Associations of plasma androgens with suicidality among men and women: A 9-year longitudinal cohort study.

BACKGROUND: Testosterone has been implicated in suicidality in cross-sectional studies. Stress that coincides with a suicide attempt may alter androgen levels, so prospective studies are needed to exclude reverse causation. We aimed to examine the associations of plasma androgens with concurrent and future suicidality, and if present, whether these associations were mediated by a behavioral trait like reactive aggression. METHODS: Baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate with a radioimmunoassay. Suicidality was assessed using the Suicidal Ideation Scale at baseline and after 2-, 4-, 6-, and 9-year follow-up. Men and women were analyzed separately, and potential confounders were considered. RESULTS: Participants (N = 2861; 66.3% women) had a mean age of 42.0 years (range 18-65) and almost half (46.9%) fulfilled criteria for a major depressive or anxiety disorder. At baseline 13.2% of men and 11.2% of women reported current suicidal ideation. In participants who were non-suicidal at baseline, slightly more men than women reported suicidal ideation during follow-up (14.7% vs. 12.5%), whereas the reverse pattern was observed for suicide attempts (3.6% vs. 4.2%). None of the associations between androgens and current and future suicidality were significant. LIMITATIONS: Androgens were determined once, which may have been insufficient to predict suicidality over longer periods. DISCUSSION: The lack of associations between plasma levels of androgens determined by 'gold-standard' laboratory methods with suicidality do not support previous cross-sectional and smaller studies in adult men and women with values within the physiological range.

Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy.

Male-to-female transsexual persons use oestrogens + antiandrogens to adapt their physical bodies to the female sex. Doses are usually somewhat higher than those used by hypogonadal women receiving oestrogen replacement. Particularly in cases of self-administration of cross-sex hormones, doses may be very high. Oestrogens are powerful stimulators of synthesis and release of prolactin and serum prolactin levels are usually somewhat increased following oestrogen treatment. Prolactinomas have been reported in male-to-female transsexual persons, both after use of high and conventional doses of oestrogens but remain rare events. We report two new cases of prolactinomas in male-to-female transsexual persons, one in a 41-year-old subject who had used nonsupervised high-dose oestrogen treatment since the age of 23 years and another one in a 42 year old who had initiated oestrogen treatment at the age of 17 years. Their serum prolactin levels were strongly increased, and the diagnosis of a pituitary tumour was confirmed by imaging techniques. Both cases responded well to treatment with cabergoline treatment whereupon serum prolactin normalised. Our two cases are added to the three cases of prolactinomas in the literature in persons who had used supraphysiological doses of oestrogens.

(Patho)physiology of cross-sex hormone administration to transsexual people: the potential impact of male-female genetic differences.

There is a limited body of knowledge of desired and undesired effects of cross-sex hormones in transsexual people. Little attention has been given to the fact that chromosomal configurations, 46,XY in male-to-female transsexuals subjects (MtoF) and 46,XX in female-to-male transsexual subjects (FtoM), obviously, remain unchanged. These differences in their genomes cause sex differences in the functions of cells. This study reviews sex differences in metabolism/cardiovascular pathology, immune mechanisms, bone (patho)physiology and brain functions and examines whether they are, maybe partially, determined by genetic mechanisms rather than by (cross-sex) hormones. There do not appear to be major genetic impacts on the changes in bone physiology. Also immune functions are rather unaffected and the evidence for an increase of autoimmune disease in MtoF is preliminary. Brain functions of transsexuals may have differed from controls before cross-sex hormones; they do undergo shifts upon cross-sex hormone treatment, but there is no evidence for changes in sex-specific brain disease. The prevalence of cardiovascular disease is higher in MtoF receiving oestrogens than in FtoM receiving androgens. While type of oestrogen and route of administration might be significant, it is reasonable to speculate that nonhormonal/genetic factors play a role.

Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review.

Administration of cross-sex hormones to male-to-female transsexual subjects, usually oestrogens + often anti-androgens, such as cyproterone acetate, carries a risk of venous thromboembolism (VTE). VTE usually occurs in the first year of oestrogen administration. Ethinyl oestradiol, due to its chemical structure, was in 2003 identified as a major factor in the occurrence of VTE. Most clinics do not prescribe ethinyl oestradiol any longer, but people who take hormones without medical supervision use often oral contraceptives containing ethinyl oestradiol, many times in overdose. Cessation of use of ethinyl oestradiol and peri-operative thrombosis prophylaxis for surgery have reduced prevalence rate of VTE. Other oral oestrogens should not be overdosed, and transdermal oestrogen is to be preferred. Thrombosis prophylaxis for surgery is mandatory. It seems advisable to stop hormone use at least 2 weeks before major surgery, to be resumed only after 3 weeks following full mobilisation.

