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.

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.

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.

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.