Dinucleotide repeat polymorphisms in the HSD3B2 gene.
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3-Hydroxysteroid Dehydrogenases↗
Biomedical subjects
F Labrie
Publications and source records attributed to F Labrie.
Functional characterization of the novel L108W and P186L mutations detected in the type II 3 beta-hydroxysteroid dehydrogenase gene of a male pseudohermaphrodite with congenital adrenal hyperplasia.
Two isoenzymes are responsible for 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) activity in humans. We analyzed the structure of types I and II 3 beta-HSD genes in a male pseudohermaphrodite suffering from a severe salt-losing form of congenital adrenal hyperplasia. We did not detect any mutation in the type I 3 beta-HSD gene, but we found two different missense mutations in exon IV of the type II 3 beta-HSD gene of the patient; a conversion of codon Leu108 into a Trp (L108W) inherited from his mother and a conversion of codon Pro186 into a Leu (P186L) inherited from his father. We assessed the effect of the L108W and P186L mutations on 3 beta-HSD activity by in vitro analysis of mutant enzymes expressed in heterologous COS-1 cells. Using homogenates from transfected cells, the Km values for PREG were 7 +/- 2 and 8 +/- 2 microM for the recombinant L108W and P186L enzymes, respectively, compared with 2.2 +/- 0.2 microM for the normal type II 3 beta-HSD enzyme. Moreover, Km values for NAD+ were much higher for the L108W and P186L proteins, being 678 +/- 166 and 920 +/- 351 microM, respectively, compared with 24 +/- 3 microM for the normal type II 3 beta-HSD enzyme. Vmax values for PREG and NAD+ were lower for both mutant enzymes; thus, the in vitro overall efficiency, relative to the normal enzyme, is approximate as 0.3% and 0.2% for the L108W and P186L enzymes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxysteroid Dehydrogenases↗
Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.
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Adolescent↗
Characterization, expression, and immunohistochemical localization of 5 alpha-reductase in human skin.
Human skin has been shown to contain a high level of 5 alpha-reductase activity, the enzyme that catalyses the conversion of the weak androgen testosterone into dihydrotestosterone, the most potent androgen. Because two types of 5 alpha-reductase genes have been characterized in humans, we have cloned 5 alpha-reductase cDNAs from adult human keratinocyte and skin fibroblast cDNA libraries to identify and gain better knowledge of the 5 alpha-reductase expressed in normal human skin. Nucleotide sequence analysis shows that the clones obtained correspond to the type I 5 alpha-reductase. RNase protection analysis using (poly A)+ RNA obtained from human skin and prostate also confirms that type I 5 alpha-reductase is the predominant type expressed in normal skin, whereas type II 5 alpha-reductase is the major form found in the prostate. Following polymerase chain reaction amplification of human keratinocyte and skin fibroblast cDNA, a low level of type II 5 alpha-reductase cDNA has been detected. Using antipeptide antibodies raised in rabbits against the peptide sequence covering amino acids 227 -240 to perform immunohistochemical localization of 5 alpha-reductase, we have found that 5 alpha-reductase is distributed in sweat and sebaceous glands, as well as in the epidermal cell layers, thus providing the basis for the important role of androgens in human skin and its appendages.
Base Sequence↗
Opposite effects of prolactin and corticosterone on the expression and activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase in rat skin.
