The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment.

Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23-41) and 1373 transmen (median age 23 years, interquartile range 18-31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9-7.7) and male population (11.9, 5.5-22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1-7.9) and males (26.5, 12.9-48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7-73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary.

Endocrine treatment of aging transgender people.

High quality empirical data assessing morbidity and mortality and cancer incidence among transgender people are almost non-existent. Sex hormone treatment of conditions in older non-transgender people might as yet be taken as the best available analogy to hormone administration to aging transgender persons. Testosterone administration to transgender men carries little risk with regard to cardiovascular disease and cancer. A dose adaptation may be needed in men with a high hematocrit or cardiac insufficiency. In transgender men, even after breast ablation, breast cancer may occur in residual mammary tissue. Treatment with estrogens (specifically oral ethinylestradiol) of transgender women, particularly in combination with progestins, carries a significant relative risk of developing cardiovascular disease (almost a twofold incidence compared to the general population). The dose of estrogens may have to be reduced with aging. A change from oral to probably safer transdermal estrogens must be considered. Though rare, tumors of the breasts, prostate, meninges and pituitary have been encountered. Based upon the available expertise, initiation of cross-sex hormone treatment in elderly subjects is without disproportionate risks.

The Amsterdam Cohort of Gender Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets.

BACKGROUND: Over the past decade, the number of people referred to gender identity clinics has rapidly increased. This raises several questions, especially concerning the frequency of performing gender-affirming treatments with irreversible effects and regret from such interventions. AIM: To study the current prevalence of gender dysphoria, how frequently gender-affirming treatments are performed, and the number of people experiencing regret of this treatment. METHODS: The medical files of all people who attended our gender identity clinic from 1972 to 2015 were reviewed retrospectively. OUTCOMES: The number of (and change in) people who applied for transgender health care, the percentage of people starting with gender-affirming hormonal treatment (HT), the estimated prevalence of transgender people receiving gender-affirming treatment, the percentage of people who underwent gonadectomy, and the percentage of people who regretted gonadectomy, specified separately for each year. RESULTS: 6,793 people (4,432 birth-assigned male, 2,361 birth-assigned female) visited our gender identity clinic from 1972 through 2015. The number of people assessed per year increased 20-fold from 34 in 1980 to 686 in 2015. The estimated prevalence in the Netherlands in 2015 was 1:3,800 for men (transwomen) and 1:5,200 for women (transmen). The percentage of people who started HT within 5 years after the 1st visit decreased over time, with almost 90% in 1980 to 65% in 2010. The percentage of people who underwent gonadectomy within 5 years after starting HT remained stable over time (74.7% of transwomen and 83.8% of transmen). Only 0.6% of transwomen and 0.3% of transmen who underwent gonadectomy were identified as experiencing regret. CLINICAL IMPLICATIONS: Because the transgender population is growing, a larger availability of transgender health care is needed. Other health care providers should familiarize themselves with transgender health care, because HT can influence diseases and interact with medication. Because not all people apply for the classic treatment approach, special attention should be given to those who choose less common forms of treatment. STRENGTHS AND LIMITATIONS: This study was performed in the largest Dutch gender identity clinic, which treats more than 95% of the transgender population in the Netherlands. Because of the retrospective design, some data could be missing. CONCLUSION: The number of people with gender identity issues seeking professional help increased dramatically in recent decades. The percentage of people who regretted gonadectomy remained small and did not show a tendency to increase. Wiepjes CM, Nota NM, de Blok CJM, et al. The Amsterdam Cohort of Gender Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets. J Sex Med 2018;15:582-590.

Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study.

This observational post-marketing study of parenteral testosterone undecanoate (TU) in a non-selected population aimed to: examine the effectiveness of TU as treatment of hypogonadism; record adverse drug reactions (ADR) quantitatively particularly regarding polycythemia, prostate safety and cardiovascular-related metabolic risk factors; and verify whether recommended injection intervals apply to routine clinical practice. Eight hundred and seventy subjects from 259 outpatient units scheduled to visit the clinic six times were included. Effectiveness and tolerability of TU administration were assessed on a 4-point scale. Body weight, waist girth, blood pressure, hemoglobin levels, hematocrit, prostate-specific antigen (PSA), and digital rectal prostate examination were assessed. Over 90% of subjects completed the observational duration of 52.8 ± 9.7 weeks (mean ± SD) and 56% judged effectiveness as very good, 30.8% as good. 63.1% judged tolerability as very good, and 24.4% as good. No adverse effects on indicators of cardiovascular risk were observed. Polycythemia occurred in one subject and a supranormal hematocrit in one subject. Four subjects developed supranormal PSA levels. Prostate carcinoma was found in one subject, one subject had recurrence of a previously surgically treated prostate carcinoma, and the other two showed no indication of malignancy. Parenteral TU is safe, effective, and well-tolerated in clinical practice proving a good therapeutic option for hypogonadism.

