The effect of diet and insulin on metabolic profiles of women with gestational diabetes mellitus.

Twenty women with abnormal glucose tolerance, detected from a routine program of antenatal screening for gestational diabetes mellitus (GDM) at 28 wk, were admitted for 24-h metabolic profiles. They were then alternately allocated to either insulin and dietary restriction or dietary restriction alone and then retested 4 wk later while on therapy. Ten normal controls were assessed twice at similar gestations to the study group. Before treatment, the 20 gestational diabetic subjects had higher mean concentrations of plasma glucose and 3-hydroxybutyrate than the controls for most of the profile, but mean insulin values were similar. Insulin therapy was associated with a reduction in mean glucose concentrations so that the profile was similar to the controls, while in the diet-alone group the reduction was less. The 3-hydroxybutyrate concentrations rose between profiles in the normal group and also rose in those treated by diet alone, but still remained within the upper range of normal even at night. Insulin therapy resulted in a similar 3-hydroxybutyrate profile to the controls. The C-peptide response to breakfast was reduced in both groups to levels below that of the controls. Neonatal outcome indices were similar in the two treatment groups, despite the differences in maternal metabolites, but because of the size of this study, conclusions about the neonate must be tentative.

Prenatal determination of fetal rhesus D status by DNA amplification of peripheral blood of rhesus-negative mothers.

We have developed a sensitive PCR-based assay for the RhD gene and used it to detect circulating fetal cells from RhD-positive fetuses from peripheral blood of RhD-negative mothers. With further improvement in diagnostic accuracy, this assay may have implications in the management of RhD-sensitized pregnancies in women whose partners are heterozygous for the RhD gene. Further studies are required to determine the relationship between maternal anti-D levels and circulating fetal cell numbers.

Inhibition of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in first- and second-trimester human pregnancy and the luteal phase using Epostane.

The effects of a competitive inhibitor of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) (Epostane, Sterling Winthrop, Guildford, England) on serum progesterone (P), estradiol (E2), and cortisol have been studied in three groups of pregnant women awaiting termination of pregnancy (5 to 8 weeks, 8 to 12 weeks, and 12 to 18 weeks of pregnancy) and 15 women in the luteal phase of the menstrual cycle. A single-dose randomized double-blind study was performed, each woman receiving a placebo, 50 mg of Epostane, or 100 mg of Epostane. In the pregnant group, there was a significant decline in the serum P concentration after both 50 mg and 100 mg of Epostane. The percentage fall increased with both drug dosage and advancing gestation. A similar fall in serum E2 was observed. Both of these effects were temporary. In the luteal phase group, a significant decline in serum P was observed after 100 mg of Epostane, but the serum E2 was not significantly different from the pretreatment concentration. Serum cortisol did not differ significantly from control values. These findings suggest that Epostane is an effective inhibitor of placental and ovarian 3 beta-HSD, which may have a role as an interceptive agent.

Progestagen-only oral contraceptives: comparison of the metabolic effects of levonorgestrel and norethisterone.

A 6-month single-blind study compared the use of a progestagen-only oral contraceptive containing norethisterone 350 micrograms/day (NE 350) with one containing levonorgestrel 30 micrograms (LN 30), to assess the metabolic effects. At the end of 6 months, there were no significant differences between the two groups with respect to plasma cholesterol, lipoproteins including HDL subfractions, triglycerides or glucose concentration. Levels of fibrinogen, plasminogen, Factor VII, Factor X and antithrombin III were also similar. Women changing from a combined oral contraceptive to LN 30 showed a significant fall in Factor X. Mean blood pressure fell on LN 30 by 7/9 mmHg, but the 6-month reading did not differ significantly from that in women on NE 350. Acceptability, and the metabolic effects of the two preparations were similar in this study. Further larger studies are warranted.

Comparison of two triphasic contraceptives with different progestogens: effects on metabolism and coagulation proteins.

This study compared the effects of two triphasic oral contraceptives (OCs) taken for 6 pill cycles. One preparation contained levonorgestrel (EE/LN), the other a new progestagen, gestodene (SHG 415G). There were no effects on body weight, dietary habits, blood pressure, HDL-cholesterol or carbohydrate metabolism. Both OCs caused a small but statistically significant increase in plasma total cholesterol, LDL-cholesterol, LDL/HDL-cholesterol ratio and triglyceride concentration. Sex hormone binding globulin was increased by both preparations. Coagulation factor VII and fibrinogen were increased and antithrombin III levels reduced, indicating that both preparations had pro-coagulant activity. The gestodene triphasic preparation was associated with minor side effects similar to those experienced on EE/LN. The metabolic effects were similar despite the lower total steroid dose of the gestodene preparation.

