Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations.
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Biomedical subjects
Publications and source records attributed to L J Gooren.
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In the last decade, transsexual patients have increasingly sought sex reassignment (cross-sex hormones and sex reassignment surgery), whilst avoiding adequate diagnostic procedures. They ask non-specialized physicians to prescribe hormones or to perform sex reassignment surgery. Sometimes hormones are ordered through the Internet or obtained from other illegitimate sources. If these patients later turn to a specialized team (for instance for sex reassignment surgery), the obligatory standard diagnostic procedure is problematic: the patient does not accept having to go through a long period of assessment and objective decisionmaking, while the attending health professional feels pressured by the patient's impatience. Non-expert health professionals should draw patients' attention to the necessity of a thorough diagnostic procedure, thus avoiding wrong decisions and future regrets.
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OBJECTIVE: To report the experience with treatment of hypogonadal men with the scrotal application of testosterone patches. DESIGN: Prospective and descriptive. METHOD: In 12 unselected hypogonadal men (aged 27-58 years; serum concentration of testosterone < 10 nmol/l) who complained of adverse effects of oral androgen treatment, the treatment was changed to scrotal application of testosterone patches (Testoderm). First the androgen substitution was stopped for 6 weeks. Follow-up was 4-5 years, during which regular laboratory tests were carried out, the patients filling in questionnaires regarding their general mood and the frequency of sexual feelings/activities. RESULTS: Testosterone levels reached physiological values and a beneficial effect was observed on general mood and sexual functioning. These effects remained stable throughout the entire period of 4-5 years of study. Skin reactions occurred in 2 men. Dihydrotestosterone levels increased to supraphysiological values. Other clinical, biochemical and haematological parameters did not reveal any detrimental effects. The patch, which should be applied to a dry and shaved scrotal skin, was a satisfying androgen replacement therapy for more than 4 years in 7 out of 12 men. CONCLUSION: In this open study in hypogonadal men with complaints about previous testosterone therapy, scrotal testosterone patches were a useful therapy, leading to the testosterone levels in the physiological range.
For more than ten years transsexual adolescents have been diagnosed and treated psychologically at the department of Child and Adolescent Psychiatry, University Medical Centre in Utrecht, the Netherlands. The medical part of the treatment takes place at the Academic Hospital of the Free University of Amsterdam. Diagnosis is done in two phases: the first diagnostic phase and the 'real life test'. In this second phase the ability to live in the opposite gender role is tested. Gender dysphoric non-transsexual adolescents are offered psychological or psychiatric interventions. For transsexual adolescents with the express wish to undergo a sex change two types of hormones are prescribed. First, hormones which halt the own pubertal development, then cross-sex hormones with irreversible effects. Surgery for adolescents is not different from surgery for adults. Although the cause of transsexuality is probably impaired sexual differentiation at cerebral level, it appears that the risk of unjustified treatment is higher when the treatment is administered at an early age than in adults; justified treatment, however, has better results when it is administered at an early age.
Blood pressure varies during the menstrual cycle, but the reason for this is unclear. Administration of (synthetic) sex hormones can influence the level of vasoactive substances such as endothelin (ET). However, it is not known whether short-term variations in sex hormone levels in physiological situations affect ET levels. We assessed the effects of the menstrual cycle on plasma ET-1 in 8 healthy premenopausal women not using oral contraceptives (OCs) and 8 premenopausal women using OCs. ET-1 levels were measured in all subjects on days 1 to 3 (menstrual phase), 9 to 12 (follicular phase), and 20 to 23 (luteal phase) of the menstrual cycle. ET-1 levels remained constant in OC users (2.4 +/- 0.4, 2.6 +/- 0.4, and 2.4 +/- 0.4 pg/mL on days 1 to 3, 9 to 12, and 20 to 23 of the pill cycle). In contrast, ET-1 levels in non-OC users decreased in all women during the follicular and luteal phase of the menstrual cycle compared with the menstrual (low-estrogenic) phase (3.6 +/- 0.5, 2.8 +/- 0.5, and 2.9 +/- 0.3 pg/mL for the menstrual, follicular, and luteal phase, respectively, P < .01 for menstrual vfollicular and P < .01 for menstrual v luteal). The differences between OC users and nonusers were significant in the menstrual phase of the cycle (P < .01). We conclude that ET levels fluctuate during the menstrual cycle. Previously reported effects of the menstrual cycle on blood pressure may be partly explained by the effects of sex hormones on the level of vasoactive mediators. This fluctuation is not present in OC users. Studies on hemodynamic parameters in premenopausal women should account for hormonal variations in the various phases of the menstrual cycle.
It has been proposed that gender identity and sexual orientation are influenced by the prenatal sex steroid milieu. Human dermatoglyphics and brain asymmetry have also been ascribed to prenatal hormone levels. This study investigated dermatoglyphics (total ridge count and finger ridge asymmetry) in 184 male-to-female transsexuals and 110 female-to-male transsexuals. In a subgroup, the relationship between dermatoglyphic asymmetry and spatial ability was tested. All investigations included controls. For all subjects hand preference and sexual orientation were noted. We hypothesized that the dermatoglyphics of male-to-female transsexuals would show similarities with control women and those of female-to-male transsexuals with control men. Our results showed a trend for a sex difference in total ridge count (P<.1) between genetic males and females, but no difference in directional asymmetry was found. Contrary to our expectations, the total ridge count and finger ridge asymmetry of transsexuals were similar to their genetic sex controls. Additionally, directional asymmetry was neither related to sexual orientation, nor to different aspects of spatial ability. In conclusion, we were unable to demonstrate that our chosen dermatoglyphic variables, total ridge count and finger ridge asymmetry are related to gender identity and sexual orientation in adult transsexuals. Hence, we found no support for a prenatal hormonal influence on these characteristics, at least insofar as dermatoglyphics may be regarded as a biological marker of organizing hormonal effects.
A role for sex steroids in the pathogenesis of AS is suggested by the male predominance, the peak age of onset in young adults, the increased number of first manifestations and flares after pregnancy, and the fact that sex steroids may modulate immune functions. There is a theoretic possibility that (normal levels of) androgens are indeed relevant in the male sex skew of AS. It has been reported that men with AS have higher than normal androgen levels; however, the evidence that serum testosterone levels are elevated in patients with AS is not robust. Elevated DHEAS and 17 alpha-hydroxyprogesterone levels have been reported in male AS patients; these may be secondary to inflammation and stress but may theoretically also be causally related to AS. These elevations might result from a partial late onset 11 beta- or 21-hydroxylase deficiency. Current data on sex steroid hormones provide no straightforward explanation for the male predominance in AS. It is fair to say that present data in patients with long-standing AS are too limited to suggest a role for androgens in the perpetuation of the disease, but a role in the initiation and the early stages of AS cannot be excluded. Such information can only be obtained from prospective studies. Cross-sectional studies cannot clearly distinguish causal relation from secondary disease effects, because blood sampling to test these hypotheses only takes place many years after the onset of disease. The impact of sex steroids on these features of AS is still unresolved. There is as yet no rationale for the use of medication that modifies sex steroid hormones in the management of AS. Alternative explanations for the higher male prevalence of AS may be found in the different chromosomal configuration and body composition of men and women.
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Oral estrogen administration decreases plasma levels of tissue-type plasminogen activator (tPA), which may be explained by a decrease in endothelial tPA synthesis, an increase in its hepatic clearance, or both. In the present study, we determined (1) differences between oral (ie, via the liver) ethinyl estradiol and transdermal (ie, systemic) 17beta-estradiol administration on plasma antigen levels of tPA and plasminogen activator inhibitor type-1 before and after 4 months of hormone administration and (2) effects on endothelial tPA synthesis, by measuring the local increase in plasma tPA during venous occlusion of the upper extremity. Thirty transsexual males (median age 32 years, range 20 to 44 years ) were randomly assigned to either oral ethinyl estradiol (n=15) or transdermal 17beta-estradiol (n=15); both treatments included the antiandrogen cyproterone acetate (CA). Ten males were treated with CA alone. Seventeen transsexual females (median age 27 years, range 18 to 37 years) were treated with intramuscular testosterone esters. Only oral ethinyl estradiol plus CA but neither transdermal 17beta-estradiol plus CA, nor oral CA, nor parenteral testosterone lowered plasma tPA and plasminogen activator inhibitor-1 (P<0.001 for both). tPA release during venous occlusion was not affected by oral ethinyl estradiol plus CA in males (P=0.52) or by parenteral testosterone in females (P=0.89). These data are consistent with a previous observation, in rodents, that the decrease in tPA after oral estrogen administration can be explained by an increase in hepatic tPA clearance, leaving endothelial tPA synthesis unchanged, and suggest that these mechanisms also explain the decrease in tPA in humans.
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The female predominance in several autoimmune diseases suggests a role for sex steroid hormones in disease susceptibility. We therefore investigated to what extent sex hormones would influence immune responsiveness. We analyzed T helper type 1 (TH1) and type 2 cytokine patterns, chemokine receptor expression (n = 2 x 10), and Ig levels (n = 2 x 25) in transsexual men and women before and after 4 months of cross-sex hormone administration. Antithyroperoxidase levels were compared between 186 transsexual males (treated >5 yr with estrogens) and 186 male controls. In men, estrogens plus antiandrogens increased free cortisol levels in 24-h urine samples, decreased natural killer cell numbers, and slightly inhibited the mitogen-induced interferon-gamma/interleukin-4 ratio, but up-regulated the expression of TH1-associated chemokine receptors, CCR1, CXCR3, and CCR5. Conversely, in women, androgens slightly decreased free cortisol levels in 24-h urine samples and enhanced the mitogen-induced interferon-gamma/interleukin-4 ratio and tumor necrosis factor-alpha production. At the single cell level no TH 1/TH2 shifts were found. Remarkably, up-regulation of TH1 cytokines was accompanied by down-regulation of CCR1, CXCR3, and CCR5 expression. Neither CD4+ lymphocyte numbers nor IgG, IgM, and antithyroperoxidase levels, although higher in women then in men, were affected by cross-sex hormonal treatment. These results demonstrate that the capacity to develop a TH1 phenotype of peripheral blood lymphocytes is stimulated by androgens and is slightly inhibited by estrogens. These changes may be direct or indirect through the effects on other hormones.
Transsexuals experience themselves as being of the opposite sex, despite having the biological characteristics of one sex. A crucial question resulting from a previous brain study in male-to-female transsexuals was whether the reported difference according to gender identity in the central part of the bed nucleus of the stria terminalis (BSTc) was based on a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide innervation from the amygdala, which was used as a marker. Therefore, we determined in 42 subjects the number of somatostatin-expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity, and past or present hormonal status. Regardless of sexual orientation, men had almost twice as many somatostatin neurons as women (P < 0.006). The number of neurons in the BSTc of male-to-female transsexuals was similar to that of the females (P = 0.83). In contrast, the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.
To investigate androgen effects on the skin pilosebaceous unit, we studied 21 male-to-female transsexuals and 17 female-to-male transsexuals receiving cross-sex hormones. At baseline and after 4, 8, and 12 months, hair growth was evaluated by the Ferriman-Gallwey score; acne by the Leeds classification; hair growth rate, density, and shaft diameter by image analysis; and sebum production by Sebutape. In males, estrogens and antiandrogens reduced plasma testosterone to below 1.0 nmol/L. Though all parameters of hair growth and sebum production declined, facial hair growth continued. After 4 months, the decrease in shaft diameter had reached its maximum and seemed inversely associated with changes in hair growth length and density. In females, testosterone increased hair growth rate and sebum production. After 12 months, hairs on the cheek and abdomen had not yet reached diameters found in males. 5alpha-Androstane-3alpha,17beta-diol glucuronide levels were only weakly associated with hair growth and sebum production. In conclusion, administration of estrogens and antiandrogens affects length and diameter of hairs at different rates. In the virtual absence of androgens, hair growth continues but at a slower rate. In women, after 12 months of androgen administration, hair diameters have not reached values of adult men.
BACKGROUND: The genes that encode prostate-specific antigen (PSA) and human glandular kallikrein (hK2) are up-regulated by androgens and progestins in cultured cells, but no published studies have described the effect of androgen administration in women on serum and urinary PSA or hK2. METHODS: We measured serum and urinary PSA and hK2 before, and 4 and 12 months post testosterone treatment by immunofluorometric methods in 32 female-to-male transsexuals. RESULTS: Mean serum PSA increased from 1.1 ng/L to 11.1 ng/L and then to 22 ng/L by 4 and 12 months post treatment, respectively; the corresponding mean values in urine were 17, 1420, and 18 130 ng/L, respectively. Serum hK2, another kallikrein closely related to PSA, remained undetectable at the three time points. However, urinary hK2 concentration rose from below the detection limit (<6 ng/L) before treatment to 18 and 179 ng/L by the 4th and the 12th month of treatment, respectively. All changes were statistically significant (P <0.001) at 4 months. CONCLUSIONS: Testosterone administration increases serum and urinary PSA and urinary hK2 in women. These measurements may be useful as indicators of androgenic stimulation in women.