Adrenal Androgen Levels Research Articles

Congenital Adrenal Hyperplasia: A Review of Current Knowledge and Future Directions

Introduction: Congenital adrenal hyperplasia (CAH) is a group of diseases in which genetic defects occur that disturb the synthesis of cortisol. The most common variant of CAH (95%-99%) is caused by 21-hydroxylase deficiency as a result of mutations in the CYP21A2 gene and is one of the most common monogenic diseases. CAH is characterized by androgen overproduction along with variable degrees of cortisol and aldosterone deficiency. Age at diagnosis can provide some information about the underlying mutations, with those diagnosed at birth/early infancy being at greater risk of developing serious enzyme defects. Classic and non-classical forms of this disorder have been described in the literature. CAH diagnosis is based on the clinical presentation, hormonal panel, Adrenocorticotropic Hormone (ACTH) stimulation test, and genetic testing. The main goals of treatment for congenital adrenal hyperplasia are glucocorticoid/mineralcorticoid supplementation, control of high adrenal androgen levels, fertility control, genetic counseling, and optimization of patients’ quality of life. Purpose of the work: This study aims to review and characterize the clinical and pathophysiological aspects of congenital adrenal hyperplasia. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 Results: Congenital adrenal hyperplasia is a heterogeneous group of genetic disorders that can lead to serious and even fatal complications in the form of adrenal crisis. Therefore, screening tests and early diagnosis are crucial and can save the lives of newborns. Treatment should be individualized and allow patients to achieve normal growth, sexual development, fertility and a better quality of life.

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia

BackgroundAdrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH.MethodsIn this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control.ResultsAll 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was −27.3% in the crinecerfont group and −10.3% in the placebo group (least-squares mean difference, −17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (−299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, −345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups.ConclusionsAmong patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.)

Fertility and sexual activity in patients with Triple A syndrome.

Triple A syndrome, caused by autosomal recessively inherited mutations in the AAAS gene is characterized by alacrima, achalasia, adrenal insufficiency, and neurological impairment. To the best of our knowledge, no patients of both sexes have been reported to have offspring. Our aim was to assess the causes of infertility in male patients with this multisystemic syndrome, and to present a female patient that spontaneously conceived a child. Cross-sectional study. Six males aged 19-48 years were included. Gonadotropins, testosterone, DHEAS, androstenedione, inhibin B, anti-Mullerian hormone measurements and testicular ultrasound were performed. All six male patients had impaired general health and neurological symptoms including erectile and ejaculatory dysfunction. None of them had an offspring. The only demonstrated cause of infertility in our male patients was erectile and ejaculatory dysfunction which precludes sexual intercourse. Our patients had normal libido but were sexually abstinent. Except for low adrenal androgen levels, the concentrations of all measured hormones as well as testicular ultrasound were normal which may indicate the possibility of spermatogenesis in male patients with triple A syndrome. Little is known about fertility in female patients, but based on our observations spontaneous pregnancies seem to be possible. Our results contribute to still scarce knowledge on fertility in patients with Triple A syndrome and as well represents a foundation for further research on causes of infertility and possible treatment options.

Ovarian reserve and fertility parameters in post-pubertal females with congenital adrenal hyperplasia: a case-control study.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder characterized by impaired activity of the enzyme required for cortisol and aldosterone production, resulting in increased adrenal androgen synthesis. Factors affecting fertility in CAH patients include ambiguous genitalia and their complications, excessive androgen secretion, adrenal progesterone hypersecretion, and various psychosocial factors. Serum anti-Müllerian hormone (AMH) level is used to assess ovarian reserve in women. A few data on serum AMH levels in CAH patients are available in the literature. The aim of the study was to evaluate ovarian reserve in a group of post-menarche females diagnosed with CAH by measuring serum AMH level and assessing the number of antral follicles sonographically. A case-control study was conducted on 17 post-pubertal CAH females and 17 age-matched healthy female controls; the mean age of the patient group was 15.09±3.55 years ranging from 11 to 24 years, while the mean age of the control group was 16.04±3.72 years ranging from 12 to 25 years, the mean post-menarchal age of the patients group was 3.29±1.37 years ranging from 1 to 6 years while the mean post-menarchal age of the control group was 4.13±1.62 years ranging from 1 to 9 years. The degree of hirsutism was compared between the two groups according to the modified Ferriman-Gallwey score, clitoral length was assessed using a digital caliber. Serum levels of adrenal androgens in addition to basal levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and serum AMH were measured in both groups. Patients had smaller uterine volumes, and smaller ovarian volumes but a comparable number of antral follicles and comparable serum AMH levels relative to controls. Good compliance with treatment in patients with CAH results in good hormonal control, low risk of PCOS, good fertility parameters, and a good ovarian reserve.

