Hyperandrogenism In Adolescents Research Articles

119. Sclerosing Stromal Ovarian Tumors: A Rare Cause of Primary Amenorrhea and Hyperandrogenism in Adolescents

119. Sclerosing Stromal Ovarian Tumors: A Rare Cause of Primary Amenorrhea and Hyperandrogenism in Adolescents

Evaluation of Hormonal Profile and Ovarian Morphology among Adolescent Girls with Menstrual Irregularities in a Tertiary Care Centre at Central India.

Menstrual disturbances are common among adolescents with a prevalence rate of 11.3–26.7%. The most frequent menstrual irregularities are oligomenorrhea, menorrhagia, polymenorrhoea, and hypomenorrhea. PCOS (polycystic ovarian syndrome) is now recognized as the most prevalent endocrine disorder among the women of reproductive age. The current study was planned to evaluate socio-demographic factors, endocrine profiles, and ovarian morphology among adolescent girls with menstrual irregularities and compare these parameters in different phenotypes of adolescent PCOS cases. It is a hospital-based cross-sectional study among 248 adolescent girls (10–19 years) with menstrual irregularities. After obtaining informed consent, history and clinical examination findings were recorded on preform proforma. All girls were assessed on day 2/3 of the menstrual cycle for hormonal profile (serum TSH, FSH, LH, prolactin, and serum testosterone) and ovarian morphology (by transabdominal ultrasonography). All participating girls were divided into three groups (groups 1, 2, and 3) corresponding to phenotypes A, B, & D as per the Rotterdam criteria. In the study, oligomenorrhea was the most common menstrual disorder (70.97%). Biochemical hyperandrogenism and thyroid dysfunction were reported in 14.91% and 8.46% of girls, respectively. Our study noted that phenotype D ,i.e., group 3 (MI + PCOM-HA; 49.43%) was the most common phenotype in the study. In a comparative analysis of different groups, significant differences (p < 0.05) in hormonal and metabolic parameters showed highest in group 2, which represents phenotype B of PCOS (hyperandrogenic anovulation). This analysis revealed that adolescent hyperandrogenism (phenotypes A and B) is associated with a more deranged hormonal and metabolic profile than nonandrogenic PCOS (phenotype D). To prevent long-term sequelae, lifestyle changes, early treatment, and close follow-up are recommended in this subset of girls.

Modern approaches to the diagnosis and treatment of polycystic ovary syndrome in adolescence

Тhe diagnosis of polycystic ovary syndrome (PCOS) in adolescence still raises many questions. The problem is that the characteristics of normal puberty often coincide with the symptoms of PCOS. The article presents the criteria of a normal menstrual cycle, clinical and laboratory hyperandrogenism. In the diagnosis of the latter, the most informative indicators are the determination of the index of free testosterone and androstenedione, and the assessment of free and total testosterone are relatively low sensitivity. Clinical hyperandrogenism in adolescents includes only severe acne and hirsutism. The level of antimullerian hormone has no independent significance. Irregular menstrual cycles during the first year after menarche represent a normal period of puberty. At the second and third year after menarche , menstrual cycles of less than 21 days and more than 45 days are considered irregular, and from the fourth year – less than 21 days and more than 35 days. From the second year after menarche, menstrual irregularities are considered to be more than 90 days for any cycle. Primary amenorrhea is indicated by the absence of menarche at 15 years, or 3 years after telarche. Ultrasound is not used as a criterion for PCOS in the first 8 years after menarche due to the high frequency of ovarian multifollicularity in adolescence. Therefore, adolescent girls in the presence of menstrual disorders and hyperandrogenism may be diagnosed with «PCOS. Phenotype B» (ultrasound signs are not taken into account). Adolescents who have signs of PCOS but do not meet the diagnostic criteria are at risk for PCOS. The most important stage of PCOS therapy is lifestyle modification, normalization of body weight and metabolic processes. Combined oral contraceptives in adolescents are more often prescribed not for direct purposes (contraception), but as off-label therapy not only at diagnosis, but also in the «risk group», which involves the treatment of irregular menstrual cycles and / or clinical hyperandrogenism. In the absence of the effect of lifestyle changes, proper nutrition to correct metabolic disorders in addition to combined oral contraceptives may be prescribed metformin, inositol and etc.

