Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body Composition and Bone Metabolism

Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body... Abstract Context Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth. Objective To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively. Design and Outcome Measurements Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones. Results Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [−2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: −0.765 to −1.145 (P = 0.002)]. L did not affect physiological bone development. Conclusion Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy. Worldwide, the number of children and adolescents presenting with gender incongruence (GI) is increasing (1). In children with persistent GI, gonadotropin-releasing hormone analogs (GnRHa), after multidisciplinary evaluation and a variable period of psychological support, are commonly used to arrest pubertal development. GnRHa suppress gonadotropin secretion and thus the gonadal production of sex hormones and the development of secondary sex characteristics of the gender recorded at birth (2). GnRHa have been reported to increase fat mass and reduce lean mass in both transgender (trans) boys and trans girls (3). In addition, concerns have been raised about the negative impact of this treatment on bone health, particularly bone mass accrual in trans girls, which may not be fully compensated by subsequent addition of cross-sex hormones (CSH) (4, 5). If secondary sex characteristics have already developed at the time GI is diagnosed, the focus of treatment shifts toward reducing the burden of isosexual pubertal signs, such as menstruation in trans boys or erections and facial and body hair growth in trans girls, while awaiting the start of CSH treatment—usually around the age of 16 years, although strict application of this age criterion is under debate. Apart from GnRHa treatment, menstruation in girls and erections and hair growth in boys can also successfully be suppressed with proandrogenic and antiandrogenic progestins such as lynestrenol (L) or cyproterone acetate (CA), respectively, provided that these drugs are available (6, 7). The low cost of progestins is an advantage over the expensive GnRHa, especially in circumstances in which these drugs are not reimbursed. L is a proandrogenic progestin that increases the endogenous serum testosterone/estradiol ratio, thereby interfering with the menstrual cycle and inducing amenorrhea, especially at higher doses (10 mg/d) (6). The antiandrogenic progestin CA is a competitive androgen receptor blocker resulting in decreased androgenic effects (7–9). Antiandrogens such as CA have previously been shown to decrease lean body mass and increase total body fat in adult trans women (10, 11), and in some adult transgender teams, proandrogenic and antiandrogenic progestins are used prior to CSH or in association with CSH as an adjuvant therapy (10, 12). It has not been investigated whether the proandrogenic and antiandrogenic effects of L and CA affect anthropometry and body composition in trans adolescents and/or have less deleterious effects on bone mass accrual as compared with GnRHa treatment. If these progestins indeed induce bodily changes toward the desired appearance in addition to suppressing endogenous pubertal signs in late pubertal adolescents, they may, in line with adult treatment regimens, represent a first step toward CSH treatment in this specific population. The aim of this study is to prospectively assess anthropometry, body composition, and bone mass changes in late-pubertal trans boys and trans girls who, respectively, received L or CA to attenuate endogenous pubertal hormone effects while awaiting CSH therapy. This will contribute to determining the place of GnRHa and progestins, respectively, in the pharmacological treatment of trans youth and to improving our knowledge on the long-term effects of these interventions, as has been suggested recently (2). Subjects and Methods Participants and treatments Sixty-five late-pubertal (Tanner stage B4/G4) trans adolescents (44 trans boys and 21 trans girls) who used progestins between March 2011 and January 2017 were included in the study. The cohort of participants in this study partially overlaps with cohorts of our previous reports on progestin-induced biochemical and hormonal changes in trans adolescents (6, 7). According to our local protocol, CSH can be added to this treatment from the age of 16 years onward and after a period of progestin use of ∼6 months. In all subjects presenting before or in early puberty (Tanner stages B2 to 3/G2 to 3), GnRHa instead of progestins are used to arrest further pubertal development. Biochemical parameters and data on muscle strength, body composition, and bone mass were collected at the start of L/CA (baseline) and before addition of CSH. The diagnosis of GI was made by a child psychologist and child psychiatrist and based on the diagnostic criteria as described in the Diagnostic and Statistical Manual of Mental Disorders 4th edition, and, later, the 5th edition, and the International Classification of Diseases 10th edition (13). The decision to start medical treatment was made by the multidisciplinary child gender team of Ghent University Hospital. A daily dose of 5 to 10 mg L (Orgametril®; MSD Belgium, Brussels, Belgium) or 50 mg CA (Androcur®; Bayer, Leverkusen, Germany) was given orally in trans boys and trans girls, respectively. In all individuals, vitamin D supplementation [cholecalciferol 25,000 IU/mo (D-CURE®; SMB Laboratories, Brussels, Belgium)] was added to the treatment, and all were advised to pursue a daily dietary calcium intake of at least 1500 mg. Methods Investigations were performed twice (i.e., before initiation of L or CA and prior to addition of CSH) and consisted of the following: anthropometric measurements, a fasting venous blood sample (between 0800 h and 0900 h), a spot urine sample, dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT) scans, and grip-strength measurements. Approval of the study by the ethics committee of Ghent University Hospital was obtained (B670201525328). Anthropometrics Body weight was measured to the nearest 0.1 kg in light, indoor clothing without shoes. A wall-mounted Harpenden stadiometer (Holtain, Ltd, Crymuch, United Kingdom) was used to measure height. Waist circumference was measured between the lower rib and the iliac crest at the end of expiration; hip circumference was measured at the widest gluteal circumference. Both measurements were performed twice. The mean of both measurements was used for analysis. SD scores of height, weight, and body mass index (BMI) were calculated based on published data obtained in Flemish peers of the same gender recorded at birth (14). Serum analyses Sex hormone–binding globulin (SHBG), total testosterone, free testosterone, total estradiol, total testosterone/estradiol ratio, follicle-stimulating hormone, luteinizing hormone, serum 25-OH vitamin D, parathyroid hormone (PTH), serum C-terminal telopeptide (s-CTX), and procollagen type I N-terminal propeptide (PINP) were measured. Electrochemiluminescence assays (Roche Diagnostics E170 Modular; Roche Diagnostics, Indianapolis, IN) were used for all parameters, except total testosterone, for which liquid chromatography–tandem mass spectrometry was used. Free testosterone was calculated as described by Vermeulen et al. (15). The detection limit for estradiol was 25 ng/L; in case of values below this limit, the limit itself was input for statistical analysis. Urinary calcium/creatinine ratio (UCa/Cr) was calculated from the calcium and creatinine levels as measured on a urine spot sample. Grip strength An adjustable handheld standard grip device (JAMAR hand dynamometer; Sammons and Preston, Bolingbrook, IL) was used to determine grip strength on both the dominant and nondominant hand. Grip strength was measured three times on both hands. The highest value was assumed to represent the maximum strength and was input for analyses. Z scores were calculated based on data published by Ortega et al. (16). DXA scans A Hologic Discovery device (Software Version 11.2.1; Hologic, Inc., Bedford, MA) was used to assess body composition of the total body minus head (total, lean, and fat mass), bone mineral content (BMC), areal