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. Author manuscript; available in PMC: 2024 Nov 20.
Published in final edited form as: Menopause. 2023 Nov 20;30(2):186–192. doi: 10.1097/GME.0000000000002106

Association of ß-glucuronidase activity with menopausal status, ethnicity, adiposity and inflammation in women

Janet L Funk 1,2,*, Betsy C Wertheim 3, Jennifer B Frye 1, Robert M Blew 2,4, Jennifer Skye Nicholas 5, Zhao Chen 5, Jennifer W Bea 1,3,4
PMCID: PMC9886315  NIHMSID: NIHMS1836621  PMID: 36696643

Abstract

Objectives:

Many dietary polyphenols with potential health promoting benefits undergo hepatic conjugation and circulate as inactive glucuronides that can be cleaved by ß-glucuronidase to reform the bioactive aglycone. While indirect evidence suggests estrogen may induce ß-glucuronidase, little is known about ß-glucuronidase regulation across women’s reproductive lifespan. Correlates of serum ß-glucuronidase activity in healthy pre- versus post-menopausal women were therefore examined.

Methods:

ß-Glucuronidase activity and C-reactive protein (CRP) were assayed in stored serum from the Women’s Breast and Bone Density Study, and dual-energy X-ray absorptiometry (DXA) and anthropometry assessed body composition. Participants were pre- (n=133) or post-menopausal (n=89), and Hispanic (37%) or non-Hispanic White (63%). Multivariate linear regression models tested associations between ß-glucuronidase and menopausal status, ethnicity, CRP, and body composition metrics, overall and stratified by menopausal status.

Results:

Post- (vs. pre-) menopausal women were older (60.4 ± 3.7 versus 44.8 ± 2.4 y) with a lower Hispanic ethnicity prevalence (27% versus 44%), and higher serum ß-glucuronidase activity (1.5 ± 0.8 versus 1.3 ± 0.5 U/L) and CRP (4.2 ± 4.4 versus 3.3 ± 4.7 mg/L). Adjusting for confounders, ß-glucuronidase was positively associated with Hispanic ethnicity, CRP, body mass index, and total fat mass (all, p<0.01), but not menopausal status nor lean mass. Central adiposity measures were also positively associated with ß-glucuronidase with the same covariates.

Conclusions:

ß-Glucuronidase enzyme activity, upon which polyphenol health-related benefits may depend, is not associated with menopausal status. Future studies are required to determine clinical significance and mechanisms driving ß-glucuronidase associations with ethnicity, inflammation, and adiposity in women.

Keywords: glucuronidase, polyphenols, menopause, obesity, Hispanic, CRP

Introduction

Endogenous sex steroids and exogenous dietary polyphenols with health promoting effects share a similar metabolic fate; both are glucuronidated by the liver to form inactive conjugates to facilitate their elimination (Figure 1)1–3. However, these circulating glucuronide conjugates, which often have prolonged half-lives due to enterohepatic circulation2, 4, can also provide a ready source of the original bioactive compound (aglycone) if hydrolyzed. Glucuronide hydrolysis is an enzymatic process mediated by beta-glucuronidase (GUSB)5, 6.

Figure 1.

Figure 1.

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Schematic of hepatic glucuronidation, a well characterized phase II inactivation pathway for polyphenols and sex steroids, and enzyme-mediated deconjugation by ß-glucuronidase (GUSB) to restore the original bioactive aglycone.

GUSB is a ubiquitous enzyme that primarily resides in lysosomes and is responsible for lysosomal processing of glycosaminoglycans (GAGs); GUSB is also secreted (e.g., by activated inflammatory cells) and undergoes receptor-mediated reuptake7. A complete absence of GUSB results in a rare lysosomal storage disorder that responds to even minimal restoration of GUSB levels (e.g., 1% of normal)7. However, as noted, GUSB can also mediate the deconjugation of compounds circulating as inactive glucuronides, a process that may occur extracellularly8 and include sex steroids and numerous dietary polyphenols9–11. In contrast to the extremely low enzyme levels required for lysosomal processing of GAGs, GUSB-mediated deconjugation of dietary polyphenol glucuronides in mice is compromised even when GUSB activity is reduced only by half6.

