Alpha-androstanediol Glucuronide Research Articles

Acne in adult women and the markers of peripheral 3 alpha-diol G activity.

Acne in adult women is a frequent hard-to-manage disease with many relapse cases. It mostly interferes with the quality of life of patients, bringing them major metabolic and social losses. As androgenic hormones play a very important role in the acne pathogenesis, the early diagnosis of hyperandrogenic states is very useful for the proper evaluation of each patient and for a better choice of therapeutic management. Defining a pattern for laboratory profile analysis is important for the control of relapses of acne breakouts in adult women, which lately has been the aim of many published studies. To establish the relation between 3 alpha-diol G levels and acne in female patients with normal androgenic status without menstrual dysfunctions. The evaluation of serum 3 alpha-androstanediol glucuronide levels through an enzymatic immunoassay method (Androstanediol Glucuronide ELISA Kit) for a direct quantitative measurement in 26 patients with grade II and III acne, ages ranging from 13 to 50. Among the analyzed patients, 83% had grade II acne, and among this total, 60% were aged 14 or over. According to age, 12 studied patients showed serum 3 alpha-diol G levels within normal range and 11 patients had increased levels. A total of 60% of adult women with acne present increased levels of androgens and among those with normal levels and without menstrual dysfunctions, 50% show an increase in 3 alpha-diol G. Therefore, a pharmacological approach with anti-androgenic drugs for acne therapy in most of these patients is advisable.

Androgens, growth factors, and risk of prostate cancer: The Multiethnic Cohort

Androgens and growth factors are thought to be associated with prostate cancer risk, although past research has produced mixed results. We conducted a nested case-control study of biomarkers of prostate cancer risk within the Multiethnic Cohort. We compared prediagnostic levels of testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), 3alpha-androstanediol glucuronide (3alpha-diol G), insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein 1 (IGFBP-1), and IGFBP-3 in serum from 467 incident prostate cancer cases and 934 cancer-free controls. Controls were matched to the cases on geographic site (HI, LA), ethnicity, age at specimen collection (+/-1 year), date (+/-1 month) and time of day (+/-2 hr) of sample collection, and fasting status (<6, 6-7, 8-9, >10 hr). Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Serum concentrations of testosterone, DHT, SHBG, 3alpha-diol G, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were not associated with risk of prostate cancer. Tests for trend of quartiles of serum concentrations also did not show any association. Results were relatively unchanged for men with advanced prostate cancer and their matched controls. However, the follow-up period was relatively short (mean of 1.9 years). Analysis by ethnic group showed an increased risk for Latino men in the second (OR = 3.67, 95% CI: 1.63-8.24) and third (OR = 2.96, 95% CI: 1.19-7.40) tertiles of IGF-I serum levels compared with the first tertile. The suggested increased risk for IGF-I in Latino men merits further study, with greater statistical power.

Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term oral dehydroepiandrosterone treatment in postmenopausal women

Some postmenopausal women use over-the-counter dehydroepiandrosterone because of its purported beneficial effects. Although without major inherent androgenic activity, it is metabolized to potent androgens and estrogens. We investigated the pharmacokinetics of dehydroepiandrosterone and its relevant metabolites after prolonged treatment of postmenopausal women with 25 mg/d of dehydroepiandrosterone. Twenty healthy postmenopausal women were randomized to either 25 mg/d of dehydroepiandrosterone or placebo for 6 months. Frequent blood samples were obtained over 24 hours on day 1 and after 3 and 6 months. Mean baseline androgen levels at day 1 and month 3 in the treated group (seven evaluable women) were the following: dehydroepiandrosterone, 1.82 and 3.56 ng/mL; dehydroepiandrosterone sulfate, 0.96 and 3.37 microg/mL; 5-androstene-3beta,17beta-diol, 0.32 and 0.66 ng/mL; androstenedione, 0.50 and 0.86 ng/mL; testosterone, 17.9 and 28.7 ng/dL; dihydrotestosterone, 6.91 and 17.4 ng/dL; and 3alpha-androstanediol glucuronide, 2.66 and 10.7 ng/mL, respectively; these increases were significant. Small changes (-6% to 16%) were observed from month 3 to month 6. Nonsignificant increases were observed in baseline estrone and estradiol levels and in Cmax and AUC0-24h values for the androgens and estrogens from day 1 to months 3 and 6 of treatment. Sex hormone-binding globulin levels were unchanged, but free testosterone increased significantly from day 1 to month 3. Baseline hormone levels did not increase in the placebo group (six evaluable women). Changes in baseline values over time differed significantly between the groups for all hormones except estrone and estradiol. In postmenopausal women treated orally with a commonly available dose of dehydroepiandrosterone, the daily exposure (AUC) of dehydroepiandrosterone and its principal androgenic metabolites was found to be similar during 6 months of treatment despite increased serum baseline concentrations of these androgens.

