Adrenal Androgen Levels Research Articles

Independence of Gonadotropin and Adrenal Androgen Secretion*

Five groups of 5 normal adult males have been studied. Group 1 received clomiphene, group 2 received exogenous FSH and group 3 testosterone. These three groups received drugs to stimulate LH and FSH, increase levels of FSH or suppress LH and FSH respectively. Circulating levels of testosterone (T), estrone (E1) and 17-hydroxyprogesterone (17-OHP) were altered while serum concentrations of androstenedione (A), dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DS) and urinary 17-ketosteroids (17-KS) were not. The other two groups of 5 adult males had adrenal androgen levels suppressed or stimulated while receiving dexamethasone or ACTH. Serum 17 OHP, A, DHA and DS levels and urinary 17 KS were affected while gonadotropins were unaltered. Hence, no relationship has been demonstrated between circulating levels of adrenal androgens and gonadotropins.

Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome

Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS. Sixty-nine healthy women (aged 19-62 yr; body mass index 19.2-35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18-59 yr; body mass index 19.0-42.9 kg/m2) participated in the study. The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min. Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels. Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.

Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome

Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS. Sixty-nine healthy women (aged 19–62 yr; body mass index 19.2–35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18–59 yr; body mass index 19.0–42.9 kg/m2) participated in the study. The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min. Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels. Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.

A Case of Pediatric Virilizing Adrenocortical Tumor Resulting in Hypothalamic-pituitary Activation and Central Precocious Puberty Following Surgical Removal

We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.

Lack of ACTH and Androgen Receptor Expression in a Giant Adrenal Myelolipoma Associated with 21-hydroxylase Deficiency

Myelolipomas of the adrenal gland are benign, nonfunctioning tumors. Patients with congenital adrenal hyperplasia sometimes develop large and bilateral myelolipomas. Although the precise pathogenesis of myelolipomas remains unclear, prolonged stimulation with high levels of adrenocorticotropic hormone (ACTH) or adrenal androgens are assumed to have a causative role. To clarify the role of ACTH and androgen in the pathogenesis of myelolipoma, we report a case of giant adrenal myelolipoma in a patient with poorly controlled congenital adrenal hyperplasia. A 43-year-old female was diagnosed with congenital adrenal hyperplasia at 6 years of age because of ambiguous genitalia. She had high plasma ACTH and 17-hydroxyprogesterone levels. Abdominal computed tomography showed a huge mass on the left adrenal gland, and an enlarged right adrenal mass. Genetic testing for CYP21A2 was performed and revealed that her genotype was IVS2-13A/C>G/I172N. Adrenalectomy for the left-side tumor was performed. Histological study revealed that the tumor consisted of fat cells and myeloid components, findings compatible with adrenal myelolipoma. Neither ACTH receptors nor androgen receptor was over-expressed in the tumor. Our finding that the tumor did not over-express ACTH or androgen receptor suggests a limited direct role for these hormones in the development of the myelolipoma.

Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche

There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA). We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA. We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). AR gene methylation-weighted CAG(n)(mwCAG(n)) via CAG(n) length and X-chromosome inactivation analysis and clinical phenotype were determined. The study took place at a university hospital. PA subjects had significantly shorter mwCAG(n) than controls [mean difference (95% confidence interval); 0.76 (0.14-1.38); P = 0.017]. AR gene mwCAG(n) did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAG(n) correlated positively with body mass index (BMI) (tau = 0.19; P = 0.02). The mean of mwCAG(n) was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI sd score < 0.79, n = 35, vs. BMI sd score > 0.79, n = 36; 1.13 (0.38-1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004). The AR gene CAG(n) polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.

