Natural Hormone Therapy

Dr. Helen Roberts MB, MPHAssociate Professor Women’s HealthDepartment Obstetrics and Gynaecology

University of Auckland

h.roberts@auckland.ac.nz

Research Advisor Family Planning

Natural /bioidentical hormone therapy

• “Natural" means the hormones in the product come from plant or animal sources; they're not synthesized in a lab. However, many of these products still need to be commercially processed to become bioidentical.

• The term "bioidentical" means the hormones in the product are chemically identical to those your body produces

• Using this definition, some examples are progesterone, estrone, estradiol, and estriol

‘Natural’ Hormones

Mexican wild yam

Laboratory synthesis

“natural” progesterone 17 ß oestradiol

Progestogen ERT

Compounded preparations

• Compounded (or custom-compounded) drugs are agents that are prepared, mixed, assembled, packaged, or labelled as a drug by a pharmacist and custom-made for a patient according to a physician’sspecifications.

• Compounded prescriptions can be made into formulations such as gels, creams,lotions, suppositories, or troches.

• Natural progesterone cream-transdermal

• Biest and Triest cream-transdermal

Salivary Testing

• No linear relationship between plasma and salivary P concentrations• Large within-patient variability in salivary hormones• Poor reproducibility ,large inter assay variability

• For most menopausal women, baseline E2 and progesterone levels are low. Testing adds little advantage.

• The current standard of care is to individualize hormone therapy based on symptom relief and side-effect profile, not laboratory results.

Sood R, et al. Counselling postmenopausal women about bioidentical hormones: Ten discussion points for practicing physicians. Journal of the American Board of Family Medicine. 2011;24:202

Progesterone cream

• The efficacy of bioidentical progesterone cream for

flushes has been compared to placebo in 3 RCTs.

• To examine efficacy of treatment for flushes , the FDA recommends that the mean change in symptoms from baseline be measured at 4 and 12 weeks.

• One study showed benefit over placebo

• Positive study used a daily dose of 20 mg.

• Rx progesterone cream 20mg/gram sig 20mg daily

• Peanut allergy/improves sleep

The Annals of Pharmacotherapy 2013 ;47:112

Compounded products

Triest cream Biest cream

10% estradiol (E2) 20% E2

10% estrone (E1)

80% estriol (E3) 80% E3

• E3 is the metabolic end product of oxidation of E2 and E1

• E3 and E1 weak estrogens

• No RCTs of E3 and E1 re efficacy for flushes over placebo

• Estradiol will be the active agent

Compounded products

Biest cream

20% E2 and 80% E3

• 2.5mg dose has 0.5mg E2 and 2mg of E3

Endometrial safety?

• Oral E3 estriol 1-2mg associated with increased risk of endometrial cancer but not 0.5mg vaginal estriol

Weiderpass E et al. Lancet 1999;353:1824-28

V 2.0_130402

NAMS statement

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

Bioidentical commercially manufactured products

• Estrofem-oral 17 ß oestradiol

• Climara/Estradot-transdermal 17 ß oestradiol

• Utrogestan-oral micronised progesterone

• Ovestin -vaginal estriol

Utrogestan-micronised progesterone

• 133 women randomised to 100mg capX3 progesterone V placebo

• 4 week run in -12 weeks study

• VMS (vasomotor system) score=hot flush/night sweat frequency X severity

• Mean reduction VMS score with progesterone =10,with placebo=4.4

• VMS score better than placebo (-4.3)Hitchcock. Menopause 2012;19:886

Cost of subsidised HT ie progynova and proverafor 3 months is $5 each

Premarin (CEE) 0.3mg $53.30

Premarin (CEE) 0.625mg $46.90

Estrofem (estradiol) 1mg and 2 mg $41.60

Climara (transdermal estradiol) 50µg $56.60

Climara (transdermal estradiol) 100µg $56.80

Estradot (transdermal estradiol) 25µg $49.70 (8)

Estradot (transdermal estradiol) 50µg $56.60 (8)

Estradot (transdermal estradiol) 100µg $56.80 (8)

Utrogestan (progesterone) 100mg $82.10

Microlut (LNG) $23.80 (6 months) (O)

Progesterone cream($45.50 pot) $91

Biest cream ($76.50 pot) $ 153

Safety?