Endogenous sex hormones and the risk of prostate cancer: A prospective study

Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case-control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Delta4-A), testosterone (T), sex hormone-binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha-diolG). A total of 727 incident Caucasian prostate cancer cases (age >/= 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (p(trend) = 0.01), mostly related to risk in older men (>/=65 years, p(trend) = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50-5.09]. No clear patterns were noted for Delta4-A and 3alpha-diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear. (c) 2008 Wiley-Liss, Inc.

Effect of oral versus transdermal steroidal contraceptives on androgenic markers

The purpose of this study was to compare biochemical androgen profiles in women treated with the contraceptive patch versus an oral contraceptive (OC). Twenty-four healthy women were randomly assigned to receive 3 cycles of either the contraceptive patch (ethinyl estradiol [EE] 20 microg/d and norelgestromin 150 microg/d) or OC (EE 35 mug and norgestimate 250 microg). Blood samples were taken at baseline and end of treatment. Serum levels of sex hormone-binding globulin (SHBG), total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), and 3alpha-androstanediol glucuronide (3alpha-diol G) were quantified by immunoassay methods; free T was calculated. The paired t and Student t tests were used for statistical analysis. Nineteen women completed the study (patch, n = 10; OC, n = 9). Despite a 1.6-fold relative increase in SHBG levels with the patch versus OC (449% vs 274%, P = .03), free T decreased equally in both groups (patch 60%, P < .0001; OC 59%, P < .0001). DHEAS decreased by 26% in the patch group (P < .01) and 32% in the OC group (P < .001). 3alpha-diol G was reduced by 52% in the patch group (P < .0001) and 51% in the OC group (P < .0001). In addition, the OC was associated with significant decreases in A and DHT. The contraceptive patch had an effect comparable to the OC on several key androgenic markers. Given these biochemical findings, the contraceptive patch has significant potential as a therapeutic agent for disorders of androgen excess.

Effects of Oral Administration of Androstenedione on Plasma Androgens in Young Women Using Hormonal Contraception

Androstenedione as a dietary supplement has been targeted at the sporting community, but there are limited data regarding its effects on plasma androgens in young women. A double-blind, cross-over study was undertaken involving 10 women (20-32 yr) using hormonal contraception. Because contamination of supplements has been reported, an in-house oral formulation was prepared containing purified androstenedione, the control being lactose only. After oral administration of a single dose of androstenedione (100 mg), blood was collected frequently up to 8 h and at 24 h. Maximum plasma androgen concentrations observed between volunteers were well above the upper limit of reference ranges for women, being 121-346 nmol/liter for androstenedione, 14-54 nmol/liter for testosterone (T), 11-32 nmol/liter for 5alpha-dihydrotestosterone, and 23-90 nmol/liter for 3alpha-androstanediol glucuronide. The free androgen index and T concentration changed in a similar manner. The mean change in area under the plasma concentration-time curve (0-24 h), compared with control data were: androstenedione approximately 7-fold, T approximately 16-fold, 5alpha-dihydrotestosterone approximately 9-fold, and 3alpha-androstanediol glucuronide approximately 5-fold; the mean conversion ratio of androstenedione to T was 12.5% (range 7.8-21.6%). Increases in T area under the plasma concentration-time curve were correlated with SHBG concentration (r = 0.80; P = 0.005). Formulation characteristics and SHBG levels appear to be important factors when considering plasma androgen increases after acute androstenedione administration.