Effects of intermission and resumption of long-term testosterone replacement therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men.

OBJECTIVE: In addition to primary and secondary ('classical') hypogonadism, hypogonadism occurring in middle-aged and elderly men has been recognized. There is evidence that restoring T levels to normal improves body weight, serum lipids and glucose levels. DESIGN: Observational registry study. PATIENTS: Two hundred and sixty-two hypogonadal, middle-aged and elderly, men received testosterone replacement treatment (TRT). After having been on TRT for a mean duration of 65·5 months, TRT was temporarily intermitted in 147 patients for a mean of 16·9 months (Group I) due to cost reimbursement issues and in seven men due to prostate cancer. All these men resumed TRT for a mean period of 14·5 months. Of the cohort, 115 men were treated continuously (designated as Group C). To compare on-treatment to off-treatment periods, three periods of equal duration were defined: pre-intermission (on TRT), during intermission (off TRT) and post-intermission (on TRT after resumption of TRT). For proper comparison, the same periods were analysed for those patients who continued TRT throughout (Group C). MEASUREMENTS: Variables of body weight, glucose metabolism, lipids, blood pressure and C-reactive protein (CRP). RESULTS: In Group C there was a continuous improvement of body weight, serum lipids, glucose, HbA1c , blood pressure and CRP. In Group I there was a similar initial improvement which was reversed upon intermission of T administration but which appeared again when T treatment was reinstated. CONCLUSIONS: Our observation indicates that T administration improves body weight and metabolic factors in men with hypogonadism but withdrawal of T reverses these beneficial effects to appear again when TRT is resumed.

Diagnosing hypogonadism and treating decisions in different parts of the world: shifts in patterns between 2006 and 2015.

AIM: Variations in diagnosing and treating testosterone (T) deficiency between different regions of the world were analyzed in 2006, and repeated in 2010. At present, the changes since 2006 were analyzed. METHODS: About 731 physicians were interviewed in Europe, South Africa, Central and South America regarding factors determining: (1) prescription of T or withholding T, (2) factors in the long-term use of T and the role of T formulations therein, (3) awareness of the wider spectrum of action of T (cardiometabolic disease) (4) reimbursement of T and its impact on (continued) use and (5) best strategies for information on T for physicians. RESULTS: Total T was a key factor in identifying hypogonadism, but for >80% of physicians, clinical symptoms were weighed during diagnosis. Once diagnosed, >85% received T treatment, but the treatment compliance was problematic. Of these patients, 36% decided not to start or continue the treatment. CONCLUSION: More hypogonadal men are treated than before, but ∼20% goes unidentified. Physicians have a greater awareness that T deficiency can be an element in cardiovascular and metabolic disease, but more education of physicians on diagnosis and treatment of hypogonadism are needed. Problems with reimbursement of T are barriers in the prescription of T and its use by patients.

Effects of long-term testosterone replacement therapy, with a temporary intermission, on glycemic control of nine hypogonadal men with type 1 diabetes mellitus - a series of case reports.

Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone ≤ 12 nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.

Sex reassignment of transsexual people from a gynecologist's and urologist's perspective.

Cross-sex hormone treatment of transgender persons is usually uneventful, but hormone-sensitive malignancies of the (reproductive) organs of the natal and new sex (breasts, neovagina) may arise. Sex reassignment surgery impacts on the urodynamics of the reassigned sex. Pathology originating from organ systems of the natal sex may be overlooked in the new sex. In male-to-female transgender individuals, malignant tumors of the breasts and prostate may occur. Neovaginas are constructed with skin or sigmoid. Shortening of the male urethra to female dimensions is usually uneventful. In female-to-male transgender individuals breast cancer may develop, sometimes in residual mammary tissue after reductive mammoplasty. Malignancies of the vagina and ovaries are rare. Testosterone may be aromatized to estrogens, with effects on the endometrium. Lengthening of the female urethra to male dimensions may cause urethral fistulae, urethral strictures, and meatal stenoses. A degree of post-voiding incontinence may occur.

Cross-sex hormone use, functional health and mental well-being among transgender men (Toms) and Transgender Women (Kathoeys) in Thailand.

