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Bio-identical Hormones
Lucija Vrabič Dežman, MD
Slovenian Menopausal Society, LjubljanaSlovenia
9th Croatian congress on Gynaecological Endocrinology, Human Reproduction and Menopause
Brijuni, 5.- 8.9.2013
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Fountain of YouthFountain of Youth
Lucas Cranach senior(1546)
Detail from Primavera S.Botticelli, 1482
The idea of eternal youth is not something new. The painting from the 16th century shows the transformation of old women into young women.
Eternal desire! BUT the reality?
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A Woman‘s Phases of LifeA Woman‘s
Phases of Life
sexual maturitychildhood post-menop. senium
0 8 12 15 45 50 55 65 years
birth menarche menopause
puberty climacteric
80 years
Expected lenght of women’s life
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4
Lack of Estrogen
After menopause – estrogen level is ↓ reduced (in particular, oestradiol) : 120 pg/ml to 18 pg/ml
The consequences are: climacteric symptoms, impaired quality of life
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PerimenopausalPerimenopausalTransitionTransition
PerimenopausalPerimenopausalTransitionTransition
+-
Decreased level od estrogensDecreased level od estrogens
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Climacteric Symptoms
Hot flashes (most common) Night sweats Irregular bleeding Sleep problems Mood changes Depression Headache Weight gain and slowed metabolism Thinning hair and dry skin Loss of breast fullness Fatigue (tiredness) occasional palpitations The medium-term consequences: uro-genital atrophy, vaginal dryness,
the decline in sexual desire Long-term consequences: cardiovascular diseases, osteoporosis
6
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Hormonal Therapy
For several decades, gynecologists have been successfully using various forms of hormonal (replacement) therapy (HT) for treating climacteric symptoms
• After 2002, as a result of Women’s Health Initiative (WHI) data →
the use of HRT has decreased
• l.2002 : 28 % postmenopausal women use HT • l.2004: only 12 % (Menon, 2007)
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Hormonal Therapy
Many women using HRT became concerned AND stop treatment immediately
Before healthcare providers had time to further analyze the WHI findings, the consumer media began to report about “natural” bioidentical
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Current Status
- „Bioidentical hormones„ are currently very popular
- In our daily clinical practise we meet women interested in BH
- On a daily basis we are also faced with articles regarding BH, in the press and other media, which are misleading
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Misleading info
Aggresive marketing andmisleading unprofesional info about„synthetic“hormones, such as:
Source: http://www.slideshare.net/DrMonicaGavin/bio-identical-hormone-replacement-therapy-presentation
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What Are Bio-identicals?
The term “bioidentical” was created by marketers
Not a scientific term, no uniform definition in any medical dictionary
Medical explanation: hormones which have exactly the same chemical structure as those found in the human body
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Terminology
�The term originated in the USA predominantely conjugated equine estrogen
(CEE) was used in HRT (animal origin: horses)
BIO IDENTICAL something new, natural -BIO: not artificial, from plants -IDENTICAL: the same as hormones in human body
In Europe, 17-beta estradiol (not CEE) was used in HRT from the beginning
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Bio-identical Hormones in Conventional HT
HT Regimen
Route of administration
Preparation Form
Registered drugRegistered
in SLO Estradiol Transdermal Patch Climara YES
Oral Tablet Estrofem YES
Vaginal Tablet Vagifem YES
Estradiol Transdermal Gel Estrogel NO
Estradiol Transdermal Lotion Estrasorb NO
Estradiol Vaginal Ring Femring NO
Estradiol and Progestin
(continuous)Transdermal Patch Climara-Pro, Combipatch NO
Combined Estradiol and
Progestin (NETA,
drospirenone)(continuous)
Oral Tablet Activelle, Angeliq YES
Combined Estradiol and
Progestin(NETA)
(sequential)
Oral Tablet Novo Fem YES
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Custom compounded
�"Bioidentical hormones" = Custom-compounded HT
Could be prepared in different dosages and forms sucs as:- creams- gels- sublingual tablets- suppositories
Clinicians prescribe them – pharmacysts make them
Also commercially prepared in standard proportions:
Bi-est: 20% estradiol, 80% estriol
Tri-est: 10% estradiol, 10% of estrone, 80% estriol
(+) testosterone, DHEAS
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Bio-identical Promotors create agressive marketing
BH:1. More effective 2. Safer3. Prescribed and compounded into tailored, exact dosages - according women’s need 4. More “natural” - Biochemically similar to native hormones?- Plant derived?-- Made without chemical synthesis?