In rat skin, type IV is the major 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzyme expressed. Although types I and II 3 beta-HSD mRNAs are also present in the skin, their level of expression is about two orders of magnitude lower than that of type IV. In this study, we have investigated the control of type IV 3 beta-HSD mRNA levels as well as 3 beta-HSD enzymatic activity in hypophysectomized adult rats of both sexes. Skin 3 beta-HSD activity was measured by the conversion of [14C]-dehydroepiandrosterone into [14C]-androstenedione, whereas ribonuclease protection assay using a specific type IV cRNA probe was used to assess mRNA levels. Intact male and female rats show a similar level of skin 3 beta-HSD activity, although hypophysectomy caused opposite effects, a decrease being observed in males while an increase was observed in hypophysectomized female animals. We next studied the effects of hyperprolactinemia, corticosterone and 1-thyroxine in hypophysectomized animals. L-thyroxine was found to stimulate 3 beta-HSD expression and activity in male rats whereas no significant effect was observed on the already elevated levels in hypophysectomized female rats. Corticosterone caused an inhibition of type IV 3 beta-HSD mRNA levels and activity in both male and female animals. Hyperprolactinemia achieved by pituitary implants inserted under the kidney capsule stimulated the expression of type IV mRNA as well as 3 beta-HSD enzymatic activity in hypophysectomized male and female animals. The present data demonstrate the multihormonal regulation of 3 beta-HSD/isomerase expression and activity in the rat skin.
Animals↗
Effect of estrone on the growth of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in the rat: a model of postmenopausal breast cancer.
Estradiol (E2) is well known as stimulator of the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The effect of estrone (E1), however, has not been described in this model of human breast cancer. As E1 is the predominant estrogen precursor in postmenopausal women, we have investigated the effect of this steroid and, simultaneously, the potential role of the enzyme required for interconversion of the weak estrogen E1 into the potent estrogen E2, namely 17 beta-hydroxysteroid dehydrogenase, in the growth of DMBA-induced mammary carcinoma in the rat. Treatment for 20 days of ovariectomized animals bearing DMBA-induced mammary tumors with twice daily doses of 0.375, 0.75, 1.5, and 3.0 micrograms E1 increased total tumor area by 48%, 101%, 116%, and 129%, respectively. Treatment with the highest dose of E1 increased progesterone receptor levels by 20.4- and 2.3-fold in the DMBA-induced tumors and uterus, respectively. After treatment with E1, the concentration of this steroid was similar in the serum and tumor tissue, whereas concentrations of E2 were approximately 3-fold higher in the tumor tissue compared to serum. Treatment with a 1.0-microgram dose of E1 caused a 60% increase in tumoral 17 beta-hydroxysteroid dehydrogenase activity in ovariectomized animals, thus favoring E2 formation from E1 in tumors. In addition, treatment with the 1.0-microgram dose of E1 or 0.1 microgram E2 gave similar stimulatory effects on tumor growth and uterine weight in ovariectomized animals; the values were comparable to those found in intact animals. The present data indicate that ovariectomized rats bearing DMBA-induced mammary tumors and treated with E1 can be a useful model of postmenopausal breast cancer.
17-Hydroxysteroid Dehydrogenases↗
Multihormonal regulation of dehydroepiandrosterone sulfotransferase messenger ribonucleic acid levels in adult rat liver.
Hydroxysteroid sulfotransferases (DHEA ST) represent a family of enzymes that catalyze the conversion of dehydroepiandrosterone and other 3 beta-hydroxysteroids into more hydrophilic water-soluble sulfate conjugates. The present study was designed to investigate the regulation of hepatic DHEA ST expression by sex steroids and pituitary hormones, namely GH and PRL, in both male and female rats. DHEA ST mRNA levels were measured by dot blot hybridization using a 332-basepair fragment of rat DHEA ST (ST-20) cDNA as a probe. Hepatic DHEA ST mRNA levels were 2.8-fold higher in females than in males. A 15-day gonadectomy did not affect DHEA ST mRNA levels in the male liver; in females, a 35% decrease in DHEA ST mRNA levels compared with those in intact controls was observed. Administration of 17 beta-estradiol (E2; 1 microgram/kg, twice daily) alone had no effect on the accumulation of DHEA ST mRNA, but the same treatment completely reversed the marked inhibitory effect of dihydrotestosterone (DHT; 400 micrograms/kg, twice daily) on this parameter in both gonadectomized males and females. In female rats, 24-day hypophysectomy (HYPOX) decreased DHEA ST mRNA levels by 62%, whereas no change was detected in males. In HYPOX animals, treatment with E2 or DHT for 9 days starting 15 days after surgery had no effect on hepatic DHEA ST mRNA levels in rats of both sexes. In intact males, the presence of pituitary implants under the kidney capsule increased DHEA ST mRNA levels by 190% (above the control), which reached levels similar to those in intact females, whereas pituitary