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Bioidentical HRT - safe and effective treatment of menopausal symptoms

 
HRT (hormone replacement therapy) with estrogen/progestin or estrogen alone has traditionally been the standard of care to alleviate menopausal symptoms and prevent post-menopausal osteoporosis.[1-4] However, in 2002, the shocking results of the Women’s Health Initiative (WHI) study were published, showing that estrogen/progestin HRT significantly increases risk of breast cancer, heart attack (myocardial infarction) and vein thrombosis.[5] A second WHI study with estrogen HRT (without progestin) on post-menopausal women with prior hysterectomy (surgery that removes the uterus) also found an increased risk of stroke and pulmonary embolism.[6] Both these studies were terminated early because of unacceptable risk-to-benefit ratio. For more info, see "Menopausal HRT with non-bioidentical hormones - the WHI studies"
 
However, it is critical to note that these notorious WHI studies used non-bioidentical estrogen and non-bioidentical progesterone, i.e. progestin. The risk-to-benefit ratio of HRT with bioidentical estrogen and progesterone is very different, with the benefits significantly outweighing any potential risks, as will be outlined in this article…
 

Estrogens


Bioidentical Estradiol vs. Non-bioidentical CEE (Conjugated Equine Estrogens)


The predominant estrogen currently prescribed in the United States is Premarin, which is a brand name for conjugated equine (horse) estrogens (CEE). CEE is derived from the urine of pregnant mares (female horses), and contains a complex mix of multiple forms of estrogens which don’t occur naturally in the human body.[7] The main types of estrogens in CEE are estrone sulfate, equilins, equilenins. In addition, CEEE contains other biologically active steroids with unknown effects.[7] It is important to note that after menopause, women lose estradiol (the major ovarian hormone), whereas levels of estrone (largely produced in non-ovarian tissues) remain unchanged.[8] CEE does not replace estradiol.[8]
 

CEE also contains several potentially harmful non-human estrogen metabolites (substances formed during metabolism). For example, the CEE metabolite 4-hydroxyequilenin is more mutagenic than its human equivalent, 4-hydroxyestrone [9], and induces considerably more cellular DNA damage in breast cells than 4-hydroxyestrone.[10-13] 4-Hydroxyequilenin also activates chemical and hormonal pathways that contribute to estrogen-dependent carcinogenesis (initiation of cancer formation).[14]
 
Also, compared with bioidentical estrogen, hormone therapy with CEE causes a greater increase in SHBG (sex hormone binding globulin) and thereby a larger drop on free estrogen and free testosterone levels.[7] The exaggerated drop in free testosterone is especially deleterious, as women by the time they enter menopause already have markedly reduced testosterone levels.[15] For more info on the importance of testosterone for women, see our previous articles
 
Another common non-bioidentical estrogen is ethinyl estradiol.[16] Terminology obscures important distinctions between CEE and estradiol. By definition, any compound that can bind to and activate estrogen receptors is an “estrogen”.[8] Thus, both CEE, ethinyl estradiol and estradiol are estrogens; however, chemically, they are different molecules and only bioidentical estradiol can replace the estrogen women lose after menopause.
 
The molecular structure of non-bioidentical estrogens (CEE and ethinyl estradiol) allows them to bind to estrogen receptors, but their inability to fit exactly in the estrogen receptor binding location prevents the correct interaction necessary to exert the same biological effects as estradiol.[8] Further, non-bioidentical estrogens do not mimic the cardiovascular protective effects of bioidentical estradiol to the fullest capacity because the cardiovascular effects of bioidentical estradiol are mediated via both estrogen receptor-dependent and estrogen receptor-independent mechanisms.[7, 8, 17] Non-bioidentical estrogens may be less able to counteract cardiovascular disease and actually may induce deleterious effects.[18] For example, CEE impairs nitric oxide production in human blood vessel (endothelial) cells, and consequently is less beneficial than bioidentical estradiol, which stimulates nitric oxide production and increases vasodilation (dilation of blood vessels).[18] Differences in nitric oxide production by different estrogens may account for the differences in cardiovascular effects seen with bioidentical (beneficial) vs. non-bioidentical (detrimental) estrogen replacement therapies.[18]
 
In a comparison of oral bioidentical estradiol versus oral non-bioidentical estrogens (CEE, ethinyl estradiol etc), it was found that non-bioidentical estrogens also exert significantly more strain on the liver [19], which contributes to their negative cardiovascular effects.[20-22] Given the potential increased risk for cancer development and liver strain, avoidance of non-bioidentical estrogens (CEE, ethinyl estradiol, diethylstilbestrol) is strongly recommended.
 