bone mineral density (aBMD) and projected bone area of the spine, left proximal femur (femoral neck and total hip), and whole body. Z scores of DXA scan parameters were based on data from the National Health and Nutrition Examination Survey (NHANES) and Bone Mineral Density in Childhood Study (17, 18). Z scores of aBMD were calculated by the manufacturer’s software based on age-matched adolescents of the same gender recorded at birth; Z scores of percentage body fat and aBMD of the experienced gender were calculated manually based on the data from the NHANES study, kindly provided by Hologic, Inc. pQCT scans A pQCT device (XCT-2000; Stratec Medizintechnik, Pforzheim, Germany) was used to evaluate both the trabecular and cortical volumetric bone mineral density (vBMD) and bone geometry at the nondominant radius, and the left tibia measured at 4% and 66% and 4% and 38%, respectively, of bone length from distal. Polar strength strain index (SSIp) was calculated based on geometrical and material properties at the nondominant radius at 66%. Muscle and fat area were measured at the midshaft radius of the nondominant arm and left tibia (at the 66% and 38% sites, respectively). Z scores of the radius were calculated by the manufacturer’s software. Z scores of the tibia were calculated manually using the formulas published by Roggen et al. (19) based on results of the same pQCT device and enabled the calculation of Z scores of periosteal and endosteal circumference (which are not available at the radius). All Z scores were based on age-matched adolescents of the same gender recorded at birth. Manual calculation of Z scores was performed using the following formulae:  Z=M((XM)L−1)Lσ or Z=X−Mσ,in which X is the physical measurement, L the age-matched skewness value, M the median age-matched reference value, and σ the age-matched population SD. Statistical analyses Statistical analysis was performed using an IBM SPSS software package (version 23). A P value of <0.05 was considered significant. Mean values and SD or medians and interquartile ranges are given, with Gaussian and non-Gaussian distributions, respectively (based on a Shapiro-Wilk test). A paired Student t test or Wilcoxon signed-ranks test was used after testing for normality with a Shapiro-Wilk test, to compare data prior to initiation of progestins and before initiation of CSH. Four of the 44 trans boys used an oral contraceptive prior to starting with L. Data for these adolescents were excluded from the hormonal analyses. Because unpaired Student t tests/Mann–Whitney U test (depending on the results of a Shapiro-Wilk test) revealed similar body composition parameters and similar changes in bone parameters, those data were included in all other analyses. Results Sixty-five adolescents (44 trans boys and 21 trans girls) were included in the study. At the start of progestin treatment, mean chronological and bone age were 16.2 ± 1.05 and 16.4 ± 1.08 years in trans boys and 16.3 ± 1.21 and 17.1 ± 1.28 years in trans girls, respectively (Table 1). The mean time interval between both examinations was 11.64 (4 to 40) months in trans boys and 10.57 (5 to 31) months in trans girls, respectively. Table 1. Descriptive Statistics   Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28    Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28  View Large Table 1. Descriptive Statistics   Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28    Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28  View Large Serum analyses Mean total testosterone and estradiol levels decreased with progestin treatment in both groups (Table 2). However, the total testosterone-to-estradiol ratio decreased significantly in trans girls (P = 0.008) but not in trans boys (P = 0.068). Because of the decreased SHBG levels, free testosterone levels increased in trans boys. In trans girls, SHBG remained stable, resulting in decreased free testosterone levels (P = 0.010). Gonadotropin levels decreased only in trans boys. Serum levels of PINP, a marker for bone formation, decreased by 9.3% in trans boys and 46.5% in trans girls. In the latter group, s-CTX levels, a marker for bone resorption, also decreased by 17.1%. Mean vitamin D levels before initiation of treatment were in the range of vitamin D insufficiency (i.e., <20 ng/mL): 17.72 ng/mL in trans boys and 17.34 ng/mL in trans girls; mean levels increased in both groups following supplementation. PTH levels decreased in both groups; however, this was only significant in trans boys versus trans girls (P = 0.001 and 0.113, respectively). UCa/Cr showed a decrease in trans boys (P < 0.001) and an increase in trans girls (P = 0.035). Table 2. Summary of Serum Markers Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Data are mean ± SD or median (interquartile range). Abbreviations: After L or CA, mean/median levels before start of CSH; Before L or CA, mean/median values before start of progestin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T/E ratio, testosterone/estradiol ratio; Vitamin D, 25-OH vitamin D. a P < 0.05. View Large Table 2. Summary of Serum Markers Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Data are mean ± SD or median (interquartile range). Abbreviations: After L or CA, mean/median levels before start of CSH; Before L or CA, mean/median values before start of progestin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T/E ratio, testosterone/estradiol ratio; Vitamin D, 25-OH vitamin D. a P < 0.05. View Large Anthropometrics Trans boys grew on average 0.8 cm and gained 2.65 kg during the study period; weight and BMI gain were more pronounced than in age-matched female peers (P = 0.001) (Table 3). Both waist and hip circumference increased (P < 0.001 and 0.002) as well as waist/hip ratio (WHR) (P = 0.041). Table 3. Anthropometrics   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306  Data are mean ± SD or median (interquartile range). Z scores are mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), and after CA (16.0–19.1), based on data published by Roelants et al. (14). Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a These rows represent reference values of age-matched peers of the same gender recorded at birth. b P < 0.05. View Large Table 3. Anthropometrics   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306  Data are mean ± SD or median (interquartile range). Z scores are mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), and after CA (16.0–19.1), based on data published by Roelants et al. (14). Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a These rows represent reference values of age-matched peers of the same gender recorded at birth. b P < 0.05. View Large Trans girls treated with CA grew on average 0.7 cm and gained 2.33 kg; weight and BMI changes were similar to age-matched male peers. Their waist and hip circumference only showed slight increases, resulting in a stable WHR. Body composition and grip strength In trans boys, lean mass (Fig. 1C), opposite to fat mass (Fig. 1D), significantly increased, leading to an increased total body mass (Fig. 1B) and decreased body fat percentage, significantly differing from their age-matched female peers, as calculated from population-based Z scores of the percentage of body fat (P = 0.010) (Supplemental Table 1). Muscle area increased at the nondominant forearm and left lower leg (radius, 66% and tibia, 38%). This increase at the forearm was higher than what was observed in age-matched peers of the same gender recorded at birth, based on Z scores (P < 0.001). There were no changes in forearm and lower leg fat area (Supplemental Table 1). An increase in grip strength was noted in the dominant and nondominant hand. This increase was higher than in age-matched peers of the same gender recorded at birth (P < 0.001) (Fig. 1A; Supplemental Table 1). Figure 1. View largeDownload slide Changes in grip strength and body composition. Box and whisker plots of (A) delta grip strength of the dominant hand, (B) delta total mass, (C) delta lean mass, and (D) delta fat mass. Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Figure 1. View largeDownload slide Changes in grip strength and body composition. Box and whisker plots of (A) delta grip strength of the dominant hand, (B) delta total mass, (C) delta lean mass, and (D) delta fat mass. Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Trans girls treated with CA showed a significant increase in fat mass (Fig. 1D) and decrease in lean mass (Fig. 1C), resulting in an increased body fat percentage (P < 0.001), without changes in total mass (P = 0.167) (Fig. 1B). This increase was higher than observed in their age-matched male peers, based on Z scores (P = 0.001) (Supplemental Table 1). At the nondominant forearm and left lower leg (radius, 66% and tibia, 38%), muscle area decreased, whereas fat area markedly increased. Based on Z scores, the changes of muscle and fat area at the forearm are different from their age-matched peers of the same gender recorded at birth (Supplemental Table 1). No significant changes in grip strength were observed in trans girls during the study period (Fig. 1A), resulting in decreased Z scores compared with age-matched peers of the same gender recorded at birth (P = 0.004 and 0.056) (Supplemental Table 1). Bone changes In trans boys, aBMD of the total hip, femoral neck, lumbar spine, and whole body before the start of L were slightly lower compared with population-based references for the same age and gender recorded at birth (Z scores: −0.162, −0.271, −0.320, and −0.783, respectively) (Table 4). Table 4. Summary of DXA Measurements   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a  Data are mean ± SD or median (interquartile range). Z scores: mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), after CA (16.0–19.1), based on data from the NHANES (17) and Bone Mineral Density in Childhood Study (18) for the lumbar spine and hip, respectively. Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a P < 0.05. b These rows represent reference values of age-matched peers of the same gender recorded at birth. View Large Table 4. Summary of DXA Measurements   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a  Data are mean ± SD or median (interquartile range). Z scores: mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), after CA (16.0–19.1), based on data from the NHANES (17) and Bone Mineral Density in Childhood Study (18) for the lumbar spine and hip, respectively. Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a P < 0.05. b These rows represent reference values of age-matched peers of the same gender recorded at birth. View Large At the total hip, an increase of BMC (P = 0.004) with a stable bone area was seen. This led to an increase in absolute values and Z scores of aBMD (both P < 0.001) (Table 4). At the femoral neck, Z scores of aBMD did not change significantly (P = 0.057) (Fig. 2C). At the lumbar spine, BMC and aBMD increased, whereas Z scores remained stable, suggesting an acquisition similar to age-matched female peers (Fig. 2B; Table 4). Figure 2. View largeDownload slide Changes in aBMD Z scores. Box and whisker plot of delta Z scores: aBMD of (A) whole body (17, 18), (B) lumbar spine (17), and (C) femoral neck (18). Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Figure 2. View largeDownload slide Changes in aBMD Z scores. Box and whisker plot of delta Z scores: aBMD of (A) whole body (17, 18), (B) lumbar spine (17), and (C) femoral neck (18). Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Total body BMC, bone area, and aBMD increased (P < 0.001), whereas Z scores remained stable (P = 0.720) (Fig. 2A). Compared with age-matched peers of the experienced (male) gender, Z scores of aBMD evolved as follows: −0.95 to −1.04 (P < 0.001) for femoral neck, 0.04 to −0.24 (P = 0.017) for lumbar spine, and −1.01 to −1.29 (P < 0.001) for whole body. Based on the pQCT scans, both trabecular and cortical bone parameters (area, BMC, and vBMD) at the radius and the tibia increased during the study period, to the same extent as in age-matched control girls. SSIp Z scores at the midshaft radius did not change throughout the study period. All pQCT data are represented in Supplemental Table 2. In trans girls, already at the start of CA, aBMD was lower as compared with their peers of the same gender recorded at birth (Z scores: −0.805, −0.791, −0.765, and −1.381 for total hip, femoral neck, lumbar spine, and whole body, respectively) (Table 4). During the study period, DXA scans of the total hip and femoral neck showed an increase in bone area and a decrease in BMC, leading to a decreased aBMD, which was statistically significant only at the total hip (P = 0.016). Compared with their age-matched male peers, Z scores of the total hip and femoral neck decreased (P = 0.006 and 0.013, respectively) (Fig. 2C; Table 4). At the lumbar spine, bone area and BMC both increased, resulting in a stable aBMD but decreased aBMD Z scores (P = 0.002) (Fig. 2B; Table 4). At the whole-body level, increases in bone area and BMC were seen. However, aBMD did not change, resulting in decreased Z scores (P = 0.008) (Fig. 2A). Compared with age-matched peers of the experienced (female) gender, aBMD Z scores further decreased from −0.45 to −0.67 (P = 0.002) for the femoral neck and showed negative trends from −1.11 to −1.29 (P = 0.063) for the lumbar spine and −0.92 to −1.01 (P = 0.147) for the whole body. Based on pQCT data, trabecular vBMD decreased at the distal radius and tibia, and Z scores of both total and trabecular vBMD at the radius decreased. Significant increases of the cortical BMC and vBMD were noted at both midshaft tibia and radius. SSIp Z scores at the midshaft radius decreased significantly. Cortical thickness and periosteal and endosteal circumferences of both radius and tibia did not change during treatment, resulting in significantly lower periosteal circumference Z scores in trans girls at the end of treatment. All pQCT data are represented in Supplemental Table 2. Discussion In our previous studies, we have shown that proandrogenic and antiandrogenic progestins, although not fully suppressing endogenous gonadotropin and sex steroid production, effectively reduce physical signs of puberty, such as menstruation in trans boys and erections and facial hair growth in trans girls (6, 7). In this study, we investigate whether these medications affect bone mass acquisition in comparison with age-matched peers and whether the induced hormonal changes are sufficiently potent to alter body composition and can therefore actually be considered a first step toward CSH treatment. In trans boys taking L, lean mass and grip strength significantly increased. Similar effects on lean body mass and grip strength have been reported in adult trans men using androgens (20, 21). Compared with the results published by Ortega et al. (16) based on a large European cohort, the increase in grip strength in our study more than doubled the increase in healthy female peers and equaled the increase observed in male teens of similar age. These findings are corroborated by our pQCT results, showing an increase in the muscle area of the forearm, which was significantly greater than in age-matched female peers. Furthermore, when comparing the observed changes in waist and hip circumference with data obtained in a similar age group in a recent Dutch normative study of healthy pubertal boys and girls (22), our data suggest interference with physiological body development in trans boys, who had greater increases in waist and hip circumference. These data combined indicate an L-induced, androgenic effect on lean body mass and body musculature in trans boys and the development of a more masculine body shape. Contrasting changes were observed in trans girls treated with CA (i.e., lean body mass decreased, whereas fat mass increased), in line with findings in adult trans women using CA in combination with estrogens, who were found to have lower lean mass and higher fat mass than male control subjects (23). In our study, cross-sectional muscle area at the radius significantly decreased in trans girls, accompanied by a stable grip strength. Compared with European peers, grip strength would be expected to increase during the same period of life in both sexes (16). As skeletal musculature in adolescents is normally still developing at this age, we consider our findings of relevance. Increased fat mass and decreased lean mass have also been observed in trans girls treated with GnRHa (3). We have previously reported, apart from a reduction in facial and body hair growth and sexual arousal, moderate breast development (B2/3) in one-third of trans