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Are published normal ranges of serum testosterone too high? Results of a cross-sectional survey of serum testosterone and luteinizing hormone in healthy men
BJU International
Abstract
To derive normal ranges of serum testosterone and luteinizing hormone (LH) concentrations in healthy men, and thus evaluate whether testosterone replacement therapy is prescribed inappropriately.
The study comprised 266 healthy male volunteers (aged 18-75 years) who were defined as healthy by strict eligibility criteria. Subjects had a body mass index (BMI) of 18.6-32.2 kg/m2, smoked 0-10 cigarettes/day, and had an alcohol intake 0-40 units/week (one unit = 8 g ethanol). We measured serum testosterone and LH concentrations in the morning (08.00-09.00 hours) and evening (20.00-21.00 hours).
Morning normal ranges of testosterone for men aged < or = 40 years were 10.07-38.76 nmol/L (2.90-11.18 microg/L), and for men age > or = 40 years, 7.41-24.13 (2.14-6.96); the respective evening normal ranges were 6.69-31.51 (1.93-9.09) and 6.46-21.93 (1.86-6.33). Both morning and evening serum testosterone declined significantly with increasing age and BMI. LH was significantly higher in the morning than in the evening, but did not vary between the age groups or with BMI. The calculated normal ranges of LH were 0.9-7.0 IU/L (morning) and 0.7-6.8 IU/L (evening).
The lower limit of normal for serum testosterone was 3-4 nmol/L (0.86-1.15 microg/L) lower than that of published ranges. The results have important implications for the diagnosis of hypogonadism and use of testosterone replacement therapy.
... Racial differences in circulating total testosterone levels have been noted due to varying SHBG levels resulting from ethnic differences in adiposity and insulin sensitivity. us, normative values for Whites have been determined in many countries such as Germany, the United States, Wales, and Britain [19][20][21][22][23] using various sampling techniques and laboratory methods. So far, no reference values for African Americans have been generated as most studies comparing African Americans and Whites showed that their testosterone levels are not significantly different [24,25]. ...
... However, the ICC deems samples from both groups as International Journal of Endocrinology valuable and acceptable. If we look at the population-based compared to healthy volunteer studies in Whites, as tabulated in Table 3, note that the 2 population-based studies, the first by Freidrich and the second by Travison, both showed comparable results with three of the four nonpopulation-based studies [21][22][23][24]. Incidentally, note also that the results were similar despite differing laboratory techniques (CLEIA and LS-MS). ...
Background:
The reference range of total testosterone needs to be established locally as ethnic differences in adiposity, insulin sensitivity, and sex hormone-binding globulin (SHBG) levels may affect total testosterone levels. The aim of this study is to establish the reference intervals of total testosterone from healthy, young adult Filipino males.
Methods:
The study included 110 healthy, Filipino male volunteers aged 21-40, studying or working at the University of the Philippines Manila. Clinical history, height, weight, body mass index (BMI), and blood pressure (BP) were obtained, and blood for total testosterone, SHBG, albumin, insulin, fasting blood sugar (FBS), and total cholesterol was collected. Free testosterone was calculated using Vermeulen's formula. The 2.5th to 97.5th percentiles of subjects for total testosterone were used as the normative range for Filipino men.
Results:
The reference range of total testosterone is 7.33-53.01 nmol/L.
Conclusion:
The present study derived reference ranges of total testosterone using data from apparently healthy, young adult men to support clinical services.
... Hence, the representativity of such studies remains low. Regarding serum testosterone, a wider range of references values are available, especially for adult men (Elmlinger et al, 2003(Elmlinger et al, , 2005Schatzl et al, 2003;Boyce et al, 2004;IMMULITE 2500Total Testosterone, 2004Mohr et al, 2005;Okamura et al, 2005). However, almost all available reference values are not adequately adjusted for age (Boyce et al, 2004;IMMULITE 2500Total Testosterone, 2004Okamura et al, 2005) and refer to nonrepresentative samples of men (Schatzl et al, 2003;Elmlinger et al, 2005). ...
... Regarding serum testosterone, a wider range of references values are available, especially for adult men (Elmlinger et al, 2003(Elmlinger et al, , 2005Schatzl et al, 2003;Boyce et al, 2004;IMMULITE 2500Total Testosterone, 2004Mohr et al, 2005;Okamura et al, 2005). However, almost all available reference values are not adequately adjusted for age (Boyce et al, 2004;IMMULITE 2500Total Testosterone, 2004Okamura et al, 2005) and refer to nonrepresentative samples of men (Schatzl et al, 2003;Elmlinger et al, 2005). ...
Dehydroepiandrosterone (DHEA) is the main adrenal androgen, which mostly exists in a sulfated version (DHEAS). Both DHEA and DHEAS are metabolic intermediates in the biosynthesis of the male sex hormone testosterone. In men, testosterone is involved in the regulation of fertility, libido, and muscle mass and is valuable for the assessment of gonadal, adrenal, and pituitary function and for the diagnosis of hypogonadism. The objective of the present study was to calculate age-specific reference ranges for serum DHEAS and serum testosterone using 1) linear regression and the mean +/- 1.96 standard deviation concept and 2) quantile regression. From the cross-sectional Study of Health in Pomerania a total of 1078 men aged 20-79 years were included in the analyses. Serum DHEAS and testosterone levels were quantified using IMMULITE 2500 immunoassays. Linear and quantile regression were performed to calculate age-specific reference ranges. Both statistical methods generated different results: The reference ranges based on linear regression identified 17 men (1.6%) with DHEAS levels and 45 men (4.2%) with serum testosterone levels outside the reference range. Using quantile regression, 54 men (5.0%) and 50 men (4.6%) with serum DHEAS and testosterone levels outside the range were detected, respectively. The present study established age-specific reference ranges for serum DHEAS and testosterone levels for men. Quantile regression should be preferred to calculate reference ranges; a better concordance with original data is possible because no distribution assumption is required and the robustness against outliers is given.
... Therefore, it is important to take samples under standardized conditions. Boyce and co-workers (2004) published different reference ranges for serum testosterone levels in men depending on the time of day [39]. The range for morning testosterone concentrations is 10.07-38.76 ...
Neuroactive steroids are a family of all steroid-based compounds, of both natural and synthetic origin, which can affect the nervous system functions. Their biosynthesis occurs directly in the nervous system (so-called neurosteroids) or in peripheral endocrine tissues (hormonal steroids). Steroid hormone levels may fluctuate due to physiological changes during life and various pathological conditions affecting individuals. A deeper understanding of neuroactive steroids’ production, in addition to reliable monitoring of their levels in various biological matrices, may be useful in the prevention, diagnosis, monitoring, and treatment of some neurodegenerative and psychiatric diseases. The aim of this review is to highlight the most relevant methods currently available for analysis of neuroactive steroids, with an emphasis on immunoanalytical methods and gas, or liquid chromatography combined with mass spectrometry.
... In females, estrogen and progesterone levels alter with menstrual cycling and at even higher levels during pregnancy (Brown 2011). Conversely, the concentrations of steroid hormones decline in women during reproductive senescence, while testosterone in males peaks in the second decade of life and thereafter gradually declines with age (Boyce et al. 2004). ...
Respiratory infections are an important and frequent cause of morbidity and mortality globally. Sex and gender-based differences in lung infection are recognized and gradually gaining importance due to the potential for gender-tailored therapeutics. While sex and gender differences are widely acknowledged in the evaluation of chronic respiratory disease states such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), acute and chronic respiratory infection complicate all of these and, in themselves, depending on age and organism, demonstrate sex differences. Males are disadvantaged in the occurrence and severity of lower respiratory tract infections such as pneumonia, while females suffer more commonly with upper respiratory tract ailments including tonsillitis and sinusitis. Differences in genetics and immunity have been forwarded as explanations for such differences; however, it is likely that a complex interplay of sex steroid hormones, host immunity, genetics, anatomical variation, and lung physiology, in addition to sociocultural and behavioral factors, influences the observed sex differences in respiratory infection. This chapter aims to assess the current state of the literature in this field and expound the range of its contributory factors.
... As shown in Fig. 1D, the amount of endogenous fusion transcript induced by antisense-5 (the most effective antisense input RNA) appears to correlate with the concentration of DHT used, presumably because the hormone induces the chromosomal proximity between the TMPRSS2 and ERG genes (13-15). Antisense-5 was effective at DHT concentrations as low as 20 nM, as revealed by sensitive nested PCR (Fig. 1D, lane 3), indicating that fusion events induced by input RNA can occur under physiologically relevant androgen conditions (16). As a control, DHT treatment alone up to 2 μM failed to induce fusion (SI Appendix, Fig. S7). ...
