Menopausal - Dr. Manuel Neves e Castro

Menopausal Medicine:
The past, the present and the future.
Where are we now?
by
Manuel Neves-e-Castro, MD
(Lisbon, Portugal)
1 st Postgraduate Academic Course on Menopause
EMAS
November 2001
Toledo

To know how to suggest
is the art of teaching
(Anonimous)

Organotherapy
History: The Past
Egipt
Greece
Rome
France (1888)
Germany (1899)

1896: the Begining of HRT
Three german groups reported
that treatments with “ovarian
powders” relieved symptoms
related to the menopause.

The devopment of Estrogens(1)
Internal secretion :Theophile de Bordeu ,1755
Hormones :Baylis, Starling
Estrogenic effects:
Claude Bernard ,1885
William Hardy (UK)
- Vagina - Stockard and Papanicolaou 1917
- Uterus - Allen and Doisy 1924

The devopment of estrogens(2)
Estrin(Parkes and Bellerby, 1926)Hormone
extracted from the ovary with fat solvents.
Estrone (Butenandt ,1929) isolated in pure
form from the urine of pregnant women.
Estriol (Marian) isolated from the urine of
pregnant women.
17ß-Estradiol (1940) isolated from the urine
of pregnant women and from the placenta.

“The therapeutic use of
amniotin in the menopause”
“For hot flashes, sweating,
irritability and libido”
SH Geist and F Spillman
Am.J.Obstet.Gynecol.1932;23:697-707

The pioneers: the Industry
Schering (Germany)
Organon (The Netherlands)

The first medicines for HRT
Progynon ( Schering)
Premarin (Ayerst)
Estradiol (Implants)
Primolut (Schering)
Norlutin (Parke Davies)

Menopausal Osteoporosis
Fuller Albright, 1940

“Feminine for ever”
Robert Wilson 1966

The Pioneers
Robert B .Greenblatt (USA)
Wulf H Utian (South Africa and
USA)
Pieter van Keep (The Netherlands)

The Present ...

« Health is a condition of physical,
mental and social wellbeing and not
only the absence of disease. »
W.H.O.

The assessment of health is
far more difficult than the
diagnosis of disease.
M.N.C. 10/99

A menopausal woman is a
middle-aged woman

As a menopausal woman:
She is hypoestrogenic and will
suffer, at various levels, from
its consequences.
MNC 04/00

As a middle-aged woman:
She will suffer from the
process of natural aging, both
from a biological and a
psychological perspective.
MNC 04/00

Menopausal Hormonal
Treatments (MHT)
The more physiologic (if
not contraindicated)

HRT is indicated for:
- Relief of symptoms
- Maintenance and improvement of
health
- Prevention (primary and secondary) of
diseases

Pharmacologic interventions
- Symptomatic
- Preventive
- Primary
- Secondary

“The compression of
morbidity”
J F Fries et al 1981

Pharmacologic interventions
- hormonal
- non hormonal

PEPI Trial
Not all progestagens are
alike

“The pharmacokinetics and
efficacy of different estrogens
are not equivalent”
R.Ansbacher –
Am.J.Obstet.Gynecol.2001;184:255-63

Breast Cancer

“1: 397 women taking ERT
over 10 yr would develop a
breast cancer that would
not have ordinarily
occurred if ERT were not
used”.
Santen RJ et al. J Clin Endocrinol Metab 2001; 86:16-23

Breast Cancer and HRT
CGHFBC-Lancet 1997;350:1047-59
Cumulative incidence/1000 women
(starting at age 50)
5 years 2 new cases
10 years 6 new cases
15 years 12 new cases

HRT and Breast Cancer link
still unclear
Bush TL et al -Hormone replacement
therapy and breast cancer: a qualitative
review. Obstet Gynecol 2001;98:498-508

“The evidence did not support the
hypotheses that estrogen use
increases the risk of breast
cancer and that combined
hormone therapy increases the
risk more than estrogen only.
Aditional observational studies
are unlikely to alter this
conclusion”.

