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The Climacteric Womantreatment options in 2006 :

what has experience taught me

Manuel Neves-e-Castro, MD

Lisbon, Portugal, 2006

I am

- a normal human being

- a medical doctor

- a feminologist (gender medicine)

- a gynecologist

- an endocrinologist

But... certainly I am not

a menopausologist ...

Is there a Menopausal Medicine?

There is only ONE Medicine (L.Speroff)

There are only TWO Medicines (MNC):

a BAD Medicine and

a GOOD Medicine

Therefore,what we must learn,is…

how to practice a GOOD

MEDICINE!

mnc/05

Looking after a menopausal woman is a most

fascinating,gratifying and

complex

vivid experience in the life of a physician.MNC/05

• It is fascinating – because one is dealing with the holistic dimension of a woman’s life where there is the interplay of her macro and micro social environments, of her self and her id , and of all her body functions.

MNC/05

• It is gratifying – because the help of a physician who is well aware of that holistic dimension may lead to very positive results in terms of the quality of her life, that are the best reward for a health care giver.

MNC/05

• It is complex – because the abundance of specific medical literature, and its often misinterpreted results, leads to a climate of scare of potential risks that overcomes the known benefits of treatments.

MNC/05

Definition

A Climacteric woman

is a woman (gender based medicine)

is an aging person (geriartrics)

is perimenopausal (hormone deficient)

Managing by Objectives:

Critical Objectives

a) The diagnosis of health

b) The identification of risk factors

c) The presence of symptoms

• gender related

• age related

• hormone related

Critical Objectives

d) The treatment of symptoms

e) The elimination of risk factors

f) The diagnosis of diseases

g) The treatment of diseases

Specific Objectives (S.O.)

1. CV and metabolica) obesity

b) dislipidemias

c) hypertension

d) insulin resistance

S.O.

2. CNSa) vasomotor symptoms

b) mood, sleep

c) sexual disfunctions, libido

S.O.

3. Bone

a) osteoarticular

S.O.

4. Reproductive organs- vaginal discharges

- atrophic vaginitis

- fibroids

- meno and metrorrhagia

S.O.

5. Breast

lumps and tenderness

S.O.

6. Bladder

incontinence

chronic cystitis

S.O.

7.Contraception

S.O. Targets

1. exercise

2. nutrition

3. mental health

4. sexual conseling

5. pharmacotherapy

a) hormonal

b) non-hormonal

S.O. Treatments

P, E+P, EAndrogensCa + vit Dbisfosfonates, strontiumStatins, IACE, diuretics, α and β blockersaspirinpsychotherapySerm’stibolonegabapantinroutes, schemes

Causes of Death Among Women*

*Percentage of total deaths in 1999 among women aged 65 years and older.Anderson RN. Natl Vital Stat Rep. 2001;49:1-13.

Heart Disease

Other Cancers

Other

Diabetes

Chronic LowerRespiratory

Disease

Cerebrovascular Disease

Breast Cancer 34%

10%10%

6%6%

3%3%

15%15%

28%

4%4%

In the light of present evidence,

doctors and women should be reassured that the suggested HT’s for the relief of symptoms in the menopause

are safe and very effective

There are controversies about the present management of the climacterium which are due to:

• a lack of culture that prevents a correct criticism of the published results

• a bad practice of medicine that ignores the woman in her totality

• political lobbies from the NIH• a lack of scientific honesty manifested by

many of the WHI writers• lobbies from several pharmaceutical

industries through the activities of many well known doctors that “offer” themselves to transmit their “messages”

Many women taking hormones were urged by their physicians to stop taking these medications immediately or decided to stop taking them on their own.

Petitti DB. JAMA. 2005;294:245-246.

Based on the WHI study group, implementation of the resultsinto clinical practice has little, if any, scientific basis.

Adam Ostrzenski and Katarzyna M Ostrzenska. Am J Obst Gynecol 2005;193:1599-604

The applicability of the WHI findings to women between age of 51.1 and 56.1 years and younger is unknown.

Ostrzenski A and Ostrzenska KM.

Am J Obst Gynecol 2005;193:1599-604

“WHI: Now that the dust has settled…”

•To publish data that may or may not be entirely true or certainly premature is a disservice to the medical profession and, most important, to our patients.

•The majority of the data that were published is not statistically significant even at the nominal level.

Creasman WT. et al. Am J Obst Gynecol 2003;189:621-626

“Lessons from the WHI”

“…most articles and broadcast segments tended to focus exclusively on either the small absolute risks or the larger relative risks, neglecting the more even-handed picture that presented both.