Диагностика и тактика ведения пациенток с гиперандрогенией в раннем репродуктивном возрасте

Hyperandrogenism is characterized by the presence of clinical symptoms and / or biochemical parameters of high androgen levels. Dermopathy and particularly acne and hirsutism are regarded as the main clinical markers of hyperandrogenism. Cosmetic problems associated with hyperandrogenism are often the reason for young woman to seek medical attention. Body hair growth in atypical areas, acne and trophic skin changes have a significant effect on the emotional state, provoke a sense of imperfection and loss of attractiveness, and reduce the quality of life. Concomitant menstrual disorders (up to 50–75%) complicate the patient’s state and determine an increased risk of gynecological disorders in the future. The causes of hyperandrogenism in early reproductive age can be varied: from more common physiological hyperandrogenism in adolescence, idiopathic hyperandrogenism, polycystic ovary syndrome (PCOS) and the atypical form of congenital adrenal hyperplasia to less common hyperthecosis, acromegaly, hyperprolactinemia, hypothyroidism, Cushing’s disease, and androgen-secreting tumors. The diagnostic search should begin with assessing complaints and clinical symptoms, and a complete physical examination. To confirm biochemical hyperandrogenism, total and free testosterone, and free androgen index are evaluated. Additional methods of examination are used to clarify the diagnosis. Treatment is prescribed in accordance with the established diagnosis. Androgen-secreting tumors require surgical intervention. Other causes of hyperandrogenism are usually treated with medication. According to current recommendations, combined oral contraceptives are the first-line therapy for the most common conditions accompanied by hyperandrogenism (hirsutism, acne vulgaris, PCOS) in early reproductive age. A clinical solution may be a combined administration of microdoses of ethinylestradiol (20 μg) and drospirenone (3 mg), progestagen with antiandrogenic property in the mode 24 + 4 (for instance: Dimia). This article presents clinical cases of diagnosis and management tactics for patients of early reproductive age with hyperandrogenism. Conclusion. The differential diagnosis of physiological and pathological conditions accompanied by hyperandrogenism is one of the current challenges for obstetrician-gynecologist. A properly developed algorithm of examination, interpretation of its results, therapy and prevention of complications are of great importance. Key words: acne, alopecia acreata, congenital adrenal hyperplasia, hyperandrogenism, hirsutism, girls, drospirenone, combined oral contraceptives, contraception, adolescents, early reproductive age, polycystic ovary syndrome, ethinylestradiol

Sex Hormones, Gonad Size, and Metabolic Profile in Adolescent Girls Born Small for Gestational Age with Catch-up Growth.

To characterize and compare sex hormone concentrations, and uterine and ovarian volumes in adolescent girls born small for gestational age (SGA) who had experienced catch-up growth and girls born at a size appropriate for gestational age (AGA), and to investigate the association between these parameters and glucose metabolism, perinatal factors, and early growth. A prospective, longitudinal, observational study from birth until adolescence. Mean age at final assessment was 12.7±0.1years. We followed 55 girls (20 SGA, 35 AGA). Sex hormone concentrations (gonadotropins, estradiol, testosterone, and sex hormone binding globulin) were analyzed, and the oral glucose tolerance test conducted. Uterine and ovarian sizes were assessed using pelvic ultrasound. Uterine and ovarian volumes were smaller in SGA-born compared with AGA-born girls (P=.013 and P=.039, respectively). SGA girls had lower sex hormone binding globulin levels (P=.039) and higher testosterone levels (P=.003), free androgen index (P<.001), and glycemia 2hours post glucose load (P=.005) compared with AGA-born girls. Birth weight and early infancy height velocity explained 37.4% of variation in ovarian volume (P=.004), and body mass index at birth, increase in peripheral skinfold thickness during second year of life, and early childhood height velocity explained 43.2% of variation in testosterone levels in adolescence (P=.006). SGA-born girls who experienced catch-up growth remain at risk of biochemical hyperandrogenism in adolescence, and have reduced uterine and ovarian volumes, which might influence future reproductive function. Ovarian size and androgen levels in adolescence might be influenced by early growth and subcutaneous fat deposition.

Polycystic Ovary Syndrome in Adolescents: Challenges in Diagnosis and Treatment.

