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National Association for Premenstrual Syndrome

Body Identical Replacements NAPS

Body Identical Hormone Replacement – the way forward ?

Nick Panay, Chair NAPS

Queen Charlotte’s & Chelsea and Chelsea & Westminster Hospitals, Imperial College London

The adverse outcomes seen in WHI1 were mainly due to an over-dosage of hormones in a relatively elderly population. However, fundemental differences exist between conjugated equine estrogens and 17 beta estradiol and between medroxyprogesterone acetate and natural progesterone. It is likely that these differences also contributed to the adverse outcomes in WHI, which were contrary to the cardiovascular benefits seen in previous observational trials. Recent studies of cardiovascular risk markers in younger women have been designed using predominantly estradiol and natural progesterone (transdermal and oral) as the primary interventions. This paper reviews the effects that body identical estradiol and progesterone can have, both in the physiological environment and also when replaced as transdermal estradiol and micronized oral progesterone.

What are bio identical hormones?
“Bio-identical hormones” are precise duplicates of estradiol, estriol, estrone, progesterone, DHEA and testosterone as synthesised by the human ovary and adrenal. However, this is a marketing term and bios is a Greek term referring to “life”. A more accurate way to refer to these hormones is “body identical.”2 This paper will focus on the possible differential effects of transdermal estradiol and micronized.
Although androgens have a vital role to play in hormone replacement there is general agreement that testosterone should be delivered non-orally in a physiological formulation and dosage.

Why is there controversy?
Compounding pharmacies market their own unregulated bio-identical products promoted in a number of countries by high profile celebrities. Some practitioners prescribing these compounded preparations claim to be able to calculate the precise level of each deficiency from salivary hormone levels and then replace the precise amount using estrogen, progesterone and testosterone delivered by lozenges or creams. This practice is not supported by evidence for efficacy nor safety. In reality, imbalances of estrogen and / or progesterone can lead to problems such as endometrial hyperplasia. It is high time the regulatory authorities took this issue seriously and introduced a statute to prevent these unregulated products from being freely sold on the open market. The US Senate are passing a bill on bio-identical hormones to bring these products under Food and Drug Administration (FDA) regulation. The North American Menopause Society (NAMS) is concerned about pharmacy compounders who operate as manufacturers without following Good Manufacturing Practices. NAMS have called for the manufacturers of body identical hormones to register with the FDA. Bulk chemicals should be identified and checked for quality and purity. Standard information should be provided on risks and benefits of the product. There should be appropriate investigation and reporting to the FDA of adverse events potentially related to the drug.

Are there any differences between bio-identical and non bio-identical hormones?
The most significant difference, in terms of biological effect, is with the progesterone component. The synthetic analogues of progesterone i.e. progestins / progestogens were developed to make the hormone available orally before the process of micronisation had been developed. Unfortunately, in addition to binding to the progesterone receptor, many of these compounds also bind to the glucocorticoid, mineralocorticoid and androgen receptors. This binding can lead to unwanted side effects  such as unfavourable glucose metabolism, fluid retention, acne and weight gain.3 The progesterone molecule binds primarily to the progesterone receptors to produce the desired effect in the endometrium ie. secretory transformation. There is some weak binding to the mineralocorticoid receptor but here there is an antagonistic effect which gives it mild diuretic properties. Progestogens and progesterone bind to the progesterone receptors in the central nervous system. Both can lower mood through stimulation of the neurotransmitter gamma amino butyric acid GABA; whilst progesterone has a mild sedative effects through its intermediate metabolites, progestogens tend to cause anxiety and irritability.4
Synthetic forms of estradiol e.g. valerate are cleaved at an early stage during GI absorption leading to delivery of bio-identical estradiol. The biological effects of conjugated equine estrogens are complex and have still not been fully evaluated.

Does the route of administration make a difference?
There are some fundamental differences between oral and transdermally administered estradiol due to the avoidance of first pass hepatic metabolism. In theory transdermal delivery manifests in a more physiological systemic effect; factors of coagulation are not activated and neither is the renin angiotensin aldosterone cascade, thus minimising the risk of venous thrombosis and hypertension.5

Effect on the cardiovascular system
Micronised progesterone has several properties which facilitate a neutral or positive effect on the cardiovascular system. There appears to be a neutral effect on lipid and glucose metabolism and on vascular tone.  Thus, the beneficial effects of estrogen are not attenuated as they are with some synthetic progestogens such as MPA which can blunt the increases in HDL.6 Progesterone also has beneficial effects by preventing the growth and movement of cells involved in the formation of arteriosclerotic plaques and relaxes arterial smooth muscle via enhancement of nitric oxide from the endothelium. Conjugated equine estrogens lead to greater increases in triglycerides than 17 beta estradiol but it is unclear how significant this is as far as cardiovascular disease risk is concerned.
New randomised trials such as KEEPS7 and ELITE have been designed to study bio-identical hormones in the expectation that there will be a more favourable effect on cardiovascular risk markers. In both studies micronised progesterone has been used as progestogenic opposition. Preliminary data from KEEPS reported at NAMS in October 2012 showed a significant improvement in quality of life with no significant effect on carotid intima media thickness, coronary calcium scores and lipids and insulin resistance. The final ELITE study report is due in 2014.

