Margery A. Smith

Progesterone and the premenstrual syndrome: a double blind crossover trial

A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Mooss menstrual distress questionnaire, Beck et als depression inventory, Spielberger et als state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.

Menstrual migraine: a double-blind trial of percutaneous estradiol

The present study investigated whether administration of percutaneous estradiol for the 7 days encompassing menstruation (the paramenstruum) would be effective in alleviating menstrual migraine. The study was a double-blind cross-over placebo comparison of percutaneous estradiol in gel form. Twenty-two women who suffered from regular recurring menstrual migraine were studied during 2 assessment menstrual cycles, 4 treatment cycles (2 of estradiol gel, 2 of placebo gel), and 1 follow-up (no treatment) cycle. Women completed daily records of the occurrence and severity of migraine and medication used. Eighteen women completed the study. There was a significant reduction in the frequency of migraine in the paramenstruum and in the amount of medication taken during use of percutaneous estradiol. Women expressed a significant preference for continuation of therapy with percutaneous estradiol.

Natural family planning

It is now well accepted that a woman can conceive from an act of intercourse for a maximum of only about 7 days of her menstrual cycle. The reliability of natural family planning depends on identifying this window of fertility without ambiguity. Several symptomatic markers, cervical mucus and basal body temperature, have been used extensively and with considerable success in most women but failures occur. Ovarian and pituitary hormone production show characteristic patterns during the cycle. Urinary estrogen and pregnanediol measurements yield reliable information concerning the beginning, peak, and end of the fertile period, provided that the assays are accurate and performed on timed specimens of urine. We have developed such enzyme immunoassays for urinary estrogen and pregnanediol glucuronides that can be performed at home. In the early versions of the assays, enzyme reaction rates were measured by eye, but more recently, a simple photoelectronic rate meter has been used. The final problem to be solved is not technologic but whether women are sufficiently motivated to expend the same time and effort each day for 10 days a month, with less cost, on fertility awareness as they spend on making a cup of tea.

AN UNEXPECTEDLY HIGH RATE OF ECTOPIC PREGNANCY FOLLOWING THE INDUCTION OF OVULATION WITH HUMAN PITUITARY AND CHORIONIC GONADOTROPHIN

Six tubal ectopic pregnancies occurred in a series of 193 pregnancies following ovulation induced with human pituitary gonadotrophin (hPG) and human chorionic gonadotrophin (hCG). The ectopic pregnancy rate of 3.1 per cent is higher than quoted incidences in the general population and occurred in the absence of predisposing factors. There was an association between ectopic pregnancy and elevated urinary oestrogen excretion in the peri‐ovulatory phases of the induced ovulatory cycles. A urinary oestrogen excretion of greater than 200 μg/24 hours on day 0 (the day after hCG was given) was associated with a 10 per cent chance of ectopic pregnancy (P <0.05).

