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Background: Estimation of serum concentrations of free testosterone (FT) and bioavailable testosterone (bioT) by calculation is an inexpensive and uncomplicated method. We compared results obtained with 5 different algorithms. Methods: We used 5 different published algorithms [described by Sodergard et al. (bioTS and FTS), Vermeulen et al. (bioTV and FTV), Emadi-Konjin et al. (bioTE), Morris et al. (bioTM), and Ly et al. (FTL)] to estimate bioT and FT concentrations in samples obtained from 399 independently living men (ages 40–80 years) participating in a cross-sectional, single-center study. Results: Mean bioT was highest for bioTS (10.4 nmol/L) and lowest for bioTE (3.87 nmol/L). Mean FT was highest for FTS (0.41 nmol/L), followed by FTV (0.35 nmol/L), and FTL (0.29 nmol/L). For bioT concentrations, the Pearson correlation coefficient was highest for the association between bioTS and bioTV (r = 0.98) and lowest between bioTM and bioTE (r = 0.66). FTL was significantly associated with both FTS (r = 0.96) and FTV (r = 0.88). The Pearson correlation coefficient for the association between FTL and bioTM almost reached 1.0. Bland-Altman analysis showed large differences between the results of different algorithms. BioTM, bioTE, bioTV, and FTL were all significantly associated with sex hormone binding globulin (SHBG) concentrations. Conclusion: Algorithms to calculate FT and bioT must be revalidated in the local setting, otherwise over- or underestimation of FT and bioT concentrations can occur. Additionally, confounding of the results by SHBG concentrations may be introduced.

Objectives The objective was to examine the effects of testosterone administration on symptom scores of lower urinary tract symptoms (LUTS). Methods The literatures on the epidemiological association between the metabolic syndrome, erectile failure and (LUTS) were reviewed. Results In men with the metabolic syndrome and erectile failure, often lower-than-normal testosterone levels are found. This is less clear for men with LUTS, but the relationship between testosterone and LUTS might be indirect and based on the association of the metabolic syndrome with an overactivity of autonomic nervous system. This overactivity may play a key role in increasing the severity of LUTS above an intrinsic basal intensity that is determined by the genitourinary factors in aging men. Androgen receptors are present in the epithelium of the urethra and the bladder. Testosterone may play a role in the reflex activity of the autonomic nervous system in the pelvis, or may interact with postsynaptic non-genomic receptors suppressing detrusor activity. Human neurons in the wall of the bladder contain nitric oxide synthase. Similar to the penis, testosterone has an impact on nitric oxide synthase. Conclusions Some studies investigating the effects of normalizing testosterone levels in elderly men have found a positive effect on variables of the metabolic syndrome and, simultaneously, on scores of the International Prostate Symptoms Score (IPSS) which is worthy of further investigation in randomized, controlled and sufficiently powered clinical trials.

Abstract Context Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer. Objective To assess the incidence of prostate cancer in trans women using hormone treatment. Design In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality. Setting Gender identity clinic. Participants Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included. Main Outcome Measures Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization. Results The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42). Conclusions Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer.

TRANSSEXUALS have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psycho-genie or biological aetiology of transsexuality has been the subject of debate for many years 1,2 . Here we show that the volume of the central subdivision of the bed nucleus of the stria terminalis (BSTc), a brain area that is essential for sexual behaviour 3,4 , is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones 5,6 .

Background: Concentrations of human tissue kallikreins (hKs), a group of 15 secreted serine proteases found in many tissues, are modulated by steroid hormones in cancer cell lines. To gain insight into in vivo kallikrein regulation we measured kallikrein concentrations in serum and urinary tissue in female-to-male transsexuals before and after testosterone administration. Methods: We collected blood and urine samples before treatment and after 4 and 12 months from 28 female-to-male transsexuals who received 250 mg of testosterone esters intramuscularly every 2 weeks. We used ELISA assays to measure multiple kallikreins in serum and urine. Results: After testosterone administration, serum testosterone concentrations increased by ∼15-fold. Serum kallikrein concentrations increased dramatically for hK3 (prostate-specific antigen) and increased moderately for hK2, hK5, hK6, hK7, hK8, hK10, and hK11. In urine, we noted major increases for hK3 and hK2 only. For all other kallikrein concentrations, we observed no considerable changes. Conclusions: We conclude that, in serum and urine of female-to-male transsexuals after testosterone administration, hK3 (prostate-specific antigen) and to a lesser extent hK2 concentrations increase dramatically, but concentration of other kallikreins increase either moderately in serum (hK5, hK6, hK7, hK8, hK10, and hK11) or not at all in either serum (hK4, hK13, hK14) or urine (hK4, hK5, hK6, hK7, hK8, hK10, hK11, hK13, hK14).

