Reconsidering female hormone

therapy    By Dr. Sylvie Demers

M.D. Ph.D. experimental medicine (human molecular genetics)

Centre ménopause-andropause Outaouais

Update on Women's Health Symposium

Jewish General Hospital

April 8, 2011

   

Introduction

Controversy breeds sciencePhysicians must be better trained with regard to female hormone

therapy so that women cease suffering and being mistreated.

Female hormone therapy = controversy!– Continuous conflicting messages are being conveyed.– We get confused!

It is time for real debates:– Why do female hormones, namely estrogens, have a

reputation of being dangerous, or even carcinogenic?– This sends a negative message to women because estrogens

truly the essence of femininity. • Incidentally, female hormones are the only human

hormones that are disregarded. This disregard has great implications on the well-being, health and dignity of women.

This conference is made This conference is made possible thanks to an possible thanks to an

unrestricted grant from unrestricted grant from Merck Canada Inc.Merck Canada Inc.

The contents of this presentation is free from outside influence and is

entirely my own scientific point of view.

Dr. Sylvie Demers

What is menopause? 

Natural menopause is caused by a radical reduction of hormones produced by the ovaries, and in particular:

17 β-estradiolProgesteroneTestosterone

Clinically, menopause results from a cessation of uterine bleeding during a period of 12 consecutive months.

 

 

Genetics of men and women

More than 99.9% of the human gene pool is not linked to gender.

The main biological difference between men and women relates to sex hormones.

And we have the same sex hormones (17 β-estradiol (principle estrogen), progesterone and testosterone)!

The main difference between genders is the levels of these hormones and the relationship between them.

When I mention female hormones, I am referring to 17 β-estradiol and progesterone.

1st Objective:

Describe the fundamental roles of female hormones on

cardiovascular, skeletal, cerebral and

endocrine health.

FEMALE HORMONES At least 153 different genes react to estrogens and 150

genes react to progesterone. This, in itself, is phenomenal and strongly suggests that female hormones encompass a vast array of functions. (Laganière J. et al. (2005) Proceedings of the National Academy of Sciences, Vol. 102, p. 11651-11656; Leo J.C.L. et al.(2005) International Journal of Cancer, Vol. 117, p. 561-568.)

Female hormones have an effect on just about every part of the human body, which explains the wide range of symptoms (insomnia, anxiety, depression, hot flashes, muscle aches, joint pain, etc.) and signs (osteoporosis, heart disease, weight gain, generalized dryness, etc.) that women may experience when their female hormone levels drop.

The roles of 17 β-estradiol

According to Dr. Robert Greene, American gynecologist (Perfect Balance (2005) Clarkson

Potter/Publishers New York, 350 p.)

– Estradiol has more functions in the human body than any other hormone, a number estimated at more than 300.

Cardiovascular Health(References in Chapter 3: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Cardiovascular diseases: ~ 31% of deaths among womenBreast cancer: ~ 2% of deaths

Let's be logical! Before menopause, women are less at risk of suffering from

cardiovascular diseases (including cerebrovascular accidents) than men of the same age. At menopause, the risk gradually increases, so that by the age of 75 years, women are equally at risk as men.

Before the publication of the WHI study, research suggested an approximate reduction of 40 to 50% in the risk of cardiovascular diseases due to female hormone therapy. (As seen in Belchetz P. E. (1994) The New England Journal of Medecine. Vol. 330, p. 1062-1071.)

Women who have had their ovaries removed before the age of 45 years (not treated with estrogens) are much more at risk of cardiovascular diseases (Rocca W. A. et al. (2006) Lancet Oncology.Vol. 7, p. 821-828.), as well as menopausal women who have had their ovaries removed before the age of 65 years. (Parker W.H. et al. (2007) Clinical Obstetrics and Gynecology. Vol. 50, p. 354-361.)

WISE study: Hypoestrogenism – defined by a mean level of estradiol lower than 184 pmol/L – would be an important risk of atherosclerosis (depicted by angiography) among premenopausal women. (Merz B. et al. (2003) Journal of the American College of Cardiology. Vol. 41, p. 413-419.)