Men and women, so different, so similar: observations from cross-sex hormone treatment of transsexual subjects.

Sexual differentiation in mammals is largely driven by the presence of androgen in males and their absence in females. The presence of androgens induces a number of irreversible changes in males: prenatally, the genital differentiation; during puberty, the development of secondary sex characteristics - the larger facial bones, hand, feet and height in males. A large number of metabolic variables are influenced by sex hormones and consequently show difference between men and women, and this helps to explain differences in pathologies, such as cardiovascular disease, bone fractures and auto immune disease. There is some recent evidence that some sex differences in brain functions are not mediated by sex hormones, but by-products of genes located on the X and Y chromosomes. This communication reviews the results of administration of cross-sex hormone treatment to transsexual persons transitioning to the other sex. Natal males are treated with anti-androgens+oestrogens and natal females with testosterone. This provides a unique opportunity to study which metabolic functions are not irreversibly sex-differentiated but are determined by the prevailing milieu of sex steroids. The insights gained with these studies should lead to a better appreciation of the role of sex steroids in cardiovascular disease and diabetes mellitus which presently do not receive due attention.

A safety study of administration of parenteral testosterone undecanoate to elderly men over minimally 24 months.

This study investigated the safety of administration of long-acting parenteral testosterone undecanoate (TU) to 122 hypogonadal, mainly elderly men, aged 59.6 ± 8.0 years (range 18-83 years old), with baseline testosterone levels between 5.8 and 12.1 nmol l(-1) (mean ± SD = 9.3 ± 1.7). Patients were followed for 24 months. Plasma testosterone rose from 9.3 ± 1.7 to 14.9 ± 4.5 nmol l(-1) (P< 0.01) at 3 months, then stabilised at 19.2 ± 4.6 nmol l(-1) after 6 months. International Prostate Symptoms Scores and Residual Bladder Volumes decreased significantly (P <0.01) over the study period. Prostate volume and prostate-specific antigen levels fluctuated over the study period but had not increased significantly after 24 month. Haemoglobin concentrations increased significantly (P < 0.001) over the 24 months while the haematocrit increased significantly (P < 0.001) during the first 15 months and then levelled off. Statistical analysis with expressing values as means ± SD masks excesses above reference values of individual patients. These excesses were noted in low numbers, were permanently present in some but not in other individuals, and did not increase in number over the 24 month study period. Over 24 months treatment with TU appeared acceptably safe, but longer and larger scale studies are needed.

Improvement of the metabolic syndrome and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with parenteral testosterone undecanoate.

This is a study of a cohort of 117 men aged between 34-69 years, with plasma testosterone levels between 5.9-12.1 nmol/L (N>14.0 nmol/L) who were treated with administration of testosterone undecanoate for 1 year as the sole intervention. There was a remarkable improvement of body weight, BMI and waist size along with an improvement of lipid profiles. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome. Hepatic inflammation secondary to liver steatosis is a potential contributor to the low-grade inflammation associated with the metabolic syndrome. Elevations of liver enzymes are associated with higher CRP concentrations. Levels of ALT (GPT) AST (GOT) and CRP had decreased significantly after one year of testosterone treatment. At baseline 74/117 met the criteria of the metabolic syndrome as defined by the NCEP and after one year of testosterone treatment this number had declined to 42/117.

Safety aspects of 36 months of administration of long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals.

DESIGN: Testosterone treatment is essential for the induction and maintenance of virilization of female-to-male (FTM) transsexuals. Aim To test the safety of a novel testosterone preparation for this purpose. METHODS: Parenteral long-acting testosterone undecanoate (TU) was administered to 17 FTM transsexuals over 36 months. Observations were made while subjects received treatment. RESULTS: Serum testosterone rose from 0.50+/-0.25 to 6.2+/-1.3 ng/ml at 6 months and remained stable thereafter. The testosterone profiles were largely identical with those in hypogonadal receiving TU. There were no side effects. Over the 36 months of the study, there was a small but significant decrease in plasma cholesterol (from 218+/-47 to 188+/-42 mg/dl) and low-density lipoprotein-cholesterol (from 139+/-48 to 139+/-48 mg/dl), while plasma levels of high-density lipoprotein-cholesterol and triglycerides did not change significantly. Liver enzymes did not change during treatment. There was an increase of both levels in hemoglobin (from 13.6+/-1.2 to 16.0+/-1.5 g/dl) and hematocrit (from 41+/-4 to 46+/-4) upon administration but they remained almost without exception within the physiological range. No special measures were needed. Breast and gonads/internal genitalia did not show pathological changes over the observation period. CONCLUSION: This study reports that TU is suited for induction of virilization in FTM transsexuals without significant side effects over a longer term.