ContextDespite the importance of timely diagnosis and treatment of polycystic ovary syndrome (PCOS) among adolescent females, considering the paucity of data focusing on this group and controversies documented on its recognition and management, the purpose of this review was to summarize challenges and recommendations of diagnosis and treatment for adolescents with PCOS.Evidence AcquisitionThis review summarizes papers documented on PCOS among adolescent females. PubMed, Scopus, Web of Science, and Google Scholar databases were searched for retrieving studies conducted on PCOS among adolescent females up to March, 2019. The final selection of papers was made based on their relevancy with the fields of diagnosis and treatment of PCOS in this age group.ResultsOligo-anovulation in adolescents, if persistent, is a matter for concern. Hirsutism and moderate to severe acne in adolescent females should be considered as clinical manifestations of hyperandrogenism (HA). Diagnosis of biochemical HA in adolescents with PCOS requires reliable tests using well-defined normal ranges. In adolescent females, an elevated androgen level (hyperandrogenemia) alone is not enough to detect HA, unless it is persistent and associated with anovulation. Metabolic disorders should not be used as diagnostic criteria of PCOS among adolescent females. Re-assessment of all adolescent females with probable PCOS, using reliable diagnostic criteria, is needed to avoid over diagnosis and unnecessary treatment in healthy normal females without HA. In adolescent females with PCOS, the main clinical problem is the control of menstrual irregularity and hirsutism; treatment approaches for these patients are primarily directed at the major clinical manifestations and complaints. Lifestyle modifications are baseline interventions, which can be added to special treatments, such as Oral Contraceptives (OCs), metformin, or antiandrogens for most adolescents with PCOS, particularly those with overweight or obesity.ConclusionsThis review emphasizes the use of standard diagnostic criteria for PCOS, developed for adolescents. Although early recognition and management of PCOS in adolescents can prevent long-term complications associated with this syndrome, clinicians should re-evaluate all such patients with features very similar to PCOS to avoid over/incorrect diagnosis using precise criteria, suggested for this age group.

Effect of metformin on clinical and biochemical hyperandrogenism in adolescent girls with type 1 diabetes.

Background Hyperandrogenism with or without polycystic ovarian syndrome is seen in adolescents with type 1 diabetes (T1D), especially those with suboptimal control. Objective To assess the effect of metformin on hyperandrogenism and ovarian function in adolescents with T1D. Methods This prospective study included 28 T1D females showing signs of hyperandrogenism. History taking (detailed diabetes history and menstrual history) and anthropometric measurements (weight, height, body mass index [BMI], waist and hip circumference) were initially performed, and then the patients were assessed for the manifestations of hyperandrogenism (acne, hirsutism as well as pelvic ultrasound [U/S] for ovarian morphology). Biochemical evaluation for ovulation (progesterone assessment during the luteal phase), sex steroids (estradiol, testosterone, dehydroepiandrosterone sulfate [DHEAS] and androstenedione), prolactin, glycemic control (hemoglobin A1c [HbA1c]) and gonadotropin levels (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) was done. Patients were subjected to 500 mg metformin twice daily orally for 1 year, and then the patients were re-evaluated for clinical and biochemical parameters. Results Metformin therapy resulted in a significant reduction in weight (p = 0.001), BMI (p = 0.002), acne (p = 0.008), hirsutism score (0.007), LH (p = 0.008), testosterone (p < 0.001) and androstenedione levels (p = 0.028) in adolescent girls with T1D. Regarding menstrual irregularities, there was a significant reduction in the number of patients with oligomenorrhea (68%) with a p value of <0.001. However, there were no significant reduction in the daily insulin requirements (p = 0.782) or HbA1c (p = 0.068). Nausea and/or abdominal pain were the commonly reported side effects of metformin (64%). Conclusions Metformin as an insulin sensitizing agent improved the BMI and cycle regularity together with clinical and biochemical hyperandrogenism in T1D adolescent girls. However, it did not improve their glycemic control.

Adolesan Dönemi Hiperandrojenizminde Bazal Hormonal Değerler ve Radyolojik Görüntüleme Yeterli mi?

Adolesan Dönemi Hiperandrojenizminde Bazal Hormonal Değerler ve Radyolojik Görüntüleme Yeterli mi?

Premature Adrenarche.

