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Background:Sex steroids are essential for sexual maturation, linear growth and bone development. However, there is no consensus on the optimal timing, dosage and dosage interval of testosterone therapy to induce pubertal development and achieve a normal adult height and bone mass in children with hypogonadism.Case presentation:A monozygotic monochorial male twin pair, of which one boy was diagnosed with anorchia at birth due to testicular regression syndrome was followed from the age of 3 until the age of 18 years. Low dose testosterone substitution (testosterone esters 25 mg/2 weeks) was initiated in the affected twin based on the start of pubertal development in the healthy twin and then gradually increased accordingly. Both boys were followed until age 18 and were compared as regards to linear growth, sexual maturation, bone maturation and bone development. Before puberty induction both boys had a similar weight and height. During puberty, a slightly faster weight and height gain was observed in the affected twin. Both boys ended up however, with a similar and normal (near) adult height and weight and experienced a normal development of secondary sex characteristics. At the age of 17 and 18 years, bone mineral density, body composition and volumetric bone parameters at the forearm and calf were evaluated in both boys. The affected boy had a higher lean mass and muscle cross-sectional area. The bone mineral density at the lumbar spine and whole body was similar. Trabecular and cortical volumetric bone parameters were comparable. At one cortical site (proximal radius), however, the affected twin had a smaller periosteal and endosteal circumference with a thicker cortex.Conclusions:In conclusion, a low dose testosterone substitution in bilateral anorchia led to a normal onset of pubertal development and (near) adult height. Furthermore, there was no difference in bone mineral density at the age of 17 and 18 years.

We provide an update of bone health in trans persons on cross-sex hormonal therapy. This drastic hormonal reversal will have direct but also indirect effects on bone, through body composition changes.Recent evidence suggests that trans women, even before the start of any hormonal intervention, already have a lower bone mass, a higher frequency of osteoporosis, and a smaller bone size vs. natal men. During cross-sex hormonal treatment, bone mass was maintained or gained in trans women. In trans men, bone metabolism seemed to increase during short-term testosterone therapy, but no major changes have been found in bone density. On long-term testosterone therapy, larger cortical bone size was observed in trans men vs. natal women.Follow-up of bone health and osteoporosis prevention in trans persons is important. We advise active assessment of osteoporosis risk factors including the (previous) use of hormonal therapy. Based on this risk profile and the intended therapy, bone densitometry may be indicated. Long-term use of antiandrogens or gonadotropin-releasing hormone agonists alone should be monitored as trans women may have low bone mass, even prior to treatment. Therapy compliance with the cross-sex hormones is of major concern, especially after gonadectomy. Large-scaled, multicenter, and long-term research is needed to determine a well tolerated dosage of cross-sex hormonal treatment, also in elderly trans persons.

Although salivary testosterone (T) is often used in clinical studies accuracy is mostly questionable. State of the art data for men is sparse and for women absent. Our objective was to perform a critical evaluation of salivary T (Sal-T) as a method for indirect assessment of serum T using state of the art methods. Saliva was collected via ‘Salivette’ and ‘passive drooling’ methods. Sal-T and free T in serum after equilibrium dialysis were measured by LC-MS/MS Results Evaluation of Sal-T results versus free T by equilibrium dialysis (ED-T) for men gave: ‘Salivette’ Sal-T = 0.05 + 0.88 x ED-T, r = 0.43; ‘passive drooling’ Sal-T = 0.17 + 0.91 x ED-T r = 0.71. In women, correlation was comparable but values are higher than free T: ‘passive drooling’ Sal-T = 0.12 + 2.32 x ED-T, r = 0.70. The higher than expected T values in saliva, appear to be explained by T binding to salivary proteins. Iso-electric focusing of saliva proteins, followed by fractionation and LC–MS/MS assay of T showed marked testosterone peaks at pH 5.3 and 8.4, providing evidence for T binding in saliva to proteins such as albumin and proline rich protein (PRP). Conclusions Passive drooling is the collection method of choice for testosterone in saliva. Sal-T is not directly comparable to serum free T due to T binding to saliva proteins, which substantially affects the low Sal-T in women but not the higher Sal-T in healthy adult men.

