Hyperandrogenism In Adolescents Research Articles

Adolescent androgen abnormalities.

Polycystic ovary syndrome is one of the most common endocrinopathies affecting premenopausal women. This review focuses on this major cause of hyperandrogenism in adolescents and young women, highlighting new diagnostic and therapeutic strategies that are under investigation. The pathophysiologic role in the disorder are the subject of several recent reports. Recent studies have found a 33% prevalence of abnormal glucose tolerance in a cohort of affected adolescents, higher fasting insulin levels and lower insulin sensitivity, and that glucose tolerance testing appears to be necessary for routine screening. The effects of hyperinsulinism may be counteracted by insulin sensitizing agents. In adult women with polycystic ovary syndrome, metformin treatment reduced hyperinsulinemia and hyperandrogenemia. In some obese adolescents, metformin therapy resulted in declines in body mass index, insulin, and glucose. Restoration of regular menses may also occur after metformin treatment. Thus, data is accumulating that insulin-sensitizing agents may be helpful in decreasing the pathophysiologic effects of hyperinsulinism and insulin resistance associated with polycystic ovary syndrome. Other hormonal alterations in polycystic ovary syndrome have also been the subject of recent reports. Leptin secretion was found to be markedly irregular in these women. Elevated LH secretion may be secondary to accelerated gonadotropin-releasing hormone pulse generator activity, although the etiology of the pulse alterations is unclear. Although polycystic ovary syndrome is the most common endocrine disorder affecting young women, it is one of the least understood, reflected by the wealth of research in this area. One area of focus has been the pathophysiologic link between insulin resistance and this disorder, including the effects of promising new agents to counteract these effects.

Inter- and intrafamilial variability in premature pubarche and polycystic ovary syndrome

Objective: To ascertain the extent of phenotypic heterogeneity for premature pubarche and polycystic ovary syndrome between and within families. Design: Association study. Setting: Academic research environment. Patient(s): Three families in which the propositus had presented with either premature pubic hair or adolescent hyperandrogenism. Intervention(s): Detailed medical histories, hormone determinations, and genotype analyses. Main Outcome Measure(s): Clinical phenotype. Genotypes for CYP21, HSD3B2, G972R variant of IRS-1, N363S variant of GRL, W64R variant of ADRB3, CAG repeat in exon 1 of AR, MspAI polymorphism in CYP17, and R264C variant of CYP19. Result(s): Significant phenotypic and genetic heterogeneity was observed both within and between families. In one family, CYP21 and IRS-1 variants were observed to co-segregate with symptoms of androgen excess and obesity. No genetic markers were consistently noted to associate with clinical features of hyperandrogenism in the other two families. Conclusion(s): The difficulties in classifying female family members as clearly affected or unaffected and lack of definitive male phenotype complicate the use of linkage analysis to identify the polycystic ovary syndrome genes. Each family is best considered on an individual basis to identify genetic markers that segregate with the clinical features of androgen excess.

Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance.

