Many biological systems vary rhythmically in response to changes in both the external and internal environment. Some rhythms, such as the menstrual cycle in women, are built into the organism and repeat themselves over time without any support from external factors. It has been acknowledged for a long time that in addition to the predictable changes in steroid hormones that occur over the menstrual cycle, many women also experience concomitant changes in their physical and emotional well being. Most of the literature concentrates on the fact that negative moods and physical changes seem to occur predominantly before and during menstruation. Given the close temporal relationship of these changes to the timing of the steroid cycle, causal mechanisms have traditionally been sought in the hormonal changes themselves. Yet the literature reveals that no causal role has consistently been found for any of a large number of hormonal parameters that change over the menstrual cycle. Further, there is good evidence that variations in well being of a similar magnitude, and with similar timing occur during the combined oral contraceptive pill cycle. This thesis is concerned with exploring the aetiology of cycle-related change in emotional and physical well being during oral contraceptive use. Its two fundamental objectives are 1) to clarify why women taking the pill have similar experiences to women with hormonally distinct, menstrual cycles, and 2) to test a novel aetiological hypothesis with women taking the pill that there exists an endogenous rhythm of well being that is coupled to, but not caused by cyclical hormones. This knowledge may help us to understand better the phenomenology of the 'normal' cycle. The role of social factors in the expression of cycle-related change is just as poorly understood as the complex influence of biological factors. Thus a third portion of this thesis is devoted to exploring the nature of women's beliefs about their cycles, and investigating how they may 'translate' in their experience and reporting.

One hundred and ninety five thousand abortions were performed in Britain in 1989, a rate of 13 per 1000 women of reproductive age. Data from England and Wales indicates that 35% of women undergoing abortion in 1989 were at less than nine weeks gestation when menstrual induction can readily be performed. The method of abortion in almost all these women was vacuum aspiration, but there is increasing interest in menstrual induction, whereby early pregnancy can be terminated medically without the need for surgical intervention. The development of the progesterone antagonist mifepristone offers the possibility of a safe method of menstrual induction (in combination with a prostaglandin), which is effective and has minimal side effects. The minimum effective dose, and the mechanism of action of mifepristone are however unknown. The work in this thesis has investigated these two questions further. When the efficacy and side effects of three different doses of mifepristone: 200mg, 400mg and 600mg followed 48 hrs later by 1mg gemeprost in women of ≤56 days amenorrhoea were compared, all three regimes were equally effective, with a mean complete abortion rate of 98% . There were no differences in the incidence of side effects between the three groups. In contrast a lower complete abortion rate of 87% was seen in women at the same gestation following gemeprost alone (1mg 6 hrly to a total of 3mg) (p< 0.01). In a randomised comparison between the two methods, there was a significantly greater requirement for analgesia following the use of gemeprost alone (p< 0.02). The effects of a new prostaglandin (misoprostol) which could be used in combination with mifepristone were also studied. A significant increase in uterine tone was observed 30-120 minutes after 200-600μg misoprostol alone (p&60 0.01); in women pretreated 48 hours earlier with 200mg mifepristone, an increase in uterine contractility measured in Montivideo units was observed 30 minutes after 200-600μg misoprostol (p< 0.01). Eighteen out of twenty one women aborted using 200mg mifepristone followed 48 hours later by 200-1000μg misoprostol.

A cell culture system was developed to study the production of prostaglandins by cervical cells from late pregnant guinea pigs. This permitted the examination of the influence of various substances on the synthesis of the prostaglandins, including progesterone and the anti-progesterone drug RU486 (Mifepristone/RU38486). RU486 has been found to promote cervical ripening in humans and guinea pigs. It is thought to increase the sensitivity of the uterus to prostaglandins and thereby promote muscle activity. It is licensed in the United Kingdom as an abortifacient. Since this antiprogestin can provoke cervical ripening alone an accessible source of tissue from an animal with a similar physiology to the human seemed to be an appropriate starting point from which to investigate the effects of this steroidal derivative and how it may affect prostaglandin production. The results show that prostaglandin output can be provoked <I>in vitro</I> by agents such as lipopolysaccharide and phorbol ester. The observed effects by RU486 were mixed. Giving the animals examined, there were, however, some instances where a significant increase was detected, apparently associated with the calcium ionophore A23187, and others where there appeared to be a reduction. The inclusion of RU486 in the culture medium with other treatments did not produce any significant differences compared to the treatment on its own, and alone RU486 only produced a significant difference where the animal had been given the drug <I>in vivo. </I>

No description available.

