Is idiopathic hirsutism (IH) really idiopathic? mRNA expressions of skin steroidogenic enzymes in women with IH.

OBJECTIVE: Hirsutism results from hyperandrogenemia and/or exaggerated androgen responsiveness. Among various causes of hirsutism, some patients do not exhibit androgen excess which is called idiopathic hirsutism (IH). The pathogenesis of IH could not so far be clearly established. DESIGN: To investigate the mRNA expression of aromatase enzyme and the other enzymes having functional roles in the steroidogenic pathway, in freshly obtained skin tissue from subumbilical skin and the arm of the patients with IH and healthy women. METHODS: Twenty-one women with IH and 15 healthy women were included in the study. We aimed to determine mRNA expressions of genes associated with local androgen synthesis and metabolism (CYP11A1, STS, CYP19A1, SRD5A1, SRD5A2, HSD3B1, AR, COMT, ESR1, ESR2, HSD3B2, CYP17A1, SULT2A1, SULT1E1, HSD17B2, IL6, TGFB1, TNFA) from skin biopsy and blood samples of patients with IH and the data compared with healthy subjects. RESULTS: Patients with IH exhibit significantly lower interleukin 6 (IL6) mRNA expression and higher steroid sulphatase (STS) and hydroxysteroid (17beta) dehydrogenase 2 (HSD17B2), gene mRNA expression, respectively, in the subumbilical region skin biopsies. Similarly, patients with IH exhibit significantly lower IL6 mRNA expression and higher STS and HSD17B2 gene mRNA expression, respectively, in the arm skin compared to healthy women's subumbilical region. CONCLUSIONS: In both arm and subumbilical skin biopsy of patients with IH, we observed an up-regulation of HSD17B2 and STS, decreased IL6 mRNA expression, probably determining an increase in the local amount of active androgens, which could then be used as substrate for other androgen metabolic routes.

Idiopathic hirsutism: local and peripheral expression of aromatase (CYP19A) and 5α-reductase genes (SRD5A1 and SRD5A2).

OBJECTIVE: To evaluate idiopathic hirsutism etiology via molecular studies testing peripheral and local aromatase and 5α-reductase expression. DESIGN: Assessment of the expression of messenger RNA (mRNA) for type 1 and 2,5α-reductase isoenzyme gene (SDR5A1, SDR5A2) and aromatase (CYP19A) in dermal papillae cells and peripheral blood mononuclear cells. SETTING: University hospital. PATIENT(S): 28 untreated idiopathic hirsute patients and 20 healthy women (controls). INTERVENTION(S): Human skin biopsies and peripheral venous blood. MAIN OUTCOME MEASURE(S): SDR5A1, SDR5A2, CYP19A gene expression in skin biopsies and peripheral blood. RESULT(S): A statistically significant reduction of SRD5A1, SRD5A2, and CYP19A gene expression was found in the dermal papillae cells and peripheral blood mononuclear cell between the study and control group. CONCLUSION(S): Further study, including protein expression and enzyme activity assays, are warranted to characterize the paradoxically low gene expression levels of local 5α-reductase and aromatase in women with idiopathic hirsutism.

Evaluation of 5-alpha reductase activity on cultured fibroblast in patients with hyperandrogenemia.

