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PubMed2003

Novel D-ring modified steroid derivatives as potent, non-estrogenic, steroid sulfatase inhibitors with in vivo activity.

In pursuit of novel steroid sulfatase (STS) inhibitors devoid of estrogenicity, several D-ring modified steroid derivatives were synthesised. In vitro evaluation of the compounds identified two highly potent inhibitors, 4a and 4b, which were 18 times more active than estrone-3-O-sulfamate (EMATE), both having IC(50) values of ca. 1nM. These 16,17-seco-estra-1,3,5(10)-triene-16,17-imide derivatives were synthesised from estrone, via the intermediate 1, which was easily alkylated, deprotected and sulfamoylated affording the final compounds in high yields. In order to assess their biological profile, the selected inhibitors were tested for their in vivo inhibitory potency and estrogenicity in ovariectomised rats. After an oral dose of 10mg/kg per day for 5 days, 4a and 4b were found to inhibit rat liver steroid sulfatase by 99%. They were also devoid of estrogenic activity in the uterine weight gain assay, indicating that these two leads have therapeutic potential for the treatment of hormone-dependent breast cancer.

Animals↗

PubMed1996

Inhibition of human steroid 5alpha reductases type I and II by 6-aza-steroids: structural determinants of one-step vs two-step mechanism.

We have discovered that 17beta-[N,N-(diethyl)carbamoyl]-6-azaandrost-4-en-3-one is a time-dependent inhibitor of type II 5alpha-reductase, as is the drug finasteride. Unlike finasteride, the 6-aza-steroid is not a time-dependent inhibitor of type I 5 alpha-reductase. Finasteride inhibition of type II enzyme proceeds in a two-step mechanism. At pH 6 and 37 degrees C, an initial finasteride-reductase complex is formed with a K(i)(app) of 11.9 +/- 4.1 nM. In a second step, an irreversible complex is formed with a rate constant of inactivation of 0.09 +/- 0.01 s(-1). In contrast, the 6-aza-steroid is a reversible inhibitor. From the results of a simplified mathematical analysis, based on the rapid equilibrium approximation, the inhibitor and the enzyme form an initial complex with a K(i) of 6.8 +/- 0.2 nM. The reversible formation of a final complex, with an overall K(i) of 0.07 +/- 0.02 nM, is characterized by a first-order isomerization rate constant 0.0035 +/- 0.0001 s(-1) for the forward step and 0.00025 +/- 0.00006 s(-1) for the backward step. All rate constants for the two-step mechanism were obtained by using a general numerical integration method. The best fit values for the association and dissociation rate constants were 5.0 microM(-1) s(-1) and 0.033 +/- 0.008 s(-1), respectively, and the isomerization rate constants were 0.0035 +/- 0.007 s(-1) and 0.000076 +/- 0.000019 s(-1). These values correspond to an initial K(i) of 6.5 nM and an overall dissociation constant of 0.14 nM. The data presented here show that both finasteride and the 6-aza-steroid analogs are potent against type II 5alpha-reductase, although their mechanisms of inhibition are different.

5-alpha Reductase Inhibitors↗

PubMed1998

Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase.

Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site-directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) were also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.

Arylsulfatases↗

PubMed2003

Effect of non-steroidal aromatase inhibitor on blood plasma ovarian steroid and thyroid hormones in laying hen (Gallus domesticus).

HyLine Brown laying hens at 30 weeks of age were treated twice daily with Fadrozole, a non-steroidal aromatase inhibitor (AI; 1 mg/kg body weight; i.m.) for six consecutive days; control hens received saline. Blood was collected every day 0.5 h after oviposition, i.e. just before AI treatment. Ovarian steroids: progesterone (P4), testosterone (T) and estradiol (E2), and iodothyronines: thyroxine (T4), triiodothyronine (T3) and reverse-triiodothyronine (rT3) were measured in blood plasma by radioimmunoassay methods. In AI-treated hens a gradual delay in oviposition time was observed. AI significantly decreased P4 and E2 levels, maximally by 43% on day 4 and by 74% on day 5, respectively, and elevated T level, maximally by 248% on day 4. Simultaneously, the increases in T4 and T3 levels with no changes in rT3 levels were observed. The maximal effect of AI on T4 and T3 levels was found on day 4 (60% increase) and day 5 (312% increase), respectively. Moreover, statistically significant, negative coefficient of correlation between E2 and T3 (r = -0.51), and positive coefficient of correlation between T and T3 (r = 0.42) in AI-treated hens were found. The results obtained indicate that in mature laying hens there is a strong relationship between ovarian steroids and thyroid hormones, and suppression of E2 synthesis not only disrupts ovarian function but also affects the activity of the thyroid gland and peripheral metabolism of thyroid hormones.

