MEASURING CONCENTRATIONS OF STEROID HORMONES

Current clinical guidance suggests there is insufficient evidence to support claims that multiple blood, serum, or saliva tests can be used to precisely individualize hormone therapy (e.g., ACOG, 2018; Endocrine Society, 2019; NAMS, 2020; Santoro et al., 2016).⁵ Because no studies have demonstrated that using hormone concentrations to guide treatment is effective or useful, the American College of Obstetricians and Gynecologists recommends using clinical symptoms to guide treatment (ACOG, 2018). Nonetheless, some prescribers of cBHT use hormone imbalance as a rationale and guide for treating the symptoms of menopause (NASEM, 2019a,b).⁶

Characterizing hormone imbalance typically involves measuring hormone concentration levels in saliva, plasma, serum, or urine, and patients interested in this approach can find websites offering hormone balance test kits. Patients collect samples of saliva and/or blood and mail them to a designated laboratory. These labs often use bioanalytical methodology that lacks the rigors of the validated bioanalytical methods required to analyze pharmacokinetic samples collected in FDA-approved clinical studies (Herold and Fitzgerald, 2003; Kane et al., 2007). In addition, differences in steroid hormone levels can depend on the matrix used to measure the hormone concentration. One study, for example, examined the distribution of progesterone in venous whole blood, venous serum, fingertip capillary blood, and saliva after topical application of either cream or gel formulations compounded at a local pharmacy (Du et al., 2013). After topical administration of progesterone, saliva and capillary blood levels were 10-fold and 100-fold greater, respectively, than those seen in serum or whole blood. The investigators who conducted this study concluded that relying on serum levels of progesterone for monitoring topical administration of progesterone could lead to underestimation of tissue levels and consequent overdose.

Furthermore, in 2007, the Centers for Disease Control and Prevention (CDC) launched a project focused on standardizing hormone measurement (Vesper et al., 2008). In the project communication materials, CDC states

Despite physician's wide spread use of hormone test results, the laboratory measurement of steroid hormones is subject to extreme variability especially when hormones are present in low concentrations, as is usually the case for testosterone in women and children, and for estradiol in men, children, and postmenopausal women. (CDC, 2008)

Measuring Hormone Concentrations: Salivary Testing

Salivary testing is often promoted by online analytical laboratories as a convenient, noninvasive method for hormone sampling. At the same time, several professional medical societies have issued public statements that saliva testing is unnecessary and has not been proven to be accurate nor reliable, mainly because the variation in the day-to-day or within-a-day hormone concentrations in an individual is large enough to make any one measurement uninformative (ACOG, 2018; Endocrine Society, 2019; Goodman et al., 2011; NAMS, 2017). In one study, for example, researchers compared salivary versus serum testosterone concentrations in postmenopausal women receiving transdermal testosterone supplementation (Flyckt et al., 2009). The data suggested there was no correlation between salivary testosterone and any of the serum testosterone measurements (see Figure 6-1), leading the researchers to conclude that the results did not support the routine use of salivary testosterone concentrations in postmenopausal women.

FIGURE 6-1

Correlation between salivary testosterone (T) and serum free (T) (nmol/L). SOURCE: Flyckt et al., 2009.

While the bioanalytical method used in the comparative analysis in Figure 6-1 is a validated radioimmunoassay (Flyckt et al., 2009),⁷ there have been specific concerns over the accuracy and reliability of immunoassays to assess testosterone measurements (Cao et al., 2007; Davis et al., 2019). A recent consensus position statement from several medical associations on the use of testosterone therapy in women stated that direct assays for the measurement of total and free testosterone are highly unreliable (Davis et al., 2019). Concerns regarding immunoassay assessments of steroid hormones are the result, in part, of a lack of immunospecificity caused by cross-reactivity with other steroids having a similar structure; poorly optimized quantification; and improper validation against standards (Clifton et al., 2016; Holst et al., 2004; Keevil et al., 2014). Recently, several authors have demonstrated that liquid chromatography–tandem mass spectrometry (LC-MS/MS) methodology can reliably and accurately measure testosterone levels in both male and female saliva samples (Clifton et al., 2016; Keevil et al., 2014), highlighting potential benefits in its use in cBHT research. (See the section “Bioanalytical Methods to Measure the Bioavailability of Steroid Hormones” in this chapter for an additional discussion on this topic.)

Measuring Hormone Concentrations: FDA Requirements for FDA-Approved Hormone Products

As a comparison to the various protocols described above, FDA requires the measurement of steroid hormones in plasma or serum in bioequivalence studies with pharmacokinetic endpoints (FDA, 2019a). For example, FDA guidance on measuring estradiol in bioequivalence studies of estradiol vaginal tablets, gels, or creams identifies “estradiol in plasma” as the appropriate biological fluid to measure estradiol (FDA, 2011a, 2014, 2019a). Similar FDA guidance specifies plasma or serum as the appropriate biological fluid for measuring the levels of other steroid hormones, such as progesterone and testosterone, in clinical studies with pharmacokinetic endpoints (FDA, 2011b, 2019b).