girls treated with CA, which is not seen in adolescents using GnRHa (7). If confirmed in other studies, this may represent an additional benefit of CA over GnRHa in late-pubertal adolescents who already have fully developed (male) secondary sex characteristics. Noteworthy is that all body composition changes in both groups occurred in <1 year of treatment and in the absence of CSH. We did not investigate whether adolescents themselves were aware of their bodies slightly changing toward the desired appearance, but the quantification of such self-perceived changes deserves to be the subject of future studies. Trans boys showed similar increases as their age-matched female peers in aBMD and vBMD at all sites, and no major changes were seen in cortical thickness. A wealth of studies has evaluated the effects of progestin-only contraceptives, mostly depot medroxyprogesterone acetate, on bone. These studies reveal an overall negative but reversible impact on aBMD in adult women (24–27). In contrast, depot medroxyprogesterone acetate and progestin-only pills protect aBMD during lactation, which is considered to be a hypoestrogenic period [28, for review, see Curtis and Martins (29)]. In line with previous studies (4, 5), negative Z scores for aBMD were present in trans girls already at the start of treatment (29). Although not further investigated in this study, we hypothesize that reduced physical activity as compared with age-matched male peers may underlie this observation. Although vitamin D levels were suboptimal in trans girls, these levels did not differ from those of the trans boys Z in our study and from the general Belgian pediatric and adult population, who have been shown to have low vitamin D levels as well (30, 31). In contrast to age-matched male peers, aBMD did not increase at any site in trans girls during the study period, and Z scores showed similar decreases at the lumbar spine and femoral neck, as has been reported for trans girls using GnRHa (4, 5). In addition, CA had a negative impact on vBMD of the trabecular bone of the distal radius. Z scores of the periosteal circumference decreased, indicating markedly less periosteal expansion as compared with their male peers. In contrast to the neutral effects of L on bone mass and geometry in trans boys, CA treatment in trans girls appears to suppress both normal pubertal periostal bone expansion as well as trabecular bone acquisition. We speculate that the reduced androgen levels seen in our adolescents taking CA underlie this observation. Indeed, it has been established that androgens are important regulators of periosteal bone apposition (32–36). SSIp at the midshaft radius increased in both patient groups; however, in trans girls, this increase was smaller than in their age-matched male peers. As SSIp strongly correlates with ultimate bone strength, this finding suggests a potentially higher future fracture risk in trans women (37, 38). Although the decline in markers of bone turnover was most pronounced in trans girls, a physiological decrease after Tanner B3/G3 has been reported in cross-sectional, population-based studies (39, 40). Therefore, these parameters were not helpful in documenting eventual treatment-induced changes. Strengths of this prospective study are the relatively large cohort of investigated adolescents and the combination of DXA and pQCT technology, allowing a more detailed and mechanistic insight in trabecular and cortical bone changes as well as the evolution of body composition. A limitation of the study is the lack of a control group and, as a surrogate, comparison with several published cohorts of adolescents to calculate Z scores. It should be emphasized that in this study, a homogenous cohort of late-pubertal trans adolescents, with advanced endogenous pubertal hormone production and attendant physical and bone development at the start of the treatment, has been investigated. In this specific age group, the focus of treatment may have shifted from full suppression of pubertal hormones, which is achieved by GnRHa, toward alleviating the burden of pubertal signs and preparing the individual for CSH therapy. Studies of longer duration and randomized trials directly comparing GnRHa and progestin-induced changes in this specific population are required to define the clinical significance and impact of both treatment strategies on overall health and quality of life, both in the short and longer term. In conclusion, treatment with proandrogenic and antiandrogenic progestins induces relevant changes in body composition and grip strength in line with gender identity in trans youth. These effects were most obvious in trans boys. In addition, similar to GnRHa treatment, CA interferes with pubertal bone development, despite general measures advised to promote bone health, such as a calcium-rich diet and routine vitamin D supplementation. This therefore warrants long-term follow-up studies on the evolution of bone strength–associated parameters, especially in trans girls, to assess whether this phenomenon is reversible after addition of CSH and whether this would result in increased fracture rates in elderly individuals. Abbreviations: Abbreviations: aBMD areal bone mineral density BMC bone mineral content BMI body mass index CA cyproterone acetate CSH cross-sex hormones DXA dual-energy X-ray absorptiometry GI gender incongruence GnRHa gonadotropin-releasing hormone analogs L lynestrenol NHANES National Health and Nutrition Examination Survey PINP procollagen type I N-terminal propeptide PTH parathyroid hormone pQCT peripheral quantitative computed tomography s-CTX serum C-terminal telopeptide SHBG sex hormone–binding globulin SSIp polar strength strain index trans transgender UCa/Cr urinary calcium/creatinine ratio vBMD volumetric bone mineral density WHR waist/hip ratio Acknowledgments The authors thank Dr. Tom Fiers for assistance with the interpretation of laboratory techniques and reference values and all of the participants who allowed use of their data in the study. Author Contributions: L.J.W.T. analyzed all data, including statistics, and drafted the manuscript. M. 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Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body Composition and Bone Metabolism

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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2017-02316
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Abstract

Abstract Context Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth. Objective To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively. Design and Outcome Measurements Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones. Results Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [−2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: −0.765 to −1.145 (P = 0.002)]. L did not affect physiological bone development. Conclusion Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy. Worldwide, the number of children and adolescents presenting with gender incongruence (GI) is increasing (1). In children with persistent GI, gonadotropin-releasing hormone analogs (GnRHa), after multidisciplinary evaluation and a variable period of psychological support, are commonly used to arrest pubertal development. GnRHa suppress gonadotropin secretion and thus the gonadal production of sex hormones and the development of secondary sex characteristics of the gender recorded at birth (2). GnRHa have been reported to increase fat mass and reduce lean mass in both transgender (trans) boys and trans girls (3). In addition, concerns have been raised about the negative impact of this treatment on bone health, particularly bone mass accrual in trans girls, which may not be fully compensated by subsequent addition of cross-sex hormones (CSH) (4, 5). If secondary sex characteristics have already developed at the time GI is diagnosed, the focus of treatment shifts toward reducing the burden of isosexual pubertal signs, such as menstruation in trans boys or erections and facial and body hair growth in trans girls, while awaiting the start of CSH treatment—usually around the age of 16 years, although strict application of this age criterion is under debate. Apart from GnRHa treatment, menstruation in girls and erections and hair growth in boys can also successfully be suppressed with