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PubMed1996

The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential.

Drospirenone is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. This specific pharmacological profile of drospirenone is defined by its pattern of binding affinities to a variety of steroid hormone receptors. In the present study the affinity of drospirenone to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for the natural hormone progesterone. Drospirenone displayed high affinity to PR and MR and low binding to AR, similar to progesterone. Unlike progesterone, which showed considerable binding to GR, drospirenone exhibited only low binding to this receptor. Neither drospirenone nor progesterone did bind to the ER. In addition to receptor binding studies, transactivation assays were carried out to investigate the effects of drospirenone and progesterone on AR-, GR-, and MR-mediated induction of transcription. Both progestins showed no androgenic but antiandrogenic activity by inhibiting AR-mediated transcription in a dose-dependent manner. This observation could be confirmed by in vivo experiments carried out with orchiectomized male rats, where the antiandrogenic potency of drospirenone was found to be about five- to ten-fold higher than that of progesterone. In contrast to progesterone, drospirenone was devoid of glucocorticoid activity. Both progestins did not show any antiglucocorticoid action. Furthermore, drospirenone and progesterone both showed considerable antimineralocorticoid activity and weak mineralocorticoid activity.

Androstenes↗
PubMed1998

Cell surface binding sites for progesterone on human spermatozoa.

This study demonstrates the presence of [3H]-progesterone binding protein on the cell surface of human spermatozoa. The binding protein is masked and is exposed after treatment of spermatozoa with surfactants such as digitonin. Specific binding of [3H]-progesterone is observed after the washed spermatozoa or the crude cell membrane fractions are treated with 0.1% digitonin at 0-4 degrees C for 30 min R5020, 17alpha-hydroxyprogesterone and testosterone only partially compete with [3H]-progesterone for binding whereas the synthetic steroids STS557, RU486, ZK98.299 and ZK98.734 do not competitively inhibit the binding of [3H]-progesterone to spermatozoa. Progesterone binding sites are located in the acrosomal region of spermatozoa, as indicated by the use of fluorescein isothiocyanate-labelled progesterone-bovine serum albumin. The binding protein cross-reacts with the monoclonal antibodies to uterine progesterone receptor and has a molecular weight of approximately 85 kDa. This is the first study which demonstrates the presence of masked progesterone binding sites on the cell surface of human spermatozoa that are exposed after treatment with surfactants. These binding sites seem to have structural homology with the intracellular progesterone receptor but differ in terms of ligand specificity and location. The study further demonstrates that follicular fluid facilitates progesterone binding to spermatozoa.

17-alpha-Hydroxyprogesterone↗
PubMed2003

Stimulatory effect of progesterone on the expression of steroidogenic acute regulatory protein in MA-10 Leydig cells.

The steroidogenic acute regulatory protein (StAR), by virtue of its ability to facilitate the intramitochondrial transport of cholesterol, plays an important role in regulating steroid hormone biosynthesis in steroidogenic cells. In agreement with published data, both StAR expression and progesterone production in MA-10 mouse Leydig tumor cells could be stimulated with hCG and 8Br-cAMP. Addition of aminoglutethimide, an inhibitor of cholesterol side chain cleavage (P450(scc)) enzyme, not only resulted in a drastic inhibition of progesterone production but also in an attenuation of StAR expression in response to either hCG or 8-Br-cAMP. Therefore, we addressed the question of whether progesterone, the end product of the steroidogenic cascade in these cells, could be in a position to regulate the StAR gene expression. In MA-10 cells, we report here that progesterone in microgram amounts can induce StAR gene expression in a time- and dose-dependent manner. StAR expression in response to a maximally effective concentration of progesterone of 10 microg/ml was highest at 6 h and started decreasing thereafter. The effect of progesterone on StAR protein and StAR mRNA induction was mimicked by its synthetic analog, progestin R5020, but not by other steroids, including dexamethasone, estradiol, testosterone, and dihydrotestosterone. Dexamethasone, in contrast, was able to inhibit StAR expression in MA-10 cells. Surprisingly, RU486, a potent antagonist of progesterone and glucocorticoid action, had a stimulatory effect on StAR mRNA levels. Reverse transcription-polymerase chain reaction analysis demonstrated the absence of the classical form of progesterone receptor in MA-10 cells. Thus, for the first time, a direct stimulatory effect of a steroid on StAR gene expression has been demonstrated. Furthermore, these results provide a new insight, indicating that progesterone mediates the activation of StAR expression exerted presumably through a novel, nonclassical progesterone receptor in mouse Leydig cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

Intracellular calcium accumulation and responsiveness to progesterone in capacitating human spermatozoa.

