To examine the contributions of obesity and race to levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in a defined cohort of black and white women.
An interventional study was conducted from October 2004 to March 2008, among 219 healthy female volunteers. Serum 25(OH)D and PTH levels were determined in 117 African American women and 102 white women and the results were compared with body mass index (BMI), percentage body fat, serum lipids, and PTH levels.
Black women had lower median levels of 25(OH)D compared with white women (27.3 nmol/L vs 52.4 nmol/L; P<0.001). Serum levels of 25(OH)D below 50 nmol/L were found in 98% of black women and 45% of white women (P<0.001). The differences between the racial groups in the levels of 25(OH)D persisted despite adjustments for body weight, percentage body fat, and BMI. Black women had higher median serum levels of PTH than white women (31.9 pg/mL vs 22.3 pg/mL; P<0.01).
African American women are at significant risk for low vitamin D levels. Studies are needed to determine if low vitamin D status in young African American women is associated with a greater risk for vitamin D-related chronic diseases that can be reduced with vitamin D supplementation.
25-hydroxyvitamin D; Obesity; Parathyroid hormone; Race; Vitamin D
Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life. (Fertil Steril® 2011;95:2595–8.©2011 by American Society for Reproductive Medicine.)
Ovarian function; insulin action; nutrition; exercise; androgen
Premarin (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase-immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17β-estradiol (17β-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17β-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, but does not increase ChAT-IR neuron number in basal forebrain, as does 17β-E2. Thus, data from prior studies suggest that 17β-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens.
estrone; 17β-estradiol; estrogen; Premarin; working memory; spatial memory; basal forebrain; choline acetyltransferase
Lower serum vitamin D (25(OH)D) among individuals with African ancestry is attributed primarily to skin pigmentation. However, the influence of genetic polymorphisms controlling for skin melanin content has not been investigated. Therefore, we investigated differences in non-summer serum vitamin D metabolites according to self-reported race, genetic ancestry, skin reflectance and key pigmentation genes (SLC45A2 and SLC24A5).
Materials and Methods
Healthy individuals reporting at least half African American or half European American heritage were frequency matched to one another on age (+/− 2 years) and sex. 176 autosomal ancestry informative markers were used to estimate genetic ancestry. Melanin index was measured by reflectance spectrometry. Serum vitamin D metabolites (25(OH)D3, 25(OH)D2 and 24,25(OH)2D3) were determined by high performance liquid chromatography (HPLC) tandem mass spectrometry. Percent 24,25(OH)2D3 was calculated as a percent of the parent metabolite (25(OH)D3). Stepwise and backward selection regression models were used to identify leading covariates.
Fifty African Americans and 50 European Americans participated in the study. Compared with SLC24A5 111Thr homozygotes, individuals with the SLC24A5 111Thr/Ala and 111Ala/Ala genotypes had respectively lower levels of 25(OH)D3 (23.0 and 23.8 nmol/L lower, p-dominant=0.007), and percent 24,25(OH)2D3 (4.1 and 5.2 percent lower, p-dominant=0.003), controlling for tanning bed use, vitamin D/fish oil supplement intake, race/ethnicity, and genetic ancestry. Results were similar with melanin index adjustment, and were not confounded by glucocorticoid, oral contraceptive, or statin use.
The SLC24A5 111Ala allele was associated with lower serum vitamin 25(OH)D3 and lower percent 24,25(OH)2D3, independently from melanin index and West African genetic ancestry.
African Continental Ancestry Group; European Continental Ancestry Group; SLC24A5; 25-hydroxyvitamin D; 24,25-Dihydroxyvitamin D 3
Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes.
We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism.
We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/− 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels.
All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH-cortisol relationship was maintained for TSH levels (uIU/L) ≤4.0, ≤3.5, ≤3.0, and ≤2.5 but not ≤2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels.
Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study.
TSH; Free T3; Free T4; Cortisol; Subclinical hypothyroidism
To estimate racial disparities in PCOS phenotype between White and Black women with PCOS.
Two academic medical centers
242 women off of confounding medications in otherwise good health
Phenotyping during the follicular phase or anovulation after overnight fast in women.
Main outcome measures
Biometric, serum hormones, glycemic and metabolic parameters, and body composition by DEXA.
