Urinary concentrations of phenols, parabens, and triclocarban in relation to uterine leiomyomata incidence and growth.

OBJECTIVE: To examine the association of urinary concentrations of phenols, parabens, and triclocarban with incidence and growth of uterine leiomyomata (UL; fibroids). DESIGN: Case-cohort study, nested within the Study of Environment, Lifestyle, and Fibroids, a prospective cohort study. SETTING: Clinic visits at baseline and every 20 months for 60 months. PATIENT(S): 754 Black women aged 23-35 years residing in the Detroit, Michigan area (enrolled during 2010-2012). INTERVENTION: None. MAIN OUTCOME MEASURE(S): At each study visit, women underwent transvaginal ultrasound for measurement of UL incidence and growth and provided urine specimens in which we quantified concentrations of seven phenols, four parabens, and triclocarban. We used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs) characterizing the relation of urinary biomarker concentrations with UL incidence during the 60 months of follow-up. In a subset of UL detected and measured at multiple time points, we used linear regression to assess the associations between biomarker concentrations and UL growth. RESULT(S): Urinary biomarker concentrations were generally inversely associated with UL incidence, but the associations were weak and nonmonotonic. For example, hazard ratios comparing concentrations ≥90th with <50th percentile were 0.77 (95% CI: 0.46, 1.27) for bisphenol A, 0.72 (95% CI: 0.40, 1.28) for bisphenol S, and 0.76 (95% CI: 0.43, 1.33) for methylparaben. Biomarker concentrations were not strongly associated with UL growth. CONCLUSION(S): In this study of reproductive-aged Black women, urinary phenols, parabens, and triclocarban biomarkers were neither strongly nor consistently associated with UL incidence and growth.

Urine pregnancy test (UPT) hCG negative molar pregnancy: a short report from Masanga/Sierra Leone.

In Masanga, Sierra Leone, a multigravid woman presented with a urine pregnancy test negative molar pregnancy. This can be explained by the 'hook-effect'. In resource-poor settings where quantitative serum hCG cannot be determined, it is of paramount importance to remain vigilant of the diagnosis of molar pregnancy. Clinical judgement and sonography remain key in diagnosing molar pregnancy in district hospitals in low- and middle-income countries (LMICs), especially since their occurrence is much more common in these countries.

An integrated serum and urinary metabonomic research of Rhizoma Curcumae-Rhizoma Sparganii drug pair in hysteromyoma rats based on UPLC-Q-TOF-MS analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Curcumae and Rhizoma Sparganii (RCRS), a celebrated traditional Chinese medicine drug pair, has been used to treat hysteromyoma (HY). AIM OF THE STUDY: We aimed to identify the endogenous biomarkers of RCRS against HY. MATERIALS AND METHODS: HY rat model was established by injecting intramuscularly estradiol benzoate and progesterone injection from inner thigh in sequence. Body weight, uterus morphological indexes, immunohistochemistry (IHC) and hematoxylin and eosin (HE) staining experiments were used to evaluate the efficacy of RCRS (The rats were treated with RCRS extract, which was made by soxhlet reflux method. The rats were administrated intragastrically with 2 mL of RCRS extract). UPLC-Q-TOF-MS based metabonomics was adopted to analyze the serum and urine biomarkers from HY rats before and after RCRS treatment. Principle component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were utilized to identify differences of metabolic profiles in rats among the four groups. RESULTS: 16 potential biomarkers from serum and 18 potential biomarkers from urine in both positive and negative mass spectrometry detection modes were identified, primarily related to Linoleic acid metabolism and Glyoxylate and dicarboxylate metabolism. RCRS drug pair has therapeutic effects on rats with HY via the regulation of multiple metabolic pathways. CONCLUSIONS: This study provides a useful method to get insight into the integrated metabonomic mechanism of RCRS drug pair on HY rats.

Assessment of oxidant-antioxidant status alterations with tumor biomarkers and reproductive system hormones in uterine MYOMAS.

