Ken N. Muse

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

Premenstrual Asthma: The Effect of Estrogen on Symptoms, Pulmonary Function, and β2‐Receptors

Study Objectives. To characterize asthma symptoms, pulmonary function, and responsiveness to β2‐agonist stimulation, and in vitro β2‐receptor density and cyclic adenosine 3′,5′‐monophosphate (cAMP) response throughout the menstrual cycle in women with premenstrual asthma (PMA); and to examine the effect of exogenous estradiol administration on asthma symptoms, pulmonary function and responsiveness, and β2‐receptor density and function in these women.

How does mild endometriosis cause infertility

30-40% of patients with endometriosis are infertile, and 6-15% of infertile women have endometriosis. Although the cause of the infertility observed in patients with mild endometriosis has not been established, several hypotheses have been proposed. Recent investigations have shown a link between endometriosis, altered prostaglandin (PG) secretion and metabolism, and infertility. Increased levels of PG metabolites have been found in the peritoneal fluid (PF) washings from patients with endometriosis; increased PF volume has also been noted. The increased PG concentration may alter ovarian function and tubal motility. Other studies have found endometriosis to coexist with anovulation. When both problems are treated, pregnancy rates improve. Many women with endometriosis may have a luteal phase defect. An autoimmune response to endometriosis has been considered as a cause of infertility as well. This response could produce rejection of the early implanted embryo or interfere with sperm transport. Endometriosis has also been regarded as a cause for some spontaneous abortion, but there may be a mediating mechanism, e.g., immune response or luteal phase defect. It is not known whether the various phenomena associated with endometriosis have a genetic basis or represent a secondary effect of endometriosis. A multivariate hypothesis, in which any or all of the factors noted in previous studies may be responsible for endometriosis-associated infertility and to varying degrees in different patients, is proposed. There may be genes that interfere with PG metabolism or lead to deficient immune status. If the multivariate causation theory is confirmed, patient evaluation may require performance of several diagnostic tests to determine the presence or absence of each factor and the extent to which that factor affects fertility. This approach will permit appropriate individualization of therapy.

Prolactin hyperstimulation in response to thyrotropin-releasing hormone in patients with endometriosis

In order to clarify the role of hyperprolactinemia as a possible cause of infertility in patients with endometriosis, baseline serum prolactin (PRL) concentrations and the PRL response to thyrotropin-releasing hormone (TRH) stimulation were measured in 14 infertile women with endometriosis and in 13 normal, fertile women. Baseline PRL concentrations were 2-fold greater in the endometriosis group than in normal subjects, but the mean values did not differ significantly. Following TRH administration, a significant increase in peak PRL concentrations was observed in patients with endometriosis (211.5 +/- 34.9 ng/ml) when compared with corresponding values in control subjects (117.1 +/- 14.9 ng/ml, P less than 0.05). This hypersecretory state was selective for PRL because no significant differences between the baseline and TRH-stimulated thyroid-stimulating hormone (TSH) concentrations or total serum thyroxine concentrations were observed. In summary, some infertile women with endometriosis exhibit a greater capacity for PRL secretion than normal women. These results suggest that relative hyperprolactinemia may be responsible for the infertility associated with endometriosis, and that PRL suppression may be indicated in these patients.

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

Abstract 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.

Successful pregnancies from men with retrograde ejaculation with the use of washed sperm and gamete intrafallopian tube transfer (GIFT)

Viable sperm were collected from men suffering from retrograde ejaculation by the technique of rapid washing of semen/urine in a buffered collection solution. The utilization of washed semen/urine from two men with retrograde ejaculation in the GIFT procedure lead to successful conceptions and the birth of two healthy female babies. Thus, the technique of rapid washing of sperm from retrograde ejaculating men coupled with GIFT represents a viable alternative for the attainment of pregnancy.

Detection of a unique 32-kd protein in the peritoneal fluid of women with endometriosis * †

OBJECTIVE To test the hypothesis that endometriotic tissue secretes endometriotic-specific proteins into the peritoneal fluid (PF) of women with endometriosis. DESIGN A prospective design was utilized in this study. SETTING Tertiary care, university-based center and reproductive endocrinology laboratory. PARTICIPANTS Women of reproductive age who were infertile with endometriosis (n = 19), as well as without endometriosis (n = 7), and fertile women undergoing tubal ligation (n = 6). INTERVENTIONS Collection of PF fluid via laparoscopy. MAIN OUTCOME MEASURES Peritoneal fluid proteins were isolated and assessed by two-dimensional polyacrylamide gel electrophoresis. RESULTS Two-dimensional electrophoresis of PF proteins isolated a group of proteins (M(r) = 32 to 40 kd, pI = 4.5 to 5.2) in all PF samples that was similar to the rat endometriotic implant-specific protein, Endo-1. This group of proteins consisted of 5 to 12 individual proteins with endometriosis PF containing a significantly higher number of proteins (median = 11) compared with either PF from infertile women without endometriosis (median = 8) or from women undergoing tubal ligation (median = 7). In addition, one protein (M(r) = 32 kd, pI = 5.8), termed EPF-32, was detected predominantly (18 of 19 samples analyzed) in PF from women with endometriosis. This protein was also detected in PF from infertile women without endometriosis (2 of 7 samples) but not in the PF of fertile women undergoing tubal ligation (0 of 6 samples). The appearance of this protein was not associated with the severity of endometriosis. CONCLUSION It is concluded from this study that PF from women with endometriosis predominantly contains a 32-kd protein (EPF-32) compared with the PF of women without the disease. The role of EPF-32 in the pathophysiology of endometriosis is not established but this protein may function as a diagnostic marker for endometriosis.