Since the sharply increased relative risks got the most play, news coverage about the trial’s findings had an alarming cast.”

Denzer S. Editorial. Ann Intern Med.2003;138:352-353

Biased opinions

be they pro or con,

dishonor the profession and

harm our patients.

Sacket DL. The arrogance of preventive medicine. Can Med Assoc J 2002;167:363-364

NNH / Year(Number Needed to Harm)

Coronary Heart Disease

WHI (RR 1.29) 1428

HERS (RR 0.99) 5000

Breast Cancer

WHI (RR 1.26) 1250

HERS (RR 1.27) 833

MNC

Effects of conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy.JAMA, 2004;291:1701-1712

Stroke

“In women 50-59 years not taking HT, ischemic stroke is expected to occur in 3 out of 1000 women during 5 years.

Five years use of HT would yield 1 additional case of stroke/ 1000 women”

EMAS Statement; 2004.

Then, why all this noise?...

Mainly because the conclusions of recent trials were severely misinterpreted by the medical professionals, the media and by the women, themselves

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“We are drowing in information, but starved for knowledge” John Naisbilt

Practioners are guided:

• by the best available information that can be extrapolated with validity to their patients,and

• by their acumulated experienceMNC/05

Public Health doctors are guided by what epidemiologists suggest ...

but ...

Most epidemiologists only establish associations of events and seldom determine cause/effect relationships

MNC/05

thus ...both,the practitioners who act as if they were public health doctors,

and the public health doctors who act as if they were clinicians,

should not overemphasize theepidemiological associations of events that are not necessarily cause/effect findings

But ... today ...

manypractitioners

manypublic health doctors

• Act in their offices as if they were public health doctors...

• Act in their departments as if they were clinicians ...

This is wrong!

Effect on the risk of CHD

WHI Significant increased risk RR 1.29 (CI 1.02-1.63); 29 % increased risk

AR 0.37% vs 0.30% (ie, 37 vs 30 events annually per 10.000 women)

HERS Nonsignificant decreased risk RR 0,99 (CI 0.84-1.17); 1% decreased risk

AR 3.66% vs 3.68% (ie, 366 vs 368 events annually per 10.000 women)

Hormones and the Heart

1 in 3 women will die from coronary heart disease (CHD) in the USA.

1 in 25 women will die from breast cancer

Fitzpatrick LA. JCEM 2003;88(12):5609-10

“HRT is associated with a 35% reduction in mortality for women who suffered myocardial infarction”.

Shlipack MG, Angeja B, Go AS, et al Circulation 2001;104:2300-2304

Hormone replacement therapy:where to now?

Recent studies suggest HRT may inhibit the process of atherosclerosis in healthy arteries soon after menopause, and observational studies in younger women starting HRT suggest a potential cardiovascular benefit

Mikkola TS, Clarkson TB. Cardiovasc Res 2002;53:605-19.

Recent reports did not find, for continuous combined treatments, any increased risk of either CHD or breast cancer.

The difference from WHI being that women were younger, symptomatic and with lower body weights

Heikkinen J. NAMS 2004, Abstract LB38 Lobo R. Arch Int Med 2004;164:482-484

• Manson et al reported a nonstatiscally significant decreased relative risk of cardiovascular events in hormone therapy users who were <10 years from the onset of menopause.

Manson JE et al. JAMA 2002;288:321-33

Hormone therapy for youngerpostmenopausal women: how can we

make sense out of the evidence?

At the moment, I believe we can say with relative certainty that hormone therapy in

younger postmenopausal women results

in lower coronary heart disease events and total mortality.

Salpeter S. Climacteric 2005;8:307-310

Younger Women May Receive Heart Protection From Estrogen Therapy

In women ages 50-59 who had undergone a hysterectomy, a significant protective effect of estrogen treatment, when both primary (heart attacks and heart attack death) and secondary (coronary artery bypass surgery, angioplasty, confirmed angina pectoris) cardiac endpoints were considered.

Dr. S. Mitchell Harman, director and president of Phoenix-based Kronos Longevity Research Institute (KLRI) in Archives of Internal Medicine 2006;106:357-363

WHI Study

WHI investigators reported a statistically significant (34%) lower risk for the combined endpoint of myocardial infarction (heart attack), coronary death, coronary revascularization and confirmed angina among women who were between the ages of 50 and 59 at the start of the study (RR 0.66; 95% CI 0.45-0.96).

Hsia J et al.Arch Intern Med 2006;166:357-363

Press Statement IMS

The estrogen plus progestogen arm of the WHI

and the estrogen-alone arm actually showed that

HT does not

increase the risk of coronary heart disease in

the peri- and early menopause,

and may even carry beneficial effects.

