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PubMed2005

Enzymic conversion of 3beta-hydroxy-5-ene-steroids and their sulfates to 3-oxo-4-ene-steroids for increasing sensitivity in LC-APCI-MS.

A method of increasing the sensitivity of 3beta-hydroxy-5-ene (Delta5)-steroids in liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) based on the structural conversion by cholesterol oxidase (ChO) was demonstrated. The Delta5-steroids were rapidly converted to their 3-oxo-4-ene (Delta4)-forms by the treatment with ChO and the obtained Delta4-forms provided 3-14-fold higher sensitivity compared to intact steroids in the positive-APCI-MS. This enzymic conversion method was also applied to the sulfated conjugates of Delta5-steroids after solvolysis. The method enabled the detection of trace levels of dehydroepiandrosterone and androstenediol 3-sulfate in human serum, which could not be detected by the usual LC-MS.

Androstenedione↗
PubMed2004

Steroids, neuroactive steroids and neurosteroids in psychopathology.

The term "neurosteroid" (NS) was introduced by Baulieu in 1981 to name a steroid hormone, dehydroepiandrosterone sulfate (DHEAS), that was found at high levels in the brain long after gonadectomy and adrenalectomy, and shown later to be synthetized by the brain. Later, androstenedione, pregnenolone and their sulfates and lipid derivatives as well as tetrahydrometabolites of progesterone (P) and deoxycorticosterone (DOC) were identified as neurosteroids. The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. NASs bind and modulate different types of membrane receptors. The GABA and sigma receptor complexes have been the most extensively studied, while glycine-activated chloride channels, nicotinic acetylcholine receptors, voltage-activated calcium channels, although less explored, are also modulated by NASs. Within the glutamate receptor family, N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors have also been demonstrated to be a target for steroid modulation. Besides their membrane effects, once inside the neuron oxidation of Ring A reduced pregnanes, THP and THDOC, bind to the progesterone intracellular receptor and regulate gene expression through this path. The involvement of NASs on depression syndromes, anxiety disorders, stress responses to different stress stimuli, memory processes and related phenomena such as long-term potentiation are reviewed and critically evaluated. The importance of context for the interpretation of behavioral effects of hormones as well as for hormonal levels in body fluids is emphasized. Some suggestions for further research are given.

Animals↗
PubMed2002

Seasonal changes in plasma steroid levels in Indian major carp Labeo rohita: influence of homologous pituitary extract on steroid production and development of oocyte maturational competence.

Circannual variations in plasma levels of testosterone (T), 17beta-estradiol (E(2)), and 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (DHP) as well as seasonal fluctuations in ovarian steroid synthetic potential were observed in Indian major carp, Labeo rohita. A study was also conducted to examine the mechanism of the development of gonadotropin-induced maturational competence in oocytes of this fish. The present study recorded the lowest values of plasma E(2) and T in L. rohita during the period from October to January. A mild increase in the levels of these steroids observed in February was followed by their rapid rise reaching peak values in April, when the ovary contained mostly the vitellogenic follicles. In the month of May, as the postvitellogenic follicles predominated in the ovary, there was a decline in plasma concentrations of both T and E(2). Low levels of these steroids in plasma remained until January, except a small elevation detectable during June and July (spawning stage). DHP was not detected in the plasma of this fish collected during the period from August to March. Existence of DHP was first recorded in blood in the month of April (vitellogenic stage) and it quickly reached the peak value in May (postvitellogenic stage), followed by a sudden decline in the month of June. Under stimulation of fish pituitary extract (FPE), as a source of gonadotropin, in vitro production of E(2) and T by the vitellogenic follicles was shown to be highest compared to their production rate in other stages, while the postvitellogenic follicles recorded the highest rate of DHP synthesis. Acquisition of oocyte maturational competence (OMC) was shown to develop either by priming the vitellogenic stage fish with a single dose of FPE or by in vitro addition of FPE in culture. In vitro treatment of trilostane, an inhibitor of 3beta-HSD, blocked the FPE-stimulated steroid production but not the development of OMC. Presence of cycloheximide and actinomycin D in the incubation was shown to inhibit FPE-induced development of OMC, indicating the requirement of de novo protein synthesis for this process.

Animals↗
PubMed2003

Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results.