The enzyme steroid 5-alpha reductase is responsible for the conversion of testosterone to dihydrotestosterone, the steroid that mediates the intracellular action of androgens in some target tissues. The goal of this study was to check the accuracy of three known biochemical methods of studying steroid 5-alpha reductase activity expressed by dermal fibroblasts, isolated from pubian skin. These methods were performed on cell lysates (spectrophotometric and spectrofluorimetric methods) and on cell culture media (Reversed Phase-HPLC) with the purpose of their use in diagnosis and monitoring of hyperandrogenic patients. We also optimized a molecular study of expression of 5-alpha reductase isoenzymes and used it in the analysis of patients diagnosed with polycystic ovary syndrome (PCOS) and hirsutism by comparison with normal women. There was noticed an increase of the isoenzyme expression level both in patients with PCOS and in the case of patients with hirsutism. In other experiments, dermal fibroblasts originating in 15 individuals were treated with androgen hormones (testosterone: 10(-7) - 10(-9) M) with the purpose of demonstrating the effect of hyperandrogenemia on the expression level of 5-alpha reductase isoenzymes. The study of 5-alpha reductase type 1 mRNA expression levels in fibroblasts resulted from 4 normal individuals, 3 patients with hirsutism and 6 patients with PCOS, demonstrated an increase with 108.3% at the patients with PCOS and 47.3% at the patients with hirsutism compared with normal women. We concluded that hyperandrogenemia is associated with high levels of expression of 5-alpha reductase type 1 and, to a less extent, of type 2 isoenzyme in pubian skin cultured fibroblasts.

The frequency of CYP 21 gene mutations in Turkish women with hyperandrogenism.

OBJECTIVE: The congenital adrenal hyperplasias (CAH) are a group of autosomal recessive disorders due to decreased activity of the enzymes responsible for cortisol biosynthesis. Since CYP21 gene mutations in non-classical CAH (NC-CAH) due to 21-hydroxylase deficiency among Turkish women have not been well characterized, we performed CYP21 genotype analyses to determine the frequency of specific mutations in our population. DESIGN: Clinical study in women with hyperandrogenism at Endocrinology Department of a University Hospital. The CYP21 genotype analysis was performed at the Children's Hospital of Pittsburgh. PATIENTS AND METHODS: The study population included 32 Turkish women with hyperandrogenism and hirsutism, 5 patients with NC-CAH due to 21-hydroxylase deficiency and their 3 first degree relatives. The following steroids were measured: cortisol, prolactin, DHEAS, free testosterone, testosterone, LH, FSH, estradiol, 17-OHP, 11-deoxycortisol, and androstenedione. The ACTH stimulation test was performed in the follicular phase of the menstrual cycle. CYP21 mutations were detected by CYP21 specific PCR followed by allele specific restriction fragment length polymorphism (RFLP) or single strand conformational polymorphism analyses. RESULTS: Among hirsute Turkish women with hyperandrogenemia 21.9% was heterozygous carriers of CYP21 mutations; all had basal and stimulated 17-OHP values within the normal range. Alleles detected were as follows: Q318X, V281L, del/gene conversion, and R356W. Thus, 21.9% of women were heterozygous CYP21 carriers. CONCLUSION: The frequency of CYP21 heterozygosity is high among Turkish women with hirsutism and hyperandrogenism. Women with hyperandrogenism who are heterozygous CYP21 mutation carriers have normal basal and stimulated 17-OHP levels. In other words, normal basal and ACTH-stimulated 17-OHP responses do not exclude heterozygosity for CYP21 mutations. The molecular differences between symptomatic carriers, e.g., our patients and asymptomatic CYP21 mutations carriers, e.g., mothers of children with classical CAH, remain to be elucidated.

3alpha-Hydroxysteroid dehydrogenase type III deficiency: a novel mechanism for hirsutism.

