Increased adrenal androgen secretion with inhibition of 11β-hydroxylase in HIV-infected women

2006 ◽  
Vol 290 (5) ◽  
pp. E808-E813
Author(s):  
Polyxeni Koutkia ◽  
Jacqueline Berry ◽  
Kristina Eaton ◽  
Jeff Breu ◽  
Steven Grinspoon
Keyword(s):  
Adrenal Insufficiency ◽  
Enzyme Inhibitor ◽  
Ideal Body Weight ◽  
Free Testosterone ◽  
Controlled Study ◽  
Total Testosterone ◽  
Adrenal Androgen ◽  
Double Blind ◽  
Anabolic Hormone ◽  
Androgen Secretion

Adrenal androgen production is reduced in association with disease severity in HIV-infected women. This response may be maladaptive in terms of maintenance of lean body mass, functional status, and immune function. The aim of this study was to assess whether the use of an adrenal enzyme inhibitor of 11β-hydroxylase might increase androgen production in this population. We conducted a randomized, double-blind, placebo-controlled study of metyrapone (500 mg po qid) or placebo for 2 wk in 10 HIV-infected women with AIDS wasting [weight <90% ideal body weight (IBW) or weight loss >10%] and reduced androgen levels. Basal and ACTH-stimulated androgen, mineralocorticoid, and glucocorticoid levels were measured at baseline and after 14 days of treatment. Subjects were similar in age (40.9 ± 0.9 yr), weight (91.7 ± 3.5% IBW) and hormone concentrations at study entry. Total testosterone (84 ± 54 vs. −0.4 ± 2 ng/dl, P = 0.024), free testosterone (6.5 ± 2.8 vs. 0.1 ± 0.1 pg/ml, P = 0.024), DHEA (5.0 ± 3.2 vs. −0.6 ± 0.5 μg/l, P = 0.024), and 11-deoxycortisol (2,145 ± 820 vs. −14 ± 22 ng/dl, P = 0.024) levels increased in response to metyrapone compared with placebo treatment. In response to ACTH, significant increases in the DHEA/cortisol ratio (174 ± 48 vs. 3 ± 3, P = 0.008) were seen in the metyrapone group compared with placebo. Blood pressure and electrolytes did not change, and signs of adrenal insufficiency were not apparent. These data demonstrate that inhibition of 11β-hydroxylase with metyrapone increases adrenal androgen secretion in HIV-infected women. Further studies are needed to assess the physiological effects of this strategy to increase anabolic hormone levels in severe stress, including detailed testing to rule out the potential risk of concomitant adrenal insufficiency.

scholarly journals Association of CYP3A7*1C and Serum Dehydroepiandrosterone Sulfate Levels in Women with Polycystic Ovary Syndrome

2008 ◽  
Vol 93 (7) ◽  
pp. 2909-2912 ◽  
Author(s):  
Mark O. Goodarzi ◽  
Ning Xu ◽  
Ricardo Azziz
Keyword(s):  
Los Angeles ◽  
Polycystic Ovary Syndrome ◽  
White Women ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Free Testosterone ◽  
Total Testosterone ◽  
Adrenal Androgen ◽  
Androgen Excess ◽  
Ovary Syndrome

Abstract Context: Adrenal androgen excess is common in polycystic ovary syndrome (PCOS) and appears to be heritable. CYP3A7 metabolizes dehydroepiandrosterone and its sulfate (DHEAS). A promoter variant, CYP3A7*1C, which results in persistent expression in adults, was associated with reduced DHEAS levels in a previous study, which led us to consider CYP3A7*1C as a modulator of adrenal androgen excess in patients with PCOS. Objective: The objective was to replicate the association between CYP3A7*1C and reduced DHEAS levels in PCOS patients and assess its possible role in modulating testosterone levels. Design: Women with and without PCOS were genotyped for CYP3A7*1C, and this variant was tested for association with DHEAS and total and free testosterone. Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center (Los Angeles, CA). Participants: A total of 287 white women with PCOS and 187 controls were studied. Main Measurements: CYP3A7*1C genotype, PCOS risk, and androgen levels were measured. Results: PCOS subjects who carried the CYP3A7*1C variant had lower levels of serum DHEAS and total testosterone (P = 0.0006 and 0.046, respectively). The variant was not associated with PCOS risk. Conclusion: This study replicated prior work of the association of CYP3A7*1C and decreased DHEAS in a different population of young PCOS women, providing further genetic evidence that CYP3A7 plays a potential role in modulation of DHEAS levels. Adult expression of CYP3A7 may modify the PCOS phenotype by ameliorating adrenal androgen excess.

