Endocrinological Management and Treatment of Adult Gender Dysphoric. Patients

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1 Endocrinological Management and Treatment of Adult Gender Dysphoric Leighton Seal PhD FRCP Consultant Endocrinologist Gender Identity Clinic Tavistock And Portman NHS Trust Patients

2 Outline Biological Model of gender development Terminology Treatment of Transgendered women Treatment of Transgendered Men Long Term outcome

9 Sexually Dimorphic Nuclei Hypothalamic Sexually dimorphic nucleus of the hypothalamus Bed nucleus of the stria terminalis Suprachisamatic nucleus Corpus callosum Spinal motor nucleus of the bulbocavernosus Dentate gyrus of the hippocampus Cortical thickness Amygdala

10 Evidence from animal Concentrate both oestrogens and androgens Highest levels of androgen receptor expression High levels of oestrogen receptor expression High Aromatase activity models Androgen and oestrogen administration at critical period can alter neuronal nuclear size and neuronal numbers

Testosterone ( nmol/l) 30 Plasma Testosterone Levels 25 20 15 10 5 0 0 4 8 12 16

11 Testosterone ( nmol/l) 30 Plasma Testosterone Levels term weeks weeks years Foetal Age Postnatal Age

12 Sexually Dimorphic Nuclei In Humans Corpus callosum Sexually dimorphic nucleus of the preoptic area

14 Sexually Dimorphic Nuclei of the Hypothalamus In Humans Allen did not find a difference in overall POA and found several neuronal clusters Interstital Nucluei of the Hypothalamus (1-4) INH 2 2x larger in males INH 3.2 larger in women of reproductive years that non reproductive INH 3 2.8x larger in males

15 male female Zhou 1995 Nature

16 Hormonally Influenced Sex Specific Behaviours in Humans Sexual Orientation Core Sexual Identity Rough Play Aggression Visio spacial ability Verbal skills Hand preference

17 Complete Androgen Insensitivity

18 Congenital Adrenal Hyperplasia

19 heterosexual male heterosexual female homosexual male transwoman Zhou 1995 Nature

20 Role of Endocrinologist in the Management of Gender Diagnosis of associated endocrine abnormalities Dysphoria Hormonal treatment of transgender patients

21 Associated Conditions Intersex Congenital adrenal hyperplasia Androgen insensitivity Gonadal dysgenesis 5α reductase deficiency Aromatase deficiency Chromosomal abnormality Kleinfelter s syndrome Turner s Syndrome Exogenous Hormone exposure

22 Incidence of Transsexualism 1:30,000 natal males. 1:100,000 natal females seek SRS. (APA, 2000) 1:7440 for natal males 1:31,153 for natal females. (Wilson, Sharp and Carr, 1999) A non-conservative estimate is that 8-10% of the United States population has some degree of GD. (Ettner,1999) 5% of population seeking trans related services (NHS Calderdale, 2009)

23 Subjects(%) Birth Gender (%) Male Female

24 Age (years) Age at Baseline Transwoman Transman

25 Terminology Gender Non Conformity Gender Dysphoria Non Binary Gender Identity

27 Gender Dysphoria DSM-V a marked difference between the individual s expressed/experienced gender and the gender others would assign him or her, and it must continue for at least six months. In children, the desire to be of the other gender must be present and verbalized. This condition causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

30 ICD-10 Transsexualism The desire to live and be accepted as a member of the opposite sex usually accompanied by the wish to make his or her body as congruent as possible with the preferred sex through surgery and hormone treatment The transgender identity has been present for a minimum of 2 years The disorder is not a symptom of another mental disorder or chromosomal disorder

31 ICD 11 Will remove Gender Identity disorders from mental health section Gender Incongruence A marked incongruence between one s experienced/expressed gender and assigned gender, of at least 6 months duration, as manifested by 2* or more of the following indicators: 1. a marked incongruence between one s experienced/expressed gender and primary and/or secondary sex characteristics (or, in young adolescents, the anticipated secondary sex characteristics) 2. a strong desire to be rid of one s primary and/or secondary sex characteristics because of a marked incongruence with one s experienced/expressed gender (or, in young adolescents, a desire to prevent the development of the anticipated secondary sex characteristics) 3. a strong desire for the primary and/or secondary sex characteristics of the other gender 4. a strong desire to be of the other gender (or some alternative gender different from one s assigned gender) 5. a strong desire to be treated as the other gender (or some alternative gender different from one s assigned gender) 6. a strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from one s assigned gender)