Feb 2006

Press Statement IMS

Also, in a subgroup of women demographicallysimilar to those in the WHI, there was nosignificant relation between HT and CHD among women who initiated therapy at least 10 years after the menopause

(RR = 0.87, 95% CI 0.69–1.10 for estrogen alone; RR = 0.90, 95% CI 0.62–1.29 for estrogen with progestogen).

Feb 2006

Press Statement IMS

The WHI study was not designed, and

therefore was not powered, to investigate the

consequences of hormone therapy (HT) in

women below 60 years of age. Therefore,

any attempt to present the results of the study

as indicating that HT may inflict damage to the

heart in general – a message that was accepted

by many medicalsocieties and regulatory Authorities

is simply wrong and must be amended.

Hsia J, Langer RD, Manson J et al. Conjugated equine estrogens and coronary heart disease. Arch Int Med 2006;166:357-65

Breast Cancer

Menopausal women and their doctors are scared about the side

effects of HRT

mainly about breast cancerMNC/05

Hormone replacement therapy and breast cancer: estimate of risk

Extended use of estrogen for

10 years increases risks by 0,5% ,and by 15 years increases risks by 0,9%

upon cessation of HRT, the relative risk quickly returns to 1.0 !

Coombs N J, Taylor R, Wilcken N. Boyages J. BMJ 2005;331:347-349

Breast cancer and the use of HRT

Considering 10.000 women on the combination HRT then for each year there would be:

Seven additional cases of heart attacks Eight cases of stroke, Eight cases of pulmonary embolus, Eight cases of invasive breast cancer, Six fewer cases of hip fractures

Baum M. The Breast 2005;14-178-80

Breast cancer survival and the use of HRT

It must be emphasized that we are talking about an increased incidence of the disease, which does not automatically translate into an increase in deaths from the disease.

Baum M. The Breast 2005;14:178-80

Many Doctors fail to persuade them to go on with HRT, in despite of telling that the

benefits are far greater than any potential risk

MNC/05

Breast Cancer

• The doubling time of an initial cancer cell ,up to the diagnosis of a resultant 1cm tumor ,is most likely greater than 10 years.

• This is why many dormant cancer cells may exist in a“normal” breast !

MNC/05

Breast Cancer

• The diagnosis of a breast cancer after the initiation of a HRT (with a duration of less than 5 years) is only a proof of its growth stimulatory effect (not of its carcinogenic effect)

• Therefore, the reversal of the risk to 1 after the cessation of HRT confirms again only its growth promoting effect and denies a carcinogenic effect.

Dietel M., Lewis MA. and Shapiro S. Human Reproduction 2005;20:2052-60

Occult Breast Cancer

Clinically occult in situ BC’s are frequent in young and middle-aged women.

Nielsen M et al-Br J Cancer 1987;56:814-9

Occult Breast Cancer

Breast malignancy was found in 22 women (20%)

Nielsen M et al-Br J Cancer 1987;56:814-9

Thus…

• Mammographies give more false negative than false positive results !

• A “normal” mammography does not exclude the presence of cancer cells that may “explode” a few months later…

MNC/05

Estrogen replacement therapy in patients with early breast cancer

The mortality rates from breast cancer for the ERT users was 4.28% compared with 22.3% in the nonusers.

Natrajan PK and Gambrell RD. Am J Obstet Gynecol 2002;187:289-95

“Recurrent breast cancer was found in 9% of HRT users and 15% of nonuser”.

O’Meara ES et al

Mortality following development of breast cancer while using

oestrogen or oestrogen plus progestin: a computer record-linkage

study

W Chen, DB Petitti and AM Geiger.British Journal of Cancer (2005) 93, 392 – 398

This study explored survival after exposure to oestrogen or oestrogen plus progestin at or in the year prior to breast cancer diagnosis

oestrogen plus progestin users had lower all-cause mortality and breast cancer mortality

Chen W, Petitti DB and Geiger AM. British Journal of Cancer 2005 93, 392-398

Breast cancer survival after hormone exposure

Overall survival after hormone exposure

Breast cancer survival after hormone exposure

Overall survival after hormone exposure

A menopausal woman expects from her attending physician

to be receptive to all of her complains,

to understand her psychic and physical concerns,

to support her insecurity and

to help overcome her crisis.MNC/05

One may easily conclude that

without an adequate technique of communication, using the proper language,

there is no possible help

Thus,

physicians must acquire expertise in the technique of communication

MNC/05

Talking about

Risks...