OR35-05 Interaction of Cortisol with Testosterone Predicts Abdominal Fat Mass in Normal-weight Polycystic Ovary Syndrome Women with Normal Serum 11-Oxygenated Androgens

Abstract Disclosure: D.A. Dumesic: Consulting Fee; Self; Ferring Pharmaceuticals, Precede Biosciences, Inc, Spruce Biosciences, Inc. Grant Recipient; Self; National Institutes of Health. A.F. Turcu: None. H. Liu: None. T.R. Grogan: None. D.H. Abbott: None. G. Lu: None. D. Dharanipragada: None. G.D. Chazenbalk: None. Adrenal and ovarian steroidogenesis are interwoven with endocrine-metabolic dysfunction into polycystic ovary syndrome (PCOS). Women with PCOS and normal weight have androgen excess along with preferential abdominal adipose deposition (1,2), which is partially reversed by androgen receptor blockade (3). The role of adrenal steroids in this relationship, however, remains unclear. The present study examines whether serum levels of 11-oxygenated adrenal androgens, cortisol and/or cortisone differ between normal-weight PCOS women and body mass index (BMI)/age-matched normo-androgenic ovulatory women (controls) and whether adrenal steroids associate with abdominal adipose deposition. Twenty normal-weight PCOS women and 20 age- and BMI-matched controls underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing and total-body dual-energy x-ray absorptiometry. Clinical characteristics and hormonal values were compared between PCOS and control subjects. An unpaired Student’s t-test and Pearson correlation coefficients, adjusting for serum cortisol, were used as appropriate. Serum total/free testosterone (T) and androstenedione (A4) levels, and android/gynoid fat mass ratio, were greater in PCOS women with low-normal insulin sensitivity than in controls (all androgens P&amp;lt;0.001; android/gynoid fat mass ratio, P=0.026). A positive correlation of serum androgens with android/gynoid fat mass ratio was observed in all women combined (total T: R=+0.41, P=0.013; free T: R=+0.49, P=0.003; A4: R=+0.45, P=0.006). Serum 11ß-hydroxyA4 (11OHA4), 11-ketoA4 (11KA4), 11ß-hydroxyT (11OHT) and 11-ketoT (11KT), cortisol and cortisone levels were comparable between PCOS women and controls, and were unrelated to body fat distribution. Serum 11-oxygenated adrenal androgens correlated negatively with % total body fat (11OHA4: R=-0.42, P=0.011; 11KA4: R=-0.34, P=0.046; 11OHT: R=-0.36, P=0.031; 11KT: R=-0.37, P=0.027), but were no longer significant when adjusting for a concomitant negative relationship of serum cortisol with % total body fat (R=-0.45, P=0.006). Serum cortisol levels also correlated negatively with android fat mass in all women combined (R=-0.38, P=0.021) and were accompanied by a trend (P=0.075) towards reduced serum cortisol to cortisone ratio, as a marker of reduced 11β-hydroxysteroid dehydrogenase type 1 (HSD11ß1) conversion of cortisone to cortisol, in PCOS women versus controls (P=0.075). Ratios of 11KT/11KA4 and 11KT/11OHT as markers of AKR1C3and HSD11ß2 activities, respectively, did not differ by female type (both enzyme markers, P=nonsignificant). Conclusion: Reduced cortisol action, mediated in part through decreased HSD11ß1, interacts with an elevated androgens pathway to determine abdominal fat mass in normal-weight PCOS women with normal serum 11-oxygenated androgens.