Background: The expression of human tissue kallikrein genes is regulated by steroid hormones, but most studies have been conducted with cancer cell lines. Our purpose was to examine serum and urinary tissue kallikrein concentration changes in male-to-female transsexuals before and after treatment with antiandrogens and estrogens. Methods: Thirty-five male-to-female transsexuals receiving cyproterone acetate and estrogens (orally or transdermally) were included in this study. Serum and urine samples were collected before initiation of therapy and 4 and 12 months post therapy. ELISAs were used to measure multiple kallikreins in serum and urine. Results: After antiandrogen and estrogen therapy, serum testosterone concentrations decreased dramatically, as did serum and urinary concentrations of human glandular kallikrein (hK2) and prostate-specific antigen (PSA; hK3). Statistically significant but relatively small changes in serum and urinary concentrations of many other kallikreins were also seen. Kallikreins in serum and urine were correlated before and after treatment. Conclusions: The concentrations of hK2 and hK3, but not of any other kallikreins, decrease dramatically after combined antiandrogen and estrogen treatment in male-to-female transsexuals. The smaller responses of the other kallikreins presumably reflect their expression in multiple tissues.

Erectile response is centrally and peripherally regulated by androgens. The original insights into the mechanisms of action of androgens were that androgens particularly exert effects on libido and that erections in response to erotic stimuli were relatively androgen‐independent. It was shown that sexual functions in men required androgen levels at the low end of reference values of testosterone. So it seemed that testosterone was not useful treatment for men with erectile difficulties, particularly following the advent of the phosphodiesterase type 5 (PDE5) inhibitors. However, approximately 50 % of those treated with PDE5 inhibitors discontinue their treatment. A number of recent developments shed new light on testosterone treatment of erectile dysfunction (ED) in aging men. (1) A recent insight is that, in contrast to younger men, elderly men might require higher levels of testosterone for normal sexual functioning. (2) Several studies have indicated that PDE5 inhibitors are not always sufficient to restore erectile potency in men, and that testosterone improves the therapeutical response to PDE5 inhibitors considerably. (3) There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, reversible upon androgen replacement. The synthesis of PDE5 is upregulated by androgens, and the arterial inflow into the penis is improved by giving androgen. The above invites a re‐examination of the merits of giving testosterone to aging men with ED. The beneficial effects of PDE5 inhibitors may only be optimally expressed in a eugonadal environment.

Testosterone replacement treatment is usually life-long. Fortunately, testosterone administration is relatively safe and until the age of 50 years few side effects are noted with normal doses of testosterone. After the age of 50 years when prostate disease becomes more prevalent, shorter-acting testosterone preparations, allowing a fast reduction of circulating testosterone levels, may be an advantage. Testosterone has an impact on sexual and non-sexual behaviour and short-acting testosterone preparations may be better suited for the initiation of long-term administration allowing the monitoring of behavioural effects. Testosterone can be delivered to the circulation through the intact skin, both genital and non-genital. Transdermal administration delivers testosterone at a controlled rate into the systemic circulation, avoiding hepatic first pass and reproducing the diurnal rhythm of testosterone secretion and without the peak and trough levels observed with the use of the traditional long-acting testosterone injections. In conclusion, both the testosterone patch and testosterone gel are valuable contributions to androgen replacement treatment meeting the requirements specified for testosterone replacement treatment.

Substantial evidence from animal research indicates that enhanced memory associated with emotional experiences involves activation of the beta-adrenergic system. This hypothesis is further supported by the finding in human subjects that blockade of beta-adrenergic receptors with propranolol selectively reduced memory for emotional events. In the present study, we compared the effects of propranolol, a lipid soluble drug which crosses the blood-brain barrier easily, with those of nadolol, a water soluble drug which crosses the blood-brain barrier to a considerably lesser extent, to determine whether the effect involved peripheral or central beta-adrenergic receptors. The effects of these drugs, taken before subjects watched a slide show that was either emotionally arousing or relatively neutral in content, were tested 1 week later with a surprise memory test. Consistent with previous results, propranolol impaired memory (recall and recognition) in the subjects who saw the emotional version of the slide show. In contrast, nadolol did not impair memory of the emotional slide show. These results indicate that the blockade of central beta-adrenergic receptors is responsible for the reduction in storage of emotional events. The results support the view that memory of a mild emotional event involves activation of central, but not necessarily peripheral beta-adrenergic receptors.

Animal and human studies lend support to the hypothesis that enhanced memory associated with emotional experiences involves activation of the beta-adrenergic system. Evidence for the role of noradrenaline in emotional memory in humans has been gathered from experimental studies where blockade of the beta-adrenergic system with a beta-blocker selectively impaired long-term memory for an emotionally arousing story (a slide show), when the beta-blocker was given before subjects were confronted with the emotional stimuli. The purpose of this study was to test whether effective beta-adrenergic blockade occurring only after the stage of encoding has a similar impairing effect on memory. In a double blind experimental design, 60 healthy adult subjects received randomly one tablet of either propranolol (Inderal, 40 mg) or placebo. Drugs were administered just before the slide show begun and (in view of its pharmacokinetics) propranolol reaches peak levels 1 h after drug intake. Physiological arousal was monitored by heart rate and blood pressure. Half of the beta-blocker and placebo groups watched either a neutral or an arousal version of an 11-slide presentation. Memory performance was tested with a surprise free recall and recognition test 1 week later. Memory performance, specifically for the second phase in which emotional elements were introduced, was better in subjects who viewed the arousal version than subjects who saw the neutral version of the slide show. However, no effect of the beta-blocker condition was found. This experiment does not support a role for noradrenaline in the post-encoding phase and on the later processes of consolidation and retrieval. Although it remains possible that with a different dosage or timing protocol a post-treatment effect of noradrenaline in humans can be found, this experiment could not find support for it.