“HRT started at age 55 for 10 years
can prolong life”.
“One excess breast cancer case is
likely to occur per 5-6 averted cases
of first myocardial infarction or hip
fracture”.
Moerman CJ, Vanhout BA, BonneuxL, et al. J Intl Med
2000;248(2):143-150

Familial Breast Cancer
“Collaborative reanalysis of individual data
from 52 epidemiological studies including 58
209 women with breast cancer and 101 986
women without the disease”
Collaborative Group on Hormonal Factors in Breast
Cancer (Oxford)
Lancet 2001;358:1389-99

Familial Breast Cancer
“1/9 women who develop breast
cancer may have an affected
mother, sister or daughter”
Collaborative Group on Hormonal Factors in Breast
Cancer (Oxford)
Lancet 2001;358:1389-99

Familial Breast Cancer
Lifetime excess incidence of breast cancer:
5.5% for women with one affected first degree relative
13.3% for women with two affected relatives
Collaborative Group on Hormonal Factors in Breast Cancer
(Oxford)
Lancet 2001;358:1389-99

Familial Breast Cancer
Estimates for death from breast cancer up to
age 80:
2.3% for no affected first degree relatives
4.2% for one affected “ “ “
7.6% for two affected “ “ “
Collaborative Group on Hormonal Factors in Breast
Cancer (Oxford)
Lancet 2001;358:1389-99

Physical Exercise Activities
and Risk of Breast Cancer
• 2 to 4 hours / week RR = 0.8
• > than 4 hours / week RR = 0.4

Relative Risk of Breast Cancer
and Body Weight
• Weight (> 60 kg) and Age (>50 years)
• increase the RR between 1.2 and 1.8

The Heart

HRT prevents a new
cardiovascular event in 1:
270 50 year old women
taking HRT for 10 yr.
Grodstein F et al. N Engl J Med.2000;335:453-461

“The risk for major coronary events
was lower among current users of
hormone therapy, including short-
term users, compared with never
users [(relative risk, 0.61 (95% CI,
0.52-0.71)]”.
Grodstein F. et al.Ann Intern Med 2000;133:933-41

“When are observational studies
adequate evidence”?
Grady D. and Hulley SB. Ann Intern Med
2000;133:999-1001

The HERS trial
Does HRT increase CVD
events?

he HERS Study, as interpreted by a
practitioner, is nothing but a phase
III Study of a particular product
(0.625 mg of conjugated equine
estrogens plus 2.5 mg of
medroxyprogesterone acetate, in one
tablet daily).
Neves-e-Castro M. Maturitas 2001;38(3):235-237

It is not a study of
estrogen/progestin replacement
in postmenopausal women.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

he protocol of the study does not
reflect good clinical practice.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

“The RH comparing risk of the
primary CHD outcome in the
hormone and placebo group was
similar”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

“The discrepancy between the
finding of HERS and the
observational studies may also
reflect important differences
between the study populations
and treatments”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

“For women who stopped taking
HERS medication, the risk of
primary CHD events was
elevated in the first month after
stopping use of the
medication”?!
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

“HERS did not evaluate the effect
of estrogens plus progestin therapy,
in women without CHD, and it is
not known whether our findings
apply to healthy women. It is also
not known whether the use of
different progestin or of estrogens
alone would have been beneficial”.
Hulley S, Grady G, Bush T, et al. JAMA 1998;280:605-13

“The disappointing results of three
recent trials indicate that clinicians
should not use hormone therapy for
prevention of coronary disease until
this practice is supported by
evidence from randomised trial”!
GradyD, Hulley SB.Ann Intern Med 2000;133:999-1001

“Perhaps post-menopausal
hormone therapy is beneficial in
women who have not yet
developed coronary disease but
not in women who already have
it”.
Grady D, Hulley SB. Ann Intern Med 2000;133:999-1001

The findings of HERS should not
discourage the use of hormone
replacement therapy in the primary
prevention of cardiovascular
disease”.
Tolbert T. and Oparil S. Circulation 2001;103:620-2

