Treatment of vaginal bleeding irregularities induced by progestin only contraceptives.

BACKGROUND: Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience irregular vaginal bleeding when using them. Current treatments to control these bleeding problems are not sufficiently effective. OBJECTIVES: We evaluated preventive and therapeutic approaches to normalise bleeding irregularities associated with the use of progestin-only contraceptives. SEARCH STRATEGY: Literature was identified through database searches, reference lists, organisations and individuals, covering the period until December 2006. SELECTION CRITERIA: Trials with random or alternate allocation, testing interventions for the prevention or treatment of bleeding irregularities associated with the use of progestin-only contraceptives were eligible. DATA COLLECTION AND ANALYSIS: Results are expressed as relative risks (RR) with 95% confidence interval (CI) for categorical data and as weighted mean difference (WMD) with 95% CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative). MAIN RESULTS: Twenty three randomised controlled trials enrolling 2674 participants were included. Seventy per cent were determined to reflect low to moderate risk of bias. Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA and Norplant users. However, treatment frequently led to study discontinuation due to gastrointestinal upset. Combinations of oral ethinyl estradiol and levonorgestrel improved bleeding patterns in Norplant users, but method discontinuation rates were unchanged. One trial reported successful use of combined oral contraceptives in treating amenorrhea among DMPA users. Norplant users, but not Implanon users, administered the anti-progestin mifepristone reported fewer days of bleeding than those given placebo. Mifepristone used monthly by new Norplant acceptors reduced bleeding, when compared to placebo.A variety of NSAIDS have been evaluated for their ability to treat abnormal bleeding, with mixed results. Norplant users receiving tamoxifen had less unacceptable bleeding after treatment and were more likely to continue using Norplant than those receiving placebo. Tranexamic acid, mifepristone combined with an estrogen and doxycycline were more effective than placebo in terminating an episode of bleeding in women using progestin-only contraceptives, according to three small studies. AUTHORS' CONCLUSIONS: Some women may benefit from the interventions described, particularly with cessation of current bleeding. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger trials. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect.

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives.

BACKGROUND: Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience disruption of their normal vaginal bleeding pattern when using these methods. Current treatments to control these bleeding irregularities are not sufficiently effective. OBJECTIVES: We evaluated preventive and therapeutic interventions of bleeding irregularities associated with the use of progestin-only contraceptives. SEARCH STRATEGY: Literature was identified through database searches, reference lists, organisations and individuals, covering the period until December 2006. SELECTION CRITERIA: Trials with random or alternate allocation, testing interventions for the prevention or treatment of bleeding irregularities associated with the use of progestin-only contraceptives were eligible. DATA COLLECTION AND ANALYSIS: Results are expressed as relative risks (RR) with 95 % confidence interval (CI) for categorical data and as weighted mean difference (WMD) with 95 % CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative). MAIN RESULTS: 19 Randomised controlled trials including 2290 participants were included. Over 60% of these trials had low to moderate risk of bias. Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA users and had a positive therapeutic effect in Norplant users. However, treatment frequently led to discontinuation due to gastrointestinal upset. Combinations of oral ethinyl estradiol and levonorgestrel taken by Norplant users experiencing bleeding irregularities, improved bleeding patterns but method discontinuation rates remained the same. Norplant users administered the anti-progestin mifepristone therapeutically reported fewer days of bleeding than those given placebo. Prophylactic oral mifepristone used monthly by new Norplant users reduced bleeding, when compared to placebo.Ibuprofen was reported to decrease the length of bleeding episodes over a year, but the data were not presented in a suitable format for our analysis. Mefenamic acid reduced continued irregular bleeding during treatment in Norplant users, but not among DMPA users. Vitamin E and aspirin had no effect on bleeding patterns in a large trial of women using Norplant. Norplant users receiving tamoxifen had less unacceptable bleeding after treatment and were more likely to continue using Norplant than those receiving placebo. AUTHORS' CONCLUSIONS: Some women may benefit from the interventions described, particularly with cessation of an ongoing bleeding episode. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger scale trials. Intermittent treatment with an agent may help some women to continue the use of a progestin-only contraceptive. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect.

Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men.

