Dating the endometrial biopsy.

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

Publisher Summary This chapter discusses the development of follicles in the mammalian ovary. The unresolved issues in follicular development are focused. Folliculogenesis culminates in the production of fully ripe, preovulatory follicles visible to the naked eye as large bulges on the surface of the ovary. Each ripe follicle contains thousands of highly differentiated cells. This complex, functional miniature organ arises from the handful of cells that constitute a simple primordial follicle, a structure so small that it is invisible at the lower magnifications of a light microscope. All regulatory influences can only permit or prevent cells from completing the full maturation process; they cannot change the course of differentiation. A plethora of modulating influences act as permissive inducers, impeding or propelling the committed follicular cells through the process of clonal expansion. As each follicle progresses through its program of limited clonal expansion and maturation, its cells proliferate more and more rapidly. With every passing generation, the proliferative potential of the granulosa and theca cells continues to diminish, while the state of maturation increases.

Development of Follicles in the Mammalian Ovary

The primary function of the corpus luteum is secretion of the hormone progesterone, which is required for maintenance of normal pregnancy in mammals. The corpus luteum develops from residual follic...

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.1.1

Mechanisms Controlling the Function and Life Span of the Corpus Luteum

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

/pdf/endocrine-and-paracrine-regulation-of-birth-at-term-and-4igz1kdkru.pdf

Endocrine and paracrine regulation of birth at term and preterm

SEVERAL RECENT STUDIES from this laboratory offer strong support of the belief (1)that at least two gonadotropins can be isolated from extracts of pituitary glands. Preliminary evidence was obtained from experiments with extracts of hog glands digested by proteolytic enzymes permitting differentiation of gametogenic (‘follicle stimulating’) and interstitial cell-Stimulating effects depending upon the enzyme used and the extent of digestion (2). Physicochemical methods were next employed to separate the gonadotropins from hog pituitary extracts which had not undergone preliminary enzymic hydrolysis (3). The interstitial cell-Stimulating hormone as a pure protein was isolated (4). The gametogenic hormone was separated as a substance with only one apparent biological effect; however, the purest preparations contained small proportions of two contaminating impurities. Work in the University of California (5) likewise led to the isolation of interstitial cell-Stimulating hormone from pituitary glands of anothe...

Gonadotropins of the swine pituitary i. various biological effects of purified thylakentrin (fsh) and pure metakentrin (icsh)

The cortex of the rat’s adrenal gland is divided morphologically into three major zones. The appearance of the cells and the width of the outer two zones, the glomerulosa and fasciculata, can be altered in different physiological states. Thus, the zona fasciculata enlarges and its cells appear active in conditions eliciting an increased production of adrenotropin, which stimulates the release of the cortical “sugar” factors. On the other hand, this zone shrinks and becomes inactive after hypophysectomy. Either change may occur without apparent alteration in the activity of the glomerulosa (Deane and McKibbin, 1946; Deane and Greep, 1946). The present paper will describe experiments indicating that the outer zone, the glomerulosa, undergoes morphological and cytochemical changes in physiological states that involve disturbance of the electrolyte balance of the body. These changes may occur without any demonstrable alteration of the fasciculata. Moreover, they develop in hypophysectomized as well as in inta...

The effect of altered sodium or potassium intake on the width and cytochemistry of the zona glomerulosa of the rat's adrenal cortex.

A morphological and histochemical study of the rat's adrenal cortex after hypophysectomy, with comments on the liver

The isolation of a protein from frozen posterior lobes of oxen is described. It appears to be pure so far as this can be demonstrated by constant solubility and by "schlieren" patterns in the ultracentrifuge. Although some inhomogeneity was found in the Tiselius electrophoresis apparatus, reasons are given for believing this to be derived from a pure protein. The molecular weight is about 30,000. The isoelectric point is about pH 4.8. Empirical analysis revealed an unusually high percentage of S (4.9 per cent) which is almost entirely present as part of cystine. Oxytocic, vasopressor, and diuresis-inhibiting activities are all present in ratios resembling those of U.S.P. reference standard. Ten micrograms of nitrogen or 61 micrograms of solids are approximately equivalent to 1 U.S.P. unit. Experiments designed to demonstrate that the oxytocic and vasopressor activities are moieties chemically united with the protein are described. Reduction of the cystine in the protein by thioglycollic acid nearly abolishes the activity. In this respect cysteine is much less effective.

The isolation of a protein from the pars neuralis of the ox pituitary with constant oxytocic, pressor and diuresis-inhibiting activities

In the majority of mammals the length of the pregnancy cycle exceeds that of the normal estrous or pseudopregnant cycles, and this prolongation is due in part, to a sustained function of the corpora lutea. The presence of foetal elements is in some way responsible for this continued activity of the maternal ovary.The function of the corpora lutea of the rat during the first half of pregnancy is under the control of the hypophysis and the mechanism involved is apparently the same as that in pseudopregnancy. Luteal function is essential throughout pregnancy, however, as shown by the fact that bilateral oophorectomy invariably terminates gestation.1-4 Removal of the pituitary gland during the first half of pregnancy is likewise followed by death and resorption of the foetuses, whereas pregnancy continues if hypophysectomy is performed after the tenth or eleventh day.5, 6 In the rat hypophysectomy results in a persistence of existing corpora lutea, but such persisting corpora are non-functional in the non-pre...

Roy O. Greep

Papers

Gonadotropins of the swine pituitary i. various biological effects of purified thylakentrin (fsh) and pure metakentrin (icsh)

The effect of altered sodium or potassium intake on the width and cytochemistry of the zona glomerulosa of the rat's adrenal cortex.

A morphological and histochemical study of the rat's adrenal cortex after hypophysectomy, with comments on the liver

The isolation of a protein from the pars neuralis of the ox pituitary with constant oxytocic, pressor and diuresis-inhibiting activities

A Corpus Luteum-Stimulating Substance in the Rat Placenta.∗