Introduction Long‐term effects and side effects of cross‐sex hormone treatment in transsexual persons are not well known. Aim The aim of this study is to describe the effects and side effects of cross‐sex hormone therapy in both transsexual men and women. Main Outcome Measures Hormone levels were measured by immunoassays. Physical health was assessed by physical examination and questionnaires on general health and specific side effects, areal bone parameters by dual energy X‐ray absorptiometry. Methods Single center cross‐sectional study in 100 transsexual persons post‐sex reassignment surgery and on average 10 years on cross‐sex hormone therapy. Results Transsexual men did not experience important side effects such as cardiovascular events, hormone‐related cancers, or osteoporosis. In contrast, a quarter of the transsexual women had osteoporosis at the lumbar spine and radius. Moreover, 6% of transsexual women experienced a thromboembolic event and another 6% experienced other cardiovascular problems after on average 11.3 hormone treatment years. None of the transsexual women experienced a hormone‐related cancer during treatment. Conclusion Cross‐sex hormone treatment appears to be safe in transsexual men. On the other hand, a substantial number of transsexual women suffered from osteoporosis at the lumbar spine and distal arm. Twelve percent of transsexual women experienced thromboembolic and/or other cardiovascular events during hormone treatment, possibly related to older age, estrogen treatment, and lifestyle factors. In order to decrease cardiovascular morbidity, more attention should be paid to decrease cardiovascular risk factors during hormone therapy management. Wierckx K, Mueller, S, Weyers S, Van Caenegem E, Roef G, Heylens G, and T'Sjoen G. Long‐term evaluation of cross‐sex hormone treatment in transsexual persons. J Sex Med **;**:**–** .

Introduction Although sexual health after genital surgery is an important outcome factor for many transsexual persons, little attention has been attributed to this subject. Aims To provide data on quality of life and sexual health after sex reassignment surgery (SRS) in transsexual men. Methods A single‐center, cross‐sectional study in 49 transsexual men (mean age 37 years) after long‐term testosterone therapy and on average 8 years after SRS. Ninety‐four percent of the participants had phalloplasty. Main Outcome Measures Self‐reported physical and mental health using the Dutch version of the Short Form‐36 Health Survey; sexual functioning before and after SRS using a newly constructed specific questionnaire. Results Compared with a Dutch reference population of community‐dwelling men, transsexual men scored well on self‐perceived physical and mental health. The majority reported having been sexually active before hormone treatment, with more than a quarter having been vaginally penetrated frequently before starting hormone therapy. There was a tendency toward less vaginal involvement during hormone therapy and before SRS. Most participants reported an increase in frequency of masturbation, sexual arousal, and ability to achieve orgasm after testosterone treatment and SRS. Almost all participants were able to achieve orgasm during masturbation and sexual intercourse, and the majority reported a change in orgasmic feelings toward a more powerful and shorter orgasm. Surgical satisfaction was high, despite a relatively high complication rate. Conclusion Results of the current study indicate transsexual men generally have a good quality of life and experience satisfactory sexual function after SRS. Wierckx K, Van Caenegem E, Elaut E, Dedecker D, Van de Peer F, Toye K, Weyers S, Hoebeke P, Monstrey S, De Cuypere G, and T'Sjoen G. Quality of life and sexual health after sex reassignment surgery in transsexual men. J Sex Med **;**:**–**.

ObjectiveTo describe sexual desire in female-to-male transsexual persons post sex reassignment surgery (SRS). The associations between serum androgen levels and sexual desire are examined.DesignSingle center cross-sectional study.MethodsForty-five female-to-male transsexual persons post SRS completed a standardized questionnaire assessing sexual desire (Sexual Desire Inventory). In addition, participants were asked questions on sexual desire before starting hormone treatment and having SRS. Serum levels of testosterone, LH and sex hormone-binding globulin were measured on fasting morning serum samples.ResultsIn retrospect, 73.9% of the participants reported an increase in sexual desire after hormone treatment and SRS. Solitary sexual desire scores were significantly correlated with frequency of masturbation (r=0.835;PPPost hocanalysis revealed that female-to-male transsexual persons with elevated levels of LH, indicating suboptimal testosterone therapy, reported significantly lower solitary sexual desire levels (than those with low LH levels;P=0.007). Suppressed LH levels were also associated with having a higher need for sexual activities (P=0.009) and a higher frequency of excessive sexual desire (P=0.007).ConclusionMost female-to-male transsexual persons report on a marked increase in sexual desire after testosterone treatment and SRS. No direct associations between levels of testosterone and solitary or dyadic sexual desire were found. However, measures of sexual desire were inversely associated with LH levels.