BACKGROUND: We assessed attitudes towards and acceptability of male hormonal contraception among volunteers participating in a clinical trial of a prototype regimen, consisting of progestin and testosterone injections. METHODS: After completing screening, eligible men were randomly assigned to the no-treatment group (n = 40) or to receive injections of norethisterone enanthate and testosterone undecanoate or placebo at different intervals (n = 50) according to a blocked randomization list. They underwent self-administered questionnaires. RESULTS: The average age of the participants was approximately 28 years; most were involved in a stable relationship and had no children. Ninety-two percentage of the respondents thought that men and women should share responsibility for contraception and 75% said they would try a hormonal contraceptive if available. At the end of the treatment phase, 66% of the participants said that they would use such a method, and most rated its acceptability very highly; none reported it to be unacceptable. The injections themselves were indicated as the biggest disadvantage. No significant changes in sexual function or mood states were detected among the men who underwent hormone injections. CONCLUSIONS: The contraceptive tested in this study was well accepted by the participants over the course of 1 year.

Epidermal growth factor-related peptides in human prostatic fluid: sources of variability in assay results.

BACKGROUND: Prostatic fluid (PF) provides a unique medium for noninvasive evaluation of critical growth and differentiation signals in the prostatic microenvironment. The purpose of this study was to establish the feasibility of measuring two prostatic mitogens, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) in PF, and specifically to quantify extraneous variability attributable to the assay itself, sample handling, or biological variation within an individual over time. METHODS: PF was collected by transrectal massage from consecutive patients attending a urology clinic. Pooled PF and individual samples from 25 men with stable benign prostatic hyperplasia (BPH) were analyzed for EGF and TGF-alpha by radioimmunoassay and for total protein. RESULTS: Reproducibility was adequate at dilutions as low as 1:50 (2-microliter pooled sample) and 1:5 (20 microliters) for EGF and TGF-alpha, respectively. Results were not affected by freeze-thaw cycles, time in storage, or protease inhibition in fresh PF. EGF and TGF-alpha were detectable in 100% and 92% of individual men, with respective means of 152 and 0.2 ng/ml. Correlations between two samples obtained from the same man within 12 months were highly significant (EGF r = 0.89, TGF-alpha r = 0.71). Protein concentrations were consistent over time; expression of either peptide per weight of protein rather than per volume did not improve within-man correlation. Between-man variability far exceeded within-man variability for both peptides, and was estimated to account for 84% and 61% of the total variability in EGF and TGF-alpha, respectively. There was no correlation between EGF and TGF-alpha in the same samples. CONCLUSIONS: We conclude that men with BPH secrete consistent and distinct levels of EGF-related peptides in PF, and that these levels can be detected with acceptable sensitivity and precision by radioimmunoassay (RIA). Measurement of TGF-alpha, which has not been reported previously, requires a relatively larger sample.

Hormonal responses to psychological stress in men preparing for skydiving.

The purpose of the study was to examine the relationship between the hormonal and psychological responses of young men about to engage in a potentially life-threatening event. Subjects were recruited to take their first skydiving jump. The scores on questionnaires designed to assess anxiety were not significantly increased at 0800 h on the morning before the jump by comparison with scores obtained from the same subjects 3-5 days previously. However, a psychological instrument for rating of events indicated significantly increased intensity, and sympathetic nervous system activity, as measured by the salivary amylase response, was increased over self-control values. Salivary cortisol and testosterone levels were significantly lower on the morning of the jump than self-control values and values in control subjects determined at the same time of day. However, plasma LH was not suppressed. The anxiety and stress measures as well as the rating of events rose to high levels just before the jump. With the exception of testosterone, which remained low, serum cortisol, PRL, and GH all increased greatly subsequent to the rise in psychological measures, reached peak values before or shortly after landing, and declined significantly within the next hour. Anxiety and subjective stress scores declined to those of the self-control values within 15 min after landing, but the rating of events scale remained significantly elevated. In summary, reported anxiety associated with a purely psychological stressor was suppressed until within a few hours preceding the event, but was preceded by an increase in sympathetic nervous system activity and suppression of plasma cortisol and salivary testosterone levels. The event itself was associated with a reversal of the cortisol decline; other stress-associated hormones increased, but salivary testosterone remained low.