Possible hormonal regulation of GUSB expression across the reproductive lifespan has not been examined in humans. However, in rodents, breast GUSB activity increases at time of puberty12, while bone GUSB activity is reduced in ovariectomized (OVX) mice, a mouse model of menopause5. GUSB expression is also upregulated in response to pharmacologic doses of estradiol or testosterone in rats11–14. In humans, circulating levels of GUSB are highest during pregnancy, although neither the tissue source nor potential role for hormonal stimuli for these elevations is known15. Stimulatory effects of pharmacologic doses of estrogenic agents on serum GUSB activity have been reported in women treated with with diethylstilbestrol or ethinyl estradiol for breast cancer16. While human findings suggest that “supraphysiologic” estrogen levels may upregulate GUSB in women, a potential role for endogenous estrogen in differentially regulating GUSB in estrogen-replete pre-menopausal versus estrogen-deficient post-menopausal women has not previously been examined.

GUSB associations with body mass index (BMI) in post-menopausal women have not been specifically studied, nor have relationships with adiposity, a potential source of estrogen in post-menopausal women, been examined in any population. Serum GUSB activity, which is reflective of tissue levels in mice and in humans6, 17 and has a wide distribution in human populations18, 19, has been reported to be lower in women than men19, 20. Interestingly, in studies where confounders were not considered, serum GUSB activity was associated with BMI in women, but not men, in a general population (age 20–79)19. In a cohort of healthy young adults (age 20–40 y), GUSB was higher in overweight (BMI ≥ 25) women, a relationship absent in young men20. Potential mechanisms explaining the association of GUSB with BMI in women have not been explored. For example, while both circulating and local GUSB levels in inflamed joints are increased in individuals with various types of inflammatory arthritis21–24, possible correlations between GUSB and and the chronic low-grade inflammatory state that occurs in older and overweight adult populations25, 26 have not been explored.

Given the lack of information on GUSB activity levels in post-menopausal women, possible GUSB regulation by sex hormones, and the under-studied association of GUSB with BMI, we examined serum GUSB activity in pre- versus post-menopausal women, with consideration for systemic inflammation, as determined by serum C-reactive protein (CPR), and body composition, as determined by anthropometry and dual-energy X-ray absorptiometry (DXA).

Methods

Study Population

GUSB associations were examined in a sample of convenience, taking advantage of existing body composition data and access to frozen (−80°C) stored serum from the University of Arizona’s Women’s Breast and Bone Density (WBBD) study. WBBD participants (n=238) were recruited between 2001–2004 from a pool of women residing in Southern Arizona who had recently undergone mammography (n=1726), with enrollment limited to pre-menopausal (age 41–50 y) or post-menopausal (56–70 y) women who were either Hispanic or non-Hispanic White (NHW)27–29. Pre-menopausal status was defined as having had a menstrual cycle in the prior 12 months and having an FSH level < 22 mIU/mL. Post-menopausal status was defined as not having had a menstrual cycle in the previous 12 months or FSH concentration 22–138 mIU/mL. Exclusion criteria included race/ethnicity other than Hispanic or NHW, weight over 127 kg, or chronic diseases that would alter bone health, including breast cancer. Importantly, given our postulate of possible differential regulation of GUSB by endogenous estrogen in menstruating versus post-menopausal women, pregnancy or breast feeding within 2 years, or use of hormone therapy or oral contraceptives within the past year, were also exclusionary.

GUSB enzyme activity assay

Circulating serum lysosomal enzyme activity levels are a standard measure of enzyme sufficiency or deficiency in humans30 that correlate with endogenous activity levels in organs5, 6. To optimize GUSB serum assay performance and reproducibility, modification of a previously described GUSB activity assay was used here6. In brief, 10 μL of serum were incubated in triplicate for 60 minutes at 37°C in 50 mM sodium acetate buffer (pH5) with substrate (4-methylumbelliferone [4-MU]-glucuronide [4-MUG]), using a 4-MUG concentration (5 mM) exceeding the Km for hGUSB, empirically determined to be ~ 1 mM, in agreement with published values for 4-MUG and human GUSB6. Quantification of the fluorescent 4-MU product formed was determined by comparison to a 4-MU standard curve (run in quadruplicate with 4-parameter fitting of log/log curve) by determination of fluorescence (360 nm/470 nm, emission/excitation). GUSB activity is reported as units of enzyme activity (U=μmol of product formed per minute) per volume (L) of serum. Intra- and inter-assay coefficients of variation (CV) were both < 5%. Participant samples were rerun if their intraassay CV was >5% (n=6 samples). Of note, the stability of GUSB and other lysosomal enzymes over years of storage (including as dried blood spots stored at room temperature) and following repeated freeze thaw cycles has been previously documented30–32 and was also confirmed here in replicate assays where GUSB levels in control serum samples across 1–8 serial freeze/thaw cycles were not significantly different by 1-way ANOVA, with a CV < 7%.