Severe and mild neonatal hypothyroidism mediate opposite effects on Leydig cells of rats.

The effects of neonatal hypothyroidism on the number of Leydig cells were studied in neonatal Wistar rats. Moderate or severe hypothyroidism were induced during neonatal life by giving different amounts of methimazole (MMI; 0.05% or 0.1%) in the drinking water of pregnant and lactating dams. Rats were sacrificed on day 21 of postnatal life. Severely hypothyroid rats had approximately 45-fold higher serum thyrotropin (TSH) values and demonstrated approximately a 65% decrease in testes weight (p < 0.05) and the number of Leydig cells. However, in moderately hypothyroid rats, in which serum TSH was only approximately 16-fold higher, testicular weight was normal and the number of Leydig cells almost doubled (p < 0.01). There were no significant differences between the serum-free testosterone levels of the moderately and severely hypothyroid rats versus controls. Serum levels of 3alpha-androstanediol glucuronide, although decreased to less than 10% in severely hypothyroid rats (p < 0.01), were not changed by mild hypothyroidism. The number of Sertoli cells was increased in moderately hypothyroid rats versus controls (p < 0.05) and even further increased in severely hypothyroid rats (p < 0.05). We conclude that (1) severe neonatal hypothyroidism impairs the development and function of the testes and (2) moderate neonatal hypothyroidism stimulates the proliferation of Leydig cells.

Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women.

To elucidate the possible role of genetic variation in androgen receptor (AR), estrogen receptor alpha (ER alpha), and ER beta on serum androgen levels in premenopausal women, the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ER alpha gene, and the CA repeat polymorphism of the ER beta gene were studied in a population-based cohort of 270 women. Total testosterone, free testosterone, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, 3 alpha-androstanediol glucuronide, 17 beta-estradiol, LH, FSH, and sex steroid hormone-binding globulin (SHBG) were measured in serum samples obtained in the follicular phase of the menstrual cycle. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH, than women with longer CAG repeat sequences. The CA repeat of the ER beta gene also was associated with androgen and SHBG levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ER alpha gene was not associated with the levels of any of the hormones measured. Our results suggest that the serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ER beta gene, respectively.

Prostate-specific antigen and human glandular kallikrein 2 are markedly elevated in urine of patients with polycystic ovary syndrome.

Prostate-specific antigen (PSA) is a well-established tumor marker of prostatic adenocarcinoma. Human glandular kallikrein 2 (hK2), another serine protease closely related to PSA, is also gaining ground as a promising diagnostic tool in prostate cancer. The expression of these 2 proteases is known to be regulated by androgens and progestins in hormonally responsive tissues, such as the male prostate and the female breast. Previously, we have shown that serum PSA levels in normal women are very low but still detectable by ultrasensitive PSA immunoassays. We have also demonstrated that some women with hyperandrogenic syndromes have elevated serum PSA levels. In this study, we have measured urinary PSA and urinary hK2 levels in 35 polycystic ovary syndrome (PCOS) patients and compared them to those of 41 age-matched controls. We found that urinary PSA levels were significantly higher (P < 0.0001) in PCOS patients (mean +/- SE = 820 +/- 344 ng/L) than in the controls (mean +/- SE = 4.3 +/- 1.8 ng/L). Similarly, the difference between urinary hK2 of patients (mean +/- SE = 8.2 +/- 3.1 ng/L) and controls (0.5 +/- 0.3 ng/L) was also significant (P < 0.001). A weak correlation was observed between urinary PSA and serum 3 alpha-androstanediol glucuronide (r(s) = 0.42, P = 0.03) as well as between urinary PSA and serum testosterone (r(s) = 0.40, P = 0.04). The results of this study indicate that urinary PSA, and possibly urinary hK2, are promising markers of hyperandrogenism in females suffering from PCOS.

Altered balance between the 5 alpha-reductase and aromatase pathways of androgen metabolism during controlled ovarian hyperstimulation with human menopausal gonadotropins.