There exists limited understanding of cross-sex hormone use and mental well-being among transgender women and, particularly, among transgender men. Moreover, most studies of transgender people have taken place in the Global North and often in the context of HIV. This exploratory study compared 60 transgender men (toms) with 60 transgender women (kathoeys) regarding their use of cross-sex hormones, mental well-being and acceptance by their family. Participants also completed a dispositional optimism scale (the Life Orientation Test Revised), the Social Functioning Questionnaire and the Short Form Health Survey 36 assessing their profile of functional health and mental well-being. Cross-sex hormones were used by 35% of toms and 73% of kathoeys and were largely unsupervised by health-related personnel. There were no differences in functional health and mental well-being among toms and kathoeys. However, toms currently using cross-sex hormones scored on average poorer on bodily pain and mental health, compared to non-users. Furthermore, compared to non-users, cross-sex hormone users were about eight times and five times more likely to be associated with poor parental acceptance among toms and kathoeys, respectively. This study was the first to compare cross-sex hormone use, functional health and mental well-being among transgender women and transgender men in Southeast Asia.

Conjectures concerning cross-sex hormone treatment of aging transsexual persons.

INTRODUCTION: Guidelines for cross-sex hormone treatment of transsexual people are now in place. However, little attention has been paid to the issue of treatment suitability for older people. Does existing treatment need to be adapted as subjects age, and does it make a difference if treatment is only started when the subject is already older? AIM: To assess the necessity of adapting cross-sex hormone administration for elderly transsexual people. MAIN OUTCOME MEASURES: Risks/benefits of continued use of cross-sex hormones with regard to bone health, cardiovascular risks, and malignancies. METHODS: Due to lack of data on the subject population, sex hormone treatment of other conditions in older non-transsexual people has been taken as the best available analogy to determine the extent to which these might be applicable to comparable transsexual persons. Findings in transsexual people receiving cross-sex hormone treatment sometimes modified the above approach of applying guidelines for the elderly to the aging transsexual population. RESULTS: Testosterone administration to female-to-male transsexual persons (FtoM) carries little risk with regard to cardiovascular disease and cancer. For those with high hematocrit or cardiac insufficiency the dose can be reduced. Administration of estrogens to male-to-female transsexual persons (MtoF), particularly when combined with progestins, does significantly increase the risk of developing cardiovascular disease (almost a twofold incidence compared with the general population). This may require dose adjustment or changing from oral to safer transdermal estrogens. Tumors of the breasts, prostate and pituitary may occur. In FtoM, breast cancer can occur even after breast ablation. Older subjects can commence cross-sex hormone treatment without disproportionate risks. CONCLUSION: Cross-sex hormones may be continued into old age but monitoring for cardiovascular disease and malignancies, both of the old and new sex, is recommended. MtoF will have more health complications in old age than FtoM requiring adaptations of treatment.

Clinical review: Breast development in trans women receiving cross-sex hormones.

INTRODUCTION: In trans women (male-to-female transsexual persons), cross-sex hormone therapy is administered to induce feminization. Breast development is an important part of feminization for most trans women. AIM: The aim of this study is to assess the effect of cross-sex hormone therapy on breast development in adult trans women. Additionally, we aimed to investigate the benefit or harm of administration of progestogens on breast development. METHODS: A review of the literature in Embase, Medline, The Cochrane Library, PsycINFO databases, PubMed, and Web of Knowledge until January 2014. MAIN OUTCOME MEASURES: Effects of cross-sex hormone therapy and progestogens on breast development in trans women. RESULTS: Only few studies with low quality of evidence addressed these topics. The available evidence suggests that breast development is insufficient for the majority of trans women and that type and dosage of hormonal therapy seem not to have an important role on final breast size. CONCLUSIONS: Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in trans women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in trans women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.

IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men.

