Dr. Liz Bartman, ND

 

Subheadline

A case-based exploration of how urinary estrogen metabolites can reveal hidden patterns of estrogen recirculation, gut-liver dysfunction, and hormone clearance that contribute to menstrual pain and heavy bleeding.

Short Description

This case report examines a 27-year-old woman with longstanding dysmenorrhea and menorrhagia whose symptoms persisted despite conventional hormone-focused interventions. Using urinary estrogen metabolite testing, the case highlights how elevated 16-hydroxyestrone and impaired estrogen clearance may reflect underlying enterohepatic recirculation and guide more personalized, root-cause–oriented hormone care.

Introduction:

Dysmenorrhea is often treated as a symptom to suppress rather than a signal to decode. Yet for many patients, underlying patterns of estrogen metabolism, microbial activity, and enterohepatic recirculation may hold the key to understanding persistent menstrual pain and heavy bleeding.

This case-based exploration will reveal how urinary estrogen metabolites—particularly 16-hydroxyestrone—can illuminate a more nuanced story of hormone clearance, gut-liver interplay, and personalized therapeutic response.

Dysmenorrhea and menorrhagia affect an estimated 45-95% of reproductive-aged women, with around 10-29% of women experiencing symptoms severe enough to interfere with work, school, or daily activities (1). As described by the American Family Physician, primary dysmenorrhea is characterized by “recurrent, crampy, suprapubic pain occurring just before or during menses, typically lasting two to three days; pain may radiate to the lower back and thighs and may be associated with nausea, fatigue, bloating, and general malaise, with normal pelvic examination findings” (2). Discomfort can impact activities of daily living and can be scored using tools like the Dysmenorrhea Severity Inventory (DSI) (3).

Diagnosis is made clinically. Although blood work is not required for diagnosis, in functional medicine, further evaluation to investigate any deeper imbalance driving symptoms can help guide treatment beyond conventional intervention.

Additional labs may include a serum mid-luteal estradiol and progesterone values, to assess for concern of an estrogen dominance presentation. This may be coupled with inflammatory, liver, thyroid, blood sugar, and iron studies that could point to underlying culprits of immune dysregulation or metabolic stress that could influence prostaglandin response or impact tissue integrity of endometrial development.

The connection between microbiome health and estrogen dominance may also warrant exploration. In the absence of stool analysis, one urinary hormone indicator may show great impact in revealing a GI/estrogen detox connection that could be driving symptoms, which is what we will dive into in greater detail through this case investigation.

Background: Estrogen Metabolism, Beyond Catechol Estrogens and Methyl Detoxification

Estrogens undergo sequential biotransformation beginning with phase I hydroxylation via cytochrome P450 (CYP450) enzymes. CYP1A1 preferentially produces 2-hydroxylated estrogens (2-OH E1/E2); CYP1B1 generates 4-hydroxylated estrogens (4-OH E1/E2); and CYP3A4 is the principal enzyme responsible for producing 16α-hydroxylated estrogens, including 16-OH E1 and estriol (16-OH E2).

The 2-OH and 4-OH intermediates are classified as catechol estrogens and require catechol-O-methyltransferase (COMT)-mediated methylation for inactivation prior to final excretion. While 2-OH estrogens are commonly labeled as “protective,” this framing warrants revision. In hormone-sensitive tumor cells, catechol estrogen accumulation is high while methylation rates are low. Both 2-OH and 4-OH intermediates can be oxidized to quinones capable of forming DNA adducts — the 3,4-quinones derived from 4-OH intermediates form more unstable, depurating adducts and are therefore considered more genotoxic, but 2-OH is not without consequence if left unmethylated (4).

A critical and often underemphasized difference in metabolites is the tissue distribution of the enzymes generating these metabolites. CYP1A1 and CYP1B1 are classified as extra-hepatic enzymes, expressed in a wide range of tissues including the gastrointestinal tract, kidneys, reproductive tissues, breast, vascular endothelium, and brain. CYP3A4, by contrast, is predominantly expressed in the liver and the duodenum. For reference, you can review the Human Protein Atlas, which catalogs through real-time tissue evaluation the percentage of mRNA and protein expression per tissue throughout the body of any given enzyme (proteinatlas.org) (5). This distinction has direct implications for urinary metabolite interpretation: elevations in specific estrogen metabolites may reflect not only systemic detoxification capacity, but also tissue-level hormone exposure and clearance patterns that cannot be captured by serum estradiol alone.