A recent review of studies concluded that significant differences exist between non-bioidentical and bioidentical estrogens in terms of hormonal bioavailability and metabolism, with implications for efficacy, potential side effects, and risk profile of different hormone therapy options.[23] Bioidentical estradiol has less pronounced effects on inflammatory and coagulation markers, and in contrast to non-bioidentical estradiol has a favorable effect on triglycerides (blood fats).[23] 
 
In addition, in contrast to bioidentical estrogen, non-bioidentical estrogen increases fat mass and reduces lean mass.[24] This is an important consideration for many women who struggle with weight gain. Finally, bioidentical estradiol does not increase SHBG (sex hormone binding globulin) level as much as non-bioidentical estradiol.[23] This is important as SHBG reduces levels of active free testosterone, which is important for libido and sexual function.[25-28] Thereby, bioidentical estradiol is more beneficial for preservation or elevation of libido and sexual vigor.
 

Progesterone


Bioidentical Progesterone versus Progestin (a non-bioidentical progesterone version)


The issue of bioidentical vs. non-bioidentical is especially important when it comes to progesterone, because non-bioidentical progestin has significantly different and undesirable effects compared to bioidentical progesterone (more on that below).
 
Progestin is non-bioidentical version of progesterone; some widely used progestins are norethindrone and MPA (medroxy-progesterone acetate, brand name Provera). When it became clear in the 1970s that unopposed estrogen therapy (i.e. estrogen only therapy) increases the risk of endometrial cancer in postmenopausal women, non-bioidentical progesterone were added to suppress estrogen-induced endometrial cell stimulation.[29] 
 
Breast Cancer

 
Bioidentical progesterone and non-bioidentical progestin generally have the same protective effects on endometrial tissue. However, there is solid evidence (from both mechanistic test tube studies and human studies) that bioidentical progesterone and non-bioidentical progestin have very different effects on breast tissue proliferation and breast cancer risk.
 
In contrast to non-bioidentical progestin, bioidentical progesterone counteracts the estrogen-induced proliferation of human breast (mammary) cells.[30] Studies have demonstrated that postmenopausal women treated with non-bioidentical progestin (MPA) have significantly greater breast cell proliferation and breast density (a well-established risk factor for developing breast cancer [31]) than women treated with estrogen only or those receiving no treatment.[30]
 
While it is well-documented that non-bioidentical progestins increases risk for breast cancer.[32-37] One reason for this is that they have some non-progesterone-like effects which can potentiate the cancer promoting action of estrogens.[32] In contrast, bioidentical progesterone does not increase breast cancer risk, and may even reduce it.[38-44]
 
In other words, bioidentical progesterone appears to reduce breast cancer cell proliferation while non- bioidentical progestin fuels it.
 
Cardiovascular Disease Risk

 
The WHI studies demonstrated that the addition of non-bioidentical progestin (MPA) to Premarin® (a preparation containing the non-bioidentical estrogen CEE) resulted in a substantial increase in the risk of heart attack and stroke.[5, 45] This is not surprising because non-bioidentical progestin has negative cardiovascular effects and counteracts the cardio-protective effects of estrogen.[46-61] Progesterone, in contrast, has the opposite effect because it maintains and augments the cardio-protective effects of estrogen, thus decreasing the risk for heart attack and stroke.[46-48, 50, 51, 55, 57]
 
One mechanism contributing to these opposing effects of bioidentical progesterone vs. non- bioidentical progestin on cardiovascular risk is their different effects on HDL (the “good” cholesterol) levels. HDL is the most important readily measured indicator of cardio-protection. Non-bioidentical progestin negate the positive HDL raising effects of estrogen and cause a consistent reduction in HDL [46, 49-52, 56, 62], while progesterone either maintains or augments estrogen’s HDL raising effect.[46, 50, 51, 63, 64]
 