Significance
This report provides striking evidence that expression of a chimeric RNA mimicking a fusion RNA can drive the formation of gene fusions in mammalian cells. However, it is the antisense rather than sense chimeric RNAs that effectively drive gene fusion. The discovery that the cellular AZI1 RNA, not AZI1 protein, can act as an “initiator” RNA to induce TMPRSS2–ERG gene fusion indicates that this mechanism may have important biological relevance to oncogenesis. RNA-mediated gene fusion, a mechanism that relies on sequence-specific interactions, can account for the “specificity” of genes that were selected to undergo gene fusion. The results could also have fundamental implications in mammalian genome stability, as well as gene-editing technology via mechanisms native to mammalian cells.
... Blood samples were drawn at a time convenient for each participant, meaning the blood was drawn at different hours of the day, the majority in the afternoons and evenings. This makes our results less reliable since, especially, testosterone is recommended to be sampled in the morning when the serum levels are highest and more sensitive to show differences between groups (Boyce et al. 2004). This is probably the reason why the majority of both groups had testosterone levels categorized within the 'grey zone (8-15 nmol/L)' rather than within the normal zone (>15 nmol/L). ...
Environmental factors during the fetal period may adversely affect reproductive functions in men being born with very low birth weight (VLBW, <1500 g). The objective of this prospective, controlled cohort study was to investigate if VLBW men have an altered reproductive hormone profile compared with men born at term. The study group initially consisted of all VLBW boys live-born between 1 February 1987 and 30 April 1988 in the south-east region of Sweden (n = 47). A control child was chosen born at term, at the same hospital, with the same parity, without malformations, and next in order after each VLBW child who survived the first four weeks (n = 45). The present follow-up was performed when the men were 26–28 years of age and included measurements of serum hormone levels, hair testosterone concentration, and anthropometric data. Also life-style questionnaires were collected from 26 VLBW men and 19 controls.
The VLBW group (n = 26) had higher median levels of serum estradiol, 84.5 pmol/L than controls (n = 19), 57.5 pmol/L (p = 0.008). There was no significant correlation between serum estradiol and BMI (r = 0.06, p = 0.74). There were no differences in other hormone levels or the reproductive pattern between the groups. In conclusion, even though there was a statistically significant difference in estradiol levels between the groups, both groups had low normal mean levels of questionable clinical significance. The reproductive pattern was similar in the two groups and in this study being born VLBW does not seem to affect these measured aspects of reproduction.
Abbreviations: ADHD: attention deficit hyperactive disorder; AGA: average for gestational age; BMI: body mass index; CP: cerebral palsy; DHT: dihydrotestosterone; FSH: follicle stimulating hormone; LBW: low birth weight; LH: luteinizing hormone; SAD: sagittal abdominal diameter; SGA: small for gestational age; SHBG: sex hormone binding globulin; TSH: thyroid stimulating hormone; T3: triiodothyronine; T4: thyroxin; VLBW: very low birth weight
... Testosterone is the primary androgen hormone that has a significant effect on human health [1]. The average level of testosterone in a healthy adult male is 300-1000 ng/dL [2]. It has been used illegally by athletes as a result of its anabolic effect, which is related to muscle mass and strength growth [3]. ...
The detection of testosterone in aqueous solutions is a difficult task due to the low concentration levels that are relevant in environmental and physiological samples. Current analytical methods are expensive and/or complex. To address this issue, we fabricated a molecularly imprinted polymer (MIP) photonic film for the detection of testosterone in water. The films were obtained using colloidal crystals as templates for the pore morphology. Monodispersed silica particles with an average diameter 330 nm were used to obtain the colloidal crystal by vertical deposition. A solution of acrylic acid with testosterone as the imprinted template was infiltrated in the colloidal crystal and polymerized via bulk polymerization; the particles were then removed by acid etching and the testosterone eluted by a suitable solvent. The material was characterized by FTIR, swelling experiments and microscopy; MIPs were investigated by equilibrium rebinding, kinetics and reuse experiments. The results showed that the MIPs exhibited selectivity to the template, a 30-min equilibration time and stability after at least six cycles of use and regeneration. After incubation, the reflectance spectra of the films showed a shift of the Bragg diffraction peak that correlated with testosterone concentration in the 5–100 ppb range.
... The reference ranges provide the basis for differentiating low from normal testosterone levels, and are, therefore, essential for making the diagnosis of hypogonadism. We have published reference ranges for circulating testosterone levels generated in healthy nonobese men who were participants in the Framingham Heart Study (FHS) (4); similar data have been published in other populations (5)(6)(7)(8)(9)(10)(11). However, an important unresolved question is whether the reference ranges generated in one population of men can be applied more broadly to men in other geographic regions and in other populations. ...
Background:
Reference ranges for testosterone are essential for making a diagnosis of hypogonadism in men.
Objective:
To establish harmonized reference ranges for total testosterone in men that can be applied across laboratories by cross-calibrating cohort-specific assays to a reference method and standard.
Population:
9054 community-dwelling men in cohort studies in the United States and Europe: Framingham Heart Study; European Male Aging Study; Osteoporotic Fractures in Men Study; Male Sibling Study of Osteoporosis.
Methods:
Testosterone concentrations in 100 participants in each of the four cohorts were measured using a reference method at Centers for Disease Control. Generalized additive models and Bland-Altman analyses supported the use of normalizing equations for transformation between cohort-specific and CDC values. Normalizing equations, generated using Passing-Bablok regression, were employed to generate harmonized values, which were used to derive standardized, age-specific reference ranges.
Results:
Harmonization procedure reduced inter-cohort variation between testosterone measurements in men of similar ages. In healthy nonobese men, 19-39 years, harmonized 2.5th, 5th, 50th, 95th and 97.5th percentile values were 264, 303, 531, 852 and 916 ng/dL, respectively. Age-specific harmonized testosterone concentrations in nonobese men were similar across cohorts and greater than in all men.
Conclusion:
The harmonized normal range (2.5th-to-97.5th percentile) in nonobese, population of European and American men, 19-39 years, is 264-916 ng/dL. A substantial proportion of inter-cohort variation in testosterone levels is due to assay differences. These data demonstrate the feasibility of generating harmonized reference ranges for testosterone that can be applied to assays, which have been calibrated to a reference method and calibrator.
... 16 Although a lot of evidence suggesting that testosterone levels gradually decrease with age which contributes to the LOH progress, [17][18][19] doubts were raised about the theory recently. [20][21][22][23] In our previous study, we found that T levels did not decline with age significantly. On the contrary, T levels showed an increased trend over 50 years old. ...
Objective:
The aim of this study is to compare calculated free testosterone (cFT) and total testosterone (T) in predicting late-onset hypogonadism (LOH) in middle-aged and elderly males.
Methods:
We surveyed a random sample of 608 males between the ages of 45 and 87 years from Shanghai, China. The Aging Male Symptoms (AMS) questionnaire and the Androgen Deficiency in Aging Male (ADAM) questionnaire were completed by the subjects. Testosterone (T), sex hormone-binding globulin (SHBG), albumin, and other blood biochemical indexes were measured in 332 males. The corresponding cFT was obtained using the Vermeulen formula and the correlations between T and cFT were analyzed by SPSS statistical software.
Results:
Among the 332 males who underwent biochemical evaluation, 289 males (87.0%) was positively screened by the ADAM questionnaire and 232 males (69.9%) by the AMS questionnaire. As suggested by linear regression, cFT exhibited a negative correlation with age in both ADAM+ and AMS+ group, whereas T did not appear to have significant correlation with age. Besides, there were statistically significant differences in cFT (P<.001) in the AMS questionnaire.
Conclusions:
Calculated free testosterone levels are more reliable than T levels for diagnosing LOH in middle-aged and elderly males.
... Halmenschlager et al. [27] (n =428) reported not only was decreased in TT with advancing years, but also was increased in variance later in life. Frost et al. [25], Boyce et al. [28] and Orwoll et al. [29] (n = 783, 266, 2,623 respectively) reported not only was there no decline in serum TT with advancing age but also no increase in variance. Rhoden et al. [30] reported that not only did serum TT not fall with advancing age, but there was also an increase in variance across the lifespan from age 40 onwards (n =1,071). ...
