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Stella MilsomEndocrinologist
Fertility Associates
Auckland
8:30 - 9:25 WS #71: Bio-Identical Hormone Therapy - Fact or Fiction
9:35 - 10:30 WS #81: Bio-Identical Hormone Therapy - Fact or Fiction
(Repeated)
Bioidentical Hormones: Fact or Fiction
Stella Milsom, Endocrinologist• Auckland DHB, University of Auckland, Fertility Associates Auckland• The Endocrine Group, Fertility Associates
Disclosures
Consultant/Scientific Advisor/Board member of the following
• Member of NZ Guidelines Committee on Menopausal hormone therapy
• Pharmac New Zealand
• Osteoporosis New Zealand
• New Zealand Endocrine Society
• Human Fertility UK
• NZ Medical Council
• High Performance Sport
• Human Rights Commission
• Royal Australasian College of Physicians
Honorariums from Pfizer Pharmaceuticals; Australian Menopause Society for medical education
Outline
• Unpick confusing definitions and terminology
• Pros and cons of conventional (MHT) versus bioidentical hormone replacement (BHT)
• Potential medico legal issues for prescribers of BHT
• How to manage consultations requesting bioidentical hormones
Linda, aged 52 yrs
• Mother of 3 teens and part time teacher, LMP 15 months ago
• Otherwise well, non smoker, and normotensive, up to date with breast screening, slightly overweight, drinks two glasses of wine at night
• Menopausal symptoms significant “can’t sleep, increasing low mood and anxiety, frequent daytime flushes affecting her teaching job
She is desperate to improve her quality of life, wonders about MHT but is worried about breast cancer risk.
She asks about BHT as an alternative, keen to be “natural” in her approach.
Linda,aged 52 yrs
Issues to consider
• Linda has significant menopausal symptoms-what evidence based solutions are available?
• How do we answer her question concerning breast cancer risk?
• She is desirous of a “natural” approach? Would BHT be a safe and cost-effective alternative?
Ineffective Minor benefit Effective
Wild yam cream Acupuncture Estrogen
Progesterone cream Hypnosis Gabapentin
Red clover Cognitive behavioral therapy (CBT)
SSRI
Black Cohosh Vitamin E SNRI
Ginseng ? Soy supplements Clonidine
Evening primrose ? Paced respiration
Don quai
Linda, aged 52 yrsWhat are the evidence based options for her symptoms?
Back to Linda
• How do we answer her question concerning breast cancer risk?
• What about other risks of MHT?
MHT can be safely
prescribed for healthy
younger symptomatic
women
Breast cancer risk
• E+P users may have small increase in risk (1 additional breast cancer/1200 women/year; may be less with natural progesterone
• E users neutral or lower risk
Risks of stroke, CHD and VTE
• very small, likely to be less with lower doses and transdermal route of estrogen
• E alone users may have positive CHD benefit
Linda, aged 52 yrs
• How is BHT different from MHT?• Would BHT be a safe and cost-effective
alternative?
Bioidentical hormones
Literal meaning of bioidentical is a hormone with the same molecular structure as a hormone endogenously produced by the body
• Implication is that this means a natural, not produced in laboratory
Production of ‘Bioidentical ’ Hormones
Mexican wild yam
“natural” progesterone
Progestogen
“natural” 17 ß oestradiol
MHT
Laboratory synthesis
• Are bioidentical hormones “natural”? Not in true sense
• Is BHT different from conventional menopausal hormone therapy?No, these products are available both as “bioidentical” compounded formulations and in commercially produced MHT
• More appropriate terminology for both “bioidentical” and commercially available versions of these hormones would be “body-identical” hormones
Bioidentical hormone therapy is marketing
terminology
• In popular culture, BHT terminology refers to
• custom made compounded hormone replacement
• dose adjustments based upon serial hormone monitoring
• multihormone regime
• Commonly compounded hormones: estradiol(E2), estrone (E1), estriol (E3), progesterone, testosterone, and dehydroepiandrosterone (DHEA)
What does compounding
mean?
• Compounded drugs are prepared, mixed, assembled, packaged, or labelled as a drug by a pharmacist
• Made into formulations such as gels, creams, lotions, suppositories, or troches.