CONTEXT: Dihydrotestosterone (DHT), the primary active androgen in peripheral target tissues, is metabolized by 3alpha-hydroxysteroid dehydrogenase type III (3alpha-HSD), encoded by the AKR1C2 gene, forming 5alpha-androstane-3alpha,17beta-diol (3alpha-diol). 3alpha-HSD may play a role in the pathogenesis of hirsutism. OBJECTIVES: Our objective was to evaluate the role of 3alpha-HSD in hirsutism by comparing 1) tissue levels of active androgens, 2) relative gene expression of AKR1C2, and 3) activity of 3alpha-HSD in genital skin from normal and hirsute women. DESIGN: Genital skin was obtained from normal and hirsute women. After homogenization, testosterone (T) and DHT levels were quantified by conventional RIA. From isolated RNA, relative expression of AKR1C2 was determined by real-time PCR. In addition, minced genital skin was incubated with [(3)H]DHT, and the product, [(3)H]3alpha-diol, was quantified by radio-HPLC. SETTING: The study took place at an inner-city hospital. PATIENTS: PATIENTS included women undergoing posterior colporrhaphy. MAIN OUTCOME MEASURES: We assessed 1) tissue levels of T, DHT, and 3alpha-diol; 2) relative expression of AKR1C2; and 3) conversion ratio of [(3)H]3alpha-diol to [(3)H]DHT. RESULTS: In genital skin, tissue DHT and T concentrations in hirsute women were 1.90-fold and 1.84-fold higher than in normal women (P =0 .002 and 0.03), and relative expression of AKR1C2 mRNA was reduced approximately 7-fold (P = 0.04). Genital skin from hirsute women showed less metabolism of [(3)H]DHT to [(3)H]3alpha-diol (conversion ratio, 0.24 +/- 0.19 vs. 0.85 +/- 0.55, P = 0.01). CONCLUSIONS: In genital skin of hirsute women, reduced AKR1C2 gene expression and 3alpha-HSD activity results in decreased DHT metabolism and elevated tissue levels of DHT. Diminished DHT metabolism may play an important role in the pathogenesis of hirsutism.

Content of 5-alpha-reductase (type 1 and type 2) mRNA in dermal papillae from the lower abdominal region in women with hirsutism.

BACKGROUND: Androgens influence the growth of terminal hair. The dermal papilla contains androgen receptors and the enzymes 5-alpha-reductase types 1 and 2. Both of these enzymes convert testosterone to the more active androgen, 5-alpha-dihydrotestosterone. The male distribution pattern of terminal hair in females is termed hirsutism. It is most common among women with hyperandrogenism; however, it may also affect patients with normal androgen levels (idiopathic hirsutism). OBJECTIVES: The aim of this study was to assess the expression of 5-alpha-reductase types 1 and 2 mRNA in dermal papillae from the lower abdominal skin in women with hirsutism. METHODS: The study included 42 subjects, 24 with a diagnosis of polycystic ovary syndrome (PCOS) and 18 with idiopathic hirsutism (IH). In all patients, free serum testosterone was measured. RESULTS: The mean +/- SD concentration of free serum testosterone was 7.2 +/-5.3 pmol/L in the total group of patients, 10.8 +/- 4.0 pmol/L in patients with PCOS, and 2.5 +/- 1.7 pmol/L in patients with IH. Quantitative analysis was then performed for the mRNA of 5-alpha-reductase types 1 and 2, both of which were found within the dermal papillae from the lower abdominal skin region. The number of mRNA copies/microg of total RNA for 5-alpha-reductase type 1 was statistically significantly higher than that for type 2 in both groups of examined patients. We also demonstrated a positive correlation between the number of mRNA copies/microg of total RNA for 5-alpha-reductase types 1 and 2 and the concentration of free serum testosterone in women with PCOS and IH. Considering all patients together, we found a positive correlation between the number of mRNA copies/microg of total RNA for 5-alpha-reductase type 2 and the concentration of free serum testosterone. There was also a tendency towards a positive correlation between the number of mRNA copies/microg of total RNA for 5-alpha-reductase type 1 and the concentration of free serum testosterone. CONCLUSION: The results of our study suggest that testosterone increases expression of 5-alpha-reductase types 1 and 2 in dermal papillae from the lower abdominal region in patients with hirsutism.

Gene expression of type 2 17 beta hydroxysteroid dehydrogenase in scalp hairs of hirsute women.