Animals↗

PubMed1998

A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity.

Estrogen receptors ERalpha and ERbeta are members of the family of nuclear hormone receptors and act as ligand-inducible transcriptional factors, which regulate the expression of target genes on binding to cognate response elements. We report here the characterization of steroid receptor coactivator-3 (SRC-3), a coactivator of nuclear receptor transcription that is a member of a family of steroid receptor coactivators that includes SRC-1 and transcription intermediate factor-2. SRC-3 enhanced ERalpha and progesterone receptor-stimulated gene transcription in a ligand-dependent manner, but stimulation of ERbeta-mediated transcription was not observed. Protein-protein interaction assays, including real-time interaction analyses with BIAcore, demonstrated that the affinity of the ERalpha interaction with SRC-3 was much higher than that observed for the ERbeta interaction with SRC-3. Mutational analysis suggests a potential interplay between the transactivation function-1 and -2 domains of ERalpha and SRC-3. Furthermore, an intrinsic transactivation function was observed in the C-terminal half of SRC-3. Finally, SRC-3 was differentially expressed in various tissues and, among several tumor cells examined, was most abundant in the nuclear fraction of MCF-7 breast cancer cells. Therefore, SRC-3, a third member of a family of steroid receptor coactivators, has a distinct tissue distribution and intriguing selectivity between ERalpha and ERbeta.

Acetyltransferases↗

PubMed1995

The effects of joint washout and steroid injection compared with either joint washout or steroid injection alone in rheumatoid knee effusion.

Patients with rheumatoid arthritis attending rheumatology out-patients who had a symptomatic knee effusion were randomly allocated to receive one of three treatments: group I, a steroid injection without washout; group II, a joint washout with normal saline; group III, a joint washout with normal saline and steroid injection. Sixty knees in all were studied. Laboratory parameters for disease activity (erythrocyte sedimentation rate, C-reactive protein) were monitored in all patients prior to the study and at 3 months. Clinical assessment of disease activity (pain, morning stiffness involving the knee, circumference of the knee, walking distance and range of movement) were recorded prior to the study, at 1 month and at 3 months. All three treatments, resulted in a reduction of pain and increased movement. However, patients who had a joint washout alone showed significantly less improvement as compared with the other two groups. Symptomatic improvement was marginally greater in patients following joint washout and injection than in those who had had joint injection alone. The results of the study indicate that the simple procedure of joint aspiration and steroid injection, which can be carried out in the out-patient clinic, provides satisfactory relief of symptoms in rheumatoid patients with knee effusions. Joint washout alone was less beneficial.

Adult↗

PubMed1991

Medical treatment of chronic otitis media: steroid or antibiotic with steroid ear-drops?

The aim of this study was to evaluate whether, in the treatment of active non-cholesteatomatous chronic otitis media, the effectiveness of gentamicin with hydrocortisone ear-drops is due solely to the contained steroid or to the combination of antibiotic and steroid. Sixty-four patients presenting to the Ear, Nose and Throat outpatient department with active non-cholesteatomatous chronic otitis media were randomly allocated to receive either gentamicin with hydrocortisone ear-drops, or betamethasone ear-drops, for up to 4 weeks. Activity in the ear was assessed at 2 and 4 weeks. Gentamicin with hydrocortisone combination drops were significantly more effective than betamethasone drops (P less than 0.001) in producing inactivity of chronic otitis media, being effective in 80% as opposed to 29% of cases. The effectiveness of gentamicin with hydrocortisone ear-drops appears to be due to the combination of antibiotic and steroid.

Betamethasone↗

PubMed1996

Electrophysiological characteristics of bipolar membrane carbon leads with and without steroid elution compared with a conventional carbon and a steroid-eluting platinum lead.