Failure of withdrawal bleeding during combined oral contraceptive therapy: "amenorrhoea on the pill".

Serum follicle stimulating hormone, luteinising hormone and oestradiol-17beta concentrations have been measured in 21 patients with failure of withdrawal bleeding during combined oral contraceptive therapy and 21 matched controls with a normal bleeding pattern. Gonadotrophin and oestradiol-17beta concentrations were effectively suppressed in all patients during the phase of contraceptive ingestion. During the week between courses of treatment, there was a significant rise in the gonadotrophin (p less than 0.02) and oestradiol (p less than 0.05) concentrations in the patients but not in the controls. It is suggested that patients with failure of withdrawal bleeding during combined oral contraceptive therapy may have higher total oestrogen levels during the treatment-free week because of a less persistent suppression of hypothalamic-pituitary-ovarian function.

Evaluating a policy of reduced consultant antenatal clinic visits for low risk multiparous women.

OBJECTIVES: To evaluate a change in antenatal care policy to reduce antenatal clinic visits, whereby low risk multiparous women were managed by the primary care team and seen at booking and at 41 weeks' gestation at the consultant antenatal clinic. DESIGN: Comparative study of low risk multiparous women retrospectively identified through the Oxford obstetric data system and cared for by three consultants who changed their policy (group A) or three consultants who maintained their routine care (group B). SETTING: Oxfordshire Health District. SUBJECTS: 2153 low risk multiparous women (1079 group A, 1074 group B) booked for consultant care at John Radcliffe Maternity Hospital between August 1985 and July 1987. MAIN MEASURES: Comparison of pregnancy outcomes, satisfaction with care, and clinic waiting times, during one year before and after the policy change (year 1, year 2). RESULTS: The proportion of women in group A with only one or two consultant clinic visits increased from 19.9% to 57.9% between years 1 and 2 (p < 0.001). Clinic waiting times did not improve. Of five perinatal deaths in group A, one (from postmaturity) could possibly be attributed to the policy change. The proportion of women reaching 42 weeks' gestation rose from 4.7% to 9.2% (p < 0.01); the proportion fully satisfied with their care rose from 68.4% to 82.1% (p < 0.025). No such changes were seen in group B. CONCLUSIONS: The change in policy was successful in reducing hospital antenatal clinic visits. The exercise identified dilemmas around evaluating changes in antenatal care settings. IMPLICATIONS: Criteria to test policy objectives should be selected carefully and rare events assessed prospectively in order to detect problems early.

Progestogen potency in oral contraceptive pills.

The most important target organs for combined oral contraceptive preparations are the anterior pituitary gland and the uterus. The long-term unopposed administration of estrogen produces endometrial hyperplasia and amenorrhea, which are unacceptable to most women and their medical advisors. Cyclic administration of progestogens in combination with the estrogen, however, produces predictable endometrial shedding and achieves a regular and acceptable bleeding pattern in most women. This was the main reason that the "delay of menses" test was adopted as the earliest clinical means of comparing the relative potencies of progestogens that were administered orally. Recently attempts have been made to compare the potency of progestogens on the other organ systems by the extrapolation of data derived from studies on the endometrium. This is inappropriate, inasmuch as the effects of progestogens and estrogens independently and in combination differ greatly depending on the target organ. In this article, the literature on this controversial subject is reviewed.

PIP: The most important target organs for combined oral contraceptive preparations are the anterior pituitary gland and the uterus. The long term unopposed administration of estrogen produces endometrial hyperplasia and amenorrhea, which are unacceptable to most women and their medical advisors. Cyclic administration of progestogens in combination with the estrogen, however, produces predictable endometrial shedding and achieves a regular and acceptable bleeding pattern in most women. This was the main reason that the "delay of menses" test was adopted as the earliest clinical means of comparing the relative potencies of progestogens that were administered orally. Recently attempts have been made to compare the potency of progestogens on the other organ systems by the extrapolation of data derived from studies on the endometrium. This is inappropriate, inasmuch as the effects of progestogens and estrogens independently and in combination differ greatly depending on the target organ. In this article, the literature on the controversial subject is reviewed.