OBJECTIVES: Uterine myomas (UM) are responsible for significant morbidity and have adverse effects on quality of life in women. Reactive oxygen species (ROS) and antioxidant enzymes (AOE), as well as sex steroids play important roles in the reproductive physiology processes. Thus, we aimed to investigate the role of oxidant-antioxidant status in UM by measuring the AOE activities and lipid peroxidation (LPO) levels. This is the first study assessing these parameters together in UM based on also menopausal status and evaluating possible correlations between AOE activities, LPO markers, tumor biomarkers, female reproductive system hormone levels, comprehensively. STUDY DESIGN: The study group consisted of patients who have undergone surgical resection with confirmed pathology of uterine myoma (UM, n = 25) and divided into subgroups; premenopausal (UMpre) and postmenopausal (UMpost). Erythrocyte copper-zinc superoxide dismutase (Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GPx1) activities were measured along with plasma malondialdehyde (MDA) and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α) levels in patients with UM. The obtained data were compared to the data of healthy individuals (C, n = 25) and its subgroups; premenopausal (Cpre) and postmenopausal (Cpost). RESULTS: All AOE activities were higher (∼40% for Cu,Zn-SOD, p = 0.003; ∼55% for CAT, p = 0.001; ∼15% for GPx1, p = 0.169) and the LPO levels were lower (∼60% for MDA, p = 0.011 and ∼45% for 8-epi-PGF2α, p = 0.055) in patients with UM vs control. Approximately similar alterations were observed in UMpre vs Cpre and in UMpost vs Cpost. A significant negative correlation between erythrocyte Cu,Zn-SOD activity and plasma MDA levels (r = -0.431, p = 0.005) was reported. CONCLUSION: Decreased LPO levels might be the consequence of compensator high antioxidant enzyme activities against mild oxidative stress in the circulation of patients with UM. The marked negative correlation between erythrocyte Cu,Zn-SOD activity and plasma MDA levels also supported this finding.

In vitro effects of phthalate esters in human myometrial and leiomyoma cells and increased urinary level of phthalate metabolite in women with uterine leiomyoma.

OBJECTIVE: To investigate the possible role of phthalate, a ubiquitous chemical used in consumer products, in the pathogenesis of uterine leiomyoma. DESIGN: Experimental and prospective case-control study using human samples. SETTING: University hospital. PATIENT(S): Fifty-three women with histologic evidence of uterine leiomyoma and 33 surgical controls without leiomyoma. INTERVENTION(S): Human myometrial and leiomyoma cells were treated with di-(2-thylhexyl)-phthalate (DEHP). MAIN OUTCOME MEASURE(S): Cell viability assay and Western blot analyses after in vitro DEHP treatment; high-performance liquid chromatography electrospray ionization tandem mass spectrometry in cases and controls. RESULT(S): In vitro treatment with DEHP led to an increased viability and increased expressions of proliferating cell nuclear antigen, B-cell lymphoma 2 protein, and type I collagen in myometrial and leiomyoma cells. The urinary concentration of mono-(2-ethyl-5-carboxypentyl) phthalate was higher in women with leiomyoma compared with controls. CONCLUSION(S): These findings suggest that exposure to phthalate may play a role in the pathogenesis of uterine leiomyoma by enhancing proliferative activity, exerting an antiapoptotic effect, and increasing collagen contents in myometrial and leiomyoma cells.

Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case-Control Study.

