Our Commitment to Provide Top-Tier Testing
The DUTCH Test® (Dried Urine Test for Comprehensive Hormones) helps practitioners answer complex clinical questions by providing the most comprehensive hormone monitoring results with simple patient collection. Our rigorous pursuit for the truth in hormone testing has produced multiple peer-reviewed studies proving the effectiveness of dried urine testing as an alternative to serum (blood) or saliva for monitoring a variety of hormone therapy applications. We use the most accurate method available (LC-MS/MS) and our tests are used by thousands of healthcare providers and their patients all over the world.
Featured Research
Menopause, Volume 30 | October 18, 2023
Comparative estrogen exposure from compounded transdermal estradiol creams and FDA-approved transdermal estradiol gels and patches
Mark S. Newman, MS, Doreen Saltiel, MD, JD, Jaclyn Smeaton, ND, and Frank Z. Stanczyk, PhD
At DUTCH, we are committed to providing you with an evidence-based approach to integrative care. We know that questions exist in the integrative medicine community about the best way to provide hormones to patients as well as the best way to monitor dosing. This study, peer-reviewed by the rigorous team at Menopause, highlights the accuracy of urine metabolite testing for monitoring of estrogen replacement therapies.
KEY HIGHLIGHTS INCLUDE:
- DUTCH methods are again validated in the peer-reviewed literature. When you choose to partner with DUTCH, you can rest assured that our lab is willing to stand up to independent evaluation for accuracy and clinical relevance, even against the toughest critics.
- The first peer-reviewed study to compare FDA approved patches and gels to compounded estrogen creams, a key therapeutic choice for many providers in the integrative medicine community.
- Estrogen exposure from compounded transdermal E2 creams increases in a dose-dependent manner; however, the amount of estrogen exposure associated with compounded creams is significantly lower than estrogen exposure associated with FDA-approved transdermal E2 patches and gels.
Research Abstracts & Commentaries
Full Manuscripts:
Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches Expand
Mark S. Newman, MS, Doreen Saltiel, MD, JD, Jaclyn Smeaton, ND, and Frank Z. Stanczyk, PhD
DOI: 10.1097/GME.0000000000002266
Objective
The aim of this study was to evaluate the amount of estrogen exposure associated with the use of compounded transdermal estradiol (E2) creams and compare it with estrogen exposure associated with the use of Food and Drug Administration (FDA)-approved transdermal E2 patches and gels.
Methods
This was a retrospective cohort study that used clinical laboratory data collected from January 1, 2016, to December 31, 2019. Participants were first divided into three groups: postmenopausal women on no menopausal hormone therapy (n = 8,720); postmenopausal women using either a transdermal E2 patch, gel, or cream (n = 1,062); and premenopausal women on no hormonal therapy (n = 16,308). The postmenopausal menopausal hormone therapy group was further subdivided by formulation (patch [n = 777], gel [n = 132], or cream [n = 153]) and dose range (low, mid, or high). The Jonckheere-Terpstra trend test was used to determine if there was a dose-dependent trend in urinary E2 with increasing dose of compounded E2 cream (dose categories for E2 cream subanalysis, <0.5 mg [n = 49], ≥0.5-≤1.0 mg [n = 50], ≥1.0-≤1.5 mg [n = 58], and >1.5-≤3.0 mg [n = 46]). Urinary E2 and other characteristics were compared across formulations (within each dose range) using Kruskal-Wallis one-way analysis of variance.
Results
A dose-dependent, ordered trend existed for urinary E2 with increasing doses of compounded E2 cream (urinary E2 medians [ng/mg-Cr], 0.80 for <0.5 mg, 0.73 for ≥0.5-≤1.0 mg, 1.39 for ≥1.0-≤1.5 mg, and 1.74 for >1.5-≤3.0 mg; Jonckheere-Terpstra trend test, P < 0.001). Significant differences in urinary E2 concentrations were observed in all three dose ranges (Kruskal-Wallis one-way analysis of variance, P = 0.013 for low dose, P < 0.001 for mid dose, P = 0.009 for high dose). Comparison of E2 concentrations of compounded creams to E2 concentrations obtained with similar doses of FDA-approved patches and gels showed that the creams had significantly lower values than the patches and gels.