INTRODUCTION: Morbidity/mortality is higher in men with below-normal serum testosterone. Restoring testosterone to normal is beneficial. AIM: Assessment of safety and effectiveness of injectable long-acting testosterone undecanoate (TU) in hypogonadal men in daily clinical practice. METHODS: An international, multicenter, one-arm, prospective observational study in 23 countries. MAIN OUTCOME MEASURES: Parameters of erectile function, libido, vigor/vitality, mood, and ability to concentrate assessed by physician interview using items and five-point Likert scales. Physical and circulatory parameters as well as hematocrit, prostate-specific antigen (PSA) levels, glucose control, and lipid profiles. IPASS: An International, multicenter, Post-Authorisation (after authorized use in respective country) Surveillance Study on long-acting-intramuscular TU conducted at 155 centers in 23 countries in Europe, Asia, Latin America, and Australia. Patients received up to five TU injections during 9-12 months. RESULTS: Of the 1,493 hypogonadal men enrolled, 1,438 (aged 49.2 ± 13.9 years) having received 6,333 injections were analyzed. Scores of mental and psychosexual functions (libido, vigor, overall mood, and ability to concentrate) improved markedly, while mean waist circumference decreased from 100 to 96 cm. Blood pressure and lipid parameters were altered in a favorable and significant manner. After four TU injection intervals, the percentage of patients with "low" or "very low" levels of sexual desire/libido decreased from 64% at baseline to 10%; moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%. At the last observation, 89% of patients were "satisfied" or "very satisfied" with TU therapy. Adverse events and adverse drug reactions (ADRs) occurred in 12% and 6% of patients, respectively, mostly mild to moderate. The most common ADRs were increase in hematocrit, increase in PSA, and injection site pain (all <1%). No case of prostate cancer was observed. CONCLUSION: In this largest worldwide sample of hypogonadal men, injectable long-acting TU was effective and well tolerated.

Breast cancer development in transsexual subjects receiving cross-sex hormone treatment.

INTRODUCTION: Transsexual people receive cross-sex hormones as part of their treatment, potentially inducing hormone-sensitive malignancies. AIM: To examine the occurrence of breast cancer in a large cohort of Dutch male and female transsexual persons, also evaluating whether the epidemiology accords with the natal sex or the new sex. MAIN OUTCOME MEASURE: Number of people with breast cancer between 1975 and 2011. METHODS: We researched the occurrence of breast cancer among transsexual persons 18-80 years with an exposure to cross-sex hormones between 5 to >30 years. Our study included 2,307 male-to-female (MtF) transsexual persons undergoing androgen deprivation and estrogen administration (52,370 person-years of exposure), and 795 female-to-male (FtM) subjects receiving testosterone (15,974 total years of exposure). RESULTS: Among MtF individuals one case was encountered, as well as a probable but not proven second case. The estimated rate of 4.1 per 100,000 person-years (95% confidence interval [CI]: 0.8-13.0) was lower than expected if these two cases are regarded as female breast cancer, but within expectations if viewed as male breast cancer. In FtM subjects, who were younger and had shorter exposure to cross-sex hormones compared with the MtF group, one breast cancer case occurred. This translated into a rate of 5.9 per 100,000 person-years (95% CI: 0.5-27.4), again lower than expected for female breast cancer but within expected norms for male breast cancer. CONCLUSIONS: The number of people studied and duration of hormone exposure are limited but it would appear that cross-sex hormone administration does not increase the risk of breast cancer development, in either MtF or FtM transsexual individuals. Breast carcinoma incidences in both groups are comparable to male breast cancers. Cross-sex hormone treatment of transsexual subjects does not seem to be associated with an increased risk of malignant breast development.

Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010.

AIM: An analysis of variations in diagnosing and treating testosterone (T) deficiency between different regions of the world in 2006 was repeated in 2010. METHODS: Physicians were interviewed in Germany, Spain, the United Kingdom, Brazil and Saudi Arabia about (1) reasons to use/not to use T. (2) safety (prostate pathology) and other concerns in the decision not to provide T treatment. (3) the actual usage of T preparations for treatment of erectile dysfunction (ED). RESULTS: More men were treated with T in 2010. ED and lack of libido (2006) but also depression and obesity (2010) were regarded as symptoms of T deficiency. For 70% of physicians, severity of complaints was more significant than the laboratory value of T to prescribe T, more so in Germany (96%) than in Spain and Saudi Arabia. Concerns about prostate disease remained strong and, therefore, 11% of eligible patients did not receive T. PDE-5 inhibitors are more often combined with T in 2010 for ED. CONCLUSION: More appropriate studies and more education of physicians are needed on diagnosing T deficiency, on the role of T in ED and on the evidence-based relative safety of T treatment.

A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up.

