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PubMed1990

Monoclonal and polyclonal antibodies to human progesterone receptor peptide-(533-547) recognize a specific site in unactivated (8S) and activated (4S) progesterone receptor and distinguish between intact and proteolyzed receptors.

We have synthesized three peptides with amino acid sequences corresponding to amino acids 533-547, 597-611, and 765-779 of the human progesterone receptor (hPR). These peptides were conjugated to keyhole limpet hemocyanin and injected into mice and rabbits to develop antibodies to hPR. Antibodies to the undenatured form of PR were elicited only by the peptide with amino acid sequence 533-547. Fusion of SP2/0 myeloma cells with spleen cells from mice immunized with this peptide produced several active clones. Rabbit sera from immunized animals produced one antiserum that reacted with the undenatured form of PR. One monoclonal antibody (PR-AT 4.14) and one antiserum (PR-AT533) raised against peptide-(533-547) were characterized. Binding of these antibodies to the undenatured form of PR was demonstrated by analysis of the antibody-receptor complexes on sucrose density gradients and by immunoprecipitation techniques. Binding of PR to the antibodies was inhibited by excess peptide. The antibodies did not react with estrogen, glucocorticoid, or androgen receptors, but recognized PR from human breast cancer as well as calf, rabbit, mouse, and rat uteri, indicating that this epitope was conserved among these species. Based on sucrose density gradient analysis of PR prepared and labeled in the presence of proteolysis inhibitors and sodium molybdate, the antibodies bound to a site on the intact undenatured PR, but failed to bind to partially degraded steroid-binding form of the receptor, suggesting that the antibody-binding domain is at or near a site sensitive to proteolysis.

Amino Acid Sequence↗
PubMed1995

Increased accumulation of oxytocin messenger ribonucleic acid in the hypothalamus of the female rat: induction by long term estradiol and progesterone administration and subsequent progesterone withdrawal.

To examine a possible role for gonadal steroid hormones in the enhanced accumulation of hypothalamic oxytocin (OT) messenger RNA (mRNA) and peptide in late pregnancy, we used an established model (22) in which sequential administration of estradiol (E2) and progesterone (P) SILASTIC capsules to ovariectomized rats is followed by removal of P. Long term and sustained E2 combined with abrupt P withdrawal mimics the gonadal steroid hormone pattern of late gestation in the rat (22). Using this paradigm, we demonstrate that OT mRNA is increased in the rat hypothalamus after long term P treatment, but only in the presence of E2 and only when P capsules are removed 48 h before killing. Furthermore, we show that P replacement in primiparous rats during late pregnancy blunts the increase in OT mRNA normally observed at the end of gestation. Our results support a role for E2 priming and P withdrawal in the enhanced accumulation of OT mRNA in the hypothalamus of the female rat.

Animals↗
PubMed2004

Responses to a saline load in gonadotropin-releasing hormone antagonist-pretreated premenopausal women receiving progesterone or estradiol-progesterone therapy.