Study conducted on castrated female monkeys: the administration of 17 β-estradiol is a powerful protective factor against atherosclerosis. (References: P. 60 in Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Menopausal women: oral administration of 17 β-estradiol (1 mg/day) is a protective factor against atherosclerosis. (Hodis H. N. et al. (2001) Annals of Internal Medicine. Vol. 135, p. 939-953.)

Among the protective properties of 17 β-estradiol:• Improvement of lipid panel• Reduction of arterial blood pressure• Prevention of vasospasms in the arteries• Protection of the arterial endothelium• Improvement in cardiac function• Anti-inflammatory properties (key role in the prevention of many diseases)

SKELETAL HEALTH(References in Chapter 5: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Menopausal osteoporosis, by far the main cause of osteoporosis among women, is primarily attributed to:– A deficiency of female hormones (and not to a

deficiency of calcium or vitamin D). • For example, the decline of estradiol levels results in calcium

being leached out of the bones.

Did you know that… According to an American study: (Parker W.H. et al. (2007) Clinical

Obstetrics and Gynecology. Vol. 50, p. 354-361.)

– Bilateral prophylactic oophorectomy (most commonly to prevent ovarian cancer) performed on menopausal women, who were not taking hormone therapy, increase their mortality risk. The earlier this procedure is performed on women, the higher their risk of mortality.

– Even after the age of 65 years, oophorectomy (without hormone therapy) increases mortality following a hip fracture.

– For example, among 10,000 women who underwent a bilateral prophylactic oophorectomy between the ages of 50 an 54 years:

• 26 to 30 years later (80 years of age):– Decrease of 47 deaths due to ovarian cancer– Increase of 838 deaths due to coronary heart disease– Increase of 158 deaths due to hip fractures

CEREBRAL HEALTH(References in Chapter 4: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

17 β-estradiol : Increases the synthesis of different neurotransmitters Is a natural antidepressant Improves memory Promotes better sleep Exerts neuroprotective effects through various

properties

ENDOCRINE HEALTH(References in Chapters 6 and 9: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Prevention of type 2 diabetes– 17 β-estradiol increases both the secretion

and the elimination of insulin• Consequence: decreased level of basal insulin• (Cagnacci A. et al. (1992) Journal of Clinical Endocrinology & Metabolism, vol. 74, p. 1396-1400;

Cagnacci A. et al. (1997) Maturitas. vol 28, p. 163-167.)

An increased level of basal insulin is associated with many health problems such as cardiovascular diseases, breast cancer, endometrial cancer and colorectal cancer.

Roles of progesterone(References in Chapters 3 to 7: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

CARDIOVASCULAR HEALTH

(References in Chapter 3: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Diuretic and antihypertensive properties– 200 mg of micronized progesterone equals to a

dose of spironolactone varying between 25 and 50 mg

Decrease of benign heart palpitations

Decrease of vascular hyper-reactivity– Possible role in the prevention of coronary

CEREBRAL HEALTH(References in Chapter 4: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Anxiolytic and calming properties Antiepileptic properties Multiple beneficial effects on the central and peripheral nervous

system– Neuroprotective and trophic effects for neurons and glial cells– Key role in the synthesis of myelin sheath– Decrease of cerebral oedema and foster regeneration of nerve fibres following

trauma

Promotes better sleep– Many beneficial effects of progesterone are due to its transformation into

allopregnanolone. • Allopregnanolone binds itself to GABAA receptors in the brain which results in the

increase of GABA action. GABA is the key inhibitory neural transmitter of the central nervous system and acts, in a way, as our own natural anxiolytic.

• Micronized progesterone (Prometrium®) increases the duration of deep sleep (in men as well as women).

– Estrogens also play an important role in the quality of sleep (e.g., regulating of melatonin). Furthermore, bioidentical female hormone therapy in adequate doses can renormalise a high cortisol level (a relatively frequent occurrence in premenopause/menopause).

Other roles of progesterone(References in Chapters 3 to 7: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.) Beneficial effect on skeletal system

– Possible role in bone formation

Some reduction of hot flashes

Possible protective effect (with the administration of estradiol in adequate doses) against colorectal cancer and endometrial cancer, and in my opinion, against ovarian cancer and breast cancer.

Antioxidant properties

2nd Objective:

Reveal the advantages of bioidentical female

hormone therapy versus those of non-bioidentical hormone

therapy

What are bioidentical female hormones?