Mitogenic growth factors in breast fluid obtained from healthy women: evaluation of biological and extraneous sources of variability.

Peptide growth factors (GFs), including epidermal GF (EGF) and transforming GF-alpha (TGF-alpha), are presumed to play an important role in the local regulation of breast cell proliferation. Breast fluid collected by nipple aspiration provides a potential means to assess the concentration of these factors in contact with the ductal epithelium. Although identification of immunoreactive EGF-like GFs in breast fluid has been reported previously, we performed this study to evaluate the sensitivity and reliability of newer RIA methods and to characterize the sources and amounts of both intra- and intersubject variability. We also evaluated the relationship of breast fluid EGF and TGF-alpha levels to each other and to plasma levels of estradiol and progesterone. Breast fluid and plasma samples were obtained two to four times at weekly intervals from 18 healthy, premenopausal women. EGF and TGF-alpha were measured by competitive binding RIA. Both GFs were detected with good precision in all breast fluid samples analyzed, using dilutions as low as 1:100 for EGF (1 microliter) and 1:25 for TGF-alpha (4 microliters). The correlations between the right and left breasts, sampled concurrently, were r = 0.78 (P = 0.003) for EGF and r = 0.89 (P = 0.0001) for TGF-alpha. For both GFs, the variation between women was substantially greater than the variation between breasts or over time in an individual woman, particularly for EGF, for which there were 100-fold differences between women in mean levels. When samples from multiple women were analyzed together, we found no apparent relationships between EGF and TGF-alpha levels or between either GF level and menstrual cycle phase or plasma hormone concentrations. However, in random effects analyses, EGF levels within an individual were significantly associated overall with both TGF-alpha (P = 0.02) and plasma estradiol levels (P = 0.01). These data, which are the first comprehensive results on the feasibility of measuring mitogenic GFs in breast fluid, support the conclusion that women secrete consistent and individually distinct levels of EGF and TGF-alpha and that, in at least some women, EGF secretion in vivo covaries with both TGF-alpha in breast fluid and circulating estradiol.

Direct radioimmunoassay of progesterone in saliva.

We have developed a simple, direct radioimmunoassay for progesterone in saliva. The correlation coefficient (r) between the direct assay and an extraction procedure was 0.92 (n = 65, P < 0.001), and the correlation between concurrent serum and salivary progesterone concentrations in the luteal phases of menstrual cycles of 48 women was 0.75 (P < 0.001). Whereas certain polystyrene and polyethylene vials and tubes were found to bind and remove up to 87% of the progesterone from saliva, other plastic and glass surfaces were satisfactory for the procedure. Intraassay and interassay CVs from values greater than 300 pmol/L were 12.0 and 12.4%, respectively. The assay sensitivity was 48 pmol/L. Collection of saliva is a more convenient and less invasive technique for frequent sample collection than phlebotomy, and is useful for monitoring ovulation and assessment of luteal function in women clinically.

Neonatal androgenization potentiates the inhibitory effects of blood withdrawal on ovulation in the rat.

Rats treated on Day 5 of life with testosterone propionate (TP) were tested for their ovulatory response to pregnant mare's serum gonadotropin (PMSG) on the 30th day of life with and without cardiac puncture under ketamine/xylazine anesthesia. TP without cardiac puncture in doses of 0.625, 1.25, or 2.5 microg did not inhibit ovulation, but 5.0 microg of TP inhibited ovulation in 15 of 16 rats. When cardiac puncture was performed at 1900 hr in rats not given TP, seven of eight ovulated on Day 33. However, none of the rats that received either 1.25 or 2.5 microg of TP ovulated after cardiac puncture at 1900 hr, and only one of seven given the 0.625-microg dose ovulated. Thus, the stress of bleeding greatly enhanced the inhibitory effect of otherwise ineffective doses of TP. The preovulatory luteinizing hormone (LH) surge was delayed and diminished by neonatal TP in a dose-related manner in animals from which blood was drawn from a previously inserted catheter. When blood drawn from similarly TP-treated animals by cardiac puncture, serum levels of LH were further reduced. Progesterone, given at 1100 hr on Day 32, was capable of partially overcoming the inhibitory effects of the combined treatments on both ovulation and serum LH levels at all but the highest dose of TP tested (5.0 microg). We conclude that neonatal exposure to androgen sensitizes rats to ovulation-inhibiting factors, such as bleeding, in a manner which appears to delay as well as inhibit the preovulatory release of LH. Such early exposure to androgen, therefore, may determine the susceptibility of individuals to reproductive failure in adult life.

