Chemokine Ligand 20: A Signal for Leukocyte Recruitment During Human Ovulation?

Ovulation is one of the cornerstones of female fertility. Disruption of the ovulatory process results in infertility, which affects approximately 10% of couples. Using a unique model in which the dominant follicle is collected across the periovulatory period in women, we have identified a leukocyte chemoattractant, chemokine ligand 20 (CCL20), in the human ovary. CCL20 mRNA is massively induced after an in vivo human chorionic gonadotropin (hCG) stimulus in granulosa (>10 000-fold) and theca (>4000-fold) cells collected during the early ovulatory (12-18 h) and late ovulatory (18-34 h) periods after hCG administration. Because the LH surge sets in motion an inflammatory reaction characterized by an influx of leukocytes and CCL20 is known to recruit leukocytes in other systems, the composition of ovarian leukocytes (CD45+) containing the CCL20 receptor CCR6 was determined immediately prior to ovulation. CD45+/CCR6+ cells were primarily natural killer cells (41%) along with B cells (12%), T cells (11%), neutrophils (10%), and monocytes (9%). Importantly, exogenous CCL20 stimulated ovarian leukocyte migration 59% within 90 minutes. Due to the difficulties in obtaining human follicles, an in vitro model was developed using granulosa-lutein cells to explore CCL20 regulation. CCL20 expression increased 40-fold within 6 hours after hCG, was regulated partially by the epithelial growth factor pathway, and was positively correlated with progesterone production. These results demonstrate that hCG dramatically increases CCL20 expression in the human ovary, that ovarian leukocytes contain the CCL20 receptor, and that CCL20 stimulates leukocyte migration. Our findings raise the prospect that CCL20 may aid in the final ovulatory events and contribute to fertility in women.

Tranexamic acid increases hemoglobin and ferritin levels in women with heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is the most common cause of iron deficiency anemia (IDA) in women. A novel, modified-release oral formulation of tranexamic acid (TA) designed to reduce gastrointestinal side effects was approved recently for treatment of HMB. We assessed improvements in objective laboratory measures of IDA in women with self-reported HMB who received long-term TA therapy. METHODS: Women enrolled in a long-term, open-label, multicenter study self-medicated with TA 3.9 g/day administered as 1.3 g orally up to three times daily for 5 days/menstrual cycle for 27 cycles. Oral iron therapy was required if serum hemoglobin (Hgb) levels decreased to <11 g/dL. RESULTS: A total of 723 women (mean age 38.3 years) were included in the intent-to-treat (ITT) population. Significant increases in mean serum Hgb and ferritin were observed throughout the study (p<0.01). Among 191 patients with low Hgb (<12 g/dL) at baseline, mean serum Hgb increased by ≥0.71 g/dL after the third cycle and all subsequent assessments (p<0.001). After 3 and 27 cycles, 34.1% and 45.7%, respectively, of patients with low Hgb at baseline shifted to within normal range, respectively. Among 233 patients with low ferritin (<10 ng/mL) at baseline, mean serum ferritin increased by >5.38 ng/mL after cycles 15 and 27. After 6 and 27 cycles, 35.2% and 58% of patients, respectively, with low ferritin levels at baseline shifted to within normal range. CONCLUSIONS: Long-term self-medication with this novel TA formulation improved Hgb and ferritin levels in women with self-reported HMB.

Long-term evaluation of safety and health-related quality of life in women with heavy menstrual bleeding treated with oral tranexamic acid.

AIMS: A multicenter, long-term, open-label study was conducted to assess the safety and health-related quality of life (HRQoL) of an oral tranexamic acid (TA) formulation in women with cyclic heavy menstrual bleeding (HMB). MATERIALS & METHODS: Following a screening menstrual cycle, women with a history of cyclic HMB initiated 27 cycles of treatment with TA 1.3 g administered three-times daily for up to 5 days per menstrual cycle (maximum of 15 doses). Safety was assessed by treatment-emergent adverse event (TEAE) monitoring, physical examinations, laboratory results, ophthalmologic examinations and electrocardiography. HRQoL was evaluated using both generic and HMB-specific instruments. RESULTS: Most of the TEAEs were mild to moderate in severity and were largely considered unrelated to study treatment. The most commonly reported TEAEs among women in the intent-to-treat population (n = 723) were headache, menstrual discomfort and back pain. Improvements in generic and disease-specific HRQoL measures were evident during the first treatment cycle and were maintained throughout the 15 cycles of measurement for most domains. CONCLUSION: Long-term TA treatment was well tolerated and improved measures of HRQoL in women with cyclic HMB.

Estimating a meaningful reduction in menstrual blood loss for women with heavy menstrual bleeding.