They are composed of transdermal 17 β-estradiol and progesterone.

They are made from sterol analogues present found in many varieties of plants, primarily the soybean.

These hormones are identical to hormones produced by the ovaries (same chemical structure).

Lack of media coverage concerning the benefits of

bioidentical female hormones! The majority of laboratory studies regarding female

hormone therapy were conducted using bioidentical female hormones.

Many clinical studies have been conducted among women.

Surprisingly, the results of those numerous studies, which are conducted by many university research groups in various countries and published in reputable research journals, rarely get media coverage.

Why is this so?

Bioidentical estrogens 1) Estrogel® gel 17 β-estradiol 2) Estradot® patch 17 β-estradiol 3) Climara® patch 17 β-estradiol 4) Estraderm® patch 17 β-estradiol 5) Sandoz estradiol dermPr patch 17 β-estradiol 6) Oesclim® patch 17 β-estradiol

7) Estrace®* oral tablet 17 β-estradiol 8) Tri-Est cream** cream estriol(80%)/est/est

9) Bi-Est cream** cream estriol(80%)/estrad.

*Estrace® should not be considered due to the way it is administered. Estrogens administered orally may increase the levels of triglycerides and C-reactive protein, as well as the synthesis of certain coagulation factors. Furthermore, Estrace® transforms itself into estrone during the digestion process.

**I do not recommend these creams (prepared by compounding pharmacists) because of their non physiological estrogenic composition, their low absorption rate in the bloodstream, as well as the lack of quality control.

Progesterone

1) Prometrium® administered orally

2) Crinone®* administered vaginally (gel) 3) Suppository** administered vaginally (cream) 4) Cream** administered transdermally

* I do not know the absorption level into the bloodstream of Crinone®. It is also important to

know that Crinone® is very expensive.

**I do not recommend the use of the progesterone creams because they are typically not well absorbed into the bloodstream, and furthermore, due to the lack of quality control.

A brief overview of the WHI study

Administering a dosage of 0.625 mg of CEE and 2.5 mg of MPA among women between the average age of 63 years (start) and 69 years (end) caused:CEE (conjugated equine estrogens, e.g., Premarin®) to be associated with an increased risk of thromboembolism.

– However, it is important to recognize that CEE were also associated with a decreased risk in fractures, breast cancer, colorectal cancer, infarctions and death. (The Women's Health Initiative Steering Committee. (2004) The Journal of the American Medical Association.Vol. 291, p. 1701-1712.)

MPA (medroxyprogesterone acetate, e.g., Provera®) to be associated with an increased risk of infarctions, breast cancer, as well as lung cancer. (Writing Group for the Women's Health Initiative Investigators (2002) The Journal of the American Medical Association. Vol. 288, p. 321-333; Mastorakos G. et al. (2006) New York Academy of Sciences. Vol. 1092, p. 331-340; Chlebowski R. T. et al. (2009) Lancet. Vol. 374, p. 1243-1251.)

– MPA is suspected of being harmful in many ways, including having carcinogenic properties.

When administered before the age of 60 years, CEE with and without MPA offer greater benefits than risks and are associated with a statistically significant decrease in deaths by 30%. Benefits are attributable to estrogens. (The Women's Health Initiative Steering Committee (2004) The Journal of the American Medical Association. Vol. 291, p. 1701-1712.)

CEE and 17 β-estradiolDo not mistake one for the

other! CEE (conjugated equine estrogens) are estrogenic

compounds isolated from pregnant mare's urine and are foreign to a woman's body (e.g., equilin). About half the CEE are in the form of estrone sulfate.

CEE, and not transdermal 17 β-estradiol, increases the levels of:– Some coagulation factors– C-reactive protein– Triglycerides

Venous thromboembolism Study published in The Lancet

(Scarabin P.-Y. et al. (2003) The Lancet. Vol. 362, p. 428-432.)

– Oral estrogens: risk of 3.5– Transdermal 17 β-estradiol: risk of 0.9

ESTHER study (Estrogen and Thromboembolism Risk)(Straczek C. et al. (2005) Circulation. Vol. 112, p. 3495-3500.)