The first part of the thesis reviews the possible aetiologies for idiopathic menorrhagia, discusses the investigation of patients complaining of abnormal menstrual bleeding in particular the role of outpatient management and summarises the medical therapies currently available, with emphasis on the synthetic progestagens. Evidence for the involvement of the endothelins, a family of powerful vasoconstrictors, and nitric oxide, a vasodilator, in endometrial homeostasis is reviewed. The structural changes seen in endometrium following exposure to synthetic progestagens are considered. A review of 400 patients referred for outpatient hysteroscopy and endometrial biopsy to investigate abnormal vaginal bleeding is presented and its clinical implications discussed. Results from a randomised comparative parallel group study comparing the efficacy of systemic and local progestagens is presented. 44 patients with objectively proven idiopathic menorrhagia were randomised to receive oral norethisterone or local progestagens via the levonorgestrel intrauterine system. Outcome measures included the change in menstrual blood loss after 3 cycles of treatment, side effect profiles and patient satisfaction with treatment. Endometrial biopsies were taken from patients participating in the above trial before and after treatment to examine the effects of exogenous progestagens on the endometrium. The following areas were investigated and are presented: changes in the distribution of endothelin A and B receptors: changes in the expression of endothelial and inducible nitric oxide synthase; the effects of exogenous progestagens on the lumenal epithelium using scanning electron microscopy and on morphological measurements of glandular and lumenal epithelium under light microscopy; alterations to the secretory function of epithelial cells using <I>Dolichos biflorus </I>agglutinin histochemistry, and to the stromal cells using α2 laminin, a marker of stromal cells which have undergone decidualisation.

In this thesis I examine the hypothesis that exposure to glucocorticoids in utero alters birth weight and might act to determine later cardiovascular risk. I present evidence that administration of low pharmacological does of dexamethasone (100-200 μg/kg/day given s.c. to the dam) leads to reductions in birth weight of 10-20% without affecting fetal or maternal viability. Further, these lower birth weight offspring have higher blood pressure as adults, with an increase in systolic blood pressure of 13mmHg in males and females when measured by direct carotid cannulation. The mechanism of the rise in blood pressure induced by in utero glucocorticoid exposure is examined. The potential for glucocorticoid exposure in utero to influence later blood pressure in normal physiology is also examined. Experimental evidence is presented that inhibition of 11-beta hydroxysteroid dehydrogenase in vivo results in increased exposure of the fetus to glucocorticoids derived from the maternal circulation. Administration of carbenoxolone, an inhibitor of 11-beta hydroxysteroid dehydrogenase, in a dose of 2.5mg/day to dams throughout pregnancy resulted in a 16% reduction in offspring birth weight and blood pressure rises in adult life in the offspring of 9mmHg in males and 7mmHg. suggesting that exposure of the fetus to maternal glucocorticoids also results in programming of blood pressure. Finally, the offspring of carbenoxolone treated pregnancies are also examined with regard to glucose tolerance. Glucose levels are shown to be higher both fasting (6.0+ 0.3 vs 4.8+ 0.2 mmoI/1: P<0.01) and in response to an oral glucose load (repeated ANOVA F=5.9, P< 0.05) in the offspring of treated animals. The potential mechanisms for this effect are examined with experimental evidence showing no difference in insulin sensitivity to injected insulin or in insulin secretion following fat feeding of the offspring of carbenooxoxlone treated pregnancies. In summary, this thesis provides evidence that increased feto-placental exposure to glucocorticoids reduces birth weight and produces long term increases in offspring blood pressure, plasma glucose and corticosterone levels, providing a mechanism to understand the 'fetal origens' hypothesis.

Background: There is a lack of commercially-available, age-appropriate formulations designed for administration to babies and children. This means that medicines may need to be manipulated to achieve the dose that is required in paediatric practice. This raises concerns about the dose accuracy and safety of the manipulated product. Though this is known and accepted as necessary, to date there has been no assessment of the evidence relating to these manipulations, the extent and nature of manipulations or of any associated practice issues. Objective: This thesis aimed to determine whether there is an evidence base for drug manipulations, to investigate the nature of manipulations, at the point of administration, in current clinical practice in neonatal and paediatric settings in the UK and to explore drug manipulations in the context of long-term medication administration by parents. Methods: Several methods were used to explore drug manipulations: a wide-ranging systematic review, an observation based study of drug manipulations in in-patient neonatal and paediatric areas, a UK wide survey of paediatric nurses and an interview based study with parents of children taking long-term medications. Outcomes: Manipulations to administer the required dose occur throughout practice and are not supported by evidence. Drug manipulation is intrinsic in neonatal and paediatric practice. Manipulations were identified more often in high dependency areas but were found throughout all clinical areas. Manipulations occurred more commonly with certain dosage forms, notably with tablets, but were found involving many dosage forms. Manipulations were identified involving drugs that are commonly prescribed and for prescriptions that had been written for babies and children of all ages and with a wide variety of diagnoses. Concerns relating to drug manipulations have been raised by those working in these areas. Parents described undertaking manipulations prior to administering medications to children, though undertaking these manipulations did not appear to cause undue concern. Conclusions: This thesis has reviewed the limited evidence, scoped out the nature of manipulations used in practice and by parents and suggested areas where future work would be appropriate. In exploring drug manipulation this thesis has added to ongoing discussion about the need for appropriate medication for paediatric use.