Androgens are the main hormonal regulators of human hair growth and they are related to clinical conditions such as hirsutism. The aim of this study was to analyze the gene expression of androgen receptor (AR) and type 2 17 beta hydroxysteroid dehydrogenase (17 beta-HSD) in keratinocytes of plucked scalp hairs from hirsute patients and normal subjects. We studied 58 women with hirsutism (31 with polycystic ovary syndrome (PCOS), 27 with idiopathic hirsutism (IH)); 15 control women; and 10 control men. Hirsutism was assessed by a modified Ferriman-Gallwey method. Hormonal status was assessed between days 2 and 10 of the menstrual cycle or on any day when the patients were amenorrheic. AR and type 2 17 beta-HSD mRNA levels were estimated by reverse transcription-polymerase chain reaction (RT-PCR). AR expression was similar in all groups. Type 2 17 beta-HSD gene expression in untreated hirsute patients was lower (2.1+/-0.10) than in normal women (3.1+/-0.17), and similar to men (1.8+/-0.22). Comparing hirsute patients, type 2 17 beta-HSD expression was higher in treated PCOS (3.0+/-0.34 versus 2.2+/-0.13) and IH patients (2.5+/-0.19 versus 2.0+/-0.15); hirsutism score was lower (P=0.003, PCOS; P=0.003, IH); and SHBG levels were higher (P=0.001, PCOS; P=0.024, IH) in treated patients. The free androgen index was lower in treated women (P=0.024 for the IH group). In conclusion, the lower expression of type 2 17 beta-HSD mRNA in scalp hairs of untreated hirsute patients suggests androgen metabolism disturbances with predominance of more potent androgens, as occurs in men. The enzyme's higher gene expression in treated hirsute patients could be an indirect evidence of restored enzyme activity and intracellular androgen metabolism.

The 5alpha-reductase type 1, but not type 2, gene is expressed in anagen hairs plucked from the vertex area of the scalp of hirsute women and normal individuals.

The aim of the present study was to determine the expression of the genes for type 1 (SDR5A1) and type 2 (SDR5A2) 5alpha-reductase isoenzymes in scalp hairs plucked from 33 hirsute patients (20 with polycystic ovary syndrome and 13 with idiopathic hirsutism) and compare it with that of 10 men and 15 normal women. SDR5A1 and SDR5A2 expression was estimated by RT-PCR using the gene of the ubiquitously expressed protein 2-microglobulin as an internal control. The results are expressed as arbitrary units in relation to beta2-microglobulin absorbance (mean SEM). SDR5A2 expression was not detected in any hair samples analyzed in this study. No differences were found in SDR5A1 mRNA levels between men and normal women (0.78+/-0.05 vs 0.74+/-0.06, respectively). SDR5A1 gene expression in the cells of hair plucked from the scalp of normal women (0.85+/-0.04) and of women with polycystic ovary syndrome (0.78+/-0.05) and idiopathic hirsutism (0.80+/-0.06) was also similar. These results indicate that SDR5A1 gene expression in the follicular keratinocytes from the vertex area of the scalp seems not to be related to the differences in hair growth observed between normal men and women and hirsute patients. Further studies are needed to investigate the expression of the 5alpha-reductase genes in other scalp follicular compartments such as dermal papillae, and also in hair follicles from other body sites, in order to elucidate the mechanism of androgen action on the hair growth process and related diseases.

Anti-androgens for the treatment of hirsutism.

Many alternatives exist for treating hirsutism. Based on an analysis of scientific literature and on the experiences of the author, the most common anti-androgen agents are discussed in this review. Androgen receptor blockers (cyproterone acetate, flutamide and spironolactone), 5 alpha-reductase inhibitors (finasteride) and androgen-suppressing agents (gonadotrophin-releasing hormone [GnRH] agonists, oestroprogestins, corticosteroids and insulin-sensitising agents) are evaluated and compared. The importance of diagnosis in choosing the most appropriate anti-androgen treatment is also discussed.

Role of the pentanucleotide (tttta)(n) polymorphism in the promoter of the CYP11a gene in the pathogenesis of hirsutism.