– Oral estrogens: risk of 4.3– Transdermal 17 β-estradiol: neutral risk

• No risk increase even among women who are genetically predisposed (carriers of Factor v Leiden and the mutation of prothrombin G20210A mutation).

E3N, prospective study conducted among 80,308 women in France (average follow-up: 10.1 years)

(Canonico M. et al. (2010) Arterioscler. Thromb. Vasc. Biol. Vol. 30, p. 340-345.)

– Oral estrogens: risk of 1.7– Transdermal 17 β-estradiol: neutral risk

• Decrease of risk (non significant) with regard to transdermal 17 β-estradiol combined with micronized progesterone: risk of 0.9

Cerebrovascular Accident

British study(Renoux C. et al. (2010) BMJ Vol. 340 , p. C2519.)

– Oral estrogens (with or without progestins): significant increased risk of 28% (CI 95%, 1.15-1.42)

– Transdermal estrogens (with or without progestins): non-significant decreased risk of 5% (CI 95%, 0.75-1.20)

MPA and progesteroneDo not mistake one for the other!

I do not like MPA (medroxyprogesterone acetate), but I love progesterone.

MPA, and not progesterone,– Cancels out in part the benefits estrogens have on the lipid panel

• E.g., Decrease of HDL-C– Promotes vasoconstriction of the arteries– Promotes water retention

• MPA stimulates aldosterone whereas progesterone inhibits it.

– Contrary to progesterone, MPA does not transform itself into allopregnanolone.

• Allopregnanolone has anxiolytic, antiepileptic and calming properties.– Many adverse effects at the cerebral level (References in Chapter 4: Hormones au féminin:

Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

– Possible carcinogenic effect in the breasts, whereas progesterone seems have a protective effect.

– Etc.

3rd Objective:

List the various anticarcinogenic

properties of female hormones.

Breast cancer and female hormones

95% of breast cancer occur after the age of 40 years.– Decreased levels of estradiol and progesterone

• Screening peaked around the age of 62 years; at this age, women on average have 5 times less estradiol than men.

Protective effect on pregnancy– Very high levels of estradiol and progesterone

• E.g., 2 days before giving birth to a baby boy, one of my patients had a:

– Level of estradiol: 61, 580 pmol/L– Level of progesterone: 544 nmol/L

Protective effect on breast feeding– High turnover rates in the mammary glands

JAMA (2006)(Stefanick M.L. et al. (2006) The Journal of the American Medical Association. Vol. 295, p. 1647-1657.)

– Estrogens do not seem to increase the risk of breast cancer – even among older women.

– Rather, progestins are the ones that increase the risk.• E.g., in the WHI study, taking CEE with MPA was associated with

an increased risk (non significant) of 0.8 cases per 1,000 women/year. CEE without MPA, on the contrary, were associated with a decreased risk.

MISSION study (2006)(Espié M. et al. (2006) Gynecological Endocrinology. Vol. 22, p. 423-431.)

– 6,600 women were monitored by gynecologists in France– Female hormone therapy “à la française”– Average follow-up of 8.3 years (average age of 62 years)– No increased risk in breast cancer

• Percentage of women having had breast cancer among the group without hormone therapy: 6.21%

• Percentage of women having had breast cancer among the group with hormone therapy: 1.01%

E3N, a French study(Fournier A. et al. (2005) International Journal of Cancer. Vol. 114, p. 448-454.)

Goal: Evaluate the risk of breast cancer associated with the different types of female hormone therapy(54,548 women were monitored over a period of 10 years; age: between 40 and 65 years).

• Estrogens alone: – No significant increased risk

• Estrogens and progestin: – Significant increased risk of 40%

• Transdermal 17 β-estradiol combined with micronized progesterone:

– Decreased (non significant) risk of 10%

Why are estrogens considered carcinogenic?

Randomized studies (4 studies)– Decreased risk of breast cancer associated with the use of

estrogens. (Collins J. A. et al. (2005) Human Reproduction Uptake. Vol. 11, p. 545-560.)

• Risk of 0.79 (CI 95%, 0.61-1.02)– E.g., In the WHI study, taking conjugated equine estrogens is

associated with a decreased risk of 23% (CI 95%, 0.57-1.06)

Ovariectomised women (follow-up period: 25 to 30 years)– Women, who had both their ovaries removed before the age of

45 years (without taking estrogens), have an increased risk of premature death of 67%. (Rocca W. A. et al. (2006) Lancet Oncology. Vol 7, p. 821-828.)