OBJECTIVE: A dichotomy exists within the treatment of heavy menstrual bleeding (HMB); guidelines and expert opinion recommend that clinical management be guided by subjective, patient-centered measures, yet clinical trials often describe treatment efficacy in terms of objective reductions in menstrual blood loss (MBL). The purpose of this investigation was to correlate subjective and objective aspects of HMB treatment by identifying the minimum change in MBL that would be considered meaningful to women. RESEARCH DESIGN AND METHODS: Receiver operating characteristic (ROC) curve analyses were performed using data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of a novel, oral formulation of tranexamic acid (Lysteda). The study enrolled women ages 18-49 years with a history of cyclic HMB. Menstrual blood loss was measured objectively using the alkaline hematin method and subjectively using the Menorrhagia Impact Questionnaire (MIQ), a patient-reported outcome instrument previously validated in an HMB population. Additional subgroup analyses were performed after stratification by low (80-160 mL/cycle) or high (> 160 mL/cycle) baseline MBL. CLINICAL TRIAL REGISTRATION: NCT00401193 (NIH Clinical Trials Registry) RESULTS: A total of 278 women were included in the ROC analyses. The best balance of sensitivity and specificity was achieved for predicting a patient-perceived meaningful improvement in MBL, at a cut point of 36 mL/cycle. Absolute reductions in MBL that were considered meaningful were more modest in women with lower baseline MBL (22 mL/cycle) and greater in women with higher baseline MBL (47 mL/cycle). However, an approximately 22% MBL reduction was meaningful to the majority of women in either the low or high baseline MBL subgroups. CONCLUSIONS: Reducing measurable MBL by 36 mL/cycle, or approximately 22%, was considered to be a meaningful improvement for the majority of women with HMB in this study population.

Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding. METHODS: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument. RESULTS: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of -69.6 mL (40.4%) compared with -12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo. CONCLUSION: In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308. LEVEL OF EVIDENCE: I.

The effects of progestins on bone density and bone metabolism in postmenopausal women: a randomized controlled trial.

OBJECTIVE: The purpose of this study was to evaluate the action of progestins on bone metabolism in early menopausal women. STUDY DESIGN: One hundred thirty-two menopausal women were randomized into a 2-year double-blinded, placebo-controlled clinical trial. There were 6 treatment groups: micronized progesterone (P 4 ) 300 mg/day; medroxyprogesterone acetate (MPA) 10 mg/day; norethindrone (NET) 1 mg/day; micronized estradiol (E 2 ) 1 mg/day; E 2 1 mg/day + MPA 10 mg/day; and placebo. All subjects received 1000 mg of calcium and 400 IU of vitamin D/day. Primary outcome variables were bone mineral density (BMD) changes at the spine and hip. Secondary variables were bone turnover markers. RESULTS: With E 2 or E 2 +MPA treatment, BMD at L2-L4 increased by 2% to 4% over 2 years. Bone mineral density (BMD) at the spine followed a decreasing trend with MPA, P 4 , and placebo treatments. With NET treatment, BMD did not change from baseline. At the femoral neck site, BMD did not change significantly for any treatment group. Bone resorption and bone formation markers decreased with E 2 or E 2 +MPA treatment, and did not change appreciably with all 3 progestin-alone treatments. There were no vertebral or hip fractures observed during the trial. CONCLUSION: Estrogen remains the primary bone active agent in hormone therapy, while progestins have significantly less activity. The selection of the appropriate progestin in hormone therapy should be based on criteria other than bone activity.

Urinary beta-FSH subunit concentrations in perimenopausal and postmenopausal women: a biomarker for ovarian reserve.

OBJECTIVE: The purpose of this study was to develop an integrative assessment of pituitary follicle-stimulating hormone (FSH) secretion and to validate these measurements in a population of perimenopausal (PERI) and postmenopausal (POST) women. DESIGN: In this cross-sectional study, 170 POST and 20 PERI women collected first-void morning urine samples and had a single blood sample drawn on the same day. For comparison, 11 midreproductive-aged women had urine samples collected for one menstrual cycle. In addition, one 48.5-year-old woman collected daily urine samples for 4 consecutive years during her menopausal transition. Urine samples were assayed for estrone glucuronide (E1G) and pregnanediol-3-glucuronide (PdG) and were normalized to creatinine. An ELISA assay was developed for measurement of the free beta-FSH subunit in urine. RESULTS: Mean age (+/- SD) of the PERI and POST women were 48.1 +/- 3.0 and 52.8 +/- 4.1 years, respectively. Mean serum FSH levels were 9.5 +/- 5.8 and 79.3 +/- 32 IU/L (P < 0.001) in the PERI and POST women. Mean urinary beta-FSH/Cr for the PERI were 1.8 +/- 1.2 ng/mg; for the POST, 9.3 +/- 4.5 ng/mg (P < 0.001). Mean estradiol, E1G/Cr, and PdG/Cr levels were also significantly different between the two groups. There was a high correlation between serum FSH and urinary beta-FSH/Cr for the PERI (r = 0.584, P = 0.007) and POST (r = 0.54, P < 0.001), with minimal overlap in the urinary beta-FSH/Cr levels between the PERI and POST groups. A significant correlation between PdG/Cr and urinary beta-FSH/Cr was observed for POST (r = 0.581, P = 0.002). No correlation was seen between urinary beta-FSH/Cr and E1G/Cr or estradiol levels. In the perimenopausal participant, who collected 4 years of daily urine samples, urinary beta-FSH/Cr levels progressively increased during the follicular phase and, by the fourth year, there were persistent, almost tonically high elevations of beta-FSH/Cr in the urine. CONCLUSIONS: Urinary beta-FSH subunit measurements are a useful marker for monitoring ovarian function during the menopausal transition. Urinary free beta-FSH subunit concentrations reflect pituitary FSH secretion and serve as a biomarker for ovarian reserve.