OBJECTIVE: To determine if the (tttta)(n) repeat polymorphism in the promoter region of CYP11a gene is associated with hirsutism and hyperandrogenism in women from Spain. DESIGN: Controlled clinical study. SETTING: Tertiary-care institutional hospital. PATIENT(S): Ninety-two hirsute women and 33 healthy control women. INTERVENTION(S): Basal and adrenocorticotropin-stimulated serum samples and genomic DNA extracted and purified from whole-blood samples were obtained during the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): CYP11a (tttta)(n) repeat-polymorphism genotype and serum ovarian and adrenal androgen levels. RESULT(S): None of the CYP11a (tttta)(n) polymorphic alleles was associated with hirsutism. The absence of the four-repeat-units allele (4R-- genotype), which has been reported by other authors to be associated with polycystic ovary syndrome (PCOS), was found in 22.4% of the women studied here and was equally distributed among patients and controls, independently of the presence of PCOS and/or ovarian or adrenal hyperandrogenism. No differences were observed in serum hormone concentrations in 4R-- individuals as compared with subjects with at least one four-repeat-units allele. CONCLUSION(S): The (tttta)(n) repeat polymorphism in the promoter region of CYP11a does not appear to play any significant role in the pathogenesis of hirsutism and hyperandrogenism in women from Spain.

Prevalence of 21-hydroxylase-deficient nonclassic adrenal hyperplasia and insulin resistance among hirsute women from Puerto Rico.

OBJECTIVE: To determine the prevalence of 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) and insulin resistance in hirsute women from Puerto Rico. DESIGN: Cross-sectional prospective study. SETTING: Clinical research center. PATIENT(S): 100 consecutive untreated hirsute women. MAIN OUTCOME MEASURE(S): Fasting total T, free T, DHEAS, insulin, and glucose were measured, and a 60-minute acute ACTH-(1-24) stimulation for 17-hydroxyprogesterone (17-HP) was performed. A diagnosis of 21-OH-deficient NCAH was considered when the stimulated 17-HP level was >30.3 nmol/L. The glucose/insulin ratio was calculated as a measure of insulin resistance (normal value, > or =4.5). RESULT(S): Patients had a mean (+/-SD) age of 26.8+/-6.6 years; 82 were oligomenorrheic. Overall, 12%, 8%, and 60% of patients had elevated levels of DHEAS, total T, or free T, respectively. One patient was identified as having 21-OH-deficient NCAH. Eight women, none of whom had NCAH, were found to be hyperglycemic; four of these women had type 2 diabetes mellitus. Excluding hyperglycemic patients, a glucose/insulin ratio of <4.5, consistent with IR, was found in 51.7%. CONCLUSION(S): The prevalence of 21-OH-deficient NCAH among patients from Puerto Rico does not differ significantly from that reported for other non-Jewish, non-Hispanic white populations.

Results of the ACTH stimulation test in hirsute women.

OBJECTIVE: To determine the incidence of late-onset congenital adrenal hyperplasia (LOCAH) due to 21-hydroxylase deficiency among hirsute women and to evaluate the results of the ACTH stimulation test with the clinical characteristics. STUDY DESIGN: Prospective, controlled study. One hundred women with hirsutism and 14 normally cycling women without hirsutism were included in this study at the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Cerrahpasa School of Medicine, Istanbul University. After basal serum progesterone (P) and 17 hydroxyprogesterone (17OHP) levels were determined, an ACTH stimulation test was performed on cycle day 3-5. The same parameters were checked 30 minutes later. We estimated the 21 hydroxylase activity by calculating the change in 17OHP (17OHP 30-0) and the summed rate of the change in P and 17OHP ([P30-0] + [17OHP30-01/30 minutes). The 95th percentile for these estimates in normal women were calculated, and values above three times the 95th percentile were considered to distinguish women with LOCAH due to 21-hydroxylase deficiency. RESULTS: The 95th percentile for 17OHP 30-0 and (P30-0) + (17OHP30-0)/30 minutes in normal women was 1.6 and 8.9 ng/dL/min, respectively. Regarding 17OHP 30-0 values, three women with hirsutism had levels above three times the 95th percentile of these estimates, and 28 women had estimates of more than the 95th percentile but less than threefold. Seventeen of 28 women had oligomenorrhea, and all had severe hirsutism. The women with severe hirsutism and oligomenorrhea had significantly higher ACTH-stimulated serum 17OHP levels and values for 17OHP 30-0 and (P30-0 + (17OHP30-0)/30 min) than did normally cycling women. CONCLUSION: The incidence of LOCAH due to 21-hydroxylase deficiency and mild 21-hydroxylase deficiency is 3% and 28%, respectively, in women with hirsutism. Clinical characteristics are not helpful in determining 21-hydroxylase deficiency. However, the incidence of 21-hydroxylase deficiency is more common among women with severe hirsutism and oligomenorrhea. The change in serum 17OHP 30-0 seems to be greater than the summed rate of change in serum 17OHP and P in the detection of 21-hydroxylase enzyme deficiency.