Quality control in compounded hormones is a major concern
• 2003 FDA tested 29 products from 12 pharmacies1/3 failed quality testing (www.fda.gov)
• 2012 – 12 “menopausal bioidentical hormone” products tested- 86% different oestrogen doses (58 – 272%), 96% inadequate progesterone
• 2012 – New England Compounding Centre shipped 18,000 intra-spinal injections, 750 cases of fungal meningitis – 64 deaths
Prescribers of compounded products are liable for any adverse event
Guidelines on compounding of
medicines(Pharmacy Board
of Australia)
Compounded medicines should ONLY be prepared if:
• appropriate commercial product not available
• Patient has allergy to an excipient in the commercial product
• when undertaking recognized research
Salivary Hormone
Testing
Hypothesis: Salivary hormones permit individualized therapy and monitoring
BUT
• reproducibility of hormone levels poor
• No standardization of assays
• No correlation with blood levels or symptoms
Wood, Ann Clin Biochem 2009; Sood, J Am Board Family Medicine 2011
The current standard of care is to individualize menopause hormone therapy based on symptom relief and side-effect profile, not laboratory results.
Compounded Multihormone Therapy
Triest cream10% estrone (E1) 10% estradiol (E2), and 80%
estriol (E3)
Biest cream20% estradiol (E2) and 80%
estriol (E3)
• Biest and Triest contain active estradiol• E1 and E3 are only weak estrogens; no evidence that they are effective
Weiderpass, Lancet 1999;353:1824-28
Body-Identical (Bioidentical) Hormones available on prescription & prepared under strict regulatory control
• Estrofem-oral 17 ß oestradiol
• Estradot patch, Sandrena Gel-transdermal 17 ß oestradiol
• Ovestin -vaginal estriol
Estrogens
• Uterogestan-oral micronized progesterone
Progestins
Why have bioidentical hormones become so popular?
• FEAR of prescription menopausal hormone therapy
• Celebrity endorsement of bioidentical hormones
• 6.2 million viewers watched Suzanne endorsing BHT on Oprah in 2009
“I get my hormones compounded so that I get my hormones individualized, just for me. This allows me to achieve a perfect balance, just like Goldilocks...not too much, not too little, just right”
2004 “The Sexy Years” Suzanne Sommers
Enthusiasm around BHT
• Concept of replacing three hormones, not just one
• Clever and persuasive marketing
• Women are beguiled with the idea of salivary hormone testing
• Woman feels she can be “proactive” in managing her wellbeing in the menopause
Back to Linda
• Would BHT be a safe and effective alternative to MHT?
Compounded Estrogen
• Triest cream
• 10% estrone (E1) 10% estradiol (E2), and 80% estriol (E3)
• Biest cream
• 20% estradiol (E2) and 80% estriol (E3)
Both contain active beta estradiol plus E1 and E3 which are weak estrogens
Weiderpass, Lancet 1999;353:1824-28
Compounded Transdermal Progesterone
• Three RCTs have compared the efficacy of bioidentical progesterone cream for menopausal hot flushes to placebo
• one study showed benefit over placebo• The Annals of Pharmacotherapy 2013 ;47:112
• two studies showed no benefit over placeboWren, Eden et al Menopause 2003; Studd et al Menopause 2003
• Systematic review: no overall benefit of Transdermal P but few harms
• Not suitable for endometrial protection
Compounded DHEA
DHEA is a precursor for testosterone and estrogen
synthesis in peripheral tissues
DHEA compared to placebo or MHT with respect to:
Cognitive function- no evidence of beneficial effect in mid to later life
(limited data)
Quality of Life-no improvement compared to placebo or MHT (8 trials)
Menopausal symptoms and/or libido-limited positive data on menopause
symptoms, mildly positive for libido but not better than MHT (poor quality
unblinded trial)
DHEA treatment was associated with more androgenic side
effects
Cochrane Database of Systematic Reviews 2009, Cochrane Database of
Systematic Reviews 2015
Back to LindaWhat if she complains about lack of libido?
Identify the symptom / problem(s)• vasomotor symptoms
• somatic symptoms
• genito-urinary symptoms
• psychological symptoms / life stressors / sleep
• relationship issues
• important to exclude organic pathology e.g. thyroid disease
• review medications – e.g. certain antidepressants contribute to ⇩sexual function
Management – female sexual
dysfunction
Targetted treatment
• Hormone therapy: systemic oestrogen +/- progesterone
• Vaginal oestrogen / moisturisers –vaginal dryness / dyspareunia
• Pelvic floor exercises
• Psychological assessment / sexual counselling
• other – e.g. Antidepressants
• ? Testosterone
Testosterone treatment
No Pharmac approved product for use in women
Treatment options
1. Ensure adequate oestrogen +/-progestogen
2. T Implant 50-100mg; 6 monthly
3. Transdermal cream 1% – daily dose; aim to keep levels within the normal female range
Potential adverse effects
1. Hirsutism / male pattern hair loss
2. Acne
3. Mood change – irritability, aggression
4. Lowered HDL
5. Clitoromegaly
6. Voice deepening
Back to LindaWould BHT be a safe and cost-effective alternative?