• In particular, an increased risk of cardiovascular diseases, cerebral diseases and cancers.

Progesterone (and not progestin) is not carcinogenic

Study among 10,000 premenopausal women– Link between a low level of progesterone and an increased rick of

breast cancer. (Bulbrook R. D. et al. (1978) European Journal of Cancer. Vol. 14, p. 1369-1375.)

Study among 1,083 women undergoing fertility treatment (follow-up conducted 12 to 33 years later)– Among those with a deficit of progesterone, the risk of breast

cancer increased 5.4 times (540%) and the risk of death increased 10-fold (1,000%). (Cowan L. D. et al. (1981) American Journal of Epidemiology. Vol. 114, p. 209-217.)

E3N, a French study– Progesterone, unlike progestins, does not increase the risk of breast cancer.

Prometrium® (micronized progesterone) used in in vitro fertilisation– (Progestins are never administered to pregnant women.)

The foetus (through its placenta) produces enormous amounts of progesterone (and estradiol)

Progesterone, and not progestins, is the result of millions of years of natural selection (likewise for 17 β-estradiol).

Did you know that...(References in Chapters 9, 10 and 11: Hormones au féminin: Repensez votre santé (2008-2009)

Éditions de l'Homme. 259 p.)

Breasts produce estrogens!– This is in favour of the beneficial effect estrogens have on breasts.

Several hormones and growth factors can make mammary cells proliferate much more than estrogens.

– Examples of mitogenic hormones and growth factors (i.e., those that stimulate mammary cell division) in the breasts:

• Numerous hormones:– Estradiol: minor mitogen– Insulin: major mitogen– Many other mitogenic hormones: prolactin, thyroid hormones,

testosterone, DHEA, DHT...

• Many growth factors, namely:– Human epidermal growth factor: major mitogen– Insulin-like growth factor: major mitogen

We must fully question the harmful role, even the carcinogenic effect, which is attributed to the presence of estrogens in the breasts. The well-being,

health and dignity of women are at stake.

Anticarcinogenic properties of female hormones

(References in Chapters 8 to 12: Hormones au féminin: Repensez votre santé (2008-2009) Éditions de l'Homme. 259 p.)

Control of cell growth– By regulating the genes responsible for cell growth

(Life cycle of cells: division- maturation – apoptosis)• Healthy cells must divide to maintain their tissular integrity, damaged and old cells must be destroyed

(e.g., to avoid accumulation of mutations)• My hypothesis is that estrogens and progesterone prescribed in adequate doses promote controlled cell

renewal (balances proliferation/apoptosis, and this, at a controlled speed).• For example:

– Estradiol controls the number of estrogen receptors in the breasts. A decreased level of estradiol increases the number of estrogen receptors. Conversely, an increased level of estradiol decreases the number of receptors.

– An increased level of estradiol promotes apoptosis of mammary cells. E.g., – Estradiol increases the production of the BRCA1 protein. BRCA1 protein plays a role in apoptosis.

Decreased level of basal insulin with estradiol Antioxidant properties Anti-inflammatory properties The number of Vitamin D receptors is controlled directly by 17 β-estradiol. (Gilad L.A. et al.

(2005) Journal of Endocrinology Vol. 185: 577-592.)

Hormone-dependent breast cancer: treatments

Estrogens in high doses:– Treatment used for nearly 60 years (As seen in Lonning P. E. et al.

(2001) Breast Cancer Research and Treatment. Vol. 67, p. 111-116.)

Antiestrogens:– I believe these are efficacious because of the

proestradiol effect they have on mammary cells.(Research project to test my hypothesis: www.drdemers.com)

• After a certain period of time, there is an:– Increased level of estradiol

– Increased number of estrogen receptors (receptors α) in mammary cells.

Évelyna, 55 years of age Underwent a bilateral oophorectomy at the age of 47 years Hormone-dependent breast cancer – diagnosed 3 years earlier (52 years of

age) Has been taking Arimidex® (aromatase inhibitor) for the last 3 years Currently, Évelyna exhibits many menopausal symptoms, including joint

pain and severe asthenia

LAB Unusually high level of estradiol for a woman who had her ovaries

removed 8 years earlier(It is not uncommon that I observe in these women levels < 18 pmol/L):

– Évelyna's estradiol level: 97 pmol/L

And yet, she is taking a drug that is supposed to inhibit that formation of estradiol!