Conclusions
Estrogen exposure from compounded transdermal E2 creams increases in a dose-dependent manner; however, the amount of estrogen exposure associated with compounded creams is significantly lower than estrogen exposure associated with FDA-approved transdermal E2 patches and gels. Clinicians should be aware of the direction and magnitude of these potential differences in estrogen exposure when encountering women who have either previously used or are currently using compounded E2 creams.
Assessing estrogen exposure from transdermal estradiol patch therapy using a dried urine collection and a GC–MS/MS assay Expand
Mark S. Newman, MS, Bryan P. Mayfield, PharmD, Doreen Saltiel, MD, JD, and Frank Z. Stanczyk, PhD
DOI: https://doi.org/10.1016/j.steroids.2022.109149
Highlights
- A GC–MS/MS dried urine assay can approximate estrogen exposure from TD E2 patch use.
- A GC–MS/MS dried urine assay captures dose-related changes in urinary estrogens.
- Urinary estrogen profiles differ significantly before and after E2 patch initiation.
Background
Transdermal estradiol patch therapy is often dosed based on patient reported symptoms. Although dosing based on serum estradiol concentrations has been considered, serum sampling is too invasive and inconvenient to use in real-world settings. The primary aim of this study was to determine if a dried urine assay could be used to assess estrogen exposure resulting from transdermal estradiol patch therapy at increasing doses.
Methods
This was a retrospective analysis of clinical laboratory data. Urinary estrogen profiles of postmenopausal women being treated with transdermal estradiol patches at differing doses (age = 56.8 ± 7.5) were selected from the database along with the profiles of women on no therapy for comparison (age = 55.1 ± 9.5). Metabolite concentrations were obtained using a multi-spot dried urine collection and a gas chromatography-tandem mass spectrometry assay. The Jonckheere-Terpstra test was used to assess for ordered differences across dose groups to determine if dose-dependent increases in urinary estrogens occurred with increasing doses.
Results
Median concentrations of estradiol and other estrogen metabolites increased with increasing doses of transdermal estradiol patch therapy (p < 0.001; Jonckheere-Terpstra test). For women who collected samples before and after initiating therapy, there were significant differences between before and after concentrations of estradiol and other estrogen metabolites.
Conclusion
This large study conducted using real-world data demonstrated that a dried urine assay offers a viable method of assessing estrogen exposure differences that occur with the use of differing doses of transdermal estradiol patches. Further studies with prospective designs that include outcome measures are needed to confirm the findings of this study.
Assessment of estrogen exposure from transdermal estradiol gel therapy with a dried urine assay Expand
Mark S. Newman, MS, Desmond A. Curran, Bryan P. Mayfield, PharmD, Doreen Saltiel, MD, JD, and Frank Z. Stanczyk, PhD
DOI: https://doi.org/10.1016/j.steroids.2022.109038
Highlights
- A GC–MS/MS dried urine assay can approximate estrogen exposure from TD E2 gel use.
- A GC–MS/MS dried urine assay captures dose-related changes in urinary estrogens.
- A dried urine assay captures pre and postmenopausal estrogen profile differences.
Abstract
Transdermal estradiol gel is a commonly used menopausal hormone therapy. In research studies investigating the pharmacokinetics and clinical utility of transdermal estradiol gels, serum is often used to measure estradiol levels. Serum results only represent a moment in time during phlebotomy and thus provide little information and allow for limited inference unless serial measurements are performed. In contrast, dried urine may provide a representation of serum estradiol levels over a longer period of time, while also being non-invasive and easier to collect. The primary aim of this study was to evaluate a dried urine method to determine if it may be a viable option for evaluating estrogen exposure resulting from transdermal estradiol gel use. A secondary aim was to explore differences in the urinary estrogen profiles of premenopausal women on no therapy and postmenopausal women who were either on transdermal estradiol gel therapy or no therapy at all. The results of this study demonstrated that the expected dose-proportional changes in estrogen exposure can be observed in the urinary estrogen profile using a GC–MS/MS dried urine assay. The GC–MS/MS assay also showed the differences in the urinary estrogen profiles of premenopausal women, postmenopausal women on estrogen replacement therapy, and postmenopausal women on no therapy.