Are there risks?

It is crucial that information be given about the difference between relative risks and absolute risks, since the latter are the major cause of misinformation and alarmism, being the favorites of the media…

MNC/05

Nurses’s Health Study

from 1980 to 1994 CHD 31%

Smoking 13% Obesity 8% THS 9% Better nutrition 16%

Hu FB, Grodstein F et al. Trends in the Incidence of Coronary Heart Disease and Changes in Diet and Lifestyle in Women. NEJM 2000;343:530-537.

“It appears that half of thebenefits in the prevention of cardiovascular diseases are not hormone related”!

Mosca L, Grundy SM, Judelson D, et al. Circulation 99;99:2480-4

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.


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 mid-aged woman’s life.


Hippocrates promoted specific diets to prevent and cure diseases such as illnesses of the heart.

Lyons AS et al. In Medicine: an illustrated History. New York:Abradale Press,1990:20719

The Polymeal Franco O et al. BMJ 2004;329:1447-50

Doctors could retrain as Polymeal chefs or wine advisers

The Polymeal—an evidence based menu that includes wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds—promises to be an effective, safe, cheap, and tasty solution to reducing cardiovascular morbidity and increasing life expectancy.

Polymeal could reduce cardiovascular disease by more than 75%.

Franco O et al. BMJ 2004;329:1447-50

The PolypillWald N and Law M. BMJ 2003;326:1419-25

Wald N and Law M. BMJ 2003;326:1419-25

A strategy to reduce cardiovascular disease by more

than 80%

One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke.

Wald N and Law M. BMJ 2003;326:1419-25

Moderate exercise cuts breast cancer biomarkers in

postmenopausal women

Increased physical activity significantly reduces serum estrogens in postmenopausal women and thus may reduce the risk of breast cancer.

McTiernan A. Cancer Res 2004;364:2923-8

Aspirin could be used to prevent cancer

Three recently published studies indicate that aspirin, already enjoying a second lease of life in the prevention of heart disease, may soon become a first line of

defense against cancer.

London O. BMJ 2003;326:565

“Not everything that can be counted counts;

and not everything that counts can be counted”

Albert Einstein

“There are no really “safe” biological active drugs.

There are only “safe” physicians”

Kaminetzy HA 1993

In conclusion …

and to make a long story short…

What are the best recommendations of the climacteric woman’s doctor?

1. Understand what is happening to the body during the climacteric and the postmenopause

2. Mental occupation3. Physical exercise4. Proper nutrition (moderate consumption of red

wine, and abundant fish, vegetables, fruits, soy, milk, garlic, chocolate, etc)

5. Keep the body mass index (BMI) within normal limits

6. Keep a normal girdle/hip ratio, waist circumference7. Refrain from smoking8. Keep a normal blood pressure9. Keep the blood lipids within normal values

(statins?)10. Examine the breasts (palpation, inspection,

mammography)

My Message is:

.To prescribe postmenopausal hormonal treatments when clinically indicated, if not contraindicated

. No answers from ongoing clinical trials are indispensable to practice today a good Medicine

MNC/05

Let us not medicalize the Menopause..instead…

Let us holistically approach the Climacteric and Aging Women.

MNC /05

To know the disease a woman has

is as important as

to know the woman who has the disease

William Osler

“Each time we learn something new, the astonishment comes from the recognition that we were wrong before.

In truth, whenever we discover a new fact, it involves the elimination of old ones. WE ARE ALWAYS, as it turns out, fundamentally IN ERROR.”

Lewis Thomas English Biologist (1913-1993)

What about the best treatments during the climacterium and

beyond?

There is a general tendency to consider that sex steroid hormones are the only instruments with which to treat women when they enter in the climacteric phase of their lives…

MNC/05

What about the best treatments during the climacterium and

beyond?

However, little attention is paid to other pharmacological interventions (non hormonal) and strategies that have been shown to be important for the prevention of such diseases and to maintain or improve health.

MNC/05

Which is the best treatment?

In general terms, is the one that is wisely indicated, if not contraindicated, after balancing benefits and risks, of all strategies and interventions, hormonal or not.

It must be aimed at specific objectives and targets that will be monitored at regular intervals in order to determine its efficacy and to estimate the occurrence of any side effects, a condition that will determine its duration.

MNC/05

Which is the best treatment?

Patient needs and preferences are decisive, based on the doctors’ advice. Let it not be forgotten that although many treatments are available, they are nevertheless not indispensable. Doctors have the duty to give their best unbiased information to their patients so that they may make the right choices and then be compliant.