Metabolism of adrenal androgen and its impacts on prostate cancer after castration

Metabolism of adrenal androgen and its impacts on prostate cancer after castration

EFFECT OF BODY WEIGHT ON BONE AGE AND HORMONAL PARAMETERS IN CHILDREN WITH PREMATURE ADRENARCHE

OBJECTIVE: Our goal was to investigate the effect of body weight on bone age (BA) and hormonal features in children with benign premature adrenarche. METHODS: We studied 221 children (175 girls, 46 boys) with premature adrenarche (pubic and/or axillary hair at &amp;lt;8 years of age in girls and &amp;lt;9 years of age in boys) and mean chronological age (CA) at presentation of 7.0 years (girls) and 7.8 years (boys). Anthropometric features and laboratory data (dehydroepiandrosterone sulfate [DHEA-S], 17-hydroxyprogesterone, Δ4-androstenedione [Δ4-A], testosterone, estradiol, insulin-like growth factor I [IGF-I], cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, and BA) were recorded. The population was divided into 3 groups according to BMI: (1) normal weight, (2) overweight (BMI: 85th–95th percentile), and (3) obese (BMI: &amp;gt;95th percentile). Children with late-onset congenital adrenal hyperplasia were excluded from study. RESULTS: Mean CA of adrenarche was 6.3 years (girls) and 7.1 years (boys). The percentages of overweight and obese children was significantly higher than those reported in the general population of children in Greece. Obese children had significantly more advanced BA compared with overweight and normal-weight children. Higher levels of DHEA-S and Δ4-A were observed in overweight and obese girls compared with normal-weight girls, whereas higher levels of DHEA-S, testosterone, and IFG-I were observed in overweight and obese boys (Table 1). No statistically significant difference was observed between the 3 groups in the levels of 17-hydroxyprogesterone, estradiol, cholesterol, triglycerides, or high- and low-density lipoprotein cholesterol. CONCLUSIONS: A higher frequency of obesity and advanced BA was observed in children with benign premature adrenarche, with a strong correlation between BA and degree of obesity. Furthermore, obese children were characterized by higher levels of adrenal androgens compared with normal-weight children. TABLE 1.Levels of Adrenal Androgens in Normal-Weight and Obese ChildrenNormal Weight Mean (Range)Overweight Mean (Range)Obese Mean (Range) P a Girls Testosterone, ng/mL0.11 (0.06–0.20)0.14 (0.10–0.21)0.16 (0.09–0.24).112 DHEAS, μg/mL0.71 (0.41–1.10)0.85 (0.61–1.15)0.88 (0.57–1.21)b.081 Δ 4-A, ng/mL0.4 (0.2–0.8)b0.6 (0.4–1.1)b0.6 (0.4–0.8)b&amp;lt;.05b IGF-1, ng/mL199 (140–318)236 (180–283)200 (190–266).681Boys Testosterone, ng/mL0.08 (0.04–0.15)b0.17 (0.06–0.26)b0.28 (0.09–0.39)b&amp;lt;.05b DHEAS, μg/mL0.51 (0.21–0.92)1.10 (0.82–1.24)b1.12 (0.20–2.12).056 Δ 4-A, ng/mL0.4 (0.2–0.7)0.5 (0.3–0.6)0.6 (0.4–1.0).524 IGF-1, ng/mL200 (89–257)b170 (116–207)b288 (267–369)b&amp;lt;.05baKruskal-Wallis test.bResults were significant.

Prenatal diagnosis and treatment of steroid 21-hydroxylase deficiency.

Steroid 21-hydroxylase deficiency (21-OHD) accounts for 90–95% of congenital adrenal hyperplasia (CAH) cases. It is classified into three distinct clinical phenotypes: the salt-wasting (SW), simple virilizing (SV) and nonclassical forms (NC). As girls with the SW and SV forms of 21-OHD are exposed to high systemic levels of adrenal androgens during fetal life, they show genital ambiguity. To ameliorate the degree of genital virilization, prenatal dexamethasone treatment has been performed for more than two decades, although mainly in the USA and Europe. This treatment has proven to be effective in preventing or reducing genital virilization. Some data also show that prenatal diagnosis and treatment are safe for the mother and fetus. However, prenatal treatment is still controversial for the following reasons. First, the risk of having an affected female fetus is only one in eight when both parents are known carriers of the autosomal recessive trait. Therefore, seven of eight fetuses will receive dexamethasone unnecessarily, and this raises ethical questions. Furthermore, maternal side effects such as excessive weight gain and hypertension have been observed. Finally, the long-term safety and outcome for dexamethasone-exposed children have not been established. In Japan, prenatal diagnosis and treatment has rarely been reported because of these reasons. Therefore, we must be cautious, and this treatment should be carried out in special centers with the approval of their ethical committees, that are capable of performing chorionic villus sampling (CVS) and subsequently determining the karyotype and genotype of 21-OHD.