In a controlled study, the following four bipolar leads with passive fixation were implanted in 46 patients with the Siemens-Multilog-VVI or Sensolog-VVIR-pacemakers: membrane covered activated porous carbon with steroid elution (Siemens 1402 T, 11 patients) and without (Siemens 1403 T, 15 patients); activated carbon (Siemens 1010 T, 10 patients); and platinum with steroid elution (Medtronic Cap-Sure 5026, 10 patients). Stimulation threshold (STH) (assessed by a vario-test), impedance (IMP), and the intracardial R wave potential (IRW) (both gauged by a telemetric method) were measured 1, 5, and 10 days as well as 3 and 6 months after implantation during unipolar and bipolar stimulation, chronaxie rheobase product (CRP) and energy consumption (EC) were systematically determined. Differing insignificantly at the first day after implantation, STH is significantly lower for the 1402 T and CapSure 5026 leads at the tenth day. However, the 1402 T lead shows a significant increase of STH in the follow-up, in contrast to the other leads. The lowest chronic STH was found in the CapSure 5026 lead (CRP is significantly lower in all other leads, too). IMP is significantly lower in the CapSure 5026 lead compared to 1010 T lead. EC does not differ significantly during chronic stimulation in spite of the best possible programming of pulse amplitude and duration. No significant changes of IRW were observed. Unipolar versus bipolar stimulation shows significantly lower STH, CRP, and IMP, differences of EC and IRW were insignificant. In conclusion, the addition of steroid in membrane covered carbon leads protracts the increase of STH, but does not prevent it. The CapSure 5026 lead shows advantageous stimulation characteristics, but energy consumption is not significantly reduced because of low impedance and impossibility of programming an appropriate low output in Multilog pacemakers.

Aged↗

PubMed1997

Comparison of electrical characteristics between a steroid-eluting single-pass VDD lead and a standard steroid-eluting ventricular lead. Thera Pacemaker Study Group.

Compared to regular ventricular leads, single-pass VDD leads have two additional floating electrodes proximal to the ventricular tip, which enables them to detect atrial signals. Because of the latter, VDD leads are thicker than ventricular leads, which could affect ventricular pacing. The purpose of the present study was to compare ventricular pacing of a steroid-eluting single-pass VDD lead (CapSure VDD, Medtronic; n = 107) with the same steroid-eluting regular lead (CapSure SP, Medtronic; n = 39) implanted in the ventricle; both leads were connected to the same types of pacemakers. At implantation, pacing thresholds were measured at 0.5-ms pulse duration and impedance by means with the PSA. At discharge, as well as after 1 and 3 months, pulse duration thresholds were determined at 2.5 V pulse amplitude and impedance by telemetry. At implantation, pacing thresholds and impedance were not different in the VDD (0.38 +/- 0.16 V; 691 +/- 122 omega) and ventricular lead group (0.44 +/- 0.17 V; 648 +/- 150 omega). During follow-ups, no differences in pulse duration threshold were detected between the two groups neither at discharge (VDD = 0.05 +/- 0.03 ms; ventricular 0.05 +/- 0.02 ms), nor after 1 (VDD = 0.05 +/- 0.02 ms; ventricular 0.08 +/- 0.07 ms) and 3 months (VDD = 0.06 +/- 0.03 ms; ventricular 0.09 +/- 0.10 ms). There were also no significant differences for impedance at discharge (VDD = 675 +/- 113 omega; ventricular = 594 +/- 113 omega), after 1 (VDD = 678 +/- 131 omega; ventricular = 627 +/- 112 omega) and 3 months (VDD = 652 +/- 99 omega; ventricular = 628 +/- 105 omega). Pacing thresholds and impedance were neither significantly different at implantation nor during follow-ups between patients with steroid-eluting VDD leads and patients with an equivalent ventricular lead indicating that the thicker VDD lead does not affect ventricular pacing.

Aged↗

PubMed1993

Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.