C-reactive protein assay

Diluted (1:100) serum samples were assayed in duplicate to determine CRP levels, reported as mg/L, in comparison with a standard curve (run in triplicate) as per manufacturer’s instructions using a commercial high-sensitivity CRP enzyme immunoassay. The Immundiagnostik AG CRP assay (Bensheim, Germany) is reported to correlate well with standard nephelometric determinations of CRP, with CRP levels remaining reproducible after storage and repeated freeze thaw cycles33. Intra- and inter-assay CV were <10% and <12% for Immundiagnostik controls, respectively. Participant samples were rerun if their intra-assay CV was >10% (n=33 samples).

Anthropometry

Weight, height, and waist circumference were measured in duplicate using standardized protocols and averaged34. Participants were measured in lightweight clothing without shoes. Weight and height were measured to the nearest 0.1 kg using a balance beam scale and to the nearest 0.1 cm using a Harpenden stadiometer, respectively. BMI was calculated as weight (kg)/height (m2). Waist circumference was measured to the nearest 0.1 cm using an anthropometric tape measure.

Dual-energy X-ray Absorptiometry (DXA)

Whole-body and regional measurements of soft tissue composition were measured by DXA (Hologic QDR 4500w, Marlborough, MA, USA), which was calibrated daily following manufacturer guidelines. Participants were postioned according to manufacturer instructions. The initial analysis using Hologic software (v8.26) algorithms was visually inspected by a single, trained technician, and adjustments to lines distinguishing bone, soft tissue, and regional demarcations were performed as necessary.

Statistical Analysis

Participant characteristics were summarized and compared across menopausal status using t-tests for continuous variables or chi-squared tests for categorical variables. Continuous variables were natural log (log)-transformed if necessary. Associations between participant characteristics and GUSB (log) were tested using multivariate linear regression. Potential confounders were determined a priori based on the literature (eg. CRP, race/ethnicity, menopausal status, BMI)15, 16, 19, 20, 25, 26. Due to the strong association between inflammation and adiposity in the literature, particularly central measures of adiposity25, 26, the main model incorporated trunk fat mass as the primary adipose measure rather than BMI. The full model included menopausal status, race/ethnicity, CRP (log), trunk fat mass, lean soft tissue mass, and height as independent variables. Subsequent models replaced trunk fat with an alternate measure of either anthropometric or DXA-derived adiposity: BMI, waist circumference, total fat mass, trunk-to-limb fat ratio, or trunk-to-leg fat ratio. When BMI was used in the model, height was not included, as height is integral to the variable. Similarly, lean soft tissue was only included in models examining DXA-derived adipose for the purposes of mutual adjustment. All statistical analysis was performed using Stata 17.0 (StataCorp, College Station, TX).

Results

Population Characteristics

Consistent with study design of excluding perimenopausal women, the mean ± SD age for pre- (44.8 ± 2.4 y) versus post-menopausal (60.4 ± 3.7 y) groups was significantly different (Table 1). The entire study population was limited to NHW or Hispanic women, with a significantly higher prevalence of Hispanic women in the pre-menopausal group. While pre-menopausal women were slightly (1.1%) but significantly taller, average BMI, weight, lean mass, and fat mass were not different between groups. However, post-menopausal participants had larger waist circumference, trunk fat mass, and trunk-to-limb or trunk-to-leg fat mass ratios than the pre-menopausal group (Table 1).

Table 1.