We studied 77 White and 43 Black women with PCOS and 35 White and 87 Black controls. Black women with PCOS were very similar reproductively to White women with PCOS. Black women with PCOS had lower serum transaminases, higher HDL-C levels[mean difference (MD): 18.2; 95% CI: (14.3, 22.1) mg/dL], lower triglycerides(MD: -43.2 mg/dL; 95% CI: (-64.5, -21.9)), and enhanced insulinogenic index on the oral glucose tolerance test compared to White women with PCOS. Blacks with PCOS had higher bone mineral density(MD: 0.1 g/cm2; 95% CI: (0.1, 0.2)) and lower percent body fat on DXA (MD: -2.8%; 95% CI:(-5.1, - 0.5)), and overall a higher quality of life. While most of these findings disappeared when the differences with racially matched controls were compared, Black women with PCOS compared to Black controls had lower estradiol levels than White PCOS women compared to White controls(MD: -12.9 pg/mL; 95% CI: (-24.9, -0.8)), higher systolic blood pressure(MD: 9.1 mm Hg; 95% CI: (0.8, 17.4)), and lower fasting glucose levels(MD: -12.0 mg/dL; 95% CI: (-22.3, - 1.7)).
Racial disparities in PCOS phenotype are minor and mixed. Future studies should explore if race impacts on treatment effects.
In order to determine the effects of statins on vascular function, inflammation and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had LDL-cholesterol levels >100 mg/dl to atorvastatin (40 mg/day) or placebo for six weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure, increased insulin levels and brachial artery conductance during reactive hyperemia, and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in PCOS women who meet current indications for statin treatment.
statin; PCOS; hyperandrogenemia; vascular function; hyperinsulinemia
The results of a phase I/II study on the use of vaginal testosterone to treat vaginal atrophy in women with breast cancer taking aromatase inhibitors are presented. A 4-week course improved signs and symptoms without increasing estradiol or testosterone levels.
After completing this course, the reader will be able to:
Evaluate early data regarding the impact of daily vaginal testosterone on estradiol and testosterone levels in breast cancer patients receiving treatment with aromatase inhibitors.Explain the potential clinical benefits of vaginal testosterone therapy to treat vaginal atrophy in women with breast cancer receiving long-term aromatase inhibitor therapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Controversy exists about whether vaginal estrogens interfere with the efficacy of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal atrophy in patients on AIs, a safe and effective nonestrogen therapy is necessary. We hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs.
Twenty-one postmenopausal breast cancer patients on AIs with symptoms of vaginal atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days. Ten women received a dose of 300 μg, 10 received 150 μg, and one was not evaluable. Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations with pH and vaginal cytology were compared before and after therapy.
Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total symptom scores improved from 2.0 to 0.7 after treatment (p < .001) and remained improved 1 month thereafter (p = .003). Dyspareunia (p = .0014) and vaginal dryness (p <.001) improved. The median vaginal pH decreased from 5.5 to 5.0 (p = .028). The median maturation index rose from 20% to 40% (p < .001). Although improvement in total symptom score was similar for both doses (−1.3 for 300 μg, −0.8 for 150 μg; p = .37), only the 300-μg dose was associated with improved pH and maturation values.
A 4-week course of vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels. Longer-term trials are warranted.
Aromatase inhibitors; Breast neoplasms; Testosterone; Vaginitis; Estradiol; Contraindications
To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls.
This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia.
Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P < 0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P = 0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P < 0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels.
Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.
polycystic ovary syndrome; androgen excess; brachial artery; conductance; cardiovascular risk
To determine if the combination of lifestyle(caloric restriction and exercise) and metformin(MET) would be superior to placebo and lifestyle(PBO) in improving PCOS phenotype.
Double-blind randomized 6 month trial of MET vs PBO
Two academic medical centers
Subjects collected urines daily for ovulation monitoring, had monthly monitoring of hormones/weight, and determination of body composition by DXA, glucose tolerance, and quality of life at baseline and completion.
Main outcome measures
Ovulation rates and testosterone levels
Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared to baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 mos compared to baseline(−3.4 kg, 95% CI:(−5.3, −1.5)). We noted divergent effects of MET vs PBO on OGTT indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density (BMD) increased significantly in MET. There were no differences in QOL measures between groups. MET had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints.
