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Androgens and Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Docetaxel.
Ryan, CJ, Dutta, S, Kelly, WK, Middleberg, R, Russell, C, Morris, MJ, Taplin, ME, Halabi, S, ,
Clinical genitourinary cancer. 2020;(3):222-229.e2
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Abstract
BACKGROUND Pre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy. MATERIALS AND METHODS Data were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401). Pretreatment serum assays for testosterone, androstenedione, and dehydroepiandrosterone (DHEA) were performed with tandem liquid chromatography-mass spectrometry. RESULTS Median values for testosterone, androstenedione, and DHEA were 1.00, 13.50, and 8.12 ng/dL, respectively. The median was used to define the midpoint between low and high values. In univariate analysis, median OS for low versus high levels was 21.4 and 24.2 months for testosterone, 23.8 and 21.9 months for androstenedione, and 20.2 and 25.2 months for DHEA (P = NS). In multivariable analysis of all androgens, baseline DHEA was prognostic of ≥ 50% PSA decline from baseline (P = .008). In multivariable analysis adjusting for 10 known prognostic values and prior ketoconazole use for metastatic CRPC, a 10-unit increase in baseline testosterone increased risk of death (hazard ratio, 1.11; 95% confidence interval, 1.01-1.23; P = .039), whereas a 10-unit increase in androstenedione lowered risk of death (hazard ratio, 0.92; 95% confidence interval, 0.88-0.97; P = .001). CONCLUSION Consistent with prior studies, higher androstenedione levels in patients with metastatic CRPC treated with docetaxel are associated with improved survival. However pretreatment levels of other androgen levels are associated with varied effects on clinical outcome in chemotherapy-treated patients.
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Testosterone Administration During Energy Deficit Suppresses Hepcidin and Increases Iron Availability for Erythropoiesis.
Hennigar, SR, Berryman, CE, Harris, MN, Karl, JP, Lieberman, HR, McClung, JP, Rood, JC, Pasiakos, SM
The Journal of clinical endocrinology and metabolism. 2020;(4)
Abstract
CONTEXT Severe energy deprivation markedly inhibits erythropoiesis by restricting iron availability for hemoglobin synthesis. OBJECTIVE The objective of this study was to determine whether testosterone supplementation during energy deficit increased indicators of iron turnover and attenuated the decline in erythropoiesis compared to placebo. DESIGN This was a 3-phase, randomized, double-blind, placebo-controlled trial. SETTING The study was conducted at the Pennington Biomedical Research Center. PATIENTS OR OTHER PARTICIPANTS Fifty healthy young males. INTERVENTION(S): Phase 1 was a 14-day free-living eucaloric controlled-feeding phase; phase 2 was a 28-day inpatient phase where participants were randomized to 200 mg testosterone enanthate/week or an isovolumetric placebo/week during an energy deficit of 55% of total daily energy expenditure; phase 3 was a 14-day free-living, ad libitum recovery period. MAIN OUTCOME MEASURE(S): Indices of erythropoiesis, iron status, and hepcidin and erythroferrone were determined. RESULTS Hepcidin declined by 41%, indicators of iron turnover increased, and functional iron stores were reduced with testosterone administration during energy deficit compared to placebo. Testosterone administration during energy deficit increased circulating concentrations of erythropoietin and maintained erythropoiesis, as indicated by an attenuation in the decline in hemoglobin and hematocrit with placebo. Erythroferrone did not differ between groups, suggesting that the reduction in hepcidin with testosterone occurs through an erythroferrone-independent mechanism. CONCLUSION These findings indicate that testosterone suppresses hepcidin, through either direct or indirect mechanisms, to increase iron turnover and maintain erythropoiesis during severe energy deficit. This trial was registered at www.clinicaltrials.gov as #NCT02734238.
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High DHEAS Level in Girls Is Associated with Earlier Pubertal Maturation and Mild Increase in Androgens throughout Puberty without Affecting Postmenarche Ovarian Morphology.
Merino, PM, Pereira, A, Iñiguez, G, Corvalan, C, Mericq, V
Hormone research in paediatrics. 2019;(6):357-364
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Abstract
OBJECTIVE To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. METHODS In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. RESULTS HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. CONCLUSION Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.
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Testicular vs adrenal sources of hydroxy-androgens in prostate cancer.