“Hormone Replacement Threrapy
and Cardiovascular Disease”.
A Statement for Healthcare Professionals
From the American Heart Association.
Mosca L et al;Circulation.2001;104:499-503

“Hormone Replacement Therapy and
Cardiovascular Disease”.
“There are insufficient data to suggest that
HRT should be initiated for the sole (?)
purpose of primary prevention on CVD”
(Circulation 2001)

“Hormone Replacement Therapy and
Cardiovascular Disease”.
The majority of data available to make clinical
recommendations are based on standard doses of
oral CEE/MPA. Evidence is insufficient to determine
whether different perparations, routes of delivery,
doses, or different progestins have a more favorable
or more adverse effect on clinical CVD end points”
(Circulation 2001)

“Hormone Replacement Therapy and
Cardiovascular Disease”.
“In conclusion, recommendations such as
these of the AHA (Circulation 2001),writen as they
are, may be less helpful than intended, both
for clinicians and women”.
Neves-e-Castro M.The ImaginaryWoman, Maturitas 2001 (in press)

HRT and CVD
“The Effect of Treatment with Estradiol
and Norethisterone Acetate on Exercise
Tolerance and on the the Frequency
and Severity of Ischemic Attacks in
Postmenopausal Women with Stable
Angina Pectoris”.
Sanderson JE et al.J Cardiovasc Pharmacol 2001;38(3):372-383

HRT and CVD
“The total number of ischemic events/24 h
during ambulatory electrocardiographic
monitoring decreased by 0.82 events after
treatment compared with an increase in the
placebo group (0.94), a highly significant
difference (p=0.006)”.
Sanderson JE et al.J Cardiovasc Pharmacol 2001;38(3):372-383

The ERA Trial

Epidemiological Studies
- How were they performed?
- What similarities do they have
with our clinical practice?
- How to interpret them?

with
Do not confuse…
Relative Risk
Absolute Risk!

with
Do not confuse…
Morbility
Mortality!

Epidemiological Studies
PLEASE!
Do not read only the tittles
Do not read only the abstracts
Do read the full paper
Be critical!
Make up your own mind!
MNC 11/01

The CNS

HRT reduces the incidence
of colon cancer

Epidemiology

Epidemiological Studies
- Observational
- Clinical trials

What is
a woman /year ?!

100 woman/years = 100 women treated
during 12 months
is it the same as
100 woman/years = 400 women treated
during 3 months
?

Women are not statistics!
They must be treated
individually.

Menopausal hormonal treatments
are very good.
but
Treatments without hormones may
also be very good for a woman’s
health

“When hormone replacement
therapy is not possible”
Neves-e-Castro M in “The Management of the Menopause; The
Millennium Review 2000” Ed.John Studd; Pathernon, NY 2000

HRT is not possible ...
- When it is not wanted by women.
- When women do not feel the need.
- When there are contraindications.

Look for risk factors
- Cardiovascular
- Cancer
- Bone
- CNS

- Tibolone
- Serm’s
New Molecules
- Bisphosphonates
- PTH
- ERß ligands
- New progestagens
- Vitamin D3 derivatives

The analysis
Benefit/risk
Benefit/cost

“All medical interventions
should be individualised to the
specific woman’s age,
characteristics and needs”.
Genazzani AR, Gambacciani M. IMS Expert Workshop, Climacteric
2000;3:233-240

Monitor
The efficacy of your interventions in
regard to the predetermined
objectives/targets

For how long?

The Future ...

Life is not to live,
but to be well.
The first wealth is health.
(Anonimous)

Hormones ?

“For a woman with high-risk
profile, the gains in health are
about twice as high as for her
counterpart in the general
population, and her risk-benefit
ratio is also more favourable”.
Moerman CJ, Vanhout BA, BonneuxL, et al. J Intl Med
2000;248(2):143-150

Those who only investigate HRT
and never see a patient may have
doubts about the enormous
benefits of HRT in terms of
quality of life.