The addition of metformin to lifestyle produced little reproductive or glycemic benefit in women with PCOS, though our study had limited power due to high dropout. It is not possible at baseline to identify women likely to drop out.
ovarian function; insulin action; nutrition; exercise; androgen
In an attempt to evaluate the association between Allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating TGF-β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8− PCOS) to 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8− Non-PCOS). A8−PCOS is associated with higher levels of TGF-β1 compared to A8+ PCOS or A8− Non-PCOS, similar levels of TGF-β2 compared to A8+ PCOS but lower levels of TGF-β2 compared to A8− Non-PCOS, and lower levels of Inhibin B and aldosterone compared to A8+ PCOS.
polycystic ovary syndrome; TGF-β; inhibin; fibrillin; genetic association study; hyperandrogenism; insulin resistance
This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05–20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated.
Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts.
F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
IGF-1R; Figitumumab; CP-751,871; NSCLC
Advanced pancreatic cancer carries the poorest prognosis of all gastrointestinal malignancies. Once the tumor has spread beyond the margins of the pancreas, chemotherapy is the major treatment modality offered to patients; however, chemotherapy does not significantly improve survival.
Opioid growth factor (OGF; [Met5]-enkephalin) is a natural peptide that has been shown to inhibit growth of pancreatic cancer in cell culture and in nude mice. The purpose of this study was to evaluate the effects of OGF biotherapy on subjects with advanced pancreatic cancer who failed chemotherapy.
In a prospective phase II open-labeled clinical trial, 24 subjects who failed standard chemotherapy for advanced pancreatic cancer were treated weekly with OGF 250 µg/kg intravenously. Outcomes measured included clinical benefit, tumor response by radiographic imaging, quality of life, and survival.
Clinical benefit response was experienced by 53% of OGF-treated patients compared to historical controls of 23.8% and 4.8% for gemcitabine and 5-fluorouracil (5-FU), respectively. Of the subjects surviving more than eight weeks, 62% showed either a decrease or stabilization in tumor size by computed tomography. The median survival time for OGF-treated patients was three times that of untreated patients (65.5 versus 21 days, p < 0.001). No adverse effects on hematologic or chemistry parameters were noted, and quality of life surveys suggested improvement with OGF.
Measurements other than survival were not allowed in control patients, and clinical benefit comparisons were made to historical controls.
OGF biotherapy improves the clinical benefit and prolongs survival in patients with pancreatic cancer by stabilizing disease or slowing progression. The effects of OGF did not adversely alter patient quality of life. The use of OGF biotherapy at earlier stages of disease or in combination with other chemotherapeutic agents may further improve the outcome of this malignancy.
phase II; pancreatic cancer; biotherapy; quality of life
To determine the effect of meal composition on postprandial testosterone levels in women with polycystic ovary syndrome (PCOS).
Randomized, crossover design.
Academic research center.
Fifteen women with PCOS.
We evaluated changes in testosterone, sex hormone binding globulin (SHBG), DHEA-S, cortisol, glucose, and insulin for six hours after a high-fat, Western meal (HIFAT) (62% fat, 24% carbohydrate, 1g fiber) and an isocaloric low-fat, high-fiber meal (HIFIB) (6% fat, 81% carbohydrate, 27g fiber).
Main outcome measure
Change in testosterone.
Testosterone decreased 27% within two hours after both meals (P<0.001). However, testosterone remained below premeal values for four hours after the HIFIB meal (P<0.004) and six hours after the HIFAT meal (P<0.004). Insulin was two fold higher for two hours after the HIFIB meal compared with the HIFAT meal (P<0.03). Glucose was higher for one hour after the HIFIB meal compared with the HIFAT meal (P<0.003). DHEA-S decreased 8−10% within 2−3 hours after both meals, then increased over the remainder of the study period (P<0.001). Cortisol decreased over the 6-hour period after both meals (P<0.001).