To evaluate androgen production and metabolism during controlled ovarian hyperstimulation. Five women, aged 33-42, were studied. All participants were undergoing controlled ovarian hyperstimulation with gonadotropin-releasing hormone agonist and human menopausal gonadotropins. Serum estradiol, estrone, androstenedione, testosterone, 3 alpha-androstanediol glucuronide, and sex hormone-binding globulin levels were measured at 6 time points during the cycle. The levels of all steroids increased significantly from baseline during controlled ovarian hyperstimulation. Mean total testosterone levels increased from 0.29 +/- 0.05 ng/mL to 0.58 +/- 0.07 ng/mL after gonadotropin stimulation. Sex hormone-binding gonadotropin levels increased from 50 +/- 16 nM to 73 +/- 12 nM after gonadotropin stimulation. Estrone/androstenedione and estradiol/testosterone ratios, reflecting the aromatase pathway, increased whereas 3 alpha-androstanediol glucuronide/androstenedione and 3 alpha-androstanediol glucuronide/testosterone ratios, reflecting 5 alpha-reductase activity, decreased. Controlled ovarian hyperstimulation with human menopausal gonadotropins results in increased serum testosterone and androstenedione levels. Whereas there is an enhancement in androgen metabolism by aromatase, 5 alpha-reductase activity with regard to androgen metabolism is diminished.

Serum androgen levels in adolescents with type 1 diabetes: Relationship to pubertal stage and metabolic control

Delayed sexual maturation is still frequently seen in adolescents with type 1 diabetes. A close relationship between insulin and androgen metabolism has been found in a number of studies. Our study was designed to investigate whether or not abnormalities in androgen secretion could play a role in the onset of sexual maturation in adolescents with type 1 diabetes. We have asked whether or not there was a correlation between daily insulin dosage, duration of diabetes, metabolic control, age, pubertal stage, and body mass index (BMI) versus serum androgen concentrations. Basal total and free testosterone, dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha diol-G) plasma concentrations were measured in 36 pubertal boys and 31 pubertal girls with type 1 diabetes and in 59 sex- and pubertal stage-matched control subjects without diabetes. Significantly higher serum total testosterone (p<0.01) and free testosterone (p<0.05) levels were found in females and males with type 1 diabetes than in controls at pubertal stage 5. DHEA-S, SHBG, DHT and 3alpha diol G concentrations in patients with diabetes were not significantly different from those in controls. There was no correlation between daily insulin requirements and serum androgen levels. These data suggest that adolescents with diabetes have similar serum levels of DHEA-S, SHBG, DHT and 3alpha diol G as healthy subjects at all stages of puberty. However, there are significant differences in serum testosterone and free testosterone levels in adolescents with diabetes when compared to healthy, sex- and pubertal stage-matched controls in late puberty. We hypothesize that the increased testosterone levels in patients with diabetes could relate to reduced fertility in females, disorders of sexual maturation and an increased risk for cardiovascular complications later in life.

Isolated Absence of Adrenarche in A Postpubertal Female

Background The development of pubic and axillary hair (adrenarche) is part of the process of normal puberty. We report a case of isolated absence of adrenarche in a post-pubertal female. A review of the literature reveals no previously reported case of isolated absence of adrenarche in a postpubertal female. An investigation was understaken to evaluate the etiology of the lack of sexual hair growth in this patient. Case A 14 year-old postpubertal female presented complaining of heavy menstrual bleeding approximately four months after her first menstrual period. The patient had been previously diagnosed with a developmental delay and speech impediment by her referring physician. Further workup revealed a normal menstrual pattern, yet the physical examination was remarkable for the absence of axillary and pubic hair, as well as short stature. A complete evaluation was performed which included chromosome analysis, serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione, testosterone, dihydrotestosterone (DHT), and 3-alpha androstanediol glucuronide. The serum androstenedione, testosterone, DHT, and 3-alpha androstanediol glucuronide levels were within normal limits. The DHEA-S levels were low yet adrenal function as analyzed by the Adrenocorticotropic hormone (ACTH) stimulation test was normal. Radiologic studies included pelvic ultrasound and bone age assessment with a bone age of 16 years. Skin biopsy of the mons pubis documents the presence of hair follicles. No previous or similar history has been noted in the patient's family history. Also of note, the patient is the product of a consanguineous relationship. Conclusion After review of our investigational findings, it is felt that this unique case likely represents an androgen receptor or post-receptor defect in the hair follicle.

