9/28/2016

POI: Clinical Management Objectives Challenges: Optimizing  To review etiology of inadequate endogenous Therapy in in Turner’s syndrome Turner’s Syndrome  To discuss impact of hormonal depletion on patients with Turner’s syndrome

Wendy Wolfman MD  To formulate optimal replacements for Professor Department of Ob/Gyn University of Toronto women with Turner’s syndrome Director Menopause and POI Clinics Mt Sinai Hospital Toronto Canada  To discuss controversial issues in replacement North American Menopause Society Orlando USA Oct 6, 2016

Oocyte Destruction in Utero - Turner’s Syndrome Determined by Karyotype

 Initially a clinical diagnosis with characteristic physical  Incidence-1 /2500 , < 1% 45X survive pregnancy features with evidence of complete or partial absence  Normally X is inactivated in somatic cells during late blastocyst of second X with or without mosaicism. but 15-25%genes on short arm are still expressed

 Broad phenotypic spectrum and good quality of life in  in 45X accelerated atresia by 15-20 wk - few follicles in fibrous general streak at birth  Chromosomal types determine any residual  50% 45X • 20-30% mosaics  about 20% one normal X and structurally abnormal X

Bondy et al J Clin Endocrinol Metab Davenport M J Clin Endocrinol Metab 2010 2007 Levitsky Curr Op in Endo, Diab and Ob 2015

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Etiology of Hormonal Diagnosis Insufficiency

 1.Short stature (5’) and 2. Delayed 60-90%  Gonadal failure from haploinsufficiency of multiple X  3. Phenotypes-Edema hands, feet, Webbed neck, low post. hairline, Rotated genes ears, small mandible, cubitus valgus, short 4th metacarpal, high arched palate, widespaced nipples or hypoplastic ,multiple naevi  Candidates-USP9X involved in protein degradation and  cardiac anomalies -coarctation, bicuspid aortic valve, dilated aortic root BMP ( morphogenetic protein 15), type of growth  Renal anomalies -horshoe kidney, double or cleft renal pelvis factor βexpressed in oocytes  Autoimmune-Increased Hashimoto’s thyroiditis ,, liver function abnormalities , , IBD,  Exact reason not known  Metabolic- , hypertension and metabolic syndrome  Short stature due to homeobox-containing gene  Hearing problems, sensorineural loss (SHOX); found on short arm of X in pseudoautosomal  Learning issues, autism ADHD region

Rao Nat Gen 1997 Fukami Mol Syndromol 2016

What hormones are How many go through missing and need to be optimized? puberty?

 70-80% have no spontaneous pubertal development Missing hormone Results 90% primary  GH  Short statue   No or delayed puberty  Correlates with karyoptype-50% 45X  -produced by oocytes  No secondary sexual • 20-30% mosaics characteristics  about 20% one normal X and structurally abnormal X  -after  No growth spurt  Study with TS in 522–puberty less with 45X (9%)  -50% from  Small  Emotional +cognitive changes  84 (16%) attained puberty with menses of these 36%  Infertility regular for 9 years -14% secondary amenorrhea within 1.6-2 years after  ?Sexual issues?

Davenport M J Clin Endocrinol 2010 Pasquino A. J Clin Endocrin. Metab 1997

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Modern Day Turner’s in Importance of Adequate Multi-disciplinary Clinic Hormones pre and post Puberty

 Interdisciplinary clinic with endocrinology, and  Attainment of height, body habitus and BMD maintenance cardiology, possible ENT, psychiatry and cognitive support  Brain development -Cognitive function and mood- nonverbal learning

 GH, step-wise estrogen maybe oxandrolone to induce puberty  CVR function

 2 groups (most with primary amenorrhoea) fewer menstruating  Secondary Sexual Development close to peers  Group 1-need optimal HT  Emotional development and Sexuality-excessive shyness, social ,  Group 2-need to follow if and when HT needed delayed sexual debut, decreased marriage rate  discussion about protecting future (freezing or )  Uterine growth-size of uterus for future fertility-prolonged doses of E  If menses sporadic and low AMH could initiate sequential HT  MAY NEED CONTRACEPTION  Liver function-improved with E  Glucose control Bondy J Clin Endocrinol Metab 2007 I Bryman Fertil Steril 2011 Deligeoroglou J Obstet Gynaecol 2016 Kim J of Ped and Adol Gyn 2016 Cleemann Hormone Research in Paed 2014 Quigley Pedicatric Diabetes 2015

Effects of E Deficiency on Brain Development BMD in Turner’s  TS-reduced BMD and increased fracture risk with HT-?  Sex steroids affect neuromodulators ,alter synapse function Inadequate doses? ,attention, learning, memory ,motor function and cell survival  Multifactorial-SHOX haploinsufficiency, reduced  critical for higher cognitive functions, social , low vit D, high PTH and abn GH/IGF-1 axis and emotional behavior –increases white matter and decreases cortical gray matter  In POI treated with long-term estrogen from adolescence, BMD maintained at LS compared to  E alters cognition and mood in women-verbal working untreated-+ increased bone formation memory better during E dominant phase of menses  ESRM-healthy lifestyle, weight-bearing exercise, no  Early replaced TS better verbal and nonverbal memory, , normal body weight to optimize faster more accurate performances on timed spatial and motor tasks.  calcium, and estrogen replacement

Rosenberg L Psychoneuroendocrinology 2002 DiSomma Inte Gravholt Clin Endocrin 2003 Ross J Neurology 2000 rnational 2016 Crofton Clin Enodrin 2010 Ross J J Clin Endocrin Metab 1998 Nissen Clin Endocrin 2007 Zuckerman-Levin Clin Endocrin 2007 Nakamura Endocrine Journal 2015 Cleemann Eur J Endocrin 2009 Kim T-W Menopause 2016

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Hormone therapies during Androgen insufficiency reproductive life

 A, DHT, free T ant total T reduced ,DHEAS normal  When to start?-usually age 12 at low dose and titrate up- adult dose by 15?--no OCP to start as it affects  study in 14 TS with methyl T-increased BMD at development (tubular) spine and femoral area increased LBM, decreased chol  Route?-Transdermal versus oral estrogens HDL and TG, increased lean body mass  Type of progestin? Progesterone or synthetic  If T is added as adults need to monitor -?long term safety and side effects  Endometrial protection considering many years of hormone therapy  ? Improvement in energy, sexuality bone and cognition-  Sequential versus daily possible not proven  Restarting hormones after delivery-?right away

Bondy et al Endocrine 20012, Sas Horm Res Paediatr 2014 Quigley J of Clin Endo and Metab 2014 Gravholt Clin Endocrin 1999 ESRM 2016 Norjavaara Endocrine Development 2016 N Zuckerman-Levin J Clin Endocrin Metab 2009 Shah Int J of Ped Endo 2014

Evidence that HRT superior How do you optimize patient to OCP response and compliance?  1. Bone-improved LS after 12 mo HRT versus OCP and  1. acknowledge effects and risks of early menopause bone formation  2. Reassure that this therapy is necessary and not risky  2. Uterus –better uterine lining 4.8 versus 3 mm- but differences between Turner’s and other POI patients I  3. rule out contraindications (very few)  3. CVR- BP and lipids –lower syst and diast BP with  4. how old is the patient? transdermal HT –also differences in lipids with OCP’s  5. decide on patient’s preferred option  4. Less androgen suppression-increase in SHBG and free T with OCP  6. Younger women need higher doses  5. ? Breast-some physiological differences on stimulation  7. does patient have a drug plan? between progestins  INDIVIDUALIZE THERAPY Critchley Br J Ob Gyn 1990 Biljan Fertil Steril 1995 O’Donnell Hum Reprod 2012 Langrish Hypertension 2009 Crofton P Clin Endocr 2010

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Why transdermal route in Menopausal aged Women?- Menopausal Issues Similar Is this data relevant for young women?  Systemic Review and Meta-analysis--low confidence