Effect on venous thromboembolic (VTE) risk
There are differential effects of transdermal estradiol and micronised progesterone on the cardiovascular system. There is lack of a procoagulant effect of transdermal estradiol with absence of thrombin generation and resistance to activated protein C. This may result in primary prevention benefits for myocardial infarction and diabetes, though larger studies would be desirable to confirm this. The type of progestogen seems to negate even the route of administration of estrogen. Observational data suggest that the use of progesterone derived progestogens may modulate the increased risk conferred by oral estrogen. There was no modification of VTE risk regardless of route of estradiol administration with an odds ratio of 0.9 (CI 0.6-1.15) in the E3N study8 and an odds ratio of 0.7 (CI 0.3-4.9) in the ESTHER study.9

Endometrial Protection
Although consistent endometrial protection was shown with micronised progesterone  in the PEPI trial,10 is it adequate if used orally? In the EPIC cohort, more endometrial cancers occurred overall in sequential combined HRT users: HR 1.41 (CI 1.08-1.83) but particularly in estradiol /micronised progesterone users: HR 2.42 (CI1.53-3.83).11 There was a significant reduction in risk in continuous combined users with a HR of 0.24 (CI 0.08-0.77).
A possible explanation is that there was less compliance in micronised progesterone users because there were two separate components to their HRT which had to be complied with.
Effect on the breast
Micronised progesterone stimulates the 17 beta hydroxy steroid dehydrogenase transformation of estradiol into less potent estrone E1. E1 competes poorly with estradiol E2  for binding to the estrogen nuclear receptor and diffuses out of the target cells more easily than E2. In addition to this, progesterone has a pro apoptotic effect on breast epithelial cells – this is in contradistinction to the effects of androgenic progestogens such as medroxyprogesterone acetate which have a proliferative effect.12
Do the laboratory / animal data translate into clinical benefits? Data from the E3N Cohort Study would suggest so. Established in 1990 with 98 995 women from a health insurance scheme covering French teachers, born 1925-1950 it is part of the European Prospective Investigation into Cancer and Nutrition (EPIC). Estrogen-progesterone combination HRT was associated with a significantly lower relative risk (neutral for “ever use” of HRT) than for other types of combined HRT (RR 1.7 – 2.0). The increased risk appeared to apply preferentially to estrogen receptor (ER) positive carcinomas and to affect both ductal and lobular carcinomas.13 However, subsequent analyses of the data from EPIC showed that if HRT was initiated less than three years post final menstrual period, more than five years use of HRT was associated with an increased risk of breast cancer, even in estradiol and micronised progesterone users.14
It has also been argued that possible preferential use of estradiol and progesterone in overweight women could explain lack of association with breast cancer as in WHI.15 Another factor needing consideration is that oral micronised progesterone is poorly absorbed; the weak effect may take longer to increase risk of breast cancer. Finally, how do we explain no increase in risk of breast cancer in the Danish Osteoporosis study with the androgenic progestogen norethisterone acetate; this may be due to the small size of the study group but follow up was long term (16 years).16 There is clearly a need for further prospective randomised studies using estrogen-progesterone combinations to confirm these data.17

Global Consensus18 and IMS Recommendations19
The recent global consensus is that the use of custom compounded bio-identical hormone therapy is not recommended.18 The IMS recommendations19 state the following….
Natural progesterone and some progestogens have specific beneficial effects that could justify their use besides the expected actions on the endometrium.  
Progestogens may not be alike in regard to potential adverse metabolic effects or associated breast cancer risk when combined with long-term estrogen therapy.

There is evidence that replication of the physiological hormonal environment with transdermal estradiol and natural progesterone can maximise the benefits and minimise the side effects and risks of hormone therapy. It is time we moved away from the notion, often propagated by epidemiologists and the media, that HRT products have a single class effect. However, regulated bio-identical products must not be confused with unregulated products from compounding pharmacists. In order to avoid confusion, the editors propose that regulated products should be referred to as “body” rather than “bio” identical. The published data thus far suggest that differential effects can be achieved by the use of body-identical HRT in comparison to synthetic non body-identical HRT. Further data from larger studies on major cardiovascular and breast endpoints are required to confirm these effects. In the interim, the logical approach would be to continue to prescribe individualised HRT regimens from the whole pharmacopeia according to the evidence base and IMS recommendations,19 taking into account each woman’s risk profile.
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