The woman is the decision maker, if the doctor sees no contraindication.

Thus,

the best treatment is what she has chosen.

MNC/05

The conclusions of these studies suggest that the “safe “ woman (NNH between 600-1000

women) to initiate HT is

- between 50-59 years of age- with vasomotor symptoms- less than 10 years after the menopause- being treated with statins- with a good lipid profile and- with a Body Mass Index >25

Neves-e-Castro M. Human Reproduction 2003;18:2512-2518

This is precisely the profile of the great majority of women who come for consultation after their menopause. Therefore it seems that what most gynecologists are doing to their predominant population of patients is not unsafe and contributes not only to a good quality of life but to prevention, as well.

Neves-e-Castro M. Human Reproduction 2003;18:2512-2518

I personally believe that in the healthy early post menopausal woman the long term HT’s, other than relieving vasomotor symptoms, may play an important role in improving QoL and in the prevention of CVD, osteoporosis and Alzheimer, under surveillance.

Systemic estrogens, added when needed to vaginal progesterone or progestagen loaded IUD’s, may be very beneficial, largely overpassing minimal risks.The well-informed woman will be the only decision- maker.

MNC/05

Continuous combined parenteral estrogen substitution and intrauterine progestogen delivery:the ideal HST

combination?

Wildemeersch D, Janssens D and Weyers S. Maturitas 2005;51:207-214

Continuous intrauterine compared with cyclic oral progestin

administration in perimenopausal HRT

This method of HRT with the Lng-IUD’s as progestin delivery system is efficient in protecting the endometrium against hyperplasia, and will make withdrawal bleedings unnecessary.

Boon J et al. Maturitas 2003;46:69-77

Relationship between breast cancer and use of the levonorgestrel-IUD

These results suggest that the use of the levonorgestrel-releaing intrauterine system is not associated with an increased risk of breast cancer

Backman T et al. Obstet & Gynecol 2005;106:813-7

Tibolone improves myocardial perfusion in postmenopausal women with ischemic heart

disease: an open-label exploratory pilot study.

In postmenopausal women with ischemic heart disease, six months of therapy with tibolone significantly improved stress myocardial perfusion and the "amount of ischemia."

Campisi R et al. J Am College Cardiol 2006;47:559-564

Postmenopausal hormone therapy: critical reappraisal and unified hypothesis

83:558-66

NAMS position statement on estrogen and progestagen use in peri-and postmenopausal women

Revised breast cancer statements indicate that the risk of breast cancer probably increases with EPT use but not with ET use.

NAMS position statement on estrogen and progestagen use in peri-and postmenopausal women

Place no limit on ET/EPT treatment duration, provided it is consistent with treatment goals; if monitored regularly, no stipulation is made regarding when to reduce or stop therapy

If there are no incoming contraindications we see no reason to establish a time limit to the duration of therapy, mainly if there is a recovery of symptoms after its discontinuation

Cochrane B, NAMS 2004, P53

IMS www.imsociety.org

NAMS www.menopause.org

http://www.imsociety.org/

http://www.menopause.org/

What has been learned from the major observational studies and

clinical trials?

the first lessonsystematically administered progestagens may in part suppress some of the beneficial effects of estrogens and may also slightly increase the risk of breast cancer after treatments with duration greater than five years.

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clinical trials?

the second lesson

estrogens, when given alone to histerectomized women, did not appear to minimally affect the risk for breast cancer when compared with controls

MNC/05


clinical trials?

the third lessonMetabolic effects of estrogens and progestagens, as a whole, can differ depending on the route of administration, i.e. oral vs. parentheral, and on the combination of both, in a sequential regimen or in continuous combined administration.

MNC/05


clinical trials?

the fourth lesson

Hormonal treatments are the first choice for vasomotor symptom relief as long as they are needed (on and off assessment). They should not be used for the secondary prevention of CVD, when atheroma plaques are already present.

MNC/05


clinical trials?

the fourth lesson (cont.)Conversely ,they may protect from CVD if started early during the transition into the post menopause.

Hormonal treatments are preventive of osteopenia and osteoporosis at any stage in life

MNC/05


clinical trials?

the fifth lesson Estrogens may prevent degenerative

lesions of the CNS since, so far, they seem to be the only available drugs with nerve growth effects

MNC/05

Convictions are more dangerous enemies of thruth than lies

Friedrich Wilhelm Nietzsche

A WOMAN

in the autumn of her life deserves an indian summer

rather than a winter of discontent ...

Robert B Greenblatt

This is what I have learned

thank you

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