INTRODUCTION: The clinical significance of low to low-normal testosterone (T) levels in men remains debated. AIM: To analyze the effects of raising serum T on lean body mass (LBM), fat mass (FM), total body mass, and health-related quality-of-life (HRQoL). METHODS: Randomized, double-blind, placebo-controlled study. Men, aged 50-80 years, with serum total T<15 nmol/L and bioavailable T < 6.68 nmol/L, and a Aging Males' Symptoms (AMS) total score >36, received 6 months treatment with transdermal 1% T gel (5-7.5 mg/day; n =183) or placebo gel (n =179), followed by 12 months open-label with T in all. RESULTS: After 6 months, LBM increased in T- treated patients by 1.28 ± 0.15 kg (mean ± SE) and FM decreased by 1.16 ± 0.16 kg, with minor changes with placebo (LBM +0.02 ± 0.10 kg and FM -0.14 ± 0.12 kg; all p < 0.001, T group vs. placebo). Changes were largely similar across subgroups of age, baseline total testosterone, and baseline BMI. Total HRQoL improved compared with placebo (p < 0.05, T group vs. placebo). CONCLUSIONS: Six months 1% T gel improved body composition and HRQoL in symptomatic men with low to low-normal T, with further improvements over the following 12 months.

Mortality trends over five decades in adult transgender people receiving hormone treatment: a report from the Amsterdam cohort of gender dysphoria.

BACKGROUND: Increased mortality in transgender people has been described in earlier studies. Whether this increased mortality is still present over the past decades is unknown. Therefore, we aimed to investigate trends in mortality over five decades in a large cohort of adult transgender people in addition to cause-specific mortality. METHODS: We did a retrospective cohort study of adult transgender people who visited the gender identity clinic of Amsterdam University Medical Centre in the Netherlands. Data of transgender people who received hormone treatment between 1972 and 2018 were linked to Statistics Netherlands. People were excluded if they used alternating testosterone and oestradiol treatment, if they started treatment younger than age 17 years, or if they had ever used puberty-blockers before gender-affirming hormone treatment. Standardised mortality ratios (SMRs) were calculated using general population mortality rates stratified by age, calendar period, and sex. Cause-specific mortality was also calculated. FINDINGS: Between 1972 and 2018, 8831 people visited the gender identity clinic. 4263 were excluded from the study for a variety of reasons, and 2927 transgender women and 1641 transgender men were included in the study, with a total follow-up time of 40 232 person-years for transgender women and 17 285 person-years for transgender men. During follow-up, 317 (10·8%) transgender women died, which was higher than expected compared with general population men (SMR 1·8, 95% CI 1·6-2·0) and general population women (SMR 2·8, 2·5-3·1). Cause-specific mortality in transgender women was high for cardiovascular disease, lung cancer, HIV-related disease, and suicide. In transgender men, 44 people (2·7%) died, which was higher than expected compared with general population women (SMR 1·8, 95% CI 1·3-2·4) but not general population men (SMR 1·2, 95% CI 0·9-1·6). Cause-specific death in transgender men was high for non-natural causes of death. No decreasing trend in mortality risk was observed over the five decades studied. INTERPRETATION: This observational study showed an increased mortality risk in transgender people using hormone treatment, regardless of treatment type. This increased mortality risk did not decrease over time. The cause-specific mortality risk because of lung cancer, cardiovascular disease, HIV-related disease, and suicide gives no indication to a specific effect of hormone treatment, but indicates that monitoring, optimising, and, if necessary, treating medical morbidities and lifestyle factors remain important in transgender health care. FUNDING: None.

Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.

OBJECTIVE: Men with the metabolic syndrome (MetS) have low plasma testosterone (T) levels. The aim of this study was to establish whether the normalization of plasma T improves the features of the MetS. DESIGN: A randomized, placebo-controlled, double-blinded, phase III trial of 184 men suffering from both the MetS and hypogonadism. PATIENTS: One hundred and eighty-four men, aged 35-70, with the MetS and hypogonadism (baseline total T level <12·0 nm or calculated free T level <225 pm.), recruited in the outpatient andrology and urology clinic, Research Center for Endocrinology in Moscow, Russia. INTERVENTION: Treatment for 30 weeks with either parenteral T undecanoate (n = 113; TU; 1000 mg IM) or placebo (n = 71), administered at baseline, and after 6 and 18 weeks. One hundred and five (92·9%) men receiving TU and 65 (91·5%) receiving placebo completed the trial. MEASUREMENTS: Body weight, body mass index (BMI), waist circumference (WC), hip circumference, waist-to-hip ratio, insulin, leptin, glucose, cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein (CRP), interleukin-1-beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-α). RESULTS: There were significant decreases in weight, BMI and WC in the TU vs placebo group. Levels of leptin and insulin also decreased, but there were no changes in serum glucose or lipid profile. Of the inflammatory markers, IL-1ß, TNF-α and CRP decreased, while IL-6 and IL-10 did not change significantly. CONCLUSIONS: Thirty weeks of T administration normalizing plasma T in hypogonadal men with the MetS improved some components of the MetS and a number of inflammatory markers.