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.

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.

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.

[Some new aspects of the Klinefelter syndrome]. / Enkele nieuwe aspecten van het klinefeltersyndroom.

Klinefelter syndrome (KS) is the most frequent form of male hypogonadism. Still, at least 50% ofcases are not diagnosed, partly because of the great variation in the clinical symptoms, partly because physicians are unfamiliar with KS. Timely treatment with testosterone can contribute to a more positive body image and, consequently, to a healthier psychosexual development in men with KS. Men with KS experience significantly more health problems and an increased risk ofa malignancy. New reproductive techniques no longer automatically mean that men with KS will remain infertile. Treatment with testosterone is in principle life-long to prevent osteoporosis and loss of muscle mass and strength.

Clubbed fingers: the claws we lost?

Clubbed digits resemble the human embryonic fingers and toes, which look like the digits of a claw. Clubbed digits, thus, may represent the return of the embryonic claw and may even represent the claws man has lost during evolution, if ontogenesis really recapitulates phylogenesis. We put forward the hypothesis that secondary clubbing, like gynecomastia, is caused by a pathologic condition, which alters hormone levels in the blood, leading to the activation of 'dormant' genes, resulting in the development of an organ. However, the nature of the diseases that cause clubbing suggests that these hormones may actually be cytokines, acting as hormones. The nature of these cytokines is not known. They may be identified by comparing their blood levels or the combination of their blood levels to the presence or absence of clubbing, but also to the degree of clubbing and its disappearance after treatment of the primary disease.

Established risk factors for coronary heart disease are unrelated to androgen-induced baldness in female-to-male transsexuals.

A high scalp sensitivity to androgens is part of the pathophysiology of male-pattern baldness (MPB). Androgens affect established risk factors for coronary heart disease (CHD), and a supposedly heightened impact on these risk factors is hypothesized to explain the epidemiological association between MPB and CHD. In this retrospective, observational study we studied 81 female-to-male transsexual (F-->M) subjects, mean age 36.7 years (range 21-61), treated with testosterone esters (n=61; 250 mg i.m./2 weeks) or testosterone undecanoate (n=20; 160-240 mg/day orally). The degree of MPB was self-assessed using a 5-point scale (i.e. type I (no hair loss) to type V (complete hair loss)). Body mass index, blood pressure and levels of lipid and insulin were retrospectively assessed at the start of testosterone administration (0.5-24 years before) and between 3 and 4 months of follow-up. We found that 31 of 81 (38.3%) F-->M transsexuals had MPB type II-V. Thinning of hair was related to the duration of androgen administration and present in about 50% of F-->M transsexuals after 13 years. None of the CHD risk factors at follow-up, nor proportional changes, was associated with the degree MPB, except that there was an unexpected tendency of lower fasting glucose levels in balding subjects. Therefore, our findings do not support the idea that MPB serves as an indicator of increased CHD risk through androgenic effects on classic CHD risk factors.

Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people.

The incidence of venous thrombosis associated with estrogen treatment in male-to-female (M-->F) transsexuals is considerably higher with administration of oral ethinyl estradiol (EE) than with transdermal (td) 17-beta-estradiol (E(2)). To find an explanation for the different thrombotic risks of oral EE and td E(2) use, we compared the effects of treatment of M-->F transsexuals with cyproterone acetate (CPA) only, and with CPA in combination with td E(2), oral EE, or oral E(2) on a number of hemostatic variables [activated protein C (APC) resistance and plasma levels of protein S, protein C, and prothombin], all of which are documented risk factors for venous thrombosis. APC resistance was determined by quantification of the effect of APC on the amount of thrombin generated during tissue factor-initiated coagulation; plasma levels of total and free protein S were determined by standard ELISA; and levels of prothrombin and protein C were determined with functional assays after complete activation of the zymogens with specific snake venom proteases. CPA-only, td-E(2)+CPA, or oral-E(2)+CPA treatment produced rather small effects on hemostatic variables, whereas oral EE treatment resulted in a large increase in APC resistance from 1.2 +/- 0.8 to 4.1 +/- 1 (P < 0.001), a moderate increase in plasma protein C (9%; P = 0.012), and a large decrease in both total and free plasma protein S (30%; P < 0.005). The large differential effect of oral EE and oral E(2) indicates that the prothrombotic effect of EE is due to its molecular structure rather than to a first-pass liver effect (which they share). Moreover, these differences may explain why M-->F transsexuals treated with oral EE are exposed to a higher thrombotic risk than transsexuals treated with td E(2). Testosterone administration to female-to-male transsexuals had an antithrombotic effect.

Significance of oestrogens in male (patho)physiology.

Traditionally conceptualized as 'female hormones', oestrogens appear to have significant effects in the male biological system. Favorable effects have been noted on bone, brain and cardiovascular physiology while a potential role in the prostate pathology of the aging male has been seriously suspected. Oestrogens in male are predominantly the products of peripheral aromatization of testicular and adrenal androgens. While the testicular and adrenal production of androgens declines with aging, levels of total plasma oestradiol do not decline. This is to be ascribed to the common increase in fat mass with aging (the substrate of peripheral aromatization) and an increased aromatase activity with aging. But free or bioavailable oestrogens may decline due to an increase in sex hormone binding globulin. Oestrogens produce significant beneficial effects on skeletal growth and bone maturation. In old age oestrogens are better predictors of bone fractures than androgens. Oestrogens exert effects on the brain: on cognitive function, co-ordination of movement, pain and affective state, and are maybe protective of Alzheimer's disease. Oestrogen effects on the cardiovascular system include those on lipid profiles, fat distribution, endocrine/paracrine factors produced by the vascular wall (such as endothelins, nitric oxide), blood platelets, inflammatory factors and coagulation. The potentially adverse effects of oestrogens on the prostate may be due to a shift in the oestrogen / androgen ratio with aging. Sources of estrogens in men are endogenous androgens, or in case of androgen deficiency, exogenous androgens. Dietary phytoestrogens or selective estrogen receptor modulators, as drugs, may be significant as well.