Relationships of Urinary Adrenal Steroids at Age 8 Years with Birth Weight, Postnatal Growth, Blood Pressure, and Glucose Metabolism

Overactivity of the hypothalamic-pituitary-adrenal axis through a program set by early growth patterns is hypothesized to lead to central obesity, insulin resistance, and hypertension. We therefore examined links between adrenal steroid production and birth weight, rapid early growth, and body mass index (BMI), blood pressure, waist circumference, and resistance to insulin in early childhood through the action of adrenal steroids. Timed overnight urine samples were collected in 461 children from a large representative birth cohort. In total 244 boys and 188 girls aged 8.2-8.4 yr completed the protocol. The excretion rates of individual steroids were measured to determine total androgen and cortisol metabolites. Indices of activity of 5alpha-androgen reduction of androgens and cortisol metabolites and 11beta-hydroxy steroid dehydrogenase activity were calculated. In both boys and girls, total urinary androgen and cortisol metabolites were positively related to current height, weight, BMI, and waist circumference. Girls had higher urine androgen metabolite levels and 5alpha-androgen indexes than boys, and in girls higher androgen metabolite excretion was associated with lower birth weight and faster postnatal weight gain. After adjustment for current BMI, total cortisol metabolites and 11beta-hydroxy steroid dehydrogenase index were not related to birth weight or postnatal weight gain in either sex. These data confirm early growth associations in this cohort seen with plasma levels of adrenal androgens at age 8 yr, at least in girls. Larger studies and follow-up during puberty are needed to exclude the possibility of programming of cortisol metabolism by early growth.

Androgens in Women With Anorexia Nervosa and Normal-Weight Women With Hypothalamic Amenorrhea

Both anorexia nervosa and normal-weight hypothalamic amenorrhea feature hypogonadism and hypercortisolemia, but it is not clear whether these abnormalities reduce levels of adrenal and/or ovarian androgens or androgen precursors, or whether relative androgen deficiency results in abnormal bone mineral density (BMD) and body composition. The investigators hypothesized that levels of androgens and the preandrogen hormone dehydroepiandrosterone sulfate (DHEAS) are reduced in women with anorexia and also in normal-body-weight women with hypothalamic amenorrhea, and that further reductions would be associated with oral contraceptive use in anorexic women. Levels of total and free testosterone and DHEAS were estimated in 137 women with anorexia nervosa who were not on oral contraception, 32 others who were, 21 women of normal body weight who had hypothalamic amenorrhea, and 27 healthy control women of reproductive age. Levels of endogenous total and free testosterone-but not DHEAS-were lower in anorexic women than in control subjects. More marked reductions in both free testosterone and DHEAS were observed in anorexic women taking oral contraceptives. In contrast, normal-body-weight women with hypothalamic amenorrhea had normal levels of androgens and DHEAS. At most skeletal sites evaluated, lower levels of free and total testosterone as well as DHEAS correlated with lower BMD. In addition, levels of free testosterone correlated positively with fat-free mass. Both total and free testosterone levels were associated with levels of sex-hormone-binding globulin (SHBG), and mean levels of SHBG were higher in those anorexic women who were taking oral contraceptives. Interventional studies will be needed to learn whether oral contraceptive use, associated with reduced levels of endogenous androgens, has adverse skeletal effects on women with anorexia nervosa. Marked reductions in DHEAS were observed in the anorexic women receiving oral contraceptives.