proandrogenic and antiandrogenic progestins such as lynestrenol (L) or cyproterone acetate (CA), respectively, provided that these drugs are available (6, 7). The low cost of progestins is an advantage over the expensive GnRHa, especially in circumstances in which these drugs are not reimbursed. L is a proandrogenic progestin that increases the endogenous serum testosterone/estradiol ratio, thereby interfering with the menstrual cycle and inducing amenorrhea, especially at higher doses (10 mg/d) (6). The antiandrogenic progestin CA is a competitive androgen receptor blocker resulting in decreased androgenic effects (7–9). Antiandrogens such as CA have previously been shown to decrease lean body mass and increase total body fat in adult trans women (10, 11), and in some adult transgender teams, proandrogenic and antiandrogenic progestins are used prior to CSH or in association with CSH as an adjuvant therapy (10, 12). It has not been investigated whether the proandrogenic and antiandrogenic effects of L and CA affect anthropometry and body composition in trans adolescents and/or have less deleterious effects on bone mass accrual as compared with GnRHa treatment. If these progestins indeed induce bodily changes toward the desired appearance in addition to suppressing endogenous pubertal signs in late pubertal adolescents, they may, in line with adult treatment regimens, represent a first step toward CSH treatment in this specific population. The aim of this study is to prospectively assess anthropometry, body composition, and bone mass changes in late-pubertal trans boys and trans girls who, respectively, received L or CA to attenuate endogenous pubertal hormone effects while awaiting CSH therapy. This will contribute to determining the place of GnRHa and progestins, respectively, in the pharmacological treatment of trans youth and to improving our knowledge on the long-term effects of these interventions, as has been suggested recently (2). Subjects and Methods Participants and treatments Sixty-five late-pubertal (Tanner stage B4/G4) trans adolescents (44 trans boys and 21 trans girls) who used progestins between March 2011 and January 2017 were included in the study. The cohort of participants in this study partially overlaps with cohorts of our previous reports on progestin-induced biochemical and hormonal changes in trans adolescents (6, 7). According to our local protocol, CSH can be added to this treatment from the age of 16 years onward and after a period of progestin use of ∼6 months. In all subjects presenting before or in early puberty (Tanner stages B2 to 3/G2 to 3), GnRHa instead of progestins are used to arrest further pubertal development. Biochemical parameters and data on muscle strength, body composition, and bone mass were collected at the start of L/CA (baseline) and before addition of CSH. The diagnosis of GI was made by a child psychologist and child psychiatrist and based on the diagnostic criteria as described in the Diagnostic and Statistical Manual of Mental Disorders 4th edition, and, later, the 5th edition, and the International Classification of Diseases 10th edition (13). The decision to start medical treatment was made by the multidisciplinary child gender team of Ghent University Hospital. A daily dose of 5 to 10 mg L (Orgametril®; MSD Belgium, Brussels, Belgium) or 50 mg CA (Androcur®; Bayer, Leverkusen, Germany) was given orally in trans boys and trans girls, respectively. In all individuals, vitamin D supplementation [cholecalciferol 25,000 IU/mo (D-CURE®; SMB Laboratories, Brussels, Belgium)] was added to the treatment, and all were advised to pursue a daily dietary calcium intake of at least 1500 mg. Methods Investigations were performed twice (i.e., before initiation of L or CA and prior to addition of CSH) and consisted of the following: anthropometric measurements, a fasting venous blood sample (between 0800 h and 0900 h), a spot urine sample, dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT) scans, and grip-strength measurements. Approval of the study by the ethics committee of Ghent University Hospital was obtained (B670201525328). Anthropometrics Body weight was measured to the nearest 0.1 kg in light, indoor clothing without shoes. A wall-mounted Harpenden stadiometer (Holtain, Ltd, Crymuch, United Kingdom) was used to measure height. Waist circumference was measured between the lower rib and the iliac crest at the end of expiration; hip circumference was measured at the widest gluteal circumference. Both measurements were performed twice. The mean of both measurements was used for analysis. SD scores of height, weight, and body mass index (BMI) were calculated based on published data obtained in Flemish peers of the same gender recorded at birth (14). Serum analyses Sex hormone–binding globulin (SHBG), total testosterone, free testosterone, total estradiol, total testosterone/estradiol ratio, follicle-stimulating hormone, luteinizing hormone, serum 25-OH vitamin D, parathyroid hormone (PTH), serum C-terminal telopeptide (s-CTX), and procollagen type I N-terminal propeptide (PINP) were measured. Electrochemiluminescence assays (Roche Diagnostics E170 Modular; Roche Diagnostics, Indianapolis, IN) were used for all parameters, except total testosterone, for which liquid chromatography–tandem mass spectrometry was used. Free testosterone was calculated as described by Vermeulen et al. (15). The detection limit for estradiol was 25 ng/L; in case of values below this limit, the limit itself was input for statistical analysis. Urinary calcium/creatinine ratio (UCa/Cr) was calculated from the calcium and creatinine levels as measured on a urine spot sample. Grip strength An adjustable handheld standard grip device (JAMAR hand dynamometer; Sammons and Preston, Bolingbrook, IL) was used to determine grip strength on both the dominant and nondominant hand. Grip strength was measured three times on both hands. The highest value was assumed to represent the maximum strength and was input for analyses. Z scores were calculated based on data published by Ortega et al. (16). DXA scans A Hologic Discovery device (Software Version 11.2.1; Hologic, Inc., Bedford, MA) was used to assess body composition of the total body minus head (total, lean, and fat mass), bone mineral content (BMC), areal bone mineral density (aBMD) and projected bone area of the spine, left proximal femur (femoral neck and total hip), and whole body. Z scores of DXA scan parameters were based on data from the National Health and Nutrition Examination Survey (NHANES) and Bone Mineral Density in Childhood Study (17, 18). Z scores of aBMD were calculated by the manufacturer’s software based on age-matched adolescents of the same gender recorded at birth; Z scores of percentage body fat and aBMD of the experienced gender were calculated manually based on the data from the NHANES study, kindly provided by Hologic, Inc. pQCT scans A pQCT device (XCT-2000; Stratec Medizintechnik, Pforzheim, Germany) was used to evaluate both the trabecular and cortical volumetric bone mineral density (vBMD) and bone geometry at the nondominant radius, and the left tibia measured at 4% and 66% and 4% and 38%, respectively, of bone length from distal. Polar strength strain index (SSIp) was calculated based on geometrical and material properties at the nondominant radius at 66%. Muscle and fat area were measured at the midshaft radius of the nondominant arm and left tibia (at the 66% and 38% sites, respectively). Z scores of the radius were calculated by the manufacturer’s software. Z scores of the tibia were calculated manually using the formulas published by Roggen et al. (19) based on results of the same pQCT device and enabled the calculation of Z scores of periosteal and endosteal circumference (which are not available at the radius). All Z scores were based on age-matched adolescents of the same gender recorded at birth. Manual calculation of Z scores was performed using the following formulae:  Z=M((XM)L−1)Lσ or Z=X−Mσ,in which X is the physical measurement, L the age-matched skewness value, M the median age-matched reference value, and σ the age-matched population SD. Statistical analyses Statistical analysis was performed using an IBM SPSS software package (version 23). A P value of <0.05 was considered significant. Mean values and SD or medians and