We conducted a retrospective analysis of all allogeneic stem cell transplantation (ASCT) patients started on extracorporeal photopheresis (ECP) for the management of steroid-dependent (SD) or steroid-refractory (SR) cutaneous chronic graft-versus-host disease (cGVHD) following ASCT during a 36-month period (9/98-8/01). Only SD or SR patients who were treated by ECP after day 100 and who received at least 4 weeks of ECP were considered evaluable for this analysis. Out of 64 ASCT patients reviewed, 32 patients met the inclusion criteria. All 32 patients had been previously treated with systemic corticosteroids with 11 (34%) being SR and 21 (66%) SD. Cutaneous cGVHD was extensive in 28 patients (88%) and was accompanied by visceral (hepatic, gastrointestinal) cGVHD in 23 patients (72%). The 32 evaluated patients had received a median of three prior therapies before ECP, most commonly systemic corticosteroids, tacrolimus, and mycophenolate mofetil. Patients received a median of 36 ECP sessions (range 12-98) over a median of 5.3 months (range 1-28), with a median of six sessions per month. The complete response (CR) rate was 22% (n=7) and the partial response rate was 34% (n=11). In all, 28 patients were on systemic corticosteroid therapy at ECP initiation and 18 patients achieved 50% dose reduction while on ECP, yielding a 64% steroid-sparing response rate. Of seven CRs, five are ongoing. A total of 11 (34%) patients have died after ECP, with all cases due to visceral cGVHD or cGVHD-related infectious complications. All 21 surviving patients remain on at least some immunosuppressive cGVHD therapy (including ECP in eight). Overall, ECP displays a substantial response rate and, in particular, steroid-sparing activity in SR/SD extensive cutaneous cGVHD. However, most patients continue to require at least some chronic therapy and cGVHD-related morbidity and mortality remain high.

Adolescent↗
PubMed2004

Intra-arterial steroid-injection therapy for steroid-refractory acute graft-versus-host disease with the evaluation of angiography.

We treated three patients with steroid-refractory acute graft-versus-host disease (aGVHD) with intra-arterial steroid-injection therapy (IAST). Two patients with gut aGVHD received IAST into both superior and inferior mesenteric arteries, while one patient with liver aGVHD received IAST into the proper hepatic artery. The volume of stools and the bilirubin level improved soon after IAST. Angiography of the superior and inferior mesenteric arteries was performed in the two patients with steroid-refractory gut aGVHD, and identical abnormal findings were obtained. IAST might be an earlier option for steroid-refractory aGVHD.

Acute Disease↗
PubMed1993

Site-directed mutagenesis of mouse steroid 7 alpha-hydroxylase (cytochrome P-450(7) alpha): role of residue-209 in determining steroid-cytochrome P-450 interaction.

We have cloned a cDNA encoding mouse steroid 7 alpha-hydroxylase P450(7) alpha (cytochrome P-450(7) alpha) and expressed it in Saccharomyces cerevisiae. Mouse P450(7) alpha is 70% identical in its amino acid sequence with the mouse steroid 15 alpha-hydroxylase P450(15) alpha (2A4). The Leu at position 209 of P450(15) alpha is the most important residue to determine the steroid hydroxylase activity of the P450 [Lindberg and Negishi (1989) Nature (London) 339, 632-634]. The P450(7) alpha contains Asn at the position corresponding to the Leu-209 of P450(15) alpha, although both P450s hydroxylate testosterone. The CO-reduced P450(7) alpha complex is unstable, so that it is quickly converted into the inactive P420, whereas the P450(15) alpha is very stable. The P450(7) alpha, however, is stabilized either by addition of testosterone or by a mutation of Asn-209 to Leu. The mutant P450(7) alpha displays a 17-fold lower Vmax. value than the wild-type enzyme. Unexpectedly, it also has 3-fold lower Km and Kd values. Residue 209 in P450(7) alpha, therefore, appears to be located at a critical site of the haem-substrate-binding pocket. Corticosterone inhibits the testosterone 7 alpha-hydroxylase activity of the wild-type P450(7) alpha, whereas it does not inhibit the mutant P450(7) alpha. Conversely, the P450(15) alpha activity becomes inhibited by corticosterone upon the replacement of Leu-209 by Asn. In addition, this mutation increases the corticosterone 15 alpha-hydroxylase activity of P450(15) alpha at least 20-fold. Whereas the inhibition by corticosterone depends on the presence of Asn at position 209, deoxycorticosterone inhibits the activities of the P450s regardless of the type of residue at 209. The results indicate, therefore, that the identity of residue 209 determines the affinity as well as specificity of steroid binding to both P450(7) alpha and P450(15) alpha.

