C19and C215β/5αMetabolite Ratios in Subjects Treated with the 5α-Reductase Inhibitor Finasteride: Comparison of Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency*

Imperato‐McGinley, Julianne; Shackleton, Cedric; Orlic, Susan; Stoner, Elizabeth

doi:10.1210/jcem-70-3-777

Cited by 57 publications

(30 citation statements)

References 23 publications

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“…This report was interesting because of the inclusion of a heterozygote mother with a reduced A/Ae ratio of 0.39, that is within our diagnostic range for SRD5A2 deficiency. Other studies also show overlap of USP results for carriers (25)(26)(27)(28). Our series extends this experience in a more heterogeneous adult group in an attempt to map the area where USP and genetic results may be discrepant.…”

Section: Discussionsupporting

confidence: 73%

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Berra¹,

Williams

Muroni

et al. 2011

European Journal of Endocrinology

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Context: The late presentation of steroid 5a-reductase-2 (SRD5A2) deficiency in females is poorly characterised. The ratios of 5a/5b-reduced metabolites of adrenal steroids in a urine steroid profile (USP) can give an indication of SRD5A2 deficiency, although the diagnostic cut-off for 5a/5b ratios are not clearly defined in genetically confirmed cases. Objective: The aim of this study was to establish the frequency of SRD5A2 deficiency in an adult clinic for disorders of sexual development (DSD) focussing on 46XY partially virilised adult female subjects. We investigated the relationship between USP results and SRD5A2 genetic sequence and determined the cut-off for USP 5a/5b-reduced steroid ratios compared with gene sequencing for the identification of SRD5A2 deficiency. Methods: USP and SRD5A2 genetic analyses were performed in 23 adult females, aged 19-57 years, with 46XY DSD and in four males with confirmed SRD5A2 deficiency. 5a-Reductase activity was assessed using the USP ratio of androsterone to aetiocholanolone (A/Ae), 5a-tetrahydrocortisol (5a-THF)/tetrahydrocortisol (THF) and 5a-tetrahydrocorticosterone to tetrahydrocorticosterone (5a-THB/THB). Results: The SRD5A2 gene mutations were found in 10/23 (43%) females and in all four males. Totally, four novel mutations were identified. All mutation-positive subjects had A/Ae and 5a-THB/THB ratios below the lower limit of normal (100% sensitivity) while the sensitivity of 5a-THF/THF ratio was 90%. Conclusion: SRD5A2 deficiency is more prevalent than expected in the adult female 46XY DSD population. The clinical spectrum of this disorder may extend to a more female phenotype than previously considered to include individuals with little or no virilisation.

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Section: Discussionsupporting

confidence: 73%

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Berra¹,

Williams

Muroni

et al. 2011

European Journal of Endocrinology

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“…There are two isozymes of 5a-reductase and both probably contribute to cortisol metabolism, since the type 1 predominates in liver while the type 2 inhibitor finasteride alters urinary cortisol metabolite excretion (49). Information on promoter regulation of these genes remains scanty and relates predominantly to sex steroid regulation (50,51), so it is unclear whether they are transcriptionally controlled by 'nutrient' receptors such as peroxisome proliferator activating receptor (PPARs).…”

Section: Discussionmentioning

confidence: 99%

Influence of short-term dietary weight loss on cortisol secretion and metabolism in obese men

Johnstone¹,

Faber²,

Andrew

et al. 2004

Eur J Endocrinol

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Objectives: Obesity is associated with increased inactivation of cortisol by hepatic A-ring 5a-and 5b-reductases, impaired hepatic regeneration of cortisol from cortisone by 11b-hydroxysteroid dehydrogenase type 1 (11HSD1), but increased subcutaneous adipose 11HSD1 activity enhancing local cortisol levels in fat. Cause and effect between obesity and abnormal cortisol metabolism is untested. Design: Acute weight loss was induced by very low calorie diet (VLCD) or starvation in obese men. Methods: Otherwise healthy males (aged 20 -55 years; body mass index (BMI) 30 -40 kg/m 2 ) were studied after 6 days on a weight maintenance diet; then after either 6 days of starvation (n ¼ 6) or 3 weeks of VLCD (2.55 MJ; n ¼ 6); then after 1 week of weight maintenance; and finally after 2 weeks of being allowed to feed ad libitum. Plasma samples were obtained from indwelling cannulae at 0930 h and 1815 h and a 24 h urine collection was completed for analysis of cortisol metabolites by gas chromatography/mass spectrometry. Results: Data are mean^S.E.M. BMI fell (kg/m 3 ) from 34.8^0.8 at baseline to 31.8^1.4 on VLCD and 32.7^1.1 on starvation. Starvation caused a rise in plasma cortisol (at 0930 h from 143^17 to 216^11 nM, P , 0.001) but no change in total urinary cortisol metabolites. VLCD did not alter plasma cortisol and markedly reduced cortisol metabolite excretion (from 15.8^1.1 mg/day at baseline to 7.0^1.1 mg/day, P , 0.001). Relative excretion of 5a-reduced cortisol metabolites fell on both diets, but there were no changes in cortisol/cortisone metabolite ratios reflecting 11HSD activities. Conclusions: Weight loss with VLCD in obesity reverses up-regulation of hepatic A-ring reductases and normalises cortisol production rate; in contrast, starvation produces acute stress and further activation of cortisol secretion. We suggest that activation of cortisol secretion is not an irreversible intrinsic abnormality in obese patients, and speculate that dietary content has an important influence on the neuroendocrine response to weight loss.

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“…The ultimate height of affected subjects is similar to the height of their fathers and normal male siblings. Thus, these pubertal events appear to be effected mainly through the actions of testos terone [2,3,5], In contrast, prostatic development and/ or enlargement, acne, normal male facial and body hair, and temporal recession of the hairline do not occur in affected male adults, and appear to be mainly mediated by DHT.Hepatic and peripheral 5a-steroid metabolism has been studied in patients in clinical trials for treatment of benign prostatic hyperplasia (BPH), using the 5a-reductase azasteroid inhibitor finasteride [1]. Comparison of their steroid profile with that found in male pseudoher maphrodites (MPHs), who have an inherited defect in 5a-reductase activity, revealed a similar pattern [1][2][3][4],…”

mentioning

confidence: 99%

5α-Metabolism in Finasteride-Treated Subjects and Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency

Imperato‐McGinley

1991

Eur Urol

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C₁₉and C₂₁5β/5αMetabolite Ratios in Subjects Treated with the 5α-Reductase Inhibitor Finasteride: Comparison of Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency*

Cited by 57 publications

References 23 publications

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Influence of short-term dietary weight loss on cortisol secretion and metabolism in obese men

5α-Metabolism in Finasteride-Treated Subjects and Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency

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