Diet plays a role in the regulation of testosterone levels in women with PCOS. Further studies are needed to determine the role of diet composition in the treatment of PCOS. (ClinicalTrials.gov Identifier: NCT0455338).
insulin resistance; hyperandrogenism; postprandial; testosterone; fiber
Conjugated equine estrogen (CEE) is the most commonly prescribed estrogen therapy, and is the estrogen used in the Women's Health Initiative study. While in-vitro studies suggest that CEE is neuroprotective, no study has evaluated CEE's effects on a cognitive battery and brain immunohistochemistry in an animal model. The current experiment tested whether CEE impacted: I) spatial learning, reference memory, working memory and long-term retention, as well as ability to handle mnemonic delay and interference challenges; and, II) the cholinergic system, via pharmacological challenge during memory testing and ChAT-immunoreactive cell counts in the basal forebrain. Middle-aged ovariectomized (Ovx) rats received chronic cyclic injections of either Oil (vehicle), CEE-Low (10 μg), CEE-Medium (20 μg) or CEE-High (30 μg) treatment. Relative to the Oil group, all three CEE groups showed less overnight forgetting on the spatial reference memory task, and the CEE-High group had enhanced platform localization during the probe trial. All CEE groups exhibited enhanced learning on the spatial working memory task, and CEE dose-dependently protected against scopolamine-induced amnesia with every rat receiving the highest CEE dose maintaining zero errors after scopolamine challenge. CEE also increased number of ChAT-immunoreactive neurons in the vertical diagonal band of the basal forebrain. Neither the ability to remember after a delay nor interference, nor long-term retention, was influenced by the CEE regimen used in this study. These findings are similar to those reported previously for 17 ß-estradiol, and suggest that CEE can provide cognitive benefits on spatial learning, reference and working memory, possibly through cholinergic mechanisms.
estrogen; hormone replacement; learning; working memory; spatial memory; reference memory
To examine the relationship of male obesity and reproductive function.
Academic medical center
87 adult males, body mass index (BMI) range from 16.1 to 47.0 kg/m2 (mean = 29.3 kg/m2 ,SD=6.5 kg/m2).
Main Outcome Measures
Reproductive history, physical examination, inhibin B, FSH, LH, testosterone, unbound testosterone (uT) levels and semen-analysis.
BMI was negatively correlated with testosterone (R = −0.38, P <0.001), FSH (R = −0.22, P = 0.042) and inhibin B levels (R = −0.21, P = 0.048), and was positively correlated with estradiol levels (R = 0.34, P = 0.001). Testosterone also negatively correlated with skin fold thickness (SFT) (R = −0.30, P = 0.005). There was no correlation of BMI or SFT with semen-analysis parameters (sperm density, volume, motility or morphology). Inhibin B level correlated significantly with sperm motility (R = 0.23, P = 0.045). Males with paternity had lower BMIs (28.0 kg/m2 vs. 31.6 kg/m2; P = 0.037) and lower SFT (24.7 mm vs. 34.1 mm; P = 0.016) than males without.
Obesity is an infertility factor in otherwise normal males. Obese males demonstrate a relative hypogonadotropic hypogonadism. Reduced inhibin B levels and diminished paternity suggest compromised reproductive capacity in this population.
Male infertility; inhibin B; semen; body fat distribution
To test for associations between urine markers, bladder biopsy features and bladder ulcers in interstitial cystitis/painful bladder syndrome (IC/PBS).
Materials and Methods
Subjects were 72 patients with IC/PBS undergoing bladder distention and biopsy. Urine was collected before the procedure. Urine marker levels were correlated with biopsy and cystoscopic findings. Patients with no previous IC/PBS treatments (n=47) were analyzed separately from previously treated patients (n=25).
For untreated patients, urine IL-6 and cGMP were associated with urothelial EGF receptor staining (for IL-6 r=0.29, 95% CI (0.07, 0.51), p=0.01; for cGMP r=0.34, 95% CI (0.13, 0.55), p=0.002). Urine IL-8 was negatively associated with urothelial HB-EGF staining (r=-0.34, 95% CI (-0.55, -0.12), p=0.002) and positively associated with lamina propria mast cell count (r=0.29, 95% CI (0.06, 0.52), p=0.01). The latter association also was seen in treated patients (r=0.46, 95% CI (0.20, 0.73), p<0.001). None of the urine markers was significantly different for ulcer vs. nonulcer patients. All of the ulcer patients had extensive inflammation on bladder biopsy: severe mononuclear cell infiltration, moderate or strong IL-6 staining in the urothelium and lamina propria, and LCA staining in >10% of the lamina propria. However, these features also were seen in 24-76% of the nonulcer patients.