We assessed the urinary concentration of 16 phthalate metabolites in 57 women with and without uterine leiomyoma (n = 30 and 27; respectively) to determine the association between phthalate exposure and uterine leiomyoma. To evaluate exposure to di-(2-ethylhexyl) phthalate (DEHP); we calculated the molar sum of DEHP metabolites; ∑3-DEHP (combining mono-(2-ethylhexyl) phthalate (MEHP); mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); and mono-(2-ethyl-5-oxohexyl) phthalate); ∑4-DEHP (∑3-DEHP plus mono-(2-ethyl-5-carboxypentyl) phthalate); and ∑5-DEHP (∑4-DEHP plus mono (2-(carboxylmethyl)hexyl) phthalate (2cx-MMHP)). The log transformed urinary levels of MEHP; MEHHP; 2cx-MMHP; ∑3-DEHP; ∑4-DEHP; and ∑5-DEHP in the leiomyoma group were significantly higher than those of controls. When we adjusted for age; waist circumference; and parity using multiple logistic regression analyses; we found log ∑3-DEHP (OR = 10.82; 95% CI = 1.25; 93.46) and ∑4-DEHP (OR = 8.78; 95% CI = 1.03; 75.29) were significantly associated with uterine leiomyoma. Our findings suggest an association between phthalate exposure and uterine leiomyoma. However; larger studies are needed to investigate potential interactions between phthalate exposure and uterine leiomyoma.

Follow-Up After Molar Pregnancy Evacuation: Feasibility of Using Semi-Quantitative Urine Pregnancy Tests.

OBJECTIVE: To evaluate human chorionic gonadotropin (hCG) trends after evacuation of complete hydatidiform moles to determine if urinary semiquantitative pregnancy tests (SQPTs) could replace blood draws. while still detecting early postmolar gestational trophoblastic neoplasia. STUDY DESIGN: A retrospective review of complete hydatidiform moles at a safety-net hospital from 2003-2013 was performed. hCG curves were used to extrapolate expected SQPT results over timefor a resolving hydatidiform mole. RESULTS: Of 61 complete moles, 37 had an uncomplicated hCG decline and at least 4 serum hCG results. All of those patients had hCG < 10,000 mIU/mL within 15 days, < 2,000 within 64 days, < 500 within 70 days (92.2% within 1 month), < 100 within 89 days (90% within 2 months), and < 25 within 152 days (95.2% within 3 months). After reaching levels < 25, hCG rose only in cases of new pregnancies. CONCLUSION: Based on this retrospective analysis, SQPT monitoring could have avoided 90% of blood draws while still flagging all patients with subsequent postmolar GTN within 45 days by limiting blood draws to (1) patients with SQPT levels of > 10,000, > 500, and >100 mIU/mL at 15, 30, and 45 days, respectively, (2) hCG > 25 after 60 days, or (3) increasing SQPT levels.

Phenolic environmental estrogens in urine and blood plasma from women with uterine leiomyoma: Epidemiological survey.

AIM: To explore the effect of phenolic environmental estrogens (EE) on women with uterine leiomyoma (UL). METHODS: Urine and blood plasma samples were collected from 300 patients diagnosed with UL at the Affiliated Zhongda Hospital of Southeast University between December 2013 and December 2014. Control urine and blood plasma samples were collected from 300 women who are either patients without UL or healthy volunteers presenting to the same hospital for physical examination during the same period. Bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP) concentration in these samples was measured using solid phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry. RESULTS: The OP concentration in urine and blood plasma was significantly higher in the UL group compared with the control group (r = 0.224, P = 0.001). Urine BPA concentration was not significantly different between the UL group and the control group (r = 0.009, P = 0.896). There was also no statistically significant difference in urine NP concentration between the two groups (r = 0.057, P = 0.419). On logistic regression, exposure concentration of urine BPA (OR, 1.129; 95%CI: 1.081-1.179) and NP (OR, 1.165; 95%CI: 1.025-1.324) was associated with UL genesis (P < 0.05). Nevertheless, there was no significant difference in blood plasma concentration of BPA, OP and NP between the two groups (P > 0.05). CONCLUSION: Urine and blood plasma EE exposure levels in women, especially the urine level, was related to the incidence of UL.

Urinary isoflavone and lignan phytoestrogen levels and risk of uterine fibroid in Jamaican women.