Progesterone induced a rapid, long-lasting, dose-dependent increase of intracellular free calcium concentration ([Ca2+]i) in human sperm capacitated overnight. This effect was not counteracted by the cytosolic progesterone receptor antagonist RU486 (1 mumol/L) nor by the GABA-A receptor antagonists bicuculline (10 mumol/L) and picrotoxin (50 mumol/L). Also, the rank order of potency of several progestative steroids on [Ca2+]i differed from that previously reported for uterine intracellular progesterone receptor or for P-GABA interaction in the central nervous system, indicating a different pathway for progesterone stimulation of human sperm. Modifications of basal and progesterone-stimulated [Ca2+]i during sperm capacitation were also studied. A progressive, parallel increase of basal and progesterone-stimulated [Ca2+]i in capacitating spermatozoa was found. In particular, progesterone-stimulated [Ca2+]i increased from a basal concentration of 147% +/- 17% at 10 minutes to 327% +/- 65% after 120 minutes of incubation in capacitating medium. This increase was well correlated with basal [Ca2+]i (r = 0.93). In contrast, basal and progesterone-stimulated [Ca2+]i concentrations were constantly low in spermatozoa incubated in noncapacitating medium. In capacitated spermatozoa, initial responsiveness to progesterone and basal [Ca2+]i was higher than in capacitating and noncapacitated samples, and remained constant throughout the duration of the experiment. The progressive, parallel increase of [Ca2+]i and response to progesterone observed during in vitro capacitation of human spermatozoa might be physiologically relevant in vivo during capacitation of sperm in the female genital tract.

Bicuculline↗
PubMed1977

Characterization and assay of progesterone receptor in human mammary carcinoma.

[3H]Pregn-4-ene-3,20-dione ([3H]progesterone)-receptor complexes from human mammary carcinoma were found to be stabilized in the presence of glycerol. The dissociation rate constant was lowered and the equilibrium dissociation constant was decreased (KD=3 nM in the absence of glycerol and 1.1 nM in the presence of 30% glycerol), whereas no clear-cut effect on the association rate was observed and no change occurred in the concentration of binding sites. Cortisol was found to compete with [3H]progesterone only at concentrations higher than 1 muM. This made it possible to distinguish [3H]progesterone binding to the receptor from binding to corticosteroid-binding globulin. Synthetic progestins [6-chloro-17-acetoxypregna-4,6-diene-3,20-dione (chlromadinone acetate), 17alpha-ethinyl, 17-hydroxyestr-4-en-3-one (norethisterone), and 17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione (R5020)] were found to have a high affinity for the receptor, whereas 5alpha-pregnane-3,20-dione had an affinity about one-half that of progesterone itself 5beta-Pregnane-3,20-dione, 17alpha-hydroxypregn-4-ene-3,20-dione (estradiol), 11beta,21-dihydroxy-pregn-4-ene-3,20-dione (corticosterone), estra-1,3,5(10)-triene-3,17beta-diol, and 17beta-hydroxyandrost-4-en-3-one (testosterone) were weak inhibitors of [3H]progesterone binding. Sedimentation on glycerol gradients showed different patterns in different tumors; i.e., [3H]progesterone specific binding having the characteristics of receptor was found either in the 8 S region, in the 4.5 S region, or in both. Activated progesterone-receptor complex from human mammary carcinoma cytosol was shown to bind to human DNA. An assay of the receptor based on these binding properties is described. This assay measures the total concentration of cytosol receptor since it makes possible the exchange of endogenous hormone for excess added [3H]progesterone. Of 55 biopsies examined by this method, 35 (64%) had a concentration of progesterone receptor-binding sites higher than 10 fmoles/mg protein. There was a positive correlation between the amounts of estrogen and progesterone receptors.

20-alpha-Dihydroprogesterone↗
PubMed2004

Effect of gonadal steroids on progesterone receptor, estrogen receptor, and vitellogenin expression in male turtles (Chrysemys picta).

