Long Term Effects of Nightly Dexamethasone Administration in Patients with Polycystic Ovarian Disease*

Lachelin, Gillian C. L.; Judd, Howard L.; Swanson, Sherri C.; Hauck, Margaret E.; Parker, Donal C.; Yen, S. S. C.

doi:10.1210/jcem-55-4-768

Cited by 36 publications

(3 citation statements)

References 11 publications

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“…Ovarian suppression with long-acting GnRH agonists leads to a significant decline in circulating androgens in both healthy and PCOS women (6 -8), but androgen levels remain higher in PCOS. Likewise, PCOS women show an exaggerated androgen response after adrenal stimulation with ACTH (9 -11); and, after adrenal suppression by dexamethasone (Dex), PCOS women still have higher circulating androgen levels than controls (12). Thus, it is generally accepted that both ovary and adrenal significantly contribute to hyperandrogenemia in PCOS.…”

mentioning

confidence: 99%

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

Faßnacht

Schlenz

Schneider

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

139

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Hyperandrogenism, a main clinical feature of polycystic ovary syndrome (PCOS), is thought to result from enhanced ovarian and adrenal androgen generation. To investigate the contribution of peripheral steroidogenesis, we used an oral challenge with dehydroepiandrosterone (DHEA) and analyzed its downstream conversion toward androgens in eight women with PCOS (age, 20-32 yr; body mass index, 20-41 kg/m(2)) and eight healthy women matched for age and body mass index. They underwent frequent serum sampling and urine collection for 8 h on three occasions: at baseline, and after 4 d of dexamethasone (Dex; 4 x 0.5 mg/d), followed by ingestion of 100 mg DHEA or placebo. Dex induced similar significant suppression of circulating steroids in both groups. The oral DHEA challenge led to similar significant increases in the area under the concentration-time curve (0-8 h after Dex) of serum DHEA, DHEA sulfate, androstenedione, and testosterone. However, after oral DHEA, PCOS women had significantly higher increases in serum 5 alpha-dihydrotestosterone (P < 0.01), its main metabolite androstanediol glucuronide (P < 0.05), and the 5 alpha-reduced urinary androgen metabolite androsterone (P < 0.05). PCOS women also had significantly higher baseline excretion of 5 alpha-reduced glucocorticoid (P < 0.01) and mineralocorticoid metabolites (P < 0.05). Taken together, these data indicate enhanced peripheral 5 alpha-reductase activity in PCOS. Thus, not only ovary and adrenal, but also liver and peripheral target tissues, significantly contribute to steroid alterations in PCOS.

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mentioning

confidence: 99%

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

Faßnacht

Schlenz

Schneider

et al. 2003

The Journal of Clinical Endocrinology & Metabolism

139

View full text Add to dashboard Cite

show abstract

“…In patients with PCOS and clinical signs of hyperandrogenism, the origin of androgen excess is diverse. While traditionally, the ovaries have been identified as the primary source of heightened androgens in PCOS, emerging clinical and biochemical evidence suggests a nuanced perspective [55][56][57][58][59][60][61][62]. The 11oxC19 androgens, particularly 11OHA4 and 11KA4, have garnered attention as significant contributors to the androgen pool in this disorder [11,63,64].…”

Section: Androgen Synthesis In Womenmentioning

confidence: 99%

The Landscape of Androgens in Cushing’s Syndrome

Nowotny,

Braun,

Reisch

2024

Exp Clin Endocrinol Diabetes

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Hyperandrogenemia in patients with Cushing’s syndrome (CS) presents a diagnostic pitfall due to its rare occurrence and overlapping symptoms with more common conditions like polycystic ovary syndrome (PCOS). This review explores the significance of androgen dysregulation in CS, focusing on both classical and 11-oxygenated androgens. While classical androgens contribute to hyperandrogenism in CS, their levels alone do not fully account for clinical symptoms. Recent research highlights the overlooked role of 11oxC19 androgens, particularly 11OHA4 and 11KT, in driving hyperandrogenic manifestations across all CS subtypes. These adrenal-specific and highly potent androgens offer stable expression throughout a woman's lifespan, serving as valuable diagnostic biomarkers. Understanding their prominence not only aids in subtype differentiation but also provides insights into the complex nature of androgen dysregulation in CS. Recognizing the diagnostic potential of 11oxC19 androgens promises to refine diagnostic approaches and improve clinical management strategies for patients with CS.

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“…Despite its name, both the adrenal and ovary independently contribute to the hyperandrogenism of PCOS. Ovarian hyperandrogenemia persists when the adrenals of PCOS women are suppressed (10,11), and PCOS theca cells in vitro secrete more androgen than theca cells from regularly ovulating women (12–16). Three lines of evidence show that PCOS women also overproduce C19 (19-carbon) androgen precursors in the adrenal (17).…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2

Tee

Speek

Legeza

et al. 2016

Molecular and Cellular Endocrinology

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Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by hyperandrogenism and metabolic disorders. The excess androgens may be of both ovarian and adrenal origin. PCOS has a strong genetic component, and genome-wide association studies have identified several candidate genes, notably DENND1A, which encodes connecdenn 1, involved in trafficking of endosomes. DENND1A encodes two principal variants, V1 (1009 amino acids) and V2 (559 amino acids). The androgen-producing ovarian theca cells of PCOS women over-express V2. Knockdown of V2 in these cells reduces androgen production, and overexpression of V2 in normal theca cells confers upon them a PCOS phenotype of increased androgen synthesis. We report that human adrenal NCI-H295A cells express V1 and V2 mRNA and that the V2 isoform is produced by exonization of sequences in intron 20, which generates a unique exon 20A, encoding the C-terminus of V2. As in human theca cells from normal women, forced expression of V2 in NCI-H295A cells resulted in increased abundance of CYP17A1 and CYP11A1 mRNAs. We also found genetic variation in the intronic region 330 bp upstream from exon 20A, which could have the potential to drive the selective expression of V2. There was no clear association with these variants with PCOS when we analyzed genomc DNA from normal women and women with PCOS. Using minigene expression vectors in NCI-H295A cells, this variable region did not consistently favor splicing of the V2 transcript. These findings suggest increased V2 expression in PCOS theca cells is not the result of genomic sequence variation in intron 20.

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Long Term Effects of Nightly Dexamethasone Administration in Patients with Polycystic Ovarian Disease*

Cited by 36 publications

References 11 publications

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5α-Reductase Activity in Women with Polycystic Ovary Syndrome

The Landscape of Androgens in Cushing’s Syndrome

Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2

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