Amino Acid Sequence↗
PubMed2005

The association of endogenous sex steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study.

Mammographic density is an independent risk factor for breast cancer. In postmenopausal women, higher levels of endogenous sex steroids are associated with an increased risk of breast cancer. Limited prior data suggest that endogenous sex steroids either are not associated (total estradiol and progesterone) or are negatively associated (free estradiol) with higher mammographic density. To analyze the associations between endogenous sex steroids and mammographic density, the authors conducted a 1998-2005 cross-sectional analysis of baseline clinical trial data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial for US women who had not used hormone therapy for at least 3.1 months prior to baseline. In models adjusted for age, body mass index, parity, prior use of hormone therapy, time since last use of hormone therapy, and the interaction between prior hormone therapy use and time since last hormone therapy use, higher levels of estrone (beta = 0.0013, p = 0.014), estradiol (beta = 0.0009, p = 0.009), and bioavailable estradiol (beta = 0.0021, p = 0.018) were statistically significantly related to greater mammographic density. (Beta coefficients express the increment in mammographic density per-unit increment (pg/ml) of each hormone.) These results suggest that some sex steroids may increase the risk of breast cancer by stimulating breast epithelial or stromal proliferation, which appears on a mammogram as higher density.

Breast↗
PubMed2005

The impact on health-related quality of life from non-steroidal anti-inflammatory drugs, methotrexate, or steroids in treatment for juvenile idiopathic arthritis.

OBJECTIVE: To assess and compare the impact of medication treatments on health-related quality of life (HRQOL), family function, and medical status in children with juvenile idiopathic arthritis (JIA). METHODS: Fifty-seven children diagnosed with JIA were assessed by a pediatric rheumatologist and placed into one of three treatment groups: (1) non-steroidal anti-inflammatory; (2) methotrexate; or (3) steroids via IV methylprednisolone. Questionnaires were administered at baseline and 4-month follow-up. The attending pediatric rheumatologist provided additional medical information. RESULTS: Data document the impact of JIA on HRQOL, particularly on physical and pain domains. Steroid patients experienced improved HRQOL at follow-up relative to other groups, despite reporting more problems with side effects. CONCLUSION: These results demonstrate positive benefits of steroids in treating JIA children, despite the greatest incidence of adverse side effects.

Adolescent↗
PubMed1986

Separate neural systems mediate the steroid-dependent and steroid-independent suppression of tonic luteinizing hormone secretion in the anestrous ewe.

In the ewe, two types of seasonal fluctuations in secretion of tonic luteinizing hormone (LH) have been described: a steroid-dependent change whereby estradiol gains the capacity to suppress LH pulse frequency in anestrus, and a steroid-independent decrease in pulse frequency in ovariectomized animals during anestrus. We have proposed that the former reflects activation, in anestrus, of estradiol-sensitive catecholaminergic neurons that inhibit gonadotropin-releasing hormone (GnRH). Three results reported here support this hypothesis: dopaminergic (pimozide) and alpha-adrenergic (phenoxybenzamine) antagonists increased LH in intact anestrous ewes without altering pituitary responses to GnRH; other dopaminergic (fluphenazine) and alpha-adrenergic (dibenamine) antagonists also increased LH in anestrus; agonists for dopaminergic (apomorphine) and alpha-adrenergic (clonidine) receptors suppressed LH secretion in both seasons, suggesting that the appropriate receptors are present in breeding-season ewes. In contrast, catecholamines do not appear to mediate the steroid-independent suppression of pulse frequency; neither pimozide nor phenoxybenzamine increased LH pulse frequency in ovariectomized ewes during anestrus. When antagonists for 6 other neurotransmitter receptors (muscarinic and nicotinic cholinergic, GABAnergic, serotonergic, opioid, and beta-adrenergic) were tested in anestrus, only cyproheptadine, the serotonergic antagonist, increased pulse frequency in ovariectomized ewes. Cyproheptadine had no effect on frequency during the breeding season. On the basis of these results, we propose that the steroid-dependent and -independent actions of anestrous photoperiod occur via catecholaminergic and serotonergic neurons, respectively.

Anestrus↗
PubMed1996

In vitro chemotherapy of steroid receptor positive human meningioma low-passage primary cultures with nitrosourea-methionine-steroid conjugates.