• Are "bioidentical" or "natural" hormones

safer than hormones used in traditional

hormone therapy for menopause symptoms?

• No RCT data –should discuss that same risks and benefits likely to apply as per WHI data

• However some observational data re transdermal delivery system of estrogen

and different progestins in combined HT

WHI-Absolute risks attributable to HT per 10,000women /yr aged 50-59 yrs during intervention

Outcome E+P (I)

CHD +5

Breast cancer +6

Stroke +5

DVT +10

PE +6

Hip fracture -3

JAMA 2013;310:1353-68

WHO classification for risk

Rare=1-10/10,000 cases exposed per year

VTE and transdermal estrogen

• Data from observational studies

• Suggest no increase in VTE risk with withtransdermal estrogen<= 50 mcg

+/- progesterone

• Oral estrogen increases APC resistance and other coagulation markers

• Transdermal does not

• Progesterone -Utrogestan -endometrial protection with 0.625 CEE was 2x100mg capsule if used 12 days (PEPI)

Risk of stroke with transdermal E

• Case control study

• Risk of stroke transdermal E v no use

• <= 50 µg patch: RR=0.81(0.62-1.05)

• >50 µg patch: RR=1.89 (1.15-3.11)

Renoux BMJ 2010;340:c2519

With combined therapy does the type of progestin alter the breast cancer risk?

• It is the addition of the progestogen that confers the increased risk of breast cancer diagnosis associated with HT.

• For combined therapy there is growing evidence that progesterone(Utrogestan) and dydrogesterone may be associated with a lower risk

than synthetic progestogens derived from C21 progesterone

and 19- nortestosterone

E3N French large observational cohort study-Risk of breast cancer

• RR=1.00 ( 0.83 – 1.22) for estrogen / progesterone,

• RR=1.16 ( 0.94 – 1.43) for estrogen / dydrogesterone

• RR=1.69 ( 1.50 – 1.91) for estrogen / other progestins

Breast Cancer Res Treat 2008:107:103

DHEA(s)-Cognitive function

• DHEA acts as a precursor for testosteroneand estrogen synthesis in peripheral tissues.

• Dehydroepiandrosterone (DHEA) supplementation for cognitive function

• Cochrane Database of Systematic Reviews- 4- 2009.

What little evidence there is from controlled trials does not support a beneficial effect of DHEA supplementation on cognitive function of non-demented middle-aged or elderly people

DHEA-other effectsCochrane review 2015

• In this review there is no evidence from the pooled sensitivity analysis of eight studies that DHEA is associated with an improvement in quality of life or wellbeing compared to placebo, hormone therapy (HT) or no treatment.

• The quality of the studies in this analysis that reported quality of life was considered to be moderate

• DHEA treatment was associated with more androgenic side effects, in 15% of women (predominantly acne) compared to less than 3% in the control group.

DHEA -menopausal symptoms

• Limited data were available on the use of DHEA for menopausal symptoms.

• The results of studies that reported on menopausal symptoms were difficult to pool as their outcomes were inconsistently reported

• Two studies reported beneficial effects on menopausal symptoms for DHEA (versus no treatment and HT), however one study was unblinded and may therefore have been biased.

• More research is needed to see whether DHEA effectively decreases menopausal symptoms

DHEA –sexual function

• The pooled studies reported that sexual function was potentially improved with DHEA compared to placebo.

• However, treatment to obtain this slight improvement would not be clinically justified in light of the possible side effects with this treatment.

• Even though DHEA might slightly improve sexual function compared to placebo there was no evidence that DHEA improved sexual function more than HT.