U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men.

PURPOSE: Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. PARTICIPANTS AND METHODS: Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. RESULTS: Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.51-0.94, P = .020; Q3: HR 0.59, 95% CI 0.42-0.83, P = .002) and hip fracture (Q2 versus Q1: HR 0.60, 95% CI 0.37-0.93, P = .043; Q3: HR 0.52, 95% CI 0.31-0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: HR 1.76, 95% CI 1.05-2.96, P = .033). CONCLUSIONS: Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non-fatal cardiovascular events, and mortality in men aged 17-97 years.

CONTEXT: Lower testosterone (T) is associated with poorer health outcomes in older men, however, the relationship between T, dihydrotestosterone (DHT) and estradiol (E2) with cardiovascular disease (CVD) in younger to middle-aged men remains unclear. OBJECTIVES: We assessed associations between endogenous sex hormones with mortality (all-cause and CVD) and CVD events, in a cohort of men aged 17-97 years. PARTICIPANTS AND METHODS: Sex hormones were assayed using mass spectrometry in 2143 men from the 1994/5 Busselton Health Survey. Outcomes to December 2010 were analysed. RESULTS: Of the 1804 men included in the analysis, mean age was 50·3 ± 16·8 years and 68·9% of men were aged <60. Mean follow-up period was 14·9 years. There were 319 deaths, 141 CVD deaths and 399 CVD events. Compared to the full cohort, men who died had lower baseline T (12·0 ± 4·4 vs 13·6 ± 4·9 nmol/l), free T (181·9 ± 52·9 vs 218·3 ± 63·8 pmol/l) and DHT (1·65 ± 0·64 vs 1·70 ± 0·72 nmol/l), but higher E2 (64·0 ± 32 vs 60·1 ± 30·2 pmol/l). After adjustment for risk factors, T was not associated with mortality (adjusted HR = 0·90, 95% CI 0·79-1·04; P = 0·164 for every increase in 1 SD of T), CVD deaths (adjusted HR = 1·04, 95% CI 0·84-1·29; P = 0·708) or CVD events (adjusted HR = 1·03, 95% CI 0·92-1·15, P = 0·661). No associations were found for free T, DHT or E2. Results were similar for men older and younger than 60 years. CONCLUSIONS: In predominantly middle-aged men, T, DHT and E2 do not influence mortality or CVD outcomes. This neutral association of hormones with CVD contrasts with prior studies of older men.

Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.

OBJECTIVES: Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone (DHT) and oestradiol (E2) are differentially associated with lung function in men. METHODS: Early-morning serum T, DHT and E2 were assayed using mass spectrometry in 1768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, body mass index, respiratory conditions and cardiovascular risk factors were used. RESULTS: Mean age was 50.1 ± 16·8 years. 16·0% were current smokers, 14·1% reported a history of asthma and 2·7% reported chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14·5 vs 13·5 nmol/l, P = 0·002) and higher E2 (65·3 vs 60·1 pmol/l, P = 0·017). In fully adjusted analyses, T was associated with FEV1 (51 ml per 1 SD increase, P < 0·001) as was DHT (62 ml, P < 0·001), E2 was not (P = 0·926). Similar results were seen for FVC (T: 76 ml, P < 0·001; DHT: 65 ml, P < 0·001; E2 P = 0·664). Higher DHT was marginally associated with the ratio FEV1/FVC (0·3% per 1 SD increase, P = 0·047). CONCLUSIONS: Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men.

Differential associations of testosterone, dihydrotestosterone and oestradiol with physical, metabolic and health-related factors in community-dwelling men aged 17-97 years from the Busselton Health Survey.

