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.

Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline

OBJECTIVE: To update the "Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2009. PARTICIPANTS: The participants include an Endocrine Society-appointed task force of nine experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: Group meetings, conference calls, and e-mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. CONCLUSION: Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender-dysphoric/gender-incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the person's genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the person's affirmed gender. Hormone treatment is not recommended for prepubertal gender-dysphoric/gender-incongruent persons. Those clinicians who recommend gender-affirming endocrine treatments-appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)-should be knowledgeable about the diagnostic criteria and criteria for gender-affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender-dysphoric/gender-incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin-releasing hormone agonists. Clinicians may add gender-affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender-affirming surgery in older adolescents. For adult gender-dysphoric/gender-incongruent persons, the treating clinicians (collectively) should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender-appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender-affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.

Meningiomas in three male-to-female transgender subjects using oestrogens/progestogens and review of the literature.

Sex hormones have been proposed as a possible risk factor for the development and growth of meningiomas. Hormonal therapy plays a fundamental role in the treatment of male-to-female transgenders and needs to be continued after sex reassignment surgery. Usually, this treatment leads to no adverse events; however, its impact on hormone-related tumours such as meningiomas has not yet been investigated thoroughly. We searched our cohort of 2810 male-to-female transgender persons, who have been treated between 1975 and 2010, for patients with meningiomas. Additionally, we conducted a literature search in PubMed and EMBASE. We found three patients who developed a meningioma in male-to-female transgenders in addition to five other who have been described in the literature. These findings support the role of female sex hormones in the development and growth of meningiomas. This might be an underrepresentation, because there is no standard protocol for screening for meningiomas in this population and meningiomas can remain asymptomatic for several years. We observed regression of multiple meningiomas in one of these three cases after discontinuation of hormonal treatment. The decision to stop or continue cross-sex hormone therapy in these particular patients should be carefully reconsidered individually.

Hypogonadal men with psoriasis benefit from long-term testosterone replacement therapy - a series of 15 case reports.

Psoriasis is increasingly recognised as a skin disease with far-reaching systemic effects, associated with a high prevalence of comorbid disease such as cardiometabolic dysfunction, shifting the focus from a single organ disease confined to the skin to a systemic inflammatory condition. Chronic and systemic inflammation plays a major role in the development of these diseases, and there are striking similarities between the molecular and inflammatory pathways in psoriasis and atherosclerosis. In a single-centre, cumulative, prospective registry study of 347 hypogonadal men (total testosterone ≤12.1 nmol l(-1) ), fifteen men with psoriasis could be studied. Upon testosterone administration, the skin disease improved considerably. Scores on the Psoriasis Area and Severity Index and Physician Global Assessment for Psoriasis showed significant improvement for the first 24 months. Thereafter, these improvements were sustained. Upon testosterone treatment, C-reactive protein declined significantly. There were significant improvements of obesity and of lipid profiles. Adipose tissue is now regarded as a source of inflammatory factors. These preliminary results deserve to be studied in a specifically designed study to investigate the effects of testosterone on psoriasis and its associated immunopathology.

Five new cases of breast cancer in transsexual persons.

Cross-sex hormone treatment of transsexual people may be associated with the induction and growth stimulation of hormone-related malignancies. We report here five cases of breast cancer, three in female-to-male (FtoM) transsexual subjects and two in male-to-female (MtoF) transsexual subjects. In the general population the incidence of breast cancer increases with age and with duration of exposure to sex hormones. This pattern was not recognised in these five transsexual subjects. Tumours occurred at a relatively young age (respectively, 48, 41, 41, 52 and 46 years old) and mostly after a relatively short span of time of cross-sex hormone treatment (9, 9-10 but in one after 30 years). Occurrence of breast cancer was rare. As has been reported earlier, breast tumours may occur in residual mammary tissue after breast ablation in FtoM transsexual people. For adequate treatment and decisions on further cross-sex hormone treatment it is important to have information on the staging and histology of the breast tumour (type, grade and receptor status), with an upcoming role for the androgen receptor status, especially in FtoM transsexual subjects with breast cancer who receive testosterone administration. This information should be taken into account when considering further cross-sex hormone treatment.

(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.

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.

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.

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.

Prostate cancer incidence in orchidectomised male-to-female transsexual persons treated with oestrogens.

Male-to-female transsexual persons (MtoF) undergo treatment with antiandrogens and oestrogens followed by bilateral orchiectomy. The aim of this study was to investigate the incidence of prostate cancer (PCa) in a cohort of MtoF individuals. Medical records 2306 MtoF treated between 1975 and 2006 of the Amsterdam Gender Clinic were reviewed. Mean age at initiation of treatment was 29.3 ± 12.7 years (range 16-83). Mean follow-up was 21.4 years, resulting in a combined total of 51 173 person-years of exposure and follow-up. Follow-up more than 20 years was available for 303 individuals, including follow-up of more than 30 years in 151 individuals. A single case of PCa was identified in this group. The overall incidence of PCa in this population was 0.04% and 0.13% for individuals who had initiated hormonal treatment after at 40 years or later. PCa in this large MtoF population was rare. However, underdiagnosis is likely due to lack of close prostate monitoring and suppression of PSA due to androgen deprivation. In addition, only a limited number of MtoF individuals have yet reached old age when PCa becomes more common. When diagnosed in this population, there appears to be a tendency for PCa to behave aggressively. Prostate monitoring should be considered in these individuals beginning at age 50 years.

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.

Advances in testosterone replacement therapy.

The major goal of androgen substitution is to replace testosterone at levels as close to physiological concentrations as is possible. The mainstay of testosterone susbstitution are parenteral testosterone esters (enanthate and cypionate) to be administered every 2-3 weeks. A major disadvantage is the strongly fluctuating levels of plasma testosterone which are at least 50% of the time not in the physiological range. A significant improvement is parenteral testosterone undecanoate producing normal plasma testosterone for 12 weeks. Subcutaneous testosterone implants provide the patient, depending on the dose of implants, with normal plasma testosterone for 3-6 months. Its use is, however, not widespread. Oral testosterone undecanoate dissolved in oil bypasses the liver via its lymphatic absorption, but resulting plasma levels are erratic. Transdermal testosterone preparations have already been available for two decades. Transdermal testosterone gel produces attractive pharmocokinetic serum testosterone profiles and offers greater flexibility in dosing. Transdermal gel has been recommended in elderly males. In case of complications its use can be discontinued immediately. Oromucosal testosterone preparations are being developed. Testosterone replacement is usually of long duration, and patient compliance is of utmost importance. Therefore, the patient must be involved in the selection of the type of testosterone preparation.

Late-onset hypogonadism.

With aging, a significant percentage of men over the age of 60 years have serum testosterone levels below the lower limits of young adult men. Testosterone is not only pivotal for male reproductive/sexual functioning but plays also a significant role in the maintenance of bone and muscle mass and is a determinant of glucose homeostasis and lipid metabolism. The metabolic syndrome, erectile dysfunction and patterns of testosterone in aging men are intertwined. Testosterone is a factor in libido but also exerts 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 of this approach. Recently, professional organizations have published guidelines in an attempt to define the condition and provide treatment. Despite this, much confusion still exists regarding the appropriate approach to diagnosing late-onset hypogonadism. Side effects concern mainly the prostate and erythropoeisis, but the currently available literature indicates that there is no increased risk of developing prostate cancer in men receiving testosterone treatment. Administration of testosterone to elderly men with testosterone deficiency is an acceptably safe practice.

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.