Functional adrenal hyperandrogenism occurs in women with polycystic ovary syndrome (PCOS). Insulin, similar to its ovarian effect, may impact the regulation of adrenal steroidogenesis by modulating the activity of P450c17alpha, the rate-limiting enzyme in androgen biosynthesis. We previously demonstrated that obese adolescents with PCOS are severely insulin resistant and are at heightened risk for impaired glucose tolerance and type 2 diabetes. In the present study we tested the hypothesis that metformin therapy in obese adolescents with PCOS will attenuate the adrenal steroidogenic response to ACTH, with reduction of insulin resistance/insulinemia. Fifteen adolescents with PCOS and impaired glucose tolerance received 3 months of metformin (850 mg, twice daily) therapy. Pre- and posttherapy they had oral glucose tolerance testing, ACTH stimulation test, a 3-h hyperinsulinemic (80 mU/m(2).min)-euglycemic clamp to assess insulin sensitivity and a hyperglycemic clamp to assess insulin secretion. After 3 months of metformin treatment, glucose intolerance improved, with eight subjects having normal glucose tolerance. Total and free T decreased [1.5 +/- 0.2 vs. 1.0 +/- 0.1 nmol/liter (P = 0.022) and 41.3 +/- 8.3 vs. 22.2 +/- 2.1 pmol/liter (P = 0.028), respectively]. Insulin-stimulated glucose disposal increased (21.5 +/- 2.2 vs. 25.0 +/- 2.2 micromol/kg.min; P = 0.041). Fasting insulin and oral glucose tolerance test insulin and glucose area under the curve decreased significantly. ACTH-stimulated increases in androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone were lower after metformin treatment [2.8 +/- 0.4 vs. 1.7 +/- 0.3 nmol/liter (P = 0.014), 7.0 +/- 0.6 vs. 5.3 +/- 0.5 nmol/liter (P = 0.011), and 30.4 +/- 3.7 vs. 25.7 +/- 4.2 nmol/liter (P = 0.054)]. Fasting insulin correlated with the 17-hydroxypregnenelone response to ACTH stimulation (r = 0.52; P = 0.008). In summary, metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels. Moreover, metformin therapy is associated with attenuation of the adrenal steroidogenic response to ACTH. Metformin therapy was well tolerated. In conclusion, double blind, placebo-controlled studies will determine whether insulin-sensitizing therapy corrects not only ovarian hyperandrogenism but also functional adrenal hyperandrogenism in adolescents with PCOS.

Candidate gene analysis in premature pubarche and adolescent hyperandrogenism

Objective: To identify genetic markers associated with premature pubarche in children and hyperandrogenism in adolescent girls. Design: Association study. Setting: Academic research environment. Patient(s): Forty children with premature pubarche (PP), 29 adolescent girls with hyperandrogenism (HA), and 15 healthy control women. Intervention(s): None. Main Outcome Measure(s): Genetic variations at five loci selected because of known associations with hyperandrogenism, insulin resistance, hyperinsulinemia, or obesity. Result(s): Heterozygosity for CYP21 mutations was identified in 14 of 40 (35%) PP, 8 of 29 (28%) HA, and 1 of 30 (3%) controls. Heterozygosity for HSD3B2 variants was identified in 3 of 40 (7.5%) PP, 5 of 29 (17%) HA, and 0/15 controls. Among the PP, 11 of 80 (14%), 5 of 80 (6%), and 7 of 80 (9%) alleles showed the IRS-1, GRL, and ADRB3 variants, respectively. Among the HA, 5 of 58 (8.6%), 3 of 58 (5%), and 6 of 58 (10%) alleles showed the IRS-1, GRL, and ADRB3 variants, respectively. Among the control participants, variant allele frequency was 1 of 30 (3.3%) for IRS-1, 2 of 30 (6.6%) for GRL, and 2 of 30 (6.6%) for ADRB3. Conclusion(s): Our findings suggest that the development of PP and HA can be associated with the occurrence of multiple sequence variants at five susceptibility loci, especially steroidogenic enzyme genes. This approach offers a novel paradigm to investigate and identify the genetic factors relevant to polycystic ovary syndrome.

Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche.

Girls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so-called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH-dependent 17-ketosteroid excess. Data were longitudinally collected from 47 girls with PP: at birth (weight for gestational age), at diagnosis of PP (age 6.7+/- 1.1 years) and in adolescence (age 15.0+/-1.9 years). Serum dehydroepiandrosterone sulphate (DHEAS) and androstenedione were measured at PP diagnosis, as well as the 17-hydroxyprogesterone (17-OHP) response to ACTH; postpubertal evaluation included assessment of adrenal and ovarian function, and of insulin responses to a glucose load. PP girls were considered to have FAH in adolescence if both DHEA and androstenedione responses to ACTH were excessive (> 1500 ng/dl and > 350 ng/dl, respectively). At diagnosis of PP, girls had high DHEAS and androstenedione levels, as well as high 17-OHP responses to ACTH. In adolescence, PP girls had a normal BMI, presented with mild hirsutism and had high baseline and post-ACTH concentrations of most adrenal androgens, low SHBG levels and tended to have hyperinsulinemia and to present biological signs of ovarian hyperandrogenism. More than a third of the PP cohort developed FAH in adolescence. Neither baseline DHEAS, androstenedione, nor post-ACTH 17-OHP values at diagnosis of PP predicted the development of FAH in adolescence. In PP girls, only a low weight at birth was found to be significantly associated with subsequent FAH. These longitudinal findings in girls with PP point to the possibility of an endocrine sequence of prenatal onset: low weight at birth, PP in childhood and adrenal hyperandrogenism in adolescence. The pathophysiological mechanisms underpinning this newly recognized sequence remain to be identified.