The presence of luteinized unruptured follicle syndrome and altered folliculogenesis in rats with surgically induced endometriosis

OBJECTIVE Our purpose was to determine in the rat model whether endometriosis could influence ovarian function by altering oocyte release or folliculogenesis. STUDY DESIGN We histologically examined the ovaries of reproductively cycling rats with (n = 16) and without (n = 10) surgically induced endometriosis. The rats in these two groups were further subdivided into unilaterally ovariectomized or ovarian-intact groups. Serial sections of ovaries were examined, and follicular development and frequency of luteinized unruptured follicles were determined. RESULTS A significant tenfold increase in the number of luteinized unruptured follicles was observed in the ovaries from rats with endometriosis (2.7 per rat) compared with unoperated and sham-operated control groups (overall mean 0.26 per rat, p < 0.05). Additionally, ovaries from unilateral ovariectomized animals with endometriosis contained four times as many luteinized unruptured follicles (four per rat) as did the ovaries from bilaterally ovarian-intact rats with endometriosis (1.40 per rat, p < 0.01). Fewer follicles were present in rats with endometriosis (180 follicles per ovary) than in control rats (231 follicles per ovary, p < 0.05). CONCLUSION In the rat model the presence of ectopic endometrium is associated with an increased frequency of luteinized unruptured follicles and altered follicular development.

Antiprogesterone (RU486) effects on metalloproteinase inhibitor activity in human and rat granulosa cells

OBJECTIVE To determine if granulosa cells are a source of metalloproteinase inhibitor activity and whether P regulates this activity. DESIGN Inhibitor activity was measured in media from human and rat granulosa cells cultured with the antiprogesterone mifepristone (RU486). Human granulosa cells were obtained at the time of oocyte retrieval from gonadotropin-stimulated patients after hCG administration. Rat cells were collected from gonadotropin-primed animals before the LH surge. Human and rat cells were cultured for 24 hours in the absence or presence of LH (100 ng/mL or 3.3 nmol/L) and/or RU486 (5 microM or 50 microM). Inhibitor activity and P were measured in the media. SETTING Reproductive Endocrinology Laboratories, University of Kentucky. RESULTS Media from human granulosa cells contained metalloproteinase inhibitor activity and the addition of LH did not change this activity. RU486 at 50 microM decreased inhibitor activity in cells cultured in the absence or presence of LH (0.59 +/- 0.12- and 0.24 +/- 0.18-fold change, respectively, versus control cultures; mean +/- SEM). In rat granulosa cells, inhibitor activity increased with LH treatment (1.97 +/- 0.12-fold change). RU486 decreased the activity present in cells cultured in the presence of LH. Progesterone production was stimulated by LH in both human and rat granulosa cells (3.71 +/- 0.90- and 7.18 +/- 0.24-fold change, respectively). In the human cells, RU486 inhibited P production whereas RU486 stimulated P production in the rat cells. CONCLUSIONS These findings demonstrate for the first time that human granulosa cells are a source of metalloproteinase inhibitor activity. The decrease in granulosa cell-derived inhibitor activity by RU486 suggests that P stimulates inhibitor activity. Thus, P may regulate proteolysis associated with follicular rupture via its ability to stimulate granulosa cell production of metalloproteinase inhibitors. Differences in P production between the human and rat cells may be due to differences in hormonal stimulation regimens (i.e., hCG exposure).

Dirithromycin increases ethinyl estradiol clearance without allowing ovulation

Objective To use a novel, sensitive study design to detect a potential oral contraceptive (OC) and dirithromycin drug interaction by assessing the pharmacokinetics of the ethinyl estradiol (E2) component of a common OC and the potential failure of OC effectiveness. Methods In this nonblinded study, 20 healthy women using Ortho Novum 7/7/7-28 were selected for a three-OC-cycle study. Baseline measures included E2 and progesterone serum levels on days 21, 23, 25, and 27 of cycle one and days 1, 3, 5, and 7 of cycle two. During cycle two, 24-hour blood sampling and radioimmunoassay analysis for ethinyl E2 pharmacokinetics were performed on day 8 and pelvic ultrasound on day 13. Oral dirithromycin 500 mg/day for 14 days began on day 21 of cycle 2. After starting dirithromycin, cycle two and three serum E2, progesterone, and serial ethinyl E2 levels and pelvic ultrasound replicated the baseline schedule. Ovulation was assumed if E2 concentration was greater than 50 pg/mL, progesterone concentration was greater than 3 ng/mL, or if an ovarian cyst greater than 10 mm was present on ultrasound. Results Pharmacokinetic analysis demonstrated a small (7.6%) but statistically significant decrease (P = .03) in the mean ethinyl E2 24-hour area under the curve and an increase in apparent oral clearance. No woman ovulated, based on E2 levels and progesterone concentrations or ultra sound. Conclusion Dirithromycin increased the apparent oral clearance of ethinyl E2. The clinical importance of the interaction may be negligible because no woman ovulated or had compromised OC effectiveness in this small series.