Estrogens and carriers of the BRCA1 mutation

In a controlled study among 472 menopausal women who are carriers of the BRCA1 mutation: – Those who took estrogens were 2 times less at risk

of developing breast cancer (decrease was statistically significant).

Relative risk: 0.51 (CI 95%, 0.27 - 0.98)

(Eisen A. et al. (2008) Journal of the National Cancer Institute. Vol. 100, p. 1361-1367.)

4th Objective:

Prescribe hormone therapy in adequate doses and the blood

dosage of female hormones

Reconsidering the question…

Several years ago, I completely called into question the widely touted idea that measuring female hormone levels is useless in treating premenopausal and menopausal women.

– Not only did I realize that there was no great research to support this idea, but also that this belief did not seem logical at all.

We contend that it is useless because female hormone levels fluctuate all the time. Therefore, it is still the norm to treat menopausal women empirically (that is, by trial and error)... In 2011! It is true that female hormones fluctuate, but that is also true for all hormones or other physiological parameters. And yet, we learn how to measure them and assess their normal variability. For example, cortisol is higher in the morning than in the evening; insulin (as well as glucose) rises after a meal; blood pressure (as well as heart rate) increases during exercise, etc.

How to dose...

I prefer measuring female hormone levels in the blood serum, and doing so in the morning. Fasting is not necessary.

  When women undergo hormone therapy, it is essential to take

into consideration the time elapsed since taking the hormones.

We are unable to dose the hormones contained in non-bioidentical female hormone therapy (Premarin®, Ogen®, Provera®, etc.) or in current contraceptives.

Marie 54 years of age, teacher No uterine bleeding for the last 2 years Many menopausal symptoms: insomnia, fatigue, hot flashes, signs

of depression, musculoskeletal pain, vaginal dryness… Has read "Hormones au féminin" and wants you to prescribe

bioidentical female hormone therapy in “adequate doses” No significant medical history, no known allergies to peanuts

Conduct:– A medical history and physical exam (including, blood

pressure reading, examination of the breasts and gynecological exam)

– Mammography (if one was not conducted in the last year)– Hormone panel: cortisol, prolactin, thyroid panel, FSH, LH,

estradiol, progesterone, testosterone, Hb

Marie Results:

– History compatible with a diagnosis of menopause– Normal physical exam– Hormone panel: cortisol slighly high, normal prolactin and thyroid panel, FSH: 72 IU/L,

LH: 36 IU/L, estradiol: 37 pmol/L, progesterone: 0.9 nmol/L, testosterone: 0.7 nmol/L, Hb: 135

Diagnosis: menopause (52 years of age)

Prescription: – Estrogel®: start with 1/2 pump HS and increase progressively until hot flashes

symptoms are relieved. Maximum: 2 pumps per day.– Prometrium®: 100 mg HS

• Generally speaking, my preference is Estrogel®, a transdermal gel (more stable, easier to adjust for patients and doctors, and often more effective)

• I prescribe the patch:– To older women (> 60-65 years of age) starting hormone thereapy (e.g., Estradot®) in order to avoid

levels of estradiol that are too high– To women whose levels of estradiol are too high using Estrogel®– To women who prefer using a patch

Advice to patients Targeted levels (12 hours after taking bioidentical hormones):

– Serum estradiol: between 200 and 400 pmol/L– Serum progesterone: between 15 and 25 nmol/L

Always explain how to apply the gel:– Very important as this is the number one reason for the ineffectiveness of the treatment

• Apply on the same location: both forearms, both thighs, and wipe on buttocks and lower abdomen

• ½ pump per body part, applied in a thin layer• Do not rub• Dries within 2 minutes• Do not put any lotion on forearms and thighs

Precautions for Prometrium® (micronized progesterone):– Must not be allergic to peanuts– Must be taken at bedtime