Hepatic vitellogenin (vtg) is a yolk precursor protein sequestered in follicular oocytes as nutrient supply for developing embryos in nonmammalian vertebrates. In prior research studies we have demonstrated that both progesterone (P) and testosterone (T) inhibit estrogen (E)-induced vitellogenesis in the male fresh water turtle (Chrysemys picta), and have suggested that these hormones may be involved in multihormonal regulation of vitellogenesis in the female turtle. However, the modes of action of progesterone and testosterone on estrogen-induced vitellogenesis are not known. We have proposed that progesterone inhibits vitellogenesis by modulation of progesterone receptor A (PRA) or B (PRB) isoforms and/or estrogen receptor (ER) gene transcription. In this study, we compare the vitellogenic responses of reproductively inactive male turtles to estradiol 17beta in the presence of exogenous testosterone or progesterone. Northern blot analysis was used to monitor the changes in vtg mRNA, ER mRNA, and PR mRNA expression; Western blotting to determine changes in PR isoform expression and a homologous ELISA for measurement of plasma vtg. Progesterone and testosterone reduced estrogen-induced vtg mRNA expression, but plasma vtg was not significantly reduced by these steroids. PRA and PRB were transcribed even though ER mRNA could not be detected, suggesting constitutive PR expression. However, in the presence of estradiol 17beta, both PR isoforms and mRNA transcripts were increased as a correlate of ER mRNA transcription, suggesting both transcriptional and translational effects; these effects were inhibited by testosterone and progesterone treatments. Since ER mRNA was sharply reduced by both testosterone and progesterone, and estradiol 17 beta increased PR mRNA transcription and translation, it is likely that the action of progesterone in reducing vtg mRNA is indirect via down regulation of ER mRNA, thus ER. This study provides further information on the role of progesterone and testosterone in the regulation of hepatic vitellogenesis, suggesting regulation of vitellogenesis mainly via modulation of hepatic ER mRNA.

Animals↗
PubMed1996

Radioligand and immunochemical studies of turtle oviduct progesterone and estrogen receptors: correlations with hormone treatment and oviduct contractility.

Progesterone (PR) and estrogen (ER) receptors were previously identified and characterized in the reproductive tract of the turtle, Chrysemys picta, and changes in PR levels were monitored during the seasonal cycle. To understand the hormonal regulation of PR, intact and ovariectomized animals were treated with estradiol, progesterone, and a combination of estradiol and progesterone, and high affinity PR and ER levels were determined by radioligand binding studies. Ovariectomy significantly decreased ER levels; in contrast, PR levels increased following ovariectomy. In both intact and ovariectomized animals, estradiol alone did not elevate PR levels above control; however, the PR was down-regulated by progesterone. ER levels in ovariectomized animals were not restored by any of the steroid regimens. By Western blot analysis, PR levels appeared to increase following ovariectomy, were unaffected by estradiol, and were somewhat decreased following progesterone treatment in estradiol-primed ovariectomized animals. While not quantitative, these results are supportive of radioligand binding studies. Immunocytochemical studies of oviduct PR followed the same pattern showing increased immunoreactivity following ovariectomy, no change with estradiol, and a decrease following progesterone treatment of estradiol-primed animals. Oviduct contractility was monitored as a physiological index of progesterone action. Estradiol significantly increased the amplitude of the contractions both in vivo and in vitro, whereas progesterone in combination with estradiol significantly inhibited the estrogen effect. This study suggests that estradiol alone may not be adequate for regulation of both ER and PR. While progesterone down-regulates its own receptor, it does not appear to influence the ER. These data are in contrast to mammalian and avian studies which show that estradiol increases both the ER and PR in the reproductive tract, and progesterone down-regulates both receptors.

Ammonium Sulfate↗
PubMed1988

Comparative activities of 2,3,7,8-tetrachlorodibenzo-p-dioxin and progesterone as antiestrogens in the female rat uterus.