implants exerted no effect on this parameter in intact females. However, treatment of HYPOX rats with ovine PRL (oPRL; 4 mg/kg, twice daily) had no significant effect on the accumulation of DHEA ST mRNA in male and female animals. In HYPOX females, administration of rat GH (80 micrograms/kg, twice daily) had no effect on DHEA ST mRNA levels, whereas continuous infusion of rat GH (3.6 micrograms/h), using osmotic minipumps to mimic the female GH secretory pattern, increased this parameter by 290% (above the control value), thus completely reversing the effect of hypophysectomy. In HYPOX males, both modes of GH administration increased DHEA ST mRNA levels by 70-90% (above the control). The present study demonstrates that in both gonadectomized male and female rats, administration of E2 completely blocks the marked inhibitory effect of DHT on hepatic DHEA ST mRNA levels.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Plasma 3 beta-hydroxy-delta 5-steroids in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
There is little information about the plasma concentrations of 3 beta-hydroxy-delta 5-steroids (delta 5-steroids) in untreated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. To further study the delta 5 pathway, we measured plasma levels of delta 5- and delta 4-steroids in 21 adult patients with different degrees of 21-hydroxylase deficiency (11 salt-wasters, 5 simple virilizers, and 5 patients with the nonclassical form of the disease). In all patients, investigations were performed after withdrawal of steroid treatment for at least 10 days. In addition, catheterization of gonadal and adrenal veins was performed in two salt-wasting male patients displaying bilateral testicular tumors to study adrenal secretion of delta 5- and delta 4-steroids. In one of them, surgical resection of the intratesticular adrenal rests gave the opportunity to measure 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. In all untreated patients, an increase in plasma delta 4-steroids was observed. In contrast, although plasma levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not significantly modified in simple virilizers, a paradoxical decrease in all delta 5-steroids was observed in salt-wasters. Catheterization of the adrenal veins confirmed the decrease in delta 5-steroids, particularly DHEA and DHEAS. The androstenedione/DHEA ratio was increased in all patients proportionally to the severity of the disease, suggesting an increase in adrenal 3 beta HSD. In vitro analysis of 3 beta HSD activity showed a 4-fold increase in intratesticular adrenal tissue compared to that in normal adrenals. A positive correlation between the androstenedione/DHEA ratio and plasma ACTH levels was observed, suggesting a long term stimulatory effect of ACTH on 3 beta HSD. Angiotensin-II could have an additive effect on ACTH-induced 3 beta HSD activity.
Adrenal Hyperplasia, Congenital↗
Detection and functional characterization of the novel missense mutation Y254D in type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene of a female patient with nonsalt-losing 3 beta HSD deficiency.
Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta HSD) deficiency is a form of congenital adrenal hyperplasia characterized by severe impairment of steroid biosynthesis in the adrenals and gonads. To better understand the molecular basis of the phenotypic heterogeneity found in 3 beta HSD deficiency, we analyzed the structure of type I and II 3 beta HSD genes in a female patient with nonsalt-losing 3 beta HSD deficiency diagnosed at puberty. We directly sequenced DNA fragments generated by polymerase chain reaction amplification of the four exons, the exon-intron boundaries, and the 5'-flanking regions of each gene. No mutation was detected in the type I 3 beta HSD gene, which is the predominant species expressed in the placenta and peripheral tissues. We detected a novel missense mutation, Y254D, in one allele of the patient's type II 3 beta HSD gene, which is the almost exclusive type expressed in the adrenals and gonads. The influence of the Y254D mutation on enzymatic activity was assessed by analyzing the recombinant mutant enzyme generated by site-directed mutagenesis after its transient expression in COS-1 monkey kidney cells. Recombinant mutant type II 3 beta HSD enzyme carrying the Y254D substitution exhibits no detectable activity with C21 delta 5-steroid pregnenolone or C19 delta 5-steroid dehydroepiandrosterone used as substrate. The absence of restriction fragment length polymorphism by Southern blot analysis and the finding that all of the amplified DNA fragments possess the expected length suggest the absence of deletions, duplications, or re-arrangements in the other allele. A putative second mutation could be located farther than 1427 basepairs upstream of the initiation codon, thus potentially affecting the normal expression of this gene or within intronic regions, generating an alternative aberrant splicing site. These are possibilities that remain to be elucidated. The present findings, which describe the novel missense mutation Y254D in the human type II 3 beta HSD gene, provide useful information on the structure-activity relationships of the 3 beta HSD superfamily.