• Maximum effect on somnolence 2 hours after taking the drug

Main symptoms of an excess of estradiol or progesterone:– Excess of estradiol

• breast tenderness, bloating, febrile sensation and uterine bleeding

– Excess of progesterone• Nausea, dizziness, fatigue, somnolence• If difficult to digest: pierce capsule and place contents on a spoon

MarieThree months later…

History:– Symptoms have been relieved (patient is very happy)– However, Marie experienced 2 uterine bleeding episodes

Results:– Level of estradiol: 729 pmol/L– Level of progesterone: 8 nmol/L– FSH (32 IU/L), LH (21 IU/L), the remainder of the panel was

normal

MarieThree months later…

Before modifying the dosage:– Ascertain that the hormones were taken 12 hours before blood sample

collection• If patch: blood sample collection 12 to 24 hours after applying the patch

– Check interactions• Main interactions with Prometrium® (micronized progesterone):

– Herbal teas, teas, calcium supplements taken in the evening or at bedtime– Taking a PPI (proton pump inhibitor), an anti-inflammatory, a narcotic, an

antiepileptic drug or an antibiotic.

– Explain once again how to take bioidentical hormones

Conduct:– Proper questioning: you learn that Marie drinks a herbal tea in the evening.

• You strongly recommend to Marie not to drink a herbal tea in the evening.

– Prescription: • Estrogel® (transdermal gel) 1 pump HS Prometrium® (micronized progesterone): 1 capsule HS (2 capsules HS if recurring

uterine bleeding)

Uterine bleeding in menopausal women undergoing female hormone therapy

Uterine bleeding is the main complication in female hormone therapy.

Causes of bleeding:– Adjustment period: at the beginning, there is an increased risk of bleeding

because of the higher number of estrogen receptors (due to a low initial level of estradiol)

• To decrease the risk of bleeding: start with a lower dose of estradiol (Estragel® transdermal gel ½ pump HS or patch of 25 μg)

– After the adjustment period, 3 reasons might explain the persistence of uterine bleeding. The first 2 reasons are much more frequent.

• The serum levels of estradiol or progesterone are not balanced• The ovaries produced 17 β-estradiol• There is an underlying uterine condition

– Eliminate the presence of endometrial hyperplasia, fibroma, polyps, or endometrial cancer

Suggested conduct for the patient:– Cease taking progesterone and 17 β-estradiol for one (1) day– Reduce by half (1/2) the dosage of 17 β-estradiol

• Increase gradually to adequately relieve symptoms

– Consult if recurrence of uterine bleeding (i.e., investigate)– If heavy bleeding: cease hormone therapy and consult (i.e., investigate)

MarieSix months later...

History:– Symptoms have been relieved– No uterine bleeding– Negative system review

Results:

– Level of estradiol: 350 pmol/L– Level of progesterone: 25 nmol/L (1 capsule without herbal tea consumption)– The remainder of the panel is normal

Prescription: – Same, that is: Estrogel® 1 pump HS

Prometrium® 1 capsule HS – Follow-up in one year or before her annual exam, or if a problem arises (e.g., bleeding)– Indicate on the blood panel that hormones must be taken 12 hours before blood sample

collection

Jo-Anne Jo-Anne, 57 years of age, menopausal for 6 years, has been

taking bioidentical female hormones (Estrogel® transdermal estrogen and Prometrium® micronized progesterone) for about 5 years. She told me that she recently suffered a bleeding episode, about two months ago:

"I was a little surprised because I had never bled in the last 6 years. Because I was coming to see you soon, I did not worry. I told myself that perhaps my hormones were not balanced. The bleeding, rather light, lasted five days. I met recently with my family physician for my annual check-up. When she learned I had been bleeding, she panicked. And then she made me panic! She told me that this was not normal at all because I was menopausal and had not bled in years. She had a strong suspicion that I had endometrial cancer. A CANCER! I could not sleep anymore… I met a gynecologist soon after, who made me undergo an endometrial biopsy. What a relief: the biopsy came back normal! The gynecologist still advised me to stop my hormone therapy. I squarely refused. I told him that the hormone therapy had already saved my life!”

Jo-Anne In questioning Jo-Anne, I learned that, a few weeks before her

bleeding episode, she had taken an antibiotic (Cipro® 500 mg twice a day) for 14 days for an upper urinary tract infection (pyelonephritis).