The effects of estradiol (E(2)) and progesterone (P(4)) on fluid and sodium regulation may have important clinical implications with respect to cardiovascular and renal disease as well as reproductive syndromes such as preeclampsia and ovarian hyperstimulation syndrome. We tested the hypothesis that sodium excretion is reduced in response to a sodium load during combined P(4)-E(2) treatment, but P(4) administration alone has little effect on sodium regulation. Fifteen women (22 +/- 2 yr) used a GnRH antagonist to suppress endogenous E(2) and P(4) for 9 d; for d 4-9, eight subjects used P(4) (200 mg/d), and seven subjects used P(4) with E(2) (two E(2) patches, 0.1 mg/d each). On d 3 and 9, isotonic saline (0.9% NaCl) was infused [120 min at 0.1 ml/kg body weight (BW).min], followed by 120 min of rest. Compared with GnRH antagonist alone, P([P4]) increased from 1.6 +/- 0.8 to 9.4 +/- 2.3 ng/ml (5.1 +/- 2.5 to 29.9 +/- 7.3 nmol/liter, P < 0.05) in the P(4) treated group, with no change in P([E2]). In the P(4)-E(2) treated group P([P4]) increased from 1.6 +/- 0.5 to 6.7 +/- 0.6 ng/ml (5.1 +/- 1.6 to 21.3 +/- 1.6 nmol/liter, P < 0.05 and P([E2]) increased from 17.9 +/- 6.3 to 200 +/- 41 pg/ml (65.7 +/- 23 to 734.6 +/- 150.0 pmol/liter, P < 0.05). Before isotonic saline infusion, renal sodium and water excretion were similar under all conditions, but during isotonic saline infusion, cumulative sodium excretion was lower in the P(4)-E(2) treated women (34.1 +/- 5.1 mEq) compared with GnRH antagonist (50.2 +/- 11.4 mEq). Sodium excretion was unaffected by P(4) treatment (48.0 +/- 8.2 and 41.2 +/- 5.1 mEq, for GnRH antagonist and P(4)). Compared with GnRH antagonist alone, P(4)-E(2) treatment increased distal sodium reabsorption and transiently decreased proximal sodium reabsorption, whereas P(4) treatment did not alter either distal or proximal sodium reabsorption. Before isotonic saline infusion, the plasma aldosterone (Ald) concentration was greater during P(4) treatment (153 +/- 25 pg/ml; 3883 +/- 1102 pmol/liter) and P(4)-E(2) treatment (242 +/- 47 pg/ml; 6373 +/- 1390 pmol/liter) than during their respective GnRH antagonist alone treatments [96 +/- 13 and 148 +/- 47 pg/ml (2598 +/- 475 and 3284 +/- 973 pmol/liter) for P(4) and combined P(4)-E(2), respectively]. Compared with GnRH antagonist alone treatments, preisotonic saline infusion plasma renin activity was greater only with P(4)-E(2) treatment, whereas the plasma atrial natriuretic peptide concentration was lower only with P(4) treatment. Isotonic saline infusion suppressed plasma Ald under all conditions, but decreased plasma renin activity only with P(4)-E(2) treatment (average decrease, 1.3 +/- 0.5 ng/ml angiotensin I.h; P < 0.05). In summary, we found that P(4)-E(2) treatment decreased sodium excretion via either renin-angiotensin-Ald system stimulation or direct effects on kidney tubules. P(4) treatment at these plasma concentrations had no independent effect on the renal response to acute sodium loading. These data suggest that E(2) is the more powerful reproductive hormone involved in sodium retention relative to P(4), and that estrogen-induced up-regulation of P(4) receptors is required for the effects of P(4) on sodium regulation.

Absorption↗
PubMed1993

The impact of subchronic hypercortisolemia on progesterone metabolism and the luteinizing hormone-progesterone axis in the cynomolgus monkey.

The purpose of the study was to assess the impact of subchronic hypercortisolemia on progesterone (P) metabolism and production and on peripheral LH levels in a nonhuman primate using a repeated measures experimental design. Osmotic pumps that released hydrocortisone phosphate (HP) at a dose of 15 mg/day were implanted sc in seven cynomolgus monkeys for two menstrual cycles. The pumps were filled with saline for the two control cycles, which either preceded (three animals) or followed (four animals) HP infusion. P metabolism, P production, and episodic secretion of LH were determined 8 +/- 1 days after the serum estradiol peak in the second control cycle and in the second cycle of HP infusion in each monkey, after iv bolus administration of 50 microCi [3H]P, followed by a 6-h blood sampling period. HP infusion elevated serum cortisol levels 1.6-fold. Serum P levels were decreased throughout the luteal phase by 58% (P < 0.01). The MCR of P and the volume of distribution at steady state of P were increased by 200% during HP infusion (both P < 0.005). The production rate of P was increased by HP treatment in five of seven monkeys. HP infusion increased the ratio of 20 alpha-[3H]dihydroprogesterone to [3H]P in serum from 0.5 to 1.0 (P < 0.05) while decreasing the fraction of [3H]P and its metabolites excreted in urine from 20% to 11% (P < 0.05). Serum LH levels, determined over a 5.25-h period in the luteal phase, were elevated by 200% during HP treatment (P < 0.05). Episodic secretion of LH during treatment was characterized by a 660% increase in the pulse amplitude (P < 0.05) and an apparent decrease in the pulse frequency. The results of this study provide evidence that moderate elevation of serum cortisol levels for two menstrual cycles in primates 1) increases the MCR of P, which may be the cause of the observed decrease in serum P levels; and 2) elevates serum LH levels by amplifying its pulse amplitude, which may result in a compensatory rise in the production rate of P.

