Prevention of Osteoporosis in early menopause

Prevention of Osteoporosis in early menopause

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  Prevention of osteoporosisin early menopause Dr. Santiago Palacios Antonio Acuña, 9 28009 Madrid Phone: +34 91 578 05 17 E-mail: ipalacios@institutopalacios.com
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  Diapositivas/Slides www.institutopalacios.com
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  EARLY MENOPAUSE Bilateral oophorectomy Bilateraloophorectomy Premature ovarian failure Premature ovarian failure Acute hypoestrogenism Acute hypoestrogenism The transition is The transition is and hypoandrogenism and hypoandrogenism similar to natural similar to natural menopause menopause ET may be higher ET may be higher
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  BILATERAL OOPHORECTOMY Ovarian, endometrialor fallopian tube cancers Severe endometriosis Bilateral tubo-ovarian abscess Familial breast-ovarian cancer syndrome Severe premenstrual syndrome
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  Surgical Menopause inUSA • Chen WY Manson JE 2006 JNCI • “Premature Ovarian Failure in Cancer Survivors: New Insights, Looming Concerns” • 598 000 hysterectomies 1994-1999 in women below 40 (1/3 with BSO) i.e. 100 000 pa! • ie. Every year in US 33 000 left menopausal and 66 000 left with increased risk of POF.
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  PREMATURE OVARIAN FAILURE Is the development of amenorrhea with Is the development of amenorrhea with concomitant sex hormone deficiency and concomitant sex hormone deficiency and elevated serum gonadotropin levels before elevated serum gonadotropin levels before age of 40 years? age of 40 years?
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  Clinical Definitions • AbnormalMenses: a history of at least 3 consecutive months of oligomenorrhea or abnormal uterine bleeding. • Evidence of Reduced Fecundity: the development of fewer than 5 follicles (>15 mm) after appropriate gonadotropin stimulation (300 IU/day) or no pregnancy after one year of unprotected intercourse. • Elevated FSH: above the normal limit (95% CI) for the early follicular phase (days 2 to 5) as defined by the assay employed.
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  PREMATURE OVARIAN FAILURE STUDYOF WOMEN ACROSS THE NATION (SWAN) CAUCASIAN 1.0% AFRICAN – AMERICAN 1.4% LATIN 1.4% CHINESE 0.5% JAPANESE 0.1% ~ 70.000 women in Spain who have experienced premature ovarian failure Coulam CB et al. Obstet Gynecol. 1986 Apr;67(4):604-6
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  Aetiology of POF 50% 45% 42% 43% 40% 35% % of patients 30% 25% 20% 15% 13% 10% 5% 2% 0% Idiopathic Cancer Benign Genetic
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  Influence of Estrogenson the development of physiologic bone geometry and bone architecture menopause peak bone mass „norma 1,2 - l“ Bone Mass (g/m2) 1,1 - 1,0 - 0,9 - mean SD 0,8 - fracture threshold menarche 0 I I I I I I I I 0 10 20 30 40 50 60 70 80 Age
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  Influence of Estrogenson Bone Remodeling Sequence Estrogen Estrogen Neg Neg Neg . Neg . . . Neg .
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  Influence of ageon Spine-BMD menopause peak bone mass „normal“ 1,2 - Bone Mass (g/m2) 1,1 - 1,0 - 0,9 - mean SD 0,8 - fracture threshold 0 I I I I I I I I 0 10 20 30 40 50 60 70 80 Age
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  Age-adjusted RR forSpine and Hip-Fracture in Relation to endogenous Serum E2-Levels 1,00 Hip-Fracture Spine-Fracture 1.0 1.0 0,75 Independent of BMD Relative Risk 0,50 0.5 0.5 0.4 0.4 0.3 0.3 0,25 0,00 <5 5-6 7-9 >9 Endogenous Serum Estradiol Level [pg/ml] Cummings et al. (1998); NEJM Vol 339 No 11, 733-740
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  Effect of estrogendeficiency on BMD in premenopausal women 1,2- Peak bone mass Lumber Spine BMD (g/m2) 1,1- 1,0- 0,9- SD Mean 0,8- Increased bone loss fracture threshold 0 0 10 20 30 40 50 60 70 80 Age Hadji et al. Frauenarzt 46, 10: 890-897 (2005)
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  T – SCORESvs Z-SCORES The Z-score compares bone mass density with that of someone of similar age, sex, weight and ethnic/racial origin. So a Z-score of -0.5 indicates a bone density one-half of a standard deviation less than the norm.
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  PREMATURE OVARIAN FAILURE Peak bone mass reaches its maximum between ages 20 to 29 years Up to 60% of adult total bone mineral is acquired during adolescence There are no normative tables for women <25 years is WHO criteria appropriate for diagnosis of osteopaenia/osteoporosis (A) Normal bone in POF ? (B) Osteoporotic bone
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  Current T scoresare invalid diagnostic markers of bone density in young POF patients POF patients require their own group specific baseline BMD values The rising incidence of premature ovarian failure in an increasingly younger age group warrants re-evaluation of our diagnostic criteria to facilitate management of reduced bone mass in this vulnerable patient group. ALTERNATIVES: Quantitative computed tomography (QCT) - evaluate bone in 3 dimensions, ‘gold standard’, primarily for research Quantitative ultrasound - no radiation exposure, inexpensive, lack adequate normative databases Magnetic resonance imaging - radiation-free, evaluate bone geometry AND quality, lack normative databases
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  EARLY MENOPAUSE ASPREDICTOR OF FRACTURES AUTHOR % INCREASED Gardsel et al. 1991 50 Mallmin et al. 1994 100 (Colles fractures) Vega et al. 1994 300 (hip fractures) Tuppurainen et al. 1995 300 Van Der Voort et al. 2003 40 Van Der Klift et al 2004 247 (vertebral fractures)
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  OOPHORECTOMY AS PREDICTOROF FRACTURE (1) Women younger than Fracture % age 45 years Oophorectomy 39 Histerectomy (non oop.) 24 Natural menopause 21 (2) Oophorectomy after Equal than natural menopause menopause (1) Johansson C et al. Maturitas 1993;17:39-50 (2) Antoniucci DM et al. J Bone Miner Res 2005;20:741-47
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  PROPHYLACTIC OOPHORECTOMY Routine prophylactic oophorectomy concumitantly with hysterectomy Routine prophylactic oophorectomy concumitantly with hysterectomy The familiar cancer syndromes The familiar cancer syndromes >40 years old >40 years old After chilbearing After chilbearing •Prevention of ovarian cancer •Prevention of ovarian cancer 1.000 cases prevented 1.000 cases prevented 300.000 oophorectomies performed 300.000 oophorectomies performed •Reoperations for ovarian pathology •Reoperations for ovarian pathology 4-5 % of women who have had aa 4-5 % of women who have had previous hysterectomy previous hysterectomy Piver MS et al. Cancer. 1993 May 1;71(9):2751-5. Christ JE, Lotze EC. Obstet Gynecol. 1975 Nov;46(5):551-6.
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  Principles of HormoneReplacement in early menopause Estrogen replacement is first line treatment 1)Pre pubertal : To induce development of secondary sexual characteristics 2)To relieve the immediate sequelae of menopause i.e. symptom relief and quality of life 3)To prevent the long term sequelae of the menopause 4)To create an environment conducive to the successful replacement of donated embryos
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  Early menopause Therapeutic Options • Route / Type HRT • Choice of oestrogen route of administration must be made on individual basis • No controlled studies regarding the ideal hormone replacement strategy for women with premature ovarian failure In principle, non oral E2 / progesterone preparations can be better monitored but what is ideal E2 level?
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  HRT preparations inEarly menopause • Progestogenic opposition if uterus present – Even after radiotherapy • Aim for minimum effective oral dose or local opposition with Mirena / Crinone / Cyclogest • ?Aim for natural progesterone replacement
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  Timing of HRTUsage • Management – Liaise with gynae oncologists / medical oncologists / haematologists re time to start – Immediately if curative procedure (after hist diagn) – Delay (1 year disease free interval) if oestrogen sensitive tumour e.g. endometrial carcinoma – Treat at least until average age of menopause – HRT “holidays” to test ovarian function
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  Hormonal Replacement Therapy •Hormonal therapy would seem warranted for women – to eliminate symptoms and prevent bone loss; data from the WHI do not apply. • Abundant data indicate that E/P in any form does not prevent ovulation and pregnancy – for unclear reasons. Thus, barrier contraception may be warranted. • Young women without ovarian function may require more estrogen than older women to alleviate symptoms of estrogen deficiency. • There are virtually no data regarding the safety and efficacy of E/P in women with POF.
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  Premature Ovarian Failure Therapeutic Options • Combined oral contraceptive pill – “Use of ethinylestradiol has been driven by practicalities rather than science” » Conway et al (1996) 33 West London 17th Nov 2005 Menopause & PMS Centre
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  Premature Ovarian Failure Therapeutic Options • Combined Pill v HRT – 0.625mg v 30mcg EE in 17 adult women with Turner’s Syndrome – 6 month cross over study :Hormones, Lipids, Bone Turnover etc – FSH most suppressed by EE, BUT HRT was superior at minimising hyperinsulinaemia & bone turnover Guttman et al Clin Endocrinol 2001 West London Menopause & PMS Centre
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  Questions for Gynecologists,ACOG 2003-5: Would you give a woman with idiopathic POF hormone therapy (HT)? • Yes – 94% • No – 6%
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  Questions for Gynecologists,ACOG 2003-5: What form of HT would you administer to women with POF? • Combination oral contraceptives 60% • Continuous combined HT 16% • Sequential HT 22% • No therapy 1%
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  Questions for Gynecologists,ACOG 2003-5: How long should a woman with POF be treated? • Until the expected age of menopause 67% • For the remainder of her life 11% • For 1 to 5 years 11% • Uncertain 11%
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  Questions for Gynecologists,ACOG 2003-5: Is a woman with POF at increased risk of side effects from estrogen? • Yes 25% • No 38% • Uncertain 37%
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  Additional Treatment inPOF • Addition of exogenous androgen? • Recommendations to prevent osteoporosis are warranted: – Calcium 1200-1500 mg/day – Daily weight bearing exercise – Daily vitamin D
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  Fertility Options inwomen at risk of POF • Surgery – Ovarian transposition – Ovarian Tissue Cryopreservation • Transplantation – e.g. (Donnez 2004, Chaim Sheba Medical Centre Israel 2005, Oktay 2006) • IVF – Own Embryo Cryopreservation – Own Oocyte Cryopreservation (1st pregnancy 2001)
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  • CONCEPT • EFFECTOF ESTROGEN DEFICIENCY ON BONE LOSS • BONE LOSS AFTER NATURAL MENOPAUSE • EFFECT OF EARLY MENOPAUSE ON BMD • EARLY MENOPAUSE AND FRACTURES • PREVENTION • CONCLUSIONS
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  FUTURE RESEARCH INWOMEN UNDERGOING PREMATURE MENOPAUSE 1. Is premature menopause a deficiency disease requiring physiologic replacement? 2. Should be treated with exogenous E with or without progestin? 3. What form of HT is most appropiate? 4. For how long should HT be administrated? 5. How safe is HT in women with premature versus natural menopause? Hendrix SL. Am J Med. 2005 Dec 19;118(12 Suppl 2):131-5.
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  Future Objectives: • Needto merge data over the long term to look at quality of life / fertility outcomes / osteoporosis / CV disease • POF patients should therefore remain under long term follow up