The Estrobolome and Enterohepatic Recirculation

The estrobolome is a group of gram-negative bacteria that generate an enzyme called beta-glucuronidase. β-glucuronidase cleaves the glucuronide sidechain from estrogens previously conjugated via biliary conjugation and preparing for phase 3 elimination. Once that side chain is removed, the estrogen is free to enter back into circulation. However, as it is entering from the gut lumen, it enters enterohepatic circulation (portal vein) and “dumps” back into the liver before going back into systemic circulation. As the liver is highest in expression of CYP3A4, the primary estrogen conjugate from recirculation becomes 16-OH E1.

16-OH E1 is a tissue proliferator via its binding potential to ERα receptors, so this recirculation can become a greater burden to estrogen receptor signaling, and is associated with increased endometrial hyperplasia, fibrocystic breast tenderness and dysmenorrhea (6,7).

Case Presentation

A 27-year-old female presented with a primary complaint of dysmenorrhea and menorrhagia. Symptoms had been present since approximately age 17.

Menstrual cycles were regular, with an average cycle length of 27 days. Her menstrual period would typically last for 6-7 days. She reported an estimated blood loss of approximately 80-100 mL throughout her menstrual period (self-recorded based on number and type of tampons used per day during menses). The patient reported one to two clots during days 1-2 of her menses, approximately the size of a nickel in diameter.

A pelvic workup and imaging performed through her gynecologist ruled out adenomyosis and ovarian cysts, while laboratory analysis and symptoms ruled out concern for PMOS. Thyroid labs and her anemia panel were unremarkable.

Using the Dysmenorrhea Symptom Interference Scale (DSI), the patient’s baseline score was 27 out of 45, consistent with moderate symptom interference affecting quality of life.

The patient’s gynecologist recommended oral contraceptive therapy and NSAID use. The patient declined contraception but continued using ibuprofen at 4-6 tablets per day during the first 2-3 days of her menses (800-1,200 mg daily).

Initial Hormone Evaluation

Luteal-phase (day 21) serum testing demonstrated:

Progesterone: 14 ng/mL (range 3-25 ng/mL)

Estradiol: 202 pg/mL (range of 20-350 pg/mL)

Ferritin of 52 ng/mL, while iron, transferrin saturation and RBCs were WNL (although surprising, this could be explained by her use of a prenatal containing iron bisglycinate).

Although the progesterone-to-estradiol ratio is not formally validated in the context of non-IVF premenopausal assessment, it has been used as a clinical screening tool (8). When estradiol and progesterone values are within a luteal range, and are converted to equivalent units and divided, a ratio below 100 has been proposed to suggest functional estrogen dominance. The patient’s calculated ratio was 69.31, consistent with relative estrogen excess in the context of adequate ovulation.

A trial of a DIM-containing estrogen detox formulation was initiated at standard dosing as the first-line intervention to shift estrogen metabolism toward the 2-OH pathway.

Unexpectedly, at our 3-month follow-up, her symptoms worsened. The patient experienced prolonged cycle length and increased pelvic discomfort during her menstrual period. The intervention was discontinued.

One possible explanation was unexpected reduction of follicular estrogen activity during the early phase of follicle maturation, prolonging the time between follicle selection, maturation and rupture (which is estrogen-dependent). Because estradiol is necessary for normal follicular maturation and the ovulatory LH surge, aggressive modulation of estrogen metabolism throughout the entire cycle may have delayed optimal estrogen signaling and contributed to cycle disruption.

This clinical response prompted reconsideration of the underlying mechanism driving her dysmenorrhea.

Gastrointestinal Findings

Review of systems revealed chronic constipation.

Stool consistency was typically hard, requiring straining (reported as Bristol Stool Types 1-2).

Comprehensive stool analysis was largely unremarkable but demonstrated mild dysbiosis and elevated beta-glucuronidase.

Although bowel support was recommended, the combination of persistent symptoms, constipation, and poor response to DIM prompted additional evaluation using urinary hormone metabolite testing.

Urinary Hormone Metabolite Findings

Urinary hormone metabolite analysis revealed:

Elevated relative preference toward 16-OH E1 production

Appropriate ratio of catechol estrogens to the parent estrone on day of testing

No significant evidence of impaired COMT activity

These findings shifted clinical interpretation. Because catechol pathways and estrogen methylation appeared adequate, additional phase 1 detox promotion was not emphasized. The working hypothesis became that recirculation of conjugated estrogens was contributing to prolonged tissue estrogen exposure resulting in her dysmenorrhea.