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Effectivenes
BHT promoters: 1.More effective
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Estrogen Dose
Estrogen is essential for alleviating climacteric symptoms
In conventional HRT – exact doses of hormones are known
Dose of estrogens is adjusted based on clinical improvement - symptom relief
Dose of hormones is determined in clinical trials needed for drug/HRT approval
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Estrogen Standard Low DoseUltra-Low
Dose
CEE 0.625 mg 0.3 mg
Oral E2 1 mg 0.5 mg 0.25 mg
Transdermal E2
0.05 mg(50 µg)
0.025 mg (25 µg)
0.014 mg (14 µg)
Nasal sprayE2
150 µg
CEE = conjugated equine estrogen; E2 = estradiol.
Friel P. Hinchcliffe C, Wright J. Hormone Replacement with Estradiol: Conventional Oral Doses Result in Excessive Exposure to Estrone. Altern Med Rev 2005; 10(1):36-41).
.
Estrogen Dose
Trend is: decreasing E2 dose.
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Progestogen dose
Why progestagens should be used?
Women with intact uterus: - The only absolute indication for the use of progestagens
(progesteron) is in to reduce risk of endometrial hyperplasia and endometrial cancer that is associated with unopposed estrogen therapy
Dose of hormones is determined in clinical trials needed for drug/ HRT approval
Weiderpass E, Adami H-O, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without
progestins. J Natl Cancer Inst 1999;91:1131- 1137
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Transformational dose of progestagens
Progestagen Daily dose in mg
Sequential Continuous
Progesterone – micronised (oral)
200-300 100
MPA 5-10 2.5
NETA 1 0.5
Drospirenone - 2
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Bio identical Evidence Based
BHT promoters: More effective
Evidence based: NO clinical trials, NO data
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Safety
BHT promoters: 2.Safer
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Approval of Estrogen Drug „„ To obtain approval for an estrogen drug, the manufacturer
must conduct at least 1- 2 clinical trials (randomized, placebo-controlled)
For indication : hot flashes - a drug must be statistically superior to placebo in reducing the frequency and intensity of hot flashes (12
weeks)
The manufacturer must establish the lowest effective dose to alleviate symptoms
Boothby et al. Bioidentical Hormone Therapy: A review. Menopause, 2004.
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Approval of Progestagen Drug ��
Requirements are even more complicated because of health risk (endometrium hyperplasia)
Manufacturer must conduct an endometrial hyperplasia prevention study;
Duration 12 – 24 months
The acceptable rate of hyperplasia is 1% or less
Boothby et al. Bioidentical Hormone Therapy: A review. Menopause, 2004.
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Safety
14,6%
0,8% 0,4% 0,4%
0%
2%
4%
6%
8%
10%
12%
14%
16%1mg 17β estradiola
1mg 17β estradiola + 0.1mg NETA
1mg 17β estradiola + 0.25mg NETA
1mg 17β estradiola + 0.5mg NETA
Statistical significance (p < 0.001) with 1mg 17β E 2
Vir: Kurman R et al.Obstet.Gynecol.2000; 96:373-379
Incidence of endometrial hyperplasia
1176 post-menopause W, 1 year
Inci
de
nce
(%
)
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Prevention of endometrial hyperplasia
NOT enough for endometrial protection!