3-Hydroxysteroid Dehydrogenases↗
Molecular basis of congenital adrenal hyperplasia in two siblings with classical nonsalt-losing 3 beta-hydroxysteroid dehydrogenase deficiency.
We report mutations of the type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene in two siblings, male and female, with congenital adrenal hyperplasia caused by classical nonsalt-losing 3 beta HSD deficiency. During childhood, the male sibling, born with ambiguous genitalia, and the female sibling, born with normal genitalia, both manifested symptoms of mild androgen excess; both apparently had normal zona glomerulosa function. Gonadal dynamic study at puberty showed the presence of partial gonadal 3 beta HSD deficiency in both siblings despite their spontaneous pubertal maturation. The 5'-region as well as exons I-II, III, and IV and portions of the adjacent introns of the type II 3 beta HSD gene were amplified by polymerase chain reaction and sequenced. In both siblings and their mother, an identical single nucleotide substitution mutation in intron III, six bases up-stream from exon IV, was identified in one allele. This mutation, G to A at nucleotide 6651, may create a new splicing junction and affect the normal splicing of the messenger ribonucleic acid. In the other allele of both siblings, a missense mutation from GGG (Gly) to AGG (Arg) at codon 129 (G129R) in exon IV was found. We assessed the effect of the G129R missense mutation on enzymatic activity by in vitro analysis of the mutant recombinant enzyme generated by site-directed mutagenesis after its transient expression in COS-1 cells. Using homogenates from transfected cells, the G129R 3 beta HSD enzyme showed a Km value for pregnenolone of 10 +/- 2 mumol/L compared with 1.00 +/- 0.03 mumol/L for the wild-type type II 3 beta HSD enzyme. When dehydroepiandrosterone was used as substrate, the Km value for G129R3 beta HSD was 14 +/- 2 mumol/L compared with 2.1 +/- 0.2 mumol/L for the wild-type II 3 beta HSD enzyme. In addition to an apparent decrease in affinity, the G129R mutation caused a marked decrease in the apparent relative specific activity, thus leading to apparent relative specific efficiencies (relative specific activity/Km) of 2.0% and 4.7% that of the normal type II 3 beta HSD using pregnenolone or dehydroepiandrosterone as substrate, respectively. It appears likely that this low level of activity is sufficient to prevent salt loss, but it is also possible that part of the enzymatic activity comes from the putative remaining percentage of correctly spliced n6651 allele in these patients.
3-Hydroxysteroid Dehydrogenases↗
Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men.
