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