Zang, T, Taplin, ME, Tamae, D, Xie, W, Mesaros, C, Zhang, Z, Bubley, G, Montgomery, B, Balk, SP, Mostaghel, EA, et al
Endocrine-related cancer. 2017;(8):393-404
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Abstract
Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3β,17β-diol (5-adiol), 5α-androstane-3α,17β-diol (3α-adiol), 5α-androstane-3β,17β-diol (3β-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3α-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5α-dihydrotestosterone (DHT), 3α-adiol and 3β-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin.
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Effects of long-term testosterone replacement therapy, with a temporary intermission, on glycemic control of nine hypogonadal men with type 1 diabetes mellitus - a series of case reports.
Saad, F, Yassin, A, Almehmadi, Y, Doros, G, Gooren, L
The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;(3):164-8
Abstract
Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone ≤ 12 nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.
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Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency.
Auchus, RJ, Buschur, EO, Chang, AY, Hammer, GD, Ramm, C, Madrigal, D, Wang, G, Gonzalez, M, Xu, XS, Smit, JW, et al
The Journal of clinical endocrinology and metabolism. 2014;(8):2763-70
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CONTEXT Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer. OBJECTIVE The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia. DESIGN This was a phase 1 dose-escalation study. SETTING The study was conducted at university clinical research centers. PARTICIPANTS We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L). INTERVENTION AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate. MAIN OUTCOME MEASURE The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (< 230 ng/dL [<8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides. RESULTS With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed. CONCLUSION AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.
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Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum.
Tamae, D, Byrns, M, Marck, B, Mostaghel, EA, Nelson, PS, Lange, P, Lin, D, Taplin, ME, Balk, S, Ellis, W, et al
The Journal of steroid biochemistry and molecular biology. 2013;:281-9
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Abstract
Prostate cancer is the most frequently diagnosed form of cancer in males in the United States. The disease is androgen driven and the use of orchiectomy or chemical castration, known as androgen deprivation therapy (ADT) has been employed for the treatment of advanced prostate cancer for over 70 years. Agents such as GnRH agonists and non-steroidal androgen receptor antagonists are routinely used in the clinic, but eventually relapse occurs due to the emergence of castration-resistant prostate cancer. With the appreciation that androgen signaling still persists in these patients and the development of new therapies such as abiraterone and enzalutamide that further suppresses androgen synthesis or signaling, there is a renewed need for sensitive and specific methods to quantify androgen precursor and metabolite levels to assess drug efficacy. We describe the development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of serum keto-androgens and their sulfate and glucuronide conjugates using Girard-T oxime derivatives. The method is robust down to 0.2-4pg on column, depending on the androgen metabolite quantified, and can also quantify dehydroepiandrosterone sulfate (DHEA-S) in only 1μL of serum. The clinical utility of this method was demonstrated by analyzing serum androgens from patients enrolled in a clinical trial assessing combinations of pharmacological agents to maximally suppress gonadal and adrenal androgens (Targeted Androgen Pathway Suppression, TAPS clinical trial). The method was validated by correlating the results obtained with a hydroxylamine derivatization procedure coupled with tandem mass spectrometry using selected reaction monitoring that was conducted in an independent laboratory.
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The effect of a very low calorie diet on insulin sensitivity, beta cell function, insulin clearance, incretin hormone secretion, androgen levels and body composition in obese young women.
Svendsen, PF, Jensen, FK, Holst, JJ, Haugaard, SB, Nilas, L, Madsbad, S
Scandinavian journal of clinical and laboratory investigation. 2012;(5):410-9
Abstract
OBJECTIVE Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women. METHODS Seventeen overweight women (BMI > 28) were recruited to the study. Glucose, insulin and lipid metabolism were evaluated by euglycemic clamp technique, indirect calorimetry and an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated as glucose disposal rate (GDR) and insulin sensitivity index (ISI), and also by HOMA-IR. Insulin secretion rate (ISR) was calculated from plasma C-peptide measurements. Secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) was measured during an oral glucose tolerance test. Abdominal fat distribution was assessed by dual x-ray absorptiometry scan and computed tomography. RESULTS Ten women completed the intervention. The subjects lost an average 11% of their baseline weight. There was a significant loss of subcutaneous abdominal fatty tissue (p < 0.01) and intra-abdominal fatty tissue (p =0.05). Whole body (HOMA-IR) (p < 0.05) insulin sensitivity increased significantly, but peripheral (ISI) insulin sensitivity was unaltered after weight loss. GIP increased (p < 0.05) and GLP-1 was unaltered after the dietary intervention. Insulin responses did not differ before and after dietary intervention, however, a significant increase in insulin clearance (p < 0.05) was observed. The weight loss resulted in a significant decrease in free testosterone. CONCLUSION A VLCD is an effective weight loss treatment, which results in an immediate improvement in several metabolic parameters.