Mechanism of action/effects of androgens on lipid metabolism.

The strongest predictors of cardiovascular disease in women have been shown to be diabetes, high blood pressure, cigarette smoking, and, to a lesser degree, hypertriglyceridemia. The difference in risk between men and premenopausal women has been explained by the following widely held hypothesis: androgens lower plasma concentrations of high-density lipoprotein (HDL), particularly the HDL-2 subfraction, and increase plasma concentrations of low-density lipoprotein (LDL). In contrast, estrogens have the opposite effect, raising plasma concentrations of HDL, particularly HDL-2, and lowering plasma concentrations of LDL. After the menopause, it is believed that the protective effect of estrogens in women is lost and the incidence of heart disease rises to equal that in men. This paper provides a brief review of the effect of endogenous and exogenous androgens on lipoprotein metabolism in men and women, and considers the relevance of these findings to the choice of progestogens used in oral contraceptive preparations.

Endometrial resection.

The development of hysteroscopy and endometrial resection is reviewed and instrumentation is described. Suitable fluids for uterine distension and methods of delivery are discussed and safe limits to fluid absorption suggested. Selection of patients, preoperative investigation and preparation are described. Anaesthesia and operative technique are discussed with particular reference to the methods used by the authors and some common operative problems and their solutions are described. The results of treatment are discussed with reference to the published literature and two additional large unpublished series; one of 500 resections carried out in Oxford by 19 surgeons, of widely differing experience, with a follow-up period from 1 to 5 years; the other a personal series of 585 cases done by one of the authors (E.M.H.) with a follow-up period of 1 to 4 years. Factors affecting the likely success of the procedure, operative and post-operative complications, the difficulty and results of repeated resections and the indications for subsequent hysterectomy are discussed. Finally, the economic aspects of the technique and the author's conclusions as to the place of endometrial resection in the treatment of menorrhagia are given.

Induction of abortion in early first trimester human pregnancy using epostane.

The role of epostane (Sterling Winthrop, Guildford, UK), a competitive inhibitor of the 3 beta hydroxysteroid dehydrogenase enzyme system (3 beta-HSD), as an abortifacient agent in early human pregnancy has been studied in 54 women. All were less than 49 days from their last menstrual period. Thirty were treated with 200 mg of epostane every 8 h for 7 days and 24 were given 200 mg every 6 h for 7 days. This caused a sustained reduction in circulating progesterone concentrations, a smaller fall in 17 beta-oestradiol and no effect on serum cortisol. Abortion occurred in 21 women (70%) in the lower dosage group and in 20 women (87%) in the higher dosage group. Abortion was incomplete in 6 of these 41 women. A worsening of pregnancy nausea and vomiting was noted by 66% of women in the first group and 84% in the second. There was no delay in the resumption of normal menstruation following abortion. This study confirms the potential of epostane as an effective inhibitor of ovarian and placental steroidogenesis and as a potent abortifacient agent in early human pregnancy.

PIP: 54 healthy women 17-41 years of age participated in a study to investigate the role of epostane as an abortifacient in early pregnancy. Epostane is a competitive inhibitor of the 3-beta hydroxysteroid dehydrogenase enzyme system. 30 subjects were treated with 200 mg of epostane every 8 hours for 7 days, while the remaining 24 subjects received 200 mg every 6 hours for 7 days. All subjects were less than 49 days from their last menstrual period. In the 1st group (600 mg of epostane/day), 21 of the 30 women (70%) aborted and the abortion was complete in 17 (80%) of these women. In the 2nd group (800 mg of epostane/day), 20 of 23 patients (87%) aborted and abortion was complete in 148 (90%). 66% of the women in the 600 mg/day regimen complained of side effects, largely a worsening of pregnancy nausea, while side-effects were experienced by 87% of those in the higher-dose group. Nausea and vomiting were successfully reduced, however, by administration of an oral antiemetic. Serum progesterone concentrations fell after the beginning of epostane treatment to 5% of pretreatment values and remained low for the duration of the treatment. There was a smaller fall in estradiol values and no effect on serum cortisol. Hematology and biochemistry measurements remained within the normal range after treatment with epostane. The higher abortion rate recorded in the higher-dose group may be a dose-response effect; alternatively, it may be due to a more constant inhibition of the hydroxysteroid dehydrogenase enzyme system. Overall, this study confirms the potential of epostane as an effective inhibitor of ovarian and placental steroidogenesis and as a potent abortifacient agent in early pregnancy.