A phase I trial of nordihydroguareacetic acid (NDGA) in patients with non-metastatic prostate cancer and rising PSA

15500 Background: NDGA is a butanediol with effects on tumor cells, including inhibition of insulin growth factor receptor (IGF-1R) autophosphorylation. In vitro studies suggest that NDGA attenuates androgen-mediated prostate cancer growth without competitive androgen receptor blockade. Its effects on PSA in pts were studied. Methods: Eligible pts included men with recurrent prostate cancer following definitive local therapy with a rising PSA and no metastasis. Both androgen dependent prostate cancer (PSA rising with a normal tesosterone - ADPC) and androgen independent prostate cancer (PSA rising with castrate level of testosterone - AIPC) was allowed. Treatment consisted of continuous oral daily dosing of NDGA according to a planned dose escalation of 750, 1,250, 1,750, 2,250 and 2,500 mg. Pts were followed for safety and changes in PSA and PSA doubling time (PSADT). Results: 15 pts were enrolled: 11 pts with ADPC and 4 pts with AIPC. Median baseline serum PSA was 3.6 ng/mL in ADPC pts and 5.74 mg/mL in AIPC pts. Median age was 66 (range 48–81). Following a median of 5.5 cycles (range 1–13), transaminase elevations occurred in five pts (33%): 1 gr 1, 1 gr 2 and 3 gr 3- all occurring in month 3 or later. Transaminase elevations resolved after drug discontinuation but recurred with repeated dosing. Doses up to 2,500 mg/day were otherwise well- tolerated. The median baseline PSADT was 6.1 months for ADPC and 6.7 months for AIPC and was and 8.4 months on therapy (p=0.12) for ADPC and 4.2 months for AIPC. Of 11 ADPC pts, one (9%) had a decline in PSA by &gt;50% compared to baseline and one (9%) had a decline of 3 fold increase in PSADT while on therapy, one from 11 to 46 months (750 mg), one from 9.5 to 49.5 months (1,750 mg), and one from 5.9 to 46.2 months (2,500 mg). There were no PSA reductions in the AIPC pts, however one pt had a &gt;3 fold increase in PSADT (from 1.4 to 7.5 months). No significant effects on testosterone, adrenal androgen or estradiol levels were observed while on study. Conclusions: NDGA is well tolerated with the exception of transaminase elevations which occur after approximately 3 cycles in a minority of patients. Combined with preclinical data, the modest effects on PSA kinetics suggest that further study on androgen dependent tumors is justified. No significant financial relationships to disclose.

Polycystic Ovary Syndrome: Implications of Corticotropin in the Regulation of Blood Pressure, Aldosterone, and Androgen Secretion

To the Editor: In a recent issue of Hypertension , Chen et al1 have described a correlation between androgen levels and blood pressure in young women with polycystic ovary syndrome (PCOS), and this correlation was independent from age, insulin resistance, obesity, and dyslipidemia. We would like to discuss other factors involved in the interpretation of these data. High adrenal androgen levels in women with PCOS can also be related to an increase of corticotropin (ACTH). The major question is why …

Adrenal Androgen Levels as Predictors of Outcome in Prostate Cancer Patients Treated with Ketoconazole Plus Antiandrogen Withdrawal: Results from a Cancer and Leukemia Group B Study

Adrenal androgens activate the androgen receptor and stimulate prostate cancer growth. Ketoconazole is used as an inhibitor of adrenal androgen synthesis in men with androgen-independent prostate cancer. This study analyzes the relationship between pretreatment androgen levels and outcome following ketoconazole treatment. Baseline levels of three adrenal androgens (androstenedione, dehydroepiandrostenedione, and dehydroepiandrostenedione-sulfate) and testosterone were measured. Regression models (logistic and proportional hazard) were used to assess the prognostic significance of these levels in predicting overall survival and prostate-specific antigen (PSA) response defined by Consensus Criteria. In 103 patients with available levels, PSA response rate was 28% and median response duration was 4.8 months. The median baseline androstenedione level was 0.64 ng/mL and was 0.88 ng/mL versus 0.53 ng/mL for those with and without a PSA response, respectively (P = 0.034). In univariate analysis, elevation of baseline androstenedione levels was predictive of PSA response [odds ratio, 2.26; 95% confidence interval (95% CI), 1.03-4.96; P = 0.043]. In multivariate analysis, both the uppermost and the middle tertile of baseline androstenedione level were associated with an improved overall survival compared with those in the lower tertile (hazard ratio, 0.59; 95% CI, 0.36-0.98; P = 0.40; hazard ratio, 0.53; 95% CI, 0.32-0.90; P = 0.018, respectively). A linear correlation was observed among all androgen levels. Higher androstenedione levels predict likelihood of response to ketoconazole and improved survival compared with patients with lower levels. These data suggest that therapy with ketoconazole is less effective in patients with low levels of androgen at baseline.