It is well recognized that aging in men is accompanied by a decline in the serum levels of some adrenal and testicular steroids, but little or no attention has focused on the multiple steroid metabolites that are formed by steroid-converting enzymes in target tissues. In the present study, we have examined in detail the serum concentrations of a large series of adrenal and testicular steroids and their most significant metabolites produced in intracrine peripheral tissues. The serum concentrations of 26 conjugated and unconjugated C21-, C19-, and C18-steroids were measured in 2423 men aged 40-80 yr. The serum concentrations of the major circulating adrenal C19-steroids, namely dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), androst-5-ene-3 beta, 17 beta-diol and its sulfate, and androstenedione, decreased by about 60% between the ages of 40-80 yr. The small decrease in the serum concentrations of progesterone and pregnenolone in the presence of increased levels of cortisol and markedly decreased levels of DHEA, androst-5-ene-3 beta, 17 beta-diol, and their polar metabolites suggests that adrenal 17,20-lyase is particularly affected by aging. In addition to a marked decline in the serum concentrations of adrenal C19-steroids, a smaller, but significant, decrease occurred in serum testosterone. However, serum dihydrotestosterone levels remained constant, but the glucuronidated derivatives of dihydrotestosterone metabolites (androstane-3 alpha, 17 beta-diol glucuronide, androstane-3 beta, 17 beta-diol glucuronide, and androsterone glucuronide) were reduced by 45-50%, suggesting that 5 alpha-reductase activity in peripheral tissues may show a compensatory increase during aging. Analysis of the fatty acid esters of DHEA (DHEA-FA) also revealed that these nonpolar steroids markedly decrease between 40-80 yr of age, although such a decrease in DHEA-FA levels was smaller than that in DHEA and DHEA-S, suggesting that the formation of DHEA-FA may be specifically increased during aging. In summary, the present study suggests that in contrast to the marked decline in activity of steroidogenic enzymes in the adrenals and the small decrease in the testis, the activity of the steroid-converting enzymes present in peripheral tissues does not decrease during aging. In fact, the marked decrease in DHEA formation by the adrenals leads to a decrease of about 50% in total androgens in men between the ages of 40-80 yr. Such a decrease probably affects many physiological processes during aging.
Adrenal Glands↗
No evidence of mutations in the genes for type I and type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) in nonclassical 3 beta HSD deficiency.
Nonclassical 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase deficiency (NC3 beta HSDD) has been diagnosed in hyperandrogenic women with an increasing frequency during the last 14 yr. Fifteen menarcheal women with androgen excess syndrome, diagnosed with NC3 beta HSDD previously were restudied, in 12 after discontinuation of glucocorticoid treatment, in 2 patients never treated with glucocorticoids, and in 1 both before and after glucocorticoid therapy. Each of the 15 patients underwent ACTH stimulation testing, in some cases on multiple occasions. Although some (very few) patients seem to have improved with time, others remained the same or got worse. Molecular DNA analysis was also performed in 6 of the patients, using the strategy successfully used to detect point mutations in the type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene, which are responsible for classical 3 beta HSD deficiency. This strategy consists of the direct sequencing of polymerase chain reaction-amplified DNA fragments corresponding to the complete coding sequence and all intron-exon junctions and to the 5'- and 3'-noncoding region of this gene. We were unable to demonstrate any mutation of the type II 3 beta HSD gene in these 6 patients. To gain additional information about potential mutations, direct sequencing of the type I 3 beta HSD gene was also performed using this same strategy, and no mutations were found. The present study strongly suggests that unlike the salt-losing and nonsalt-losing forms of classical 3 beta HSD deficiency, NC3 beta HSDD is not due to a mutant type II 3 beta HSD enzyme. However, the possibility remains of a mutation(s) in the unsequenced regions of the type II 3 beta HSD gene or elsewhere, such as in a gene for modulatory protein, playing a specific role in the expression of the type II 3 beta HSD gene. On the other hand, knowing the multiple hormonal controls to which 3 beta HSD activity is subject, it cannot be excluded that at least in some cases, NC3 beta HSDD may be an acquired defect, the result of endogenous or environmental factors.
3-Hydroxysteroid Dehydrogenases↗
Mechanism of action and pure antiandrogenic properties of flutamide.