High serum luteinizing hormone levels induce ovarian delta4 cytochrome P450c17alpha down-regulation in hirsute women: complete effect on 17-hydroxylase and partial effect on 17,20-lyase.

It is well known that normal and mildly elevated luteinizing hormone (LH) levels induce increased activity of ovarian 17-hydroxylase and 17,20-lyase, the cytochrome P450cl7alpha (P450) enzymes. This leads to increased ovarian 17alpha-hydroxyprogesterone (17-OHP) and androstenedione production. In contrast, it has been shown in both in vitro and in vivo studies in animals and in in vitro studies in women that high LH concentrations have opposite effects on these enzymes. These LH down-regulating effects appear to be more marked on 17,20-lyase than on 17-hydroxylase. Finally, these LH effects have not been reported in vivo in women. Therefore, we investigated the relationships between serum LH levels and serum 17-OHP and androstenedione concentrations in 263 consecutive hirsute women (HW) with normal serum 17-OHP responses to acute adrenocorticotropin (ACTH) stimulation. The patterns of basal serum steroid concentrations differed according to the basal serum LH levels. Indeed, for relationships between LH and 17-OHP concentrations, a positive correlation (P < 0.001) was found between the levels of these parameters when LH levels ranged from 0.2 to 9.0 IU/l. Conversely, for LH levels greater than 9.0 to 21.0 IU/l, LH values were negatively correlated (P<0.001) with 17-OHP concentrations. Similar results were observed for relationships between LH and androstenedione levels but the LH peak level related to decreasing androstenedione concentrations was 12.0 IU/l. Finally, the mean 17-OHP level in patients with LH levels which induced marked P450 down-regulation (i.e. more than 12 IU/l) was similar to that in patients with LH levels within the normal range (i.e. less than 6 IU/l). In contrast, the mean androstenedione level in the former patients was markedly higher (P<0.001) than that in the latter patients. In conclusion, as previously reported in in vitro studies, this in vivo study indicates that LH induces stimulating and down-regulating effects on both ovarian delta(4)17-hydroxylase and delta(4)17,20-lyase activities as serum LH levels gradually increase. However, in contrast to in vitro studies, LH levels which induce P450 down-regulation appear to be less effective on delta(4)17,20-lyase than on delta(4)17-hydroxylase in HW. This strongly suggests that serum factors induce, in most HW, a marked increase in delta(4)17,20-lyase, but not in delta(4)17-hydroxylase, activity leading to both partial impairment of LH-induced delta(4)17,20-lyase down-regulation and complete LH-induced delta(4)17-hydroxylase down-regulation in these patients.

Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist?