An Infant Case of Hyperprolactinemia Induced by a Functional Disorder of the Hypothalamus

Although functional hyperprolactinemia originating in the hypothalamus has been observed, there have so far been few reports of this condition occurring in children. This report describes a 1-yr-and-4-mo old boy with hyperprolactinemia due to functional disorder of the hypothalamic region. He was referred to our hospital because of left gynecomastia which had been observed for one month. His left breast development was stage II, right breast stage I, and pubic hair stage I by Tanner stages, and his bilateral testicular volume was 1 ml. Both his height and growth velocity were normal and his bone age was not advanced. The basal PRL level was high (40.4 ng/ml), but other sex steroids and adrenal androgen levels were normal. GnRH demonstrated the prepubertal stage. PRL response to TRH was normal and levodopa suppressed the increased basal PRL level. His chromosomal finding was 46, XY and macroprolactinemia was ruled out. Repeated MRI examinations did not demonstrate any organic lesions in the brain. He was diagnosed as having hyperprolactinemia induced by a functional disorder of the hypothalamus. His gynecomastia reduced and the high PRL level decreased without medication after 1 year.

Plasma testosterone and dehydroepiandrosterone sulfate in male and female patients with dysthymic disorder

Background Depressive symptomatology has been connected with an activation of the hypothalamus–pituitary–adrenal axis and, in several studies, with reduced androgen levels, while administration of androgens, usually in older subjects, may have positive effects on mood, both in males and females. Regarding dysthymic disorder (DD), low serum testosterone levels have been reported in older males, while information on younger male or on female patients is lacking. Methods We assessed the serum levels of testosterone (T), dehydroepiandrosterone sulfate (DHEAS) and cortisol in male and female patients with DD, and compared them to the levels of sex and age matched controls. Eighteen male and 43 female patients in the age range of 22 to 71 years were studied and diagnosed according to the Scheduled Diagnostic Interview for DSM-IV axis I disorders (SCID). Depressive symptomatology was assessed using the Hamilton Depression Rating Scale. Subgroups with subjects below or over 50 years of age were also built and compared. Results Serum T levels were lower than controls mainly in the subjects aged below 50 years, in both genders. More pronounced were reductions in DHEAS levels both in male and female patients, while cortisol levels were normal or reduced. T levels were positively correlated to both DHEAS and cortisol. The negative correlations of DHEAS and T to age were significant for all groups and subgroups, except in the group of male patients. Four male patients (22%) had T levels below 2.0 ng/ml. Conclusions Male and female patients with DD aged below 50 years show reduced gonadal and adrenal androgen levels, and normal to low cortisol levels. These neuroendocrine characteristics differentiate DD from depression, and place this diagnostic group closer to posttraumatic stress disorder.

Adrenal androgen and gonadal hormone levels in adolescent girls with conduct disorder

There are few data on the biological correlates of female antisocial behavior. This study compared adrenal androgen and gonadal hormone levels in adolescent girls with conduct disorder (CD) to girls without any psychiatric disorder (NC). We studied 87 girls, (47 CD; 36 NC), ages 15-17 years, obtaining three blood samples, drawn 20 min apart between 8 and 9 AM in the first 72 h of the onset of menstrual flow. Plasma was assayed for testosterone, estradiol, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), sex hormone binding globulin (SHBG), and cortisol; area under the curve (AUC) for each of the three samples was used in the data analysis. We also calculated the Free Testosterone Index, Free Estrogen Index, Index of Hyperandrogenism and cortisol to DHEA ratio. In addition to receiving a full psychiatric interview, each girl completed a self-report questionnaire on general aggression. Main hormone analyses controlled for potentially confounding variables such as psychiatric comorbidity and race. Girls with CD had significantly lower cortisol to DHEA ratios, but did not differ from NC girls on any other hormone variable. Girls with symptoms of aggressive CD had significantly higher mean free testosterone indexes, lower SHBG levels, and lower cortisol to DHEA ratios than girls with non-aggressive CD. Girls with CD scored higher on the aggression questionnaire, but there was no association between general aggression and any hormone variable for the sample. Our data suggest that girls with CD, particularly aggressive CD, have lower cortisol to DHEA ratios, higher levels of free testosterone, and lower levels of SHBG. Clinical and research implications of these findings are discussed.

