fetus, and maternal genes will be selected to limit transfers in excess of some maternal optimum. Thus a process of evolutionary escalation is predicted in which fetal actions are opposed by maternal countermeasures. The phenomenon of genomic imprinting means that a similar conflict exists within fetal cells between genes that are expressed when maternally derived, and genes that are expressed when paternally derived. During implantation, fetally derived cells (trophoblast) invade the maternal endometrium and remodel the endometrial spiral arteries into low-resistance vessels that are unable to constrict. This invasion has three consequences. First, the fetus gains direct access to its mother's arterial blood. Therefore, a mother cannot reduce the nutrient content of blood reaching the placenta without reducing the nutrient supply to her own tissues. Second, the volume of blood reaching the placenta becomes largely independent of control by the local maternal vasculature. Third, the placenta is able to release hormones and other substances directly into the maternal circulation. Placental hormones, including human chorionic gonadotropin (hCG) and human placental lactogen (hPL), are predicted to manipulate maternal physiology for fetal benefit. For example, hPL is proposed to act on maternal prolactin receptors to increase maternal resistance to insulin. If unopposed, the effect of hPL would be to maintain higher blood glucose levels for longer periods after meals. This action, however, is countered by increased maternal production of insulin. Gestational diabetes develops if the mother is unable to mount an adequate response to fetal manipulation. Similarly, fetal genes are predicted to enhance the flow of maternal blood through the placenta by increasing maternal blood pressure. Preeclampsia can be interpreted as an attempt by a poorly nourished fetus to increase its supply of nutrients by increasing the resistance of its mother's peripheral circulation.

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Genetic conflicts in human pregnancy.

A profile characteristic of fuel economy in the mother during normal pregnancy has been delineated. The evidence indicates that pregnancy changes the metabolism of every class of foodstuff. The mechanisms by which the conceptus may be implicated are reviewed. The gestational interactions create a pattern of “accelerated starvation” whenever food is withheld, especially in late pregnancy, and they tend to “facilitate anabolism” when food is ingested. The consequent heightened metabolic oscillations during the shuttlings from fed to fasted state provide a basis for more aggressive therapy with exogenous insulin when endogenous insulin is lacking in pregnancy. It is emphasized that developing fetal structures may be exquisitely attuned to fine alterations in maternal fuel economy and that pregnancy complicated by diabetes may merely exaggerate these normal dependencies since maternal insulin affects all maternal fuels. The manifest changes in the offspring of mothers with. even the mildest limitations in insulin reserve, i.e., gestational diabetes, attest to the sensitivity of the relationships. It is suggested that concepts of teratogensis should be expanded to include alterations occurring subsequent to organogenesis during the differentiation and proliferation of fetal cells. Such changes could cause long-range effects upon behavioral, anthropometric, and metabolic functions. It is hypothesized that all of these could constitute expressions of fuel-mediated teratogenesis and that the potentialities should be incorporated into any evaluation of the outcome of pregnancy in gestations attended by disturbances in maternal fuel metabolism.

Banting Lecture 1980: of Pregnancy and Progeny

A previously undescribed substance has been discovered in the peripheral and retroplacental sera of human pregnancy at term. This substance is immunochemically closely related to human pituitary growth hormone (HGH) and has been isolated in relatively large amounts and purified form from term human placentas. It is highly lactogenic both in pigeon crop sac assays (local intradermal injections) and in milk-promoting activity in the pseudopregnant rabbit, but is devoid of growth-promoting activity in the hypophysectomized rat tibial plate growth assay at the dose levels tested. The possible biologic role of this lactogenic material in pregnant primates is discussed. The findings encountered give further support to the theory that a small portion of a protein hormone molecule may determine major differences in its physiologic function.

Presence in the Human Placenta and Term Serum of a Highly Lactogenic Substance Immunologically Related to Pituitary Growth Hormone

The 24-hr urinary excretion of cyclic 3′5′-adenosine monophosphate (cyclic AMP) in 21 control subjects (3544 ± 175 nmoles, mean ±sem) was contrasted with the cyclic AMP excretion in patients with hyperparathyroidism (5719 ± 1200 nmoles, p <.01), hypoparathyroidism (1943 ±312 nmoles, p <.001), renal disease (596 ±208 nmoles, p <.001), and women during the menstrual cycle and pregnancy. An effect of parathyroid hormone on the urinary excretion of cyclic AMP was implied from: 1) the increased urinary excretion of the nucleotide in patients with hyperparathyroidism and the low excretion in patients with hypoparathyroidism, and 2) the acute reduction to normal in urine cyclic AMP following removal of a parathyroid adenoma. An effect of steroid and/or pituitary or placental hormones on the urinary excretion of cyclic AMP was suggested from observing a midcycle peak in nucleotide excretion during ovulatory menstrual cycles, and a progressive increase in urinary excretion of the nucleotide during pregnan...

Factors influencing the urinary excretion of 3',5'-adenosine monophosphate in humans.

Administration of 1–10 mg ovine pituitary prolactin (oPRL) into the amniotic fluid of 10 rhesus monkeys in the last third of gestation consistently caused a decrease in amniotic fluid volume not seen when saline, vasopressin, or bovine serum albumin were injected into 9 other monkeys. The effects lasted for 24 h. Intraamniotic injection of 10 mg oPRL prevented or reversed a doubling of water and electrolyte content of the fetal extracellular fluid (ECF) volume in the face of hypertonic amniotic fluid. Efflux of these substances from the fetal ECF in the face of hypotonic amniotic fluid was similarly prevented or reversed by intraamniotic prolactin injection. Ovine PRL had no effect on fetal ECF water and electrolytes in the face of isotonic amniotic fluid. Possible sites of these oPRL effects were amnion, placenta, fetal lung and/or fetal gastrointestinal tract. (Endocrinology 100: 564, 1977)

Amniotic Prolactin Control Over Amniotic and Fetal Extracellular Fluid Water and Electrolytes in the Rhesus Monkey

Experiments performed at 130 days gestation in 11 rhesus monkeys revealed a positive correlation between pituitary prolactin concentrations in maternal plasma, but not fetal plasma, and those in amniotic fluid. Minute amounts of radioactively-labeled prolactin passed between maternal and fetal circulation. Small amounts of labeled hormone also passed from the mother, but not from the fetus, to the amniotic cavity. Fetal plasma prolactin was elevated by fetalinjection of thyrotropin-releasing factor (TRF), but not to an extent comparable to maternal plasma rises seen after the hypothalamic hormone was injected into the mother. Fetal tissues andthe placenta acquired protein-bound radioactivity when l25I-labeled prolactin was injected intothe amniotic fluid, the 125I in the former organ being displaced by incubation with nonlabeled prolactin. It was concluded that the maternal circulation may be a major source of amniotic fluid prolactin, while fetal and maternal circulations show mutually, essentially indep...

John B. Josimovich

Papers

Presence in the Human Placenta and Term Serum of a Highly Lactogenic Substance Immunologically Related to Pituitary Growth Hormone

Factors influencing the urinary excretion of 3',5'-adenosine monophosphate in humans.

Amniotic Prolactin Control Over Amniotic and Fetal Extracellular Fluid Water and Electrolytes in the Rhesus Monkey

Sources and Disposition of Pituitary Prolactin in Maternal Circulation, AmnioticFluid, Fetus and Placenta in the Pregnant Rhesus Monkey

Placental lactogen in maternal serum as an index of fetal health.