Adrenarche is when a child's adrenal cortex starts to secrete adrenal androgen precursors. Dehydroepiandrosterone (DHEA) is the most abundant product of the adrenal cortex, and is a weak androgen agonist thought to be responsible for the clinical signs of pubarche by conversion to more potent androgens, testosterone, and dihydrotestosterone. DHEA's extra-adrenal sulfation product, dehydroepiandrosterone sulfate, is a stable marker for adrenal androgenic activity. Pubarche is the physical manifestation of androgenic hormone production, and includes the development of pubic and axillary hair, adult body odor, and acne. This stage is usually considered premature if it commences before age 8 years in girls or age 9 years in boys. Premature adrenarche is a diagnosis of exclusion, as true centrally mediated precocious puberty, congenital adrenal hyperplasia, exogenous androgen exposure, and androgen-secreting tumors must be ruled out. Premature adrenarche may be associated with a history of an infant who was small for gestational age at birth who then gained weight rapidly thereafter or became obese. In some instances, premature adrenarche may predict functional ovarian hyperandrogenism in adolescence. Management of premature adrenarche is largely aimed at observation, lifestyle adjustments for weight concerns, and monitoring for future possible persistent androgen excess and insulin resistance. [Pediatr Ann. 2018;47(1):e7-e11.].

Very low dose of flutamide in the treatment of hyperandrogenism

Hyperandrogenism is a condition affecting 5–10% of adolescents. The aim of this study was to evaluate the efficacy of very low dose of flutamide in the treatment of hyperandrogenism in adolescence. One hundred and fifty-eight patients, presenting severe acne and/or hirsutism, received 62.5 mg/day of flutamide + ethinylestradiol + gestodene for 18 months. The patients were subjected to assessments of hepatic enzymes levels. Thirty subjects treated with drospirenone + ethinylestradiol represented the control group. After 18 months of treatment, it was obtained a decrease of hirsutism (−39.9%), an almost recovery of acne (98% of patients) with better results of those obtained in control group. Only one case of light hypertransaminasemia was recorded, regressed spontaneously. Very low dose of flutamide was successful and safe and in the treatment of hyperandrogenism in adolescence.

Progesterone Suppression of Luteinizing Hormone Pulse Frequency in Adolescent Girls With Hyperandrogenism: Effects of Metformin.

Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely. To test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA. Nonrandomized, interventional trial. Academic clinical research unit. Ten adolescent girls with HA. The girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed. Metformin-related change in hypothalamic P4 sensitivity index [percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level]. Free T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use. Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.

Can the source of hyperandrogenism in adolescents with polycystic ovary syndrome predict metabolic phenotype?

In this study, we demonstrated an association between adrenal hyperandrogenism, as determined by dehydroepiandrostenedione-to-free testosterone (DHEA-S/FT) ratio, and metabolic phenotype in obese and lean adolescents with polycystic ovary syndrome (PCOS). We compared 64 overweight/obese adolescents with PCOS (PCOS-O) with 18 lean (PCOS-L) adolescents. We analyzed the association between DHEA-S/FT ratios and metabolic parameters. Patients in the PCOS-O group were younger (median [interquartile range]) than those in the PCOS-L group (15 [15-17] vs. 16 [16–17] years; p = .04). The median DHEA-S/FT ratio and total testosterone concentrations did not differ. However, androstenedione concentrations were higher in the PCOS-L group (p = .02) and free testosterone levels lower in the PCOS-L group compared with the PCOS-O group (p = .02). Insulin resistance was present in 30 of 64 (46.9%) adolescents with PCOS-O compared with 1 of 18 (5.6%) with PCOS-L (p = .001). A significant negative correlation between DHEA-S/FT ratios and insulin concentrations in PCOS-O (p = .03) and PCOS-L (p = .04) groups was noted. In the PCOS-O group, the DHEA-S/FT ratio was negatively associated with serum triglyceride (p = .03) and total cholesterol concentrations (p = .02). We conclude that in adolescents with PCOS, a higher ratio of adrenal to ovarian androgens, signified by DHEA-S/FT, may be associated with a more favorable metabolic phenotype.

Anti-Müllerian hormone: correlation with testosterone and oligo- or amenorrhoea in female adolescence in a population-based cohort study.