OBJECTIVES: Lower testosterone (T) levels are associated with poorer health outcomes in older men, but associations in younger or middle-aged men are uncertain, and data for dihydrotestosterone (DHT) and oestradiol (E2) are limited. We assessed the associations of circulating T, DHT and E2 with physical and health-related factors in a cohort comprising men aged 17-97 years. PARTICIPANTS AND METHODS: Serum from 2143 community-dwelling men from the 1994/95 Busselton Health Survey was assayed for T, DHT and E2 using liquid chromatography-tandem mass spectrometry. Men receiving hormonal therapy or reporting the use of testosterone, or with prostate cancer or orchidectomy were excluded. RESULTS: Of the men, 43% had never smoked, 6·1% had diabetes and 16·8% cardiovascular disease (CVD). Mean (±SD) age was 50·3 ± 17·0 years. Total T was moderately correlated with DHT (r = 0·56), E2 (r = 0·35) and sex hormone-binding globulin (r = 0·53). In age-, smoking-, body mass index (BMI)- and sex hormone-binding globulin (SHBG)-adjusted analyses, T was inversely associated with metabolic syndrome score, while DHT and E2 were not associated. In multivariable models, higher total T was associated with lower age, BMI and C-reactive protein, and with higher creatinine and haemoglobin, independently of SHBG. Higher DHT was associated with lower age, BMI and glucose level, and higher creatinine and haemoglobin. E2 was positively associated with age, BMI and haemoglobin. CONCLUSIONS: In men spanning younger, middle and older ages, circulating androgens are more related to age and metabolic factors than CVD or chronic disease. Further investigation is required to clarify whether androgens and oestrogens have contrasting roles as risk predictors for CVD.

A diagnostic conundrum: heterophilic antibody interference in an adrenocorticotropic hormone immunoassay not detectable using a proprietary heterophile blocking reagent.

CONTEXT: Heterophilic antibodies are a well-described interferent but poorly appreciated and are often not a recognized problem affecting most immunoassays. We describe for the first time heterophilic antibodies interference affecting an adrenocorticotropic hormone (ACTH) assay in a patient with Cushing's syndrome due to bilateral nodular adrenal hyperplasia. CASE: A 60-year-old retired female nurse underwent extensive invasive investigations, which were ultimately unnecessary, as a result of initial analytical interference in the ACTH assay, which could not be resolved using a proprietary heterophilic binding reagent. RESULTS: This case highlights the inherent difficulty of diagnosing Cushing's syndrome and the large emphasis placed on laboratory tests. The consequence of not initially identifying interference in this patient's laboratory test results led to unnecessary and costly investigations with potentially adverse outcomes. CONCLUSIONS: Clinicians and the laboratory community need to be continuously vigilant and view laboratory results with caution when they are inconsistent with the clinical picture. This approach is paramount, especially at a time of increasing automation and ever-diminishing scientist involvement in sample processing.

Usability, participant acceptance, and safety of a prefilled insulin injection device in a 3-month observational survey in everyday clinical practice in Australia.

BACKGROUND: SoloSTAR (SOL; sanofi-aventis, Paris, France) is a prefilled insulin pen device for the injection of insulin glargine and insulin glulisine. This is the first Australian survey to determine its usability, participant acceptance, and safety in clinical practice. METHODS: A 3-month, nonrandomized, noncomparative, observational survey in Australia was conducted in individuals with diabetes. Participants were given SOL pens containing glargine, the instruction leaflet, and a toll-free helpline number. Training was offered to all participants. Safety data, including product technical complaints (PTCs), were gathered from ongoing feedback given by the participant or health care professional (HCP) and by independent interviews conducted 6-10 weeks after study start. RESULTS: Some 2674 people consented to take part across 93 sites (150 HCPs), and 2029 participated in interviews. Of these, 52.6% had type 1 diabetes, 16.3% had manual dexterity problems, and 15.5% had poor eyesight not corrected by glasses. At the time of interview, 96.8% of participants were still using SOL. None of the eight PTCs reported were due to technical defects; most were related to handling errors. Some 62 participants reported 77 adverse events; none were related to a PTC. The vast majority of participants (95.4%) were "very satisfied" or "satisfied" with using SOL, and 89.7% of the participants had no questions or concerns using SOL on a daily basis. Similar positive findings were reported by participants with manual or dexterity impairments. CONCLUSIONS: In this survey of everyday clinical practice, SOL had a good safety profile and was very well accepted by participants.

Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts.

