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.

The Effect of Etanercept Therapy on Adrenal Steroid Metabolism in Juvenile Idiopathic Arthritis: A Steroid Metabolomics Approach

Objective To evaluate the impact of anti-tumor necrosis factor-alpha (TNFα: etanercept [Enbrel®]) on adrenal activity in the acute phase of juvenile idiopathic arthritis (JIA) during which there is a decrease in adrenal androgen and cortisol levels. Method Eleven JIA patients aged 12±6.2 years with a disease duration of 6.3±5.2 years were enrolled. They were treated once weekly with etanercept (0.8 mg/kg) for 3±2.8 years. Urine samples for gas chromatography-mass spectrometry steroid hormone analysis were collected before, and 1 and 3 days after etanercept injection and compared to age- and sex-matched healthy control. Results The levels of 23 of the 35 metabolites were low before etanercept treatment. Those 23 metabolites included 2 C19 steroids (androgens), 3 C21 steroid hormone intermediates, 14 cortisol metabolites, 2 corticosterone metabolites and 2 C18 steroids (estrogens). One day post-treatment, only 5 of the 23 metabolite levels remained low. They included 2 C19 metabolites, 2 21 steroid metabolites and 1 cortisol metabolite b-c. Three days post-treatment, the only metabolite levels that continued to be low were 1 C19 metabolite, 2 C21 steroid hormone intermediates and 1 cortisol metabolite (a-Cl), while the remaining 18 metabolites had already normalized after 1 day. DHEAS and 17 OH pregnenolone metabolite levels were the last ones to recover. Urinary metabolite ratios reflecting CYP21 and 11β-HSD2 enzymatic activities were lower in JIA patients than in controls. Conclusion Almost all of the pre-etanercept treatment cortisol urinary metabolite levels were significantly lower than normal, and almost all rose to normal values by 1 day post-treatment. Blocking TNFα restores adrenal function in JIA.

Genome-Wide Association Study And Polygenic Risk Scores Of Serum Dheas Levels In A Chilean Children Cohort

Background Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (e.g., DHEA/DHEAS) from ages ~5-15 years. We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. Subjects and methods Genome-wide genotyping was performed in participants of the Chilean pediatric GOCS cohort (n=788). We evaluated the genetic determinants of DHEAS levels at genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score for age at pubarche, based upon the discovered variants, in children from the same cohort. Results We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81x10 -8). In addition, variants suggestive of association (P <1x10 -5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher polygenic risk scores for greater DHEAS based on these newly identified variants. Conclusions Our results disclose one variant associated with DHEAS concentrations at the level of GWAS significance, and several variants with suggestive association, which may be involved in the genetic regulation of adrenarche.

Crinecerfont Lowers Elevated Hormone Markers in Adults with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

Context Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective To evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Design Open-label, phase 2 study, with sequential cohort design (NCT03525886). Setting United States (6 centers). Participants Men and women, 18-50 years, with 21OHD. Interventions Four crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg oncedaily at bedtime (Cohorts 1 and 2, respectively); 100 mg once-daily in the evening (Cohort 3); 100 mg twice-daily (BID, Cohort 4). Participants could enroll in >1 cohort. Main Outcomes Changes from baseline to Day 14 in adrenocorticotropic hormone (ACTH), 17hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eighteen participants (11 women, 7 men) were enrolled: Cohort 1 (n=8), Cohort 2 (n=7), Cohort 3 (n=8), Cohort 4 (n=8). Mean age was 31 years; 94% were white. Median percent reductions were >60% for ACTH (-66%), 17OHP (64%), and androstenedione (64%) with crinecerfont 100 mg BID. In female participants, 73% (8/11) had ≥50% reduction in testosterone levels; male participants had median 26-65% decreases in androstenedione/testosterone ratios. Conclusions Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical endpoints of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

Castration failure in prostate carcinoma due to a functioning adrenocortical carcinoma

Summary We report concurrent metastatic prostatic adenocarcinoma (PC) and functioning androgen-secreting adrenocortical carcinoma (ACC) in a 77-year-old man. The failure to achieve adequate biochemical castration via androgen deprivation therapy (ADT) as treatment for PC metastases, together with elevated DHEA-S, androstenedione, and discordant adrenal tracer uptake on FDG-PET and PSMA-PET, suggested the presence of a concurrent functional primary adrenal malignancy. On histopathological analysis, scant foci of PC were present throughout the ACC specimen. Castration was achieved post adrenalectomy with concurrent drop in prostate-specific antigen. We outline the literature regarding failure of testosterone suppression on ADT and salient points regarding diagnostic workup of functioning adrenal malignancies. Learning points Failure to achieve castration with androgen deprivation therapy is rare and should prompt careful review to identify the underlying cause. All adrenal lesions should be evaluated for hormone production, as well as assessed for risk of malignancy (either primary or secondary). Adrenocortical carcinomas are commonly functional, and can secrete steroid hormones or their precursors (androgens, progestogens, glucocorticoids and mineralocorticoids). In this case, a co-incident, androgen-producing adrenocortical carcinoma was the cause of failure of testosterone suppression from androgen deprivation therapy as treatment for metastatic prostate cancer. Pathological adrenal androgen production contributed to the progression of prostate cancer.

