Hormone Replacement Therapy
Menopausal symptoms are annoying and sometimes debilitating to many women. For many years, standard therapy was Premarin, a form of estrogen from horse urine. Rarely was progesterone included. Eventually, it was recognized that the most important issue with hormones is balance. Estrogens must be balanced with progesterone. Without progesterone in adequate amounts, one has what is called “estrogen dominance”. It is estrogen dominance that causes many of the side effects of hormone inadequacy.
Because one cannot patent natural substances, pharmaceutical companies modify natural products so they will have a similar effect but they can patent the modified compound and thus make a profit from it. Such a substance is progestin, a synthetic progesterone.
The National Institutes of Health (NIH) established the Women's Health Initiative (WHI) in 1991 to address the most common causes of death, disability and impaired quality of life in postmenopausal women. The WHI addressed cardiovascular disease, cancer, and osteoporosis. The WHI was a 15 year multi-million dollar endeavor, and one of the largest U.S. prevention studies of its kind. The three major components of the WHI were:
¥ a randomized controlled clinical trial of promising but unproven approaches to prevention;
¥ an observational study to identify predictors of disease;
¥ a study of community approaches to developing healthful behaviors.
The study was discontinued after seven years because it was clear that the synthetic hormones were increasing risks---see below. This has made many women fear the use of hormones of any type.
It appears that the use of bioidentical (same of the human makes) hormones instead of synthetic hormones have the reverse effect. These hormones must be compounded by a compounding pharmacy since regular drug companies have no interest in these natural compounds since they can’t patent and pay the cost of getting the FDA to approve them. If one company paid the FDA the millions of dollars it would take to get them approved, all of their competitors could make/sell them with no opportunity for the first company to recover the millions of dollars paid to the FDA to approve them. Thus there is a constant effort to discredit bioidentical hormones in the U.S. Since the FDA can’t control the use of natural substances, they have recently received authority to enforce severe requirements upon compounding pharmacies. This increases the cost of bioidentical hormones above the price affordable by most consumers. Thus there is a problem: synthetic hormones are harmful and bioidentical hormones are helpful but difficult to afford. However, women who can find them at an affordable price usually feel amazingly better without the risks of synthetic hormones.2
2 Int J Pharm Compd. 2004 Jul-Aug;8(4):313-9.; Efficacy and tolerability of compounded bioidentical hormone replacement therapy.
WHI In dbGAP
On Wednesday January 13, 2010, NCBI released the Women's Health Initiative (WHI) SNP Health Association Resource (SHARe) dataset on dbGAP. The dataset includes extensive phenotypic and genotypic data on 12008 African American and Hispanic women aged 50-79 enrolled in one or more components of the WHI program. Genotyping was done on the Affymetrix 6.0 platform. Information on the dataset are to be found at: dbGAP
Additional release information may be found at: Study Release Notes
Any investigator can apply for access to the dataset through the dbGAP procedures; however, per NIH GWAS policy the WHI investigators have a 12-month protected publication window. WHI investigators welcome collaboration from other investigators within the 12-month protected time and beyond. WHI investigators also invite collaboration on publications and ancillary studies beyond SHARe. Information on how to collaborate with WHI investigators on SHARe and on other WHI resources are found at: WHI Scientific Resources Website
The Women's Health Initiative (WHI) was a major 15-year research program to address the most common causes of death, disability and poor quality of life in postmenopausal women -- cardiovascular disease, cancer, and osteoporosis.
Findings from the WHI Postmenopausal Hormone Therapy Trials
The WHI was launched in 1991 and consisted of a set of clinical trials and an observational study, which together involved 161,808 generally healthy postmenopausal women.
The clinical trials were designed to test the effects of postmenopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer.
The hormone trial had two studies: the estrogen-plus-progestin study of women with a uterus and the estrogen-alone study of women without a uterus. (Women with a uterus were given progestin in combination with estrogen, a practice known to prevent endometrial cancer.) In both hormone therapy studies, women were randomly assigned to either the hormone medication being studied or to placebo. Those studies have now ended. The women in these studies are now participating in a follow-up phase, which will last until 2010.