Reliability of a dried urine test for comprehensive assessment of urine hormones and metabolites Expand
Mark S. Newman, MS, Desmond A. Curran
DOI: https://doi.org/10.1186/s13065-021-00744-3
Background
Mass spectrometry allows for analysis of multiple hormone and organic acid metabolites from small urine volumes; however, to assess the full extent of daily hormone production, 24-h urine collections are usually required. The aims of this study were, first, to confirm that mass spectrometric analysis of an array of hormones and organic acids would yield similar results in both liquid and dried urine, and, second, to determine if collection of four dried spot urine samples could be substituted for a 24-h collection when measuring reproductive hormones.
Methods
Two study populations were included in this prospective observational study. Twenty individuals collected both a spot liquid urine and dried urine on filter paper to analyze eight organic acids. A second group of 26 individuals collected both a 24-h urine and four dried spot urines during waking hours throughout the same day for evaluation of 17 reproductive hormones and metabolites; data from 18 of these individuals were available to compare liquid versus dried urine results. Dried urine was extracted, hydrolyzed, and derivatized before analysis by mass spectrometry; all analytes from dried urine were normalized to urine creatinine.
Results
Reproductive hormone results from dried and liquid urine were in excellent agreement with intraclass correlation coefficients (ICCs) greater than 0.90; comparison of dried to liquid urine for organic acids showed good to excellent agreement (ICC range: 0.75 to 0.99). Comparison between the 4-spot urine collection and 24-h urine collection methods showed excellent agreement (ICC > 0.9) for 14 of the 17 urine metabolites and good agreement for the others (ICC 0.78 to 0.85) with no systematic differences between the two methods of collection.
Conclusions
The burden of urine collection can be reduced using collection of four spot dried urines on filter paper without compromising comparability with hormone results from a 24-h urine collection. A large number of urine analytes can be assessed from the dried urine with similar results to those from liquid urine. Given the ease of sample handling, this 4-spot dried urine assay would be useful for both clinical assessment of patients and for large epidemiologic studies.
Dried urine and salivary profiling for complete assessment of cortisol and cortisol metabolites Expand
Mark S. Newman, MS, Desmond A. Curran, and Bryan P. Mayfield, PharmD
DOI: https://doi.org/10.1016/j.jcte.2020.100243
Aims/Objectives
The primary aim of this study was to determine the utility of dried urine sampling in obtaining measures of cortisol and cortisol metabolites. Additional aims were to evaluate if a 4-spot dried urine collection is representative of a 24-hour urine collection and if expected diurnal cortisol patterns can be observed in samples from both urine and saliva.
Methods
Data from individuals with cortisol measures available from both a 4-spot dried urine collection and a 24-hour urine collection (n = 28) were evaluated. Of these 28, 20 also had concurrent liquid and dried 24-hour urine measures. Consistency between these methods was evaluated using paired t-tests and intraclass correlation coefficients (ICCs). In addition, data from individuals with concurrent measures of both urinary and salivary cortisol (n = 68) were assessed for consistency in the diurnal pattern of change in cortisol.
Results
Near ideal consistency was observed between liquid and dried urine for measures of total urine free cortisol, total urine cortisone, and total cortisol metabolites (n = 20; ICCs = 0.99, 0.97 and 0.96, respectively). Good to excellent consistency was observed between the 4-spot method and the 24-hour collection (n = 28; ICCs = 0.89, 0.95 and 0.92, respectively). In mixed model analysis, no difference was seen in the diurnal pattern of cortisol between salivary and urinary free cortisol (n = 68; P = 0.83).
Conclusions
Dried urine is a viable alternative to liquid urine for the measurement of cortisol and cortisol metabolites. Additionally, if the 4 measures are added together, 4-spot urine collections can be representative of diurnal cortisol patterns commonly assessed using saliva and 24-hour urine collections.
Evaluating urinary estrogen and progesterone metabolites using dried filter paper samples and gas chromatography with tandem mass spectrometry (GC–MS/MS) Expand
Mark S. Newman, MS, Suzanne M. Pratt, DVM, Desmond A. Curran, and Frank Z. Stanczyk, PhD
DOI: https://doi.org/10.1186/s13065-019-0539-1
Background
Measuring concentrations of metabolites of estradiol and progesterone in urine, instead of measuring serum concentrations, is common in research and also is used in patient care. The primary aim of this study was to demonstrate that analysis of urine samples dried on filter paper by gas chromatography with tandem mass spectrometry (GC–MS/MS) provides results similar to serum analyzed by radioimmunoassay (RIA). Secondary aims were to show that collection of four samples during the day (4-spot method) can be substituted for a 24-h collection, and that analysis of urine from dried samples is equivalent to liquid urine samples.