Background
Level of the testosterone in a man’s life span is very important. Studies on the serum testosterone concentrations in different age groups of healthy men were controversial. The aim of this study was to investigate dynamic changes of serum reproductive hormones with aging in healthy Chinese male and to compare its correlation with age.
Methods
Total of 1,093 healthy Chinese men from Shanghai aged from 20 to 87 years old was enrolled in the study. Concentrations of serum total testosterone (T), luteinizing hormone (LH) and sex hormone binding globulin (SHBG) were quantified by EIA. Testosterone secretion index (TSI) and free testosterone index (FTI) were then calculated. Data were analyzed by SPSS program. Non-parametric tests and univariate linear regression analyses were used.
Results
The 1,039 male participants were grouped into 12 groups by 5-year apart for each group. Significant differences in T, LH, SHBG, FTI and TSI were found between the 12 different age groups. Average of serum total T was 15.36 ± 4.86 nmol/L; LH was 4.76 ± 2.76 IU/L, SHBG was 32.61 ± 17.24 nmol/L. Compared to age 20 ~ 24 group, serum T level of age 35 ~ 39, 40 ~ 44, 45 ~ 49, 50 ~ 54, and 55 ~ 59 was significantly decreased (p < 0.05). Intriguingly, however, serum T level of age 60 or older did not significantly reduced compared to the age of 20 ~ 24 group. Serum LH and SHBG were positively correlated with aging (p <0.01), while TSI and FTI were negatively correlated with aging (p <0.01). In addition, BMI was negatively and significantly correlated with levels of T (r = −0.585, p < 0.001), LH (r = −0.090, p < 0.001), SHBG (r = − 1.817, p < 0.001), and TSI (r = − 0.104, p < 0.001), but positively and significantly correlated with FTI level (r = 0.011, p < 0.001).
Conclusion
Serum total testosterone fluctuated with aging in adult men, and FTI and TSI decreased gradually with aging. While age was not significantly correlated with T level, BMI was significantly and negatively correlated with T level, suggesting body weight may affect testosterone level.
... Muller et al. [32], Mohr et al. [31] and Simon et al. [35] all report a small annual decline of 0.4%, 0.3% and 0.5% respectively (n = 400, 1,677, 1,408 respectively) and show no increase in variance, also in qualitative disagreement with our two key findings. Frost et al. [25], Boyce et al. [46] and Orwoll et al. [30] (n = 783, 266, 2,623 respectively) all report no decline in serum TT with advancing age but also no increase in variance. Rhoden et al. [34] report that not only does serum TT not fall with advancing age, but there is also an increase in variance across the lifespan from age 40 onwards (n = 1,071). ...
The diagnosis of hypogonadism in human males includes identification of low serum testosterone levels, and hence there is an underlying assumption that normal ranges of testosterone for the healthy population are known for all ages. However, to our knowledge, no such reference model exists in the literature, and hence the availability of an applicable biochemical reference range would be helpful for the clinical assessment of hypogonadal men. In this study, using model selection and validation analysis of data identified and extracted from thirteen studies, we derive and validate a normative model of total testosterone across the lifespan in healthy men. We show that total testosterone peaks [mean (2.5-97.5 percentile)] at 15.4 (7.2-31.1) nmol/L at an average age of 19 years, and falls in the average case [mean (2.5-97.5 percentile)] to 13.0 (6.6-25.3) nmol/L by age 40 years, but we find no evidence for a further fall in mean total testosterone with increasing age through to old age. However we do show that there is an increased variation in total testosterone levels with advancing age after age 40 years. This model provides the age related reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism.
... The resultant alteration in androgen levels may produce a state of hypogonadism, with symptoms of ED, in the presence of normal total testosterone levels. In addition, some have suggested using age-adjusted total testosterone levels to determine normal ranges for males [31][32] . ...
This study describes the prevalence of erectile dysfunction (ED) among 57 men using illicit opioids who presented to a primary care program for buprenorphine therapy. Participants' mean age was 40 years and 34% reported ED. Low total testosterone was detected in 17% of those reporting ED, but total testosterone was not significantly associated with ED. Examining multiple comorbidities and laboratory parameters, only older age was significantly associated with ED (r = .27, P< .05). ED is highly prevalent among men abusing opioids, but low total testosterone is rarely the cause.
... Diurnal variations, with lower afternoon fT levels, might have led to a certain overestimation of the prevalence of hypogonadism . However, diurnal variations are mostly seen in young, healthy men and tend to disappear with increasing age [18,19]. In conclusion, our data show that a considerable proportion of treatment-naive HIV-positive men have abnormally low age-adjusted levels of fT, which is not reversible after 2 years of successful cART. ...
To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART).
Multicentre cohort of HIV-infected adults.
We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated.
At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+ T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART.
Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.
Background
Testosterone (T) plays a crucial role in various physiological functions in men, and understanding the variations in T levels during the day is essential for diagnosing and treating testosterone deficiency (TD).
Aim
We sought to evaluate the reduction in serum total T (TT) levels throughout the day in men with symptoms of testosterone deficiency and to determine the variables having an impact on the extent of this decline.
Methods
The study population consisted of a group of men who within 3 months of each other had all undergone both early morning and afternoon TT level measurements. We did not include patients with a history of a prior orchiectomy, testosterone levels below 100 ng/dL or above 1000 ng/dL, a history of androgen deprivation therapy, or patients on T therapy. Statistical analyses were conducted using descriptive statistics, t-tests, chi-square tests, and correlation calculations. Liquid chromatography–tandem mass spectrometry was used to measure TT, and a change in TT levels greater than 100 ng/dL was considered significant. Using multivariable and univariable analysis, we attempted to define predictors of a decrease in afternoon TT levels.
Outcomes
The majority of men showed no significant difference in T levels between morning and afternoon.
Results
In total, 506 men with a median age of 65 years were analyzed. The most common comorbidities were hypertension and hyperlipidemia. Levels of TT were measured in the morning and afternoon, and no significant differences in mean T levels based on the time of the test were found. Age was not significantly associated with T levels.
Clinical Implications
There was a weak negative correlation between age and the difference between morning and afternoon T levels, with younger men showing more significant variations in T levels. The most considerable differences in T levels were observed in men younger than 30 years. There were no predictors of the magnitude of the T decrease in the afternoon.
Strengths and Limitations
Strengths of the study include the number of subjects and the use of liquid chromatography–tandem mass spectrometry for T measurement. Limitations include failure to measure morning and afternoon T levels on the same day, the retrospective nature of the study, and a smaller sample size of patients younger than 30 years.
Conclusion
In this study we found no strong link between age and daily T fluctuation, but we observed a decrease in the magnitude of variation with aging. The group experiencing the most significant decline in daily T had higher morning and consistently normal afternoon T levels.
In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex and gender specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path towards achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all.
The selective, sensitive, and real‐time detection of testosterone was performed from both testosterone aqueous solution and artificial urine samples by using the advantages of surface plasmon resonance sensor (SPR) with molecular imprinting technique. The testosterone imprinted (MIP) and non‐imprinted (NIP) nanoparticle based poly(2‐hydroxyethyl methacrylate‐methacrylic acid (poly(HEMA‐MAA)) SPR sensors were prepared for detection of testosterone. After characterization of MIP and NIP nanoparticles, nanoparticles were attached on the SPR chip surfaces. The characterization of SPR sensor surfaces was carried out with characterization methods such as atomic force microscopy, ellipsometer and contact angle measurements. The real‐time measurements for detection of testosterone were performed with testosterone imprinted SPR sensor in the linear range of 0.5‐20 ng/mL concentration in testosterone aqueous solution. The imprinting factor and the limit of detection was found 4.16 and 0.049 ng/mL, respectively. The validation studies were performed with both SPR sensor and enzyme‐linked immunosorbent assay using testosterone samples prepared in artificial urine samples for the detection of testosterone.