Animals↗
PubMed1997

Concentration of GnRH receptor and GnRH receptor mRNA in pituitary tissue of orchidectomized sheep: effect of oestradiol, progesterone, and progesterone withdrawal.

The effect of progesterone (P4) and P4 withdrawal on oestradiol (E2)-induced change in gonadotrope responsiveness (GR) and concentration of GnRH receptor and GnRH receptor mRNA in pituitary tissue of orchidectomized sheep (wethers) was determined. Thirty wethers were assigned at random to one of six treatment groups (n = 5 animals/group). Wethers received E2 (2 micrograms/h; groups 2, 4, and 6) in 10% ethanol-saline (vehicle), or vehicle alone (groups 1, 3, and 5), as a continuous infusion for 24 h beginning 7 days after insertion (s.c.) of blank (groups 1 and 2) or P4-containing (groups 3-6) implants. The effect of P4 withdrawal was assessed by removing P4-containing implants at the beginning of vehicle (group 5) or E2 (group 6) infusion. Gonadotrope responsiveness (increase in serum LH induced by 500 ng GnRH, i.v.) was assessed at the end of infusion. In a companion study, anterior pituitary tissue was collected at the end of the 24-h infusion period. Infusion of E2 increased (P < 0.05) GR relative to GR noted in control wethers receiving vehicle alone. The magnitude of E2-induced augmentation of GR was not affected by concurrent administration of P4 or P4 withdrawal. Pituitary tissue concentrations of GnRH receptor and GnRH receptor mRNA were significantly reduced in wethers implanted with P4. This P4-induced decrease in tissue concentration of GnRH receptor and GnRH receptor mRNA was not reversed during the 24-h period after P4 withdrawal. Steady-state concentrations of GnRH receptor and GnRH receptor mRNA were significantly increased by E2. However, the magnitude of oestrogen-induced increase in tissue concentrations of GnRH receptor mRNA was not significantly affected by P4 or P4 withdrawal. Conversely, concurrent progestin stimulation potentiated the E2-induced augmentation of tissue concentrations of GnRH receptor. However, this P4-induced potentiation of the oestrogenic response was not evident 24 h after removal of the P4-containing implants. Steady-state concentrations of mRNA encoding the LH beta and FSH beta subunits were reduced (P < 0.05) by P4. Infusion of E2 had a similar affect. These data indicate that prolonged progestin stimulation leads to a decrease in tissue concentrations of GnRH receptor and GnRH receptor mRNA. This P4-induced suppression of GnRH receptor activity is not reversed within 24 h of P4 withdrawal. In addition, the increase n steady-state concentrations of GnRH receptor and GnRH receptor mRNA induced by E2 is not compromised by concurrent progestin stimulation.

Animals↗
PubMed1993

Administration of GnRH at estrus influences pregnancy rates, serum concentrations of LH, FSH, estradiol-17 beta, pregnancy-specific protein B, and progesterone, proportion of luteal cell types, and in vitro production of progesterone in dairy cows.