To study ovarian and adrenal steroid profiles of women with idiopathic hirsutism, we compared sex steroid and basal and corticotropin (ACTH)-stimulated adrenal steroid levels before and after ovarian suppression induced by a long-acting gonadotropin-releasing hormone agonist analog (GnRH-a) in 24 hirsute women without hyperandrogenemia. Twelve healthy women served as controls for basal and ACTH-stimulated adrenal steroid levels. Serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estradiol (E2), basal and ACTH-stimulated 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), delta 4-androstenedione (delta 4-A), 11-deoxycortisol (S) and cortisol (F), and basal and luteinizing hormone-releasing hormone (LHRH)-stimulated gonadotropin levels were measured before and 21 days after 3.75 mg intramuscular triptorelin in hirsute women. Basal T levels and basal and ACTH-stimulated delta 4-A, DHEA, and DHEAS levels were not different in hirsute women with respect to controls. Basal and ACTH-stimulated 17OHP was elevated, and decreased to normal after ovarian suppression with triptorelin. Although basal and ACTH-stimulated delta 4-A levels were normal, the delta delta 4-A/delta F and delta delta 4-A/delta 17OHP ratios were elevated and remained elevated after ovarian suppression, suggesting enhanced adrenal delta 4-17,20-lyase activity. T, F, S, and DHEAS levels were not affected by ovarian suppression. Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids. We conclude that idiopathic hirsute women with normoandrogenemia show an increase in ovarian secretion of 17OHP and a minimally increased adrenal delta 4-17, 20-lyase activity, suggesting that mild forms of ovarian and adrenal functional hyperandrogenism may be present in these patients with otherwise unexplained hirsutism.

Late onset adrenal hyperplasia due to 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency in north Indian hirsute women.

The presence of late onset 3 beta-hydroxy steroid dehydrogenase (3 beta-HSD) type of congenital adrenal hyperplasia was studied in 58 north Indian hirsute women. The age range of these patients was 15 to 42 yr. Fifty two per cent of these patients had body mass index > 25. Basal serum testosterone, luteinizing hormone, follicle stimulating hormone, dehydroepiandrosterone sulphate (DHEAS), and 17 hydroxy progesterone (17 OHP) were estimated. All the patients underwent adrenocorticotropin (ACTH) stimulation test after an overnight dexamethasone suppression for the estimation of DHEAS, 17 OHP, and 17 hydroxy pregnenolone (delta 5-17p). Five (8.6%) hirsute women showed an exaggerated 17 OHP response to ACTH indicating 21-hydroxylase deficiency. Eight (13.8%) hirsute women had elevated basal DHEAS and ACTH-stimulated DHEAS as well as delta 5-17P responses indicative of 3 beta-HSD deficiency. In one patient hirsutism was the presenting manifestation of tumoural hyperandrogenism. Our findings indicate the presence of both 21-hydroxylase and 3 beta-HSD deficiency in north Indian hirsute women, with, 3 beta-HSD deficiency being the major cause of hirsutism in this population.

No genetic mutation in type II 3 beta-hydroxysteroid dehydrogenase gene in patients with biochemical evidence of enzyme deficiency.

Nonclassic or the mild form of 3 beta-hydroxysteroid dehydrogenase (NC3 beta-HSD) deficiency is an entity which is identified with typical features of premature pubarche, hirsutism, or oligomenorrhea. In this study, type II 3 beta-HSD gene from 4 girls who were diagnosed as NC3 beta-HSD deficient, base on the adrenal steroidogenic responses to ACTH, was analyzed to determine whether NC3 beta-HSD deficiency was an allelic variant of classical 3 beta-HSD deficiency by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). We could not detect any alterations of type II 3 beta-HSD gene from these patients. Our result strongly suggests that unlike classical 3 beta-HSD deficiency, NC3 beta-HSD deficiency may be secondary adrenal biosynthetic defects, rather than dual inherited deficiencies.

Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women.