Overall, urine markers did not associate robustly with biopsy findings. The strongest association was a positive association between urine IL-8 levels and bladder mast cell count. Ulcer patients consistently had bladder inflammation, but the cystoscopic finding of ulcers was not a sensitive indicator of inflammation on bladder biopsy.
interstitial cystitis, urine; interstitial cystitis, pathology; interstitial cystitis, physiopathology
To evaluate changes in urine markers and symptom scores after bladder distention in interstitial cystitis (IC) patients.
Materials and Methods
Subjects were 33 new patients with no prior IC treatments. Urine specimens were taken before and one month after bladder distention. University of Wisconsin (UW) symptom scores were done the same day as the urine specimen collection. Urine marker levels and symptom scores before and after distention were compared. Changes in markers were tested for associations with changes in symptom scores and other markers. Pre-distention markers and specific pre-distention symptoms were tested for their association with post-distention symptom improvement.
After distention, the median total UW score decreased significantly (28.5 before, 10 after, p<0.001). Twelve patients (36%) had at least 30% improvement in UW score, and eight patients (24%) had at least 50% improvement. No pre-distention markers or symptoms predicted which patients would have a good response. Two of the urine markers improved significantly after distention: anti-proliferative factor (APF) activity (median −96% before, −17% after, p< 0.001) and heparin binding-epidermal growth factor-like growth factor (HB-EGF) levels (median 0.34 ng/mg creatinine before, 4.1 after, p<0.001). None of the changes in urine markers associated with changes in symptom scores.
The median symptom score for newly diagnosed IC patients decreased after distention, but only a minority of patients had at least 30% symptom improvement. Bladder distention altered urine APF activity and HB-EGF levels towards normal, but the mechanism of symptom relief after distention is still unknown.
interstitial cystitis, urine; interstitial cystitis, surgery; interstitial cystitis, therapy; interstitial cystitis, physiopathology
Polyamines affect proliferation, differentiation, migration and apoptosis of cells, indicating their potential as a target for cancer chemotherapy. Ornithine decarboxylase converts ornithine to putrescine and is the rate-limiting step in polyamine synthesis.
α-Difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase and MDA-MB-435 human breast cancer metastasis to the lung without blocking orthotopic tumor growth. This study tested the effects of DFMO on orthotopic tumor growth and lung colonization of another breast cancer cell line (MDA-MB-231) and the effects on bone metastasis of MDA-MB-435 cells.
MDA-MB-231 cells were injected into the mammary fat pad of athymic mice. DFMO treatment (2% per orally) began at the day of tumor cell injection or 21 days post injection. Tumor growth was measured weekly. MDA-MB-231 cells were injected into the tail vein of athymic mice. DFMO treatment began 7 days prior to injection, or 7 or 14 days post injection. The number and incidence of lung metastases were determined. Green fluorescent protein-tagged MDA-MB-435 cells were injected into the left cardiac ventricle in order to assess the incidence and extent of metastasis to the femur. DFMO treatment began 7 days prior to injection.
DFMO treatment delayed MDA-MB-231 orthotopic tumor growth to a greater extent than growth of MDA-MB-435 tumors. The most substantial effect on lung colonization by MDA-MB-231 cells occurred when DFMO treatment began 7 days before intravenous injection of tumor cells (incidence decreased 28% and number of metastases per lung decreased 35–40%). When DFMO treatment began 7 days post injection, the incidence and number of metastases decreased less than 10%. Surprisingly, treatment initiated 14 days after tumor cell inoculation resulted in a nearly 50% reduction in the number of lung metastases without diminishing the incidence. After intracardiac injection, DFMO treatment decreased the incidence of bone metastases (55% vs 87%) and the area occupied by the tumor (1.66 mm2 vs 4.51 mm2, P < 0.05).
Taken together, these data demonstrate that DFMO exerts an anti-metastatic effect in more than one hormone-independent breast cancer, for which no standard form of biologically-based treatment exists. Importantly, the data show that DFMO is effective against metastasis to multiple sites and that treatment is generally more effective when administered early.