BACKGROUND: Isoflavones and lignans are phytoestrogens, and therefore, are able to bind to and activate estrogen receptors. The resultant estrogenic or antiestrogenic effect is dependent on the concentration of these phytoestrogens relative to endogenous estrogens and the site of their action, among others. Thus, isoflavones and lignans act as selective estrogen receptor modulators; having a beneficial effect in some tissues while simultaneously causing deleterious changes in others. OBJECTIVE: This case-control study investigates the relationship between urinary concentrations of genistein, daidzein, equol, and enterolactone, and the presence of uterine leiomyomas (fibroids) in Jamaican women. DESIGN: Phytoestrogen concentration in spot urine samples from 157 uterine fibroid cases and 171 fibroid-free controls diagnosed by ultrasonography, were assessed by Time-resolved Fluoroimmnoassay. Statistical evaluations were performed using SPSS 12.0. RESULTS: The median concentration of urinary enterolactone was significantly different between uterine fibroid cases and controls (p=0.029). However, this was not observed to affect risk of uterine fibroid, as trends across quartiles of urine enterolactone did not differ significantly between cases and controls. Median urinary genistein (p=0.510), daidzein (p=0.838), equol (p=0.621), total isoflavones (0.510) and total phytoestrogens (p=0.084) were similar for both groups. Binary logistic regression analysis of quartiles of urine genistein, daidzein, equol, enterolactone, total isoflavones, and total phytoestrogens showed no association with uterine fibroid. CONCLUSIONS: Uterine fibroid cases had a higher median urine concentration of enterolactone compared with controls. However, this was not observed to affect ones risk of fibroid. Neither was urine genistein, daidzein, equol total isoflavones, and total phytoestrogens observed to be associated with risk of uterine fibroid.

Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study.

Multiple trace elements have estrogen receptor activity, but the association of these elements with uterine leiomyoma has not been defined. A cohort of 473 women aged 18-44 undergoing surgery for benign gynecologic indications provided whole blood and urine specimens for trace element analysis, which was performed by inductively coupled plasma mass spectrometry. Twenty elements were analyzed in blood and 3 in urine. The surgeon documented whether fibroids were present. Geometric mean concentrations were compared between women with and without fibroids, and logistic regression models were generated to assess the impact of the concentration of each trace element on the odds of fibroids. In multivariate regressions, odds of a fibroid diagnosis were higher with increased whole blood cadmium (AOR 1.44, 95% CI 1.02, 2.04) and lead (AOR 1.31 95% CI 1.02, 1.69), and urine cobalt (AOR 1.31, 95% CI 1.02, 1.70). Urinary cadmium and lead were not related to fibroid diagnosis. Increased exposure to trace elements may contribute to fibroid growth, and fibroids may serve as a reservoir for these elements. Differences between urinary and whole blood findings merit further investigation, as urinary cadmium has been considered a superior marker of exposure.

Identification of patients with persistent trophoblastic disease after complete hydatidiform mole by using a normal 24-hour urine hCG regression curve.

OBJECTIVE: The aim of this study was to establish a reference 24-hour urine human chorionic gonadotropin (hCG) regression curve in patients with complete hydatidiform mole (CHM) as diagnostic tool in the prediction of persistent trophoblastic disease (PTD). METHODS: From 2004 to 2011, 312 cases suitable for this study were registered at the Hydatidiform Mole Registry of the Royal Women's Hospital Melbourne, Australia. hCG levels of 61 patients diagnosed as having PTD according to FIGO 2000 criteria were compared with the 95th-percentile (p95) of the normal regression curve derived from hCG levels of 251 cases of uneventful CHM. RESULTS: In the test group of 61 patients PTD was diagnosed by FIGO 2000 criteria after a mean (±SD, min.-max.) of 7.6 (±3.4, 3.0-16.7) weeks after evacuation of the mole while in the same group hCG values for the first time exceeded the upper limit of the 95th percentile significantly earlier after 4.5 (±1.9, 2.0-9.9) weeks (P<0.001). However, hCG levels of 14% of the cases of uneventful CHM at least once exceeded the upper limit of p95, showing that one single value above p95 is not accurate enough for the diagnosis of PTD. CONCLUSIONS: The normal 24-hour urine hCG regression curve may be used as a tool in the follow-up of an individual case of CHM after evacuation. At least one hCG level exceeding the upper limit of p95 within 11weeks after evacuation could be added to the current FIGO criteria, in order to diagnose PTD early, but the lack of it may also prevent unnecessary treatment.