Challenges in the treatment of late-identified untreated congenital adrenal hyperplasia due to CYP11B1 deficiency: Lessons from a developing country.

Congenital Adrenal Hyperplasia (CAH) due to CYP11B1 is a rare autosomal recessive adrenal disorder that causes a decrease in cortisol production and accumulation of adrenal androgens and steroid precursors with mineralocorticoid activity. Clinical manifestations include cortisol deficiency, ambiguous genitalia in females (differences of sex development (DSD)), and hypertension. Medical treatment recommendations are well defined, consisting of glucocorticoid treatment to substitute glucocorticoid deficiency and consequently normalize adrenal androgen and precursors levels. Current guidelines also emphasize the need for specialized multidisciplinary DSD teams and psychosocial support. In many developing countries, care for DSD patients, especially when caused by an adrenal disease, is challenging due to the lack of infrastructure, knowledge, and medication. The study aims to report the conflicting decision-making process of medical treatment and sex assignment in late-identified CAH patients in developing countries. We describe the clinical and biochemical findings and the psychological assessment of five affected but untreated family members with CAH due to CYP11B1 deficiency. All patients had a 46,XX karyotype, ambiguous genitalia, low cortisol levels, and hypertension. Two identified as males, two as females, and one had undecided gender. The patients were counselled that refusing treatment will lead to infertility and the potential risk of developing Addisonian crisis and severe hypertension. However, all 46,XX CAH males refused treatment with glucocorticoids due to the expected lowering of adrenal androgens as their main source of testosterone. None of the patients developed Addisonian crisis, probably due to some residual cortisol activity and glucocorticoid activity of elevated adrenal steroid precursors. Medical treatment and sex assignment in late-identified 46,XX CAH patients in Indonesia may often depend on local and cultural factors. The management of DSD conditions may have to be individualized and integrated into the psychological and social context of the affected family.

Challenges in treatment of patients with non-classic congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.

This Month in Adult Urology.

This Month in Adult Urology.

Changes in Serum Testosterone and Adrenal Androgen Levels in Transgender Women With and Without Gonadectomy.

Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy. Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry. After 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, -19.4 to -17.4, P < 0.001 [ie, -97.1%]), 383 pmol/L (95% CI, -405 to -362, P < 0.001 [ie, -98.3%]), and 1.2 nmol/L (95% CI, -1.4 to -1.0, P < 0.001 [ie, -36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, -9.7 to -5.1 [ie, -28.0%]) and 1.8 µmol/L (95% CI, -2.2 to -1.4 [ie, -20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy. Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.