Methods
This prospective observational study compared results of urine and serum analyses. Urine samples from women throughout the menstrual cycle and single samples from postmenopausal women were evaluated. Urine was collected onto filter paper and dried. Dried urine was extracted, hydrolyzed, and derivatized prior to analysis by GC–MS/MS. Hormone concentrations were normalized to creatinine. Single samples were used to compare results of 24-h urine collection to the 4-spot method from a separate population of women and men. A subset of these samples were used to compare results from dried urine to liquid urine.
Results
The primary study showed good reliability in the comparisons between the dried urine and serum assays. During the menstrual cycles of a subset of four women, urine metabolite concentrations followed the same pattern as serum concentrations. Comparison of 4-spot to 24-h urine collections and of dried to liquid urine measurements had intraclass correlation coefficients (ICC) greater than 0.95, indicating excellent agreement.
Conclusions
For estradiol and progesterone, the dried urine assay is a good surrogate for serum testing. The 4-spot method can be used instead of 24-h urine collections and dried urine results are comparable to liquid urine. The dried urine assay is useful for some clinical assessments of hormone disorders and may be useful in large epidemiologic studies due to ease of sample handling.
Presented Abstracts:
Sensitivity, specificity, and predictive value of urinary androgen metabolites for the diagnosis of polycystic ovary syndrome Expand
Mark Newman, MS, Doreen Saltiel, MD, JD, Bryan P. Mayfield, PharmD, and Frank Z. Stanczyk, PhD
DOI: https://doi.org/10.1016/j.fertnstert.2022.08.594
Objective
The objective of this study was to determine if urinary androgen metabolite concentrations measured using an at-home dried urine sampling method and an accompanying gas chromatography-tandem mass spectrometry (GC-MS/MS) assay could be used to confirm or rule out polycystic ovary syndrome (PCOS).
Materials and Methods
This was a retrospective observational cohort study conducted using a database containing 144,561 laboratory accessions that were submitted between January 1, 2016 and December 9, 2019 by 129,883 patients. These patients collected urine samples on filter paper at home and sent the collections to the laboratory to be processed. Urinary concentrations of androsterone, dehydroepiandrosterone sulfate (DHEA-S), epitestosterone, etiocholanolone, testosterone, 5α-androstanediol, 5β-androstanediol, and 5α-dihydrotestosterone (DHT) were measured. The database included a total of 2050 patients with a reported diagnosis of PCOS and 27488 patients who did not report a PCOS diagnosis. A "urinary androgen index" was created comprising all measured androgen metabolites. Mixed models were then created to determine sensitivity, specificity, and predictive values of the components of this urinary androgen index.
Results
Mixed models determined that for patients with a measured urinary androgen index greater than or equal to 4 (4 or more androgen metabolites above the reference range) the sensitivity was 0.44, the specificity was 0.78, the positive predictive value was 0.13, and the negative predictive value was 0.95. For patients with a measured epitestosterone, etiocholanolone, or testosterone above the reference range the sensitivity was 0.70, the specificity was 0.53, the positive predictive value was 0.10, and the negative predictive value was 0.96. For patients with a measured urinary testosterone higher than the 75th percentile of the reference range, the sensitivity was 0.47, the specificity was 0.76, the positive predictive value was 0.13, and the negative predictive value was 0.95.
Conclusions
Urinary androgen metabolites measured using a dried urine sample and a validated GC-MS/MS assay demonstrated low positive predictive values, but high negative predictive values for PCOS suggesting that these measures may be of use in ruling out PCOS.
Impact Statement
In this large general population study, a dried urine sampling method measuring androgen metabolites demonstrated the potential to be effective at ruling out PCOS. This method may represent a new, convenient, at-home, non-invasive tool for clinicians and researchers to use in settings where barriers exist to in-person patient evaluation or ultrasonography. When combined with additional information available from urine sampling, this tool may provide a comprehensive panel of results to inform both clinical investigation and decision making.
Urinary estrogen and progesterone metabolite patterns in ovulatory and anovulatory women Expand
Mark Newman, MS, Doreen Saltiel, MD, JD, Bryan P. Mayfield, PharmD, and Frank Z. Stanczyk, PhD
DOI: https://doi.org/10.1016/j.fertnstert.2022.08.599
Objective
To determine if monthly urinary patterns of estrogens and progesterone metabolites, collected as dried urine samples and measured with a validated GC-MS/MS assay, differ between women with laboratory evidence of ovulation and women with no laboratory evidence of ovulation.
Materials and Methods
This was a retrospective observational cohort study conducted using a database containing 144,561 laboratory accessions that were submitted between January 1, 2016 and December 9, 2019 by 129,883 patients. These patients collected urine samples on filter paper at home and sent these collections to the laboratory to be processed. From this database, 1604 individuals completed a cycle collection and met inclusion criteria for the study (female sex, age between 17 and 50 years, body mass index [BMI] between 16 and 55 kg/m2, and urinary creatinine > 0.1 ng/mL). Progesterone was measured as its urinary progesterone metabolites 5α-pregnane-3α, 20α-diol (α-pregnanediol) and 5β-pregnane-3α, 20α-diol (β-pregnanediol), with total pregnanediols calculated as α-pregnanediol plus β-pregnanediol. Estrogen was also measured via the urinary metabolites with total estrogens calculated as the sum of all 10 measured metabolites. Ovulation was defined as a peak β-pregnanediol > 600 ng/mg-Cr and a peak α-pregnanediol > 200 ng/mg-Cr or a change in total pregnanediols > 650 ng/mg-Cr. Mixed models to account for repeated measures were used to compare hormone patterns between women who showed evidence of ovulation and those who did not.
Results
Of the 1604 patients included in the study, 83% (1336) showed evidence of ovulation. The mean age (± SD) was 36.5 ± 6.8 for the group that showed evidence of ovulation and 34.3 ± 9.3 for the group that did not. The mean BMI was 24.1 ± 4.6 for the ovulation group and 24.6 ± 5.5 for the anovulatory group. No statistically significant difference existed between either the mean age (p = 0.15) or BMI (p = 0.43). A mixed model showed that the difference in the trajectories of total pregnanediols between those who ovulated and those who did not differed significantly (mean difference = 545.67 ± 28.2 ng/mg-Cr/day; p<0.0001).Similarly, in the mixed model evaluating differences in the patterns of total estrogens over the month, the trajectories differed between those who did and did not ovulate (mean Δ = 13.2±3.5 ng/mg-Cr/d). The individual pregnanediol and estrogen measures resulted in similar findings when analyzed separately.
Conclusions
The method used in this study effectively captured the expected estrogen and progesterone metabolite patterns in women who showed laboratory evidence of ovulation. The results also showed clear and significant differences in these patterns between women who ovulated and women who did not. Further research comparing this method with more definitive methods of ovulation confirmation, such as ultrasonography, is needed.
Impact Statement
The results of this study demonstrate the potential for this tool to provide an easy to collect, lower cost, non-invasive option for clinicians and researchers investigating clinical scenarios involving ovulation status.
Comparison of cyclic urinary estrogen and progesterone metabolite patterns between women reporting menses and women reporting no menses Expand
Mark Newman, MS, Doreen Saltiel, MD, JD, Bryan P. Mayfield, PharmD, and Frank Z. Stanczyk, PhD
DOI: https://doi.org/10.1016/j.fertnstert.2022.08.600
Objective
To determine if monthly urinary patterns of estrogen and progesterone, collected as dried urine samples and measured with a GC-MS/MS assay, differ between women who reported menses and women who reported no menses.
Materials and Methods
This was a retrospective observational cohort study conducted using a database containing 144,561 laboratory accessions that were submitted between January 1, 2016 and December 9, 2019 by 129,883 individuals. From this database, 1604 individuals completed a cycle collection and met inclusion criteria for the study (female sex, age between 17 and 50 years, body mass index [BMI] between 16 and 55 kg/m2, and urinary creatinine > 0.1 ng/mL). Progesterone was measured as its urinary metabolites 5α-pregnane-3α, 20α-diol (α-pregnanediol) and 5β-pregnane-3α, 20α-diol (β-pregnanediol), with total pregnanediols calculated as α-pregnanediol plus β-pregnanediol. Estrogen was also measured via the urinary metabolites with total estrogens calculated as the sum of all 10 measured metabolites. Mixed models to account for repeated measures were used to compare urinary estrogen and progesterone patterns between women who reported menses and women who reported no menses.
Results
Of the 1604 patients included in the study, 93% (1494) reported menses and 7% (110) reported no menses. The mean age (± SD) was 36.2 ± 7.1 for the group reporting menses and 34.9 ± 9.6 for the group reporting no menses. The mean BMI was 24.2 ± 4.6 for the group reporting menses and 24.6 ± 6.0 for the group reporting no menses. No statistically significant difference existed between either the mean age (p = 0.15) or BMI (p = 0.43). A mixed model showed that reporting vs. not reporting menses had an effect on the trajectories of pregnanediols that was highly significant (p<0.0001) with an overall effect of increasing total pregnanediols an average of 246.9 (46.2) ng/mg-Cr/day. The model also showed that the observed pregnanediol patterns between the two groups of women (menses vs. no menses) were significantly different (p<0.0001). Similarly, women reporting menses had a significantly different trajectory of total estrogens than women reporting no menses (Average effect: Δ = 18.1 ± 5.0 ng/mg-Cr/d; p<0.0001). The individual estrogen metabolites, including estradiol, showed similar findings when analyzed separately.
Conclusions
The method used in this study effectively captured the expected estrogen and progesterone patterns in women who reported menses. Additionally, there were clear and significant differences in these patterns between women who reported menses and women who reported no menses.
Impact Statement
This convenient, at-home collection method and the accompanying validated assay represents a tool that may be useful in a variety of clinical and research settings as it decreases the need for office visits and staff to perform collections needed to evaluate estrogen and progesterone patterns over the course of a menstrual cycle.
Clinical Applications & Best Practices
Mark S. Newman, MS
Treatment/Dosing
- The scientific literature suggests doses as low as 0.014-0.025mg for E2 patches and 0.25mg for E2 gel products can be clinically impactful, though doses are highly product specific for E2 gels. Higher doses increase the clinical impact at the expense of higher E2 exposure.
- Low dose patches contain 0.4-5.0mg of E2 and deliver 0.025mg of E2 daily. This dose increases bone mineral density (BMD) and improves vasomotor symptoms (VMS), vulvovaginal (VVA) symptoms, and other related symptoms.
- Low dose offerings of FDA-approved E2 gels contain 0.25-1.5mg of E2 daily. These doses are also effective but do show some delay in improving BMD and VMS compared to low dose E2 patches, implying the doses are effectively “low.”
- Higher doses of FDA-approved gels are more effective at improving BMD and VMS symptoms showing no delay, at the expense of higer total estrogen exposure.
Laboratory Monitoring
- Serum or urine levels just outside the postmenopausal range and into the lower part of the premenopausal (luteal) range may be optimal targets for both E2 patches and gels. Serum, 20-60pg/mL; DUTCH, 0.7-1.8ng/mg.
- Serum levels correlate to clinical improvements for both E2 patches and gels as it relates to VMS, BMD, VVA, and changes in FSH, lipids, SHBG, and the endometrium.
- Urine levels generally parallel serum levels and clinical outcomes with TD E2 gels (DUTCH data) and patches (DUTCH and published data), although no studies have tied clinical outcomes directly to urine levels. The DUTCH test also includes estrogen metabolites.
- Saliva testing should not be used with creams or gels as its exaggerated values do not appear to correlate to any studied clinical outcomes.
- DUTCH may be optimal with E2 creams and gels given the rapid up-and-down serum pattern.
Doreen Saltiel, MD, JD, and Mark S. Newman, MS
A thorough literature review affirms that in peri-and postmenopausal (PMP) women, estradiol (E2) effectively relieves vasomotor (VMS) and vulvovaginal atrophy (VVA) symptoms, while increasing bone mineral density (BMD). Estrogen (E)/Estradiol (E2)-alone is associated with a reduced cardiovascular disease (CVD) event rate and breast cancer risk. Additionally, if the progesterone (preferably oral progesterone – OMP) dose balances E/E2’s proliferative effects, there is no increase in endometrial cancer. In fact, transdermal estradiol (TD E2) therapy with OMP (especially in women with a uterus) may be continued beyond what current guidelines recommend. The most appropriate dose, duration, regimen, and route of administration is best determined by the clinician and patient while considering the risks and benefits.
