Progestational Proliferation Research Articles

Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions.

Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.

90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation.

Progesterone's ability to maintain pregnancy in eutherian mammals highlighted this steroid as the 'hormone of pregnancy'. It was the unique 'pro-gestational' bioactivity of progesterone that enabled eventual purification of this ovarian steroid to crystalline form by Willard Myron Allen in the early 1930s. While a functional connection between normal progesterone responses ('progestational proliferation') of the uterus with the maintenance of pregnancy was quickly appreciated, an understanding of progesterone's involvement in the early stages of pregnancy establishment was comparatively less well understood. With the aforementioned as historical backdrop, this review focuses on a selection of key advances in our understanding of the molecular mechanisms by which progesterone, through its nuclear receptor (the progesterone receptor), drives the development of endometrial receptivity, a transient uterine state that allows for embryo implantation and the establishment of pregnancy. Highlighted in this review are the significant contributions of advanced mouse engineering and genome-wide transcriptomic and cistromic analytics which reveal the pivotal molecular mediators and modifiers that are essential to progesterone-dependent endometrial receptivity and decidualization. With a clearer understanding of the molecular landscape that underpins uterine responsiveness to progesterone during the periimplantation period, we predict that common gynecologic morbidities due to abnormal progesterone responsiveness will be more effectively diagnosed and/or treated in the future.

Expression of Progesterone Receptor Form A and B mRNAs in Uterine Leiomyoma

This study was designed to determine the expression pattern of progesterone receptor form A (PR-A) and B (PR-B) mRNAs in uterine leiomyoma. Approximately equal expression of PR-A and PR-B mRNAs was designated as type AB and dominant expression of PR-B mRNA as type B. In all cases of normal uterine myometrium, PR mRNA expression was type AB. Alteration to type B in the superficial part of uterine leiomyoma was observed in approximately 40% of cases. Therefore, the relative overexpression of PR-B mRNA in the surface of uterine leiomyoma might reveal an activated phenotype of progestational proliferation, plausibly related to the growth of uterine leiomyoma.

Effects of Sex Steroids on Silver Stained Proteins of Nucleolar Organizer Regions (Ag-NOR) in the Rabbit Uterus

Silver staining of argyrophilic proteins of nucleolar organizer regions (Ag-NOR) has been used to evaluate a hyperactive state of cells. We studied the effects of sex steroids on the Ag-NOR proteins in the rabbit uterus. Estradiol-17β (E2) caused uterine hypertrophy and increased the number of Ag-NOR dots in epithelial and stromal cells of the endometrium and smooth muscles cells in a dose dependent manner without proliferative change in the endometrium. Progestins including progesterone, medroxyprogesterone acetate (MPA), and norethindrone following E2 caused progestational proliferation of the endometrium with an increase in the Ag-NOR number to various extents, whereas methyltestosterone, a synthetic androgen, caused only a minimal proliferative change in the endometrium without an increase in the Ag-NOR number. Western blot analysis revealed that progesterone and MPA increased the amounts of a 100 kDa protein (nucleolin) and a 37 kDa protein (B23 protein) in the endometium and a marked proliferative change, whereas E2 did not. These results suggest that although the Ag-NOR number was enhanced by both progestin and estrogen, only progestins substantially increase the Ag-NOR protein in the rabbit uterus. This implies that an increase in the amount of nucleolin and B23 protein is associated with the proliferative potential of the cells.

The Mechanism of Action of the Copper Intrauterine Device

The effects of copper ions on the binding of steroids to receptors revealed that the inhibitory effect of Cu++ was apparent at 10(-6)M, ANd the binding capacities decreased to 10% at 10(-2)M Cu++. The kinetic study demonstrated that Cu++ was a competitive inhibitor of steroid hormone-receptor binding (Ki divided by 2.7 X 10(-5)M to estrogen receptor; Ki divided by 5.1 X 10(-6)M to progesterone receptor). These results indicate that copper ions interfere at the steroid-binding site of receptor and that progesterone receptor is more affected by copper ions than is estrogen receptor. The sedimentation pattern showed the dissociation and aggregation of receptor macromolecules by copper. These phenomena may indicate the biologic inactivation of receptor. In fact, morphologically, progestational proliferation was severely inhibited and estrogenic action seemed to be inhibited. The Timm stain showed copper uptake by endometrial epithelium and superficial stromata. The copper content apparently increased in the cytoplasm of uteri bearing a copper intrauterine device, compared with controls. In vivo, the concentration of cytoplasmic copper was approximately 1.4 X 10(-6)M, which was obviously inhibitory to steroid hormone-receptor interaction. However, complete morphologic suppression of the progestational effect by copper cannot exclude the coexistence of some other mechanism in these phenomena.