Testosterone and obesity in men under the age of 40 years.

The study assessed anthropometric and laboratory variables, in particular testosterone (T) in a group of obese men of <40 years. Of 60 men with a body mass index (BMI) of >27 kg m(-2), 34 met the criteria of the metabolic syndrome (MS). Twenty men <40 years (with a BMI <25 kg m(-2)) were studied for comparison. It was found that with increasing BMI, levels of serum leptin, triglycerides, insulin, the ratio high-density lipoprotein (HDL) cholesterol/low-density liporotein (LDL) cholesterol, the waist circumference (WC), the area of visceral fat and systolic/diastolic blood pressure were higher, whereas insulin sensitivity (HOMA) and serum T were lower. Obesity (BMI 27-30 kg m(-2)) was associated with a decline in plasma T, but not with a decline in plasma sex hormone-binding globulin (SHBG). The latter was the case in more severe obesity (>30 kg m(-2)) qualifying as MS. In patients with MS, 58% variability of T levels could be predicted by combination of independent factors - SHBG, ratio LDL/HDL, insulin and leptin. On the other hand, in men with MS, 80% variance of concentrations of SHBG were predicted by triglycerides, HDL, glucose, leptin and surface of visceral adipose tissue. It is concluded that plasma T is significantly correlated with a number of features of the MS and, therefore, plasma T could serve as a marker of the MS.

Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men.

Central obesity in adulthood, the metabolic syndrome, erectile failure and lower urinary tract symptoms (LUTS) are all associated with lower-than-normal testosterone levels, although the relationship between testosterone and LUTS appears weak. The metabolic syndrome is associated with an overactivity of the autonomic nervous system. Alternatively, the metabolic syndrome is associated with markers of inflammation, such as C-reactive protein (CRP), maybe signalling intraprostatic inflammation. A large cohort of 95 middle-aged to elderly hypogonadal men (T levels 5.9-12.1 nmol l(-1)) were treated with parenteral testosterone undecanoate and its effects on the metabolic syndrome {waist circumference, cholesterol, CRP and LUTS [residual bladder volume (RBV), International Prostate Symptoms Score (IPSS), prostate volume, prostate-specific antigen (PSA)]} were evaluated. Along with the improvements of the metabolic syndrome, there was a significant decline of the values of the IPSS, RBV and CRP. There was a (low) level of correlation between the decline of waist circumference and residual volume of urine but not with IPSS and prostate size. Along with the improvement of the metabolic syndrome upon testosterone administration, there was also an improvement of the IPSS and of RBV of urine and CRP. The mechanism remains to be elucidated.

ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males.

The new ISA, ISSAM, EAU, EAA and ASA recommendations on the investigation, treatment and monitoring of late-onset hypogonadism in males provide updated evidence-based information for clinicians who diagnose and treat patients with adult onset, age related testosterone deficiency.

C-reactive protein levels and ageing male symptoms in hypogonadal men treated with testosterone supplementation.

C-reactive protein (CRP) is a marker of systemic low-grade inflammation, and may be associated with subjective symptoms of androgen deficiency. We studied the effects of normalisation of plasma testosterone levels in an open, nonrandomised study. Hypogonadal men (T levels: 5.9-12.1 nmol l(-1), aged 34-69 years) were treated for 15 months with parenteral testosterone undecanoate (1000 mg per 12 weeks). In 100 men, plasma CRP and Aging Male Symptom (AMS) self-report data were available at baseline, of 91 men at 6 months, of 59 men at 12 months and of 60 men at 15 months. Testosterone administration resulted in a profound decline in CRP levels and AMS scores (both P < 0.001). There was a positive association between CRP levels and AMS scores over time (r = 0.22; P < 0.001), while adjusting for smoking, alcohol use, age, and body mass index. Low-grade inflammation may be involved in the pathogenesis of subjective symptoms of androgen deficiency in ageing men.

Decline of plasma 5alpha-dihydrotestosterone (DHT) levels upon testosterone administration to elderly men with subnormal plasma testosterone and high DHT levels.