OVARIAN FUNCTION AFTER HYSTERECTOMY WITH CONSERVATION OF THE OVARIES IN PRE-MENOPAUSAL WOMEN

OPINION is still divided on the proper treatment of normal ovaries at hysterectomy in premenopausal women. There is now clear evidence that ovarian hormonal function before the menopause protects against the onset of osteoporosis and cardiovascular disease for many years later and therefore preservation of ovarian function up to the age of the natural menopause is highly desirable (Osler, 1898; Levy and Boas, 1936; Albright, Smith and Richardson, 1941 ; Griffith, 1956; Oliver and Boyd, 1959; Robinson, Higano and Cohen, 1959; Henneman, 1964; Randall et al., 1964; Nordin, MacGregor and Smith, 1966). On the other hand, many gynaecologists have advocated the removal of normal ovaries at hysterectomy as a prophylaxis against the subsequent development of ovarian pathology, particularly of ovarian cancer for which there is no method for early detection and the chances of eradication are slight (Pemberton, 1940; Speert, 1949; Fagan, Allen and Klawans, 1956; Grogan, 1967). When considering the arguments for and against conservation, precise information is still lacking on the duration and quality of ovarian function to be expected after hysterectomy. It was once thought that residual endometrium was necessary for ovarian function to continue, and in the ewe the presence of a uterus is essential for ovarian function. In Macacus rhesus and irus monkeys normal ovarian function continues after hysterectomy (Burford and Diddle, 1936 ; TeLinde and Wharton, 1960). In women, normal ovarian function has been recorded in the congenital absence of the uterus (Brown, Kellar and Matthew, 1959), and structures consistent with continuing function have been observed in conserved ovaries when examined several years after hysterectomy (Grogan, 1958, 1967). While there is thus no doubt that ovarian function can continue after hysterectomy, there is no agreement on the incidence of ovarian failure, and whether the ovarian function, when it continues, is completely normal and lasts until the expected time of the menopause. Using the development of menopausal symptoms as a guide, Sessums and Murphy (1932) investigated 91 women who had been treated by hysterectomy before the age of 36 years. They concluded that the incidence of ovarian failure before the age of 40 years was 32 per cent after total conservation of the ovaries and 52 per cent after partial conservation, compared with 6 per cent in women without hysterectomy. Richards (1951) found that hot flushes developed within two years of operation in 27 per cent of women treated before 45 years of age by total conservation of the ovaries and in 52 per cent treated by partial conservation. Using vaginal cytology as the index, BancroftLivingston (1954) found continuing ovarian function for up to three years after operation in 95 per cent of patients treated by hysterectomy before the age of 45 years, and in 59 per cent of such patients more than five years after opera-

A study of returning fertility after childbirth and during lactation by measurement of urinary oestrogen and pregnanediol excretion and cervical mucus production

Urinary estrogen and pregnanediol excretion was measured at weekly intervals over a 1-year period in 55 postpartum women ages 22-41 to identify the patterns of returning fertility. The women who were members of the Australian Nursing Mothers Association and familiar with the ovulation method of natural family planning (Billings) kept records of breastfeeding episodes cervical mucus production and bleeding. Complete ovarian quiescence during lactation amenorrhea was observed in 2/3 of subjects whereas the remaining 1/3 showed a gradual return of ovarian activity. The 1st bleed was associated with anovulatory ovarian activity in 40% of cases with normal ovulation in 19% ovulation but short luteal phases in 25% and ovulation but deficient luteal phases in 16%. The incidence of normal ovulatory cycles increased with time after delivery and eventually reached 85% even though many women were still breastfeeding. 22 pregnancies occurred in the study population 14 of which were unplanned. 8 women were fully breastfeeding at the time of conception. Mucus symptoms correlated with the hormone valves in about 60% of cycles examined. Peak mucus symptoms occurred an average of 0.46 days after the estrogen peak. In some cases women had symptoms that were difficult to interpret during their early cycles or potential fertility was not indicated by raised mucus scores or the presence of the peak mucus symptom contributing to the unplanned pregnancies. To improve the performance of natural family planning after childbirth it is recommended that breastfeeding women be warned that normal mucus and temperature patterns may not yet be established in the 1st 5 or more ovarian cycles. Thus caution is required until the peak mucus symptom becomes clearly established. Readily available hormone assays would be of help to women who have difficulty in recognizing mucus symptoms during the early phases of returning fertility. Overall the results of this study confirm the observation that prolonged breastfeeding significantly delays the return of fertility after childbirth. Future research should aim to identify the factors that prolong absolute infertility and also to provide means of identifying fertile cycles when they return.