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Effects of anabolic androgenic steroids on chylomicron metabolism.
Morikawa, AT, Maranhão, RC, Alves, MJ, Negrão, CE, da Silva, JL, Vinagre, CG
Steroids. 2012;(13):1321-6
Abstract
OBJECTIVE To evaluate the effects of anabolic androgenic steroids (AAS) on chylomicron metabolism. METHODS An artificial lipid emulsion labeled with radioactive cholesteryl ester (CE) and triglycerides (TG) mimicking chylomicrons was intravenously injected into individuals who regularly weight trained and made regular use of AAS (WT+AAS group), normolipidemic sedentary individuals (SDT group) and individuals who also regularly weight trained but did not use AAS (WT group). Fractional clearance rates (FCR) were determined by compartmental analysis for emulsion plasma decay curves. RESULTS FCR-CE for the WT+AAS group was reduced (0.0073 ± 0.0079 min(-1), 0.0155 ± 0.0100 min(-1), 0.0149 ± 0.0160 min(-1), respectively; p<0.05), FCR-TG was similar for both the WT and SDT groups. HDL-C plasma concentrations were lower in the WT+AAS group when compared to the WT and SDT groups (22 ± 13; 41 ± 7; 38 ± 13 mg/dL, respectively; p<0.001). Hepatic triglyceride lipase activity was greater in the WT+AAS group when compared to the WT and SDT groups (7243 ± 1822; 3898 ± 1232; 2058 ± 749, respectively; p<0.001). However, no difference was observed for lipoprotein lipase activity. CONCLUSIONS Data strongly suggest that AAS may reduce the removal from the plasma of chylomicron remnants, which are known atherogenic factors.
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Relationship between Day 0 dosimetric parameters and biochemical relapse-free survival in patients treated with transperineal permanent prostate interstitial brachytherapy with (125)I seeds.
Garrán, C, Ciérvide, R, Cambeiro, M, Moreno-Jiménez, M, Ramos, LI, Martínez-Monge, R
Brachytherapy. 2010;(1):8-14
Abstract
OBJECTIVES To determine the relationship between dosimetric parameters obtained on postimplantation Day 0 and biochemical relapse-free survival (bRFS) in patients treated with (125)I transperineal interstitial permanent prostate brachytherapy (TIPPB). METHODS Two-hundred twenty men with low-risk (n=155, 70.4%), low-volume intermediate-risk (n=63, 28.7%), or high-risk (n=2, 0.9%) prostate cancer were treated with TIPPB between December 2000 and June 2006. Seventy-four (33.6%) patients received short-term (3-6 months) androgen suppression therapy before TIPPB. The median followup for patients free of biochemical failure was of 37.9 months (range, 24.0-84.5 months). RESULTS The receiver operating characteristic (ROC) analysis established a best-fit cutoff value for the quantifiers D(90) and V(100) of 147Gy and 92%, respectively. The Kaplan-Meier analysis of bRFS at the cutoff value of D(90)=147Gy using the ASTRO, nadir+2, and combined (ASTRO and nadir+2) definitions showed a trend toward statistical significance for the ASTRO (p=0.076) and nadir+2 (p=0.064) definitions and a statistically significant correlation for the combined definition (p=0.033). The corresponding 7-year bRFS for the D(90) >147Gy and D(90) ≤147Gy subsets using the ASTRO, nadir+2, and combined definitions were 96.5% vs. 89.7% (ASTRO, p=0.076); 93.7% vs. 70.5% (nadir+2, p=0.064); and 94.4 vs. 75.5% (combined, p=0.033). The V(100) (%) cutoff value of 92% predicted by the ROC analysis was not significant. Among other cutoff values, only D(90)=140Gy (p=0.050) and D(90)=160Gy (p=0.098) showed a trend toward statistical significance when the nadir+2 and the ASTRO definitions were used. The rest of dosimetric, tumor, and patient parameters did not show statistical correlation with bRFS in the Kaplan-Meier analysis. CONCLUSIONS The cutoff value of D(90)=147Gy obtained on postimplantation Day 0 showed a trend toward significant correlation with bRFS when the standard ASTRO and nadir+2 definitions were used and a weak but statistically significant correlation with bRFS as per the nonstandard combined definition in a series of patients with predominantly low-risk disease (70.4%) treated at high radiation doses (median D(90)=152.9Gy, median V(100)=92.5%).