Cyclins and proto-oncogenes including c-myc have been implicated in eukaryotic cell cycle control. The role of cyclins in steroidal regulation of cell proliferation is unknown, but a role for c-myc has been suggested. This study investigated the relationship between regulation of T-47D breast cancer cell cycle progression, particularly by steroids and their antagonists, and changes in the levels of expression of these genes. Sequential induction of cyclins D1 (early G1 phase), D3, E, A (late G1-early S phase), and B1 (G2 phase) was observed following insulin stimulation of cell cycle progression in serum-free medium. Transient acceleration of G1-phase cells by progestin was also accompanied by rapid induction of cyclin D1, apparent within 2 h. This early induction of cyclin D1 and the ability of delayed administration of antiprogestin to antagonize progestin-induced increases in both cyclin D1 mRNA and the proportion of cells in S phase support a central role for cyclin D1 in mediating the mitogenic response in T-47D cells. Compatible with this hypothesis, antiestrogen treatment reduced the expression of cyclin D1 approximately 8 h before changes in cell cycle phase distribution accompanying growth inhibition. In the absence of progestin, antiprogestin treatment inhibited T-47D cell cycle progression but in contrast did not decrease cyclin D1 expression. Thus, changes in cyclin D1 gene expression are often, but not invariably, associated with changes in the rate of T-47D breast cancer cell cycle progression. However, both antiestrogen and antiprogestin depleted c-myc mRNA by > 80% within 2 h. These data suggest the involvement of both cyclin D1 and c-myc in the steroidal control of breast cancer cell cycle progression.

Breast Neoplasms↗

PubMed1993

Steroid hormones and receptors of the GABAA supramolecular complex. I. Benzodiazepine receptor level changes in some extrahypothalamic brain areas of the female rat following sex steroid treatment.

The effects of sex steroid hormones on the different receptor binding sites of the GABAA molecule remain unclear. In this report we have demonstrated, using autoradiography techniques, that the distribution pattern of the benzodiazepine receptors (a component of the GABAA molecule) in some extrahypothalamic brain regions is altered by both in vivo and in vitro sex steroid hormone treatment. In vivo administration of the sex steroids estradiol and progesterone induced a significant change in [3H]flunitrazepam (benzodiazepine agonist) binding levels in the amygdala, and cortico and posterior brain nuclei of the female rat. In fact, elevated and diminished receptor-binding levels were obtained in the corticomedial amygdala nucleus and in the pontine central gray matter respectively, following the administration of estradiol. Significant hormonal effects were also shown for animals that received only a progesterone dose, as demonstrated by the increased and decreased receptor levels in the basolateral amygdala nucleus and cortex lamina VI and in the substantia nigra pars reticulata, respectively. It was interesting, at this point, to investigate whether the hormone effects on [3H]flunitrazepam binding changes might be mediated through a GABA-dependent activity, because the benzodiazepine and GABAA receptors are coupled to a chloride ion channel in an allosteric manner. When 50 microM GABA was added to the incubation medium, substantially altered binding levels were recorded in animals that received progesterone replacement therapy only. The GABA-induced progesterone effects both increased substantially the binding levels in the oriens-pyramidalis CA1 layer of the hippocampus and in the intermediate gray layer of the superior colliculus as well as reducing receptor levels in the substantia nigra pars reticulata.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Endometrial endothelial cell steroid receptor expression and steroid effects on gene expression.

Controversy exists regarding the expression of specific steroid receptor proteins and mRNA in human microvascular endometrial endothelial cells (HEECs). Thus, we studied steroid receptor expression in early passaged HEEC cultures and freshly isolated HEECs. Analysis of estrogen receptor (ER) and progesterone receptor (PR) mRNA levels was carried out with real-time quantitative RT-PCR, and the repertoire of genes activated by their respective steroid ligands was assessed by mRNA microarray analyses of 18,400 genes and expressed sequence tags. We observed that cultured and freshly isolated HEECs each express ER-beta mRNA but not ER-alpha. In addition, PR mRNA was also detectable in both HEEC sources. Microarray analysis demonstrated that treatment of HEEC cultures with either estradiol or medroxyprogesterone acetate produced differential effects on a wide variety of genes, and cluster analysis demonstrated that many of the genes are involved in intracellular signaling and enzymatic pathways. Thus, quantitative RT-PCR and microarray analyses demonstrate that HEECs express ER-beta and PR mRNA and that gene expression by HEECs is differentially regulated by treatment with estrogen or progestin.

Cells, Cultured↗

PubMed1999

Post-ovulatory secretion of pituitary gonadotropins GtH I and GtH II in the rainbow trout (Oncorhynchus mykiss): regulation by steroids and possible role of non-steroidal gonadal factors.