Four experiments were conducted to examine effects of GnRH administered at estrus on various reproductive characteristics in repeat-breeding dairy cows (eligible for third service). In Exp. 1, cows (n = 8 per group) received (i.m.) either saline or 50, 100, or 250 micrograms of GnRH at 12 h after onset of estrus. There was a positive linear (P < .05) effect of dose on concentrations of LH, but not of FSH, in serum at 2 h after the injection. Concentrations of progesterone (P4) were higher (P = .10) through 16 d after estrus in nonpregnant cows that returned to estrus 18 to 24 d after GnRH treatment than in nonpregnant cows given saline. Likewise, among cows with elevated concentrations of P4 through 30 d after estrus (diagnosed pregnant by increased concentrations of pregnancy-specific protein B; PSPB), P4 was higher (P = .10) in those given GnRH than in those given saline. In Exp. 2, concentrations of LH, FSH, and estradiol-17 beta (E2) were similar among 12 cows during the periestrual period before they received (i.m.) 100 micrograms of GnRH or saline at estrus. Concentrations of P4 after estrus were increased 2 d earlier (P < .05) in GnRH- than in saline-treated cows. Among cows with elevated concentrations of P4 and PSPB through 40 d after AI, P4 was higher (P < .05) in those given GnRH than in those given saline. In Exp. 1 and 2, a greater proportion (43 vs 14%; P = .07) of cows given GnRH was pregnant 42 to 56 d after estrus than of those given saline, but calving rate was similar (27 vs 14%). In Exp. 3, average number of LH pulses per 8 h was similar between saline- and GnRH-treated cows on d 1, 3, and 8, but overall concentrations of LH were reduced (P < .05) in GnRH-treated cows. Concentrations and number of pulses of FSH were increased (P < .05) on d 8 after treatment with GnRH. Concentrations of P4 were increased earlier (P < .05) after estrus in GnRH-treated (69 +/- 12 h) than in saline-treated cows (126 +/- 12 h), with higher (P < .05) concentrations of P4 on d 4 to 8. In Exp. 4, eight cows received either 100 micrograms of GnRH or saline at 12 h after onset of estrus (d 0) in a cross-over design.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Reproductive responses, progesterone profiles and ovarian characteristics of cycling, fine-wool ewes treated with an inhibitor of progesterone synthesis (epostane).

In Exp. 1, 45 fine-wool ewes received (sc) either 0, 50 or 100 mg epostane (3-beta-hydroxysteroid dehydrogenase inhibitor) to examine effects on return to estrus and conception rates. Treatments were imposed on d 10 of an estrous cycle (estrus = d 0) and jugular blood samples were collected once daily on d 8 and 9, twice daily on d 10 through 13 and once daily from d 14 until first post-treatment estrus or d 20 (15 ewes/treatment). Intensive samples were obtained hourly for 6 h after treatment (d 10; five ewes/treatment). Serum progesterone (P4) before treatment was similar among groups; but by 2 h after treatment, epostane-treated ewes had lower (P less than .10) values than controls. By 6 h post-treatment, serum P4 in ewes receiving 50 (1.0 ng/ml) and 100 (.9 ng/ml) mg epostane was well below control values (3.2 ng/ml). By 7 d after treatment, 93.3% of ewes treated with 50 mg epostane had recycled compared with 66.7 and 33.3% of those receiving 100 and 0 mg, respectively (P less than .10). Similarly, 93.3, 53.3 and 26.7% of ewes receiving 50, 100 or 0 mg epostane, respectively, lambed to breeding within 7 d of treatment (P less than .05). Overall conception rates during a 34-d breeding season were similar among groups. Preweaning performance of offspring did not differ among maternal treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstenols↗
PubMed1997

The duration of estradiol and progesterone exposure prior to progesterone withdrawal regulates oxytocin mRNA levels in the paraventricular nucleus of the rat.

The nonapeptide oxytocin (OT) is important for milk ejection during lactation, uterine contractility at parturition, and the onset of maternal behavior. Sequential exposure to estradiol (E2) and progesterone (P) followed by P withdrawal increases OT mRNA in the paraventricular nucleus (PVN), and to a lesser degree the supraoptic nucleus (SON), of the rat 48 hours after the P is removed. Although increases in PVN OT mRNA are not accompanied by changes in posterior pituitary OT peptide content, the PVN contains OT neurons that project to both the posterior pituitary (magnocellular group) and extra pituitary sites (parvocellular groups). Steroid-induced increases in OT mRNA occur in both the magnocellular and the parvocellular regions of the PVN. The latter are believed to contribute to CNS release of OT which may be important for certain behaviors including the onset of maternal behavior. The same steroid sequence that increases PVN OT mRNA also induces maternal behavior in virgin ovariectomized rats. Exposure of animals to E2 and P for 2 weeks resulted in the shortest latency to the onset of maternal behavior in ovariectomized rats, whereas exposure for 6 days was associated with a longer latency. In this study we questioned if the duration of E2 and P exposure prior to P withdrawal is an important regulator of PVN OT mRNA levels. We compared OT mRNA levels in the PVN of virgin ovariectomized rats administered no steroid or sequential E2 and P for 2 weeks versus 6 days. On day 1 animals received steroid-filled or empty capsules followed by P-filled or empty capsules on day 3. In one steroid-treated group, E2 and P were continued for 6 days and in the other group for 14 days prior to P removal. Animals were sacrificed 48 hours after P removal. Levels of OT mRNA were compared among 6 day and 2 week steroid-treated animals and sham-treated animals. The relative abundance of OT mRNA was significantly increased, P < 0.05, in animals receiving the 2-week, but not the 6-day, steroid treatment compared to sham-treated animals. Pituitary OT peptide content was not significantly different among the three groups. We conclude that the duration of steroid exposure may be an important regulator of the level of OT mRNA in the PVN of the rat.