• No evidence to support effectiveness or superiority of compounded hormones; in fact compounded hormones may pose extra risk
• No rationale to monitor salivary hormone levels
• Effective Pharmac approved products available, less expensive or fully funded, with secure data concerning risk/benefit ratio
For example: • Estradot patch 50 ug twice weekly • or Progynova 1mg daily plus Progesterone 200mg for 12
days per month
“Body Identical” pharmaceutical grade registered MHT
Cases from an endocrinologist…
Adverse reaction from Compounded Testosterone cream
• 60 year old female, surgical menopause 10 yrs ago, 18/12 history of acne
• Examination: mild acne, facial hirsutism, clitoromegaly (grade 2/4)
• Results: Total Testosterone 33 nmol/L!! ( N <2.5); N CT adrenals and ovaries
• Further history obtained is use of compounded testosterone cream to support libido (she has a partner 13 yrs younger than her )
Diagnosis: Virilization from excess absorption of transdermal testosterone
Cream stopped – T returned to 0.6 nmol/L 2 months later
Milsom, et al ANZJOG 2009
Cases from an endocrinologist…
Adverse reaction from compounded estrogen therapy
• 59 year old woman presents with dysfunctional uterine bleeding and history of surgical menopause age 33yrs
• Meds: Climara 100mcg patch weekly; progesterone cream 20 mg daily
• Results: Pelvic USS – thickened endometrium; Hysteroscopy and pipelle biopsy – complex endometrial hyperplasia
• Diagnosis: Precancerous endometrium from unopposed estrogen therapy; required hysterectomy followed by estradiol patch
Cases from an endocrinologist…
Adverse reaction from whole thyroid therapy
• 49 year old woman presents with irregular menses, hot flushes, fatigue and weight gain
• T4 12.3 ( N 10-20) and TSH 5 ( N < 4); thyroid antibody negative; diagnosed as subclinical hypothyroidism and treated with whole thyroid, not monitored
• 3 months later: chest pain, breathless; prolonged episodes of ventricular tachycardia, T4 29, T3 14, TSH < 0.01
• Diagnosis: iatrogenic thyrotoxicosis; menopausal symptoms; whole thyroid discontinued, referred to endocrinologist; TSH 2.4 off all medication
• Started Progynova and cyclical Provera with good symptom control
How to manage the consultation
and move forward….
• Listen to your patient
• What are specific concerns?
• Patient get information from multiple sources
• Be aware patient may not disclose
In face of no recognized endocrine diagnosis…
Patients are suffering:
• My hormones are out of whack
• I can’t lose weight – but I don’t eat anything
• My thyroid is unbalanced – the normal tests are unrepresentative
• I have been tired for 10 years, it must be hormonal
• I hate my husband – it is a hormone problem
Pseudo-diagnoses offered by BHT practitioners very appealing
Positive steps
• Try to engage the patient; have position statements to hand out; discuss the discrepancies between advertising and facts with respect to BHT
• Offer option of evidence based therapy
• Consider lifestyle and mood
• Look for strategies which do no harm
• Final decision is patient’s choice
The medicolegal responsibility of BHT rests with the prescriber
• Prescribers of compounded products may be personally exposed should there be an adverse event resulting from a product that neither the prescriber nor compounder can prove was the correct dose of the specific product and was free of contaminants.
Possible consequences include the invalidation of their malpractice insurance, personal liability, and criminal prosecution
NAMS 2017
Information for women and practitionersAustralasian Menopause Society at: www.menopause.org.au
• Position statement from American Endocrine Society (ESA) on Bioidentical hormone therapy
• Position statement from North American Menopause Society (NAMS) on Bioidentical hormones
• Position statement from American College of Obstetricians and Gynaecologists
• Lay article in more.com “ The Hormone Hoax” 2013 http://bit.ly/2ADtgE9
• Lay article in NZ Listener Feb 2017