STUDY QUESTIONSCan serum anti-Müllerian hormone (AMH) levels measured in female adolescents predict polycystic ovary syndrome (PCOS)-associated features in adolescence and early adulthood?SUMMARY ANSWERAMH levels associated well with PCOS-associated features (such as testosterone levels and oligoamenorrhoea) in adolescence, but was not an ideal marker to predict PCOS-associated features in early adulthood.WHAT IS KNOWN ALREADYSeveral studies have reported that there is a strong correlation between antral follicle count and serum AMH levels and that women with PCOS/PCO have significantly higher serum AMH levels than women with normal ovaries. Other studies have reported an association between AMH serum levels and hyperandrogenism in adolescence, but none has prospectively assessed AMH as a risk predictor for developing features of PCOS during adulthood.STUDY DESIGN, SIZE, DURATIONA subset of 400 girls was selected from the prospective population-based Northern Finland Birth Cohort 1986 (n = 4567 at age 16 and n = 4503 at age 26). The population has been followed from 1986 to the present.PARTICIPANTS/MATERIAL, SETTING, METHODSAt age 16, 400 girls (100 from each testosterone quartile: 50 with oligo- or amenorrhoea and 50 with a normal menstrual cycle) were selected at random from the cohort for AMH measurement. Metabolic parameters were also assessed at age 16 in all participants. Postal questionnaires enquired about oligo- or amenorrhoea, hirsutism, contraceptive use and reproductive health at ages 16 and 26.MAIN RESULTS AND ROLE OF CHANCEThere was a significant correlation between AMH and testosterone at age 16 (r = 0.36, P < 0.001). AMH levels at age 16 were significantly higher among girls with oligo- or amenorrhoea compared with girls with normal menstrual cycles (35.9 pmol/l [95% CI: 33.2;38.6] versus 27.7 pmol/l [95% CI: 25.0;30.4], P < 0.001). AMH at age 16 was higher in girls who developed hirsutism at age 26 compared with the non-hirsute group (31.4 pmol/l [95% CI 27.1;36.5] versus 25.8 pmol/l [95% CI 23.3;28.6], P = 0.036). AMH at age 16 was also higher in women with PCOS at age 26 compared with the non-PCOS subjects (38.1 pmol/l [95% CI 29.1;48.4] versus 30.2 pmol/l [95% CI 27.9;32.4], P = 0.044). The sensitivity and specificity of the AMH (cut-off 22.5 pmol/l) for predicting PCOS at age 26 was 85.7 and 37.5%, respectively. The addition of testosterone did not significantly improve the accuracy of the test. There was no significant correlation between AMH levels and metabolic indices at age 16.IMPLICATIONS, REASONS FOR CAUTIONAMH is related to oligo- or amenorrhoea in adolescence, but it is not a good marker for metabolic factors. The relatively low rate of participation in the questionnaire at age 26 may also have affected the results. AMH was measured in a subset of the whole cohort. AMH measurement is lacking international standardization and therefore the concentrations and cut-off points are method dependent.WIDER IMPLICATIONS FOR THE FINDINGSUsing a high enough cut-off value of AMH to predict which adolescents are likely to develop PCOS in adulthood could help to manage the condition from an early age due to a good sensitivity. However, because of its low specificity, it is not an ideal diagnostic marker, and its routine use in clinical practice cannot, at present, be recommended.STUDY FUNDINGS AND COMPETING INTERESTSThe study was funded by a grant from Wellcome Trust (089549/Z/09/Z) to H.L., S.F. and M.-R.J. Study funding was also received from Oulu University Hospital Research Funds, Sigrid Juselius Foundation and the Academy of Finland. None of the authors have any competing interest to declare.

Metformin for the Treatment of Hyperandrogenism in Adolescents with Type 1 Diabetes Mellitus

Background: A high prevalence of hyperandrogenism has been reported in women with type 1 diabetes (T1D). Metformin has been used as a therapeutic agent in patients with polycystic ovarian syndrome and in T1D patients without hyperandrogenism. This study sought to determine the effect of metformin on hyperandrogenism and ovarian function in adolescents with T1D. Methods: We recruited 24 girls with T1D. The participants had hyperandrogenism and displayed suboptimal metabolic control. The patients were enrolled in a randomized, double-blind, placebo-controlled trial. One group received metformin (850 mg bid) and the other group received a placebo. Treatment was administered for 9 months. Ovulation, steroids and gonadotropin levels were evaluated. Results: Metformin treatment was associated with decreases in testosterone, free androgen index, androstenedione, 17-OH progesterone and estradiol levels. The girls who were treated with placebo showed stable steroid, gonadotropin and sex hormone-binding globulin levels during the analysis. No differences were observed in the Ferriman-Gallwey scores, ovulation rates, HbA_1c levels or daily insulin doses of the girls treated with metformin compared with the placebo group. Conclusion: Treating hyperandrogenic T1D adolescents with metformin significantly decreased the serum androgens compared to the placebo, but metformin therapy did not significantly affect clinical parameters, such as hirsutism, ovulation and metabolic control.