047 Multifactorial obesity: The influence of obesity on pubertal development and the HPG axis

Around 370 million children worldwide are overweight or obese [DiCesare], which poses a serious threat to global health perspective. Obesity is a disease, which means that once obese, the biological systems change to a different setpoint which makes losing weight with lifestyle intervention only very difficult. We know that nutritional status is an important regulator of growth and puberty. This presentation will focus on the impact of obesity in children on growth and puberty. BMI gain as well as obesity are related to an increased height gain during childhood and taller stature. However, not at birth or at 18 years. One of the explanations is that obese children stop growing earlier because they have an advanced bone age. Several hormones are suggested as possible mediators for this effect on growth and bone age: insulin, leptin or sex steroids like androgens or estrogens. No definite candidate has been identified yet, but both leptin and estrogen are important hormones in activating the hypothalamic-pituitary-gonadal axis. Leptin is a hormone produced by fat tissue. It informs the brain on the body’s energy storage. When there is too little, the body will not enter puberty, which costs a lot of energy. Estrogen is produces by gonads, but also by adipose tissue by aromatization of androgens into estrogens. Adrenal androgen levels are increased in children with obesity. Data from large cohort studies show that BMI and obesity are associated with early start of puberty, early pubarche and younger age of menarche. Physicians treating children and adolescents need to bear in mind that childhood obesity is associated with alterations in growth and pubertal development [ 1 Di Cesare M. Sorić M. Bovet P. Miranda J.J. Bhutta Z. Stevens G.A. Laxmaiah A. et al. The epidemiological burden of obesity in childhood: a worldwide epidemic requiring urgent action. BMC Med. 2019; 17: 212 Crossref PubMed Scopus (269) Google Scholar , 2 de Groot C.J. van den Berg A. Ballieux B. Kroon H.M. Rings E.H.H.M. Wit J.M. et al. Determinants of advanced bone age in childhood obesity. Horm Res Paediatr. 2017; 87: 254-263 Crossref PubMed Scopus (21) Google Scholar , 3 He Q. Karlberg J. Bmi in childhood and its association with height gain, timing of puberty, and final height. Pediatr Res. 2001; 49 Crossref PubMed Scopus (319) Google Scholar , 4 Sørensen K. Mouritsen A. Aksglaede L. Hagen C.P. Mogensen S.S. Juul A. Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty. Horm Res Paediatr. 2012; 77: 137-145 Crossref PubMed Scopus (215) Google Scholar , 5 Eckert-Lind C. Busch A.S. Petersen J.H. Biro F.M. Butler G. Bräuner E.V. Juul A. Worldwide secular trends in age at pubertal onset assessed by breast development among girls: A systematic review and meta-analysis. JAMA Pediatr. 2020; 174: e195881 Crossref PubMed Scopus (84) Google Scholar ].

RARE CASE OF OVARIAN STEROID CELL TUMOR NOT OTHERWISE SPECIFIED IN A POSTMENOPAUSAL WOMAN

Ovarian steroid cell tumors, not otherwise specified (NOS), are rare ovarian sex cord–stromal tumors with malignant potential. They represent less than 0.1% of all ovarian neoplasms. Little is known about this tumor, it is rare, and only a small number of case reports are available in the literature. This type of tumor can &nbsp;produce testosterone, leading to hyperandrogenism, virilization and amenorrhea. Postmenopausal occurrences are rare. We present&nbsp; a 60-year-old woman with onset of virilization, worsening alopecia and excessive growth of hair on abdominal and genital parts of the body. She has elevated levels of adrenal androgens. Radiologic studies were consistent with left sided ovarian changes. A diagnostic and therapeutic bilateral salpingo-oophorectomy confirmed steroid cell tumor NOS in both ovaries. Post-operatively, the patient had complete resolution of her symptoms and normalization of testosterone levels. Keywords: ovarian steroid cell tumor, ovarian neoplasma, hyperandrogenism, virilization. &nbsp

Cellular Senescence in Adrenocortical Biology and Its Disorders.

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

Statins and adrenal androgen levels in prostate cancer: A new twist

Statins inhibit HMGCoA reductase, the rate-liming step in the mevalonate (MVA) synthesis pathway that generates metabolites essential in multiple metabolic and signaling pathways, including both cholesterol-derived (e.g. steroid hormones, oxysterols, vitamin D, bile acids) and non-sterol derived products (e.g. lipoproteins, dolichol, ubiquinone, isoprenoid intermediates.) Statins are associated with pleiotropic cholesterol-related and unrelated anti-tumour properties including anti-oxidant, anti-inflammatory, immune-modulatory and anti-proliferative effects.

Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess

CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)

Changes in Adrenal Androgens and Steroidogenic Enzyme Activities From Ages 2, 4, to 6 Years: A Prospective Cohort Study.