Box

Conclusion 6-2.

BIOANALYTICAL METHODS TO MEASURE THE BIOAVAILABILITY OF STEROID HORMONES

LC-MS/MS is the gold standard methodology used today to support clinical studies with pharmacokinetic endpoints (FDA, 2018). LC-MS/MS is typically used because of the selectivity and specificity of the detection methodology, a requirement of validated bioanalytical methods. Examples of commercially available validated LC-MS/MS bioanalytical assays exist for many of the bioidentical hormones on the market today (see Table 6-1).

Recently, investigators evaluated urinary estrogen and progesterone metabolites using dried filter paper samples and gas chromatography with tandem mass spectrometry (Newman et al., 2019). This prospective observational study compared the results of urine and serum analyses. A secondary aim of the study compared results from dried urine samples collected at four times over a 10- to 14-hour time period (the 4-spot method) and the 24-hour collection method, which collects liquid urine samples over a full 24-hour period. Researchers obtained similar results from the 4-spot dried urine and the 24-hour liquid urine collection methods. Furthermore, based on the results of a comparison between dried urine and serum assays, the authors concluded that the dried urine assay may be a good surrogate for serum testing in clinical assessments of hormone disorders.

BIOAVAILABILITY OF COMPOUNDED BIOIDENTICAL HORMONE THERAPY PREPARATIONS

From the limited bioavailability data on cBHT preparations that exist in the literature, the following four studies on compounded estrogen cream, testosterone pellets, progesterone cream, and a lozenge containing estradiol, progesterone, testosterone, and dehydroepiandrosterone (DHEA) serve as examples of how such studies are conducted.

Example Study 1: Compounded Estrogen Cream

Study Design and Results

One group of investigators (Sood et al., 2013) conducted a pharmacokinetic evaluation of cBHT preparations as part of a randomized, blinded, four-arm, 16-day clinical trial of 40 postmenopausal women. The study arms assigned women to receive a compounded cream containing a commonly used 80:20 ratio of estriol and estradiol (Bi-est) and 100 mg of compounded oral progesterone or a conventional estradiol patch (Vivelle-Dot 0.05 mg) and oral progesterone capsule (Prometrium 100 mg). The Bi-est creams were compounded to include a dosage of 2.0 mg (1.6 mg estriol/0.4 mg estradiol), 2.5 mg (2 mg estriol/0.5 mg estradiol), or 3.0 mg (2.4 mg estriol/0.6 mg estradiol).

The investigators measured serum concentrations of estradiol, estrone, estriol, and progesterone, and generated a 24-hour pharmacokinetic profile after the first and last application of the cream or patch. The resulting analysis showed that estradiol exposure at steady-state—as determined after the last application—for all strengths of the compounded cream was less than that from the patch, though hormone levels for test subjects who received 3.0 mg of the compounded Bi-est preparation were not statistically different from those who received the patch (see Figure 6-2). The American Medical Association commented on this study, concluding that given the unpredictable pharmacokinetics of compounded formulations, the use of cBHT cannot be supported in comparison to well-tested FDA-approved hormone therapy options (AMA, 2016).

FIGURE 6-2

Steady-state serum estradiol concentration time course. NOTE: Serum estradiol (pg/mL) as a function of time in hours (measured on days 15 and 16). SOURCE: Sood et al., 2013.

Study Limitations

In this study, participants who received one of the compounded estrogen preparations using the Bi-est ratio had wide fluctuations in their estradiol concentrations both after the initial administration as well as at steady-state. In contrast, estradiol absorption with the patch was more consistent across subjects. Participants receiving one of the three compounded dosage formulations based on the Bi-est 80:20 ratio had lower estrone concentrations than those from the patch. There were certain limitations with the assay for measuring estriol, and as a result most subjects had estriol concentrations that were below the lower limit of detection. Progesterone concentrations were relatively similar after administration of the compounded and conventional bioidentical progesterone dosage forms in all four groups, suggesting that micronized progesterone is similarly absorbed across compounded and conventional dosage forms (Sood et al., 2013). However, the most informative bioavailability comparisons are those conducted between identical dosage forms, so a more appropriate reference in the study would have been an FDA-approved hormone product such as estradiol cream, estradiol gel, or estradiol spray products.

Another limitation of the study was the small number of subjects—between 7 and 10—in comparative arms of the study. Furthermore, given that Vanicream was used as the base for all three compounded estrogen formulations, the study results are not generalizable to all possible dosage formulations using the 80:20 Bi-est ratio. Variations in the content uniformity of estradiol and progesterone in compounded combined forms of oral capsule and transdermal cream preparations sourced from different compounding pharmacies is a concern among some professional medical associations (Davis et al., 2014; Stanczyk et al., 2019).

