Advances in HRT Research—Safety
One of the earliest uses of HRT was documented in an 1897 publication highlighting the use of desiccated ovarian extracts to alleviate vasomotor symptoms.4 As science evolved, publications emerged describing the extraction of hormones from pregnant female urine (Emmenin®) in 1934 and eventually pregnant mare urine (Premarin®) in 1937 for the therapeutic relief of menopausal symptoms.11,12 Premarin®, or conjugated estrogens (CE), rapidly became the dominant form of HRT. Although progesterone was first isolated shortly after the production of Emmenin®, synthetic progestins were not used for uterine protection until the 1970s.13-17 However, extensive safety research was not performed on CE or progestins until the 1990s and early 21st century.
The HERS was the first of the CHT safety publications.18 The authors of the study concluded that conventional HRT should not be used for cardiovascular protection. Women were found to have an increased risk for developing cardiovascular disease and the risk persisted with continued use as shown in their follow-up trial. The WHI, the largest CHT study to date, similarly demonstrated that CE did not provide cardiovascular protection and increased the risk for venous thromboembolism. Additionally, the WHI identified the use of combination CE and progestins as a significant risk factor for breast cancer and cardiovascular disease. 19,20
Although not as large in size or scope as CHT studies, several BHRT studies have been conducted to assess the safety of bioidentical hormones. Concerning cardiovascular disease, studies by the Postmenopausal Estrogen/Progestin Interventions Group (PEPI) and Gerhard et al demonstrated that natural progesterone does not negatively impact cardiovascular disease progression, unlike synthetic progestins.21,22 Additionally, vascular reactivity was improved with percutaneous estradiol in Gerhard’s trial. In further support of these findings, Hodis et al demonstrated that estradiol reduces subclinical vascular diseases and may serve as a possible alternative to lipid lowering therapy.23 Canonico and colleagues found that percutaneous estradiol and progesterone does not increase the risk of venous thromboembolism, unlike oral estrogen and/or progestin therapy.24 With regard to breast cancer, Chang and Foidart conducted identical trials which demonstrated that progesterone counteracts breast epithelial proliferation and prevents breast epithelial hyperplasia.25,26 Fournier and colleagues have shown that estriol and combination estradiol and progesterone does not increase the risk of breast cancer in their observational cohort study of 80,000 women. 27 From the available data, BHRT may prove to be cardioprotective and not increase the risk for breast cancer. Practioner’s must rely on the available medical literature to make clinical decisions for their patients.
Advances in BHRT Research—Routes of Administration
The most common routes of BHRT administration include oral, transdermal, vaginal, and sublingual. The use of oral estrogen replacement has fallen out of favor due to the risk of VTE highlighted in trials such as Canonico’s ESTHER trial.24 Additionally, oral progesterone has sedative effects due to metabolites produced from hepatic metabolism.28 Thus, routes of administration with fewer side effects, such as topical administration, have been utilized. However, trials have demonstrated inconsistent therapeutic outcomes despite various anecdotal claims of effectiveness. These inconsistent outcomes are generally attributed to the pharmacokinetic profiles of topical BHRT. Moreover, the pharmacokinetics of topical progesterone is not well defined. Studies have demonstrated that topical progesterone administration does not result in significant elevations in serum hormone levels, yet can achieve measureable levels in the uterine lining.29-31 Additionally, studies which have sought to determine the effectiveness of topical progesterone for the relief of vasomotor and mood symptoms have shown mixed results, some favoring effectiveness and other not.30, 32-34 Vaginal delivery methods have not gained attraction aside from administration of bioidentical estrogens to aid with vaginal dryness. Thus, alternative routes are continuously examined for improved outcomes while maintaining a favorable safety profile.
The sublingual route of administration is being used at increasing rates in the United States. Sublingual administration is non-invasive and provides several clinical benefits. First, hormones are rapidly absorbed into the bloodstream, owing to the high vascularization sublingually. This allows for significant increases in blood hormone levels within hours, providing for more rapid relief of menopausal symptoms compared to topical dosage forms. Secondly, the sublingual route allows for the bypass of first pass metabolism. First pass metabolism is responsible for the significant reduction in hormone bioavailability following oral administration. By bypassing this effect, the sublingual route provides for hormone levels significantly higher than those provided by oral administration. For example, progesterone serum levels have been measured to be 10-fold higher with sublingual administration compared to oral administration. 35-37
Questions to Ask
The decision to begin BHRT is complex and involves evaluation of several patient-specific factors. A physician will evaluate the patient’s age, laboratory values, medical history, surgical history (e.g., hysterectomy), and symptoms (including severity). Patients who exhibit low hormone levels in conjunction with hormone imbalance/deficiency symptoms will likely be candidates for BHRT, with consideration taken for other medical conditions, such as prior history of breast cancer or cardiovascular disease.
Patient should be highly involved in the decision to begin a BHRT regimen. Some important questions to ask your provider before beginning BHRT include the following:
What are the risks involved with using BHRT?
How long should BHRT be continued?
How soon will I recognize a change in symptoms?
What benefits, other than symptom relief, evolve from using BHRT?
It is also important for the patient to provide the practitioner with an accurate medical history and medication list. These factors are important for the practitioner because some symptoms commonly seen in menopause are also associated with other medical conditions or medications. Also, some medications may have additional effects in the body when used in combination with BHRT.
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