The levels of adrenal androgens are increased through the action of steroidogenic enzymes with morphological changes in the adrenal zona reticularis. We investigated longitudinal changes in androgen levels and steroidogenic enzyme activities during early childhood. From a prospective children's cohort, the Environment and Development of Children cohort, 114 boys and 86 girls with available blood samples from ages 2, 4, and 6 years were included. Serum concentrations of adrenal androgens using liquid chromatography-tandem mass spectrometry and steroidogenic enzyme activity calculated by the precursor/product ratio. During ages 2 to 4 years, 17,20-lyase and dehydroepiandrosterone (DHEA) sulfotransferase activities increased (P < 0.01 for both in boys). During ages 4 to 6 years, 17,20-lyase activity persistently increased, but 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD activities decreased (P < 0.01 for all). Serum DHEA sulfate (DHEA-S) levels persistently increased from 2, 4, to 6 years, and DHEA, 17-hydroxyprogesterone, and androstenedione levels increased during ages 4 to 6 years (P < 0.01 for all). Serum DHEA-S levels during early childhood were associated with body mass index z-scores (P = 0.001 in only boys). This study supports in vivo human evidence of increased 17,20-lyase and DHEA sulfotransferase activities and decreased 3β-HSD activity during early childhood.

SUN-173 A Gigantic Uterine Leiomyoma and Big Bilateral Adrenal Myelolipomas as a Result of Untreated Congenital Adrenal Hyperplasia

IntroductionPatients with untreated congenital adrenal hyperplasia (CAH) can present early with severe symptoms of salt wasting, adrenal insufficiency and hyperandrogenism. Late consequences as a result of long term untreated CAH are rarely seen nowadays. We present a patient who presented with a massive uterine leiomyoma and bilateral adrenal myelolipomas due to longstanding treatment noncompliance.Clinical CaseA female was born with ambiguous genitalia and diagnosed with CAH at birth. She was raised as a female and received steroids until age 29 when she stopped taking steroids on her own with the intention of identifying as a male. At age 37, he presented with abdominal distension, vomiting, and hypotension. Physical exam was notable for hypotension, significantly distended abdomen, hirsutism, gynecomastia and clitoromegaly. Labs revealed sodium 126 meq/L (136–145) cortisol 78.5 ug/dL (3.7–19.4), ACTH 166 pg/mL (6–50), 17-hydroxyprogesterone 4356 ng/dL (≤285), androstenedione 7188 ng/dL (35–250), total testosterone 737 ng/dL (2–45), estradiol 142 pg/mL (48–440), aldosterone <1 ng/dL (3–16), renin 0.45 ng/mL/hr (0.25–5.82), metanephrines 56 pg/mL (≤205), normetanephrines 56 pg/mL (≤148). CT abdomen and pelvis revealed a large 31 x 35 x 31 cm pelvic mass, a 5.9 x 2.4 cm right adrenal mass and an 11.8 x 8.8 cm left adrenal mass. The patient underwent total abdominal hysterectomy and bilateral adrenalectomy. Pathology of the pelvic mass was consistent with uterine leiomyoma (gross tumor was 12.4 kg) and pathology of the bilateral adrenal masses were consistent with bilateral adrenal myelolipomas.DiscussionGlucocorticoids and mineralocorticoids are the mainstays of treatment in CAH, with the goal of providing adequate replacement while reducing levels of ACTH and adrenal androgens. Persistently elevated levels of ACTH and androgens can lead to many serious sequela, even outside of adrenal insufficiency and virilization. Due to the conversion of androgens to estrogens, untreated females with CAH have significantly elevated levels of both hormones. These high levels of androgens and estrogen can then stimulate growth of estrogen-dependent organs as exemplified by our patient. Chronic ACTH stimulation can cause adrenal hyperplasia, but has also been associated with the development of other adrenal masses including adrenal myelolipomas. Adrenal myelolipomas can become hormonally functional or cause mass effect, hemorrhage, necrosis when reaching a large enough size.ConclusionThis case demonstrates the importance of CAH treatment compliance as there are many serious sequela outside of the expected adrenal insufficiency and virilization. Even when the desired effect is virilization with physical male features, other means of hormonal therapy should be considered as there remains the risks of abnormal growth of certain organs sensitive to the excessive hormones.

