Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood

Abstract

Context We hypothesize that impaired glucocorticoid sensitivity (GC Sensitivity) plays a role in the development of Premature Adrenarche (PA) and polycystic ovarian syndrome (PCOS) by increasing androgen synthesis. Objective To study glucocorticoid sensitivity in vitro in subjects with Premature Adrenarche and PCOS. Patients and Methods 14 subjects (10 girls, 4 boys, 6.9 ± 0.6 yrs.) with Premature Adrenarche; 27 subjects with PCOS (17 ± 2.5 yrs.) and 31 healthy controls were enrolled in the study. All subjects and controls underwent GC sensitivity analysis in vitro using a F-DEX assay. A GC sensitivity index (GCSI) was calculated as area under the curve of the F-DEX assay results. Subjects were classified as GC resistant, if the GCSI ≤ 264 and GC sensitive if the GCSI ≥ 386. Results In the Premature Adrenarche group, 8 out of 14 subjects were resistant with GCSI of 179.7 ± 39.9, 4 were within the normal range with GCSI of 299.6 ± 27.9 and 2 had increased GC sensitivity with GCSI of 423.5 ± 47.9. In the PCOS group, 18 out of 27 subjects were GC-resistant with GCSI of 180.9 ± 58.2; 8 were within the normal range with GCSI of 310.7 ± 26.4 and 1 had increased GCSI of 395.4. In the PCOS GC-resistant subgroup, cortisol was higher compared to PCOS with normal GCSI (p<0.05). In the combined PCOS plus female control group GCSI correlated negatively with cortisol and testosterone (p<0.05). Conclusion GC resistance was found in more than 50% of patients with PCOS and Premature Adrenarche. The findings strongly suggest that GC resistance is associated with states of Premature Adrenarche and PCOS.

Response to Letter to the Editor from Rosenfield: “Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood”

“…In summary, we conclude that this novel F-Dex binding assay is accurate and reproducible as shown in our paper [ 4 ]. We conclude that in patients with premature adrenarche and PCOS, the F-Dex binding assay can be used as an additional tool in the more detailed characterization of this patients.…”

“…Hence, we were able to identify patients with alterations in GC sensitivity. This in vitro assay has demonstrated that GC resistance exists in the subgroup of patients as described in our study and etiology of this resistance can be heterogenous [ 4 ].…”

“…In our study [ 4 ], we have proposed that by using a novel fluorescein-labeled dexamethasone (F-Dex) mononuclear cell-binding assay, we are able to identify abnormalities in the binding of GCs to the GCR. Hence, we were able to identify patients with alterations in GC sensitivity.…”

A data mining and semantic analysis reveals novel insights into the genetic characteristics of the glucocorticoid receptor interactome

“…PCOS also appears to be connected to impaired GC signaling. GC resistance was found in almost 67% of patients with PCOS in the study by Panayiotopoulos et al (80). Corticosteroids have also been used in the treatment of certain cancer types, such as hemangiomas, taking advantage of their ability to inhibit angiogenesis.…”

Letter to the Editor: “Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood”

“…The conclusion of Panayiotopoulos et al that glucocorticoid resistance (GR) accounted for 57% to 67% of their premature adrenarche and polycystic ovary syndrome (PCOS) cases [ 1 ] cannot be accepted from the data presented. This is because proper validation of their method for determining glucocorticoid sensitivity is not presented.…”