Animals↗
PubMed2004

Resynchronizing estrus with progesterone or progesterone plus estrogen in cows of unknown pregnancy status.

Two experiments were conducted to test 2 progesterone (P4)-based treatments that were applied to lactating dairy cattle of unknown pregnancy status to resynchronize estrus of nonpregnant cows. In experiment 1, cows were assigned randomly before a timed AI (TAI) to 1) treatment with a CIDR (controlled internal drug-releasing intravaginal insert containing P4) for 7 d starting on d 13 after TAI (CIDR; n = 300) or 2) no P4 treatment (control; n = 330). Compared with controls, P4 increased the synchrony of those detected in estrus, but failed to increase the overall return rates of non-pregnant cows during the 6 d after CIDR removal (27% vs. 31%; d 20 to 26 after TAI) and did not alter synchronized conception rates (32% vs. 20%) of those inseminated. Use of P4 did not compromise pregnancies resulting from TAI compared with controls (38% vs. 42%), but increased embryo survival between d 29 and 57 after TAI (65.5% vs. 44.3%). In experiment 2, on d 13 after TAI, 196 cows were treated with a CIDR insert for 7 d. Controls received no further treatment. Remaining cows were treated with 1 of 3 estrogen regimens: 1 mg of estradiol benzoate (EB), 0.5 mg of estradiol cypionate (ECP), or 1 mg of ECP on both d 13 and 21. Only 60% of nonpregnant, estrogen-treated cows were detected in estrus between d 20 and 26, and rates of return and conception did not differ among treatments. Estrogen on d 13 did not consistently turn over the dominant follicle when given at CIDR insertion but did increase concentrations of estradiol and reduced luteal function when administered on d 13 and 21 (24 h after CIDR removal). Treatments had no negative effects on milk yield, dry matter intake, or established pregnancies. Use of P4 alone had little effect on overall rates of return to estrus or conception at the first eligible estrus in experiment 1. Combining estrogen with P4 in experiment 2 had no detrimental effects on established pregnancies or subsequent conception and failed to improve return rates beyond P4 alone.

Administration, Intravaginal↗
PubMed1991

Elevation of serum progesterone with oral micronized progesterone after in vitro fertilization. A randomized, controlled trial.

In a randomized, controlled trial, oral micronized progesterone (P4) supplementation effectively elevated luteal phase serum P4 levels after in vitro fertilization (IVF). Of 34 nonconception IVF cycles, 12 were supplemented with oral micronized P4, 200 mg four times daily, beginning the day of oocyte retrieval, while 22 control cycles did not receive supplementation. With oral micronized P4 supplementation the P4 levels were higher (P less than .001) and the luteal phase longer (P less than .05). Oral micronized P4 supplementation appears to be a convenient method of supporting serum P4 levels during the luteal phase after IVF.

Administration, Oral↗
PubMed1991

[The effect of progesterone and RU486 on progesterone production in the ovulatory process of rats].