“I believe that controlling hormone levels and
improving their communication within the
body will become the central focus of health
care in the future. I also believe they are the
key to reversing the aging process. And that is
the real goal everyone desires”.
Barry Sears-”The anti-aging Zone”. chap.29 Regan Books,NY.1999

HRT seems to be the best
pharmacological available
strategy to improve brain
function and to prevent colon
cancer

Vitamin D derivates convert
colon cancer cells
Alberto Muñoz et al.
Spanish Society for Biochemistry and Molecular
Biology (Valencia, 18-19 September 2001)
Lancet Oncology,2:593(October 2001)

Estrogens and Vascular System
Estrogens protect the heart against
coronary artery disease and they are
now regarded as being as important as
aspirin and antihypertensive drugs were
in the past.

Lipid-lowering therapy promotes
clinically stable plaque
- Prolonged intensive lipid-lowering therapy is
associated with a markedly decreased lipid
content in carotid atherosclerotic plaques
- The clinical implication of this is that the low
plaque lipid composition would predict greater
plaque stability, and would thus reduce clinical
ischemic events such as myocardial infarction or
stroke.
Zhao X-Q et al. Arterioscler Thromb Vasc Biol 2001;21:1623-1629,1563-
1564 (October)

“Nitroglycerin Therapy Is As
Efficacious As Standard Estrogen
Replacement Therapy (Premarin) in
Prevention of Oophorectomy-Induced
Bone Loss: A Human Pilot Clinical
Study”
Wimalawansa, SJ. J Bone Miner Res,2000 Nov, 15(11) p2240-2244

“This study showed for the first
time that NG is as effective as
estrogen in preventing bone loss
in these surgically induced
menopausal women.”
Wimalawansa SJ

“Although estrogen decreased
serum osteocalcin and bone-
specific alkaline phosphatase
levels, NG therapy significantly
increased these two markers of
bone formation.”
Wimalawansa

In the future...
Will phytoestrogens be
usefull for breast
protection ?
MNC 3/01

In the future...
Will hCG be used, in
nuliparous women on
HRT, to protect their
breast from a cancer risk?
(J.Russo)
MNC 3/01

In the future
Will progesterone medicated
IUD’s replace oral
progestagens in HRT?
MNC 3/00

To give, or ...
Not to give?...
HRT

- The important issue, after all, is
not HRT
-What is important is the best
possible approach to preventive
medicine in a middle-aged
woman
MNC 3/01

Can side effects be minimized ?

First of all, there are many different
post-menopausal hormone
therapies: different estrogens,
different progestins, different
routes of administration, different
regimens, which have different
profiles.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

Second, there are those who know
and those who do not know to
tailor-make it to a particular
woman and to monitor its efficacy
in the targets that have justified its
selection.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

Third, there are those who think
that the menopause is a disease to
be treated solely with sex hormones,
and there are those who believe that
the menopause is an event in a
middle-aged woman’s life.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

The support of good health and
- Aerobic exercise
- Rational nutrition
- Reduced smoking
longevity
- Reduced Alchool consumption
- Develop Mental ocupations
- Pharmacologic interventions

“Menopausal” Treatments
for the future?
Casper’s “continuous estrogen/intermittent progestin”
(Endometrium protection)
DHEA-S (Brain, Bone, CNS)
Testerone + Estradiol (CNS, Bone)
Melatonin (CNS, Cancer)
Phytoestrogens (CNS, CV, Cancer)
hCG (Breast protection)
Estrogens only (Oral or Parenteral) + Progesterone medicated
IUD’s (Breast and Endomentrium protection)
MNC 11/01

What do we know today?

There are today in the
World 470 million women
over 50 years of age
E.Barrett-Conor, 1993

Some
concepts
to remember ...

Health
Is an essential wealth that
must be enriched
by all means

Health
“Is a state of physical, psychic
and social wellbeing and not
only the absence of disease”
WHO

This is the global (holistic)
dimension of Health

The Science of
- Diagnosing
- Treating and
Medicine
- Preventing diseases

Preventive Medicine
“The branch of medical science
concerned with the prevention of
diseases ,with with promotion of
physical and mental health through
study of aetiology and epidemiology of
disease processes”
Stedman’s Medical Dictionary

Gynaecology:
What is it?

