1. A longitudinal study of bone density in reassigned transsexuals R. A. Jones 1, C. G. Schultz 2, B. E. Chatterton 2 1. The Adelaide Private Menopause Clinic, North Adelaide, SA, Australia 2. Nuclear Medicine, PET & Bone Densitometry, Royal Adelaide Hospital, ADELAIDE, SA, Australia

2. Introduction Sex hormones required for –attainment of maximal bone density during growth and development –maintenance during adult life Hormone withdrawal likely to result in osteoporosis if BMD is low Hypothesis: –Hormonally reassigned individuals at increased risk of bone loss during & after treatment –Potential for rapid bone loss on removal of phenotypic hormones Hormonally reassigned patients routinely given hormone replacement to: –effect the reassignment –maintain bone density ?

3. Aim Examine bone density and hormone data prospectively collected in subjects presenting for hormone reassignment Male to female subjects only in this study Subjects sorted into –baseline scans of lumbar spine & femur –those with serial bone density of lumbar spine and femur

4. Methods - subjects Records of subjects undergoing gender reassignment investigated with DXA scans over a 15 year period Treated with –anti-androgen (Cyproterone at doses 50mg to 100mg/day) –synthetic oestrogen suitable for HRT after oophorectomy (Premarin at doses from 1.25 to 3.75mg/day+/- oestrogen implant 50 mgm per 5-6/12- ie supra-physiological) Not all subjects underwent surgical reassignment including orchidectomy

5. Methods – data collection Data available for analysis in 68 subjects with DXA at least one lumbar spine & femur scans – the baseline group Subset of 21 of 68 had serial spine and femur scans spanning up to 10 years Determined mean & standard deviation of age, height, weight, T and Z score Serial DXA group further analysed at each DXA time point using: –DXA data GE-Lunar DPX, Expert and Encore scanners Lunar Australian normal ranges used applying normal range of final gender for comparison –treatment and sex hormone levels

6. Methods - Analysis Serial group data normalised to baseline values: –DXA normalised to baseline scan results expressed as % baseline value baseline scan corresponded closely to commencement of treatment –Oestrogen and testosterone levels normalised to mean of upper & lower limits of normal range serial time interval results expressed as % of mean value Data grouped into baseline and 2.5 year wide time intervals (up to 10 years) Statistical tests at each time interval –Mean, standard deviation and standard error determined –Compared to baseline for each variable with student’s t-test

7. Baseline results (all subjects) MaleFemale 0.14 ± 1.61 -0.08 ± 1.58 -0.002 ± 1.003 -0.45 ± 1.07 0.49 ± 1.68Z score 0.23 ± 1.58T score Spine 0.54 ± 1.17Z score 0.21 ± 1.17T score Femur 73.5 ± 12.8 (popn 83.7) Weight (kg) 176 ± 8.04 (popn 174.8) Height (cm) 41.3 (18-67.5)Age Average ± SD

8. Baseline only results Average ± SD Age41.3 (18-67.5) Height (cm)176 ± 8.04 (popn 174.8) Weight (kg)73.5 ± 12.8 (popn 83.7) Femur T score0.21 ± 1.17 Z score0.54 ± 1.17 Spine T score0.23 ± 1.58 Z score0.49 ± 1.68

9. Serial group results Average ± SD Age43.2 (22.9-63.6) Height (cm)174.2 ± 7.2 (popn 174.8) Weight (kg)77.8 ± 11.8 (popn 83.7) Femur T score-0.06 ± 1.27 Z score0.3 ± 1.19 Spine T score-0.45 ± 1.68 Z score-0.18 ± 1.66

10. MaleFemale -0.65 ± 1.69 -0.96 ± 1.54 -0.34 ± 1.06 -0.74 ± 1.17 -0.18 ± 1.66Z score -0.45 ± 1.68T score Spine 0.3 ± 1.19Z score -0.06 ± 1.27T score Femur 77.8 ± 11.8 (popn 83.7) Weight (kg) 174.2 ± 7.2 (popn 174.8) Height (cm) 43.2 (22.9-63.6)Age Average ± SD Baseline results (serial group only)

12. Results The serial group not significantly different from baseline only group at the p<0.05 level for any parameter Changes in BMD & sex hormone levels were almost all significant compared to baseline The typical replacement dose of Premarin was 2.5 to 5mg/day whilst the recommended replacement dose in pre-menopausal females is up to 0.625mg per day.

13. Results Changes in BMD & sex hormone levels were almost all significant compared to initial time point Oestrogen above the pre-menopausal normal range in 8.3%, 21.4%, 22.2% and 25.0% at each time interval post baseline

14. Discussion Testosterone: –fell rapidly – both cyproterone and oestrogen mediated (SHBG stimulation) Oestrogen: –Supra-physiological levels of oestrogen likely to have had a positive effect on bone formation (more than 20% of cases had oestrogen above the normal range)

15. Discussion Theoretical possibility of conversion of the administered oestrogen to testosterone or other androgen, which might provide an explanation for bone accretion This is unlikely both in terms of the lack of measured testosterone and the cyproterone mediated testosterone receptor suppression

16. Conclusion The results demonstrate that BMD, after gender re-assignment on a high oestrogen dose regime, increases with time Oestrogen rises to the upper end of the normal range for females Testosterone falls to insignificant levels

18. About Cyproterone Cyproterone acetate (Androcur, Cyprostat,Cyproteron, Procur, Cyprone, Cyprohexal, Ciproterona, Cyproteronum,Neoproxil, Siterone) is an antiandrogen, i.e. it suppresses the actions of testosterone (and its metabolite dihydrotestosterone) on tissues. It acts by blocking androgen receptors which prevents androgens from binding to them and suppresses luteinizing hormone (which in turn reduces testosterone levels). Its main indications are prostate cancer, benign prostatic hyperplasia, priapism, hypersexuality and other conditions in which androgen action maintains the disease process. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgender people. Until the development of leuprolide, cyproterone was one of the few drugs used to treat precocious puberty. It was also used in animal experimentation to investigate the actions of androgens in fetal sexual differentiation. In addition, cyproterone acetate has weak progestational activity (e.g., it acts like progesterone) and can be used to treat hot flashes. As part of some combined oral contraceptive pills (Dianette in UK and Diane-35 in other countries) it decreases acne and hirsutism (male-pattern hair growth).