J. W. W. Studd

Transdermal oestrogen for treatment of severe postnatal depression

BACKGROUND Postnatal depression can have long-term adverse consequences for the mother, for the marital relationship, and for the infants psychological development. Such depressions can be severe and resistant to both support and counselling and to therapy with antidepressant drugs. We investigated the antidepressant efficacy of oestrogen given transdermally. METHODS In a double-blind, placebo-controlled study, 61 women with major depression, which began within 3 months of childbirth and persisted for up to 18 months postnatally, were allocated randomly active treatment (n=34; 3 months of transdermal 17 beta-oestradiol 200 micrograms daily alone, then 3 months with added cyclical dydrogesterone 10mg daily for 12 days each month) or placebo (n=27; placebo patches and tablets according to the same regimen). The women were assessed monthly by self-ratings of depressive symptoms on the Edinburgh postnatal depression scale (EPDS) and by clinical psychiatric interview (schedule for affective disorders and schizophrenia [SADS]-change scale). FINDINGS On pretreatment assessments the women in both groups were severely depressed (mean EPDS score 21.8 [SD 3.0] active group, 21.3 [2.9] placebo group; SADS scores, 66.3 [11.4] and 64.3 [10.7]). During the first month of therapy the women receiving oestrogen improved rapidly, and to a significantly greater extent than controls (mean EPDS scores 13.3 [SD 5.7] vs 16.5 [5.3]. Patients receiving placebo also improved over time but, on average, their scores did not fall below the screening threshold for major depression for at least 4 months. The estimated overall treatment effect of oestrogen on the EPDS was 4.38 points (95% Cl 1.89-6.87). None of a range of other factors (age, psychiatric, obstetric and gynaecological history, severity and duration of current episode of depression, and concurrent antidepressant medication), influenced the response to oestrogen. INTERPRETATION This study has shown that transdermal oestrogen is an effective treatment for postnatal depression. Further studies are required to establish the minimum effective dose and shortest necessary duration of treatment as well as the mechanism of antidepressant action of oestrogen.

Long‐term effects of the menopause and sex hormones on skin thickness

Summary. Skin collagen content and skin thickness in a group of postmenopausal women who had been treated with sex hormone implants were compared with those in an untreated group of similar women. Both skin collagen content and thickness were found to be significantly greater in the treated than in the untreated group. In the untreated women skin collagen content declined in relation to menopausal age but not to chronological age. No correlation was found with menopausal age, chronological age or duration of therapy in the treated group. These data suggest that skin collagen is influenced by the sex hormone status arid declines after the menopause. contributing to the increase in urinary hydroxyproline excretion that has been reported to occur a t this time.

EFFECT OF OESTROGEN AND TESTOSTERONE IMPLANTS ON PSYCHOLOGICAL DISORDERS IN THE CLIMACTERIC

In a double-blind trial oestradiol, oestradiol/testosterone, or placebo implants were assessed for their effects on psychological symptoms in women attending a menopause clinic. After two months, women receiving active treatment scored better than the placebo group on a self-rating scale of distress, on anxiety, and on depression (p less than 0.05). Postmenopausal but not perimenopausal women improved after placebo, and at 4 months the scores in the three groups no longer differed significantly.

The effects of norethisterone in postmenopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome

Summary. The influence of norethisterone on mood and behaviour was investigated in prospective placebo‐controlled study in 58 postmenopausal hysterectomized women who were being treated with subcutaneous oestradiol and testosterone implants. Norethisterone, 2·5 or 5 mg daily, was given for 7 days and a placebo for two periods of 7 days. Psychological, behavioural and physical variables were assessed using the Menstrual Distress Questionnaire. There were widespread adverse effects which were dose‐related. Significant changes in five of the eight symptom complexes studied (pain, concentration, behavioural change, water retention and negative affect) were found with 5 mg/day of the progestogen. The symptoms were similar to the typical complaints of the premenstrual syndrome, such that a combination of oestradiol and testosterone implants with cyclical oral norethisterone appears to be a model for this condition. The dose of this progestogen should therefore be the minimum to achieve the desired therapeutic effect.

Sex hormones and skin collagen content in postmenopausal women.