Major Risks Associated with Estrogen Therapy
Endometrial Hyperplasia and Cancer – Unopposed TD E2 increases endometrial hyperplasia and endometrial cancer risk
- The endometrial cancer risk is essentially eliminated with OMP dosing which balances TD E2’s proliferative effects.
Breast Cancer - Estrogen/Estradiol-alone decreases breast cancer risk!
- Study results are confusing, and often inconsistent.
- TD E2 may be continued safely for > 10 years if meticulous surveillance and risk stratification is ongoing.
- A woman’s age (< 60 or > 60) and years since menopause onset (< 10 years or > 10 years) probably have no impact on either breast cancer risk or breast cancer mortality.
- TD E2 combined with OMP does not increase breast cancer.
Risks Associated with Estrogen Deprivation
VMS and VVA – FDA-approved E2 patches/gels are effective and the treatment of choice for both VMS and VVA symptoms
- TD E2 patch doses as low as 0.014mg/d relieve VMS and VVA symptoms.
- Low-dose DIVIGEL 0.25mg/d relieves VMS but takes longer than patches for significant symptomatic relief. Higher doses are clinically effective without delay.
- ESTROGEL 0.75mg/d, and 0.375mg/d (0.27mg/d did not), as well as ELESTRIN 0.52mg/d, relieve VVA symptoms.
Osteoporosis – E2 patches and gels improve BMD, but only E2 patches are FDA-approved for BMD
- All FDA-approved TD E2 patches improve BMD and are FDA-approved for osteoporosis prevention.
- TD E2 gels are not FDA-approved for osteoporosis prevention, but show some effectiveness, i.e. ≥ 0.75mg/d ESTROGEL.
Cardiovascular disease (CVD) – TD E2 decreases CVD, with no increase in stroke or venous thromboembolic events
- TD E2’s mortality reduction is positively related to E2 exposure time.
- TD E2 patches (as low as 0.025mg/d) and gels (1-2mg/d) have been associated with decreased CVD mortality.
Cognition – Results in the literature are inconsistent and the reasons for this are multifactorial
- ESTRADERM 0.05mg/d and 0.1mg/d improve cognitive performance in healthy, PMP women with mild-moderate AD.
- CLIMARA 0.05mg/d improves cognitive performance in perimenopausal and recently menopausal women.
- MENOSTAR 0.014mg/d does not improve cognitive performance in predominantly asymptomatic, older PMP women.
Mark S. Newman, MS
Treatment/Dosing
- In most male patients, 50-100mg TD T gel produces clinical changes in alignment with typical T injections.
- Doses applied to the scrotum may have >20x higher absorption and doses <50mg are used.
- In female patients, 1-5mg TD T gel/cream is common, but doses as high as 20mg have been used without significant side effects.
- No published studies have assessed the clinical impact of TD T creams. Available data implies somewhat higher (~2x) doses may be needed to increase serum similarly to TD T gels.
Laboratory Monitoring
- Serum testing for TD T monitoring appears to be a reasonable approach for clinical practice, especially when using alcohol-based gels.
- No studies have been found where serum values lag behind the clinical impact and multiple studies have shown clinical improvement only when serum levels increase.
- Urine testing provides a useful complement to serum testing for monitoring TD T.
- Serum testing may be more reliable in patients with abnormal phase II metabolism (a harmless variant is seen in especially high percentages of Asians, resulting in falsely low urine levels).
- The DUTCH Test offers additional information (progesterone, estrogen & androgen metabolites, free cortisol and cortisol metabolites, organic acids, melatonin, and 8-OHdG) to improve the overall interpretation.
- Salivary and capillary blood spot testing should not be used to monitor TD T creams or gels.
- Values following therapy are routinely supraphysiological with doses not proven to be effective. The observed exaggerated responses seen are not known to be consistent with any clinical parameters from any published study.
Mark S. Newman, MS
Treatment/Dosing
- TD Pg should not be used in peri/postmenopausal women with a uterus for either endometrial protection or symptom relief without endometrial surveillance. Clinicians may prefer oral or vaginal Pg in estrogen sufficient women as both have been proven to consistently protect the endometrium.