Attention was focused on the observation that 16-OH E1 is the intermediate of hydroxylation through CYP3A4 expression and requires sulfation and glucuronidation for elimination. CYP3A4 transcription can be promoted by elevated glucocorticoid activity (either exogenous or endogenous). High fat intake, caffeine and pesticides, polyaromatic hydrocarbons, alcohol and excess adipose tissue can all contribute to higher CYP3A4 activity and may need to be addressed depending on history and clinical concerns (9, 10, 11). When approaching hormone metabolites, while increased expression of CYP3A4 may be a concern when 16-OH E1 metabolites are elevated, the idea is never to inhibit hydroxylation – as our cyp450 family of enzymes are not just responsible for the elimination of estrogens, but also for the appropriate clearance of medications, xenoestrogens and environmental toxins. Instead, the question becomes: how do we remove any agent resulting in increased transcription, while supporting removal of downstream conjugates.

Treatment Strategy

Consistent with the naturopathic therapeutic order, interventions began by supporting digestive health and optimizing bowel movements, with additional focus on stress management, optimizing hydration and increasing daily intentional movement. As menstrual symptoms persisted, more targeted nutraceutical interventions were also incorporated.

The nutraceutical protocol included:

Calcium-D-Glucarate – Calcium-D-glucarate is found in fruits and cruciferous vegetables and supports estrogen metabolism by inhibiting intestinal β-glucuronidase activity and reducing enterohepatic recirculation of estrogen (12).

Taurine – Taurine supports bile acid conjugation and bile flow, helping enhance biliary estrogen excretion and promote estrogen elimination through the gastrointestinal tract (13).

Lactobacillus gasseri OLL2809 Probiotic – Multiple randomized controlled trials have demonstrated that L. gasseri OLL2809 supplementation significantly reduces menstrual pain scores in women with primary dysmenorrhea and endometriosis-associated dysmenorrhea, as compared to placebo (14,15). The mechanism may involve modulation of prostaglandin activity and local immune response in endometrial tissue, as well as beneficial effects on gut microbiota composition.

Glucoraphanin + Myrosinase – Glucoraphanin is the stable biogenic precursor to sulforaphane. Sulforaphane is the most potent naturally occurring inducer of the Keap1/NRF2 pathway, which governs the transcriptional upregulation of endogenous phase II detoxification enzymes including NQO1, glutathione-S-transferase, heme oxygenase-1, and superoxide dismutase (16,17). A 2025 review of sulforaphane’s sex-specific effects further characterizes its relevance to female reproductive hormone metabolism through NRF2-mediated estrogen detoxification (18).

Clinical Outcomes

First Treatment Cycle

Cycle length remained unchanged at 27 days. Initial symptomatic changes observed during the first 3-month cycle following initial treatment included:

Ibuprofen use declined from 4-6 tablets per day, to a maximum of 4 tablets taken in total, generally needed just the day prior to and day of her menstrual period.

Six-month follow-up

Reduced reliance on NSAIDs

Improved stool frequency; Bristol Stool Types 2-3 on average

Reduced menstrual clots, with self-reported menstrual blood loss of approximately 60 mL per cycle

Follow-up DSI assessment demonstrated improvement in subjective symptoms from 27/45 to 7/45

Nutraceutical interventions were simplified to daily L.gasseri probiotic and continuation of her prenatal multivitamin. Symptom improvements were maintained.

Conclusion

Reconsidering Estrogen Dominance: A Clearance-First Framework

In this patient with chronic dysmenorrhea and menorrhagia, traditional estrogen-modulating therapy with DIM worsened symptoms and disrupted cycle length. Urinary hormone metabolite evaluation revealed a predominance of 16-hydroxyestrone despite appropriate catechol estrogen synthesis and methylation, suggesting impaired GI conjugation and elimination rather than a methylation deficit.

Targeted support of glucuronidation, sulfation, biliary function, and gastrointestinal elimination resulted in meaningful improvements in menstrual symptoms, bowel function, and quality of life.

This shifts the conversation of 16-OH E1 from being more than just a bioactive estrogen intermediate to rather an indicator of deeper metabolic, environmental and GI dysfunction.

This case is a good reminder that estrogen dominance symptoms do not necessarily indicate excessive estrogen production. In some patients, impaired elimination and enterohepatic recirculation may contribute substantially to tissue estrogen exposure. It also suggests that urinary estrogen metabolite patterns may help clinicians identify patients who would benefit more from improving estrogen elimination via targeted GI support, rather than from further modulation of estrogen catechol production pathways. Such an approach may represent an important evolution in the personalization of hormone-focused naturopathic care and may shift the way we review hormone metabolites.