Skin biopsy specimens were taken from 29 postmenopausal women who had not been given hormone replacement therapy and from 26 women who had been treated with oestrogen and testosterone implants for two to 10 years. The mean hydroxyproline content and therefore the mean collagen content in the skin was found to be 48% greater in the treated than the untreated women, who were matched for age. This difference was significant (p less than 0.01). The implication of this finding is that oestrogen or testosterone, or both, prevents the decrease in skin collagen content that occurs with aging and protects skin in the same way as it protects bone in postmenopausal women.

Treatment of the premenstrual syndrome by subcutaneous estradiol implants and cyclical oral norethisterone: placebo controlled study.

The hypothesis that the many non-specific changes normally associated with cyclical ovarian activity are the primary aetiological factors in the premenstrual syndrome was tested by suppressing ovulation with subcutaneous oestradiol implants. Sixty eight women with proved premenstrual syndrome were treated under placebo controlled conditions for up to 10 months in a longitudinal study. Active treatment was combined with cyclical oral norethisterone to produce regular withdrawal periods. Symptoms were monitored with daily menstrual distress questionnaires, visual analogue scales, and the 60 item general health questionnaire. Of the 35 women treated with placebo 33 improved, giving an initial placebo response rate of 94%. The placebo effect gradually waned, but the response to the active combination was maintained for the duration of the study. Analysis of the prospective symptom ratings showed a significant superiority of oestradiol implants over placebo after two months for all six symptom clusters in the menstrual distress questionnaire. Changes seen in the retrospective assessments were less significant but the trend was the same. Treatment with oestradiol implants and cyclical progestogen was well tolerated and appears to be both rational and effective for severe cases of the premenstrual syndrome.

Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone.

40 patients with premenstrual symptoms were randomly allocated to receive placebo patches or active treatment with transdermal oestradiol patches (2 x 100 micrograms) to suppress ovulation. Norethisterone 5 mg was given in each group from day 19-26 of the cycle to ensure a regular withdrawal bleed. Treatment was for 6 months with crossover at 3 months. Patients completed the Moos menstrual distress questionnaire (MDQ) and the premenstrual distress questionnaire (PDQ) daily throughout the study. 5 patients withdrew, 4 because of skin reactions and 1 because of considerable improvement with initial (active) treatment. After 3 months, both groups showed improvement in MDQ and PDQ scores. In general, between 3 and 6 months, patients who switched from active treatment to placebo had deteriorating scores while patients who switched from placebo to active treatment maintained or improved upon their initial gains. Significant improvements occurred after changing to active treatment in five of six negative MDQ symptom clusters and in six of ten PDQ symptoms.

THE EFFECT OF LUMBAR EPIDURAL ANALGESIA ON THE RATE OF CERVICAL DILATATION AND THE OUTCOME OF LABOUR OF SPONTANEOUS ONSET

A study of 1955 spontaneous labours is presented relating progress and outcome to the presence of a lumbar epidural block in 282 of these patients and to the need for oxytocin augmentation in 427. Graphs for cervical dilatation starting at admission to hospital were constructed for normal and dysfunctional labours of spontaneous onset. Patients requiring augmentation of labour had a lesser cervical dilatation on admission to hospital, a longer first stage, more instrumental deliveries, more Caesarean sections and a greater number of babies with a low Apgar score. An epidural block had no effect on either the duration of first stage or the rate of cervical dilatation but was associated with a 20‐fold increase in rotational forceps delivery and no increase in Caesarean section rate. With an epidural block there was no increase in the number of babies with cerebral irritation or low Apgar scores and there was a statistically significant improvement in the Apgar scores of babies of mothers in augmented dysfunctional labour who had an epidural block. The incidence of rotational forceps delivery in patients with an epidural block could be reduced with safety by allowing such patients to have a longer second stage before considering interference purely for delay.

Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement

Summary. The thigh skin collagen content and the metacarpal index were measured in 69 untreated postmenopausal women and in 37 postmenopausal women who had been receiving oestradiol and testos terone implants for 2–10 years. There was a significant positive correlation between the skin collagen content and the metacarpal index in both groups of patients. In the untreated group, there was a statistically significant decrease both in the thigh skin collagen content and in the metacarpal index with the years since the menopause. This decrease was preventable in women who were on sex hormone replacement therapy.

PREVENTION AND TREATMENT OF ENDOMETRIAL DISEASE IN CLIMACTERIC WOMEN RECEIVING ŒSTROGEN THERAPY

Abstract The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed œstrogen therapy without progestagen. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of adenomatous hyperplasia but in neither of the 2 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed œstrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7-13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma.