1. Prevention of osteoporosis in
early menopause
Dr. Santiago Palacios
Antonio Acuña, 9
28009 Madrid
Phone: +34 91 578 05 17
E-mail: ipalacios@institutopalacios.com

2. Diapositivas/Slides
www.institutopalacios.com

3. • 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

4. EARLY MENOPAUSE
Bilateral oophorectomy
Bilateral oophorectomy 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

5. BILATERAL OOPHORECTOMY
Ovarian, endometrial or fallopian tube
cancers
Severe endometriosis
Bilateral tubo-ovarian abscess
Familial breast-ovarian cancer syndrome
Severe premenstrual syndrome

6. 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.

7. 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?

8. 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.

9. PREMATURE OVARIAN FAILURE
STUDY 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

11. Aetiology of POF
50%
45% 42% 43%
40%
35%
% of patients
30%
25%
20%
15% 13%
10%
5% 2%
0%
Idiopathic Cancer Benign Genetic

12. • 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

13. Influence of Estrogens on 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

14. Influence of Estrogens on Bone Remodeling Sequence
Estrogen Estrogen
Neg Neg
Neg . Neg
.
. .
Neg
.

15. • 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

16. Influence of age on 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

17. Age-adjusted RR for Spine 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

18. • 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

19. Effect of estrogen deficiency 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)

20. 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.

21. 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

22. Current T scores are 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

23. • 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

24. 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)

25. OOPHORECTOMY AS PREDICTOR OF
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

26. • 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

27. 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.

28. 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

29. 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?

30. 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

31. 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

32. 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.

33. 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

34. 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

35. Questions for Gynecologists, ACOG 2003-5: Would
you give a woman with idiopathic POF hormone
therapy (HT)?
• Yes – 94%
• No – 6%

36. 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%

37. 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%

38. 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%

39. 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

40. 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)

41. • 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

42. FUTURE RESEARCH IN WOMEN 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.

43. 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