The role of polymorphism in various potential genes on polycystic ovary syndrome susceptibility and pathogenesis

Polycystic ovary syndrome (PCOS) is the most common endocrinopathies affecting the early reproductive age in women, whose pathophysiology perplexes many researchers till today. This syndrome is classically categorized by hyperandrogenism and/or hyperandrogenemia, menstrual and ovulatory dysfunction, bulky multi follicular ovaries on Ultrasonography (USG), and metabolic abnormalities such as hyperinsulinemia, dyslipidemia, obesity. The etiopathogenesis of PCOS is not fully elucidated, but it seems that the hypothalamus-pituitary-ovarian axis, ovarian, and/or adrenal androgen secretion may contribute to developing the syndrome. Infertility and poor reproductive health in women’s lives are highly associated with elevated levels of androgens. Studies with ovarian theca cells taken from PCOS women have demonstrated increased androgen production due to augmented ovarian steroidogenesis attributed to mainly altered expression of critical enzymes (Cytochrome P450 enzymes: CYP17, CYP21, CYP19, CYP11A) in the steroid hormone biosynthesis pathway. Despite the heterogeneity of PCOS, candidate gene studies are the widely used technique to delineate the genetic variants and analyze for the correlation of androgen biosynthesis pathway and those affecting the secretion or action of insulin with PCOS etiology. Linkage and association studies have predicted the relationship between genetic variants and PCOS risk among families or populations. Several genes have been proposed as playing a role in the etiopathogenesis of PCOS, and the presence of mutations and/or polymorphisms has been discovered, which suggests that PCOS has a vital heritable component. The following review summarizes the influence of polymorphisms in crucial genes of the steroidogenesis pathway leading to intraovarian hyperandrogenism which can result in PCOS.

Latent Adrenal Insufficiency: From Concept to Diagnosis

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

P–598 Further evidence for a functional hormonal adrenal-ovarian axis affecting female infertility

Study question How does here presented case offer further evidence for existence of a functional hormonal adrenal-ovarian axis? Summary answer This is the first case of iatrogenic Cushing syndrome leading to severe adrenal and ovarian insufficiency, as evidenced by undetectable estrogen and low androgen levels. What is known already Animal models and human data have convincingly demonstrated that hypo-androgenism affects follicle recruitment and growth, especially at small growing follicle stages, in most severe cases even mimicking primary ovarian insufficiency (POI). In milder forms, hypoandrogenism reduces follicle number, egg numbers as well as egg quality, unless reconstituted in timely fashion before IVF cycle start. Study design, size, duration We here report a 34-year-old G1P1, who presented for a second opinion with a diagnosis of secondary “unexplained” infertility after two IVF cycles at another fertility center. Participants/materials, setting, methods Since our center considers a diagnosis of “unexplained” infertility as subjective, the patient underwent a thorough diagnostic evaluation. She was using oral contraceptive pills for one week at the time her laboratory results were drawn. Main results and the role of chance: Her free (FT) and total testosterone (TT) (0.4 pg/ml and 5.0 ng/dL, respectively), DHEA and DHEAS (103.0 ng/dL and 92.0 µg/dL, respectively) were low and her estradiol was undetectable (<25 pg/mL), reflecting significant adrenal as well as ovarian suppression. Morning ACTH was undetectable at < 5 pg/mL but cortisol was abnormally elevated (17.7mcg/dL), leading to diagnoses of secondary adrenal insufficiency as well as secondary ovarian insufficiency (SOI) due to adrenal hypo-androgenism from lack of ACTH production. She, in addition, revealed a positive ANA titer (1:160). Because of eczema, she for over a year had been on a super-potent topical steroid ointment. Upon termination of this steroid, adrenal as well as ovarian function, as evidenced by her hormonal values, normalized. Limitations, reasons for caution This is the first case in the literature where iatrogenic-induced insufficiency of adrenal androgen production resulted in secondary ovarian insufficiency (SOI), characterized by undetectable estradiol, reversible by withdrawal of topical steroid treatment. Wider implications of the findings: This case offers further evidence that the traditional hypothalamic-pituitary-ovarian axis (HPAA) extends downstream to ovaries (HPAOA), reaffirming the ability of adrenals to control ovarian function. Trial registration number n/a