Further, non-bioidentical progestin (but not bioidentical progesterone) can significantly decrease insulin sensitivity [58, 59, 65], while a low-moderate dose of estrogen increases insulin sensitivity.[59] An additional negative effect of non-bioidentical progestin is that on atherosclerosis development. One of the earliest events in the atherogenic process is the expression of VCAM-1 (vascular cell adhesion molecule-1).[66, 67] In a comparison of non-bioidentical progestin and bioidentical progesterone, is was found that bioidentical  progesterone inhibits VCAM-1. This protective effect was not observed with non-bioidentical progestin.[57]
 

Symptomatic Efficacy of Bioidentical Progesterone vs. Synthetic Progestins 

 
Knowing the different side effects of non-bioidentical progestin and bioidentical progesterone, the next question is how do they compare in symptomatic efficacy?
 
A recent study demonstrated that HRT with bioidentical estradiol and bioidentical progesterone (both oral and transdermal) is effective for reducing menopausal symptoms.[68] Several other studies compared the efficacy, patient satisfaction, and quality of life when adding bioidentical progesterone vs. non-bioidentical progestin to traditional estrogen HRT.[69-72] Women in all studies reported greater satisfaction, fewer side effects, and improved quality of life when they were switched from non-bioidentical progestin to bioidentical progesterone.[69-72]
 
One study compared patient satisfaction and quality of life related to physiological, somatic, and vasomotor effects, as well as other symptoms (anxiety, depression, sleep problems, menstrual bleeding, vasomotor symptoms, cognitive difficulties, and sexual functioning) in menopausal women on HRT with non-bioidentical progestin versus HRT with bioidentical progesterone.[69] Significant improvements were seen for all somatic, vasomotor, and psychological symptoms when bioidentical progesterone was used rather than non-bioidentical progestin.[69] Majority of women felt that HRT combined with bioidentical progesterone was better than the HRT combined with non-bioidentical progestin.[69]


Summary


Estrogen and progesterone are the only hormones that come in non-bioidentical versions (don’t get fooled by marketing claims trying to sell you another hormone that has no non-bioidentical version).  
 
Because non-bioidentical hormones have side effects not seen with bioidentical hormones, the effects of HRT (hormone replacement therapy) with non-bioidentical hormones (as shown in the notorious Women’s Health Initiative studies) cannot be extrapolated to HRT with bioidentical hormones.
 
Over the years, numerous scientific publications have used the word “progesterone” as a catchall term that includes both non-bioidentical and bioidentical progesterone. This misrepresentation of progesterone has created confusion among both researchers, clinicians, and the general public, as it erroneously suggests that non-bioidentical progesterone (i.e. progestin) has the same effect as bioidentical progesterone. As outlined in this article, this is not the case.
 
The bottom line is that bioidentical hormone therapy, in contrast to traditional non-bioidentical HRT, is a safe and effective treatment for women who suffer from menopausal symptoms. Importantly, bioidentical estrogen does not increase fat mass or reduce lean mass like non-bioidentical estrogen does. As many women struggle with weight gain, this is an important benefit. Finally, bioidentical estradiol does not reduce levels of active free testosterone as much as non-bioidentical estradiol does. Thereby, bioidentical estradiol is more beneficial that non-bioidentical estrogen for preservation or elevation of libido and sexual vigor.
 
 
References:
 

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68.       Ruiz, A.D., et al., Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study. BMC Womens Health, 2011. 11: p. 27.

69.       Fitzpatrick, L.A., C. Pace, and B. Wiita, Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Womens Health Gend Based Med, 2000. 9(4): p. 381-7.

70.       Lindenfeld, E.A. and R.D. Langer, Bleeding patterns of the hormone replacement therapies in the postmenopausal estrogen and progestin interventions trial. Obstet Gynecol, 2002. 100(5 Pt 1): p. 853-63.

71.       Greendale, G.A., et al., Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol, 1998. 92(6): p. 982-8.

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Dr. Pierce's Medical Organization Affiliations

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