The antiproliferative activity of two nitrosourea-methionine-steroid conjugates, N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl] (CNC)-L-methionine-testosterone-17-ester and CNC-L-methionine-dihydrotestosterone-17-ester, was investigated in two meningioma low-passage primary cultures that had been derived from human meningiomas and characterized with regard to proliferation pattern and progesterone receptor content. Treatment was given over 4 days. Cytotoxicity (concentrations investigated: 50, 100, and 200 microM) was compared with the effects of the equimolar mixtures of CNC-Met plus steroid. The steroid-linked nitrosoureas were superior to their unlinked components. CNC-Met itself displayed no or marginal activity, whereas the steroid component displayed significant activity.

Antineoplastic Agents↗
PubMed2006

Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up.

OBJECTIVE: We and others have reported the use of tacrolimus in refractory inflammatory bowel disease (IBD). Little is known about its long-term efficacy and safety. METHODS: In this retrospective, observational single center study the charts of 53 adult patients with steroid-dependent (n = 18) or steroid-refractory (n = 35) IBD, Crohn's disease (CD) (n = 11), ulcerative colitis (UC) (n = 40), or pouchitis (PC) (n = 2) were reviewed. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in all and initially intravenously in 2 patients (0.01 mg/kg body weight per day), aiming for serum trough levels of 4-8 ng/mL. Forty-one of 53 (77.1%) patients were receiving concomitant azathioprine. The mean treatment duration was 25.2 +/- 4.6 SD months (0.43-164 months). Patients were followed for a mean of 39 +/- 4.1 SD months (5-164 months). Response was evaluated using a modified clinical activity index (M-CAI). RESULTS: Thirty-one UC (78%), 10 CD (90.1%), and both PC (100%) patients experienced an immediate clinical response or went into remission at 30 days. A statistically significant drop on the M-CAI was documented for UC and CD patients. Nine UC patients (22.5%) underwent colectomy between 1.6 and 41.3 months following initiation. Mean colectomy-free survival was 104.8 +/- 15.5 (95% CI 74.4-135.2) months (limited to 164.4 months). Cumulative colectomy-free survival was estimated 56.5% at 43.8 months. Steroids were reduced or discontinued in 40 of 45 UC and CD patients (90%) taking steroids. Side effects included a temporary rise of creatinine (n = 4, 7.6%), tremor or paresthesias (n = 5, 9.4%), hyperkalemia (n = 1, 1.9%), hypertension (n = 1, 1.9%), and opportunistic infections (n = 2, 3.8%). CONCLUSION: Long-term tacrolimus therapy appears safe and effective in refractory IBD.

Adult↗
PubMed2006

Enantiomers of neuroactive steroids support a specific interaction with the GABA-C receptor as the mechanism of steroid action.

Neuroactive steroids can either potentiate or inhibit a variety of membrane channels. Most studies have suggested that the effects are mediated by specific association of the steroid with the affected channel. However, a recent study of the rho1 (GABA-C) receptor (Mol Pharmacol 66:56-69, 2004) concluded that the actions were consistent with an action of the steroid in the lipid bilayer to alter the lateral pressure profile in the membrane. The enantiomers of an optically active compound are expected to have identical physical properties, including interactions with hydrophobic portions of the cell membrane. We have used two pairs of enantiomers (pregnanolone and ent-pregnanolone, allopregnanolone and ent-allopregnanolone) and show that the ability to potentiate (allopregnanolone) or inhibit (pregnanolone) the rho1 receptor is enantioselective. Therefore, these results strongly suggest that the actions of these neuroactive steroids are mediated by interactions with chiral regions of the target protein, rather than by a change in membrane properties (including lateral pressure).

Animals↗
PubMed2006

Urinary proteome of steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome of childhood.

The response to steroid therapy is used to characterize the idiopathic nephrotic syndrome (INS) of childhood as either steroid-sensitive (SSNS) or steroid-resistant (SRNS), a classification with a better prognostic capability than renal biopsy. The majority (approximately 80%) of INS is due to minimal change disease but the percentage of focal and segmental glomerulosclerosis is increasing. We applied a new technological platform to examine the urine proteome to determine if different urinary protein excretion profiles could differentiate patients with SSNS from those with SRNS. Twenty-five patients with INS and 17 control patients were studied. Mid-stream urines were analyzed using surface enhanced laser desorption and ionization mass spectrometry(SELDI-MS). Data were analyzed using multiple bioinformatic techniques. Patient classification was performed using Biomarker Pattern Software and a generalized form of Adaboost and predictive models were generated using a supervised algorithm with cross-validation. Urinary proteomic data distinguished INS patients from control patients, irrespective of steroid response, with a sensitivity of 92.3%, specificity of 93.7%, positive predictive value of 96% and a negative predictive value of 88.2%. Classification of patients as SSNS or SRNS was 100%. A protein of mass 4,144 daltons was identified as the single most important classifier in distinguishing SSNS from SRNS. SELDI-MS combined with bioinformatics can identify different proteomic patterns in INS. Characterization of the proteins of interest identified by this proteomic approach with prospective clinical validation may yield a valuable clinical tool for the non-invasive prediction of treatment response and prognosis.

Adolescent↗
PubMed1997

Glucocorticoids and anabolic/androgenic steroids inhibit the synthesis of GABAergic steroids in rat cortex.

Cerebral side effects of therapy with glucocorticoids include mental alterations and behavioral disturbances such as nervousness, insomnia, changes in mood or psychological state and psychopathies of manic-depressive or schizophrenic type. We have investigated the effects of glucocorticoids, anabolic/androgenic steroids and the 5-alpha-reductase inhibitor N,N-bis (1-methyl)-3-oxo-4-aza-5-alpha-androstane-17-beta-carboxamide (1-MAC) on the synthesis of the GABAergic steroids 5-alpha-pregnane-3.20-dione (5-alpha-dihydroprogesterone) and 5-alpha-pregnane-3-alpha-ol-20-one (5-alpha-tetrahydroprogesterone) in rat cortex in vitro. We found potent inhibition of progesterone-3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSDH) by prednisone, prednisolone, dexamethasone and fluocortolone. Inhibition of progesterone 5-alpha-reductase by glucocorticoids was not found. In addition, inhibition of 3-alpha-HSDH and 5-alpha-reductase by androgenic/anabolic steroids and inhibition of 5-alpha-reductase by 1-MAC could be demonstrated. The inhibition of progesterone metabolism in the cerebral cortex by exogenous steroids might lead to altered neuronal activity. We conclude that this mechanism could induce the cerebral side effects, such as mental modifications and behavioral disturbances, of the drugs investigated.

Animals↗
PubMed1979

Interrelationships of circulating maternal steroid concentrations in third trimester pregnancies. II. C18 and C19 steroids: estradiol, estriol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, delta 5-androstenediol, delta 4-androstenedione, testosterone, and dihydrotestosterone.

This report describes aggregate time trend effects of advancing gestational age on circulating maternal concentrations of 17beta-estradiol (E2), estriol (E3), dehydroepiandrosterone (D), dehydroepiandrosterone sulfate (D-S), delta 5-androstenediol (delta 5 diol), delta 4-androstenedione (delta 4 A), testosterone (T), and dihydrotestosterone (DHT) in a sequential series of 155 blood samples obtained from 19 normal pregnant women ranging from 26-40 weeks gestational age. Only E2, E3, and D-S show aggregate time trend effects. Log (E2) plots as a linear positive sloping curve from 26-40 weeks. Log (E3) plots as a positive sloping curve that is significantly steeper than log (E2) (P less than 0.05). Log (D-S) plots into a negative sloping curve which mirrors the pattern for log (E2) but cannot be statistically associated with log (E2) except for the opposite sign of their slopes, which are both significantly different from a zero slope (P less than 0.05). delta 4 A, T, DHT, delta 5 diol, and D show no aggregate time trends; however wide, comoving undulations for delta 4 A, T, DHT, and delta 5 diol between 26-28 and 38-40 weeks are confirmed in time by comparison of log mean plots and in magnitude by regressing the C19 steroids on one another. D shows virtually no association with the other C19 steroids. All C19 steroids, except for T, circulate at nonpregnant concentrations, implying that there is little placental secretion of these steroids into the maternal circulation.

Androgens↗
PubMed1996

Steroid hormone-induced expression of the chicken ovalbumin gene and the levels of nuclear steroid hormone receptors in chick oviduct.

The induction of the chicken ovalbumin (OVA) gene by different classes of steroid hormones and the mRNA levels of estrogen (ER), progesterone (PR), and glucocorticoid (GR) receptors were studied in chick oviducts. Combined treatment with two hormones increased the induction of the OVA gene more than single treatment, when the levels of OVA mRNA were measured with Slot blot analysis. To discover the role of nuclear steroid hormone receptors as transcriptional factors in the OVA gene induction, we analyzed the levels of ER (with RT-PCR), PR, and GR mRNAs (with Northern blotting). The level of PR mRNA was increased only by estrogen, while no steroid hormone affected the levels of ER and GR mRNAs. Thus, these findings show that the levels of nuclear receptors do not reflect the OVA mRNA level in the oviduct of steroid hormone-treated chicks.