The association between hypogonadism symptoms and the levels of serum hormones are still in debate. To investigate the relationship between hypogonadism symptoms and serum hormones in middle-aged and elderly Chinese men, this community-based cross-sectional study was conducted based on a total of 965 ageing men. The ageing males' symptom (AMS) scale, International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS) questionnaires and related variables were assessed. Blood tests for total testosterone (TT), sex hormone-binding globulin (SHBG) and luteinising hormone (LH) were performed. Serum level of free testosterone (FT) and bioavailable testosterone (Bio-T) was calculated. The mean age was 56.34 ± 8.85 years. Total AMS score was significantly associated with all five serum hormones (LH: p < 0.001; SHBG: p < 0.001; TT: p =.043; FT: p = 0.007; Bio-T: p < 0.001). We identified sexual and somatic symptoms were obviously related to five serum hormones, while psychological symptoms seemed to have no association with serum hormones. After adjusting for age and BMI, multiple linear regression analysis indicated that LH had positive correlations with total AMS score, somatic and sexual symptom score (p < 0.05). In conclusion, LH and SHBG had the strongest correlation hypogonadism and might be used as early predictors for symptomatic hypogonadism in the near future.
Pharmacological agents have an important role in treating and reducing risk in some sexual offenders, but also attract controversy, misunderstanding, misrepresentation, and opposition. Sexual offenders can have paraphilic disorders or paraphilia‐related disorders. This chapter covers medications used in current clinical practice to reduce sexual urges and drive the so‐called antilibidinal medications (antiandrogens and gonadotrophin‐releasing hormone agonists which reduce testosterone activity) and nonhormone‐mediated treatments like selective serotonin reuptake inhibitors (which potentiate serotonin activity). It outlines basic science, agents available, effects (wanted and unwanted), research evidence, clinical guidelines, and practice issues such as psychiatric assessment, ethical issues and legal issues. Practice experience in many countries, supported by underlying science and theory, suggests medication and treatment of sexual offenders has an important role in a significant minority of cases, as part of a comprehensive biopsychosocial, interdisciplinary, and multiagency treatment and management plan.
Testosterone deficiency is frequent among men with chronic kidney disease (CKD). Aberrations at all levels of the hypothalamic-pituitary-gonadal (HPG) axis contribute to testicular dysfunction and low testosterone levels in CKD. Testosterone levels decline as CKD progresses with further reductions in the estimated glomerular filtration rate (eGFR). Both CKD and low serum total testosterone concentrations are independent predictors of mortality risk, and combined evaluation of the GFR and circulating testosterone improves mortality risk stratification even further. Testosterone deficiency may have important clinical implications with regard to sexual dysfunction, anemia, loss of muscle mass and function, mobility, well-being, and health-related quality of life. Patients with CKD also suffer from high rates of erectile dysfunction and decreased fertility. Hypogonadism associated with CKD is seldom improved with the initiation of hemodialysis alone, but impairment of the HPG axis and sexual dysfunction are often improved by renal transplantation. In healthy hypogonadal men with normal renal function, testosterone replacement improves sexual desire, erectile function, sexual activity, muscle mass and maximal voluntary strength, as well as bone mineral density and bone quality. Randomized clinical trials are needed to determine the efficacy and safety of administering testosterone replacement therapy in patients with CKD.
In clinical practice, it is fundamental to compare the results of hormonal examinations obtained in the laboratory with reliable reference values. This is particularly difficult when faced with rare conditions, such as disorders of sex development, where not routinely assayed peptide hormones as well as intermediate steroid metabolites are often needed and local reliable reference values are not available. There are considerable differences among techniques and assays used in clinical and research laboratories. In fact, laboratory hormonology is undergoing a critical transition between techniques for quantitative determination: established immunoassays and mass spectrometry. Harmonizing results from different laboratories is a major challenge along the path leading to the establishment of consensus reference intervals for steroid hormones. Most of the efforts are being concentrated on testosterone, with very encouraging results being provided by the harmonization of liquid chromatography-tandem mass spectrometry results. However, this goal is still far from being achieved for the other steroid and small-molecule hormones, and a much more challenging perspective is foreseeable for protein hormones. In addition to technical issues, the importance of the definition and of the characterization of the reference population as well as sampling and processing methodology should not be underestimated, as these aspects may impact on hormonal axis and compound stability. The aim of the present review is to provide a comprehensive overview of the circulating reference values in basal condition of the hormones and proteins involved in sex development reported to date in the peer-reviewed literature. We present a series of tables where we have collected the reference intervals for each specific hormone and protein.
Background:
Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory).
Methods:
JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference.
Results:
JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3.
Conclusions:
Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the treatment of AR-overexpressed CRPC driven by AR splice variants that are not clinically actionable at present. Prostate © 2016 Wiley Periodicals, Inc.
Sexual functions and behaviour are complex processes occurring at the level of neural and vascular systems. They are closely connected with metabolic processes, and the whole of this system is controlled by sex hormones and neurotransmitters. Basing on the literature and the findings of my own research studies, I present in the paper the up-to-date opinions on how and when sex hormones and neurotransmitters correlate with sexual functions and behaviour. The paper shows how hormones and neurotransmitters influence both male and female sexuality; and how hormones influence erectile dysfunction and sexual pathologies, it also describes the influence of hormonal substitution on human sexuality and general condition.
The diagnosis of an endocrine problem should satisfy the following: the clinical features, comprising symptoms, and signs (if present) must be consistent; biochemically, the level of the hormone concerned must be shown to be inappropriately below the age- and gender-specific reference ranges.
The present study aims to determine reference ranges for sex hormone concentrations measured on the Siemens ADVIA Centaur
The study sample consisted of 1638 individuals (814 men and 824 women) aged 18–60 years with measured serum concentrations of total testosterone (TT), sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS). Values for free testosterone (free T) and free androgen index (FAI) were calculated. Sex- and age-specific (18 to <25, 25 to <35, 35 to <45, and ≥45 years) reference ranges for these sex hormones were determined using quantile regression models for each sex hormone separately.
Sex hormone reference ranges were determined across each single year of age separately for men (TT: 5.60–29.58 nmol/L, SHBG: 17.65–73.64 nmol/L, DHEAS: 0.96–4.43 mg/L, free T: 0.10–0.51 nmol/L, and FAI: 15.04–70.37 nmol/L) and women (TT: 0.77–2.85 nmol/L, SHBG: 27.06–262.76 nmol/L, DHEAS: 0.50–3.15 mg/L, free T: 0.005–0.05 nmol/L, and FAI: 0.51–8.30 nmol/L), respectively.
Introduction:
Based on studies demonstrating the circadian rhythmicity of testosterone levels, the optimal time of day to draw total testosterone (TT) in men has classically been reported as between 8 and 11 AM. However, further studies have demonstrated that the circadian rhythmicity of testosterone levels becomes blunted with age.
Methods:
Charts of 2,569 men presenting with erectile dysfunction (ED), were retrospectively reviewed for TT and draw times and were compared by age group. Men were grouped to: less than 40, and then by 5 year groupings. TT was analyzed for variability over the most common draw time hours (7 AM – 2 PM).
Results:
The mean TT for 7-9 AM versus 9 AM-2 PM were both clinically and statistically different only for men in the age groups of < 40 and 40-44, with mean TT differences of 207 ng/dL [95% CI 98-315 p = 0.0004], and 149 ng/dL [95% CI 36-262 p = 0.01] respectively. All other groupings did not demonstrate both a clinically and statistically significant difference between those time periods.
Conclusion:
A TT level in men with ED who are younger than 45 years should be drawn as close to 7 AM as possible as a statistically and a clinically relevant drop in testosterone levels will occur over the course of the day. Men older than age 45 years with ED can have their TT drawn at any time before 2 PM without fear of misleading results.
The Internet is used by lay people interested in their well-being and health. The objective in this article is to study male menopause by analysing the themes the Internet provides about male menopause and its treatments and to evaluate the quality of commercial web-based information by comparing it to the scientific information. The data were drawn from a selection of Finnish websites that Finnish men would be able to access. Seven different themes emerged in the material: healthism, a quasi-professional attitude, uncertainty, risk, mood-enhancement effects, good sex and similarity to women. The online information did not correspond to current scientific medical information. These seven themes produce a new form of illness — male menopause — and its treatment with male hormone therapy. The themes contribute to the constitution of medicalized bodies by encouraging men to use testosterone medication.
To evaluate the influence of age on serum levels of total testosterone (TT), bioavailable testosterone (BT), free testosterone (FT), and sex-hormone binding globulin (SHBG), considering the presence of fasting blood glucose levels and body mass index (BMI) in a selected male population.