Heritability of dehydroepiandrosterone sulfate in women with polycystic ovary syndrome and their sisters

To test the hypothesis that adrenal androgen (AA) secretion is an inherited trait in PCOS and that serum DHEAS concentrations, as a marker of AA secretion, will be correlated between women with PCOS and their sisters. Prospective case-control. Tertiary care center. Sixty-two PCOS probands and 69 sisters. None. The DHEAS concentrations and clinical phenotypes were obtained. Familial correlation between sisters was estimated. A variance components model was used to estimate the heritability (h(2)) of the DHEAS levels. Body mass index (BMI)-adjusted DHEAS levels were used in all of the analyses. There was no difference in age between the proband and sister groups (28.7 +/- 8.1 years vs. 28.0 +/- 8.8 years, P=.65), and probands had higher BMI values (33.4 +/- 7.6 kg/m(2) vs. 27.9 +/- 7.0 kg/m(2), P<.001). Sixteen of the 69 (23.2%) sisters were affected by PCOS. The sister-sister correlation of DHEAS level was 0.28 +/- 0.12 for the whole group (P<.05), and this correlation was higher, at 0.38 +/- 0.14 (P< or =.05), after excluding 31% of the affected sisters and 34% of the unaffected sisters who received hormonal therapy at or within 3 months of the time of the study. The h(2) estimates of DHEAS were 0.43 (P=.037) and 0.44 (P=.062) when all sisters and only untreated sisters, respectively, were included in the analysis. The correlation of serum DHEAS levels between PCOS probands and their sisters suggests a familial component in the regulation of DHEAS levels and possibly AA production in PCOS. The h(2) estimates of 0.43-0.44 for BMI-adjusted DHEAS suggest that genetic factors account for between 40% and 50% of the overall variation in DHEAS levels in these women. Our results support the hypothesis that circulating AA levels represent an inherited trait in PCOS.

Early and late weight gain and the timing of puberty

Nutrition is an important regulator of the tempo of growth and obesity is usually associated with tall childhood stature and earlier pubertal development. Several longitudinal studies have demonstrated that timing of puberty is most closely linked to infancy weight gain: suggesting an early window for programming of growth and development. Earlier puberty in the UK MRC 1946 birth cohort was related to smaller size at birth and rapid growth between 0 and 2 years. Rapid early weight gain leads to taller childhood stature and higher insulin-like growth factor I (IGF-I) levels, possibly through early induction of growth hormone (GH) receptor numbers, and such children are also at risk of childhood obesity. In the Avon Longitudinal Study of Parents and Children, rapid infancy weight gain was associated with increased risk of obesity at 5 and 8 years, with evidence of insulin resistance, exaggerated adrenarche and reduced levels of sex hormone binding globulin (SHBG). Potentially the elevated IGF-I and adrenal androgen levels, increased aromatase activity and increased ‘free’ sex steroid levels consequent to lower SHBG levels could all promote activity of the GnRH pulse generator. In addition obese children have higher leptin levels, a proven permissive factor in initiating LH pulsatility. Obesity could also affect the rate of progression through puberty as nutrition and SHBG may act respectively as an accelerator and brake on peripheral sex steroid action. Early weight gain and early pubertal development might also be associated with loss of the pubertal growth spurt perhaps through obesity-related suppression of GH secretion. Trans-generational recurrence of low birth weight, early catch-up weight gain, earlier menarche, and shorter adult stature have been observed in women, and could contribute to the strong heritability in age at menarche.

Anti–interleukin‐6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: A randomized, double‐blind, placebo‐controlled study

Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti-TNF therapy. This study investigated the influence on steroidogenesis of an interleukin-6 (IL-6)-neutralizing strategy using IL-6 receptor monoclonal antibodies (referred to as MRA). In a placebo-controlled, double-blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17beta-estradiol, as well as their respective molar ratios, were determined. MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA-treated patients (minimum P < 0.004). Serum levels of estrone and 17beta-estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001). Neutralization of IL-6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.