In order to determine the factors of ovarian origin which can modulate the postovulatory secretion of the FSH-like gonadotropin (GtH I) and the LH-like gonadotropin (GtH II), freshly ovulated female rainbow trout were divided into two groups. In the first group the fish were stripped in order to eliminate the eggs and ovarian fluid from the body cavity, while in the second group the eggs were kept in the body cavity. Subsequently, fish from both groups were implanted with testosterone (10 mg/kg), 17beta-estradiol (10 mg/kg) or 17,20beta-ddihydroxy-4-regnen-3-one (17,20betaP) (1 mg/kg) or injected every 2 days with desteroidized ovarian fluid (1.5 ml/kg). The secretion of GtH I dramatically increased in stripped fish, reaching its maximum levels 2 weeks after ovulation. The preservation of eggs in the body cavity led to the suppression of this increase. The profiles of GtH II secretion were opposite to those encountered for GtH I because the increase of GtH II was observed only in unstripped fish. The administration of steroids showed that testosterone is able to inhibit GtH I release and stimulate that of GtH II in stripped fish, having no effect on the release of these gonadotropins in non-stripped animals. 17beta-Estradiol failed to modify GtH I secretion, however it decreased the release of GtH II in fish containing retained eggs in the body cavity. 17,20betaP had a delayed stimulating influence on GtH I release in unstripped fish. Finally, multiple injections of desteroidized ovarian fluid into stripped fish led to a significant decrease of GtH I release and to an increase of GtH II secretion. This study demonstrates that factors, which are present in ovarian fluid, modulate the post-ovulatory secretion of both gonadotropins--their net action is negative on GtH I and positive on GtH II. Among the steroids, testosterone is of major importance, being able to inhibit GtH I release and to stimulate that of GtH II. We also show that non-steroidal factors present in the ovarian fluid can influence the release of both gonadotropins, which indirectly supports the previous findings about the existence of inhibin/activin-like factors in fish.

Animals↗

PubMed2001

The steroid receptor antagonists RU40555 and RU486 activate glucocorticoid receptor translocation and are not excreted by the steroid hormones transporter in L929 cells.

RU40555 is a recently available glucocorticoid receptor (GR) antagonist that differs from RU486 by a methyl radical. We have used the mouse fibroblast cell line L929 to study the in vitro effects of RU40555 on GR translocation and function and on the membrane steroid hormones transporter. The results showed that: 1) RU40555 competed for the binding of labelled dexamethasone (Dex) with a K(i) of 2.4 nM; 2) both RU40555 and RU486 were equally potent inhibitors of Dex-induced GR-mediated gene transcription; 3) maximum GR translocation induced by micromolar concentrations of Dex and the GR antagonists was approximately 30-55% loss in the cytoplasmic GR and approximately 40-90% increase in the nuclear GR (assessed by GR immunostaining in cytoplasm and nucleus and western blots of immunoprecipitated GR protein in cytosolic and nuclear fractions) and was similar for the two antagonists; 4) at nanomolar concentrations, RU40555 and RU486 induced more GR translocation than Dex (assessed by [(3)H]Dex binding and western blot of immunoreactive GR in the same cytosolic homogenates); 5) blocking the steroids membrane transporter with verapamil (100 microM) in the presence of Dex (10 nM) increased GR translocation to levels similar to those induced by RU40555 (10 nM) and RU486 (10 nM) alone; 6) verapamil did not affect GR translocation in the presence of RU40555 or RU486. These data demonstrate similar quantitative effects on GR translocation by RU486 and the new GR antagonist, RU40555. Moreover, RU40555, like RU486, is an effective GR antagonist. Finally, there is no evidence that the intracellular concentrations of RU40555 or RU486 are regulated by the steroids membrane transporter in L929 cells.

Analysis of Variance↗

PubMed2005

Non-steroidal steroid receptor modulators.

The last ten years much attention has been focused on the finding of non-steroidal ligands for steroidal nuclear receptors for reasons such as diminishing cross-reactivity to eliminate side effect profiles, changing physicochemical properties which might cause different tissue distribution profiles and altering binding modes which influence the binding of cofactors. Compounds with a selective functionality profile are referred to as selective nuclear receptor modulators (e.g., SARMs or SPRMs). In the following paragraphs non-steroidal ligands which have full or partial agonistic activity will be described for the following receptors: PR, GR, AR, LXR and FXR.

