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

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?

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

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

PerimenopausalPerimenopausalTransitionTransition

PerimenopausalPerimenopausalTransitionTransition

+-

Decreased level od estrogensDecreased 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 andmisleading 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 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

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. 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?

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 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.

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

Boothby et al. Bioidentical Hormone Therapy: A review. Menopause, 2004.

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

(%

)

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

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 steroids2. Class B steroids3. Class C steroids4. 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

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Conclusion