prevention of osteoporosis in early menopause
TRANSCRIPT
Dr. Santiago PalaciosAntonio Acuña, 9
28009 MadridPhone: +34 91 578 05 17
E-mail: [email protected]
Prevention of osteoporosis in early menopause
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
EARLY MENOPAUSE
Bilateral oophorectomyBilateral oophorectomy
Acute hypoestrogenismand hypoandrogenism
Acute hypoestrogenismand hypoandrogenism
ET may be higherET may be higher
Premature ovarian failurePremature ovarian failure
The transition issimilar to natural
menopause
The transition issimilar to natural
menopause
BILATERAL OOPHORECTOMY
Ovarian, endometrial or fallopian tubecancersSevere endometriosisBilateral tubo-ovarian abscessFamilial breast-ovarian cancer syndromeSevere premenstrual syndrome
Surgical Menopause in USA
• 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.
PREMATURE OVARIAN FAILURE
Is the development of amenorrhea with concomitant sex hormone deficiency and elevated serum gonadotropin levels before age of 40 years?
Is the development of amenorrhea with concomitant sex hormone deficiency and elevated serum gonadotropin levels before age of 40 years?
Clinical Definitions• Abnormal Menses: 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.
PREMATURE OVARIAN FAILURESTUDY OF 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
Aetiology of POF
42% 43%
13%
2%
0%5%
10%15%20%25%30%35%40%45%50%
Idiopathic Cancer Benign Genetic
% o
f pat
ient
s
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
Influence of Estrogens on the development of physiologic bone geometry and bone architecture
Age
Bon
e M
ass
(g/m
2 )
„normal“
menopausepeak bone mass
menarche
SD
mean
1,2
1,1
1,0
0,9
0,8
00 10 20 30 40 50 60 70 80
I I I I I I I I
-
-
-
-
-
fracture threshold
Influence of Estrogens on Bone Remodeling Sequence Influence of Estrogens on Bone Remodeling Sequence EstrogenEstrogen
Neg.
Neg.
EstrogenEstrogenNeg.Neg
.
Neg.
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
Influence of age on Spine-BMD
Age
Bon
e M
ass
(g/m
2 )
„normal“
menopausepeak bone mass
SD
mean
1,2
1,1
1,0
0,9
0,8
00 10 20 30 40 50 60 70 80
I I I I I I I I
-
-
-
-
-
fracture threshold
Age-adjusted RR for Spine and Hip-Fracturein Relation to endogenous Serum E2-Levels
1.0 1.0
0.4 0.40.3 0.3
0.5 0.5
Cummings et al. (1998); NEJM Vol 339 No 11, 733-740
0,00
0,25
0,50
0,75
1,00
Rel
ativ
e R
isk
< 5 5-6 7-9 > 9Endogenous Serum Estradiol Level [pg/ml]
Hip-Fracture Spine-Fracture
Independent of BMDIndependent of BMD
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
SD
Age0 10 20 30 40 50 60 70 80
Peak bone mass
Mean
1,2
1,1
1,0
0,9
0,8
0
-
-
-
-
-
Lum
ber S
pine
BM
D (g
/m2 )
fracture threshold
Increased bone loss
Effect of estrogen deficiency on BMD in premenopausal women
Hadji et al. Frauenarzt 46, 10: 890-897 (2005)
T – SCORES vs 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.
Peak bone mass reaches its maximum between ages 20 to 29 yearsUp to 60% of adult total bone mineral is acquired during adolescenceThere are no normative tables for women <25 years
PREMATURE OVARIAN FAILURE
(A) Normal bone (B) Osteoporotic bone
is WHO criteria appropriate for diagnosis of
osteopaenia/osteoporosisin POF ?
Current T scores are invalid diagnostic markers of bone density in young POF patients POF patients require their own group specific baseline BMD valuesThe 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 researchQuantitative ultrasound
- no radiation exposure, inexpensive, lack adequate normative databases Magnetic resonance imaging
- radiation-free, evaluate bone geometry AND quality, lack normative databases
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
EARLY MENOPAUSE AS PREDICTOR 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)
OOPHORECTOMY AS PREDICTOR OF FRACTURE
(1) Women younger than age 45 years Fracture %
Oophorectomy 39
Histerectomy (non oop.) 24
Natural menopause 21
(2) Oophorectomy after menopause
Equal than natural menopause
(1) Johansson C et al. Maturitas 1993;17:39-50(2) Antoniucci DM et al. J Bone Miner Res 2005;20:741-47
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
PROPHYLACTIC OOPHORECTOMYRoutine prophylactic oophorectomy concumitantly with hysterectomyRoutine prophylactic oophorectomy concumitantly with hysterectomy
The familiar cancer syndromesThe familiar cancer syndromes
After chilbearingAfter chilbearing •Prevention of ovarian cancer 1.000 cases prevented 300.000 oophorectomies performed
•Reoperations for ovarian pathology 4-5 % of women who have had a previous hysterectomy
•Prevention of ovarian cancer 1.000 cases prevented 300.000 oophorectomies performed
•Reoperations for ovarian pathology 4-5 % of women who have had a previous hysterectomy
>40 years old>40 years old
Piver MS et al. Cancer. 1993 May 1;71(9):2751-5.
Christ JE, Lotze EC. Obstet Gynecol. 1975 Nov;46(5):551-6.
Principles of Hormone Replacement 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
Early menopauseTherapeutic 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?
HRT preparations in Early 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
Timing of HRT Usage• 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
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 ofE/P in women with POF.
17th Nov 200533 West London
Menopause & PMS Centre
Premature Ovarian FailureTherapeutic Options
• Combined oral contraceptive pill
– “Use of ethinylestradiol has been driven by practicalities rather than science”
» Conway et al (1996)
Guttman et al Clin Endocrinol 2001 West London Menopause & PMS Centre
Premature Ovarian FailureTherapeutic 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
Questions for Gynecologists, ACOG 2003-5: Would you give a woman with idiopathic POF hormone
therapy (HT)?
• Yes – 94%• No – 6%
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%
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%
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%
Additional Treatment in POF
• Addition of exogenous androgen?• Recommendations to prevent osteoporosis are
warranted:– Calcium 1200-1500 mg/day– Daily weight bearing exercise– Daily vitamin D
Fertility Options in women 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)
• CONCEPT• EFFECT OF ESTROGEN DEFICIENCY ON
BONE LOSS• BONE LOSS AFTER NATURAL
MENOPAUSE• EFFECT OF EARLY MENOPAUSE ON BMD• EARLY MENOPAUSE AND FRACTURES• PREVENTION• CONCLUSIONS
FUTURE RESEARCH IN WOMEN UNDERGOINGPREMATURE MENOPAUSE
1. Is premature menopause a deficiency diseaserequiring physiologic replacement?
2. Should be treated with exogenous E with or withoutprogestin?
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.
Future Objectives:
• Need to 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