Androgen Receptor Antagonists↗

PubMed1997

Inhibition and inactivation of equine aromatase by steroidal and non-steroidal compounds. A comparison with human aromatase inhibition.

In order to approach the detailed structure-function relationships of aromatase, we studied the inhibitory and inactivatory potencies of several steroidal androstenedione analogues (1: 4-hydroxyandrostenedione, 2: 4-acetoxyandrostenedione and 3: 7 alpha-(4'-amino)phenylthio-4-androstene-3, 17-dione) and non-steroidal imidazole derivatives (4: ketoconazole, 5: miconazole and 6: fadrozole) on equine aromatase in placental microsomes, a well established mammalian model. Human placental microsomes and the purified enzyme from equine testis were also used to compare inhibition by 1 and 2. In equine microsomes, all compounds tested exhibited a competitive inhibition, with Ki values of 4.1, 26 and 1.8 nM for 1, 2 and 3, and of 2400, 1.4 and 4 nM for 4, 5, and 6, respectively. The Km for androstenedione, the substrate mainly used in these studies, was 1.8 +/- 0.13 nM. The three non-steroidal derivatives did not inactivate equine aromatase, but 1 and 2 acted as comparable inactivators to a much higher degree than 3. Compound 1 inhibited in a similar manner (89-94%) purified or equine and human microsomal aromatases, whereas 2 inhibited microsomal aromatase more efficiently in the horse than in man (92% and 33% inhibition, respectively). There was only a 40% inhibition with 2 on the purified equine enzyme, which is no more in the natural membrane environment. The comparisons between equine and human microsomal aromatases allow precise functional and structural differences to be observed with these enzymes.

Androstenedione↗

PubMed1976

Steroids and hematopoiesis. III. The response of granulocytic and erythroid colony-forming cells to steroids of different classes.

Selected androgenic and nonandrogenic steroids enhance in vitro granulocytic and erythroid colony formation by mouse marrow cells, but do so by influencing either different target cells or cells in different states of cell cycle. Etiocholanolone, a naturally occurring nonandrogenic testosterone metabolite, permits cells not in active cycle to respond to colony-stimulating factor or erythropoietin. Fluoxymesterone, a synthetic androgen, appears to enhance colony growth by increasing the responsiveness of target cells to tropic stimuli. The majority of cells responding to this androgen are in active DNA synthesis. Direct comparison, however, of etiocholanolone-dependent erythroid or granulocytic colony-forming cells demonstrates nonidentity of the target cells. Thus colony-forming units responding to different classes of steroids are in different states of cell cycle and are physically separable. The enhancement of the in vitro response of colony-forming cells to regulating hormones by steroids such as etiocholanolane suggests a mechanism by which such agents may be therapeutically effective in certain cases of marrow failure in man.

Animals↗

PubMed1975

Steroid-protein interactions. Stopped flow fluorescence studies of the interaction between steroid hormones and progesterone-binding globulin.

Stopped flow fluorometry, measuring changes in the intrinsic fluorescence of progesterone-binding globulin (PBG), was used to determine the association and dissociation rates of the interaction of PBG with seven delta4-3-ketosteroids. The rates of formation and dissociation of the PBG-progesterone complex were measured as a function of concentration and temperature. At 20 degrees, kon = 8.7 X 10(7) M-1 S-1 and koff = 0.060 S-1. The association rate constants for progesterone, deoxycorticosterone, testosterone, testosterone acetate, and medrogestone were found to be the same within experimental error. The different affinities of PBG for these steroids result from the dissociation rate constants of the steroids which ranged from 0.43 S-1 for testosterone to 0.024 S-1 for medrogestone. Two corticosteroids, corticosterone and cortisol, were both bound somewhat more slowly (approximately 5 X 10(7) M-1 S-1). Reflecting their very low affinity for PBG both steroids dissociate very rapidly: corticosterone at 1.4 S-1 and cortisol at 90 S-1. The ratio of association to dissociation rate constants gave affinity constants in agreement with independently determined constants.

Animals↗