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Objective: To develop a theory-informed behaviour change intervention to promote appropriate hospital antibiotic use, guided by the Medical Research Council's complex interventions framework., Methods: A phased approach was used, including triangulation of data from meta-ethnography and two qualitative studies. Central to intervention design was the generation of a robust theoretical basis using the Behaviour Change Wheel to identify relevant determinants of behaviour change and intervention components. Intervention content was guided by APEASE (Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity) criteria and coded using a Behaviour Change Technique Taxonomy. Stakeholders were involved throughout., Results: From numerous modifiable prescribing behaviours identified, active 'antibiotic time-out' was selected as the target behaviour to help clinicians safely initiate antibiotic reassessment. Prescribers' capability, opportunity, and motivation were potential drivers for changing this behaviour. The design process resulted in the selection of 25 behaviour change techniques subsequently translated into intervention content. Integral to this work was the development and refinement of a Digital Antibiotic Review Tracking Toolkit., Conclusion: This novel work demonstrates how the Behaviour Change Wheel can be used with the Medical Research Council framework to develop a theory-based behaviour change intervention targeting barriers to timely hospital antibiotic reassessment. Future research will evaluate the Antibiotic Toolkit's feasibility and effectiveness.

Background: Antimicrobial resistance poses a serious global public health threat. Hospital misuse of antibiotics has contributed to this problem and evidence-based interventions are urgently needed to change inappropriate prescribing practices. This paper reports the first theoretical stage of a longer-term project to improve antibiotic prescribing in hospitals through design of an effective behaviour-change intervention., Methods: Qualitative synthesis using meta-ethnography of primary studies reporting doctors' views and experiences of antibiotic prescribing in hospitals for example, their barriers to appropriate prescribing. Twenty electronic databases were systematically searched over a 10-year period and potential studies screened against eligibility criteria. Included studies were quality-appraised. Original participant quotes and author interpretations were extracted and coded thematically into NVivo. All study processes were conducted by two reviewers working independently with findings discussed with the wider team and key stakeholders. Studies were related by findings into clusters and translated reciprocally and refutationally to develop a new line-of-argument synthesis and conceptual model. Findings are reported using eMERGe guidance., Results: Fifteen papers (13 studies) conducted between 2007 and 2017 reporting the experiences of 336 doctors of varying seniority working in acute hospitals across seven countries, were synthesised. Study findings related in four ways which collectively represented multiple challenges to appropriate antibiotic medical prescribing in hospitals: loss of ownership of prescribing decisions, tension between individual care and public health concerns, evidence-based practice versus bedside medicine, and diverse priorities between different clinical teams. The resulting new line-of-argument and conceptual model reflected how these challenges operated on both micro- and macro-level, highlighting key areas for improving current prescribing practice, such as creating feedback mechanisms, normalising input from other specialties and reducing variation in responsibility for antibiotic decisions., Conclusions: This first meta-ethnography of doctors` experiences of antibiotic prescribing in acute hospital settings has enabled development of a novel conceptual model enhancing understanding of appropriate antibiotic prescribing. That is, hospital antibiotic prescribing is a complex, context-dependent and dynamic process, entailing the balancing of many tensions. To change practice, comprehensive efforts are needed to manage failures in communication and information provision, promote distribution of responsibility for antibiotic decisions, and reduce fear of consequences from not prescribing., Trial Registration: PROSPERO registration: CRD42017073740 ., (© 2021. The Author(s).)