scholarly journals Acute hormonal response to sublingual androstenediol intake in young men

2002 ◽  
Vol 92 (1) ◽  
pp. 142-146 ◽  
Author(s):  
Gregory A. Brown ◽  
Emily R. Martini ◽  
B. Scott Roberts ◽  
Matthew D. Vukovich ◽  
Douglas S. King
Keyword(s):  
Peak Concentration ◽  
Young Men ◽  
Serum Testosterone ◽  
Free Testosterone ◽  
Total Testosterone ◽  
Serum Estradiol ◽  
Hormonal Response ◽  
Double Blind ◽  
First Pass ◽  
Serum Hormone

The effectiveness of orally ingested androstenediol in raising serum testosterone concentrations may be limited because of hepatic breakdown of the ingested androgens. Because androstenediol administered sublingually with cyclodextrin bypasses first-pass hepatic catabolism, we evaluated the acute hormonal response to sublingual cyclodextrin androstenediol supplement in young men. Eight men (22.9 ± 1.2 yr) experienced in strength training consumed either 20 mg androstenediol in a sublingual cyclodextrin tablet (Sl Diol) or placebo (Pl) separated by at least 1 wk in a randomized, double-blind, crossover manner. Blood samples were collected before supplementation and at 30-min intervals for 3 h after supplementation. Serum hormone concentrations did not change with Pl. Serum androstenedione concentrations were increased ( P < 0.05) above baseline (11.2 ± 1.1 nmol/l) with Sl Diol from 60 to 180 min after intake and reached a peak concentration of 25.2 ± 2.9 nmol/l at 120 min. Serum free testosterone concentrations were increased from 86.2 ± 9.1 pmol/l with Sl Diol from 30 to 180 min and reached a peak concentration of 175.4 ± 12.2 pmol/l at 60 min. Serum total testosterone concentrations increased above basal (25.6 ± 2.3 nmol/l) from 30 to 180 min with Sl Diol and reached a peak concentration of 47.9 + 2.9 nmol/l at 60 min. Serum estradiol concentrations were elevated ( P < 0.05) above baseline (0.08 ± 0.01 nmol/l) from 30 to 180 min with Sl Diol and reached 0.14 ± 0.02 nmol/l at 180 min. These data indicate that sublingual cyclodextrin androstenediol intake increases serum androstenedione, free testosterone, total testosterone, and estradiol concentrations.

scholarly journals Effect of Eurycoma longifolia standardised aqueous root extract– Physta® on testosterone levels and quality of life in ageing male subjects: a randomised, double-blind, placebo-controlled multicentre study

2021 ◽  
Author(s):  
Sasikala M. Chinnappan ◽  
Annie George ◽  
Pragya Pandey ◽  
Govinda Narke ◽  
Yogendra Kumar Choudhary
Keyword(s):  
Quality Of Life ◽  
Free Testosterone ◽  
Total Testosterone ◽  
Double Blind ◽  
Testosterone Levels ◽  
Eurycoma Longifolia ◽  
Ageing Male ◽  
Secondary Endpoints ◽  
Male Subjects

Background: Low testosterone levels cause physiological changes that compromise the quality of life in ageing men. A standardised water extract from the root of Eurycoma longifolia (EL), known as Physta®, is known to increase testosterone levels. Objective: To evaluate the safety and efficacy of Physta® in improving the testosterone levels and quality of life in ageing male subjects. Design: This randomised, double-blind, placebo-controlled study enrolled 105 male subjects aged 50–70 years with a testosterone level <300 ng/dL, BMI ≥ 18 and ≤30.0 kg/m2. The subjects were given either Physta® 100 mg, 200 mg or placebo daily for 12 weeks. The primary endpoints were changes in serum total and free testosterone levels. The secondary endpoints included changes in the level of sex hormone-binding globulin (SHBG), dihydroepiandrosterone (DHEA), glycated haemoglobin (HbA1c), insulin-like growth factor-1 (IGF-1), thyroid function tests (T3, T4, TSH and Free T3) and cortisol. Changes in Ageing Male Symptoms (AMS) score, Fatigue Severity Scale (FSS) score and muscle strength are other secondary endpoints. The safety of the intervention products was measured by complete blood count, lipid profile, liver and renal function tests. Results: There was a significant increase in the total testosterone levels at week 12 (P < 0.05) in the Physta® 100 mg group and at weeks 4 (P < 0.05), 8 (P < 0.01) and 12 (P < 0.001) in the Physta® 200 mg group compared to placebo. No significant between-group differences in free testosterone levels were observed but a significant within-group increase occurred at weeks 4 (P < 0.01), 8 (P < 0.001) and 12 (P < 0.001) in the Physta®100 mg group and at weeks 2 (P < 0.01), 4 (P < 0.01), 8 (P < 0.001) and 12 (P < 0.001) in the Physta® 200 mg group. The AMS and FSS showed significant reduction (P < 0.001) in total scores at all time-points within- and between-group in both Physta® groups. DHEA levels significantly increased (P < 0.05) within-group in both Physta® groups from week 2 onwards. Cortisol levels significantly (P < 0.01) decreased in the Physta® 200 mg group, while muscle strength significantly (P < 0.001) increased in both Physta® groups at week 12 in the within-group comparison. There were no significant changes in SHBG. No safety related clinically relevant changes were observed. Conclusion: Supplementation of Physta® at 200 mg was able to increase the serum total testosterone, reduce fatigue and improve the quality of life in ageing men within 2 weeks’ time. Trial registration: This clinical study has been registered in ctri.nic.in (CTRI/2019/03/017959).