A total of 428 men were analyzed. Anthropometry was taken from all, considering BMI as general obesity indicative variable. Fasting blood samples were drawn for determination of plasma glucose levels and serum levels of albumin, TT, and SHBG. The values of BT and FT were calculated from TT, SHBG, and albumin, by Vermeulen's equation. Statistical significance was set at P ≤ 0.05.
Age was negatively correlated to BT (r = -0.301; P < 0.001) and FT (r = -0.273; P < 0.001), but not to TT levels (r = 0.002, P = 0.974). Age was positively correlated to SHBG (r = 0.376; P < 0.001). Age was independently associated with the occurrence of high SHBG levels (OR = 1.07, 95%CI = 1.05-1.10, P < 0.001) and of low BT (OR = 1.04, 95%CI = 1.02-1.07, P < 0.001) and FT levels (OR = 1.05, 95%CI = 1.03-1.08, P < 0.001), but not with low levels of TT (P = 0.08).
Age was significantly associated to high levels of SHBG and to low levels of BT and FT, without significant association to TT. This pattern was independent of BMI and glucose levels.
Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men.
TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study.
In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes.
Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.
Evaluation of potential candidates for testosterone replacement therapy (TRT) includes a complete medical history, physical examination, and hormonal screening. The choice of testosterone assay is important in clinical decision making. TRT should, in theory, approximate natural endogenous production of the hormone. There is no apparent association between TRT and the development of prostate cancer. The administration of exogenous testosterone is not a means of reversing the aging process in men with normal testosterone levels, but it may offer considerable benefit for those with hypogonadism.
The LH receptor (LHCGR) drives fetal testosterone secretion, which is vital for human masculinization. Maternal smoking is associated with defective masculinization, but the relationship between smoking, tropic hormones, testosterone, and functional LHCGR expression is poorly understood.
This study aimed to investigate developmental changes in fetal gonadotropins, human chorionic gonadotropin (hCG), and expression of fetal testicular LHCGR isoforms and the effects of maternal cigarette smoking.
We conducted an observational study of the male fetus, comparing pregnancies in which the mothers did or did not smoke.
The study was conducted at the Universities of Aberdeen and Glasgow.
Testes and blood were collected from 54 morphologically normal human male fetuses of women undergoing elective termination of normal second-trimester pregnancies.
We measured circulating testosterone, hCG, LH, prolactin, FSH, and testicular LHCGR isoform expression.
Fetal testosterone and hCG, but not LH, significantly declined between 11 and 19 wk gestation with no significant change in testicular responsiveness. The proportion of nonfunctional LHCGR transcript in fetal testes was 2.3-fold lower than in adults. Fetal hCG was reduced 38% (P = 0.021) and the ratio of inactive vs. active LHCGR isoforms lowered by smoking.
Falling second-trimester fetal testosterone is probably due to declining maternal hCG because Leydig cell LH/hCG responsiveness remains constant. Although maternal cigarette smoking reduces fetal hCG, the ratio of inactive LHCGR isoforms is reduced and gonadotropin drive maintains testosterone production near control levels. The lower relative abundance of inactive isoforms compared with the adult testis reflects the importance of LHCGR.
Our aim was to establish sex hormone reference intervals measured with a new AutoDelfia immunoassay method for aged men free of medication and/or conditions known to influence sex hormone levels.
The reference population consisted of 466 individuals between 64 and 97 years (mean 72 years) and a mean body mass index (BMI) of 26.9 kg/m(2).
Because age correlated significantly with most sex hormones studied, we calculated reference intervals for three age groups (64-69, 70-74 and > or =75 years). In clinical practice, single ranges can be used for men aged 64 years or over for testosterone, estradiol and follicle-stimulating hormone (FSH) with the AutoDelfia method. For free testosterone and luteinizing hormone (LH), separate reference intervals should be used for men aged 64-74 years and those aged 75 years or over. For sex hormone-binding globulin, two separate reference intervals by age (64-69 and > or =70 years) are also needed for aged men. LH and FSH reference ranges should be judged with caution, because they may be too high due to cases of subclinical hypogonadism included in the reference population.
To determine whether sex hormones alone or in combination with body mass index (BMI) influence mood in men.
Blood samples were taken from 669 manual workers (aged 43-67 years) to measure sex hormone levels, in particular bioavailable testosterone (BAT). At the same time BMI was calculated. All participants completed the Beck's Depression Inventory (BDI) for the evaluation of depression. Then BMI and BAT were correlated to the BDI scores, to determine a possible interaction.
There was a quadratic main effect for BAT on the BDI scores, i.e. an increased risk of depression with an odds ratio of 1.871 (P = 0.029) for hypo- and hypergonadal men. Also, there was an interaction between BAT and BMI, which was mainly detected in underweight and obese men. This U-shaped effect for underweight and obese men was not detected in men with a 'normal' weight, who had a significantly linear decrease in the risk of depression by changing from the hypogonadal to the eugonadal subgroup, as well as for changing from the eugonadal to the hypergonadal subgroup, with a mean odds ratio of 0.513 (P = 0.032).
Depression depends on BAT and BMI; in men of normal weight, an increase in BAT reduces the risk of depression, which is not the case in underweight and obese men. Consequently eugonadal men with normal testosterone levels have the lowest risk of depression.
To assess testosterone patterns during clinical hours in a large population of men participating in a national screening programme for prostate cancer, as the effect of time of day on serum testosterone concentration is unclear and largely reported in small studies.
Testosterone levels were measured in 3006 men attending the national Prostate Cancer Awareness Week screening programme. Blood samples were obtained between 06.00 and 18.00 hours, whenever men presented for screening. All men completed questionnaires on age, comorbidities, height and weight. Testosterone levels were compared based on four periods, i.e. T1, 06.00-10.00 (632 men), T2, 10.00-12.00 (812), T3, 12.00-14.00 (388), and T4, 14.00-18.00 hours (1174).
The mean (sd, range) age of the men was 60.3 (9.9, 40-94) years and the mean (sd) testosterone level was 415.2 (190.9) ng/dL. There was no change in mean (sd) testosterone levels over T1, T2 and T3, at 444.9 (206.2), 433.5 (195.8) and 434.4 (181.2) ng/dL, respectively, but levels at T4, at 380.4 (176.4) ng/dL, were lower by approximately 13% (P < 0.05). Advancing age, diabetes and obesity were associated with lower testosterone levels. The percentage of men with biochemical hypogonadism (<300 ng/dL) did not change across all four periods.
Testosterone levels in older men are stable throughout the morning and early afternoon, declining only modestly thereafter. Further case-controlled studies are needed to confirm these findings.
Adverse secular trends in male reproductive health have been reported to be reflected in increased testicular cancer risk and decreased semen quality in more recently born men. These secular trends may also be reflected by changes in Leydig cell function.
The objective of the study was to examine whether an age-independent time trend in male serum testosterone levels exists.
Testosterone and SHBG were analyzed in 5350 male serum samples from four large Danish population surveys conducted in 1982-1983, 1986-1987, 1991-1992, and 1999-2001. Free testosterone levels were calculated. The effects of age, year of birth, and time period on hormone levels were estimated in a general linear statistical model.
Testosterone, SHBG, and calculated free testosterone levels in Danish men in relation to age, study period, and year of birth were measured.
Serum testosterone levels decreased and SHBG levels increased with increasing age. In addition to this expected age effect, significant secular trends in testosterone and SHBG serum levels were observed in age-matched men with lower levels in the more recently born/studied men. No significant age-independent effect was observed for free testosterone. Adjustment for a concurrent secular increase in body mass index reduced the observed cohort/period-related changes in testosterone, which no longer were significant. The observed cohort/period-related changes in SHBG levels remained significant after adjustment for body mass index.
The observed age-independent changes in SHBG and testosterone may be explained by an initial change in SHBG levels, which subsequently lead to adjustment of testosterone at a lower level to sustain free testosterone levels.
We compared androgen and gonadotropin values in HIV-infected men who did and did not develop lipoatrophy on combination antiretroviral therapy (cART).
From a population of 136 treatment-naïve male Caucasians under successful zidovudine/lamivudine-based cART, the 10 patients developing lipoatrophy (cases) were compared with 87 randomly chosen controls. Plasma levels of free testosterone (fT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone and luteinizing hormone (LH) were measured at baseline and after 2 years of cART.