The comparative antiestrogenic effects of progesterone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cytosolic and nuclear estrogen (ERc and ERn, respectively) and progesterone (PRc and PRn, respectively) receptor levels were determined in female Long Evans rats. Estradiol treatment typically increases ER and PR levels in target cells or tissues and these proteins have been proposed as markers of estrogen action. 2,3,7,8-TCDD causes a dose-dependent decrease in uterine ERc, ERn, PRc, and PRn levels which persist up to 7 days. Progesterone treatment caused significant decreases in uterine ERc, ERn, and PRn levels; however, after 7 days, the effects of the hormone on receptor levels were diminished. The effects of 2,3,7,8-TCDD and progesterone on hepatic ER and PR levels were comparable to those observed in the uterus. Treatment of the rats with estradiol (5 micrograms/kg), estradiol (5 micrograms/kg) plus progesterone (1 mg/animal), or 2,3,7,8-TCDD (80 micrograms/kg) showed that both progesterone and 2,3,7,8-TCDD significantly antagonized the estradiol-mediated increases in uterine (and hepatic) ERc, ERn, PRc, and PRn levels and for 2,3,7,8-TCDD the decreased receptor levels persisted for up to 7 days. In vitro studies with freshly isolated uterine strips demonstrated that both 2,3,7,8-TCDD and progesterone antagonized the estradiol-mediated increases in ER and PR levels. Previous studies suggest that the antiestrogenic activity of progesterone is due, in part, to the induction of proteins which are involved in decreasing ERn levels in target cells. Moreover in the uterine strip assay procedure, it was previously shown and reproduced in this study that the decrease in uterine ERn by progesterone was inhibited by both protein and RNA synthesis inhibitors over a 4-hr incubation period. In contrast, the 2,3,7,8-TCDD-mediated decrease in uterine ERn was inhibited only by actinomycin D and not by cycloheximide or puromycin. These in vitro studies thus confirm that both progesterone and 2,3,7,8-TCDD exhibit comparable antiestrogenic effects in vivo and in vitro; however, the results suggest that these effects are expressed through different mechanisms.

Animals↗
PubMed2005

Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures.

We have previously demonstrated that progesterone significantly increases the rate of myelination in organotypic slice cultures of 7-day-old rat and mouse cerebellum. Here, we show that progesterone (20microM) stimulates the proliferation of oligodendrocyte precursors in cultured cerebellar slices of 7-day-old rats. The steroid increased the number of pre-oligodendrocytes (NG2(+), O4(+)) and to some extent of oligodendrocyte precursors, corresponding to an earlier developmental stage (nestin(+), PDGFalphaR(+), NG2(+), O4(-)). Progesterone stimulated the proliferation of both NG2(+) and O4(+) cells as shown by increased double-immunolabeling with the cell proliferation marker Ki67. The mitogenic effect of progesterone was inhibited by the progesterone receptor antagonist mifepristone (10microM) and could not be mimicked by its GABA-active metabolite 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone), even at the high concentration of 50microM. Results indicate that progesterone first strongly and transiently stimulates the proliferation of oligodendrocyte precursors, and that it may thereafter accelerate their maturation into myelinating oligodendrocytes. Although oligodendrocyte precursors may be a direct target for the actions of progesterone, their number may also be indirectly influenced by the effects of the steroid on neurons and microglial cells, since treatment of the cerebellar slices with progesterone enhanced staining of the neuronal cytoskeleton marker microtubule-associated protein-2 and increased the number of OX-42(+) microglia. A small percentage (about 0.1%) of the NG2(+) cells transiently became OX-42(+) in response to progesterone. These results point to novel mechanisms by which progesterone may promote myelination in the CNS, specifically by stimulating the proliferation and maturation of oligodendrocyte precursors into myelinating oligodendrocytes.

Animals↗
PubMed1984

Estrogen and progesterone receptor and hormone levels in human myometrium and placenta in term pregnancy.