Q. Can you summarize the results of the estrogen-plus-progestin and estrogen-alone studies?
A. Summaries of the findings are given below. However, be aware that the findings for the two studies should not be compared directly because of differences in the women's characteristics at the time of their enrollment in the studies. For example, those in the estrogen-alone study had a higher risk of cardiovascular disease than those in the estrogen-plus-progestin study. Women in the estrogen-alone study were more likely to have such heart disease risk factors as high blood pressure, high blood cholesterol, diabetes, and obesity.
Compared with the placebo, estrogen (Premarin = horse estrogen) plus progestin (a synthetic form of progesterone) resulted in:
• Increased risk of heart attack
• Increased risk of stroke
• Increased risk of blood clots
• Increased risk of breast cancer
• Reduced risk of colorectal cancer
• Fewer fractures
• No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)
Compared with the placebo, estrogen (Premarin = horse estrogen) alone resulted in:
• No difference in risk for heart attack
• Increased risk of stroke
• Increased risk of blood clots
• Uncertain effect for breast cancer
• No difference in risk for colorectal cancer
• Reduced risk of fracture
Int J Womens Health. 2014 Jan 11;6:47-57. doi: 10.2147/IJWH.S38342. eCollection 2014.
Prescribing menopausal hormone therapy: an evidence-based approach.
Sood R1, Faubion SS1, Kuhle CL1, Thielen JM1, Shuster LT1.
The constantly changing landscape regarding menopausal hormone therapy (MHT) has been challenging for providers caring for menopausal women. After a decade of fear and uncertainty regarding MHT, reanalysis of the Women's Health Initiative data and the results of recent studies have provided some clarity regarding the balance of risks and benefits of systemic MHT. Age and years since menopause are now known to be important variables affecting the benefit-risk profile. For symptomatic menopausal women who are under 60 years of age or within 10 years of menopause, the benefits of MHT generally outweigh the risks. Systemic MHT initiated early in menopause appears to slow the progression of atherosclerotic disease, thereby reducing the risk of cardiovascular disease and mortality. During this window of opportunity, MHT might also provide protection against cognitive decline. In older women and women more than 10 years past menopause, the risk-benefit balance of MHT is less favorable, particularly with regard to cardiovascular risk and cognitive impairment. For women entering menopause prematurely (<40 years), MHT ameliorates the risk of cardiovascular disease, osteoporosis, and cognitive decline. Nonoral administration of estrogen offers advantages due to the lack of first-pass hepatic metabolism, which in turn avoids the increased hepatic synthesis of clotting proteins, C-reactive protein, triglycerides, and sex hormone-binding globulin. The duration of combined MHT use is ideally limited to less than 5 years because of the known increase in breast cancer risk after 3-5 years of use. Limitations to use of estrogen only MHT are less clear, since breast cancer risk does not appear to increase with use of estrogen alone. For women under the age of 60 years, or within 10 years of onset of natural menopause, MHT for the treatment of bothersome menopausal symptoms poses low risk and is an acceptable option, particularly when nonhormonal management approaches fail.
Int J Pharm Compd. 2004 Jul-Aug;8(4):313-9.
Efficacy and tolerability of compounded bioidentical hormone replacement therapy.
Vigesaa KA Pharmd1, Downhour NP Pharmd, Chui MA Phd Pharmd, Cappellini L Rph Faca, Musil JD Pharmd Faca, McCallian DJ Pharmd Faca.