Short-term impact of a lactovegetarian diet on adrenocortical activity and adrenal androgens.

The aim of this study was to determine whether definite diet changes affect adrenocortical activity and/or adrenal androgen metabolism. A controlled experimental diet study with four consecutive diet periods (repeated measure design) was carried out in six healthy adult volunteers. Four nearly isoenergetic diets, two normal (N) moderately protein-rich, one protein-rich (P), and one low protein lactovegetarian (L), were fed. At the end of each 5-day diet period a blood sample and two 24-h urine specimens were obtained from each subject. Plasma levels of dehydroepiandrosterone sulfate (DHEAS) were elevated with diet L (6.5 +/- 1.4 vs. 5.3 +/- 1.1 mumol/L; P < 0.05) compared to diet N, whereas other plasma hormones, including cortisol and insulin-like growth factor I did not vary markedly. A marked increase of 60% was seen in the urinary 24-h output of 3 alpha-androstanediol glucuronide with diet P. Urinary 24-h excretion rates for C peptide, free cortisol, DHEAS, and total 17-ketosteroid sulfates were clearly reduced with diet L compared to those with diet N or P. Our results show that a lactovegetarian diet can reduce adrenocortical activity (at least after a short term diet change). In addition, this vegetarian nutrition leads to a particular metabolic situation (elevated plasma DHEAS and reduced urinary DHEAS output) that usually is characteristic of fasting. Peripheral androgen metabolism as reflected by urinary 3 alpha-androstanediol glucuronide appears to be influenced only by high protein intake (diet P). Further research (controlled dietary long term investigation) is required 1) to validate whether the effects of diet on adrenocortical activity represent sustained endocrine changes and 2) to elucidate the underlying mechanism.

Serum levels of 3alpha-androstanediol glucuronide in hirsute and non hirsute women.

This study has evaluated the behaviour of 3alpha-androstanediol glucuronide (3alpha-diol G) in 170 women of whom 85 had polycystic ovary syndrome (PCOS), 35 had idiopathic hirsutism (IH) and 50 had regular cycles (control group). Of the women with PCOS, 45 were hirsute (PCOS-H) and 40 were non hirsute (PCOS-NH). Women in the control group were not hirsute. Hirsutism was assessed by the same physician using the Ferriman-Gallway score. The body mass index (BMI) was estimated in all of the women. Plasma concentrations of 3alpha-diol G were elevated only in hirsute patients, both with PCOS and with IH. Even in PCOS-NH, concentrations of 3alpha-diol G were higher compared with controls (P < 0.001), but significantly lower (P < 0.001) than those of the PCOS-H and of the IH groups. The behaviour of 3alpha-diol G was not affected by BMI.

Developmental patterns of serum 3 alpha-androstanediol glucuronide.

3 alpha-androstanediol glucuronide (3 alpha diolG) is a marker of peripheral tissue androgen metabolism. There are no previous data regarding complete paediatric reference ranges for 3 alpha diolG. In order to obtain reference values for 3 alpha diolG we have measured serum levels of 3 alpha diolG in 283 healthy children and adolescents, 146 boys and 137 girls, age 1 month to 20 years and 28 adults. A non-extraction, solid phase radioimmunoassay employing a polyclonal antiserum that is specific for 3 alpha diolG was used to measure serum 3 alpha diolG levels (intra assay variation 5.1-10.1%, inter assay variation 2.7-9.0%). There was a strong sex and age dependence (r = 0.8; p < 0.0001) of 3 alpha diolG levels throughout childhood and adolescence with males showing significantly higher levels of the androgen than females (p < 0.05). 3 alpha diolG serum levels (nmol/l +/- SD) correlated significantly with pubertal stage (p < 0.01). Interestingly, in 35 children with CAH serum 3 alpha diolG levels correlated well with clinical and metabolic status, i.e. 17OHP serum levels. In summary, we have established percentile curves for 3 alpha diolG levels in healthy children and adolescents. We hypothesize that on the basis of our reference values the single measurement of serum 3 alpha diolG could serve as a means to determine androgen status in children with disorders of puberty and sexual development.