Pulmonary oedema is a life threatening complication of pregnancy. This project investigates lung structure in pregnancy using the MF1 mouse lung as a model in pursuit of knowledge applicable to human obstetrics. As well as histological examination of lungs from groups of normal nonpregnant control mice and normal pregnant mice at term, fine structural changes associated with pregnancy are studied quantitatively, employing stereological methods. Pulmonary interstitial volume doubles in pregnancy, this change being localised to ground substance especially which shows early pulmonary oedema. Significant increases in volume of basal lamina, endothelium, squamous (type 1) pneumocyte and alveolar luminal projections from the latter cell are seen. The histological significance of these adaptations is discussed. Alveolar surface area in pregnancy is 50&'37 more than in controls, the increase being mainly type 1 pneumocyte. There is, however, no change in number of alveoli or thickness of the pulmonary diffusion barrier. Haematological and protein biochemical studies in MF1 mice show changes in accord with accepted human findings. A quantitative method for measuring the concentration of endogenous albumin in aldehyde fixed resin embedded tissue sections by stereological immunogold electron microscopy is described. Control strategies are described and discussed. Results indicate an overall reduction in endogenous albumin staining in pregnancy; plasma concentration falls 22&'37 in pregnancy compared with controls (biochemically, albumin falls 29&'37). Similar changes are seen in interstitium, again localised to the ground substance. Staining in endothelium is 10&'37 that of plasma; endothelial cytoplasma shows a lower concentration of albumin staining than vesicle but, in contrast, more stainable albumin molecules. The relationships between concentrations of staining and between quantities of stainable albumin molecules are consistent between pregnant and control groups. The effective barrier to passage of albumin from plasma to interstitium is the luminal surface of the endothelium. It is concluded that significant changes in amounts of albumin in pulmonary compartments are seen in pregnancy compared with nonpregnant controls. It is argued that these changes probably do not relate to altered endothelial permeability in pregnancy.

The purpose of this research has been to study individual variations in the yield and composition of human milk and the factors related to these differences, and to assess their practical effects in terms of breast feeding. Although breast milk is acknowledged to be the best food for the young baby, surprisingly little is known about the variations in yield and composition which occur. That there are wide variations in yield is clinically obvious, but variations of composition can only be discovered by chemical analysis. Since it is difficult to collect milk for analysis under standard sampling conditions, chemical data reported in the literature are often unreliable and even contradictory. The management of breast feeding by many doctors and nurses in this country seems to rest largely on the assumption that virtually all women are capable of adequate lactation. No biochemical data are given to support this assertion, and the findings reported here support the opposite view, namely that many women do produce milk of poor quality. Part I of the thesis deals with the fundamental and difficult problem of removing milk from the breasts. A recently developed milking machine was used throughout this study. Part II deals with the physiological variations in milk which occur (a) within a nursing, that is during the emptying of the breast (b) during the course of 24 hours, and (c) during the course of lactation. The changes in composition which occur during nursing were studied in greater detail than hitherto. The fat content was found to increase progressively throughout the feed, slowly at first and rapidly towards the end; there was an associated decrease in the content of the water soluble constituents. It was concluded that adsorption of fat globules in the alveolar and duct surfaces is responsible for this phenomenon in the breast. During the first week of lactation, the protein content of the milk falls steeply, and the lactose content tends to rise. By obtaining serial samples from a number of women, the fat content was shown to have a haphazard variation during the first few days, but to stabilize by the end of the first week. During the following two or three weeks it rises to its definitive level, but the rise is small, and a fat content which is low on the 7th day will be low at any subsequent point in lactation. Thus, in the first parts of the thesis, it is established that the minimum sample which will give a reliable picture of milk composition is an entire 24 hours secretion, and that by the 7th day of lactation this picture is sufficiently stable to give a reliable estimation of lactation as a whole. 24 hour samples from the 7th day of lactation are examined. The fat content was not related to the content of the other constituents, and seemed to be an entirely individual characteristic. There was a very low correlation between the size of the breast and the milk yield. Of very much greater predictive value was the amount of enlargement which occurred in the breast during pregnancy. This was established in a number of women by measuring the breast early in pregnancy and again in the puerperium, the difference probably being due almost entirely to an increase in the functional tissue. The wide variation in the response of the breast to pregnancy was not related to the initial size of the breast. In primaparae, the milk yield was negatively correlated with age and with net weight gain during pregnancy, at a high level of significance. That is, the milk yield tends to be low in older primaparae and in those who have stored body fat during pregnancy. There was no relationship between the milk yield and composition and the mother's diet during pregnancy. The duration of breast feeding and the weight gain of the baby were shown to be strongly related to the 7th day yield of milk and to its fat content. About one-third of women examined were so deficient in one or both of these respects, that maintenance of breast feeding for more than a few weeks would seem to be impossible. If this finding---that many women are incapable of satisfactory lactation---is generally applicable, and there is no reason to believe that the sample of women studied is unrepresentative or that local conditions are unique, then some modifications of existing attitudes to breast feeding and its management are called for.

No description available.