21-hydroxylase (21-OH) deficiency accounts for the vast majority of nonclassic (NC) forms of congenital adrenal hyperplasia (CAH), and is associated with symptoms detectable either in childhood (precocious puberty) or sometimes only later in adulthood (hirsutism, acne, amenorrhea). While the severe forms of the disease responsible for salt wasting or simple virilization have been extensively studied, the NC 21-OH deficiency is less well characterized, especially in adults. We studied the 21-OH gene (CYP21) in a population of 69 unrelated hyperandrogenic subjects suspected to be homozygous or heterozygous for NC 21-OH deficiency, based on basal and adrenocorticotrophin (ACTH)-stimulated plasma 17-hydroxyprogesterone (17-OHP, 17-OHPSI) and 21-desoxycortisol (21-DOF, 21-DOFSI) levels. To identify all mutations involved, determination of the whole gene sequence, including exons, exon-intron junctions, and promoter region, was performed, followed by a study of large rearrangements and identification of compound heterozygotes. Alterations were identified in at least one allele of 55 hyperandrogenic subjects. Two NC alterations, Val282Leu and Pro454Ser, were detected in 68% and 7% of the affected alleles, respectively, whereas mutations involved in severe forms were identified in 21% of them. These results document the utility of a molecular diagnosis in hyperandrogenic women suspected of being either heterozygous or homozygous for NC 21-OH deficiency and clearly indicate the importance of genetic counseling in such a population.

Aspectos genéticos e dúvidas diagnósticas da deficiência da 3 beta-hidroxiesteróide desidrogenase: atualizaçäo / Genetic and diagnostic aspects on 3 beta-hidroxisteroid dehidrogenase defficiency: an update

Nos últimos 10 anos, muito tem-se publicado sobre a diminuiçao da atividade da 3 beta-hidroxiesteróide desidrogenase (3 beta-HSD) por ocasiao da infância, menarca ou mesmo após, determinando por um lado hiperplasia supra-renal congênita e na área ginecológica síndrome dos ovários policísticos devido a instalaçao de um meio androgênico coadjuvante do desvio da funçao ovulatória. Tida como a deficiência enzimática mais freqüente na forma de início tardio das hiperplasias supra-renais, seu diagnóstico era feito através apenas de estudos hormonais em que se comparavam os precursores delta 5 aos delta 4 da esteroidogênese. Tais dados, aceitos como universais, começaram a ser questionados a partir das descobertas recentes da localizaçao dos genes que codificam a atividade enzimática da 3 beta-HSD. Esta revisao procura mostrar os avanços na conduçao diagnóstica desta patologia a partir das últimas publicaçoes sobre o tema. Questiona-se por fim a existência da forma tardia desta enzimopatia.

Evidence for independent modulation of human 11-HSD and 5 alpha/5 beta reductase activities.

The increased ratio of 5 alpha to 5 beta reduced steroids associated with apparent mineralocorticoid excess (AME) may be a necessary consequence of altered 11 beta-hydroxysteroid dehydrogenase (11-HSD) activity. In order to test this hypothesis we have compared changes in 11-HSD activity and 5 alpha/5 beta reduction in a variety of clinical and experimental conditions. The ratio of 11-oxo/11 beta-hydroxy metabolites of cortisol (11-oxo/11-OH FM) was used as an index of 11-HSD activity and the ratio of allotetrahydrocortisol/ tetrahydrocortisol (allo THF/THF) was used as an index of 5 alpha/5 beta reduction. Ratios were derived from 24 hour urinary steroid profiles measured by high resolution gas chromatography. The clinical conditions studied were Cushing's Syndrome, Major Depression and hirsutism. In each study, the patient group were compared with age-matched healthy controls. For the experimental conditions, subjects treated with either hydrocortisone, dexamethasone, metyrapone or finasteride acted as their own controls. No consistent relationship was found between changes in the ratios of 11-oxo/11-OH FM and allo THF/THF. We conclude that there is no evidence of consistent metabolic interaction between 11-HSD and 5 alpha/5 beta reductase activities under a wide range of conditions. Furthermore, the patterns of metabolic changes seen in these conditions are no less characteristic, although more subtle, than the well-documented metabolic changes seen in inborn errors of steroid metabolism.