MON-183 Adrenal Androgen Control and Steroidal Side Effects in Adolescents and Adults with Congenital Adrenal Hyperplasia Treated with Glucocorticoids

Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive disorder that results in little or no cortisol biosynthesis, increased production of precursor steroids, and excess production of adrenal androgens. Glucocorticoid (GC) treatment, the current standard of care for CAH, is used to correct cortisol deficiency and reduce excessive androgens. Elevated 17-hydroxyprogesterone (17OHP) is used for diagnosis and management. GC titration to achieve 17OHP <1000 ng/dL may be targeted for adrenal androgen control; however, patients with 17OHP <1000 ng/dL might be at risk for complications of long-term GC excess. This real-world study evaluated adrenal androgen levels and potential GC complications in adolescents and adults with CAH. Methods: TriNetX, a research network that includes electronic medical records from >37 million U.S. patients, was searched on 30Aug2019 for patients who met the following criteria: diagnosis code of E25.0 (ICD-10) or 255.2 (ICD-9); history of GC use; available 17OHP laboratory result; and ≥15 years of age (“grown”) at the most recent 17OHP assessment. Patients were categorized as “adequately controlled” (17OHP <1000 ng/dL) or “poorly controlled” (17OHP ≥1000 ng/dL). Assessments included: demographics; laboratory results for 17OHP, adrenocorticotropic hormone (ACTH), and androstenedione (A4); and low-density lipoprotein (LDL). Adequately vs. poorly controlled groups were compared using Chi-square tests and t-tests. Results: Of 511 grown CAH patients, 352 were adequately controlled and 159 were poorly controlled. Mean concentrations for 17OHP were 244 and 5939 ng/dL in the adequately and poorly controlled cohorts, respectively (p<0.01). Adequately controlled patients also had lower ACTH and A4 than poorly controlled patients: ACTH (72 vs 389 pg/mL, p<0.01); A4 (82 vs 256 ng/dL, p<0.01). Compared to poorly controlled patients, adequately controlled patients were more likely to be female (81% vs 57%, p<0.01) and older (mean birth year: 1981 vs 1986, p<0.01). Adequately controlled patients also had evidence of more metabolic and infection complications, including higher mean LDL (105 vs 94.3 mg/dL, p=0.02), more type 2 diabetes mellitus (9% vs 4%, p=0.08), and more respiratory tract infections (21% vs 11%, p=0.01). Conclusions: In this retrospective analysis, patients with adequately controlled CAH (17OHP <1000 ng/dL) had better adrenal androgen control (lower A4) but also higher rates of complications potentially related to excessive GC exposure. These findings highlight the current challenges of managing CAH with GC regimens alone.

A prospective study examining trigger factors and hormonal abnormalities in adult female acne

Background:Numerous triggers have been implicated in adult female acne including endogenous (hormonal dysfunction and genetic predisposition) and exogenous causes (drugs, cosmetics, sunscreens, stress, and smoking).Aims:To evaluate the role of various trigger factors in adult female acne and to analyze the androgenic hormone pattern including anti-Mullerian hormone (AMH) in these patients.Materials and Methods:Patients having acne of age ≥25 years were analyzed using a pre devised proforma to elicit trigger factors while the severity was graded using the Global Acne Grading System (GAGS). A detailed hormonal assessment was undertaken that assessed total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), AMH, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin.Results:Out of the 165 cases seen and sub-analyzed for triggers, premenstrual flare, diet, cosmetics, and stress were the most commonly implicated causes. Among cosmetics, fairness creams and foundations were implicated. The hormonal analysis revealed deranged values of all hormones with the most common being 17-OHP and AMH. Almost 42.8% patients with DHEAS derangement and 58.75% females with raised 17-OHP suffered from moderate to severe stress.Limitations:A prospective cohort correlation study of the implicated triggers is needed to confirm the association with adult female acne.Conclusions:Adult female acne may be triggered by diet, stress, and cosmetics and there is a distinct hormonal milieu that accounts for hyperandrogenemia. We noted high levels of adrenal androgens which have been known to be associated with stress and sleep deprivation. Our study shows the value of counseling adult female acne patients about various acne triggers.