Cancer is a key priority worldwide, and caring for children and young people with cancer requires a range of specific knowledge, skills and experience in order to deliver the complex care regimes both within the hospital or community environment. The aim of this paper is to disseminate work undertaken to design and develop pedagogical practice and innovation through an eLearning resource for health care professionals caring for children and young people with cancer across the globe. The work undertaken evaluated an existing cancer course (which has been withdrawn) that was developed and delivered through the Paediatric Oncology Nurses Forum, Royal College Nursing (Nurse Educators) and Warwick University. The evaluation consisted of 26 open and closed questions relating to the previous resource and was circulated to all health and social care professionals involved directly within specialist oncology services through the Children's Cancer and Leukaemia Group. Questionnaires were sent out to a convenience sample of 773 health care professionals and the response rate was 14%. The findings identified that the course was predominantly accessed by nurses, but other health care professionals also found it useful. Participants highlighted several areas where they believed content could be developed or was lacking. This included areas such as palliative and end of life care, nutrition, sepsis and teenagers and young people. This feedback was then used to develop a site dedicated to the care of children and young people with cancer.

Background: Screening children for autism has gained wider acceptance within clinical practice, and early intervention has improved outcomes. Increasingly, adapting an existing screening instrument is a common, fast method to create a usable screening tool, especially for countries with limited resources and/or expertise. However, concerns have been raised regarding adaptation adequacy and the feasibility of screening across cultural groups. This study systematically examined the levels of cultural adaptation and feasibility aspects considered when screening for autism in non-English speaking countries to build upon the sparse knowledge that exists on this topic in the literature., Methods: Nineteen studies, obtained from five electronic databases, were examined. PRISMA guidance was used for this review. The Ecological Validity Framework model, and Bowen Recommendations for Feasibility were adopted to extract relevant data, which was synthesised narratively., Results: Cultural adaptation within the included studies mostly involved language translation with little information offered to enable conclusions on how the processes were guided and maintained. Few cultural adjustments involved modifying screening methods; clarifying difficult concepts and changing instrument content were employed to address the core values, competence, beliefs, and norms of the adapted culture. However, less attention was given to adapt the screening goals within the context of cultural values, and customs or to consider interactional match between the clients and assessors. The review also highlighted an acceptable level of practicality to screen for autism but did not encourage integrating autism screening within routine practice or beyond the study context for different cultures., Conclusion: Concurring with previous literature, we agree that knowledge on cultural adaptation for autism screening instruments is limited and not sufficiently documented to establish adaptation levels (process and/or contents), and prove adequacy. However, this review provides an infrastructure to improve future adaptation processes. Integrating autism screening as routine medical practice is not encouraged and warrants further feasibility studies to minimize wasted resources and improve screening effectiveness in various health care systems.

Some children with Down syndrome may experience difficulties in recognizing facial emotions, particularly fear, but it is not clear why, nor how such skills can best be facilitated. Using a photo-matching task, emotion recognition was tested in children with Down syndrome, children with nonspecific intellectual disability and cognitively matched, typically developing children (all groups N = 21) under four conditions: veridical vs. exaggerated emotions and emotion-labelling vs. generic task instructions. In all groups, exaggerating emotions facilitated recognition accuracy and speed, with emotion labelling facilitating recognition accuracy. Overall accuracy and speed did not differ in the children with Down syndrome, although recognition of fear was poorer than in the typically developing children and unrelated to emotion label use. Implications for interventions are considered.

Background: Reflective writing is a mandatory part of nurse education but how students develop their skills and use reflection as part of their experiential learning remains relatively unknown. Understanding reflective writing in all forms from the perspective of a student nurse is therefore important., Objectives: To explore the use of reflective writing and the use of poetry in pre-registered nursing students., Design: A qualitative design was employed to explore reflective writing in pre-registered nursing students., Setting: A small university in Scotland., Participants: BSc (Hons) Adult and Mental Health Pre-registration Student Nurses., Methods: Two focus groups were conducted with 10 student nurses during March 2012. Data was analysed thematically using the framework of McCarthy (1999)., Results: Students found the process of reflective writing daunting but valued it over time. Current educational methods, such as assessing reflective accounts, often lead to the 'narrative' being watered down and the student feeling judged. Despite this, reflection made students feel responsible for their own learning and research on the topic. Some students felt the use of models of reflection constricting, whilst poetry freed up their expression allowing them to demonstrate the compassion for their patient under their care., Conclusions: Poetry writing gives students the opportunity for freedom of expression, personal satisfaction and a closer connection with their patients, which the more formal approach to reflective writing did not offer. There is a need for students to have a safe and supportive forum in which to express and have their experiences acknowledged without the fear of being judged., (Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.)