BACKGROUND: Cross-sectional studies from different populations show a variable decline in blood testosterone concentrations as men age. Few population representative cohorts have been followed up over time. OBJECTIVE: The objective of the study was to quantify longitudinally the change in serum testosterone and SHBG concentrations with age in two well-defined, representative but geographically widely separated regional Australian cohorts. SUBJECTS AND SETTING: The Busselton cohort comprises individuals aged 18-90 yr residing in Western Australia assessed prospectively since 1981. Sera were assayed from 910 men, from whom further samples were available 14 yr later in 480. The Dubbo cohort involves individuals aged 61-90 yr living in Eastern Australia. Baseline sera were collected from 610 men and additional sera on a second (n = 370) and third (n = 200) occasion from 1989 to 2004. Men from both cohorts are community dwelling and of predominately European origin. RESULTS: Longitudinal analyses show the following: 1) total testosterone declines comparably (P > 0.9) by 1.3% (Busselton) and 0.9% (Dubbo) per annum with the same rates of decline when analyses were restricted to men older than 60 yr of age; 2) annual changes in SHBG were also very similar in age-restricted analyses (2.3% vs. 2.5%, P = 0.48); and 3) the annual increase in SHBG was steeper in middle-aged and older men (P < 10(-3) vs. young men). These longitudinal changes were all up to 4-fold greater in magnitude, compared with cross-sectional analyses of baseline data. CONCLUSION: In two separate regional Australian populations, blood testosterone fell and SHBG increased comparably with age. Age-related changes in blood testosterone and SHBG previously described in urban-dwelling men are the same in men who reside in smaller regional cities of another continent.

Increased frequency of long androgen receptor CAG repeats in male breast cancers.

We have investigated the possible link between androgen hyposensitivity caused by long androgen receptor (AR) CAG repeats, and breast carcinogenesis, in men. AR gene mutations have been described in men with androgen insensitivity syndrome and breast carcinoma, and some studies have shown long CAG repeats are associated with increased risk of breast cancer in women. DNA was isolated from male breast cancer biopsies, and the AR CAG repeat sized. Forty one male breast cancer samples were studied, including one sample from a man with spinal and bulbar muscular atrophy (SBMA), which is caused by an AR CAG repeat expansion. The man with breast cancer and SBMA had 49 CAG repeats (normal range 6-35), but all other breast cancer samples had repeats within the normal range. The frequency of CAG repeats > or =24 was significantly higher in the breast cancer group (excluding the SBMA subject) than in the normal population (p<0.05), and was more marked in grade I and II tumors (p=0.001). There was no correlation between AR CAG repeat length and age at diagnosis. In conclusion, longer AR CAG repeats are more common in men with breast cancer than in the control male population. Androgen hyposensitivity, caused by long AR CAG repeats, may increase the risk of breast cancer in men.

Polymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy's disease.

Kennedy's disease (spinobulbar muscular atrophy) is an X-linked form of motor neuron disease affecting adult males carrying a CAG trinucleotide repeat expansion within the androgen receptor gene. While expression of Kennedy's disease is thought to be confined to males carrying the causative mutation, subclinical manifestations have been reported in a few female carriers of the disease. The reasons that females are protected from the disease are not clear, especially given that all other diseases caused by CAG expansions display dominant expression. In the current study, we report the identification of a heterozygote female carrying the Kennedy's disease mutation who was clinically diagnosed with motor neuron disease. We describe analysis of CAG repeat number in this individual as well as 33 relatives within the pedigree, including two male carriers of the Kennedy's mutation. The female heterozygote carried one expanded allele of the androgen receptor gene with CAG repeats numbering in the Kennedy's disease range (44 CAGs),with the normal allele numbering in the uppernormal range (28 CAGs). The subject has two sons, one of whom carries the mutant allele of the gene and has been clinically diagnosed with Kennedy's disease, whilst the other son carries the second allele of the gene with CAGs numbering in the upper normal range and displays a normal phenotype. This coexistence of motor neuron disease and the presence of one expanded allele and one allele at the upper limit of the normal range may be a coincidence. However, we hypothesize that the expression of the Kennedy's disease mutation combined with a second allele with a large but normal CAG repeat sequence may have contributed to the motor neuron degeneration displayed in the heterozygote female and discuss the possible reasons for phenotypic expression in particular individuals.