At baseline, 60% of the cases and 71% of the controls showed abnormally low fT values. LH levels were normal or low in 67 and 94% of the patients, respectively, indicating a disturbance of the hypothalamic-pituitary-gonadal axis. fT levels did not significantly change after 2 years of cART. Cases showed a significant increase in LH levels, while controls showed a significant increase in DHEA levels. In a multivariate logistic regression model, lipoatrophy was associated with higher baseline DHEA levels (P=0.04), an increase in LH levels during cART (P=0.001), a lower body mass index and greater age.
Hypogonadism is present in the majority of HIV-infected patients. The development of cART-related lipoatrophy is associated with an increase in LH and a lack of increase in DHEA levels.
Many men in old age demonstrate symptoms consistent with hypogonadism. With the introduction of new and more convenient methods of testosterone replacement treatment of these men is more practical. The diagnosis of hypogonadism in the older male has been controversial with some clinicians suggesting that symptoms should be treated without due reliance on testosterone concentrations. However, most professional bodies have proposed that a low testosterone concentration should be part of the diagnosis. This is, in turn, reliant on the testosterone measurement being reliable and read against an appropriate reference range. This review looks at the factors that can influence the interpretation of testosterone results for the ageing male.
Previous studies concerning the relationship of serum testosterone levels to aging in normal men have yielded apparently inconsistent results. Studies performing blood sampling in the morning have often shown an age-related decrease in testosterone levels, while those using afternoon samples have failed to show such a decrease. These results suggested to us the possibility that the circadian rhythm in serum testosterone levels might be altered with normal aging in men. Hourly blood samples were obtained for 24 h from 1 young (mean age, 52.2 yr) and 12 old (mean age, 17 yr) healthy men. Total testosterone levels were measured by RIA. The circadian rhythm in serum testosterone levels found in normal young men was markedly attenuated or absent in healthy elderly men; the early morning rise in testosterone levels characteristic of young men was not present in old age. Mean testosterone levels for the entire 24-h day were lower in healthy old men than in young men. These results demonstrate a clear decrease in serum testosterone levels in healthy old men compared to those in young men and provide an explanation for the inability to demonstrate an age-related decline in testosterone levels in earlier studies using serum samples obtained in the afternoon.
The diagnosis of male hypogonadism requires the demonstration of a low serum testosterone (T) level. We examined serum T levels in pedigreed samples taken from 62 eugonadal and 60 hypogonadal males by four commonly used automated immunoassay instruments (Roche Elecsys, Bayer Centaur, Ortho Vitros ECi and DPC Immulite 2000) and two manual immunoassay methods (DPC-RIA, a coated tube commercial kit, and HUMC-RIA, a research laboratory assay) and compared results with measurements performed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Deming's regression analyses comparing each of the test results with LC-MSMS showed slopes that were between 0.881 and 1.217. The interclass correlation coefficients were between 0.92 and 0.97 for all methods. Compared with the serum T concentrations measured by LC-MSMS, the DPC Immulite results were biased toward lower values (mean difference, -90 +/- 9 ng/dl) whereas the Bayer Centaur data were biased toward higher values (mean difference, +99 +/- 11 ng/dl) over a wide range of serum T levels. At low serum T concentrations (<100 ng/dl or 3.47 nmol/liter), HUMC-RIA overestimated serum T, Ortho Vitros ECi underestimated the serum T concentration, whereas the other two methods (DPC-RIA and Roche Elecsys) showed differences in both directions compared with LC-MSMS. Over 60% of the samples (with T levels within the adult male range) measured by most automated and manual methods were within +/- 20% of those reported by LC-MSMS. These immunoassays are capable of distinguishing eugonadal from hypogonadal males if adult male reference ranges have been established in each individual laboratory. The lack of precision and accuracy, together with bias of the immunoassay methods at low serum T concentrations, suggests that the current methods cannot be used to accurately measure T in females or serum from prepubertal subjects.
Androgen deficiency in women is increasingly recognized as a new clinical syndrome and has raised our awareness of the importance of accurate and well-validated measurements of serum free testosterone (T) concentrations in women. Therefore, we compared serum free T levels measured by equilibrium dialysis to those measured by a direct RIA (analog method) and to those calculated from the law of mass action (requires the measurement of total T and SHBG). We also calculated the free androgen index, 100 x T/SHBG, as a simple index known to correlate with free T. Subjects were 147 women with variable androgen and estrogen statuses. All were studied three times in 1 month and included women 1) with regular menses (estrogen positive, T positive), 2) more than 50 yr old and not receiving estrogen (estrogen negative, T positive), 3) receiving estrogen (estrogen positive, T negative), and 4) with severe androgen deficiency secondary to hypopituitarism (estrogen negative, T negative). Calculated values for free T using the laws of mass action correlated well with those obtained from equilibrium dialysis (r = 0.99; P < 0.0001). However, the agreement depended strongly on the specific assays used for total T and SHBG. In contrast, the direct RIA method had unacceptably high systematic bias and random variability and did not correlate as well with equilibrium dialysis values (r = 0.81; P < 0.0001). In addition, the lower limit of detection was higher for the direct RIA than for equilibrium dialysis or calculated free T. Free androgen index correlates well with free T by equilibrium dialysis (r = 0.93; P < 0.0001), but is a unitless number without reference to the physical reality of free T. We conclude that the mass action equation and equilibrium dialysis are the preferred methods for use in diagnosing androgen deficiency in women.
The role of endogenous sex hormones in many diseases makes understanding factors that influence levels of these hormones increasingly important. This study examined age-associated variations in total and bioavailable testosterone and estradiol levels among community-dwelling Caucasian men in Rancho Bernardo, California. Plasma samples obtained from 810 men aged 24-90 years in 1984-1987 were analyzed in 1993 using radioimmunoassay. Analyses of age-hormone associations, adjusting for weight, body mass index, alcohol ingestion, smoking, physical activity, caffeine intake, specimen storage time, and disease status, were undertaken. Bioavailable testosterone and bioavailable estradiol levels decreased significantly with age independently of covariates. Total testosterone and estradiol levels decreased with age only when analyses were controlled for confounders. The importance of the age-associated decline in endogenous sex hormone levels, particularly levels of bioavailable testosterone and bioavailable estradiol, and their relation to disease and function in men deserve further research.
To evaluate the hypothesis that endocrine profiles change with aging independently of specific disease states, we examined the age trends of 17 major sex hormones, metabolites, and related serum proteins in 2 large groups of adult males drawn from the Massachusetts Male Aging Study, a population-based cross-sectional survey of men aged 39-70 yr conducted in 1986-89. Group 1 consisted of 415 men who were free of obesity, alcoholism, all prescription medication, prostate problems, and chronic illness (cancer, coronary heart disease, hypertension, diabetes, and ulcer). Group 2 consisted of 1294 men who reported 1 or more of the above conditions. Each age trend was satisfactorily described by a constant percent change per yr between ages 39-70 yr. Free testosterone declined by 1.2%/yr, and albumin-bound testosterone by 1.0%/yr. Sex hormone-binding globulin (SHBG), the major serum carrier of testosterone, increased by 1.2%/yr, with the net effect that total serum testosterone declined more slowly (0.4%/yr) than the free or albumin-bound pools alone. Among the major androgens and metabolites, androstane-3 alpha,17 beta-diol (androstanediol; 0.8%/yr) and androstanediol glucuronide (0.6%/yr) declined less rapidly than free testosterone, while 5 alpha-dihydrotestosterone remained essentially constant between ages 39-70 yr. Androstenedione declined at 1.3%/yr, a rate comparable to that of free testosterone, while the adrenal androgen dehydroepiandrosterone (3.1%/yr) and its sulfate (2.2%/yr) declined 2-3 times more rapidly. The levels of testosterone, SHBG, and several androgen metabolites followed a parallel course in groups 1 and 2, remaining consistently 10-15% lower in group 2 across the age range of the study. Subgroup analyses suggested that obese subjects might be responsible for much of the group difference in androgen level. Serum concentrations of estrogens and cortisol did not change significantly with age or differ between groups. Of the pituitary gonadotropins, FSH increased at 1.9%/yr, LH increased at 1.3%/yr, and PRL declined at 0.4%/yr, with no significant difference between groups 1 and 2.(ABSTRACT TRUNCATED AT 400 WORDS)
The study of testosterone is likely to be prominent in future epidemiological work on endocrine function and the clinical treatment of age-related diseases. Thus, understanding the hormonal changes involved in the normal male aging process will be critical. Using techniques of meta-analysis, the authors examined 88 published studies of the age-testosterone relation in men. These studies reported conflicting results: age-testosterone correlations ranged from -0.68 to +0.68. In cross-study comparisons, certain research design characteristics (e.g. time of day of blood sampling) and various sample characteristics (e.g. volunteers vs patients as subjects) were related to both mean testosterone level and the slope of the age-testosterone relation. For example, for subgroups of subjects that did not exclude ill men, the mean testosterone levels were low, and did not decline with age. Subgroups that included only healthy subjects, in contrast, had higher overall testosterone levels and showed a decline of testosterone with age. Implications of these results for design, analysis and reporting of future epidemiologic studies will be discussed. These results also illustrate the utility of meta-analysis for research with the aged.