Randomized double-blind placebo-controlled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects

2004 ◽  
Vol 107 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Morris J. BROWN ◽  
John COLTART ◽  
Kulasiri GUNEWARDENA ◽  
James M. RITTER ◽  
Timothy R. AUTON ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Antibody Titre ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Primary Objective ◽  
Controlled Study ◽  
Double Blind ◽  
Show Evidence

Immunization against components of the renin–angiotensin system offers a potential alternative to daily medication in some patients with hypertension or heart failure. Our primary objective was to determine whether a sustained antibody titre to Ang I (angiotensin I) can be achieved in hypertensive patients. The secondary objective was to determine whether the antibodies block the renin system. Patients (n=27) with essential hypertension responsive to an ACEi (angiotensin-converting enzyme inhibitor) or ARB (angiotensin blocker) were randomly assigned to receive three or four injections of the Ang I vaccine PMD3117 or aluminium hydroxide (Alhydrogel™) over a 6 week period. Antibody titre was measured prior to each injection and every 30 days until disappearance. Indices of renin blockade were changes in renin and aldosterone (blood and urine) and a within-patient comparison of the pre- and post-vaccination rise in 24 h ambulatory blood pressure after 2 weeks of withdrawal of ACEi or ARB. The anti-(Ang I) antibody titre rose from the second injection in both regimes and peaked on day 64. Median half-life was 85 (95% CI, 44 and 153) days (where CI is confidence interval). Vaccination did not influence blood pressure, but significantly blunted the fall in plasma renin following withdrawal of ACEi or ARB. At 42 days after the first injection, aldosterone excretion was decreased by PMD3117 to 6 (95% CI, 1 and 31)% of values in patients receiving Alhydrogel™ (P=0.012). In patients with essential hypertension, PMD3117 generated a prolonged antibody response to Ang I. Biochemical measurements show evidence of blockade of the renin system, but higher titres will be required to achieve a decrease in blood pressure.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE Hyperandrogenic states in women: pitfalls in laboratory diagnosis

2018 ◽  
Vol 178 (4) ◽  
pp. R141-R154 ◽  
Author(s):  
Michel Pugeat ◽  
Ingrid Plotton ◽  
Aude Brac de la Perrière ◽  
Gérald Raverot ◽  
Henri Déchaud ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Limit Of Detection ◽  
High Specificity ◽  
Free Testosterone ◽  
Laboratory Diagnosis ◽  
Sex Hormone Binding Globulin ◽  
Total Testosterone ◽  
Adrenal Androgen ◽  
Androgen Excess ◽  
Specificity And Sensitivity

Measuring total testosterone level is the first-line approach in assessing androgen excess in women. The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific anti-testosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone-binding globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women.

Effects of Angiotensin II on Insulin Sensitivity: A Placebo-Controlled Study

1993 ◽  
Vol 85 (4) ◽  
pp. 431-436 ◽  
Author(s):  
A. D. Morris ◽  
J. R. Petrie ◽  
J. Anderson ◽  
J. M. C. Connell ◽  
R. Donnelly
Keyword(s):  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Angiotensin Ii ◽  
Enzyme Inhibitor ◽  
Serum Insulin ◽  
Whole Body ◽  
Controlled Study ◽  
High Dose ◽  
Double Blind ◽  
Plasma Angiotensin

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min−1 kg−1) and pressor (5 ng min−1 kg−1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulin-aemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +SD) were 11+5 pg/ml after placebo, and 27+9 and 125+28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 + 2 mg of glucose min−1 kg−1 after placebo, and 10.5 +2.2 and 10.9+3.4 mg of glucose min−1 kg−1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacyl-glycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

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