Estradiol and progesterone receptors in the myometrium, decidua, placenta, chorion, and amnion of eight women who underwent elective cesarean section at term were determined by means of an exchange assay. The hormone levels in the peripheral plasma and cytosol of these tissues were measured by radioimmunoassays. Maternal plasma and the placenta had high concentrations of estradiol and progesterone, with the placenta having 12 times more progesterone than in maternal plasma but only half the concentrations of estradiol in maternal plasma. The decidua and placenta had detectable levels of cytosol and nuclear estradiol receptors, but the myometrium had no measurable cytosol estradiol receptors, whereas the chorion and amnion had neither cytosol nor nuclear estradiol receptors. However, the chorion and amnion had significantly higher concentrations of estradiol in the cytosol than those in the decidua and myometrium. Only the decidua and myometrium had cytosol and nuclear progesterone receptors, but the placenta, amnion, and chorion had neither cytosol nor nuclear progesterone receptors. In contrast, progesterone hormone levels were significantly higher in the placenta, amnion, and chorion than in the decidua and myometrium. The findings indicate that, in the term pregnant uterus, (1) the placenta, amnion, and chorion are rich in progesterone, estradiol, and nuclear estradiol receptors but have no progesterone receptors, (2) the decidua and myometrium have nuclear estradiol and progesterone receptors, and (3) the myometrium has a higher progesterone/estradiol ratio than that of the peripheral plasma, thus suggesting a highly progesterone-dominated uterus.

Amnion↗
PubMed2001

Developmental changes in progesterone biosynthesis and metabolism in the quail brain.

We have recently demonstrated that the quail brain possesses the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) and produces pregnenolone, pregnenolone sulfate and progesterone from cholesterol. To elucidate the developmental changes in progesterone biosynthesis and its metabolism in the quail brain, we examined the expression and activity of 3beta-HSD and progesterone metabolite(s) during embryonic and post-hatched ages. Both the progesterone concentration and 3beta-HSD mRNA expression in the brain were almost constant during embryonic and post-hatched ages. The conversion of pregnenolone to progesterone (net 3beta-HSD enzymatic activity) was also constant during development and at maturity. However, without radioinert progesterone, the production of progesterone was drastically reduced in the embryonic brain, indicating active progesterone metabolism at the embryonic stage. Biochemical analysis together with HPLC and TLC revealed that only the embryonic brain actively produced 5beta-dihydroprogesterone from progesterone. Thus, progesterone production may be constant during embryonic and post-hatched development and in adulthood, whereas 5beta-dihydroprogesterone may be produced actively only in embryonic life due to 5beta-reductase.

Aging↗
PubMedDate not supplied

Identification of functional binding sites for progesterone in rat Leydig cell plasma membrane.

Steroid hormones influence cell functions by binding to intracellular receptors and then acting within the nucleus. There is now evidence that steroids affect cell functions also via interaction with plasma membrane receptors in a number of different cell types. In this regard, progesterone appears to be one of the most active steroids. In this paper, we evaluate the effects of progesterone on rat Leydig cell functions, determining variations of ion homeostasis and testosterone production. This steroid was able to effect a depolarization of the plasma membrane that was due to an influx of sodium (Na+) from the external medium since it was absent when extracellular Na+ was iso-osmotically substituted with choline chloride or sucrose. The determination of intracellular sodium concentration ([Na+]i) with the Na+ -sensitive fluorescent dye sodium-benzofuran-isophtalate (SBFI) confirmed these observations. Progesterone did not modify Leydig cell intracellular calcium concentration ([Ca2+]i) at any dose tested. Furthermore, using a cell impermeant progesterone conjugate, we demonstrated that progesterone was able to stimulate Leydig cell steroidogenesis in a dose-dependent manner. The exclusion of calcium (Ca2+) from the extracellular medium did not modify the depolarizing action of progesterone and its steroidogenetic effect while in Na+ -free medium (sucrose supplemented) progesterone-stimulated effects were completely blunted. Finally, using fluorescence microscopy with a fluorescein isothiocyanate-coupled cell impermeant progesterone conjugate, we identified plasma membrane binding sites for progesterone in rat Leydig cells. These results suggest that rat Leydig cells possess progesterone receptors located on the plasma membrane, which when occupied achieves a plasma membrane depolarization, dependent on an influx of Na+ from the external medium, and the subsequent activation of steroidogenesis.

Animals↗
PubMed2001

Progesterone receptor: some viewpoints on hypothalamic seasonal fluctuations in a lower vertebrate.