Glucocorticoid Resistance in Premature Pubarche and Adolescent Hyperandrogenism

To determine whether glucocorticoid resistance due to mutations in the glucocorticoid receptor (GRL) gene is associated with premature pubarche, hirsutism, or oligo/amenorrhea, we performed single-strand conformational polymorphism analysis of genomic DNA obtained from 25 children and 16 adolescent girls referred for the evaluation of premature pubarche, hirsutism, or oligo/amenorrhea. A missense mutation, N363S, and a presumed polymorphism in the 3′-UTR of exon 9α were identified. We conclude that glucocorticoid resistance due toGRLmutations is an infrequent cause of mild hyperandrogenism.

17α-Hydroxylase/17,20-Lyase Dysregulation Is Not Caused by Mutations in the Coding Regions of CYP17

Study ObjectiveTo determine whether mutations occur in the 17α-hydroxylase/17,20-lyase (CYP17) gene in patients with mild hyperandrogenism. DesignClinical and molecular genetic study. SettingPediatric endocrine outpatient clinic in an academic research environment. ParticipantsGirls (n = 11) referred for evaluation of premature pubic hair and adolescent girls (n = 16) referred for evaluation of hirsutism and/or oligomenorrhea. InterventionsNone. Main Outcome MeasuresMutation detection analysis of the coding regions and intron/exon boundary regions of the CYP17 gene. ResultsTwo polymorphic nucleotides were identified in the CYP17 gene. No mutations were detected in the 27 subjects. ConclusionMutation detection studies presented herein exelude CYP17 as a candidate gene for premature pubic hair and adolescent hyperandrogenism.

Hyperandrogenism and Manifesting Heterozygotes for 21-Hydroxylase Deficiency

Premature adrenarche and functional adolescent androgen excess are common disorders which may evolve into polycystic ovary syndrome (PCOS). In all three disorders, ACTH-stimulated 17-hydroxyprogesterone concentrations are often somewhat elevated. To determine the role of 21-hydroxylase (CYP21) gene mutations in these disorders, we performed molecular genotype analysis on 48 children and adolescents referred for evaluation of hyperandrogenic findings and diagnosed as having premature adrenarche or functional androgen excess. For comparison, DNA samples from 80 healthy adults were genotyped. Seventeen of the 48 hyperandrogenic patients were found to be heterozygotic carriers of CYP21 mutations. The frequency of heterozygosity was significantly greater among symptomatic patients (35%) than among the healthy controls (6%),P< 0.001. Seven mutation-positive patients (50%) and only one mutation-negative patient had ACTH-stimulated 17-hydroxyprogesterone concentrations typical for heterozygotic carriers of 21-hydroxylase deficiency, 400–1000 ng/dl. The significant difference in heterozygote frequency between symptomatic patients and healthy controls suggests that heterozygosity for 21-hydroxylase deficiency may be associated with premature adrenarche and functional adolescent hyperandrogenism. Longitudinal studies are necessary to determine if heterozygosity for 21-hydroxylase deficiency predicts risk for PCOS.