interquartile ranges are given, with Gaussian and non-Gaussian distributions, respectively (based on a Shapiro-Wilk test). A paired Student t test or Wilcoxon signed-ranks test was used after testing for normality with a Shapiro-Wilk test, to compare data prior to initiation of progestins and before initiation of CSH. Four of the 44 trans boys used an oral contraceptive prior to starting with L. Data for these adolescents were excluded from the hormonal analyses. Because unpaired Student t tests/Mann–Whitney U test (depending on the results of a Shapiro-Wilk test) revealed similar body composition parameters and similar changes in bone parameters, those data were included in all other analyses. Results Sixty-five adolescents (44 trans boys and 21 trans girls) were included in the study. At the start of progestin treatment, mean chronological and bone age were 16.2 ± 1.05 and 16.4 ± 1.08 years in trans boys and 16.3 ± 1.21 and 17.1 ± 1.28 years in trans girls, respectively (Table 1). The mean time interval between both examinations was 11.64 (4 to 40) months in trans boys and 10.57 (5 to 31) months in trans girls, respectively. Table 1. Descriptive Statistics   Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28    Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28  View Large Table 1. Descriptive Statistics   Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28    Trans Boys  Trans Girls  Number of participants  44  21  Age at start of progestin, y  16.2 ± 1.05  16.3 ± 1.21  Bone age at start of progestin, y  16.4 ± 1.08  17.1 ± 1.28  View Large Serum analyses Mean total testosterone and estradiol levels decreased with progestin treatment in both groups (Table 2). However, the total testosterone-to-estradiol ratio decreased significantly in trans girls (P = 0.008) but not in trans boys (P = 0.068). Because of the decreased SHBG levels, free testosterone levels increased in trans boys. In trans girls, SHBG remained stable, resulting in decreased free testosterone levels (P = 0.010). Gonadotropin levels decreased only in trans boys. Serum levels of PINP, a marker for bone formation, decreased by 9.3% in trans boys and 46.5% in trans girls. In the latter group, s-CTX levels, a marker for bone resorption, also decreased by 17.1%. Mean vitamin D levels before initiation of treatment were in the range of vitamin D insufficiency (i.e., <20 ng/mL): 17.72 ng/mL in trans boys and 17.34 ng/mL in trans girls; mean levels increased in both groups following supplementation. PTH levels decreased in both groups; however, this was only significant in trans boys versus trans girls (P = 0.001 and 0.113, respectively). UCa/Cr showed a decrease in trans boys (P < 0.001) and an increase in trans girls (P = 0.035). Table 2. Summary of Serum Markers Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Data are mean ± SD or median (interquartile range). Abbreviations: After L or CA, mean/median levels before start of CSH; Before L or CA, mean/median values before start of progestin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T/E ratio, testosterone/estradiol ratio; Vitamin D, 25-OH vitamin D. a P < 0.05. View Large Table 2. Summary of Serum Markers Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Serum markers  Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Total testosterone, ng/dL  33.00 (17.39)  23.85 (19.86)  0.039a  438.21 ± 211.07  253.35 ± 172.96  <0.001a  Free testosterone, ng/dL  0.41 (0.22)  0.62 (0.33)  0.024a  9.64 (± 4.40)  5.69 (± 3.09)  0.010a  Total estradiol, ng/L  53.20 (58.43)  25.00 (13.75)  <0.001a  25.8 (11.0)  25.0 (0)  0.002a  T/E ratio  0.518 (0.800)  0.824 (0.710)  0.068  15.593 ± 5.751  11.024 ± 6.557  0.008a  SHBG, nmol/L  54.7 (54.38)  22.10 (14.15)  <0.001a  28.44 ± 9.54  26.38 ± 9.23  0.366  LH, U/L  7.60 (7.73)  2.90 (3.9)  <0.001a  3.77 ± 1.33  5.33 ± 2.30  0.007a  FSH, U/L  5.96 ± 2.06  4.49 ± 2.66  0.009a  3.1 (2.60)  2.1 (4.85)  0.614  Vitamin D, ng/mL  17.72 ± 8.96  23.20 ± 7.89  0.001a  17.34 ± 6.66  24.82 ± 8.37  0.008a  PTH, ng/L  44.2 (11.6)  30.95 (16.05)  0.001a  40.15 (24.10)  26.9 (9.7)  0.113  PINP, µg/L  140.10 (82.12)  127.05 (74.65)  0.018a  232.0 (377.7)  124.10 (137.9)  0.005a  s-CTX, ng/mL  0.784 ± 0.266  0.799 ± 0.273  0.747  1.211 ± 0.466  1.004 ± 0.318  0.042a  UCa/Cr, mg/mg  0.095 ± 0.056  0.051 ± 0.029  <0.001a  0.054 ± 0.045  0.080 ± 0.067  0.035a  Data are mean ± SD or median (interquartile range). Abbreviations: After L or CA, mean/median levels before start of CSH; Before L or CA, mean/median values before start of progestin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T/E ratio, testosterone/estradiol ratio; Vitamin D, 25-OH vitamin D. a P < 0.05. View Large Anthropometrics Trans boys grew on average 0.8 cm and gained 2.65 kg during the study period; weight and BMI gain were more pronounced than in age-matched female peers (P = 0.001) (Table 3). Both waist and hip circumference increased (P < 0.001 and 0.002) as well as waist/hip ratio (WHR) (P = 0.041). Table 3. Anthropometrics   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306  Data are mean ± SD or median (interquartile range). Z scores are mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), and after CA (16.0–19.1), based on data published by Roelants et al. (14). Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a These rows represent reference values of age-matched peers of the same gender recorded at birth. b P < 0.05. View Large Table 3. Anthropometrics   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Reference height,a cm  165.9 ± 6.0  166.2 ± 6.0  —  176.5 ± 7.2  178.4 ± 7.0  —  Height, cm  165.2 ± 6.5  166.0 ± 6.5  <0.001b  173.7 ± 7.1  174.4 ± 6.9  0.016b  SD-score height  −0.039 ± 0.988  −0.025 ± 0.980  0.560  −0.177 ± 0.974  −0.441 ± 1.019  0.004b  Reference weight,a kg  57.5 ± 6.7  58.6 ± 6.7  —  63.7 ± 8.0  66.3 ± 7.9  —  Weight, kg  58.50 (20.00)  60.50 (19.50)  0.001b  66.24 ± 11.20  68.57 ± 13.18  0.167  SD-score weight  −0.041 ± 1.379  0.203 ± 1.265  0.001b  0.413 ± 1.167  0.194 ± 1.255  0.118  Reference BMI,a kg/m2  20.9 ± 2.2  21.1 ± 2.1  —  20.3 ± 1.9  20.7 ± 1.9  —  BMI, kg/m2  21.50 (5.80)  22.35 (5.37)  <0.001b  20.25 (4.45)  21.52 (2.84)  0.164  SD-score BMI  0.020 ± 1.400  0.306 ± 1.222  0.001b  0.625 ± 1.025  0.506 ± 1.025  0.406  Waist circumference, cm  72.00 (13.81)  75.25 (13.00)  <0.001b  75.00 (12.25)  76.15 (11.63)  0.586  Hip circumference, cm  96.23 ± 11.92  99.24 ± 9.77  0.002b  91.53 ± 7.40  92.88 ± 9.17  0.462  WHR  0.749 (0.070)  0.781 (0.090)  0.041b  0.810 (0.080)  0.828 (0.090)  0.306  Data are mean ± SD or median (interquartile range). Z scores are mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), and after CA (16.0–19.1), based on data published by Roelants et al. (14). Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a These rows represent reference values of age-matched peers of the same gender recorded at birth. b P < 0.05. View Large Trans girls treated with CA grew on average 0.7 cm and gained 2.33 kg; weight and BMI changes were similar to age-matched male peers. Their waist and hip circumference only showed slight increases, resulting in a stable WHR. Body composition and grip strength In trans boys, lean mass (Fig. 1C), opposite to fat mass (Fig. 1D), significantly increased, leading to an increased total body mass (Fig. 1B) and decreased body fat percentage, significantly differing from their age-matched female peers, as calculated from population-based Z scores of the percentage of body fat (P = 0.010) (Supplemental Table 1). Muscle area increased at the nondominant forearm and left lower leg (radius, 66% and tibia, 38%). This increase at the forearm was higher than what was observed in age-matched peers of the same gender recorded at birth, based on Z scores (P < 0.001). There were no changes in forearm and lower leg fat area (Supplemental Table 1). An increase in grip strength was noted in the dominant and nondominant hand. This increase was higher than in age-matched peers of the same gender recorded at birth (P < 0.001) (Fig. 1A; Supplemental Table 1). Figure 1. View largeDownload slide Changes in grip strength and body composition. Box and whisker plots of (A) delta grip strength of the dominant hand, (B) delta total mass, (C) delta lean mass, and (D) delta fat mass. Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Figure 1. View largeDownload slide Changes in grip strength and body composition. Box and whisker plots of (A) delta grip strength of the dominant hand, (B) delta total mass, (C) delta lean mass, and (D) delta fat mass. Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Trans girls treated with CA showed a significant increase in fat mass (Fig. 1D) and decrease in lean mass (Fig. 1C), resulting in an increased body fat percentage (P < 0.001), without changes in total mass (P = 0.167) (Fig. 1B). This increase was higher than observed in their age-matched male peers, based on Z scores (P = 0.001) (Supplemental Table 1). At the nondominant forearm and left lower leg (radius, 66% and tibia, 38%), muscle area decreased, whereas fat area markedly increased. Based on Z scores, the changes of muscle and fat area at the forearm are different from their age-matched peers of the same gender recorded at birth (Supplemental Table 1). No significant changes in grip strength were observed in trans girls during the study period (Fig. 1A), resulting in decreased Z scores compared with age-matched peers of the same gender recorded at birth (P = 0.004 and 0.056) (Supplemental Table 1). Bone changes In trans boys, aBMD of the total hip, femoral neck, lumbar spine, and whole body before the start of L were slightly lower compared with population-based references for the same age and gender recorded at birth (Z scores: −0.162, −0.271, −0.320, and −0.783, respectively) (Table 4). Table 4. Summary of DXA Measurements   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a  Data are mean ± SD or median (interquartile range). Z scores: mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), after CA (16.0–19.1), based on data from the NHANES (17) and Bone Mineral Density in Childhood Study (18) for the lumbar spine and hip, respectively. Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a P < 0.05. b These rows represent reference values of age-matched peers of the same gender recorded at birth. View Large Table 4. Summary of DXA Measurements   Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a    Trans Boys  Trans Girls  Before L  After L  P (L)  Before CA  After CA  P (CA)  Hip               Total hip area, cm2  33.826 ± 3.870  33.789 ± 3.948  0.774  38.742 ± 3.157  39.038 ± 2.765  0.341    BMC, g  29.356 (6.840)  30.060 (6.870)  0.004a  35.941 ± 6.202  35.614 ± 5.450  0.383    Reference aBMD,b g/cm2  0.957 ± 0.109  0.970 ± 0.108  —  1.029 ± 0.137  1.068 ± 0.143  —    aBMD, g/cm2  0.926 ± 0.102  0.942 ± 0.104  <0.001a  0.914 ± 0.125  0.897 ± 0.130  0.016a    Z scores: BMD  −0.162 ± 0.888  −0.024 ± 0.889  <0.001a  −0.805 ± 0.987  −1.010 ± 0.983  0.006a   Femoral neck                BMC, g  4.074 ± 0.675  4.163 ± 0.702  0.021a  4.527 ± 0.784  4.518 ± 0.781  0.845    Reference aBMD,b g/cm2  0.874 ± 0.106  0.883 ± 0.106  —  0.945 ± 0.131  0.975 ± 0.138  —    aBMD, g/cm2  0.815 ± 0.103  0.826 ± 0.104  0.026a  0.823 ± 0.128  0.811 ± 0.126  0.059    Z scores: BMD  −0.271 ± 0.906  −0.191 ± 0.933  0.057  −0.791 ± 1.122  −0.991 ± 1.020  0.013a  Lumbar spine               Total area, cm2  56.015 ± 5.102  56.496 ± 4.944  0.069  58.392 ± 4.640  59.438 ± 4.355  0.005a   BMC, g  52.917 ± 9.297  54.097 ± 9.226  0.004a  51.687 ± 8.611  53.175 ± 7.872  0.015a   Reference aBMD, g/cm2  0.988 ± 0.105  1.005 ± 0.103  —  0.957 ± 0.117  0.997 ± 0.119  —   aBMD, g/cm2  0.951 ± 0.106  0.964 ± 0.107  0.001a  0.870 ± 0.119  0.878 ± 0.107  0.386   Z score: BMD  −0.320 ± 1.088  −0.315 ± 1.094  0.938  −0.765 ± 1.083  −1.145 ± 0.936  0.002a  Data are mean ± SD or median (interquartile range). Z scores: mean of Z scores of individual participants; age ranges: before L (11.9–18.4), after L (16.0–21.7), before CA (13.5–18.4), after CA (16.0–19.1), based on data from the NHANES (17) and Bone Mineral Density in Childhood Study (18) for the lumbar spine and hip, respectively. Abbreviations: After L/CA, mean/median levels before start of CSH; Before L/CA, mean/median values before start of progestin. a P < 0.05. b These rows represent reference values of age-matched peers of the same gender recorded at birth. View Large At the total hip, an increase of BMC (P = 0.004) with a stable bone area was seen. This led to an increase in absolute values and Z scores of aBMD (both P < 0.001) (Table 4). At the femoral neck, Z scores of aBMD did not change significantly (P = 0.057) (Fig. 2C). At the lumbar spine, BMC and aBMD increased, whereas Z scores remained stable, suggesting an acquisition similar to age-matched female peers (Fig. 2B; Table 4). Figure 2. View largeDownload slide Changes in aBMD Z scores. Box and whisker plot of delta Z scores: aBMD of (A) whole body (17, 18), (B) lumbar spine (17), and (C) femoral neck (18). Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Figure 2. View largeDownload slide Changes in aBMD Z scores. Box and whisker plot of delta Z scores: aBMD of (A) whole body (17, 18), (B) lumbar spine (17), and (C) femoral neck (18). Boxes indicate the 25th and 75th percentiles; horizontal lines within the shaded boxes indicate the median. Whiskers indicate the minimum and maximum; mild and extreme outliers (circles and stars, respectively) are defined as 1.5 and 3 times the interquartile range below or above the 25th and 75th percentile, respectively. *P < 0.05. Total body BMC, bone area, and aBMD increased (P < 0.001), whereas Z scores remained stable (P = 0.720) (Fig. 2A). Compared with age-matched peers of the experienced (male) gender, Z scores of aBMD evolved as follows: −0.95 to −1.04 (P < 0.001) for femoral neck, 0.04 to −0.24 (P = 0.017) for lumbar spine, and −1.01 to −1.29 (P < 0.001) for whole body. Based on the pQCT scans, both trabecular and cortical bone parameters (area, BMC, and vBMD) at the radius and the tibia increased during the study period, to the same extent as in age-matched control girls. SSIp Z scores at the midshaft radius did not change throughout the study period. All pQCT data are represented in Supplemental Table 2. In trans girls, already at the start of CA, aBMD was lower as compared with their peers of the same gender recorded at birth (Z scores: −0.805, −0.791, −0.765, and −1.381 for total hip, femoral neck, lumbar spine, and whole body, respectively) (Table 4). During the study period, DXA scans of the total hip and femoral neck showed an increase in bone area and a decrease in BMC, leading to a decreased aBMD, which was statistically significant only at the total hip (P = 0.016). Compared with their age-matched male peers, Z scores of the total hip and femoral neck decreased (P = 0.006 and 0.013, respectively) (Fig. 2C; Table 4). At the lumbar spine, bone area and BMC both increased, resulting in a stable aBMD but decreased aBMD Z scores (P = 0.002) (Fig. 2B; Table 4). At the whole-body level, increases in bone area and BMC were seen. However, aBMD did not change, resulting in decreased Z scores (P = 0.008) (Fig. 2A). Compared with age-matched peers of the experienced (female) gender, aBMD Z scores further decreased from −0.45 to −0.67 (P = 0.002) for the femoral neck and showed negative trends from −1.11 to −1.29 (P = 0.063) for the lumbar spine and −0.92 to −1.01 (P = 0.147) for the whole body. Based on pQCT data, trabecular vBMD decreased at the distal radius and tibia, and Z scores of both total and trabecular vBMD at the radius decreased. Significant increases of the cortical BMC and vBMD were noted at both midshaft tibia and radius. SSIp Z scores at the midshaft radius decreased significantly. Cortical thickness and periosteal and endosteal circumferences of both radius and tibia did not change during treatment, resulting in significantly lower periosteal circumference Z scores in trans girls at the end of treatment. All pQCT data are represented in Supplemental Table 2. Discussion In our previous studies, we have shown that proandrogenic and antiandrogenic progestins, although not fully suppressing endogenous gonadotropin and sex steroid production, effectively reduce physical signs of puberty, such as menstruation in trans boys and erections and facial hair growth in trans girls (6, 7). In this study, we investigate whether these medications affect bone mass acquisition in comparison with age-matched peers and whether the induced hormonal changes are sufficiently potent to alter body composition and can therefore actually be considered