Steroids secreted by the ovary, specifically estrogen and progesterone, influence the expression of behaviors associated with reproduction by interacting with a specific binding protein, or receptor, located in target cells in certain hypothalamic nuclei. The present paper reviews the progesterone receptor studies in the vertebrates brain, the progesterone receptor fluctuations throughout the reproductive cycle and suggests a role for progesterone receptors in the regulation of hypothalamic functions in amphibians. Furthermore, we report here a combined biochemical and immunohistochemical analysis of the hypothalamic progesterone receptor during the reproductive cycle of a lower vertebrate, the female amphibian anura Rana esculenta. 3H-Progesterone binding activity was found in both cytosol and nuclear extract samples. The progesterone binding moiety showed typical characteristics of a true receptor, such as high affinity, low capacity and specificity for progesterone. Further characterization was performed by using monoclonal antiserum raised against both the subunits A and B of the chicken progesterone receptor. Immunostained neurons were located mainly in two specific regions of the hypothalamus: the preoptic area and the infundibular hypothalamus. An immunoreactive band of about 67 kDa was observed using Western blotting, both in the cytosol and in the nuclear extract. Progesterone receptor levels fluctuated throughout the cycle along with plasma steroids and vitellogenin synthesis.

Animals↗
PubMed1999

Progesterone signaling and mammary gland morphogenesis.

Progesterone was identified as a mammogenic hormone several years ago but until now its precise role in mammary development has remained obscure. Recently with the generation of several transgenic mouse models and development of reagents for analysis of progesterone receptor expression, the role of progesterone signaling in mammary development is becoming more clear. The most significant observations to emerge from these studies are (1) progesterone receptors (PR) are present in a heterogeneous manner in the epithelial cells and undetectable in the surrounding fat pad; (2) they are essential for lobuloalveolar and not for ductal morphogenesis; (3) progesterone signaling through progesterone receptors, leading to lobuloalveolar development, is initiated in the epithelium and may occur through paracrine mechanisms; and (4) a regulated expression of the two isoforms of progesterone receptor is critical for maintaining appropriate responsiveness to progesterone and hence, epithelial cell replicative homeostasis. These studies also reveal that the consequences of progesterone signaling through progesterone receptor may depend on the cell context, cell-cell and cell-extracellular matrix interactions, the dynamics of PR turnover and the fate of PR positive cells.

Animals↗
PubMed2000

Identification of XPR-1, a progesterone receptor required for Xenopus oocyte activation.

Quiescent full-grown Xenopus oocytes remain arrested at the G(2)/M border of meiosis I until exposed to progesterone, their natural mitogen. Progesterone triggers rapid, nontranscriptional responses that lead to the translational activation of stored mRNAs, resumption of the meiotic cell cycles, and maturation of the oocyte into a fertilizable egg. It has long been presumed that progesterone activates the oocyte through a novel nontranscriptional signaling receptor. Here, we provide evidence that a conventional transcriptional progesterone receptor cloned from Xenopus oocytes, XPR-1, is required for oocyte activation. Overexpression of XPR-1 through mRNA injection increases sensitivity to progesterone and accelerates progesterone-activated cell cycle reentry. Injection of XPR-1 antisense oligonucleotides blocks the ability of oocytes to respond to progesterone; these oocytes are rescued by subsequent injection of XPR-1 or the human progesterone receptor PR-B. Antisense-treated oocytes can be activated in response to inhibition of protein kinase A, one of the earliest known changes occurring downstream of progesterone stimulation. These results argue that the conventional progesterone receptor also functions as the signaling receptor that is responsible for the rapid nontranscriptional activation of frog oocytes.

Amino Acid Sequence↗
PubMed1994

Hypothalamo-pituitary effects of RU486: inhibition of progesterone-induced hyperprolactinaemia.

Monkeys given oestrogen priming at physiological levels for at least 1 week become hyperprolactinaemic upon the addition of physiological progesterone administration. Here, using RU486, we test whether that this oestrogen/progestin-induced hyperprolactinaemia results from classical progesterone actions at the hypothalamo-pituitary level. Blood samples were collected daily from study day 1-67. Each monkey (n = 2) received daily injections of 25 micrograms/kg oestradiol benzoate, i.m., on study days 5-60. Progesterone-filled silastic capsules (3 cm) were inserted on study day 14 and removed on day 53. On study days 39-45, each monkey received RU486 (25 mg/day, p.o.). Serum samples were stored at -20 degrees C until assayed for prolactin, oestradiol, progesterone and RU486 by radioimmunoassay. Hyperprolactinaemia was induced in all three monkeys upon insertion of progesterone capsules. Prolactin concentrations fell sharply during RU486 treatment to nadirs some 10-fold less than prior to RU486 treatment. The time series was modelled by the Box-Jenkins autoregressive-integrated moving average (ARIMA) method with progesterone producing a gradual increase in prolactin concentrations and RU486 producing a sudden decrease. Statistically significant effects of progesterone and RU486 were found. Thus, the addition of progesterone to an oestrogenized milieu significantly increased prolactin concentrations, and RU486 fully reversed this effect. This evidence indicates that the progesterone-induced hyperprolactinemia in an oestrogenized milieu results from classical progesterone effects.