Animals↗
PubMed2004

Expression of enzyme associated with steroid hormone synthesis and local production of steroid hormone in endometrial carcinoma cells.

Endometrial carcinoma is a common malignancy of the genital tract. In the present study, we examined the expression of human steroidogenic acute regulatory (StAR) protein, P450 side-chain cleavage enzyme (P450 scc), 17alpha-hydroxylase/17,20-desmolase (P45017alpha) and aromatase (P450 arom) in endometrial carcinoma cells to clarify the ability of these cells to produce steroid hormones. The results of RT-PCR analysis showed that StAR, P450 scc and P45017alpha genes were expressed in endometrial carcinoma cells. To examine the protein expression of StAR and P450 scc, we performed Western blotting using extracts from carcinoma cells. StAR protein and P450 scc were detected in both HHUA and HOUA-1 cells. The production of pregnenolone in HHUA cells increased 2.4-fold with transfection of a StAR expression vector and 4.3-fold with transfection of an F2 side-chain cleavage system. The RT-PCR product of 3beta-hydroxysteroid dehydrogenase was present in endometrial carcinoma cells. In endometrial carcinoma cells, the production of progesterone also increased with over-expression of StAR and the F2 system. Results of steroid metabolic assays showed that endometrial carcinoma cells produced not only 17alpha-hydroxyprogesterone but also androstenedione. Endometrial carcinoma cells express enzymes that are associated with the production of steroid hormones. Locally produced steroid hormones may have effects on tumor proliferation and tumorigenesis.

17-alpha-Hydroxyprogesterone↗
PubMed1986

Hormonal regulation of rat liver microsomal enzymes. Role of gonadal steroids in programming, maintenance, and suppression of delta 4-steroid 5 alpha-reductase, flavin-containing monooxygenase, and sex-specific cytochromes P-450.

Neonatal gonadectomy studies and hormonal replacement regimens were employed to characterize the regulation of delta 4-steroid 5 alpha-reductase, microsomal flavin-containing monooxygenase, and several forms of rat hepatic microsomal cytochrome P-450, including three that are sexually differentiated. Rats of both sexes that had been gonadectomized at birth were either untreated or were administered testosterone propionate or estradiol benzoate neonatally (subcutaneous injection on days 1 and 3 of life), postpubertally (an implant of a hormone-packed capsule at 5 weeks of age), or both neonatally and postpubertally. At the age of 10 weeks, all rats were killed, and several liver microsomal enzymes were assayed using immunochemical and catalytic techniques. Expression in the 10-week-old male and female rats of two male-specific cytochrome P-450 forms, termed P-4502c/UT-A and P-4502a/PCN-E, and their associated respective 16 alpha- and 6 beta-steroid hydroxylase activities could either be imprinted (programmed) by androgen exposure during the early neonatal period or, alternatively, could be stimulated by continuous hormone treatment after the age of 5 weeks. By contrast, hepatic expression of two female-specific enzymes, P-4502d/UT-1 and delta 4-steroid 5 alpha-reductase, was only partially dependent on estradiol; birth-gonadectomized rats expressed as much as 30-50% of the enzyme levels present in untreated adult females. Expression of both female-specific enzymes was fully suppressed upon postpubertal exposure to testosterone. In another study, birth sham-operated female rats were administered testosterone using the same regimens described above for the birth-gonadectomized rats. Although neonatal testosterone treatment alone did not affect the expression in these females of the four sex-specific enzymes examined in this study, it did enhance significantly the masculinization effected by postpubertal androgen exposure. This resulted in expression of the male-specific enzymes P-4502c/UT-A and P-4502a/PCN-E in these females at levels comparable to those found in adult males, while simultaneously suppressing the two female-specific enzymes, P-4502d/UT-I and delta 4-steroid 5 alpha-reductase, by approximately 70-75% to levels characteristic of prepubertal rats of either sex. The levels of another microsomal enzyme, flavin-containing monooxygenase, were also measured and found to be regulated by testosterone, but the ontogenic profiles and the effects of gonadectomy and hormone replacement indicated clear differences in its regulation when compared to the other male-specific enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