Achieved with 200 mg of oral micronized progesterone or 80 mg progesterone skin cream
16 nmol/l serum progesterone
Safety
2.9 nmol/l serum progesterone
Serum progesterone levels, achieved with 1% BH progesterone cream usually used – ½ to 1 tea spoon daily
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Safety
BHT promoters:• 2.safer
Evidence based:• NO
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Tailored dose
BHT promoters:• 3. Prescribed and compounded
into tailored, exact dosages according to “womens needs”
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Saliva Testing
„
Treatment ,individualized for each patient based on laboratory measurements makes sense only for a certain class of drugs
Sex hormones are not such a drug
BUT
Despite this fact, saliva testings are recommended by BH promotors to find out which hormones are deficient
„
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Saliva Testing
Hormone levels vary:
on the time of day on the diet of the individual poor reproducibility and larger interassay variability
undermine the precision of saliva hormone testing
Saliva testing is not suitable method
Dose of estrogens is adjusted based on clinical improvement - symptom relief - NOT lab values!!
Boothby et al. Bioidentical Hormone Therapy: A review. Menopause, 2004.
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Bio identical Evidence Based
BHT promoters:• Prescribed and
compounded into tailored, exact
dosages- according to women’s need
Evidence based:• NO
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Bio-identicals
BHT promoters:
• 4. More “natural”?
- Biochemically similar to native hormones?
- Plant derived?- Made without chemical synthesis?
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Classification of Steroids
4 groups:
1. Class A steroids2. Class B steroids3. Class C steroids4. Class D steroids
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Classification of Steroids
Class A: -found in nature- formulated into drugs without undergoing any chemical modifications ( conjugated equine estrogens - simply extracted from pregnant mare's urine)
Class B: - they are semisynthetic- they need to be chemically synthesized from precursors- a natural starting material: soy, Mexican sweet potatoes (contain sterols -diosgenin, stigmasterol)- precursors for the synthesis of steroids: estradiol, estrone, estriol, progesterone, dehydroepiandrosterone, testosterone, cortisol, aldosterone etc
natural precursor (diosgenin) estradiol requires at least 15 chemical reactions.
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Classification of Steroids
Class C:-are synthesized by a process called “total synthesis” -have the same chemical structure as that of the naturally occurring hormone ( and the same biological activity)
-differentiating between B and C classes of steroid hormones is very difficult- precise analytical procedures required
Class D:- includes steroids NOT identical to human hormones (MPA,NETA, ethinyl estradiol)
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Bio-identicals Evidence Based
BHT promoters:
• More “natural”
- Biochemically similar to native hormones
- Plant derived- Made without chemical
synthesis
Evidence based:
- Biochemically similar to native hormones ✔
- Plant derived ✔- Made without chemical
synthesis x
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Control
Control over the BH ?
In the USA - not under regulatory (FDA) control
No control of content, purity, stability...
Creams with BH - classified as dietary supplements (l.1994: Dietary Supplement Health Education Act) – even poorer control
Also available online – difficult to control
Europe/SLO – BH are regulated and should be controled us any other drug
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ACOG opinion
In 2005, the American College of Obstetricians and Gynecologists (ACOG) issued a statement:
there is no scientific evidence to support claims of increased efficacy or safety of BH
BH have not undergone rigorous clinical testing for either safety or efficacy
ACOG also expressed concern about the purity, potency, and quality of compounded BH products
Understanding the Controversy: Hormone Testing and Bioidentical Hormones . Proceedings from the Postgraduate Course presented prior to the 17th Annual Meeting of The North American Menopause Society October 11, 2006 Gaylord Opryland Hotel Nashville, Tennesseehttp://www.menopause.org/publications/clinical-practice-materials/bioidentical-hormone-therapy/nams-postgraduate-course
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Slovenia Associations
The same opinion was accepted by Slovenian medical associations:
Združenje za ambulantno ginekologijo – SZD Slovensko menopavzno društvo Združenje ginekologov in porodničarjev Slovenije Strokovni kolegij Kliničnega oddelka za endokrinologijo, Interna
klinika, UKC Ljubljana Strokovni kolegij za ginekologijo in porodništvo
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42
Conclusion