a first step toward CSH treatment. In trans boys taking L, lean mass and grip strength significantly increased. Similar effects on lean body mass and grip strength have been reported in adult trans men using androgens (20, 21). Compared with the results published by Ortega et al. (16) based on a large European cohort, the increase in grip strength in our study more than doubled the increase in healthy female peers and equaled the increase observed in male teens of similar age. These findings are corroborated by our pQCT results, showing an increase in the muscle area of the forearm, which was significantly greater than in age-matched female peers. Furthermore, when comparing the observed changes in waist and hip circumference with data obtained in a similar age group in a recent Dutch normative study of healthy pubertal boys and girls (22), our data suggest interference with physiological body development in trans boys, who had greater increases in waist and hip circumference. These data combined indicate an L-induced, androgenic effect on lean body mass and body musculature in trans boys and the development of a more masculine body shape. Contrasting changes were observed in trans girls treated with CA (i.e., lean body mass decreased, whereas fat mass increased), in line with findings in adult trans women using CA in combination with estrogens, who were found to have lower lean mass and higher fat mass than male control subjects (23). In our study, cross-sectional muscle area at the radius significantly decreased in trans girls, accompanied by a stable grip strength. Compared with European peers, grip strength would be expected to increase during the same period of life in both sexes (16). As skeletal musculature in adolescents is normally still developing at this age, we consider our findings of relevance. Increased fat mass and decreased lean mass have also been observed in trans girls treated with GnRHa (3). We have previously reported, apart from a reduction in facial and body hair growth and sexual arousal, moderate breast development (B2/3) in one-third of trans girls treated with CA, which is not seen in adolescents using GnRHa (7). If confirmed in other studies, this may represent an additional benefit of CA over GnRHa in late-pubertal adolescents who already have fully developed (male) secondary sex characteristics. Noteworthy is that all body composition changes in both groups occurred in <1 year of treatment and in the absence of CSH. We did not investigate whether adolescents themselves were aware of their bodies slightly changing toward the desired appearance, but the quantification of such self-perceived changes deserves to be the subject of future studies. Trans boys showed similar increases as their age-matched female peers in aBMD and vBMD at all sites, and no major changes were seen in cortical thickness. A wealth of studies has evaluated the effects of progestin-only contraceptives, mostly depot medroxyprogesterone acetate, on bone. These studies reveal an overall negative but reversible impact on aBMD in adult women (24–27). In contrast, depot medroxyprogesterone acetate and progestin-only pills protect aBMD during lactation, which is considered to be a hypoestrogenic period [28, for review, see Curtis and Martins (29)]. In line with previous studies (4, 5), negative Z scores for aBMD were present in trans girls already at the start of treatment (29). Although not further investigated in this study, we hypothesize that reduced physical activity as compared with age-matched male peers may underlie this observation. Although vitamin D levels were suboptimal in trans girls, these levels did not differ from those of the trans boys Z in our study and from the general Belgian pediatric and adult population, who have been shown to have low vitamin D levels as well (30, 31). In contrast to age-matched male peers, aBMD did not increase at any site in trans girls during the study period, and Z scores showed similar decreases at the lumbar spine and femoral neck, as has been reported for trans girls using GnRHa (4, 5). In addition, CA had a negative impact on vBMD of the trabecular bone of the distal radius. Z scores of the periosteal circumference decreased, indicating markedly less periosteal expansion as compared with their male peers. In contrast to the neutral effects of L on bone mass and geometry in trans boys, CA treatment in trans girls appears to suppress both normal pubertal periostal bone expansion as well as trabecular bone acquisition. We speculate that the reduced androgen levels seen in our adolescents taking CA underlie this observation. Indeed, it has been established that androgens are important regulators of periosteal bone apposition (32–36). SSIp at the midshaft radius increased in both patient groups; however, in trans girls, this increase was smaller than in their age-matched male peers. As SSIp strongly correlates with ultimate bone strength, this finding suggests a potentially higher future fracture risk in trans women (37, 38). Although the decline in markers of bone turnover was most pronounced in trans girls, a physiological decrease after Tanner B3/G3 has been reported in cross-sectional, population-based studies (39, 40). Therefore, these parameters were not helpful in documenting eventual treatment-induced changes. Strengths of this prospective study are the relatively large cohort of investigated adolescents and the combination of DXA and pQCT technology, allowing a more detailed and mechanistic insight in trabecular and cortical bone changes as well as the evolution of body composition. A limitation of the study is the lack of a control group and, as a surrogate, comparison with several published cohorts of adolescents to calculate Z scores. It should be emphasized that in this study, a homogenous cohort of late-pubertal trans adolescents, with advanced endogenous pubertal hormone production and attendant physical and bone development at the start of the treatment, has been investigated. In this specific age group, the focus of treatment may have shifted from full suppression of pubertal hormones, which is achieved by GnRHa, toward alleviating the burden of pubertal signs and preparing the individual for CSH therapy. Studies of longer duration and randomized trials directly comparing GnRHa and progestin-induced changes in this specific population are required to define the clinical significance and impact of both treatment strategies on overall health and quality of life, both in the short and longer term. In conclusion, treatment with proandrogenic and antiandrogenic progestins induces relevant changes in body composition and grip strength in line with gender identity in trans youth. These effects were most obvious in trans boys. In addition, similar to GnRHa treatment, CA interferes with pubertal bone development, despite general measures advised to promote bone health, such as a calcium-rich diet and routine vitamin D supplementation. This therefore warrants long-term follow-up studies on the evolution of bone strength–associated parameters, especially in trans girls, to assess whether this phenomenon is reversible after addition of CSH and whether this would result in increased fracture rates in elderly individuals. Abbreviations: Abbreviations: aBMD areal bone mineral density BMC bone mineral content BMI body mass index CA cyproterone acetate CSH cross-sex hormones DXA dual-energy X-ray absorptiometry GI gender incongruence GnRHa gonadotropin-releasing hormone analogs L lynestrenol NHANES National Health and Nutrition Examination Survey PINP procollagen type I N-terminal propeptide PTH parathyroid hormone pQCT peripheral quantitative computed tomography s-CTX serum C-terminal telopeptide SHBG sex hormone–binding globulin SSIp polar strength strain index trans transgender UCa/Cr urinary calcium/creatinine ratio vBMD volumetric bone mineral density WHR waist/hip ratio Acknowledgments The authors thank Dr. Tom Fiers for assistance with the interpretation of laboratory techniques and reference values and all of the participants who allowed use of their data in the study. Author Contributions: L.J.W.T. analyzed all data, including statistics, and drafted the manuscript. M. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Apr 16, 2018

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