Kelly Daniels, PharmD

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One of the earliest uses of HRT was documented in an 1897 publication  highlighting the use of desiccated ovarian extracts to alleviate vasomotor  symptoms.

 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.

 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.

 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.

 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. 

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.

 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.

 Canonico and colleagues found that percutaneous estradiol  and progesterone does not increase the risk of venous thromboembolism, unlike  oral estrogen and/or progestin therapy.

 With regard to breast  cancer, Chang and Foidart conducted identical trials which demonstrated that  progesterone counteracts breast epithelial proliferation and prevents breast  epithelial hyperplasia.

 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. 

  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.

 Additionally, oral progesterone has sedative effects due to  metabolites produced from hepatic metabolism.

 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.

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.

 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. 

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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Articles

One of the earliest uses of HRT was documented in an 1897 publication highlighting the use of desiccated ovarian extracts to alleviate vasomotor symptoms. 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.

Author | Kelly Daniels, PharmD

Articles

Bioidentical Hormones: Advances in Research and What to Ask Your Provider