Gynaecology = gynaeco + logos
i.e.
the Science or the Study of the
Woman, as a whole .

However, today
Gynaecology = gynaeco-pathology
i.e.
the study and treatment of the
diseases of women

Gynaecology:
Is today more concerned with the
organic pathology of women,
without much consideration of
their psychic dimension ,and
even less with their physical and
mental health.

The attending physician must
- adopt a holistic vision of the middle
age woman who comes to him for
support.
- be concerned and involved in all the
aspects that define health.
M.N.C. 10/99

Attention!
-The therapeutic support during the menopause is not
confined only to drugs.
-It is not the menopause that is going to be
treated:
-It is a woman,in a very special period of her
life,with affective and hormonal imbalances,who
needs to be supported and treated as a whole,as
she is.
M Neves-e-Castro

A modern gynecologist must ...
know how to identify risk
factors and to modify them in
order to prevent diseases.
M.N.C. 10/99

As physicians - gynaecologists:
Our mission is:
1. To preserve and to promote the
physical and mental health of women.
2. To identify and to modify the risk
factors that may lead to diseases.
3. To diagnose and to treat their diseases.
MNC 10/99

Modern gynaecologists :
must be:
- “People”
- Physicians
- and ... Specialists
MNC 10/99

A Menopausal Woman?
or
A Middle Aged Woman?

“The Menopause: an
opportunity”
Leon Speroff

“The Menopause: an alarm
clock!”
M Neves-e-Castro

Science ...
is an art of probability
Medicine...
is an art of uncertainty
Sir William Osler

Evidence based Medicine
and
Medicine based Evidence

HRT
Hormone replacement therapy?
or
MHT
Menopusal hormonal therapy?
MNC 03/00

The take home message
The prescription of long-term
hormonal treatments must depend
always on a benefit/risk analysis in
comparison with other non-hormonal
medications and strategies.

Every discussion about the
Menopause (the Queen...) seems to
implicate that there is nothing but
HRT!
Neves-e-Castro M. Maturitas 2001;38(3):235-237

The Queen... Is naked!
Neves-e-Castro M. Maturitas 2001;38(3):235-237

It is very important that the woman
understands what is being done and
how the objectives are being fulfilled.
This is the best way to ensure
continuity.

The physician must give advice.
The woman must take the decision.

The physician must give advice.
The woman must make the decision.

Preventing a woman from the
benefits of a sound
postmenopausal hormone
therapy because of the fear
of rare side effects does not
seem to be satisfactory
Medicine...
MNC 3/01

White woman’s risk of death between
the ages of 50 and 94 are:
After Preventing all ...
For a 10 year a woman long HRT from itthe
“Only is benefits likely 20% that of women of one may a who avert sound start
HRT Good 6 31.0% postmenopausal cardiovascular seem clinical from to continue heart judgement events disease hormone treatment per
after 1 must therapy 2.8% diagnosed 4 years”. prevail! from because breast of cancer. cancer the fear
of rare side effects does not
2.8% from hip fracture
seem to be satisfactory
Medicine...
Henderson BE et al.Arch Intern Med 1991;151:75-8
Pilon D, Castilloux A, Le Lorier J. Obstet Gynecol
MNC
2001;97:97-100.
MNC
2001
3/01
Brinton LA, Schairer C. N Engl J Med.1997;336:1769-1775

Menopausal Medicine?
Woman’s Medicine?
Medicine?

A Woman
in the autumn of her life
deserves an indian summer
rather than a winter of a discontent ...
Robert B Greenblatt

WEB SITES
• http://www.yourcancerrisk.harvard.edu
• http:// www.menopause.org
• http://www.imosociety.org
• http://www.obgyn.net/meno
• http://www.spmenopausa.pt
(see “ligações”=links)