Introduction Karyotyping is often performed in transsexual individuals. Aim Quantification and characterization of karyotype findings and abnormalities in transsexual persons. Main Outcome Measures Karyotypes were listed both in male‐to‐female and in female‐to‐male transsexual persons. Methods The data were collected through a retrospective study. Results Karyotypes of 368 transsexual individuals (251 male‐to‐female, 117 female‐to‐male) are described. Normal findings were found in 97.55%. Prevalence of abnormal karyotypes was 3.19% among male‐to‐female, and 0.85% among female‐to‐male transsexuals. Nine karyotypes showed variations; Klinefelter syndrome was confirmed in three persons, whereas others displayed autosomal aberrations. Conclusion Karyotyping is only of very limited information in the transsexual population. Inoubli A, De Cuypere G, Rubens R, Heylens G, Elaut E, Van Caenegem E, Menten B, and T'Sjoen G. Karyotyping, is it worthwhile in transsexualism?

Gender nonconformity refers to the extent to which a person's gender identity, gender role and/or gender expression differs from the cultural norms prescribed for people of a particular sex, within a certain society and era. Most data on gender nonconformity focus on the prevalence of gender dysphoria (which also includes a distress factor) or on the number of legal sex changes. However, not every gender nonconforming individual experiences distress or applies for treatment. Population-based research on the broad spectrum of gender nonconformity is scarce and more information on the variance outside the gender binary is needed. This study aimed to examine the prevalence of gender incongruence (identifying stronger with the other sex than with the sex assigned at birth) and gender ambivalence (identifying equally with the other sex as with the sex assigned at birth) based on two population-based surveys, one of 1,832 Flemish persons and one of 2,472 sexual minority individuals in Flanders. In the general population, gender ambivalence was present in 2.2 % of male and 1.9 % of female participants, whereas gender incongruence was found in 0.7 % of men and 0.6 % of women. In sexual minority individuals, the prevalence of gender ambivalence and gender incongruence was 1.8 and 0.9 % in men and 4.1 and 2.1 % in women, respectively. With a current Flemish population of about 6 million, our results indicate a total of between 17,150 and 17,665 gender incongruent men and between 14,473 and 15,221 gender incongruent women in Flanders.

Serum levels of brain-derived neurotrophic factor (BDNF) are reduced in male-to-female transsexual persons (MtF) compared to male controls. It was hypothesized before that this might reflect either an involvement of BDNF in a biomechanism of transsexualism or to be the result of persistent social stress due to the condition. Here, we demonstrate that 12 month of cross-sex hormone treatment reduces serum BDNF levels in male-to-female transsexual persons independent of anthropometric measures. Participants were acquired through the European Network for the Investigation of Gender Incongruence (ENIGI). Reduced serum BDNF in MtF thus seems to be a result of hormonal treatment rather than a consequence or risk factor of transsexualism.

Introduction Data on the effects of cross‐sex hormone therapy (CHT) are limited due to the low prevalence of gender dysphoria, small number of subjects treated at each center, lack of prospective studies, and wide variations in treatment modalities. Aim The aim of this study is to report the short‐term effects of CHT on hormonal and clinical changes, side effects, and adverse events in trans men (female‐to‐male gender dysphoric persons) and trans women (male‐to‐female gender dysphoric persons). Methods This was a multicenter 1‐year prospective study in 53 trans men and 53 trans women. Trans men received injections of testosterone undecanoate every 3 months. Trans women younger than 45 years received 50 mg cyproterone acetate (CA) and 4 mg estradiol valerate daily, whereas those older than 45 years received 50 mg CA daily together with 100 μg/24 hours transdermal 17‐β estradiol. Main Outcome Measures Sex steroids, prolactin, liver enzymes, lipids, hematocrit, blood pressure, anthropometrics, Ferriman and Gallwey score, and global acne grading scale were measured. Side effects, adverse events, and desired clinical changes were examined. Results No deaths or severe adverse events were observed. Two trans men developed erythrocytosis, and two had transient elevation of the liver enzymes. Trans men reported an increase in sexual desire, voice instability, and clitoral pain (all P ≤ 0.01). Testosterone therapy increased acne scores, facial and body hair, and prevalence of androgenetic alopecia. Waist–hip ratio, muscle mass, triglycerides, total cholesterol (C), and LDL‐C increased, whereas total body fat mass and HDL‐C decreased. Three trans women experienced transient elevation of liver enzymes. A significant increase in breast tenderness, hot flashes, emotionality, and low sex drive was observed (all P ≤ 0.02). Fasting insulin, total body fat mass, and prolactin levels increased, and waist–hip ratio, lean mass, total C, and LDL‐C decreased. Conclusions Current treatment modalities were effective and carried a low risk for side effects and adverse events at short‐time follow‐up. Wierckx K, Van Caenegem E, Schreiner T, Haraldsen I, Fisher A, Toye K, Kaufman JM, and T'Sjoen G. Cross‐sex hormone therapy in trans persons is safe and effective at short‐time follow‐up: Results from the European Network for the Investigation of Gender Incongruence. J Sex Med 2014;11:1999–2011.