Characteristics of WBBD participants, by menopausal status

Characteristic Total
n = 222		 Premenopausal
n = 133		 Postmenopausal
n = 89		 p-valuea
Demographics
 Age (y), mean ± SD 51.1 (8.2) 44.8 (2.4) 60.4 (3.7) < 0.001
 Race/ethnicity, n (%) 0.01
  Non-Hispanic White 140 (63.1%) 75 (56.4%) 65 (73.0%)
  Hispanic 82 (36.9%) 58 (43.6%) 24 (27.0%)
Anthropometrics, mean ± SD
 Height (m) 1.627 (0.062) 1.634 (0.063) 1.616 (0.059) 0.03
 Weight (kg) 72.0 (15.6) 71.8 (16.2) 72.2 (14.9) 0.7
 BMI (kg/m2) 27.1 (5.5) 26.9 (5.7) 27.6 (5.0) 0.2
 Waist circumference (cm) 83.0 (13.1) 81.1 (13.8) 85.9 (11.5) 0.003
Body composition, mean ± SD
 Fat mass (kg) 26.4 (9.9) 25.5 (10.1) 27.6 (9.4) 0.1
 Lean soft tissue mass (kg) 39.2 (6.0) 39.8 (6.2) 38.4 (5.7) 0.08
 Truncal fat (kg) 12.3 (5.4) 11.7 (5.7) 13.2 (4.8) 0.04
 Trunk-to-limb fat ratio 0.93 (0.23) 0.88 (0.22) 0.99 (0.23) < 0.001
 Trunk-to-leg fat ratio 1.23 (0.36) 1.16 (0.33) 1.34 (0.36) < 0.001
Serum biomarkers, mean ± SD
 GUSB (U/L) 1.4 (0.6) 1.3 (0.5) 1.5 (0.8) 0.02
 CRP (mg/L) 3.6 (4.6) 3.3 (4.7) 4.2 (4.4) 0.003
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a

t-test (continuous variables, log-transformed if skewed) or chi-squared test (categorical variables)

Association of GUSB with menopausal status

Unadjusted average serum ß-glucuronidase activity levels (GUSB) were higher in post-menopausal women (p= 0.02), as were CRP levels (p=0.003), a measure of systemic inflammation, as compared to pre-menopausal women (Table 1). GUSB remained higher in post-menopausal women after adjusting for CRP, ethnicity and BMI (p < 0.04). However, after adjusting for CRP, ethnicity, and body composition (trunk fat, lean mass, and height), GUSB no longer differed by menopausal status (Figure 2A, p=0.3). GUSB was also not associated with age in pre- or post-menopausal women after adjusting for CRP, ethnicity, trunk fat, lean mass, and height (data not shown), or when pre- and post-menopausal groups were combined (ß, 0.00; p=0.4).

Figure 2.

Figure 2.

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Box plots of GUSB in WBBD study participants by menopausal status or ethnicity. (A) GUSB did not significantly differ by menopausal status in a linear regression model adjusted for race/ethnicity, CRP (log), trunk fat, lean mass, and height: beta-coefficient, 0.046; p-value, 0.3. (B) Box plot of GUSB in WBBD study participants, by race/ethnicity. Hispanic women had significantly higher GUSB (log) than NHW women in a linear regression model adjusted for menopausal status, CRP (log), trunk fat, lean mass, and height: beta-coefficient, 0.144; p-value, 0.004. Plots depict medians and interquartile ranges.

Association of GUSB with ethnicity and CRP in pre- and post-menopausal women

When pre- and post-menopausal groups were combined, GUSB activity was significantly higher in Hispanic versus NHW women (p=0.004), after adjusting for menopausal status, CRP, trunk fat mass, height, and lean mass (Figure 2B). When examined separately in pre- and post-menopausal women, GUSB remained significantly higher in Hispanic (versus NHW) women in both groups (data not shown). Significantly higher GUSB levels in Hispanic women persisted when substituting BMI for trunk fat mass in the model (data not shown). GUSB activity was also significantly positively associated with CRP levels in the combined cohort, after adjusting for menopausal status, ethnicity, trunk fat mass, height, and lean mass (p=0.007; Figure 3). The association between GUSB and CRP did not significantly differ by menopausal status (test for menopause-by-CRP interaction, p = 0.3).

Figure 3.

Figure 3.