  When Jo-Anne had her blood drawn in anticipation of her visit

to the Centre, by pure coincidence, she was taking her antibiotics: - Level of progesterone: 8.2 nmol/L

(compared to ~20 nmol/L on her previous panels)

- Level of estradiol: 300 pmol/L(similar to the levels indicated on her previous panels)

  Why, with the same dosage of hormone therapy, had Jo-Anne's

progesterone serum level dropped by more than half? This drop in the level of progesterone was caused by her antibiotic. Cipro® may significantly increase the catabolism of progesterone (probably through the induction of the cytochrome P-450 enzymes found in the liver).

Jo-Anne A reduced progesterone serum level can therefore be insufficient in

preventing the thickening of the endometrium. Estrogens, at a certain level (greater than ~ 125 pmol/L), cause the proliferation of the endometrium, while progesterone, on the contrary, has an anti-proliferative effect.

  My clinical observations have taught me that, in the presence of an

estradiol serum level of ~ 300 pmol/L, as was measured in Jo-Anne, a progesterone serum level between 15 and 25 nmol/L is generally necessary to prevent the thickening of the endometrium. Thus, a progesterone level of about 8.2 nmol/L for 14 days (duration of the Cipro® treatment) was insufficient in preventing the thickening of Jo-Anne's endometrium, which explains why she suffered a bleeding episode.

– We finally have a rational explanation that puts Jo-Anne's mind at rest. Moreover, tests results now revealed an adequate level of progesterone (~ 20 nmol/L).

 

Jacynthe Requested a consultation for a hormone evaluation Brief overview of history: 48 years of age, underwent a

ureterectomy at 46 years of age (for menorrhagia), otherwise in good health

Symptoms: – For almost a year: hot flashes, de novo anxiety, irritability,

insomnia, fatigue, muscular pain and de novo heart palpitations (negative cardiac investigation).

According to her family physician, Jacynthe is menopausal (FSH: 40 IU/L)

– Prescription: Premarin® 0.625 mg DIE • Jacynthe's symptoms are exacerbated, in particular anxiety, irritability

and heart palpitations. Her physician does not understand and asks my opinion.

Jacynthe

2 panels were conducted at 2 week intervals:– Despite the high levels of FSH and LH:

• 1st panel = Estradiol serum level: 500 pmol/L Progesterone serum level:

1.3 nmol/L• 2nd panel = Estradiol serum level: 340 pmol/L

Progesterone serum level: 1.1 nmol/L

– Diagnosis: Premenopause (and not menopause)• Progesterone deficiency

– Treatment: Prometrium® (micronized progesterone)

• Decrease – read: relief – of various symptoms: patient very satisfied and sent me a thank you letter.

Dosing female hormones allows…

To properly diagnose and provide better treatment to premenopausal and menopausal women.Some examples:

- Persistence of symptoms due to the gel not being properly applied (this is suspected due to low level of estradiol) or a drug that interferes with the hormones (e.g., taking PPI that decreases the level of progesterone).- Side effects due to levels of estradiol or progesterone being unbalanced or too high (bleeding, palpitations, anxiety, nausea, dizziness, mastalgia…)

Research project developed in order to optimize benefits of bioidentical female hormone therapy and to minimize the risks. (www.drdemers.com).

Conclusion

A better understanding leads to better treatments

With the current life expectancy, women spend approximately half their life in premenopause/menopause.

It is, therefore, of the utmost importance to:– Recognize the multisystemic benefits of female hormones and their

impact on the quality of life and health;– Always differentiate non-bioidentical hormones from bioidentical

hormones in our interpretation of results stemming from clinical studies;

– Promote strict, multisystemic and innovative research in order to optimize benefits of bioidentical female hormone therapy;

So as to offer the highest standard of care to all women.

For more information Dr. Sylvie Demers, Hormones au féminin: Repensez votre santé

(2008; 2009) Les Éditions de l'Homme. Montréal, Canada. 259 p.– References taken from paragraphs within the book

• http://www.edhomme.com/hormones.aspx

Website: www.drdemers.com– Petition so that bioidentical female hormone therapy is completely

covered by the RAMQ– Research projects– Foundation– Satellite sites

Practical training offered to physicians– For information: 819-771-1936

Thank you!