Relative weight and Body Mass Index (BMI) are commonly used as measures of body fatness in epidemiologic and clinical studies. In order to determine their accuracy, they were compared to body fat measured by underwater weighting and total body water determination in 29 males and 75 females who varied widely in body composition. Relative weights calculated from the Metropolitan Life Insurance Tables correlated so highly with BMI that these measures can be considered to be identical (R2 = 0.992 to 0.999). Linear regression analysis showed a significant correlation between BMI and percentage body fat in men (R2 = 0.68, %fat = 0.99 X BMI -1.32, p less than 0.001) and women (R2 = 0.74, %fat = 0.94 X BMI + 10.77, p less than 0.001). We conclude that relative weight and BMI are nearly identical, and that they are reasonable estimates of body fatness.
The circadian pattern in levels of serum total testosterone (T) in men becomes blunted with normal aging. However, because T not bound to sex hormone-binding globulin (non-SHBG-T) is felt to be a better representative of biologically available T than is total T, the possibility of a 24-h variation in non-SHBG-T in young men and the possibility that aging is associated with a blunting of that rhythm were investigated. Hourly blood samples were drawn on 10 normal young men (mean age 27.3 years) and 10 normal elderly men (mean age 70.7 years) over a 24-h period and the serum was assayed for total T, sex hormone-binding globulin (SHBG), and total protein; non-SHBG-T was calculated. SHBG was determined by radioimmunoassay as well as by a steroid-binding assay. Young men had a significantly higher (p less than 0.05) mean 24-h level of non-SHBG-T (1.91 +/- 0.62 nm/l) than did the elderly men (0.86 +/- 0.01 nM/l). Also, each young man showed a significant circadian rhythm in non-SHBG-T, with a group mean daily variation of 1.42 +/- 0.38 nM/l. In contrast, only 60% of the elderly men demonstrated a significant circadian rhythm in non-SHBG-T, and the group mean rhythm was blunted (maximum excursion 0.38 +/- 0.07 nM/l) compared with that of the young men. SHBG and total protein levels demonstrated similar 24-h variations in the two age groups. It was concluded that non-SHBG-T serum levels, similar to serum total T levels, demonstrate a circadian pattern in young men and this circadian rhythmicity becomes blunted with normal aging.
Normal aging in men frequently is associated with a decline in serum testosterone levels below the normal range for young adult men. These changes in serum testosterone with age may impact negatively on androgen target organs such as bone, muscle, and psychosexual functioning. Androgen replacement therapy may be of benefit in certain older men, but the potential benefits must be balanced with the potential risks.
The relationships of cigarette smoking, age, relative weight, and dietary intake to serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, cortisol, 3-alpha-androstanediol, 3-alpha-androstanediol-glucuronide, testosterone, albumin-bound testosterone, free testosterone, dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) were examined cross-sectionally in 1241 randomly sampled middle-aged U.S. men. Compared with nonsmokers and independent of relative weight (body mass index) and age, cigarette smokers had increased serum levels of DHEA (18% higher, P = 0.0002), DHEAS (13% higher, P = 0.0007), cortisol (5% higher, P = 0.01), androstenedione (33% higher, P = 0.0001), testosterone (9% higher, P = 0.009), DHT (14% higher, P = 0.004), and SHBG (8% higher, P = 0.004). Androstenedione, total plasma testosterone, albumin-bound testosterone, DHT, and SHBG decreased with increasing relative weight. Age was positively associated with serum SHBG and negatively associated with albumin-bound testosterone, DHEA, and DHEAS. An association was found between alcohol intake and DHEA (r = 0.15; P = 0.0001), cortisol (r = 0.10; P = 0.0007), and 3-alpha-androstanediol-glucuronide (r = 0.08; P = 0.0004). Cortisol was the only hormone that was associated with carbohydrate intake (r = -0.09; P = 0.002). The only hormones associated with dietary lipids were DHT (for vegetable fat, r = 0.07; P = 0.02), cortisol (for total fat, r = 0.08; P = 0.007), and SHBG (for animal fat, r = -0.06; P = 0.05). In addition, SHBG was positively associated with dietary (r = 0.07; P = 0.008) and crude (r = 0.08; P = 0.007) fiber. These data suggest that serum adrenal steroid and sex hormone concentrations in middle-aged men are more influenced by cigarette smoking, age, and obesity than by dietary intake; however, serum adrenal steroids were influenced by alcohol intake.
Measuring levels of steroid hormones in epidemiologic studies is difficult because pulsatile release can cause the levels of many hormones to vary markedly over short intervals, leading to a loss of precision in between-subject comparisons. Clinicians often control this variation by collecting several samples from each subject at defined intervals and pooling these samples for assay. The number of samples per subject that would adequately control such variation in an epidemiologic study has not been fully investigated. This study examines the effects of collecting 1, 2, or 3 samples per subject on the variances of 11 hormones and sex hormone binding globulin in men and 6 hormones in women. Three samples were collected at 30-minute intervals from each of 20 men and 59 women and were assayed separately. Variances that would be obtained in studies collecting one, two, or three samples per subject were then estimated. Collecting more than one sample substantially reduced the variances of several hormones in men but not in women.
Cross-sectional studies have demonstrated a decline in testosterone and free and bioavailable testosterone with age. This occurs in a majority of older persons without an increase in luteinizing hormone (LH), suggesting that a component of the testosterone decrease is due to secondary hypogonadism. To determine whether these findings could be duplicated in a longitudinal study, we measured testosterone, LH, follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) levels in 77 men participating in the New Mexico Aging Process Study who had sera available in 1980 or 1981 and two or more serial samples in 1982, 1984, 1989, and/or 1994. Thirty-nine subjects had samples available from both 1980 and 1994. The age at entry into the study ranged from 61 to 87 years. Testosterone levels decreased over the 15 years of the study. In persons who were alive for the duration of the study, testosterone levels were significantly lower 5 years before termination of the study (P < .05). Testosterone levels did not differ at entry into the study among those who died and those who were alive at the end of the study period. Eight of 77 subjects (10%) had LH levels above the normal range at some time during the study. In contrast, 43% of subjects had elevated FSH levels. Both LH and FSH increased significantly with age. SHBG levels were measured in 1980 and 1994 and increased significantly with age (P < .0001). LH and FSH were highly correlated with one another, but neither correlated with testosterone. This study demonstrated a longitudinal decline in testosterone and an increase in LH and FSH in older men. The average rate of decrement in testosterone concentration was 110 ng/dL every decade.
To establish reference intervals for serum free testosterone for DPC's Free Testosterone assay.
We used data from healthy subjects and patients to determine reference intervals by parametric and non-parametric methods after partitioning by sex and age.
In males, there was a significant decrease in free testosterone concentrations with age. Reference intervals derived from a combination of 2075 "healthy" and patients' results gave similar values by parametric and nonparametric methods. However, the subgroups failed the test for Gaussian distribution. For each decade from 20 years on and > or = 60 years, the intervals based on 2.5th and 97.5th percentiles were: 24.1-94.8, 25.0-89.3, 23.4-81.7, 22.5-80.4, and 21.5-74.3 pmol/L respectively, in females, there was little change with age. The frequency distribution of 1915 patients was positively skewed, and showed a wider range than "healthy." Using square roots of values gave a Gaussian distribution. The central 95% intervals based on 187 "healthy" subjects were: 0.5-8.1 and 0.0-6.4 pmol/L for 20-59 and > or = 60 years, respectively.
Developing reference intervals for free testosterone was complicated by the need to partition data by gender and age, difficulty in establishing disease in subjects and presence of physiological and other factors which can affect concentration in health and disease.
This article has no abstract; the first 100 words appear below.