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Unadjusted (dashed line) and adjusted (solid line) association between CRP and GUSB in WBBD study participants. In a linear regression model adjusted for menopausal status, race/ethnicity, trunk fat, lean mass, and height, CRP (log) is significantly positively associated with GUSB (log): beta-coefficient, 0.066; p-value, 0.007.

GUSB association with BMI in pre- and post-menopausal women

GUSB was positively associated with BMI in the combined pre- and post-menopausal groups (p=0.003) when menopausal status, ethnicity, and CRP were included as covariates (Figure 4). When the model was stratified by menopausal status, a significant association between GUSB and BMI persisted for both pre- and post-menopausal women (p < 0.03).

Figure 4.

Figure 4.

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Unadjusted (dashed line) and adjusted (solid line) association between BMI and GUSB in WBBD study participants. In a linear regression model adjusted for menopausal status, race/ethnicity, and CRP (log-transformed), BMI (log-transformed) is significantly associated with GUSB (log-transformed): beta-coefficient, 0.457; p-value, 0.003.

GUSB association with adiposity in pre- and post- menopausal women

There was no association between GUSB and total lean soft tissue mass in the total cohort when adjusting for menopausal status, ethnicity, CRP, height, and fat mass (or trunk fat) (ß, −0.002; p, 0.7). The findings were similarly non-significant in the stratified model of pre- versus post-menopausal women (data not shown). GUSB was positively associated with total fat mass in the combined cohort (p=0.006), without any significant interaction of menopausal status, when adjusted for menopausal status, ethnicity, CRP, lean soft tissue mass and height (Figure 5A). GUSB associations with regional fat measures were alternately assessed. GUSB was significantly associated anthropometric or DXA measures of central adiposity, including waist circumference (Figure 5B, p<0.001), trunk fat (Figure 5C, p<0.001), and the ratio of trunk-to-limb (ß, 0.379; p < 0.001) or trunk-to-leg fat (Figure 5D, p<0.001).

Figure 5.

Figure 5.

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Unadjusted (dashed line) and adjusted (solid line) association between measures of regional fat and GUSB in WBBD study participants in a linear regression model adjusted for menopausal status, race/ethnicity, CRP (log-transformed), lean soft tissue mass, and height. (A) fat mass is significantly associated with GUSB (log-transformed): beta-coefficient, 0.011; p-value, 0.006. (B) Waist circumference is significantly associated with GUSB (log-transformed): beta-coefficient, 0.014; p-value, < 0.001. (C) Trunk fat is significantly associated with GUSB (log-transformed): beta-coefficient, 0.029; p-value, < 0.001. (D) trunk-to-leg fat ratio is significantly associated with GUSB (log-transformed): beta-coefficient, 0.243; p-value, < 0.001.

Discussion

Contrary to our initial postulate that GUSB activity levels would be lower in post-menopausal women due to estrogen deficiency, GUSB levels instead were significantly higher in post- versus pre-menopausal women in the unadjusted model (or after adjusting for ethnicity, CRP and BMI). However, this relationship was attenuated to null after adjusting for the more precise body composition measures instead of BMI in our primary model. Taken together, these findings clearly do not support the postulate that GUSB levels are lower in menopausal women.

A particular strength of the study for analysis of GUSB levels in estrogen-deficient versus estrogen-replete women was exclusion of perimenopausal women. Similarly, exclusion of exogenous estrogen use, pregnancy, or breast feeding was also a strength of the study design when querying possible associations of GUSB activity with menopause-related changes in endogenous estrogen levels, given prior reports that these hormonal “extremes” are associated with increased GUSB levels11–16. It should be noted that the study design, which lacked longitudinal data, did not allow for GUSB associations with menopausal status to be distinguished independent of age. However, a relationship between GUSB and age was not noted between or within cohorts after adjusting for covariates in the primary model. In total, the findings from this hypothesis generating study, levaging a convenience sample, suggest that GUSB levels are maintained in menopausal women, and provide helpful initial information for powering future longitudinal studies examining GUSB with aging.