Metabolism during normal and diabetic pregnancy and its effect on neonatal outcome.

Diurnal profile studies have been used to define the fetal carbohydrate and lipid substrate environment in normal and diabetic women during late pregnancy. In women with normal glucose tolerance the diurnal plasma glucose concentration was maintained within close limits (mean +/- S.D., 4.70 +/- 0.38 mmol/l) but in chemical and insulin-dependent diabetics there was a marked increase in both the mean diurnal glucose value and in the variability of the plasma glucose levels observed through the day (mean +/- S.D., 5.61 +/- 5.61 +/- 1.03 and 6.02 +/- 1.26 mmol/l respectively, P less than 0.01). No difference was observed between the peripheral insulin activity of the normal and chemical diabetic women, and the impaired glucose tolerance of the latter group was due to a deficient insulin response to goucose. The diurnal glucose variability, expressed as the standard deviation of the mean, was found to be inversely correlated with the residual C-peptide response in insulin-requiring diabetics. The mean diurnal plasma free fatty acid (FFA) concentration was slightly raised in chemical diabetic subjects compared to normal women (mean +/- S.D., 0.77 +/- 0.34 and 0.68 +/- 0.20 mmol/l respectively) but this difference was not significant. Insulin treatment produced a marked reduction in circulating FFA concentration, with a mean value in the insulin-dependent diabetic group of 0.45 +/- 0.11 mmol/l (P less than 0.001). Neonatal glucose assimilation during the first two hours of life correlated strongly with several functions of maternal carbohydrate tolerance. This was associated with higher plasma insulin concentrations at birth, and a marked tendency to hypoglycaemia in the infants of untreated chemical diabetic women. Impaired mobilization of triglyceride stores was also observed during the two hours after birth in the infants of diabetic women. This, however, appears to be due not to impaired lipolysis but to rapid re-esterification of FFA. These findings all indicate a state of functional hyperinsulinism in the infant of the diabetic women secondary to maternal hyperglycaemia.

Pyridoxine treatment of chemical diabetes in pregnancy.

Thirteen women with chemical diabetes diagnosed in late pregnancy were found to excrete excessive amounts of urinary xanthurenic acid after a tryptophan load, indicative of a relative pyridoxine (vitamin B6) deficiency. Treatment with 100 mg pyridoxine daily for 14 to 23 days restored the urinary xanthurenic acid excretion to normal in all patients. Improvement of glucose tolerance was observed in only two of the patients studied, deterioration in six, and no significant change in the remaining five. The insulin response to glucose was unaltered during pyridoxine therapy.

Amielle vaginal trainers-a patient evaluation.

Ten consecutive patients presenting to a gynaecology clinic with a principal diagnosis of secondary vaginismus and superficial dyspareunia were given a set of Amielle vaginal trainers and instructed in their use. They were subsequently sent a questionnaire asking for their evaluation of the efficacy of the trainers. Nine patients (90%) reported a substantial improvement or complete cure of their symptoms. All patients who used the vaginal trainers gave favourable reports on the physical characteristics of the product. Amielle vaginal trainers seem both effective in the treatment of vaginismus and superficial dyspareunia and aesthetically acceptable to majority of patients.

Hysterectomy following failed endometrial resection.

Of the first 500 women in Oxford to undergo transcervical resection of the endometrium, 101 (20%) have subsequently undergone hysterectomy. This study was undertaken to assess the reasons for failure of endometrial resection. An audit of the case notes of the 101 women requiring hysterectomy was performed. Data collection included the patient's age, weight, parity, reasons for endometrial resection, details of the endometrial resection, reasons for hysterectomy, hysterectomy findings and uterine histology. Six (6%) hysterectomies were performed as emergency operations during endometrial resection, 33 (33%) were performed for persistent menorrhagia, 39 (39%) for recurrent menorrhagia and in 18 women (18%) for pelvic pain. The duration of success following endometrial resection ranged from 0 to 21 months. Hysterectomy was significantly more common in older women under 40 years of age, in the presence of an enlarged fibroid uterus, when complications at endometrial resection had occurred and in women operated on by relatively inexperienced surgeons. Endometrium ws present in 96% of hysterectomy specimens. Uterine malignancy that had not been diagnosed at transcervical resection of the endometrium was present at hysterectomy in two women. Hysterectomy should be considered in preference to endometrial resection for treatment of menorrhagia in women who are less than 40 years old and in the presence of large intramural fibroids.

