Transcript Bio-identical Hormone Therapy: What’s the Harm?

Bio-identical Hormones
Lucija Vrabič Dežman, MD
Slovenian Menopausal Society, Ljubljana
Slovenia
9th Croatian congress on Gynaecological Endocrinology,
Human Reproduction and Menopause
Brijuni, 5.- 8.9.2013
Fountain of Youth
Lucas Cranach senior(1546)
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?
Detail from Primavera S.Botticelli, 1482
A Woman‘s
Phases of Life
Expected lenght of women’s life
0
8 12 15
45 50 55
puberty
childhood
birth
climacteric
sexual maturity
menarche
65 years
post-menop.
menopause
senium
80 years
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
4
Perimenopausal
Transition
-
+
Decreased level od estrogens
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
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)
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
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
Misleading info
Aggresive marketing and
misleading unprofesional info about
„synthetic“hormones, such as:


Source: http://www.slideshare.net/DrMonicaGavin/bio-identical-hormone-replacement-therapy-presentation
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
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
Bio-identical Hormones in Conventional HT
HT Regimen
Route of
administration
Preparation Form
Registered drug
Registered
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
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
Bio-identical
Promotors create agressive marketing
BH:
1. More effective
2. Safer
3. 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?
Effectivenes
BHT promoters:
1.More effective
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
Estrogen Dose
Trend is: decreasing E2 dose
.
Ultra-Low
Dose
Estrogen
Standard
Low Dose
CEE
0.625 mg
0.3 mg
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 spray
E2
150 µg
Oral E2
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).
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
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
Bio identical Evidence Based
BHT promoters:

More effective
Evidence based:

NO clinical trials, NO data
Safety
BHT promoters:

2.Safer
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.
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
Safety
Incidence of endometrial hyperplasia
1176 post-menopause W, 1 year
16%
14,6%
1mg 17β estradiola
14%
1mg 17β estradiola + 0.1mg NETA
Incidence (%)
12%
10%
1mg 17β estradiola + 0.25mg NETA
8%
6%
1mg 17β estradiola + 0.5mg NETA
4%
2%
0,8% 0,4% 0,4%
0%
Vir: Kurman R et al.Obstet.Gynecol.2000; 96:373-379
Statistical significance (p < 0.001) with 1mg
17β E 2
Safety
Prevention of endometrial hyperplasia
16 nmol/l serum progesterone
Achieved with 200 mg of oral micronized progesterone or 80 mg
progesterone skin cream
2.9 nmol/l serum progesterone
Serum progesterone levels, achieved with 1% BH progesterone cream
usually used – ½ to 1 tea spoon daily

NOT enough for endometrial protection!
Safety
BHT promoters:
•
2.safer
Evidence based:
• NO
Tailored dose
•
BHT promoters:
3. Prescribed and compounded into
tailored, exact dosages according to
“womens needs”
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
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.
Bio identical Evidence Based
BHT promoters:
•
Prescribed and
compounded into tailored,
exact dosages- according
to women’s need
Evidence based:
• NO
Bio-identicals
BHT promoters:
•
4. More “natural”?
- Biochemically similar to native hormones?
- Plant derived?
- Made without chemical synthesis?
Classification of Steroids
4 groups:
1. Class A steroids
2. Class B steroids
3. Class C steroids
4. Class D steroids
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.
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)
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
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
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
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
Conclusion
42