Although treatment of intact adult male rats with the pure antiandrogen flutamide or a luteinizing hormone-releasing hormone (LHRH) agonist alone leads to partial inhibition of ventral prostate weight, maximal inhibition is achieved by combination of the two drugs. Potentializing effects of the two compounds were observed even on prostatic ornithine decarboxylase activity. Because LHRH agonists are widely used to achieve medical castration in men treated for prostate cancer, it is of interest to observe that in the dog, known for being the best model for studies of the action of LHRH agonists, flutamide does not interfere with the potent desensitizing action of the LHRH agonist on pituitary LH secretion, thus supporting the combined use of flutamide with an LHRH agonist for maximal androgen blockade without loss of efficiency of the LHRH agonist. Because prostate cancer is known to show a high degree of heterogeneity of its sensitivity to androgens, we analyzed the effect of combined antiandrogen therapy on parameters more sensitive to androgens than ventral prostatic weight itself. In agreement with its pure antiandrogenic characteristics, flutamide alone has no stimulatory effect on the intraprostatic level of mRNA encoding the C1 or C3 component of prostatic binding protein (PBP), whereas cyproterone acetate (CPA), megestrol acetate (MEG), and, especially, medroxyprogesterone acetate (MPA) markedly stimulate PBP-C1 and PBP-C3 mRNA levels, an effect reversed by flutamide, thus further supporting the intrinsic androgenic activity of all these steroidal derivatives. Similar androgenic effects of the steroidal derivatives were observed on prostatic ornithine decarboxylase activity. Androgen-sensitive Shionogi tumor cells were then used to assess the antiandrogenic/androgenic properties of flutamide and the above-indicated steroidal derivatives. MPA, MEG, CPA as well as spironolactone-stimulated cell proliferation under both in vivo and in vitro conditions, thus illustrating the intrinsic androgenic activity of all these compounds. Flutamide was inactive by itself and reversed the stimulatory effect of all other compounds, thus indicating its pure antiandrogenic activity. Although castration reduces intraprostatic dihydrotestosterone (DHT) to undetectable levels in the rat and guinea pig, the concentration remains at about 50% of the value found in intact men after castration, thus indicating an important contribution of the adrenals to DHT in the human prostate, a finding that requires the addition of an antiandrogen to block the action of this important amount of DHT remaining after castration.
Androgen Antagonists↗
Structure and tissue-specific expression of a novel member of the rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) family. The exclusive 3 beta-HSD gene expression in the skin.
Structures of cDNA clones encoding three members of the rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) family were characterized. To search for potential new types of 3 beta-HSD, rat types I and II 3 beta-HSD cDNAs were used as probes to screen a rat genomic DNA library. Among the clones isolated, one encodes a novel predicted rat 3 beta-HSD isoenzyme, chronologically designated type IV. The corresponding full-length cDNA was thereafter isolated by selective polymerase chain reaction amplification from rat ovary and day-15 placenta cDNA libraries. The rat type IV 3 beta-HSD cDNA encodes a predicted 372-amino acid protein of 41,854 daltons, which shares 90.9, 87.9, and 78.8% sequence identity with rat types I, II, and III proteins, respectively. Ribonuclease protection assay reveals that type IV 3 beta-HSD is the sole 3 beta-HSD mRNA species detectable in the skin and represents the predominant species in the placenta while being also detectable in the ovary and, to a lower degree, in the adrenal gland. Transient expression of type IV cDNA in SW-13 cells indicates 3 beta-HSD activity similar to that of rat type I 3 beta-HSD. The presence of multiple 3 beta-HSD genes should permit differential and tissue-specific regulation of this rate-limiting enzymatic activity essential in the biosynthesis of all classes of steroid hormones in both classical steroidogenic and intracrine peripheral tissues.
Amino Acid Sequence↗
Combination therapy for prostate cancer. Endocrine and biologic basis of its choice as new standard first-line therapy.