Plasma 3 alpha-androstanediol glucuronide in normal children and in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Monitoring therapy for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase is difficult, although plasma determinations of 17 alpha-hydroxyprogesterone (17OHP), delta 4-androstenedione (delta 4A) and testosterone are helpful. We have studied the usefulness of monitoring plasma 3 alpha-androstanediol glucuronide (3 alpha-AG) in group of 24 CAH patients aged from birth to 18 years. For comparison, normal values for age and pubertal stage were determined in a control group of 115 girls and 118 boys. Mean plasma levels were higher during the first year of life, decreased to a nadir between 1 and 4 years, and increased steadily thereafter, there was also a significant increase with pubertal stage. In 24 pairs of blood samples obtained at the time of venopuncture and 2 h after, 3 alpha-AG levels did not change (p > 0.05) demonstrating that 3 alpha-AG levels were not affected by stress. In the patients with CAH, positive correlations between plasma 3 alpha-AG and delta 4A (females, r = 0.73; males, r = 0.98), 17OHP (females, r = 0.58; males, r = 0.84) and testosterone (females, r = 0.83; males, r = 0.97) were observed. Concordance between 3 alpha-AG and delta 4A was observed in 90% of all samples, and in 91% between 3 alpha-AG and testosterone. Our study demonstrates that 3 alpha-AG is a valid marker of control and its determination appears to be a reliable tool to monitor CAH.

Outcome of long-term treatment with the 5α-reductase inhibitor finasteride in idiopathic hirsutism: clinical and hormonal effects during a 1-year course of therapy and 1-year follow-up

To evaluate the long-term efficacy of the 5 alpha-reductase inhibitor finasteride in idiopathic hirsutism. Prospective clinical study. Outpatients in a university hospital. Fourteen young women with idiopathic hirsutism. Finasteride, 5 mg once daily, was given for 12 months. Degree of hirsutism, graded by a modified Ferriman and Gallwey score, serum sex hormones, and serum and urinary markers of 5 alpha-reductase activity. Clinical outcome was evaluated up to and including the 1-year post-treatment period. The Ferriman and Gallwey score showed a remarkable reduction after 12 months of finasteride treatment (4.4 +/- 0.7 versus 11.8 +/- 1.0; mean +/- SEM). Serum levels of the two 5 alpha-reductase activity markers, dihydrotestosterone and 3 alpha-androstanediol glucuronide, decreased, and urinary C19 and C21 5 beta:5 alpha steroid metabolite ratios consistently increased during finasteride administration. These changes were reversed readily after cessation of treatment. No significant adverse effect was reported. Nine of 14 women completed the 1-year post-treatment follow-up. Their hirsutism scores were increased substantially as compared with values recorded at the end of therapy, but still were lower than baseline values. The 5 alpha-reductase inhibitor finasteride is effective and well tolerated in longterm treatment of women with idiopathic hirsutism. Post-treatment follow-up suggests that drug effects on hair growth are sustained in the majority of subjects with this disorder.

Prospective study of sex hormone levels and risk of prostate cancer.

Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 4 years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (> 2.5 ng/mL) were excluded from the analyses. High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.

Hormones and Prostate Cancer: Where Do We Go From Here?

