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

Mice carrying a germ-line null mutation of the prolactin receptor gene have been produced by gene targeting in embryonic stem cells. Heterozygous females showed almost complete failure of lactation attributable to greatly reduced mammary gland development after their first, but not subsequent, pregnancies. Homozygous females were sterile owing to a complete failure of embryonic implantation. Moreover, they presented multiple reproductive abnormalities, including irregular cycles, reduced fertilization rates, defective preimplantation embryonic development, and lack of pseudopregnan cy. Half of the homozygous males were infertile or showed reduced fertility. This work establishes the prolactin receptor as a key regulator of mammalian reproduction, and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.

/pdf/null-mutation-of-the-prolactin-receptor-gene-produces-4gdn9d17x7.pdf

Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse.

https://www.fertstert.org/article/S0015-0282(00)01705-2/pdf

Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.

Ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation occurring during the luteal phase or during early pregnancy. Fortunately, the reported prevalence of the severe form of OHSS is small, ranging from 0.5 to 5%. Nevertheless, as this is an iatrogenic complication of a non-vital treatment with a potentially fatal outcome, the syndrome remains a serious problem for specialists dealing with infertility. The aim of this literature review was to determine whether it is possible to identify patients at risk, and which preventive method should be applied when an exaggerated ovarian response occurs. Data pertaining to the epidemiology and prevention of OHSS in women were searched using Medline, Current Contents and PubMed, and are summarized. Preventive strategies attempt either to limit the dose or concentration of hCG or to find a way to induce luteolysis without inducing a detrimental effect on endometrial and oocyte quality. The following particular preventive strategies were reviewed: cancelling the cycle; coasting; early unilateral ovarian follicular aspiration (EUFA); modifying the methods of ovulation triggering; administration of glucocorticoids, macromolecules and progesterone; cryopreservation of all embryos; and electrocautery or laser vaporization of one or both ovaries.

/pdf/epidemiology-and-prevention-of-ovarian-hyperstimulation-2sp2m8oeef.pdf

Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review

Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.

In spontaneous cycles both LH and FSH are secreted in a surge at midcycle. In in vitro fertilization (IVF) cycles, hCG administration results in elevation of LH-like activity only. The objective of this study was to compare the effectiveness of a single midcycle dose of GnRH agonist with hCG on follicular maturation. Eighteen IVF cycles in 14 women were randomized to receive either 0.5 mg leuprolide acetate or 5000 IU hCG at midcycle. Both groups underwent identical ovarian stimulation and cycle monitoring. On the day of GnRH agonist or hCG administration, estradiol concentrations and the number of follicles 1.5 cm or larger were the same in both groups. Mean serum LH and FSH levels were elevated for 34 h after GnRH agonist administration. In contrast, mean serum hCG levels were elevated for approximately 6 days after the administration of hCG, and serum FSH levels did not change. Mean luteal phase serum estradiol concentrations were lower in the GnRH agonist group than in the hCG group (P less than 0.02). No differences were observed in mean serum progesterone or PRL during the luteal phase or in the length of the luteal phase in the two groups. The mean number of oocytes retrieved and embryo number and quality did not differ between the two groups. Three of nine GnRH agonist cycles and none of nine hCG cycles resulted in clinical pregnancy (P = 0.1). The results of this study indicate that GnRH agonist is able to simulate a midcycle surge of gonadotropins, leading to follicular maturation and pregnancy. Further work is needed to determine whether there is any clinical advantage of GnRH agonist over hCG administration with regard to pregnancy rates.

Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization.

The texture and the thickness of the endometrium as assessed by transvaginal sonography were prospectively evaluated in 123 patients undergoing IVF treatment. Three different types of endometrial patterns could be distinguished: (A) an entirely homogenous, hyperechogenic endometrium; (B) an intermediate type characterized by the same reflectivity of ultrasound as the myometrium, with a nonprominent or absent central echogenic line; and (C) a multilayered endometrium consisting of prominent outer and midline hyperechogenic lines and inner hypoechogenic regions. On the day before oocyte retrieval, endometrial thickness was significantly greater in the group of patients who achieved pregnancy than in the group who did not (8.7 +/- 0.4 vs 7.5 +/- 0.2 mm, respectively; P less than 0.01) and significantly more patients had multilayered, pattern C, endometrium (75% in pregnant women vs 42.4% in nonpregnant women; P less than 0.01). No pregnancy occurred when the endometrial thickness was less than 6 mm. When type C endometrium greater than or equal to 6 mm thick was seen, the pregnancy rate per embryo transfer was 39%. When type A or B endometrial pattern was seen, the negative predictive value for the occurrence of pregnancy was 90.5%. Our results suggest that transvaginal sonographic evaluation of endometrial texture and thickness may be an indicator of the likelihood of achieving pregnancy.

Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF)

Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization

We recently demonstrated, using transvaginal sonography, that conception cycles in in-vitro fertilization (IVF) are associated with a significantly thicker endometrium at midcycle than non-conception cycles, suggesting that endometrial growth may influence implantation. In the present study, to examine whether the type of stimulation protocol affects endometrial development, we compared the sonographic appearance of the endometrium in 22 patients randomized to receive clomiphene citrate and human menopausal gonadotrophin (CC/HMG) and in 19 who received HMG alone. A significantly thicker endometrium was observed in the HMG patients compared to the CC/HMG group (P less than 0.005) throughout the follicular phase of the cycle, although serum concentrations of oestradiol (E2) did not differ in the two groups. Twenty-three patients (13 in the HMG group and 10 in the CC/HMG group) had previous IVF cycles with CC/HMG stimulation in which endometrial thickness was measured. A thin endometrium recurred with subsequent CC/HMG cycles while increased growth occurred with HMG only compared to previous CC/HMG cycles. Therefore, ultrasound examination of the endometrium in this study demonstrated that CC results in a thinner endometrium than HMG alone. We believe these findings may be of importance in improving pregnancy rates in IVF and possibly in other infertility therapy which involves the use of clomiphene citrate.

Yael Gonen

Papers

Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization.

Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF)

Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization

Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth

Gonadotropin suppression with oral contraceptives before in vitro fertilization.