Reduced level of uterine norepinephrine transmitter during hCG-induced pseudopregnancy in the rabbit.

The bulk of rabbit uterine norepinephrine is present in short adrenergic neurons which have unique functional properties. Pseudopregnancy was induced in adult nulliparous rabbits by a single injection of 1,500 IU of human chorionic gonadotrophin (hCG). By the 6th day of pseudopregnancy, the total uterine content of norepinephrine was reduced to a level only 40% of that found in untreated controls. At 12 days after the injection the amine level was greater than at 6 days but still significantly less than in controls. By 18 days, when the progestational proliferation of the endometrium had subsided, the levels in uteri of control and injected animals were similar. The findings support previous findings indicating the presence of a peripheral neuro-endocrine mechanism influencing uterine motor function.

Some observations on the gonadotrophin inhibiting and anti-progestational properties of 20 -dihydroprogesterone.

ABSTRACT 20α-dihydroprogesterone (20α-OH-P) was administered for 10 days either alone (2 or 4 mg/rat, sc) to explore its biological properties or in combination with progesterone (2 or 4 mg/rat, sc) to test its potential as an antiprogestin. When administered alone to intact rats the hydroxylated steroid, unlike progesterone, failed to disturb the oestrous cycle, cause ovarian or uterine atrophy, mucify the vagina or significantly modify pituitary stores of LH or FSH. In unilaterally spayed rats, 20α-OH-P proved ineffective in decreasing ovarian compensatory hypertrophy. Thus the loss of progestational properties in 20α-OH-P was associated with diminution in gonadotrophin-inhibiting properties. When administered to animals primed with oestrogen, 20α-OH-P exerted either an additive or synergistic effect on the trauma-induced deciduomata in bilaterally spayed rats and on the progestational proliferation in the immature rabbit. 20α-OH-P by itself had no significant effect under these conditions. In no instance did the hydroxylated steroid antagonize the effects of progesterone. In the pregnant rats bilaterally spayed and maintained on suboptimal doses of progesterone (1 mg/rat/day), simultaneous administration of 20α-OH-P (2 mg/day) did not antagonize the pregnancy supporting effect of progesterone. Thus under the conditions of these experiments 20α-OH-P failed to manifest any antiprogestin potential. It appears that 20α-OH-P may play a physiological role by potentiating or augmenting the effect of progesterone on decidualization.

Effect of Formulation of Anagestone Acetate on Progestational Proliferation of Rabbit Uterus after Oral Administration

A method is presented for the determination of in vitro dissolution rates for anagestone acetate, which yields results representative of in vivo bioavailability in animal studies. This procedure appeared to be satisfactory in preliminary screening of tablet formulations of anagestone acetate.

Suppression of progestational uterine mucosal activity by anthrarufin.

The effect of anthraquinone sodium anthraquinone-beta-sulfonate anthrarufin anthrone alpha-naphthaquinone lecithin and tannic acid on progestational proliferation produced by progesterone in the rabbit uterus was investigated. Immature rabbits were primed with estradiol-17beta and received simultaneously 2-mg progesterone and 1 of the test compounds in logarithmically graded doses of .001-1000 mg/animal. 24 hours later the animals were sacrificed uteri were excised and the carbonic anhydrase activity of endometrium homogenates were analyzed. Oral anthrarufin inhibited the enzyme activation by progesterone. 1 mg the most effective dose caused a 50% inhibition to the action of 2-mg progesterone (p less than .01). When administered subcutaneously little or no inhibition was observed. These results revealed that of the compounds studied only anthrarfin antagonized the action of progesterone on the rabbit endometrium.

Experimental observations on the ferret corpus luteum of pregnancy.

The pioneer work of Klein on unilaterally pregnant rabbits, rats and hamsters (Klein, 1933, 1935, 1938) established the role of the pregnant uterus in maintaining, independently of the foetuses, the histological structure and function of the corpora lutea of pregnancy. If the pregnant horn were removed from unilaterally pregnant animals in mid-pregnancy, degeneration of the corpora lutea followed, the progestational proliferation in the sterile horn broke down and a fresh ovulation took place. From these, and from hypophysectomy experiments on the pregnant rat,

Anti-progestational activity of rutin on the rabbit uterus.