A striking phenomenon in prostate cancer epidemiology is that the prevalence of latent prostate tumors in most populations is similar (7), but the rates for clinical prostate cancer in U.S. men are 30-50 times higher than those for Asian men (7). Reasons for these disparities are unclear, although previous studies (7-5) have suggested racial differences in dietary fat intake, circulating levels of testosterone, intraprostatic activity of 5-alpha reductase (the enzyme that converts testosterone to the more potent dihydrotestosterone [DHT]), and polymorphisms of the androgen receptor (AR) gene (the intracellular receptor that binds DHT to form the DHT-AR complex that then binds to DNA to activate cell proliferation). Other than age, race, and a family history of prostate cancer, risk factors for prostate cancer are unknown (7). There are compelling reasons to believe that hormones, especially androgens, play a central role in prostate carcinogenesis. The growth and maintenance of the prostate are dependent on androgens (4), prostate cancer regresses following ablative or antiandrogen therapy (5), and testosterone can induce prostate cancer in laboratory rodents (6). However, epidemiologic data addressing hormonal hypotheses are limited and conflicting (7). In this issue of the Journal, Gann et al. (8) report their findings from a nested case-control study, using sera collected prior to prostate cancer diagnosis from a cohort of male physicians. In this study, higher levels of circulating testosterone and lower levels of estradiol and sex hormone-binding globulin (SHBG), a protein that binds about 56% of the circulating testosterone (9), are associated with increased risks of prostate cancer, while no association is found with DHT (the principal androgen within the prostate) or 3-alpha androstanediol glucuronide (a terminal metabolite of DHT that is used as an indirect measure of intraprostatic 5-alpha reductase activity) (9). Prospective nested case-control studies of this type provide better data for the tests of hormonal hypotheses than do casecontrol studies. Because blood was collected before the diagnosis of cancer, the possible impact of disease on hormonal levels is less profound and a temporal relationship can be established. To date, there are only five studies in which prediagnostic sera were used to examine the relationships of circulating hormones with subsequent prostate cancer risk (8,10-13). Results from these studies are inconsistent; positive associations were reported with androstenedione in one study, with testosterone-DHT ratio in two, and (weakly) with luteinizing hormone in one. Of these, Gann et al. is the largest and the first study to evaluate the role of 5-alpha reductase activity, using plasma levels of 3-alpha androstanediol glucuronide as a proxy measure. Although Gann et al. provide data consistent with a role for testosterone, a recent study by Nomura et al. (70), using a similar approach in a Japanese-American cohort in Hawaii, did not confirm this finding. The inconsistent results in these two well-designed studies may reflect, in part, the difficulties of measuring serum/plasma hormones in epidemiologic investigations. Sensitivity, specificity, and reliability of hormonal assays developed for clinical use need to be improved before they can be used for epidemiologic studies. The numbers of study subjects in most nested case-control studies are relatively small (<100) and the observed case-control differences are less than 15%, so that any potential noise, such as intra- and inter-person and laboratory variation, may influence hormonal assessment and case-control comparisons, leading to inconsistenci es between studies (14). To better interpret the case-control results, we need additional data on the reproducibility of hormonal assays, interrelationships among hormones, and factors influencing circulating levels of hormones.

The biochemical and phenotypic characterization of females homozygous for 5 alpha-reductase-2 deficiency.

The biochemical and physiologic manifestations of decreased 5 alpha-dihydrotestosterone (DHT) in females are characterized. Three females from the large Dominican kindred with 5 alpha-reductase-2 deficiency were identified as homozygous for a point mutation (R246W, C-->T) on exon 5 of the 5 alpha-reductase-2 gene by single strand DNA conformational polymorphism analysis and DNA sequence analysis. Body hair was decreased; there was no history of acne. Despite delayed menarche, all were fertile, and two had twins. Urinary 5 beta/5 alpha C19 and C21 steroid metabolite ratios were elevated. Plasma testosterone was normal to elevated, with low DHT, resulting in an increased testosterone/DHT ratio. 3 alpha,5 alpha-Androstanediol glucuronide was low. Menstrual cycle profiling performed in two subjects showed ovulatory gonadotropin peaks. Sebum production was normal. 5 alpha-Reductase-2-deficient homozygotic females demonstrate the importance of DHT in the physiology and pathophysiology of body hair growth. Normal sebum implies regulation by the 5 alpha-reductase-1 isoenzyme. Delayed puberty suggests involvement of 5 alpha-reductase-2 in menarche at the hypothalamic/pituitary and/or ovarian level. As two had nonidentical twins, DHT and/or the DHT/estradiol ratio may regulate follicular development, with lower levels permitting more than one dominant follicle per cycle and higher levels impairing follicular development and ovulation. Thus, females with 5 alpha-reductase-2 deficiency highlight a role for DHT in hirsutism and/or menstrual disorders.