A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Is oestrogen therapy effective in the treatment of menopausal depression? Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Effect of progesterone and its 5 alpha and 5 beta metabolites on symptoms of premenstrual syndrome according to route of administration. Prevention of postpartum depression: a pilot randomized clinical trial. Two hormone replacement therapy (HRT) regimens for middle-eastern postmenopausal women. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.
To determine the effect of postnatal administration of the long-acting progestogen contraceptive, norethisterone enanthate, on postnatal depression and on serum hormone concentrations, and their association with depression.
                Double-blind randomised placebo-controlled trial.
                A tertiary care hospital in Johannesburg, South Africa. POPULATION Postnatal women using a non-hormonal method of contraception (n = 180).
                Random allocation within 48 hours of delivery to norethisterone enanthate by injection, or placebo.
                Depression scores in the three months postpartum as rated by the Montgomery-Asberg Depression Rating Scale (MADRS) and the Edinburgh Postnatal Depression Scale (EPDS); 2. serum 17beta-oestradiol, progesterone, testosterone and the 17beta-oestradiol:progesterone ratio at six weeks postpartum.
                There was a chance excess of caesarean section deliveries in the progestogen group. Mean depression scores were significantly higher in the progestogen group than in the placebo group at six weeks postpartum (mean MADRS score 8.3 vs 4.9; P = 0.0111; mean EPDS score 10.6 vs 7.5; P = 0.0022). Mean serum 17beta-oestradiol and progesterone concentrations were significantly lower in the progestogen group compared with the placebo group at six weeks postpartum. There were no correlations between any of the hormone parameters and depression at six weeks except in the formula feeding subgroup of the placebo group, where formula feeding and 17beta-oestradiol concentrations were positively associated with depression.
                Long-acting norethisterone enanthate given within 48 hours of delivery is associated with an increased risk of developing postnatal depression and causes suppression of endogenous ovarian hormone secretion. Fifty-five depressed menopausal patients took part in a randomized double-blind cross-over trial using ;Harmogen' (piperazine oestrone sulphate) and placebo. The Beck depression inventory, hot flush counts, and patients' subjective assessment of well-being were used to assess clinical status. Hormonal, biochemical and coagulation profiles were carried out. Hot flushes improved significantly on oestrogen compared with placebo. Depression scores and well-being showed significant and equal improvement on oestrogen and placebo. Significant improvement in flushes in patients on placebo was observed in the first half of the trial but did not occur in the second half, in patients who had previously taken oestrogen. No significant changes occurred in biochemistry. Coagulation tests showed acceleration of the prothrombin time in patients taking ;Harmogen' compared with those on placebo. Piperazine oestrone sulphate is a relatively weak but safe oestrogen preparation, effective in treatment of vasomotor symptoms but no more effective than placebo in the treatment of depression. Steroid pre-treatments may be useful to program GnRH antagonist IVF/ICSI cycles. This prospective study assessed hormonal and ultrasound data collected during the free period after the discontinuation of three different pre-treatments to provide information on the optimal time interval required before starting stimulation.
                Women were randomized to receive oral contraceptive pill (OCP) [ethinyl estradiol (E(2)) 30 microg + desogestrel 150 microg] (n = 21) or norethisterone 10 mg/day (n = 23) or 17-betaE(2) 4 mg/day (n = 25) or no pre-treatment (n = 24) for one cycle before IVF. Assessments were performed on post-treatment day (PD) 1, 3 and 5, or on spontaneous cycle day (CD) 1 and 3.
                After OCP and progestogen administration, FSH and LH concentrations shifted from strongly suppressed PD1 levels to PD5 values similar to those observed on CD1. Meanwhile, follicle sizes remained small up to PD5. In contrast, estrogen pre-treatment poorly reduced FSH levels on PD1 compared with OCP or progestogen. Consequently, follicle size was more heterogeneous. FSH rebound was maximal on PD3, whereas LH levels were slightly increased up to PD5.
                A 5-day free interval after OCP or progestogen offers the advantages of gonadotrophin recovery and homogeneous follicular cohort, whereas early FSH rebound occurring after estrogen pre-treatment argues for a short free period. Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury.
                This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury.
                Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo.
                In this small study, progesterone caused no discernible harm and showed possible signs of benefit. The purpose of this study was to evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high-risk population.