A DIET containing 0.4 or 1.0 per cent of rutin, a flavonol glycoside with vitamin P activity, has been shown to have no effect on reproduction1,2. However, Cutting et al.3 observed that a diet containing 0.1 per cent rutin significantly impaired the fertility of female mice. Therefore, using carbonic anhydrase determination in the uterine endometrium as an indicator of the progestational proliferation in Clauberg rabbits4, an attempt was made to elucidate whether or not rutin is capable of affecting the progestational proliferation of the rabbit endometrium.

Interruption of early pregnancy in the rabbit by a single injection of oestradiol cyclopentylpropionate.

SUMMARY Female rabbits were injected i.m. with various doses of oestradiol cyclopentylpropionate (OECP) immediately after coitus. The percentage of embryonic deaths 8 days post coitum after a single injection of 25, 50, 100 or 250 μg. of OECP was, respectively, 86, 97, 100 and 100%. However, the cornua of rabbits receiving as much as 100 μg. of OECP had normal 3 to 4 + progestational proliferation 8 days after mating. The high embryonic mortality resulted from disturbances in the rate of egg transport through the oviduct. Thus, with 25 μg. OECP most of the ova were expelled from the reproductive tract 48 hours post coitum, whereas with 250 μg ova were retained at the ampullary-isthmic junction of the tube for at least 5 days. Under these circumstances, small viable blastocysts developed in 4 days, but 24 hr. later all eggs were degenerating. These experiments suggest that embryonic death indirectly results from administration of OECP and that the hormone only briefly disrupts postovulatory development of the reproductive tract.

Variation in progestational proliferation induced by differential estrogenic priming of the immature rabbit endometrium

Variation in progestational proliferation induced by differential estrogenic priming of the immature rabbit endometrium

Estrogen-progesterone antagonism on endometrial carbonic anhydrase activity.

There is ample evidence concerning estrogen-progesterone antagonism in the uterine endometrium. Much has been demonstrated by the histological test based on the proliferative changes in the uterus, the response being rated on the semiquantitative scale. However, little has been done to utilize enzyme determinations in the endometrium as an indicator of hormonal antagonism.Lutwak-Mann and Adams1 have studied the effect of stilbestrol on development of progestational activity by the measurements of uterine carbonic anhydrase and progestational proliferation. They observed that in the enzymic test stilbestrol prevented progestational development, and noted that with few exceptions there was good agreement between the enzymic and histological test in evaluating the antagonism.More recently a work of Miyake and Pincus2, concerning the antiprogestational activities of estrogens, namely estradiol, estrone, estriol and stilbestrol, in Clauberg rabbits provided quantitative evidence of the antagonism by estimating...

RATE OF PREGNANEDIOL EXCRETION FOLLOWING INTRAPORTAL OR INTRASYSTEMIC INTRAVENOUS ADMINISTRATION OF PROGESTERONE IN HUMAN SUBJECTS

INTRODUCTION THE in activation of progesterone and its conversion to pregnane-3α-20α-diol by the liver, is by now a well documented fact. In the studies of Masson and Hoffman (1) and Ferin and Merteus (2), progesterone was found to be much less effective in inducing progestational proliferation in the rabbit uterus after oral than after parenteral administration; but its oral effectiveness increased ten-fold after partial hepatectomy (1). Similar findings were obtained earlier by Kochakian, Haskins and Bruce (3). (En gel (4), however, observed practically no difference, except with very small doses, in the effectiveness of progesterone in this reaction when the intraportal was compared with the systemic route of administration.) Dosne (5) similarly found progesterone less effective in preventing fibrotic changes in guinea-pig uteri after implantation of progesterone pellets in the spleen than after subcutaneous implantation. Selye and Stone (6) showed that the anesthetic effect of this hormone was decreas...

THE BIOASSAY OF PROGESTERONE1

IT WAS first observed by Lutwak-Mann (1) that gonadotrophins, progesterone and certain other luteoids injected into estrous adult or estrogen-primed immature rabbits produced marked increases in the content of uterine carbonic anhydrase, the extent of which depended upon the dosage, and this was accompanied by histological evidence of progestational proliferation (2). It was therefore suggested that the measurement of endometrial carbonic anhydrase might be used as a basis for progestin assay, and subsequently Lutwak-Mann and Adams (3) have compared endometrial carbonic anhydrase titers and the degree of progestational proliferation as measured by the Robson (4) scale, using progesterone and other steroids. The specificity of the enzyme reaction appears to be substantiated by their data, but quantitation and definition of sensitivity were not attempted. In this paper we present: (a) a statistical analysis of the dosage response data for progesterone in the conventional Clauberg rabbit, (b) a comparison of...