Is endometrial pre-treatment of value in improving the outcome of transcervical resection of the endometrium?

The aim of this study was to determine whether or not the use of medical pre-treatment of the endometrium improves the outcome of transcervical resection of the endometrium with regards to long-term operative outcome, histological findings and patient satisfaction. A prospective randomized trial comparing three endometrial pre-treatment agents (danazol, medroxyprogesterone acetate or nafarelin) with no pre-treatment was conducted. The main outcome measures were: (i) thickness of the endometrium and myometrium resected; (ii) histological stage of the endometrium at the time of operation; (iii) the presence or absence of menses and (iv) patient satisfaction 1 year post-operatively. Of the three pre-treatments studied, danazol produced a lower median endometrial thickness than the control, showed the greatest ability to induce atrophy of the endometrial glands and stroma (not statistically significant) and produced the highest rate of amenorrhoea (not different to the control). Danazol and nafarelin produced significantly lower median endometrial thickness than no pre-treatment. There were, however, no significant differences in the rates of amenorrhoea in any of the pre-treatment groups compared with that in the control group. No improvement in clinical outcome or patient satisfaction is conferred by the use of medical pre-treatments if transcervical resection of the endometrium is performed in the proliferative phase of the menstrual cycle.

Management of diabetic pregnancies in the United Kingdom.

The aim of this postal questionnaire survey was to identify facilities currently available for the care of pregnant diabetic women in the United Kingdom and determine how closely these reflect the standards recommended by The St Vincent Declaration Action Programme. A questionnaire was sent to a physician and an obstetrician in each of the 255 obstetric hospitals in the UK. Two hundred and forty-five (96.1%) hospitals replied, with most of these managing 20 or less insulin dependent diabetics per year. Of the hospitals, 58.4%, had a special combined diabetic antenatal clinic; 86.6% of the units had a single physician responsible for diabetic care, whilst more than one obstetrician was involved in 50.6% of the units. Prepregnancy counselling was provided in 87.4% of the hospitals. Home blood glucose monitoring was used in 97.9% of the units. Ideal mean pre- and postprandial blood glucose concentrations were 6.0 mmol/1 (SD 0.82) and 7.9 mmol/l (SD 0.91), respectively. Ultrasound was routinely used to assess fetal growth in 98.7% of the units. The mean gestational age for elective caesarean section was 38.2 weeks (SD 0.55), compared with 39.0 weeks (SD 0.35) for planned vaginal delivery. During labour, 98% of the units used a dextrose and insulin infusion, but only 53.7% of the units maintained an intrapartum maternal blood glucose of between 4 and 6 mmol/l. We conclude that there is widespread variation in the management of the pregnant diabetic patient, and much practice is suboptimal. Many of the recommendations of the St Vincent Declaration are not being met by current UK practice.

Plasma unconjugated oestriol in late pregnancy: circadian variation and the effect of meals and a glucose load.

Plasma unconjugated oestriol (E3) concentrations were determined by radioimmunoassay in 10 normal subjects in late pregnancy, throughout a normal day and night, and after a 50 g oral glucose load. There was a circadian pattern in E3 concentration characterized by an abrupt increase of 15 per cent at night. There was no significant rhythm during the day or night, taken separately. However there was a 10 to 11 per cent reduction in E3 concentrations soon after some meals and after a glucose load, possibly due to expansion of the plasma volume. Excluding the effect of meals, the fluctuation of E3 concentrations in individuals (median of the coefficients of variation) was 11.5 per cent in the day. Overall, it was 13.2 per cent in the day, 12.1 per cent at night and 15.9 per cent over the whole period studied. Since the variation in plasma unconjugated E3 concentrations through 24 hours was no greater than random fluctuations or day-to-day variation there is no need to restrict the time of blood sampling in clinical practice.