32 ICD 10 Diagnosis Adult Specialist Mental health professional with appropriate qualification in that field Specialised training in the diagnosis of DSM/IDC-10 Sexual Disorders Training in psychotherapy CPD in gender disorders

33 Tridadic Therapy The principal of treatment is Tridadic Therapy Social Gender Role Change Hormonal Therapy of the Desired Gender Genital Reconstrucitve Surgery GRS Hormones SGRC

34 Screening tests LH FSH Testosterone Oestradiol SHBG Prolactin Dihydrotestosterone PSA (Karyotype) LFT FBC Lipids Glucose Weight BMI BP

35 Vitamin D levels in those taking and not taking hormones prior to clinic attendance

36 Aim of therapy To Suppress genetic sex hormone production Induce sexual development of desired gender Prevent long term complications of hypogonadism

37 Hormone Regimens Used Moore JCEM

38 Transwomen

39 Oestrogen Effects in Transwomen EFFECT ONSET MAXIMUM Redistribution of body fat months Decrease in muscle mass and strength Softening of skin/decreased oiliness Decreased libido Decreased spontaneous erections Male sexual dysfunction Breast growth Decreased testicular volume Decreased sperm production Decreased terminal hair growth Scalp hair Voice changes months 3 6 months 1 3 months 1 3 months Variable 3 6 months 3 6 months Unknown 6 12 months No regrowth None 2 3 years 1 2 years Unknown 3 6 months 3 6 months Variable 2 3 years 2 3 years > 3 years > 3 years Hembree JCEM 2009, 94(9):

40 Time Course of Breast Development in Transwomen Mayer III 1986 Arch of Sex Behav 15 (2)

41 Hormone Replacement Maximum effect takes up to 2 years Transwomen 5 years Transmen Increasing doses does not lead to increasing effect Response is individual Genetic make up limits the tissue response

42 Need for Augmentation by Selfmedication Status 12 * 10 Subjects (%) Augmentation No Augmentation Seal JECM :

43 Need for Augmentation by Oestrogen Type Subjects (%) 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% Augmentation No Augmentation 0% Oestrogen Valerate Ethinyl Estradiol Premarin Seal JECM :

44 Need for Augmentation by Testosterone Suppression Type Subjects (%) ** Augmentation No Augmentation 0 Antiandrogen Cyproterone Acetate Finasteride Spironolactone Dutasteride GnRH Seal JECM :

46 Endocrine Society Guidelines 2017 JCEM 2017, 102(11):1 35

47 Standard preoperative treatment protocol at Charing Cross Hospital Gender Identity Clinic Oestrogen Valerate 2-10mg/day Decapeptyl 11.25mg/12wk or Transdermal Oestrogen Valerate Gel 1-4mg/day Patches (50-200mgx2/week) or Ethinyl oestradiol μg/d

48 Standard preoperative treatment protocol at Charing Cross Hospital Gender Identity Clinic Monitoring 8 weeks after starting a new dose of medication Dose increased every 3 months until target range achieved or maximum dose Level of Oestradiol is sub optimal on oral dosing change to topical preparations

49 Oestradiol (pmol/l) A Comparison Between oral and Topical Oestrogen 11.3% have suboptimal oestrogen level on oral oestrogen Oral

50 Post GRS Doses Doses reduce by half post operatively if on suppressive oestrogen Preop dose continued if on GnRH analogues

51 Contraindications History of Breast Cancer History of Prostate cancer Thromboembolism Active Recurrent Focal migraine Dubin-Johnston and Rotor syndromes

52 Relative Contraindications Obesity Smoking Ischaemic heart disease Single DVT Family history of breast cancer Family history of thromboembolism Migraine Sickle cell disease Gall stones

53 VTE Risk in Women Taking Oral Contraceptive Pill Pomp Am J Haematol

54 VTE by Weight Category in Combined Oral contraceptive users Farmer 2000 Br J Clin Pharmacol, 49, 580±590

55 Morbidity in 816 Transwomen Venous thrombosis/pe Postoperative After Trauma Without Cause Myocardial Infarction (6 fatal) Angina Pectoris Cerebrovascular Disease TIA Intracranial Haemorrhage Occlusion of Leg Artery Hypertension (>160/95mmHg) Prostatic Carcinoma Elevation of Prolactin (>1000mU//l) Elevation of Liver Enzymes Transient (<6 months) Persistent (>6 months) Hepatitis B Alcohol related Others Cholelithiasis (5 Preexistent) HIV Seroconversion (3 died of AIDS) No. Observed SIR (95% CI) [ ] 0.05 [ ] NA 1.71 [ ] NA 0.98 [ ] 0.91 [ ] [ ] [ ] [ ] NA Van Kesteren Clin Endo