Measurement of phenolic environmental estrogens in human urine samples by HPLC-MS/MS and primary discussion the possible linkage with uterine leiomyoma.

A method was established for the determination of three phenolic environmental estrogens, namely bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP), in urine from women of uterine leiomyoma group (n=49) and control group (n=29), by using solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Urine samples were spiked with 2,4,6-tribromophenyl-terminated tetrabromobisphenol-A carbonate oligomer (TBBPA) and nonylphenol D8 (NP-D8) as internal standard (I.S.) and de-conjugated by adding ß-glucuronidase and sulfatase before the SPE. The extraction recoveries of BPA, NP and OP were more than 73.3%; the standard curve was linear over the validated concentrations in the range of 1.0-100.0ng/mL and the limits of detection (LOD) of BPA, NP and OP were 0.32ng/mL, 0.18ng/mL and 0.15ng/mL, respectively. Moreover, by analysing quality control urine samples in 5 days, the results showed that the method was precise and accurate, for the intra- and inter-day CV% within 15.2%. Except that OP was not found (3). NP levels were significantly higher in uterine leiomyoma patients than control group in low gravidity subgroup. Though BPA levels in experimental and control groups were not significantly different, the mean levels and concentration distribution were different. The study suggested that there is certain relationship between exposure concentrations of phenolic environmental estrogens and uterine leiomyoma disease.

The need for an hCG assay that appropriately detects trophoblastic disease and other hCG-producing cancers.

This report was conceived at the 13th World Congress of Gestational Trophoblastic Disease after multiple presentations indicated widespread discrepancies in human chorionic gonadotropin (hCG) use and results. There appears to be a need for a discussion to describe the advantages and limitations of commonly used hCG tests in the management of gestational trophoblastic disease, and to monitor testicular, germ cell and other hCG-producing malignancies. In most countries hCG tests are certified only for pregnancy testing. Use in managing gestational trophoblastic diseases and other malignancies is considered an "off-label" use. Tests are not optimized or calibrated for these applications, and their use and the results therefore have to be considered experimental. Widespread variations in results occur and may lead to needless or inappropriate therapy. It therefore seems important for laboratory directors and treating physicians to familiarize themselves with which hCG test their laboratory is using and, if necessary, to contract an external laboratory for measuring hCG in the management of gestational trophoblastic disease and cancer.

Endogenous urinary steroids in premenopausal women with uterine leiomyomas.

OBJECTIVES: To study the effect of endogenous steroids on the presence of uterine leiomyomas. METHODS: Urine samples of 27 premenopausal women with leiomyomas and 25 age-matched healthy premenopausal women were collected. The concentration of estrogens and androgens in the urine samples of the two groups were determined using a gas chromatography mass spectrometer and the two groups were compared. To study metabolic changes in patients indirectly, the concentration ratios of precursor metabolite to product metabolite of the two groups were also compared. RESULTS: Urinary concentrations of 17beta-estradiol, 5-androstene-3beta, 16beta, 17beta, triol, 11-keto-ethiocholanolone, 11beta-hydroxy-androsterone, 11beta-hydroxy-etiocholanolone, THS, THA, THE, alpha-cortol and beta-cortol were significantly higher in patients than in controls. The concentration ratios of 17beta-estradiol/estrone and 11/beta-hydroxy-ethiocholanolone/11beta-hydroxy-androsterone increased in patients. CONCLUSIONS: The presence of uterine leiomyomas correlates with an increase in urinary concentrations of estrogens and androgens, and it appears to be caused by a decrease in patients' metabolism of steroids.

Persistent low-level "real" human chorionic gonadotropin: a clinical challenge and a therapeutic dilemma.