Rate of pregnanediol excretion following intraportal or intrasystemic intravenous administration of progesterone in human subjects.

INTRODUCTION THE in activation of progesterone and its conversion to pregnane-3α-20α-diol by the liver, is by now a well documented fact. In the studies of Masson and Hoffman (1) and Ferin and Merteus (2), progesterone was found to be much less effective in inducing progestational proliferation in the rabbit uterus after oral than after parenteral administration; but its oral effectiveness increased ten-fold after partial hepatectomy (1). Similar findings were obtained earlier by Kochakian, Haskins and Bruce (3). (En gel (4), however, observed practically no difference, except with very small doses, in the effectiveness of progesterone in this reaction when the intraportal was compared with the systemic route of administration.) Dosne (5) similarly found progesterone less effective in preventing fibrotic changes in guinea-pig uteri after implantation of progesterone pellets in the spleen than after subcutaneous implantation. Selye and Stone (6) showed that the anesthetic effect of this hormone was decreas...

Carbonic anhydrase in the female reproductive tract. II. Endometrial carbonic anhydrase as indicator of luteoid potency: correlation with progestational proliferation.

SUMMARY In an attempt to establish the measurement of uterine carbonic anhydrase activity as a quantitative test for progestationally active substances, the activity of carbonic anhydrase in the rabbit endometrium has been correlated with the conventional histological method of assaying progestational activity. The following steroids have been tested in this manner with special regard to the duration of their effect: (a) progesterone, deoxycorticosterone (DC), deoxycorticosterone acetate (DCA), 3-acetoxy-pregna-3,5-diene-20-one, 17α-hydroxy-progesterone, 17α-hydroxyprogesterone caproate (Delalutin); (b) 17α-ethinyl-19-nortestosterone, 17β-acetoxy-isoprogesterone, 3α-hydroxy-pregnane-12:20-dione, 12α-hydroxy-pregnane-3:20-dione, pregnane-3:12:20-trione, 2β-acetoxy-progesterone, 2 α-acetoxyprogesterone, pregna-5-ene-20-one. The action of DCA was weak and transient; that of progesterone and 3-acetoxy-pregna-3,5-diene-20-one was marked but of limited duration; Delalutin was powerful as well as sustained; DC and 17α-hydroxyprogesterone failed to produce true progestational changes. Ethinyl-19-nor-testosterone was the only steroid in group (b) endowed with progestational potency. Stilboestrol (2 mg) administered a day before or simultaneously with DCA (16 mg), progesterone (4 mg) or Delalutin (2 mg), suppressed the endometrial response for 5 days but did not interfere with the late (8-day) progestational effect of the long-acting progestogen Delalutin. Small doses of purified FSH induced a few ovulations in the rabbit when injected intravenously, the endometrium showed some proliferative changes by bioassay but the activity of carbonic anhydrase was not appreciably increased. Subcutaneous injections had no effect. When progesterone was administered subcutaneously with FSH its effect was curtailed. With few exceptions, there was satisfactory agreement between the enzymic and histological method of determining progestational activity.

Progestational activity of halogenated corticosteroids and related compounds in rabbit and monkey.

SummaryProgestational activity of 9 alpha-chlorohydrocortisone acetate, 9 alpha-fluorohydrocortisone acetate and 9 alpha-fluoro-11-beta-hydroxyprogesterone has been demonstrated using progestational proliferation of the rabbit endometrium (Clauberg test) as index of activity. Hydrocortisone acetate and cortisone acetate show a lack of activity in the same test. Progestational activity of 9 alpha-fluorohydrocortisone is further demonstrated by prevention of estrogen withdrawal bleeding and characteristic histological changes in the endometrium of the ovariectomized rhesus monkey pre-treated with estrogen.

MODE OF ACTION OF OESTROGENS ON THE CORPUS LUTEUM

It is well known that oestrogens can maintain the activity of the corpus luteum in the rabbit, in the absence of the pituitary. That such luteal tissue exerts its normal secretory activity is shown by the fact that in non-pregnant animals it produces its typical effect on the endometrium, i.e. progestational proliferation, and in pregnant animals, it maintains a normal gestation (Westman & Jacobson, 1937; Robson, 1937, 1939). The question arises whether the oestrogens act directly on the luteal cells or whether there is some intermediate mechanism which ultimately results in the effect on the corpus luteum. There is indeed other evidence that oestrogens can exert an action on the ovary (Aron &Aron, 1946) and the results of Bullough (1943) suggest that this effect is a direct one, involving action on the ovarian cells by the oestrogen present in the follicular fluid.