Salivary alpha-amylase as a measure of endogenous adrenergic activity.

This investigation was designed to evaluate the production rates and concentrations of salivary alpha-amylase as a measure of adrenergic activity under several conditions of stress in human subjects. Saliva and blood samples were simultaneously collected from men at four 15 min intervals both before and after regimens for exercise, a written examination, or a rest period. The regressions of salivary alpha-amylase on plasma norepinephrine (NE) concentrations were significant for both exercise (P < 0.001) and examination (P < 0.01) protocols. Aerobic exercise induced a 3-fold mean increase in alpha-amylase; both NE and epinephrine (EP) increased approximately 5-fold over control levels. Levels of alpha-amylase and NE returned to control levels within 30-45 min after exercise, but EP remained elevated by approximately 2-fold during the remaining hour of observation. During the written examination, alpha-amylase and NE, but not EP, concentrations increased in parallel. In further studies the effects of exercise and exposure to heat and cold on the relationship of salivary alpha-amylase to heart rate and body temperature were investigated. Greater intensities of exercise were associated with greater increases in alpha-amylase concentrations. During heat exposure in a sauna (66 degrees C for 40 min) amylase, heart rate and body temperature all increased progressively. However, during exposure to cold (4 degrees C for 40 min) amylase increased rapidly, though heart rate and body temperature remained unchanged. Salivary cortisol concentrations were unchanged during exposure to heat or cold. We conclude that salivary alpha-amylase concentrations are predictive of plasma catecholamine levels, particularly NE, under a variety of stressful conditions, and may be a more direct and simple end point of catecholamine activity than are changes in heart rate.

Neuroendocrine regulation of the luteinizing hormone-releasing hormone pulse generator in the rat.

We have analyzed the mechanisms by which several known regulators of the LHRH release process may exert their effects. For each, we have attempted to determine how and where the regulatory input is manifest and, according to our working premise, we have attempted to identify factors which specifically regulate the LHRH pulse generator. Of the five regulatory factors examined, we have identified two inputs whose primary locus of action is on the pulse-generating mechanism--one endocrine (gonadal negative feedback), and one synaptic (alpha 1-adrenergic inputs) (see Fig. 29). Other factors which regulate LHRH and LH release appear to do so in different ways. The endogenous opioid peptides, for example, primarily regulate LHRH pulse amplitude (Karahalios and Levine, 1988), a finding that is consistent with the idea that these peptides exert direct postsynaptic or presynaptic inhibition (Drouva et al., 1981). Gonadal steroids exert positive feedback actions which also result in an increase in the amplitude of LHRH release, and this action may be exerted through a combination of cellular mechanisms which culminate in the production of a unique, punctuated set of synaptic signals. Gonadal hormones and neurohormones such as NPY also exert complementary actions at the level of the pituitary gland, by modifying the responsiveness of the pituitary to the stimulatory actions of LHRH. The LHRH neurosecretory system thus appears to be regulated at many levels, and by a variety of neural and endocrine factors. We have found examples of (1) neural regulation of the pulse generator, (2) hormonal regulation of the pulse generator, (3) hormonal regulation of a neural circuit which produces a unique, punctuated synaptic signal, (4) hormonal regulation of pituitary responsiveness to LHRH, and (5) neuropeptidergic regulation of pituitary responsiveness to LHRH. While an attempt has been made to place some of these regulatory inputs into a physiological context, it is certainly recognized that the physiological significance of these mechanisms remains to be clarified. We also stress that these represent only a small subset of the neural and endocrine factors which regulate the secretion or actions of LHRH. A more comprehensive list would also include CRF, GABA, serotonin, and a variety of other important regulators. Through a combination of design and chance, however, we have been able to identify at least one major example of each type of regulatory mechanism.