The primary purpose of this six-week survey study of women currently taking compounded bioidentical hormone replacement therapy was to determine if compounded bioidentical hormone replacement therapy relieves symptoms of menopause and is well tolerated. The secondary purpose of this study was to compare the symptom relief and tolerability of compounded bioidentical hormone replacement therapy to previously used commercially available products. All strengths and dosage forms of bi-estrogen and tri-estrogen were included, whether used alone or in combination with progesterone, dehydroepiandrosterone or testosterone. The survey instrument consisted of nineteen questions and evaluated the outcomes and side effects for commercially available versus compounded bioidentical hormones. A total of 160 surveys was distributed and 78 were completed. Overall, 57.7% of the women surveyed reported fewer side effects and 71.8% of the women had better relief of menopausal symptoms when using bioidentical hormone replacement therapy. The occurrence and severity of menopausal symptoms decreased significantly after beginning bioidentical hormone replacement therapy. Before treatment, moderate-to-severe symptoms of hot flashes, night sweats, sleep problems, dry skin/hair, vaginal dryness, foggy thinking, mood swings and decrease in sex drive were reported in 52 % to 70% of the women. After initiating treatment the moderate-to-severe range of symptoms dropped to between 4% and 20%. The most commonly reported side effects with bioidentical hormone replacement therapy were weight gain (37.2%), breast tenderness (19.2%) and bloating (23.1%). Weight gain (56.2%), breast tenderness (54.5%), bloating (40%) and mood swings (36.4%) were most commonly seen with commercially available products. Bioidentical hormone replacement relieved the symptoms of menopause and was well tolerated.
Int J Pharm Compd. 2013 Jan-Feb;17(1):74-85.
The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women.
Stephenson K1, Neuenschwander PF, Kurdowska AK.
Menopause impacts 25 million women world wide each year, and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030. Menopause has been associated with symptoms of hot flashes, night sweats, dysphoric mood, sleep disturbance, and conditions of cardiovascular disease, depression, osteoporosis, osteoarthritis, depression, dementia, and frailty. Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women's Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors. Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile, yet long-term studies of this treatment model are lacking. The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol, estradiol, progesterone, DHEA, and testosterone on cardiovascular biomarkers, hemostatic, inflammatory, immune signaling factors; quality-of-life measures; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care. A prospective, cohort, closed-label study received approval from the Human Subjects Committee. Recruitment from outpatient clinics at an academic medical center and the community at large resulted in three hundred women giving signed consent. Seventy-five women who met strict inclusion/exclusion criteria were enrolled. Baseline hormone evaluation was performed along with baseline experimental measures. Following this, women received compounded transdermal bioidentical hormone therapy of BiEst (80%Estriol/20%Estradiol), and/or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women. The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic, ischemic, or neuronal injury. Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of androgens of DHEA and Testosterone if indicated. Experimental subjects were monitored for 36 months. Baseline, 2-month, and annual values were obtained for: blood pressure, body mass index, fasting glucose, Homeostasis Metabolic Assessment of Insulin Resistance (HOMA-IR), fasting triglycerides, total Factor VII, Factor VIII, fibrinogen, Antithrombin III, Plasminogen Activator Inhibitor1(PAL-1), C-reactive protein (CRP), Interleukin-6 (IL-6), Matrix Metalloproteinase-9 (MMP-9), Tumor Necrosis Factor-alpha (TNF), Insulin-like Growth Factor (IGF-1), and sex steroid levels. Psychosocial measures included: Greene Climacteric Scale, Visual Analog Pain Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Holmes Rahe Stress Scale, Job Strain, and Home Strain. Health outcome measures included the number of prescribed medications used, number of co-morbidities, and endometrial thickness in postmenopausal women with intact uteri. Subjects receiving compounded transdermal bioidentical hormone therapy showed significant favorable changes in: Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, Insulin-Like Growth Factor 1, and health outcomes of co-morbidities and a number of prescribed medications. Antithrombin III levels were significantly decreased at 36 months. All other measures did not exhibit significant effects. Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes were favorably impacted, despite very high life stress, and home and work strain in study subjects. The therapy did not adversely alter the net prothrombotic potential, and there were no associated adverse events. This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in populations with high perceived stress and a history of stressful life events prior to, or during the menopausal transition.