To clarify the autoregulatory mechanism of progesterone (P) production in the ovulatory process, we examined the ovarian concentration of P 46 hrs after PMSG and the effects of P and RU486 (RU) injected 4-2 hrs before hCG administration on the serum concentrations of P and estradiol (E2), and ovarian 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activities in PMSG/hCG treated immature rats. The effect of RU on the number of ovulated ova was also studied. The ovarian concentration of P 46 hrs after PMSG was 0.96 +/- 0.03,ng/mg protein (mean +/- SEM). When P (100,mg/kg) was injected 2 hrs before hCG, ovarian 3 beta-HSD activities had significantly increased by 4 hrs after hCG. However, P at a dosage of 10 and 20,mg/kg had no effect on ovarian 3 beta-HSD activities. The administration of RU (20,mg/kg) 2 hrs before hCG significantly inhibited ovarian 3 beta-HSD activities measured 4 and 6 hrs after hCG (p less than 0.01 and p less than 0.05, respectively). In addition, the serum P concentration 4 hrs after hCG was significantly lower than that of the control (p less than 0.01). However, RU (20 mg/kg) in concomitant with hCG had no effect on ovarian 3 beta-HSD activities within 6 hrs after hCG. The suppression of ovarian 3 beta-HSD activities by RU was the concomitant reversed by the concomitant treatment with P (10 mg/kg). RU (10, 20, or 40 mg/kg) injected 2 hrs before hCG significantly reduced the number of ovulated ova (p less than 0.01, p less than 0.01 and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Comparison of an immunocytochemical assay for progesterone receptor with a biochemical method of measurement and immunocytochemical examination of the relationship between progesterone and estrogen receptors.

Using a rat monoclonal antibody raised against human progesterone receptor (PR) we have developed an immunocytochemical technique to detect PR in human normal and malignant breast tissue and have compared the distribution of this with that obtained by the conventional dextran-coated charcoal steroid-binding assay. Immunoreactive PR was detected exclusively in the nuclei of epithelial cells in 29/51 (56.9%) of breast cancers studied. There was an excellent correlation between the immunocytochemical and dextran-coated charcoal techniques, with concordance in 43/51 (84.3%) cases [regression coefficient (Spearman) = 0.78; P less than 0.001]. The relationship between PR and estrogen receptor (ER) was also examined immunocytochemically using a monoclonal antiserum to ER. Twenty-eight out of 51 (54.9%) tumors were positive for both receptors and 13/51 (25.5%) negative for both. ER-positive, PR-negative tumors were found in 9/51 (17.6%) cases whereas only one case (2%) was PR-positive, ER-negative.

Antibodies, Monoclonal↗
PubMed1987

Serum progesterone levels following vaginal administration of progesterone during the luteal phase.

We measured serum progesterone (P) levels after administration of 400 mg P vaginal suppositories to women during the luteal phase of the menstrual cycle. Blood samples were obtained before suppository insertion and at five intervals up to 8 hours after insertion. On the first day of treatment with P suppositories, there was a substantial elevation in serum P above baseline after insertion. However, on subsequent days of administration a smaller increment in serum P was observed. In 4 women studied on days 1 and 8 of the same treatment cycle in the luteal phase, a smaller rise in serum P following suppository administration on day 8, compared with day 1, was found. Overall, a highly significant negative correlation between change in serum P from baseline and duration of vaginal suppository treatment was found. This observation does not appear to be related to the achievement of a pharmacokinetic steady state. Possible mechanisms for this observation are discussed.

Administration, Intravaginal↗
PubMed1979

[OEstradiol and progesterone steroid hormone receptors in cancer of the endometrium. The significance of the progesterone receptor (author's transl)].

It would seem that the satisfactory way for the clinician to orientate the treatment by hormones in cancers of the endometrium lies in the presence at the same time of oestrogen and progesterone receptors and in particular of the latter. This applies when treating cancers of the endometrium with hormones in a way that is directed by chemical determination of hormone susceptibility.

Endometrium↗
PubMed1995

The presence of progesterone receptors in arachnoid granulations and in the lining of arachnoid cysts: its relevance to expression of progesterone receptors in meningiomas.

Progesterone receptors (PR) were identified with an enzyme immunoassay in cytosols from human arachnoid granulations and arachnoid cysts. Meningiomas presumably originate from subdural endothelium which is abundantly present in these structures. In the three cases studied, oestrogen receptors were absent. The presence of PR in subdural endothelium may provide further ground for the expression of PR in meningiomas.

Adult↗
PubMed1977

Progesterone-binding components of chick oviduct. Biochemical characterization of purified oviduct progesterone receptor B subunit.