Animals↗
PubMed1983

The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol.

1 Canrenone, the major active metabolite of spironolactone, decreased [3H]-progesterone binding to isolated uterine cytosolic progesterone receptors. The inhibition was concentration-dependent. 2 Canrenone did not alter [3H]-oestradiol binding to isolated uterine cytosolic oestrogen receptors. 3 Canrenone inhibition of progesterone binding to isolated cytosolic receptors was strictly competitive: Kd (apparent dissociation constant for progesterone binding) was increased in a concentration-dependent manner by canrenone, whereas Bmax (maximal number of progesterone binding sites/mg cytosolic protein) was unaltered. There was marked cooperativity in progesterone binding at high canrenone and low progesterone concentrations. The implication is that canrenone alters the subunit interaction of the receptor protein. 4 Kd for progesterone was 3.2 X 10(-9)M. Ki (the inhibition constant for canrenone with respect to progesterone binding) was 300 X 10(-9)M. Reports in the literature suggest that, following spironolactone administration, canrenone may rise to concentrations sufficiently high to inhibit progesterone binding. This action may contribute to the effect of spironolactone in inducing menstrual disturbances in female patients.

Canrenone↗
PubMed1994

Acute administration of a 3 beta-hydroxysteroid dehydrogenase inhibitor to rhesus monkeys at the midluteal phase of the menstrual cycle: evidence for possible autocrine regulation of the primate corpus luteum by progesterone.

Colocalization of progesterone receptors and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), a key enzyme in progesterone biosynthesis, in macaque luteal cells suggest that progesterone has an autocrine role in the regulation of primate luteal function. To test this hypothesis, we administered trilostane, a 3 beta HSD inhibitor, to rhesus macaques at the midluteal phase of spontaneous menstrual cycles to rapidly and reversibly reduce progesterone production. Animals received trilostane (600 mg/dose; treated group; n = 5) or vehicle (control group; n = 4) orally on days 6-7 of the luteal phase. Trilostane significantly (P < 0.05) elevated pregnenolone levels within 1 h of treatment compared to those in vehicle-treated animals; after 1 day of treatment, the mean pregnenolone level (173 nmol/L) was 86-fold greater than the control value. Pregnenolone levels dropped after cessation of drug administration and became indistinguishable from control levels by day 13. Trilostane significantly reduced serum progesterone levels within 3 h of initial administration (P < 0.01), and levels remained near baseline (1.0 nmol/L) throughout the 2 days of treatment. Progesterone levels also remained low after cessation of trilostane treatment in four of five monkeys, and trilostane-treated animals experienced a shorter luteal phase than vehicle-treated animals (7.8 +/- 0.2 vs. 16 +/- 1 days; P < 0.01). Histological analysis (n = 3/group) revealed indexes of premature structural luteolysis by 4 days after the onset of trilostane administration. Exposure to trilostane had no effect on the percentage of luteal cells expressing progesterone receptors, as determined by immunocytochemistry. Serum LH levels were not different between treatment and control groups throughout the experimental period. As trilostane dramatically reduced serum progesterone and induced premature menses without major concurrent alteration in serum cortisol, we conclude that trilostane ios an effective, rapidly acting inhibitor of 3 beta HSD in the macaque corpus luteum during the midluteal phase of the menstrual cycle. Progesterone production did not typically resume after cessation of trilostane treatment despite continuing gonadotropin support luteolysis. Thus, progesterone or a related metabolite may be required to maintain the function and structural integrity of the primate corpus luteum during the normal menstrual cycle.

3-Hydroxysteroid Dehydrogenases↗