The study was performed to measure the impact of testosterone (T) administration on circulating levels of 5alpha-dihydrotestosterone (DHT). Group 1 (32 men; mean age 61 years; mean T 6.9 +/- 1.9 nmol l(-1)) were treated for 15 months with long-acting T undecanoate. Group 2 (23 men, mean age 60 years, mean T 7.6 +/- 2.0 nmol l(-1)) were treated for 9 months with T gel. Plasma T and DHT were measured before and after 9 months T administration. In the men treated with T undecanoate plasma T and DHT were also measured after 12 and 15 months. Before T administration, plasma DHT ranged from 0.39 to 1.76 nmol l(-1) (0.30-1.90 nmol l(-1)). Mean DHT declined upon T administration from 0.95 +/- 0.50 to 0.55 +/- 0.30 nmol l(-1) (P < 0.05). With an arbitrary cut-off at 0.60 nmol l(-1), all 21 values of DHT > 0.60 nmol l(-1) had fallen from 1.29 +/- 0.50 to 0.70 +/- 0.60 nmol l(-1) (P < 0.01). Below this cut-off point 13 values rose and 21 fell upon T administration. Below this cut-off point values on average declined from 0.39 +/- 0.12 to 0.30 +/- 0.14 nmol l(-1) (P < 0.05). The study revealed that in a cohort of elderly men with subnormal plasma T levels plasma DHT levels declined upon T administration when they were in the higher range of normal (>0.6 nmol l(-1)), with a profound shift of DHT/T ratios presumed to be an indicator of a reduced 5alpha-reductase activity. Below plasma DHT levels of 0.6 nmol l(-1), responses of plasma DHT to T administration varied.

Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone.

Until a decade ago the ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus, lower urinary tract symptoms and erectile dysfunction (ED), were regarded as distinct diagnostic/therapeutic entities but there is a growing awareness that these entities are not disparate and, to improve the health of the ageing male, require an integral approach. There is an inter-dependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. A new concept of the role of testosterone in male physiology suggests that testosterone plays also a significant role in the development and maintenance of bone and muscle mass and is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but exerts also essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. Treatment of testosterone deficiency is to become part and parcel of this approach.

Three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone.

This study tested 60 men, aged <40 years, with a BMI 27-35 kg/m(2) to determine whether they had metabolic syndrome. The three definitions used to test this were from the National Cholesterol Education Program (NCEP), the World Health Organization (WHO) and the International Diabetes Federation (IDF). Further, the relationship between a positive definition and plasma testosterone (T) and calculated free T was analysed. Using the above three definitions of metabolic syndrome (MetS), there was a large degree of overlap of identifying obese men as having the syndrome, but there were quantitatively significant differences as well. So, it is relevant in studies to identify which of the present definitions of the syndrome has been used. With aging there is an increasing prevalence of the syndrome and age itself might be a factor in the lower T levels encountered in these men. But low plasma total T and calculated free T were also consistent features of men <40 years with metabolic syndrome, regardless of which definition had been applied. Including low T levels in the definition of metabolic syndrome, may be helpful.

Testosterone treatment of hypogonadal men participating in competitive sports.

Testosterone has a steeply dose-dependent effect on muscle mass and strength irrespective of gonadal status. So, for reasons of fairness, people who engage in competitive sports should not administer exogenous testosterone raising their blood testosterone levels beyond the range of normal. There is a ban on exogenous androgens for men and women in sports, but an exception has been made for men with androgen deficiency due to pituitary or testicular disease. Men who receive testosterone administration for the indication hypogonadism have an interest in the use of testosterone preparations generating blood testosterone levels within the normal range of healthy, eugonadal men. On the grounds of a positive correlation between blood testosterone concentrations muscle and volume/strength, they are best served with a parenteral testosterone preparation, rather than transdermal testosterone, but they should not run the risk of being excluded from competition because of supraphysiological testosterone levels. The latter is a realistic risk with the traditional parenteral testosterone esters. The new parenteral testosterone undecanoate preparation offers much better perspectives. Its pharmacokinetics have been investigated in detail and there is a fair degree of predictability of resulting blood testosterone levels with use of this preparation.

Effects of cross-sex hormones on cerebral activation during language and mental rotation: An fMRI study in transsexuals.

Androgens and estrogens affect the performance on certain cognitive tests, particularly those measuring verbal fluency and mental rotation. Their effects on cognition have frequently been attributed to changes in cerebral lateralization. This study tested the impact of a reversal of the sex steroid milieu on cerebral activation and lateralization during verbal and spatial tasks in transsexuals. fMRI scans were obtained from 6 female-to-male and 8 male-to-female transsexuals at baseline and after cross-sex steroid treatment. Activation was measured during language and mental rotation tasks. Language activation increased after sex steroid treatment in both groups (F(1,12) =3.7, p=0.08), and total language activity was correlated to post-treatment estradiol levels (rho=0.54, p=0.05). Lateralization was not affected by the reversal of sex steroid milieus (F(1,12)=1.47, p=0.25). Activation during mental rotation did not increase during treatment (F(1,12)=0.54, p=0.34), but post-treatment testosterone levels correlated to total activation during mental rotation (rho=0.64, p=0.01). Findings suggest that sex steroids may influence cerebral activation, but lateralization remains stable.