56 Morbididty: Male to Female Thromboembolism x20 (14%) 60% in first year 0.4% annual incidence Hyperprolactinaemia x80 Gall Stones X5 MI rate half expected

57 Thromboembolism Risk By Oestrogen Type 6 * 5 Thromboemolism (%) Oestrogen Valerate Ethinyestradiol Premarin

58 Effect of Oestrogens on Coagulation factors in Transpeople CPA-only (open bars), td-e2+cpa (shaded bars), and oral-ee+cpa (solid bars), F M transsexuals with T esters (hatched bars). PT, Prothrombin; PS, protein S; PC, protein C. 1 Toorians AW, J Clin Endocrinol Metab 2003; 88(12):

59 Side effects of Hormone Treatment in Transwomen Type of oestrogen Adverse event Oestrogen Valerate N= 163 Ethinyl Estradiol N= 132 CEE N= 45 Total (of population) N=342 Depression Thromboembolism * 1.2 Flushing Hair Loss 2.5* Hyperprolactinaemia Hypertension Diabetes Abnormal Liver Function Seal JECM :

60 Other Therapies Anti androgens Cyproterone acetate Finasteride

61 Other Therapies Anti androgens Cyproterone acetate Finasteride Abnormal LFT Liver Tumours Depression Meningioma

62 Other Therapies Anti androgens Cyproterone acetate Finasteride Abnormal LFT Liver Tumours Depression Meningioma Oestrogen receptor agonists Spironolactone

63 Other Therapies Anti androgens Cyproterone acetate Finasteride Abnormal LFT Liver Tumours Depression Meningioma Oestrogen receptor agonists Spironolactone Abnormal U +E Abnormal LFT Hyperkallaemia

64 Other Therapies Anti androgens Cyproterone acetate Finasteride Abnormal LFT Liver Tumours Depression Meningioma Oestrogen receptor agonists Spironolactone Abnormal U +E Abnormal LFT Hyperkallaemia GnRH analogues

65 Other Therapies Anti androgens Cyproterone acetate Finasteride Abnormal LFT Liver Tumours Depression Meningioma Oestrogen receptor agonists Spironolactone Abnormal U +E Abnormal LFT Hyperkallaemia GnRH analogues (Menopausal symptoms)

66 Progesterone Not produced until ovulatory Menstruation Increases Body temperature Secretory endometrium Thick cervical mucus Low vaginal ph Pregnancy Inhibits uterine contraction Decrease in smooth muscle tone Alveolar growth in the breast Increased fluid in stroma

67 Action of Progesterone Not produced until ovulatory No role in pubertal breast development Induces 17β HSD to inactivate Oestradiol Inhibits oestrogen induced proliferation Natriuretic Decreases Mood

68 Gender Identity Clinic Charing Cross Hospital

69 Monitoring Preparation Dose Frequency Oestradiol Values Oestradiol Valerate: Progynova Climaval Or Oestradiol Hemihydrate: Zumenon Patches: Estradot Everol Topical Gel: Sandrena Implants Oestrogen Implant 1mg and 2mg tablets 50mcg 200mcg twice weekly 0.5mg to 1mg sachets mg Take all at same time Change patch/es twice a week Apply to anywhere on body except breasts 6-24monthly pmol/L As above Monitoring Method Bloods should be drawn 4-6 hours after taking tablets Blood 48 hours after patch application As above Bloods 4 6 hours after application and no gel on the arms. Trough value of pmol/l 5 months after implant then repeated monthly Maximum Dose 8mg daily 200mcg x2/week 5mg daily 150mg

70 Monitoring LFT s, Oestradiol Testosterone SHBG Prolactin. For timings see previous If dose changed bloods to taken 8 weeks after the change. Once stabilised bloods should be taken six monthly for two years then annually

71 Considerations with Age Treatment is Lifelong Breast Cancer risk Background male risk Over 40 (Consider topical therapy) Over 50 as recommended by national guidelines Mammography PSA screen DEXA Aortic Aneurysm

Information About Hormonal Treatment for Trans women

Information About Hormonal Treatment for Trans women Leighton J Seal PhD FRCP Consultant Endocrinologist, Gender Identity Clinic, (Charing Cross) West London Mental Health NHS Trust 12/12/2016 1 Introduction...