Ovarian hyperandrogenism in adolescents and young women with type I diabetes is primarily related to birth weight and body mass index

To clarify the effects of insulin therapy on ovarian androgen production, hyperandrogenism and polycystic ovary syndrome (PCOS) in adolescents and young women with type 1 diabetes (T1D). Case-control study. Children's research hospital. Fifty-four consecutive T1D subjects (age, 15-25 years), without residual endogenous insulin secretion, treated by intensive insulin therapy (multiple injection therapy [MI] or continuous SC insulin infusion [CSII]); and one-hundred fifty age-matched healthy women. Analysis of the prevalence and risk factors of ovarian hyperandrogenism and PCOS in T1D adolescents and young women. Biometric, glycemic, and metabolic parameters. Evaluation of androgen levels and ovary ultrasound during the early follicular phase of the menstrual cycle. Androgen levels were significantly higher in T1D subjects than in the control group (T, 68.8 ± 23.4 vs. 46.1 ± 20.8 ng/dL). Four subjects (7.4%) were affected by PCOS according to the Rotterdam criteria. No correlation was evident between HbA1c% and androgen levels. No significant differences were evident between subjects on MI or CSII therapy. Multivariable linear regression analysis showed a direct and independent effect of age and body mass index on T levels. T levels were also negatively affected by birth weight. Androgen levels are significantly increased in T1D adolescents and young women treated by intensive insulin therapy. The presence and severity of ovarian hyperandrogenism seem to be primarily related to common risk factors such as age, low birth weight, overweight, and obesity.

Polycystic Ovary Syndrome: A Model of Combinatorial Endocrinology?

The clinical research study reported herein by Blank et al. (1) identified insulin as the factor that explained the variable sensitivity to progesterone-induced slowing of GnRH-LH drive previously described in Tanner stage 3–5 hyperandrogenic adolescent girls (2). Specifically, the current analysis revealed that resistance of LH pulsatility to progesterone-induced slowing was proportional to fasting insulin in that group. The authors posited that increased GnRH drive in adolescent girls is a form fruste or precursor of polycystic ovary syndrome (PCOS). This line of investigation buttresses the notion that understanding the neuromodulation of GnRH is critical to explicating the pathobiology of PCOS (3). By providing an explicit example of a critical concept in what could be termed combinatorial endocrinology, namely, that the action of a hormone depends on its context, the study also provides another lesson that is not specific to understanding PCOS. Using this latest insight into the brain phenotype of PCOS as an example, we can infer that the final phenotype of other complex syndromes that present with variation in key features likely represents the interaction of several relevant parameters. Context in endocrinology would include not only age and sex but also time of day and current and possibly past endocrine and metabolic status among other variables. The authors found that LH sensitivity to suppression by progesterone was not due to insulin resistance or androgen excess, a notion that has consumed the field for decades, but rather insulin resistance and androgen excess. That both insulin resistance and increased androgen action confer the full brain phenotype in PCOS may explain the group’s earlier results showing that dampening of androgen action with the anti-androgen flutamide restored GnRH-LH sensitivity to progesterone suppression in PCOS (4). An interaction between insulin resistance and androgen excess appears to explain the brain phenotype of PCOS better than either parameter alone. Argument by analogy would suggest that PCOS is unlikely to be the only endocrine syndrome attributable to a complex interaction of multiple parameters. Dichotomization is a fundamental analytic approach used to isolate causality and the foundation of scientific inquiry and design, but it has limits. Unless explicitly built into the study design, dichotomization into an either/or question does not permit a test of interaction. But physiology and pathophysiology reflect systems biology and combinatorial dynamics. Failure to account for interaction likely explains some of why cellular studies often do not a whole organism describe; conversely, understanding context-specific hormone action may well help to put into perspective the physiological relevance of cellular studies. For instance, ovarian steroids have been shown to alter potassium channel functioning on hypothalamic GnRH neurons and to modulate GnRH neuronal output via this mechanism (5, 6). Not surprisingly, K(ATP) channels also mediated responsiveness to glucose and metabolic inhibition (7). The cellular and rodent models help us to understand the mechanisms that might underlie the current pathophysiological results in the uniquely human condition of female adolescent hyperandrogenism and, vice versa, the human results provide a firm rationale for conducting rodent and cellular studies. It is but a small leap to now imagine that alterations of this type in GnRH cellular physiology would confer differential sensitivity to subsequent insulin exposure and that both the past and current hormone soup might determine the functional characteristics of the GnRH pulse generator. Because synergism exists between insulin and LH in theca cells and because that insight helped to explain the ovarian phenotype found in PCOS, it should come as no surprise that the neuroendocrine apparatus would operate similarly. Indeed, when attempting to discern whether stress-induced suppression of GnRH drive was due to psychogenic or energy challenge, we found profound synergism between psychogenic and metabolic challenge (8). Likewise, Gibbs et al. found that estradiol restored learning in aged female rats, but only in the presence of a cholinesterase inhibitor (9). Given these considerations, the astute study designer is advised to consider whether the investigative approach will permit elucidating “and” as well as “or.” In complex disease, adaptations, and aging, the whole really is greater than the sum of the parts. It is time to remember this dictum not only in the clinic when we are treating patients but also in the experimental setting

Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

Adult women with polycystic ovary syndrome (PCOS) have decreased GnRH pulse generator sensitivity to progesterone (P)-mediated slowing. This defect is androgen mediated because it is reversed with androgen receptor blockade. Adolescent hyperandrogenism often precedes PCOS. The aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls. We conducted a controlled interventional study. The study was conducted in a general clinical research center. A total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied. Frequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P. We measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope). Overall, Tanner 3-5 HA subjects were less sensitive to P-mediated slowing than Tanner 3-5 NC (slope, 4.7 +/- 3.4 vs. 10.3 +/- 7.7; P = 0.006). However, there was variability in the responses of HA subjects; 15 had P sensitivities within the range seen in NC, whereas nine were relatively P insensitive. The two groups had similar testosterone levels. Fasting insulin levels were higher in P-insensitive HA girls (39.6 +/- 30.6 vs. 22.2 +/- 13.9 microIU/ml; P = 0.02), and there was an inverse relationship between fasting insulin and P sensitivity in HA girls (P = 0.02). Tanner 1-2 NC had lower testosterone levels and were more P sensitive than Tanner 3-5 NC (slope, 19.3 +/- 5.8; P = 0.04). Hyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity.

Variation in Ovarian Morphology and Biochemical Markers of Hyperandrogenism in Adolescents with Polycystic Ovary Syndrome

Background: Perimenarchal onset of polycystic ovary syndrome (PCOS), the most common endocrinopathy of the premenopausal years, is increasingly appreciated. In adolescents meeting clinical criteria for PCOS, transabdominal pelvic ultrasonography (TAUS) is often utilized for evaluation of ovarian morphology. While polycystic appearing ovaries (PCO) constitute a diagnostic criterion for PCOS (Rotterdam criteria 2003), it remains to be determined if PCO as assessed by TAUS in adolescents tracks with other diagnostic criteria of PCOS such as biochemical hyperandrogenism.

Clinical expression of polycystic ovary syndrome in adolescent girls

Polycystic ovary syndrome (PCOS) is one of the major causes of adolescent hyperandrogenism and menstrual disorders. Because there is no universal definition for adolescent PCOS, we recommend four out of five criteria: clinical and biologic evidence of hyperandrogenism, hyperinsulinism, oligo-/amenorrhea, and polycystic ovaries on ultrasonography.

Adolescents with Hyperandrogenism: When It's More Than Puberty

To characterize hyperandrogenism in adolescents and identify clinical and laboratory features that facilitate its diagnosis and treatment, investigators performed a retrospective chart review of female patients seen at an adolescent medicine clinic who had at least one abnormal lab parameter. The 154 patients had abnormal levels of total or free testosterone or sex-hormone-binding globulin. Their mean age was 16.1 years, 70% were white, and their mean body-mass index (BMI) was …