Analysis of the Type II 3β-Hydroxysteroid Dehydrogenase Gene in Patients with Nonclassical Congenital Adrenal Hyperplasia, Premature Pubarche, and Hyperandrogenism. † 407

Mild 3β-hydroxysteroid dehydrogenase deficiency (NC3βHSDD) may cause premature pubarche (PP) and adolescent hyperandrogenism (HA). To test our hypothesis, we analyzed the type II 3β-HSD gene for mutations in 7 female patients (3PP, 4HA) who fit diagnostic criteria for NC3βHSDD, including steroid hormone responses to ACTH stimulation. An additional 37 female patients (22PP, 15HA) were also studied. Polymerase chain reaction(PCR) oligonucleotide primers specific for the type II 3β-HSD gene were used for single strand conformational polymorphism (SSCP) analysis of the coding region of the gene. Of the 44 patients studied, 4 patients (Table) were heterozygous for the same conformer. Sequence analysis of this conformer showed 2 point mutations in the 3′-untranslated region (3′-UTR), C8815G and A8921G. Restriction digest of PCR amplified genomic DNA confirmed these base changes occurred on the same allele. A fifth patient had a different conformer due to heterozygosity for a missense mutation (A167V). Neither unique conformer was detected in 100 healthy controls, p <0.008 by Fischer Exact Test.

Antiandrogen cyproterone acetate as an alternative treatment for polycystic ovary syndrome, acne and hirsutis in adolescence

Period of adolescence has been identified as age group of otherwise healthy population, but at risk. During maturational processes of hypothalamo-pituitary-ovarian axis menstrual dysfunction and anovulatory cycles are common and often short lived; yet in some cases they may lead into persistent hyperandrogenism like PCOS, acne and hirsutism. In the Adolescent Clinics in National University Hospital and School Health Services long follow-up of cases with menstrual disorders has been conducted, also relating to 150 adolescents with PCOS, 52% of them had acne and hirsutism. Uniform investigations of patients included clinical features, hormonal investigations, ultrasound findings and psychological screening. Typical features for the group, treatment options and prognosis for future reproductive abilities are discussed in detail. The majority of patients (82.6%) were treated with anti-androgen cyproterone acetate in a preparation containing 2mg + 35ug ethinyl Estradiol in three weeks course per month. Following treatment acne resolved completely or showed visible improvement in 93.7%. Varying degree of improvement in hirsutism were noted in 60.8% of girls. Importantly cyclic function either was normalised or improved in 62.7% of girls. However the situation remained unchanged in 11.3% and in 26% worsened. In our opinion complete management of adolescent PCOS should include medical correction of hormonal disbalance, body weight correction and psychological intervention to ensure healthy adulthood and normal reproductive function. Implications of hyperandrogenism in adolescence are multifaceted. Immediate concerns are menstrual irregularities, hirsutism and acne associated with PCOS, but long standing possible hazards in adult life are impaired fertility, oestrogen dependent maJignancies and insulin resistance related conditions. In addition to mentioned health hazards it has become clear that adolescent girls with PCOS show low self-esteem and high degrees of psychological distress.

Effect of a combination of ethinylestradiol and desogestrel in adolescents with oligomenorrhea and ovarian hyperandrogenism

Nine oligomenorrheic adolescent girls with a clinical and hormonal picture of ovarian hyperandrogenism were treated with a monophasic oral contraceptive (OC) containing 0.03 mg ethinylestradiol (EE) plus 0.150 mg desogestrel (DOG) for six months. The same treatment was administered in eight eumenorrheic adolescents. In both groups the treatment induced a decrease in LH, FSH, androstenedione (Δ4-A), testosterone (T) and dehydroepiandrosterone sulphate (DHEA-S) levels associated with a significant sex-hormone-binding globulin (SHBG) increase. In oligomenorrheic adolescents a marked decrease in both the total ovarian volume and the number of cystic follicles was observed. All parameters, except SHBG and ovarian volume in hyperandrogenic girls, returned to pre-treatment values 3 months after treatment. Subjective improvement of skin problems occurred in six of the nine oligomenorrheic girls. Although temporary, the EE + DOG formulation pill is effective in the treatment of ovarian hyperandrogenism in adolescents. It may also be useful for the prevention of the progressive transformation in the ‘classical’ and ‘irreversible’ micropolycystic ovary of adult age.