Regardless of the limitations of the study, the low and variable concentrations of serum estradiol obtained with the 2.0 and 2.5 mg Bi-est preparations in this study are concerning and cast doubts on the ability of compounded creams to provide relief of vasomotor symptoms and protect against bone loss. One case, for example, found that a patient treated for vasomotor symptoms with a dosage formulation using the Tri-est ratio (80 percent estriol, 10 percent estrone, and 10 percent estradiol) for several months experienced an initial relief of symptoms that returned even after increasing the dose (Davis et al., 2014). The patient's symptoms later improved after the prescribing physician switched the patient to an FDA-approved estradiol transdermal delivery system.

Example Study 2: Compounded Testosterone Subcutaneous Pellet

Study Design and Results

Investigators (Glaser et al., 2013) conducted a pharmacokinetic study in 12 previously untreated postmenopausal women who each received 100 mg testosterone as a subcutaneous implant compounded by a local pharmacy in Cincinnati, Ohio. The research team measured serum total testosterone at baseline, 4 weeks, and 16 weeks following the testosterone pellet implantation. Total testosterone was measured by an immunoassay (Bayer Advia Centaur), and for comparison a duplicate specimen was sent to a second lab for measurement by liquid chromatography. There were significant interindividual variability in testosterone concentrations at week 4, mean serum level was 190.8 ± 80 ng/dL (range 83–368 ng/dL, CV 41.9 percent) (see Figure 6-3) and week 16 (CV 41.6 percent). These levels exceed the serum total testosterone reference range of 8–60 ng/dL in women (Mayo Clinic Laboratories, 2020).

FIGURE 6-3

Serum testosterone concentrations in 12 female patients 4 weeks after therapy with a 100 mg testosterone implant. SOURCE: Glaser et al., 2013.

The authors stated that the concept of using a single serum testosterone concentration measurement to guide therapy is inherently unreliable, extremely variable, and ignores the complexity of the physiologic events that controls hormone production and release. Instead, the authors concluded, safety, tolerability, and clinical response should guide therapy (Glaser et al., 2013).

Considerations Related to the Use of Compounded Testosterone

In contrast to the conclusions reached by Glaser et al. (2013), a 2019 global consensus position statement, endorsed by multiple professional medical societies, recommended against the use of compounded testosterone in women (Davis et al., 2019). The report states that “blood total testosterone level should not be used to diagnose hypoactive sexual desire disorder/dysfunction.” The report recommended that treatment should be with formulations that achieve blood concentration of testosterone that approximate premenopausal physiological concentrations (Davis et al., 2019).

The potential differences in the use of testosterone in therapeutic treatment plans for women versus men is another consideration regarding compounded testosterone. In women, measurement of serum total testosterone is used only to exclude high baseline or supraphysiological concentrations (Davis et al., 2019). In men with hypogonadism, however, measuring total testosterone during hormone therapy in conjunction with symptoms relief is part of the treatment plan (Bhasin et al., 2018).

Researchers have also expressed concerns regarding the quality control of compounded testosterone preparations, in terms of a lack of uniformity in testosterone content and its potential to compromise the safety and efficacy of treatment (Grober et al., 2015). One study tested 7 gel testosterone preparations and 3 cream testosterone preparations from 10 compounding pharmacies within the Toronto, Canada, area. Results showed significant variability both within and between pharmacies in terms of the measured concentrations of testosterone in the finished compounded preparations (Grober et al., 2015).

Finally, to serve as a potential reference point, transdermal testosterone cream is available as a traditionally manufactured product in Australia, 1 percent Androfeme (Lawley Pharmaceuticals, 2016), and has publicly available bioavailability data to consider. The steady-state pharmacokinetics of Androfeme was investigated after daily application for 21 days in healthy postmenopausal women (Fooladi et al., 2015). Serum total testosterone, free testosterone, sex hormone binding globulin, and metabolic concentrations were measured using LC-MS/MS. On day 22, 5 mg testosterone cream restored both total and free testosterone levels to levels above and within the reference range, respectively, for premenopausal women.

BIOAVAILABILITY OF TRADITIONALLY MANUFACTURED BIOIDENTICAL HORMONE THERAPY PRODUCTS

As discussed in Chapter 8 of this report, patients may not be aware of or understand that FDA-approved bioidentical hormone therapy (BHT) products exist and are readily available. As more FDA-approved forms of BHT products become available, some patient concerns about conventional hormone therapy may be allayed, and other therapy options (e.g., nonhormonal or conventional BHT) may have greater appeal (L'Hermite, 2017; Thompson et al., 2017). To serve as a reference point for the example studies discussed above, the following sections provide examples of bioavailability studies for traditionally manufactured bioidentical hormone products.

CONCLUDING STATEMENTS

In summary, optimal bioavailability of an active ingredient in a compounded preparation is essential for exerting its intended pharmacological action. The paucity of bioavailability data from cBHT preparations is problematic and casts doubts on both safety and efficacy of these preparations. Even the small number of available clinical trials that attempted to evaluate bioavailability of cBHT lack the rigor of those conducted for FDA-approved BHT products.¹⁰ Most of the existing studies do not have an active control and thus lack meaningful comparative data. In addition, most existing studies relied on the use of radioimmunoassays or methods used at clinical labs that are not as selective and specific as LC-MS/MS bioanalytical methods.

Box

Conclusion 6-3.

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