The following is a table of reference values, methods, and conversion factors for tests commonly ordered at the Massachusetts General Hospital (MGH) and recorded in the Case Records. The table revises the most recently published data (Normal Reference Laboratory Values. N Engl J Med 1992;327:718-24). Laboratory values are expressed in the units used at MGH (MGH units) and the units of the Systeme International d'Unites (SI units), with a factor to convert MGH units to SI units by multiplication. This table is not intended to provide a comprehensive review of reference values, since this information is widely available in standard . . .
Serum testosterone levels decline slowly with normal ageing in men and, although all men are not destined to become hypogonadal as they age, the prevalence of androgen deficiency in the older male is not insignificant. Over the past several decades, there has been an increasing interest in evaluating whether testosterone therapy (male HRT) might be beneficial for certain older men in preventing or reversing some aspects of ageing. The major androgen target organs of interest with regard to beneficial effects of male HRT include bone, muscle, adipose tissue, the cardiovascular system and the central nervous system (libido and aspects of mood). At the same time, potential adverse effects of male HRT on target organs such as the prostate continue to be evaluated. It is the purpose of this review to summarize the information to date with regard to testosterone replacement therapy in the older man and to discuss areas where more research and clinical information need to be forthcoming.
Hormonal replacement therapy (HRT) for post-menopausal women has been studied and discussed for many years. The idea of male HRT, however, is a relatively recent development, with increasing interest in this area occurring only over the past two decades. Reasons for this nascent enthusiasm include burgeoning evidence that testosterone levels decline with normal male ageing (and with age-associated diseases) and an interest in preventing age-related dysfunction and prolonging quality life among an ever increasing population of older adults. The decline in testosterone with age often parallels unfavourable changes in organs upon which androgens act and the goal of male HRT would be to prevent, stabilize or even reverse some of these detrimental target-organ changes.
The objective was to examine prospectively the association between low testosterone and sex hormone-binding globulin (SHBG) levels and the subsequent development of type 2 diabetes in men.
Analyses were conducted on the cohort of the Massachusetts Male Aging Study, a population-based random sample of men aged 40-70. Of the 1,709 men enrolled in 1987-1989 (T1), 1,156 were followed up 7-10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2.
After controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and SHBG. The odds ratio for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l), both significant at P < 0.02.
Our prospective findings are consistent with previous, mainly cross-sectional reports, suggesting that low levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.
Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis, and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in exaggerated effects, and/or have been of relatively short duration or employed previously treated men, which could result in dampened effects. The goal of this study was to determine the magnitude and time course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle mass and strength, erythropoiesis, prostate volume, energy, sexual function, and lipids in previously untreated hypogonadal men. We selected 18 men who were hypogonadal (mean serum testosterone +/- SD, 78 +/- 77 ng/dL; 2.7 +/- 2.7 nmol/L) due to organic disease and had never previously been treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14 men completed 36 months. The mean serum testosterone concentration reached the normal range by 3 months of treatment and remained there for the duration of treatment. Bone mineral density of the lumbar spine (L2-L4) increased by 7.7 +/- 7.6% (P < 0.001), and that of the femoral trochanter increased by 4.0 +/- 5.4% (P = 0.02); both reached maximum values by 24 months. Fat-free mass increased 3.1 kg (P = 0.004), and fat-free mass of the arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not statistically significant. Strength of knee flexion and extension did not change. Hematocrit increased dramatically, from mildly anemic (38.0 +/- 3.0%) to midnormal (43.1 +/- 4.0%; P = 0.002) within 3 months, and remained at that level for the duration of treatment. Prostate volume also increased dramatically, from subnormal (12.0 +/- 6.0 mL) before treatment to normal (22.4 +/- 8.4 mL; P = 0.004), principally during the first 6 months. Self-reported sense of energy (49 +/- 19% to 66 +/- 24%; P = 0.01) and sexual function (24 +/- 20% to 66 +/- 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat-free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the other tissues took only 3-6 months. These results provide the basis for monitoring the magnitude and the time course of the effects of testosterone replacement in hypogonadal men.
To design a self-administered screening questionnaire to inform men about their risk for testosterone deficiency.
The screener was developed in two phases. First was a construction phase in which relevant risk factors and a scoring algorithm were defined from multiple logistic regression analyses of survey data. In the second phase, the screener's accuracy (based on sensitivity, specificity, and Receiver Operating Characteristic (ROC) curves) was tested using patients from a primary care clinic. All subjects provided blood samples for endocrine testing.
Survey data from 1660 men aged 40–79 years participating in the Massachusetts Male Ageing Study (MMAS) were analysed in the first phase. The clinic sample consisted of 304 men aged 40–79 years presenting at a large Massachusetts primary health care clinic for routine check-ups or minor medical problems.
The primary outcome was testosterone deficiency, defined as serum total testosterone below 12·1 nmol/l. Self-reported variables considered as potential risk factors included age, obesity, chronic diseases, health behaviour, the Jackson dominance scale, and symptoms of stress.
The prevalence of testosterone deficiency was 20·4% in the MMAS and 42·1% in the clinic sample. An eight-item screener was developed based on age, body mass index, diabetes, asthma, headaches, sleep patterns, dominance preferences, and smoking status. The screener performed significantly better than chance in identifying men with low testosterone levels; the area under the ROC curve was 0·66 in the MMAS sample and 0·67 in the clinic sample.
The self-scored screener developed in this study reliably detects men at risk of hypogonadism. The screener encourages at risk men to seek professional evaluation of their testosterone levels.
The decrease in testosterone levels with age is both central (pituitary) and peripheral (testicular) origin. Because serum levels of sex-hormone-binding globulin increase with aging, the decrease in free testosterone is of even greater magnitude. Recent long-term studies of testosterone therapy in hypogonadal elderly men have shown beneficial effects on bone density, body composition, and muscle strength without any substantial adverse effects on lipids and the prostate. Total testosterone level is the test of choice for initial screening of elderly men who present with signs and symptoms of hypogonadism. If the level is below 300 ng/dL, replacement therapy should be initiated. If the level is normal in a symptomatic patient, free or bioavailable testosterone should be determined. The pros and cons of testosterone therapy should be discussed in depth with every patient, and decisions should be made on an individual basis. This review summarizes the trials of testosterone replacement therapy in elderly men and outlines a diagnostic approach to these patients.
We used longitudinal data from the Massachusetts Male Aging Study, a large population-based random-sample cohort of men aged 40–70 yr at baseline, to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends. Of 1,709 men enrolled in 1987–1989, 1,156 were followed up 7–10 yr afterward. By repeated-measures statistical analysis, we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data, the cross-sectional trend between subjects within the follow-up data, and the longitudinal trend within subjects between baseline and follow-up.
Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data, whereas both free and albumin-bound T declined at about 2%/yr, all significantly more steeply than within the baseline data. Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data, similarly to baseline. The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T (1.6%/yr) and bioavailable T (2–3%/yr). Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and PRL rose longitudinally.
Apparent good health, defined as absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10–15% to the level of several androgens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends.
The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.
To investigate the impact of health status on androgen levels in men and to assess the age-related changes in androgen levels.
Sera were obtained from 526 men (age 20 to 89 years) participating in a health screening project and 35 men selected according to the SENIEUR protocol, which excludes those with underlying disease. The health screening project participants were divided into two groups: healthy men (n = 133; group 1) and the remainder (n = 393; group 2). The total testosterone and sex hormone-binding globulin levels were quantified, and the amount of free testosterone (cfT) was calculated.
The lowest annual declines in androgen level were observed in group 3 (testosterone 0.2%; cfT 0.4%), followed by group 1 (testosterone 0.4%; cfT 0.8%) and group 2 (testosterone 0.8%; cfT 0.9%). Body mass index and levels of cholesterol, triglycerides, and glucose correlated negatively (P <0.01) with testosterone and cfT. Decade-adjusted reference values (mean +/- 2 standard deviations) for testosterone and cfT were defined. The proposed lower testosterone reference value declined gradually from 3.1 ng/mL (20 to 29 years) to 1.7 ng/mL (70 years or older).
In this cross-sectional study, serum androgens declined in aging men, and the extent of this decrease correlated with health status. A fixed, non-age-adjusted reference value does not adequately reflect this and might lead to a false diagnosis of androgen deficiency, particularly in elderly men. The clinical value of age-related reference values, however, needs to be determined in prospective studies.
Accurate measure for testosterone made national
- Andrology Australia