                A randomized, double-blind, placebo-controlled study included 142 high-risk singleton pregnancies. Progesterone (100 mg) or placebo was administered daily by vaginal suppository and all patients underwent uterine contraction monitoring with an external tocodynamometer once a week for 60 minutes, between 24 and 34 weeks of gestation. Progesterone (n = 72) and placebo (n = 70) groups were compared for epidemiologic characteristics, uterine contraction frequency, and incidence of preterm birth. Data were compared by chi(2) analysis and Fisher exact test.
                The preterm birth rate was 21.1% (30/142). Differences in uterine activity were found between the progesterone and placebo groups (23.6% vs 54.3%, respectively; P <.05) and in preterm birth between progesterone and placebo (13.8% vs 28.5%, respectively; P <.05). More women were delivered before 34 weeks in the placebo group (18.5%) than in the progesterone group (2.7%) (P <.05).
                Prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity. Orally administered progesterone may have advantages over other routes of administration in the treatment of premenstrual syndrome (PMS) because of substantially higher levels of the anxiolytic metabolites 5 alpha and 5 beta pregnanolone. The only previous placebo-controlled trial which used oral progesterone reported beneficial effects in the treatment of PMS. The present study, a double-blind crossover trial, compared the administration of 300 mg daily oral progesterone with 200 mg daily vaginal progesterone and matched placebos for 10 days premenstrually. Although there was a significant treatment effect on symptoms, no difference between active treatments and placebo was found. The trial was terminated with 25 women completing treatment as it was evident that no clinically significant effect of either form of progesterone was likely to be detected even with twice the sample size. Serum levels of progesterone and metabolites showed that oral administration resulted in supraphysiological levels of 5 alpha and 5 beta metabolites and there was a negative correlation between 5 alpha pregnanolone levels and anxiety. However, this did not translate to overall reduction in premenstrual distress or anxiety beyond that achieved by placebo, as measured by validated questionnaires. The authors attempted to reduce the rate of postpartum depression in high-risk women and to increase the time to recurrence.
                Nondepressed pregnant women with at least one past episode of postpartum major depression were recruited into a randomized clinical trial. Mothers were assigned randomly to a 17-week trial of sertraline or placebo immediately after birth and assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression.
                Of 14 subjects who took sertraline, one (7%) suffered a recurrence. Of eight subjects who were assigned to placebo, four (50%) suffered recurrences. This difference was significant. The time to recurrence was significantly longer in the sertraline-treated women than in the placebo-treated women.
                Sertraline conferred preventive efficacy for postpartum-onset major depression beyond that of placebo. Most previous studies designed to evaluate the efficacy of hormone replacement therapy (HRT) have been carried out in Europe, North America and Australia, involving Caucasian women for 6 months or less.
                To evaluate the 12-month effects of two different HRT regimens on postmenopausal symptoms of Middle-Eastern women.
                Hundred healthy Libyan women with postmenopausal symptoms, 12 months or more since their last menstrual period, were enrolled in a 12-month prospective study. Participants were randomly prescribed one of the two formulations, 50 in each group. These regimens were a continuous regimen of tibolone 2.5 mg oral tablets and a continuous regimen of 17beta-oestradiol sequentially combined with dydrogesterone (2/10 mg) oral tablets. The presence and severity of short- and intermediate-term symptoms were reported at 0, 3, 6 and 12 months of treatment. Observed symptoms were hot flushes, night sweating, palpitations, insomnia, depression, nervousness, loss of memory, vaginal dryness, loss of libido and joint pain.
                Forty-nine women (98%) in each group completed the 12-month study period. Participants, in the two groups, experienced a significant improvement within the first 3 months of treatment. The observed symptoms were completely relived by the sixth month without any significant difference between the two groups. Improvements were sustained over the 12-month period of the study. HRT users showed their acceptance to the two regimens.
                Tibolone and 17beta-oestradiol/dydrogesterone oral tablets were effective and safe to treat short- and intermediate-term symptoms in Middle-Eastern postmenopausal women, within 6 months, and with no significant differences between the groups. Thus, the use of HRT to relieve menopausal symptoms is highly recommended, at least in this region. Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy.
                In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581.
                Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51).
                Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy.
                Chief Scientist Office of the Scottish Government Health Directorate.
Synthetic progestogens should be used with significant caution in the postpartum period. The role of natural progesterone in the prevention and treatment of postpartum depression has yet to be evaluated in a randomised, placebo-controlled trial. Oestrogen therapy may be of modest value for the treatment of severe postpartum depression. Its role in the prevention of recurrent postpartum depression has not been rigorously evaluated. Further research is warranted.