OBJECTIVE: The finding of persistent low-level human chorionic gonadotropin (hCG) with or without a preceding pregnancy event presents a rare but clinically important challenge and a therapeutic dilemma. These are patients with "real" hCG shown by the positive test in both serum and urine or by specialized testing. The problems associated with "phantom" hCG have been recognized and should now be clinically resolvable. Four cases of low-level "real" hCG are described to illustrate the problems encountered, the management, and the resolution achieved. METHODS: Two patients presented with persistent low-level hCG after hydatidiform mole pregnancy, one after an early pregnancy loss and one as amenorrhea and irregular bleeding. A detailed clinical description is provided to illustrate the difficulties encountered. RESULTS: All patients have real hCG. The hCG level of Patient 1 was responsive to hormonal contraception and disappeared with such medication. Over a period of 3 years hCG reappeared whenever estrogen was stopped. Patient 2 achieved two pregnancies and the hCG subsequently disappeared. The hCG in Patient 3 persisted over a period of 6 years although she is now menopausal. Patient 4 developed metastatic placental site trophoblastic tumor after 2 1/2 years of observation of low-level hCG. CONCLUSIONS: The finding of unexplainable low-level hCG in a patient without evidence of a uterine lesion or of trophoblastic metastases provides a therapeutic challenge. The administration of single-agent chemotherapy had no effect on the level of hCG in the three patients to whom it was administered. The administration of multiple-agent chemotherapy appears unjustified in the absence of a demonstrable trophoblastic tumor. A small number of trophoblastic cells must be providing this hCG and these cells may be quiescent for years. Nevertheless these cells may proliferate and manifest themselves as trophoblastic tumor. Continuing long-term surveillance of these patients is necessary.

Capillary electrophoretic profiling and pattern recognition analysis of urinary nucleosides from uterine myoma and cervical cancer patients.

Capillary electrophoretic (CE) profiling analysis combined with pattern recognition methods is described for the correlation between urinary nucleoside profiles and uterine cervical cancer. Nucleosides were extracted from urine specimens by solid-phase extraction in affinity mode using phenylboronic acid gel. CE separation was carried out with an uncoated fused-silica capillary (570 mm x 50 microm I.D.) maintained at 20 degrees C, using 25 mM borate-42.5 mM phosphate buffer (pH 6.7) containing 200 mM sodium dodecyl sulfate as the run buffer under the applied voltage of 20 kV. A total of 15 nucleosides were positively identified in urine samples (2 ml) from eight uterine myoma (benign tumor group), 10 uterine cervical cancer (malignant tumor group) patients and 10 healthy females (normal group) studied. The star symbol plots drawn based on each mean concentration of nucleosides normalized to that in normal group enabled one to discriminate malignant and benign groups from normal group. In addition, canonical discriminant analysis performed on the nucleoside data of 28 individual urine specimens correctly classified into three separate clusters according to groups in the canonical plot.

Following metastatic placental site trophoblastic tumor with urine beta-core fragment.

OBJECTIVE: We document a case with metastatic placental site trophoblastic tumor in a 47-year-old postmenopausal women. METHODS: beta-core fragment was measured in urine using the Triton UGP kit. hCG was also measured using the Bayer Immuno-1hCG assay (at Memorial Sloan-Kettering Cancer Center). RESULTS: Over 2 years the patient underwent two courses of chemotherapy and two debulking operations. During this time, hCG levels decreased from 227 to 4.1 mIU/ml. hCG levels were close to the limit of detection (<3 mIU/ml), indicating complete or near-complete regression of disease. At this point urine beta-core fragment levels were determined. High levels were detected 7.9 fmol/ml, consistent with the continued existence of tumor (>1.9 fmol/ml). High-dose chemotherapy (CEM) was started with stem cell harvesting. In the following weeks hCG levels failed to identify the tumor (4.1 to <3 mIU/ml). In the first week (during therapy) beta-core fragment levels increased (12 fmol/ml), and in the following weeks (after therapy) levels regressed to 1.2 fmol/ml. CONCLUSION: Urine beta-core fragment may be a useful tumor maker when serum hCG levels are near to or below the limit of detection.