Symptoms Other Issues  15 observational studies oral HT versus transdermal  Vasomotor Symptoms  Cardiovascular Aging therapy- 3-20 yrs, 22,489 on oral 5671 on transdermal  Sleep disturbances  Osteoporosis  Oral ET increased risk of first VTE (RR 1.63 CI 1.4-1.9 )  Mood changes and  Metabolic issues,BP DVT 2.09 CI 1.35-3.23) and possibly RR 1.24 CI  Diabetes and Cirrhosis 1.03-1.48)  Joint aches  Earlier neurological problems  But not MI (RR 1.17 CI 0,80-1.71)  Vaginal Dryness   Sexual Issues-,   No increase in TG or CRP Decreased  Parkinson’s  Irregular  Earlier death-50% excess -CVR  Bergendal+ Simon Menopause 2016-support findings o M, et al. Circulation. 2007;115:840. 2. Shifren JL, et al. Endocrinol Metab. 2008;93:1702. 3. Sanada M, et al. Menopause. 2004;11:331. 4. Walsh BW, et al. N Engl J Med. 1991;325:1196. 5. Modena MG. et al. Am J Med 2002; 113: 331‐4. 6. Lewandowski KC. J Clin Endo 2006; 91: 3123‐30. 7. Chu MC. Am J Ob Gyn 2008; 199: 526.e1‐526.e7. (K Mohammed J Endocrin Metab-Nov 2015)

What is the Best Controversies re Optimal Replacement ? Hormone therapy

 Depends on patient and compliance-Individualize • Does the patient want to menstruate?  younger patients tend to prefer OCP’s, older HT • What to do in patient intolerant to progestins? 100 mg P may be inadequate for long term endometrial  Average estrogen level during 382 pmol/L- • be physiologic -try and match protection • Are local therapies needed? (usually no symptoms with  Prefer transdermal therapies with 100μgm patches or 2 mg estrace-Higher doses these dosages) • Should we add testosterone?  12 days sequential (300 mg P) versus daily progestin- however optimal dose for daily P unknown with higher doses • Body identical (physiological) therapies of E- • For how long?  May be benefit to adding T and local estrogens vaginally

Rebaar R Obstet Gynecol 2009 Kaunitz Obste Gynecol 2015 N Am Men Society 2012 Stute P Climacteric 2016 Stute P Climacteric 2016 Sassarini Cl Endo and Metab 2015 Sassarini Cl Endo and Metab 2015

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Spontaneous fertility Fertility Options  Correlates with karyoptype:  90% primary amenorrhea, 2-5% conceive  Fertility from 0.8% 45X to 69% 45X/47XXX  10% may have small residual follicles at birth or early childhood  45X does not rule out ovarian function-usually not persistent  Need long arm of X for maintaining fertility  levels and AMH may be useful for predicting future gonadal function and determining timing of estrogen replacement  ?Cryopreservation of mature oocytes or ovarian tissue  Performed as young as 13-results unknown  AMH < 2 pmol/L predictor of failure to enter puberty imminent POI • Pre high risk multi-disciplinary and cardiac  Increased incidence of spontaneous abortion, stillborn congenital evaluation anomalies and aneuploidy in any pregnancies  donation Gestational surrogacy  Adoption

Lunding S J Clin Endocrinol Metab 2015 Oktay K J Pediatr Adolesc Gynecol 2015 Visser et al Hum Reprod 2013

ESHRE Guidelines 2016 for Consequences of untreated POI and Turner’s POI  Untreated POI associated with reduced life expectancy, due to CVR disease  Reduced life expectancy  “HRT has role in primary prevention of CVR disease and for bone  Increased CVR disease protection and should be offered throughout normal reproductive lifespan”  Earlier Parkinson’s, dementia, Alzheimer’s  No increased risk of breast CA in this age group  Osteoporosis  Patient preference for route and method should be considered  have limited data-evaluate after 3-6 mo and limit to 24 mo Ossewaarde Epidemiology 2005 Amagai J Epidemiol 2006  Most alternative and complementary treatments have limited data Rocca Lancet Oncol 2006, Neurology 2007 &2008 and efficacy Hong Maturitas 2007 Wu 2014 ESHRE Guideline Reproduction 2016

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Conclusion  Turner’s syndrome patients have many of the same issues of women with early menopause but are unique.  Best estrogen replacement is currently an individual decision.  More evidence accumulating that transdermal HT is preferable and should be prescribed until the average age of menopause or beyond  Adequate progestins need to be prescribed in patients using replacements for many years.

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