A number of physical and chemical properties of pure hen oviduct progesterone receptor B subunit have been determined. The molecule consists of a single polypeptide chain with a molecular weight of 115,000 g/mol as determined by gel filtration in the presence of 6 M guanidine hydrochloride and by gel electrophoresis in sodium dodecyl sulfate. The labeled subunit has retained the biologically important properties which it displayed in cruder preparations: it binds to nuclei (Kd = 1 X 10(-9) M) and chromatin (Kd = 1.5 X 10(-9) M) but does not bind to DNA. Reaction of the purified subunit with dansyl (5-dimethylaminonaphthalene-1-sulfonyl) chloride revealed a single NH2-terminal lysine. The amino acid composition has been determined and has been shown to be distinct from that of other steroid-binding proteins and consistent with the known properties of the molecule. In addition, no evidence for carbohydrate or phosphorylated amino acids was observed. The protein contains about 12% alpha helix as determined by circular dichroism. The ultraviolet spectrum of intact steroid receptor complexes revealed that the purified subunit had no pyridine nucleotide cofactor or nucleic acid, and that each receptor molecule contains a single hormone binding site. Electron microscopic analysis confirms the prolate-ellipsoid shape of the protein, with a long axis of 114 A. The purified protein isolated as described in a companion paper is shown here to have the characteristics of the crude receptor subunit B. Due to the apparent role in the hormone response, this protein has been named progestophilin B.

Amino Acids↗
PubMed1997

Urinary progesterone and pregnanediol. Use for monitoring progesterone treatment.

OBJECTIVE: To compare progesterone (P) and pregnanediol glucuronide (PDG) levels in urine with respect to their potential use for monitoring luteal activity and P treatment. STUDY DESIGN: Two different experiments were carried out. In the first experiment, each of seven normal, ovulatory women collected first morning urines daily throughout an entire menstrual cycle. The day of ovulation was determined by transvaginal ultrasound scanning. P, PDG, estrone glucuronide, luteinizing hormone and creatinine were measured in each urine specimen. In the second experiment, each of three normal, ovulatory women was given a single oral dose of 200 mg of micronized P and, 2 days later, a single intramuscular injection of 25 mg of P during days 2-5 of the cycle. Blood and urine were collected prior to each treatment and 1, 4, 8, 12 and 24 hours after treatment. P was measured in both serum and urine; PDG was quantified only in urine. RESULTS: The mean initial rises and peak days, as well as the patterns of urinary excretion of P and PDG during the menstrual cycles, were similar; however, the variability of PDG was much greater. Concentrations of PDG were 1,000-4,000 times greater than those of P. A significant correlation was observed between urinary P and PDG. Following either intramuscular or oral P treatment, serum P levels rose rapidly and reached peak levels (7.0-11.8 ng/mL) by one hour. In contrast, both urinary P and PDG peaked considerably later (4-12 hours). Twenty-four hours after intramuscular treatment, serum and urinary P and urinary PDG were still elevated. Following oral treatment the levels of these compounds decreased after peaking and were 10- to 20- fold lower at 24 hours. Also, after oral P treatment, urinary PDG levels were considerably higher and more variable as compared to urinary P levels. CONCLUSION: Urinary P appears to be as good a clinical marker of luteal activity and therapeutic P administration as PDG and may be measured in place of this metabolite. There appears to be greater variability in urinary PDG as compared to urinary P when P is administered.

Adult↗
PubMed1996

Methylation of estrogen and progesterone receptor gene 5' CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors.

Hormonal factors have a profound influence on the development, treatment, and outcome of breast cancer. The absence of steroid hormone receptors is highly correlated with resistance to antihormonal treatments. Work in cultured human breast cancer cell lines has shown that the absence of estrogen receptor (ER) gene expression in ER- cells is associated with extensive methylation of the ER gene 5' CpG island, and treatment with agents that demethylate the ER gene CpG island results in the production of functional ER protein. The current study shows that CpG islands in the 5' region of the ER and progesterone receptor (PR) genes are methylated in a significant fraction of primary human breast cancer tissues. The ER CpG island is methylated at the methylation-sensitive NotI restriction site in 9 of 39 (25%) of primary ER- breast cancers but remains unmethylated in 53 ER+ breast cancers and 9 normal breast specimens. Three methylation-sensitive restriction sites in the PR gene CpG island are not methylated in normal breast specimens and PR+ human breast cancers but are hypermethylated in 40% of PR- human breast tumors. These data demonstrate that methylation of the ER and PR gene CpG islands is associated with the lack of ER and PR gene expression in a significant fraction of human breast cancers.

Breast Neoplasms↗