Premenstrual Tension-Hormonal Profiles

Urinary oestrogen and pregnanediol excretion were measured daily throughout the menstrual cycle in 30 patients with premenstrual tension (PMT). These comprised 19 patients with the premenstrual syndrome (PMS) and 11 patients with menstrual distress (MDS). The results were compared with those obtained in 86 controls and in a subset of the control women matched for age and parity. Significant abnormalities of ovarian function were found in the premenstrual tension women when compared with the matched and total control groups. Significantly lower pregnanediol values were found during both the follicular and luteal phases; asynchrony was observed between the first pregnanediol rise and the pre-ovulatory oestrogen peak, the pregnanediol rise occurring later than in the controls; lower thannormal pre-ovulatory peak oestrogen and either very high or very low oestrogen values in the luteal phase were observed. Other major abnormalities in the PMT women included anovulatory cycles and short luteal phases. These re...

Treatment of premenstrual syndrome: A double-blind trial of dydrogesterone

A double-blind randomised crossover trial of oral micronised progesterone and placebo had demonstrated that progesterone had beneficial effects over placebo for some mood and physical premenstrual symptoms. A further trial using identical methodology was carried out to assess whether dydrogesterone would have the same beneficial effects. Prospective assessment confirmed the presence of a premenstrual syndrome in 30 women. Of these, six withdrew during the 4 months of the study. Twenty-four women completed the double-blind crossover protocol. All women were interviewed premenstrually before treatment and in each month of treatment. They completed the Moos Menstrual Distress Questionnaire, Beck Depression Inventory, Spielberger State Anxiety Inventory, Mood Adjective Checklist and a Daily Symptom Record. Analysis of data found an overall beneficial effect of being treated for most variables. Further analysis showed that the most major effects occurred in the first 2 treatment months. This study could find no evidence that dydrogesterone was more effective than placebo in treating premenstrual complaints.

Human albumin in exchange transfusion: A quantitative study of the influence of added human albumin on bilirubin removal

Summary 1. The percentage exchange of plasma, of fetal red blood cells, and of bilirubin was determined in 20 infants with erythroblastosis fetalis. 2. In 10 of these patients salt-poor concentrated serum albumin was introduced into the exchange medium. 3. A striking improvement in extraction of bilirubin was observed in the albumin-treated group. 4. Only trivial technical difficulties were encountered. 5. No deaths occurred in either series. 6. The possible mode of action of human albumin is discussed. 7. Indications and contraindications for the use of human albumin are outlined.

Oestrogen and pregnanediol excretion through childhood, menarche and first ovulation

Urinary oestrogen and pregnanediol values were measured in 24 boys and 38 girls between the ages of 2 and 13 years. Longitudinal studies were conducted on eight girls, two of whom collected for periods of 4 and 5 years which included menarche and in one case establishment of ovulation. Highly sensitive assay methods were developed for measuring the very small amounts of oestrone, oestradiol and oestriol and pregnanediol present in the urine of young children. The total oestrogen values were within the submicrogram range of 0·1–0·5 μg/24 hr in the children aged 2–8 years, with no differences seen between the boys and girls. After the age of 8 years, oestrogen values above 1 μg/24 hr began to be encountered and by age 11½ years the majority of subjects were recording oestrogen values above this figure. The rise in the oestrogen values was more rapid in the girls than in the boys. Evidence was presented that a value of approximately 1 μg/24 hr represents the minimum oestrogen production for the initiation of breast development. The oestrogen values were fluctuating with irregular periodicities at all ages and the gradual general rises seen after the age of 8 years could be arrested at any stage for a year or more. Menarche was preceded by marked periodic fluctuations in oestrogen output which peaked above 15 μg/24 hr. In all subjects studied, the initial bleeding cycles were anovulatory as judged by the low pregnanediol values, the usual pattern being one of fluctuating oestrogen production. One subject was studied fully through to the establishment of ovulation, which first occurred 12 months after menarche. The approach of ovulation was indicated by pre-menstrual rises in pregnanediol which increased in amplitude from 0·4 mg/24 hr until finally 2 mg/24 hr was exceeded (the value accepted for ovulation). Evidence was presented that the interval from menarche to ovulation in different individuals was very variable, extending from ovulation at menarche itself to periods of more than a year. Recording of self-observed symptoms of production of cervical mucus could be of considerable value in documenting these events in larger populations.