Our knowledge concerning the effects of testosterone (T) therapy on the skin of trans men (female-to-male transsexuals) is scarce.The aim of this study was to evaluate the short- and long-term clinical effects of T treatment on the skin of trans men.We conducted a prospective intervention study in 20 hormone naive trans men and a cross-sectional study in 50 trans men with an average of 10 years on T therapy.Acne lesions were assessed using the Gradual Acne Grading Scale, hair patterns using the Ferriman and Gallwey classification (FG), and androgenetic alopecia using the Norwood Hamilton Scale.T treatment increased facial and body hair growth. The FG score increased progressively from a median value of 0.5 at baseline to a value of 12 after 12 months of T administration. After long-term T treatment, all but one trans man achieved an FG score indicative of hirsutism in women, with a median value of 24. Only one trans man acquired mild frontotemporal hair loss during the first year of T treatment, whereas 32.7% of trans men had mild frontotemporal hair loss and 31% had moderate to severe androgenetic alopecia after long-term T therapy. The presence and severity of acne increased during the first year of T therapy, and peaked at 6 months. After long-term T treatment, most participants had no or mild acne lesions (93.9%). Dermatological outcome was not demonstrably related to individual serum T or dihydrotestosterone levels.T treatment increased facial and body hair in a time-dependent manner. The prevalence and severity of acne in the majority of trans men peaked 6 months after beginning T therapy. Severe skin problems were absent after short- and long-term T treatment.

Background: Hormonal therapy and sex reassignment surgery (SRS) in transsexual persons lead to an irreversible loss of their reproductive potential. The current and future technologies could create the possibility for female-to-male transsexual persons (transsexual men) to have genetically related children. However, little is known about this topic. The aim of this study is to provide information on the reproductive wishes of transsexual men after SRS. Methods: A self-constructed questionnaire was presented to 50 transsexual men in a single-center study. Results: The majority (64%) of transsexual men were currently involved in a relationship. Eleven participants (22.0%) reported having children. For eight participants, their female partner was inseminated with donor sperm, whereas three participants gave birth before hormonal therapy and SRS. At the time of interview, more than half of the participants desired to have children (54%). There were 18 participants (37.5%) who reported that they had considered freezing their germ cells, if this technique would have been available previously. Participants without children at the time of investigation expressed this desire more often than participants with children (x2 test: P ¼ 0.006). Conclusions: Our data reveal that the majority of transsexual men desire to have children. Therefore, more attention should be paid to this topic during the diagnostic phase of transition and to the consequences for genetic parenthood after starting sex reassignment therapy.

Male-to-female (M--F) transsexual persons undergo extreme changes in gonadal hormone concentrations, both by pharmacological and surgical interventions. Given the importance of sex steroids for developing and maintaining bone mass, bone health is a matter of concern in daily management of these patients.To provide data on bone metabolism, geometry and volumetric bone mineral density in M--F transsexual persons.Twenty-three M--F transsexual persons, recruited from our gender dysphoria clinic and at least 3 yrs after sex reassignment surgery, together with 46 healthy age- and height-matched control men were included in this cross-sectional study.Body composition, areal and volumetric bone parameters determined using DXA and peripheral quantitative computed tomography. Hormone levels and markers of bone metabolism assessed using immunoassays. Peak torque of biceps and quadriceps muscles and grip strength assessed using an isokinetic and hand dynamometer, respectively.M--F transsexual persons presented lower total and regional muscle mass and lower muscle strength as compared to controls (all P0.001). In addition, they had higher total and regional fat mass (P0.010) and a lower level of sports-related activity index (P0.010). Bone mineral content and areal density (aBMD) of the lumbar spine, total hip and distal radius, as well as trabecular vBMD of the distal radius was lower as compared to controls (P0.010). At cortical sites, no differences in cortical vBMD were observed, whereas M--F transsexual persons were characterized by smaller cortical bone size at both the radius and tibia (P0.010). Lower levels of biochemical markers of bone formation and resorption (P0.010) suggested decreased bone turnover.M--F transsexual persons have less lean mass and muscle strength, and higher fat mass. In addition, they present lower trabecular vBMD and aBMD at the lumbar spine, total hip and distal radius, and smaller cortical bone size as compared to matched controls. Both the lower level of sports-related physical activity as well testosterone deprivation could contribute to these findings. These results indicate that bone health should be a parameter of interest in the long-term follow-up care for M--F transsexual persons.