References:

Carlson K, Nagy H, Khan MAB. Dysmenorrhea. In: StatPearls. StatPearls Publishing; 2026. Updated May 18, 2026. Accessed June 16, 2026. https://www.ncbi.nlm.nih.gov/books/NBK560834/

Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014;89(5):341-346.

Chen CX, Murphy T, Ofner S, et al. Development and testing of the Dysmenorrhea Symptom Interference (DSI) Scale. West J Nurs Res. 2021;43(4):364-373. doi:10.1177/0193945920942252

Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention. Clin Transl Med. 2016;5(1):12. doi:10.1186/s40169-016-0088-3.

Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi:10.1126/science.1260419

Hu S, Ding Q, Zhang W, Kang M, Ma J, Zhao L. Gut microbial beta-glucuronidase: a vital regulator in female estrogen metabolism. Gut Microbes. 2023;15(1):2236749. doi:10.1080/19490976.2023.2236749.

Klyushova LS, Perepechaeva ML, Grishanova AY. The role of CYP3A in health and disease. Biomedicines. 2022;10(11):2686. doi:10.3390/biomedicines10112686

Tokgoz VY, Ekici GC, Tekin AB. The efficiency of progesterone/estradiol and progesterone/follicle ratio without elevated trigger-day progesterone levels on the reproductive outcomes of GnRH antagonist IVF/ICSI cycles. Gynecol Endocrinol. 2021;37(10):885-890. doi:10.1080/09513590.2021.1878137

Huang Z, Guengerich FP, Kaminsky LS. 16α-hydroxylation of estrone by human cytochrome P450 3A4/5. Carcinogenesis. 1998;19(5):867-872. doi:10.1093/carcin/19.5.867

Luckert C, Ehlers A, Buhrke T, Seidel A, et al. Polycyclic aromatic hydrocarbons stimulate human CYP3A4 promoter activity via PXR. Toxicol Lett. 2013;222(2):180-188. doi:10.1016/j.toxlet.2013.06.243

Medina-Díaz IM, Arteaga-Illán G, de León MB, et al. Pregnane X receptor-dependent induction of the CYP3A4 gene by o,p’-1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane. Drug Metab Dispos. 2007;35(1):95-102. doi:10.1124/dmd.106.011759

Dwivedi C, Heck WJ, Downie AA, et al. Effect of calcium glucarate on beta-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Biol. 1990;43(2):83-92. doi:10.1016/0885-4505(90)90012-P

Santulli G, Kansakar U, Varzideh F, et. al. Functional role of taurine in aging and cardiovascular health: an updated overview. Nutrients. 2023;15(19):4236. doi:10.3390/nu15194236

Itoh H, Uchida M, Sashihara T, et al. Lactobacillus gasseri OLL2809 is effective especially on the menstrual pain and dysmenorrhea in endometriosis patients: randomized, double-blind, placebo-controlled study. Cytotechnology. 2011;63(2):153-161. doi:10.1007/s10616-010-9326-5

Vallibhakara O, Tosiri W, Vallibhakara SA, et al. Efficacy of probiotic supplementation in reducing primary dysmenorrhea: a double-blinded randomized controlled trial. Sci Rep. 2026;16(1):13873. doi:10.1038/s41598-026-44327-5

Houghton CA. Sulforaphane: its “coming of age” as a clinically relevant nutraceutical in the prevention and treatment of chronic disease. Oxid Med Cell Longev. 2019;2019:2716870. doi:10.1155/2019/2716870

Fahey JW, Talalay P. Antioxidant functions of sulforaphane: a potent inducer of phase II detoxication enzymes. Food Chem Toxicol. 1999;37(9-10):973-979. doi:10.1016/S0278-6915(99)00082-4

Fahey JW, Raphaely M. The impact of sulforaphane on sex-specific conditions and hormone balance: a comprehensive review. Appl Sci. 2025;15(2):522. doi:10.3390/app15020522

Author Bio:

Dr. Liz Bartman, N.D. is a naturopathic physician, educator, and clinical researcher specializing in hormone health, urinary hormone metabolite testing, nutrigenomics, and environmental medicine. She earned her Bachelor of Science in Cellular and Molecular Biology from Pacific University and completed her naturopathic medical training at the National University of Natural Medicine (NUNM) in Portland, Oregon. Dr. Bartman currently serves as Chief Medical Officer of EndoAxis, where she leads clinical innovation, practitioner education, and the development of advanced hormone assessment tools and targeted nutraceutical solutions designed to address the root causes of hormone imbalance. She is passionate about translating complex science into practical clinical strategies that empower practitioners to deliver personalized, evidence-based care.

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