A sex-specific association of GUSB with BMI has previously been reported in pre-menopausal women and in a general female population19, 20. This study confirms and extends these findings, validating this relationship in both pre- and post-menopausal women. Further, novel data presented here document a specific association of GUSB with fat, not lean, mass. The reason for this association is not clear. Whether fat is serving as reservoir/contributor to circulating GUSB levels and/or has more complex relationship with GUSB cannot be assessed here, with the cross sectional design precluding temporal analyses that could shed light on the possible mechanistic directionality of the association. Nonetheless, the association of GUSB with anthropometric and DXA predictors of abdominal adiposity, a deleterious fat depot associated with inflammation and insulin resistance35, is intriguing. Since GUSB was associated with CRP independent of adiposity, these adiposity associations cannot be simply attributed to obesity-associated inflammation. A possible role for obesity-associated insulin resistance in driving the association of GUSB with central adiposity is supported by older studies reporting higher serum GUSB levels in individuals with diabetes36–38. Resource limitations prevented assessment of insulin resistance in this study; thus future studies, including those with longitudinal data to help assess causality, will be required to assess this relationship for which mechanisms driving a possible association of GUSB with insulin resistance are not known.

Given the importance of adipose tissue as a site of estrogen production in post-menopausal women and the presence of GUSB in relevant estrogen target tissues, such as breast and bone5, 6, 9, it is intriguing to postulate a possible paracrine role for GUSB at these sites that could contribute to local and/or circulating levels of bioavailable estrogen. Interestingly, it has been reported that tissue levels of estrogen and GUSB are correlated in breast adipose tissue, with GUSB expression at this site being futher associated with BMI9.

A positive association between GUSB activity in Hispanic (versus NHW) pre- and post-menopausal women is another novel finding of this study. While most previous population-based GUSB studies have been done in Western Europe18, 19, a single prior U.S. study reported higher GUSB levels in Asian or other (not defined) populations versus White20. Possible genetic determinants of GUSB activity to date have only been identified for loss-of-function GUSB mutations associated with complete lack of activity in individuals suffering from Sly syndrome, a rare lysosomal storage disorder18, 39. Whether ethnic differences in GUSB activity identified here could have a genetic basis is currently unknown. A role for insulin resistance in explaining this association is also possible, since the prevalence of insulin resistance for a given BMI is higher in Hispanic populations40.

Lastly, the association of serum GUSB activity with circulating CRP, an inflammation biomarker, is also a novel finding in a healthy adult population. While the cross sectional design of this study does not allow for assessment of temporality, one could postulate that increased inflammation could lead to higher circulating GUSB levels, as is reported in individuals with rheumatoid arthritis (RA), due to enhanced secretion by activated inflammatory cells. In contrast, there is no a priori evidence to suggest that circulating GUSB could increase inflammation or CRP. However, interestingly, GUSB levels in individuals with rheumatoid arthritis do not correlate with disease activity, including systemic markers of inflammation24. Similarly, while it is attractive to postulate that the association of GUSB with CRP could be attributable to a general level of inflammatory cell activation, since hemaopoietic cells are abundant cells with secretory GUSB-containing lysosomes41, the relative tissue or cellular sources of serum GUSB activity in health and disease, while lysosomal in orgin, are not well understood.

Conclusion

Very little is currently known about GUSB regulation in healthy adults. Novel evidence presented here describing GUSB associations with markers of inflammation, ethnicity, and adiposity, including fat distributions associated with metabolic dysfunction, suggest the possibility that a complex interplay of metabolic, inflammatory, and genetic determinants may effect GUSB levels, a postulate that will require future testing. The wide variation in GUSB activity in healthy women documented here and by others18, 19 is also of interest since only moderate (50%) differences in GUSB activity can alter glucuronide metabolism and, thus, in vivo bioactive aglycone availability in pre-clinical studies5, 6. Future research will also be required to explore whether GUSB expression in normal human populations is an important determinant of glucuronide metabolism and bioactivity.

Sources of funding:

Funding provided by the NIH (CA023074, CA174926, AR078424, CA217725).

Financial disclosures/conflicts of interest:

Janet L Funk received a past research grant from Metavivor Foundation. Jennifer W Bea received grant funding from Disarm Therapeutics to her institution for an unrelated IIT to study biomarkers of chemotherapy induced peripheral neuropathy. She is also a board member of Global Health and Body Composition Institute. The other authors have nothing to disclose.

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