Bio-identical Hormones Lucija Vrabič Dežman, MD Slovenian Menopausal Society, Ljubljana Slovenia 9th Croatian congress on Gynaecological Endocrinology, Human Reproduction and Menopause Brijuni,

Fountain 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 Life sexual maturitychildhoodpost-menop.senium years birth menarche menopause pubertyclimacteric 80 years Expected lenght of women’s life

4 Lack of Estrogen After menopause – estrogen l evel is ↓ reduced (in particular, oestradiol) : 120 pg/ml to 18 pg/ml The consequences are: climacteric symptoms, impaired quality of life

PerimenopausalTransitionPerimenopausalTransition + - 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:

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 FormRegistered drug Registered in SLO EstradiolTransdermalPatchClimaraYES OralTabletEstrofemYES VaginalTabletVagifemYES EstradiolTransdermalGelEstrogelNO EstradiolTransdermalLotionEstrasorbNO EstradiolVaginalRingFemringNO Estradiol and Progestin (continuous) TransdermalPatchClimara-Pro, CombipatchNO Combined Estradiol and Progestin (NETA, drospirenone) (continuous) OralTabletActivelle, AngeliqYES Combined Estradiol and Progestin (NETA) (sequential) OralTabletNovo FemYES

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

EstrogenStandardLow Dose Ultra-Low Dose CEE0.625 mg0.3 mg Oral E21 mg0.5 mg 0.25 mg Transdermal E mg (50 µg) mg (25 µg) mg (14 µg) Nasal spray E2 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:

Transformational dose of progestagens ProgestagenDaily dose in mg SequentialContinuous Progesterone – micronised (oral) MPA NETA 10.5 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 Statistical significance (p < 0.001) with 1mg 17β E 2 Vir: Kurman R et al.Obstet.Gynecol.2000; 96: Incidence of endometrial hyperplasia 1176 post-menopause W, 1 year Incidence (%)

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 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://

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

42 Conclusion