Postmenopausal Androgen Metabolism and Endometrial Cancer Risk in the Women’s Health Initiative Observational Study

After menopause, several androgens continue to be produced primarily by the adrenal glands; these can be converted into estrogens via aromatization or into androgen metabolites. It is unclear if androgens are associated with endometrial cancer risk independently of their being precursors to estrogens or if alternative metabolic pathways influence risk. We measured prediagnostic serum concentrations of 12 androgens and their metabolites using highly sensitive liquid chromatography-tandem mass spectrometry assays in a nested case-control study of postmenopausal women from the Women's Health Initiative Observational Study (313 endometrial cancer case subjects, 354 matched control subjects). Estrogens were previously assayed. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for endometrial cancer with adjustment for confounders. Compared to the lowest concentrations, the highest levels of adrenal androgens were associated with increased endometrial cancer risk: dehydroepiandrosterone (5th vs 1st quintile: OR = 1.85, 95% CI = 1.06 to 3.25), androstenedione (OR = 2.36, 95% CI = 1.34 to 4.16), and testosterone (OR = 1.91, 95% CI = 1.12 to 3.24). Downstream androgen metabolites were not associated with endometrial cancer. Although increased risks for the parent androgens were still suggested after adjustment for unconjugated estradiol, the associations attenuated, and with the exception of androstenedione, were no longer statistically significant. We also evaluated ratios of estrogens relative to their androgenic precursors; both higher unconjugated estrone:androstenedione and higher unconjugated estradiol:testosterone were associated with increased endometrial cancer risk. We identified increased risks for endometrial cancer with the highest levels of adrenal androgens and high levels of estrogens relative to these androgens. As adrenal androgens can be aromatized to estrogens, this suggests androgens likely influence endometrial carcinogenesis via estrogen metabolism.

Novel GC-MS/MS Technique Reveals a Complex Steroid Fingerprint of Subclinical Hypercortisolism in Adrenal Incidentalomas.

Improvement of imaging methods has led to more incidental adrenal tumor findings, especially adenomas. Routine hormonal evaluation uses only a few steroids to evaluate possible hormonal hypersecretion of these adenomas, but a wide spectrum of serum steroid hormone changes has not been published. To measure the serum levels of 83 steroids from patients with unilateral and bilateral adrenal incidentalomas to uncover full steroid profile changes in patients with subclinical hypercortisolism (SH). Cross-sectional study. The study was conducted at a tertiary inpatient clinic. Fifty-two patients with adrenal incidentalomas (unilateral, n = 29; bilateral, n = 23), including nonfunctioning (n = 11) vs SH (n = 41), and 26 age- and sex-matched controls from the general population were included. Eighty-three serum steroids were measured by gas chromatography-tandem mass spectrometry (GC-MS/MS) before and after 1 mg dexamethasone, ACTH, midnight serum cortisol, and urinary free cortisol/24 hour. Of 83 measured steroids, 10 were significantly decreased in patients with SH, including dehydroepiandrosterone sulfate (DHEAS), androsterone sulfate, epiandrosterone sulfate, androstenediol sulfate, conjugated 5α-androstane-3β,17β-diol, and conjugated 5α-androstane-3α,17β-diol. This finding was observed even when unilateral, bilateral, male, and female subgroups were analyzed separately. When we compared routine clinical methods and GC-MS/MS‒measured steroids, the most discriminatory was DHEAS followed by midnight serum cortisol, epiandrosterone sulfate, androsterone sulfate, ACTH, and 16α-hydroxypregnenolone. SH was associated with decreased levels of adrenal androgens, their metabolites, and pregnenolone metabolite. GC-MS/MS is a powerful tool for measuring serum levels of these undescribed changes in steroid metabolism, which are characteristic of SH in adrenal incidentalomas.