RESULTS. All double-blind randomized and prospective clinical trials in advanced prostate cancer have shown that combination therapy using a nonsteroidal antiandrogen in association with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy has significant benefits according to all the subjective and objective parameters used, the most important being a prolongation of survival ranging from 5.4-15.0 months compared with LHRH agonists or orchiectomy alone (standard therapy). The benefits observed are probably the result of the blockade by the antiandrogenic agents of the androgens of adrenal origin, which represent, on average, 40% of the total androgens in men and which, otherwise, are left free to continue to stimulate prostate cancer after castration. These data are supported well by the demonstration of the expression of the genes encoding all enzymes required for the formation of active androgens in prostatic tissue from the inactive adrenal steroid precursors; this new specialty is called intracrinology. Both fundamental and clinical data indicate that low androgen levels cause changes in the cancer cells that lead to no or a poor response to antihormonal therapy. CONCLUSIONS. It is thus imperative that combination therapy be used as first treatment in all patients in whom endocrine therapy is indicated. Prior exposure to monotherapy shortens the patient's life by many months and produces a poor quality of life.
Adrenal Cortex Hormones↗
Ontogeny of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) in rat testis as studied by immunocytochemistry.
The enzymatic complex 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) is a step essential in the biosynthesis of all biologically active steroids, including androgens. In order to obtain information about the expression of 3 beta-HSD during testis development, we have localized this enzyme by light microscope immunocytochemistry during fetal and postnatal periods of development in the rat. In fetal testis, the enzyme was first detected in a few Leydig cells on the 17th day of gestation. The number of labeled cells and intensity of labeling increased with fetal development. From days 19 to 21 of gestation, strongly immunoreactive Leydig cells were arranged in clusters between seminiferous tubules. During the first days following birth, the number and size of positive cells rapidly decreased so that on postnatal days 5 and 10 only small, poorly stained cells could be seen. Fifteen days after birth, positive Leydig cells appeared more numerous and localized in peri- and intertubular spaces. At the onset of puberty, the intensity of labeling markedly increased. After puberty, and during adulthood, both strongly and weakly stained Leydig cells were mainly localized in intertubular spaces. Since the fluctuations in 3 beta-HSD content revealed in the present study by immunocytochemistry appear similar to those already observed for androgen secretion, such data suggest that regulation of 3 beta-HSD by trophic hormones might play an important role in regulating testicular androgen production during fetal as well as postnatal development.
3-Hydroxysteroid Dehydrogenases↗
Controlled release low dose medroxyprogesterone acetate (MPA) inhibits the development of mammary tumors induced by dimethyl-benz(a) anthracene in the rat.
Medroxyprogesterone acetate (MPA) is well recognized to have beneficial effects for the treatment of advanced breast cancer which are comparable to those achieved with other forms of endocrine therapy. Using mammary tumors induced in the rat by dimethylbenz(a)anthracene (DMBA) as a model, we have studied the possibility that low dose MPA could prevent the development of these tumors. Single subcutaneous injection of Depo-Provera (crystalline suspension of MPA) or MPA encapsulated in biodegradable microspheres of 50:50 poly[DL-lactide-co-glycolide] was given 7 days before oral DMBA. While 63% of intact animals developed palpable mammary tumors within 85 days after DMBA administration, tumor incidence decreased to 28% and 23% in animals who had received 30 mg and 100 mg of Depo-Provera, respectively. The same amounts of MPA delivered in microspheres caused a further decrease in tumor incidence to respective values of 7% and 6%. Average tumor area, on the other hand, decreased from 4.89 cm2 in intact rats to about 0.75 (0.57-0.88) cm2 and approximately 0.20 (0.14-0.22) cm2 in the Depo-Provera and microsphere-treated groups, respectively. Using the 50:50 formulation of poly[DL-lactide-co-glycolide] designed to release MPA at a constant rate for a 4-month period, the serum MPA concentration at 3 months was measured at 4.99 +/- 0.43 ng/ml. Such data suggest that administration of a low dose controlled-release formulation of MPA in 50:50 poly[DL-lactide-co-glycolide] microspheres could well be an efficient and well tolerated approach for the prevention of breast cancer in women.
9,10-Dimethyl-1,2-benzanthracene↗