- TD Pg can be considered for symptom relief in postmenopausal women without a uterus if not taking estrogen. If premenopausal women have modestly insufficient Pg, TD Pg may be used for symptom relief.
Laboratory Monitoring
- There are no laboratory tests that have been proven to provide meaningful feedback regarding whether a particular dose of TD Pg is appropriate or effective.
- Salivary and capillary blood spot testing cannot be used to monitor TD Pg therapy.
- Salivary levels far exceed premenopausal levels on typical Pg doses and have been proven to be highly variable from day to day while on therapy.
- Salivary values may remain elevated for months after the cessation of therapy.
- Elevations in salivary and capillary blood spot have never been shown to correlate to a clinical outcome.
- Neither serum nor urine values increase linearly with increased dosing of TD Pg.
- Serum Pg levels go up slightly, but not to luteal (premenopausal) levels, with typical doses.
- Increasing dosing until luteal levels of serum or urine are achieved is not advisable.
Doreen Saltiel, MD, JD, and Mark S. Newman, MS
Clinical Recommendations for OMP Dosing
A key reason for prescribing OMP is endometrial protection in women with a uterus. OMP protects the endometrium from estradiol’s (E2) proliferative effects. The OMP dose MUST balance E2’s proliferative effects. Therefore, the OMP dose is dependent on the E2 dose. The evidence supports that both OMP 100mg/d and 200mg/d protect the endometrium. Continuous OMP provides more complete endometrial protection compared to sequential OMP.
Research has proven that 200mg/d, combined with a standard dose TD E2, i.e., a 0.05mg/d patch, protects the endometrium. The OMP dose is dependent on the E2 dose. Lower OMP doses (100-200mg/d) may be used when prescribing ultra-low or low-dose TD E2, i.e. 0.014mg/d or 0.025mg/d, respectively. In fact, when OMP 50mg was combined with either oral estradiol 0.5mg/d in a single capsule, the endometrium was protected with both doses.
In addition to protecting the endometrium in women with a uterus, OMP is an important physiologic partner to estradiol in decreasing morbidity and improving a woman’s quality of life. Listed below are comorbidities where OMP is either helpful or has a neutral effect.
- Breast Cancer: OMP 200mg, when added to TD E2, DOES NOT increase breast cancer incidence. TD E2 and OMP may be continued safely for > 10 years with ongoing surveillance. There is indirect data that OMP 100mg does not increase breast cancer incidence.
- Vasomotor Symptoms (VMS): OMP 300mg/d, without TD E2 preparations, relieves VMS, including severe VMS. Lower OMP doses have not been extensively tested.
- Cardiovascular Disease (CVD): All commonly used OMP doses (100mg/d, 200mg/d, and 300mg/d) are safe and do not negatively affect the vascular tree, and specifically the coronary arteries. OMP does not increase Deep Vein Thrombosis (DVT) or pulmonary embolism (PE) risk.
- Cognition: OMP 200mg/d is safe; it neither adversely affects, nor improves cognitive function.
Laboratory Assessment of OMP
OMP works via increasing systemic progesterone (Pg) levels AND through the clinical impact of Pg metabolites. These metabolites, like α-pregnanolone, are created in supraphysiological levels when Pg is taken orally. The clinical effects, such as biopsy documented endometrial protection, have been correlated to OMP dosing but have not been standardized to any testing modality or Pg level.
Serum and saliva should never be used for OMP monitoring for two reasons:
- OMP is typically dosed around bedtime, peaks in 1-4 hours, and is back to baseline within 8 hours; an AM sample is meaningless and may lead to overdosing.
- While typical serum and saliva tests (immunoassays) are accurate when patients are not taking OMP, they dramatically overestimate Pg values when taking OMP (metabolites cross-react).
Urine testing can be used to measure metabolism patterns (α-pregnanediol and ß-pregnanediol).
- Because much of OMP’s clinical impact comes from its metabolites (alpha metabolites are particularly helpful with sleep disturbances), urine metabolite testing is helpful.
- Urine testing shows which pathways predominate (alpha pathway or less active beta pathway).
- Metabolism patterns vary significantly between patients, and their consideration may be helpful. For example, patients preferring the less active beta pathway may not get adequate relief from sleep disturbances with typical OMP dosing.
- Some in vitro research implies alpha metabolites may increase breast cancer proliferation.
DUTCH Research Inquiries
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