The cancer needs of people with intellectual disabilities are increasingly being debated. This paper explores the views and experiences of paid- and family-carers when supporting women with intellectual disabilities through breast screening. An ethnographic approach was drawn on and purposive sampling methods were employed. One-to-one semi-structured interviews with 13 carers (10 paid-carers, three family-carers) were undertaken and supported by periods of focused observation on behaviour related to breast awareness and breast screening. Findings indicated that most women with intellectual disabilities needed some support but the quality and quantity of support depended upon both the woman's level of intellectual disability and who was supporting them. In terms of breast screening, the findings suggested that the women were potentially being let down at all the different stages of the breast screening process, from the arrival of the invitation letter to the experience of having a mammogram. The conclusion drawn was that there was evidence of equality of service provision but inequality of service delivery and uptake., (© 2014 John Wiley & Sons Ltd.)

Background: Increased longevity will mean an increase in people presenting with cognitive and physical disabilities, such as sight loss or dementia. The Patient Rights (Scotland) Act 2011 states that health care should be patient-focussed, taking into account patient needs. This will necessitate nursing curricula to reflect the needs of people who have disabilities and equip the future workforce with knowledge and skills to provide appropriate care. This study explores student nurses' strengths and weakness when working with people with disabilities and identifies opportunities and threats to developing their knowledge and skills to meet the needs of this population., Methods: As part of a study day, students from the year one Nursing programme were asked to take part in a SWOT analysis and post comments under the categories: strengths, weakness, opportunity and threats on a central wall about working with people with disabilities., Results: Students acknowledged some of the challenges of being disabled especially in a health setting but also believed they were developing their skills to provide holistic care that ensured autonomy. Communication was viewed as both a strength and weakness and was identified as an essential skill to working effectively with people who had a disability. Students acknowledged that clinical staff were not always experts in working with people who were disabled and welcomed the opportunity to work with experts and clients as well as being directed to resources to increase their knowledge., Conclusions: Integration of disability into the nursing curriculum is needed to ensure students have awareness of and the confidence to work effectively with people who have a range of cognitive and physical disabilities alongside other medical problems., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Context: Treatment of congenital adrenal hyperplasia (CAH) in childhood focuses on growth and development and adult final height (FH) is a measure of effective treatment. We hypothesized that shorter adults will have more severe underlying disease and worse health outcomes., Methods: This was a cross-sectional analysis of 199 adults with CAH. FH and quality of life were expressed as z-scores adjusted for midparental target height or UK population height., Results: FH correlated inversely with age (men, r = -0.38; women, r = -0.26, P < .01). Men and women had z-scores adjusted for midparental target height of -2 and -1, respectively, and both groups had UK population height z-scores of -1 below the UK population (P < .01). In women, FH was shorter in non-salt-wasting than salt-wasting classic CAH (P < .05) and in moderately affected genotype group B women than either more severely affected groups null and A (P < .01) or the mildest group C (P < .001). Short stature and a higher prevalence of hypertension were observed in classic CAH patients diagnosed late (after 1 y) compared with those diagnosed early and in women treated with glucocorticoid only compared with those treated with both glucocorticoids and mineralocorticoids (P < .05). FH did not associate with insulin sensitivity, lipid profile, adiposity, or quality of life., Conclusions: Adult CAH patients remain short, although height prognosis has improved over time. The shortest adults are those diagnosed late with moderate severity CAH and are at increased risk of adult hypertension; we hypothesize that these patients are exposed in childhood to high androgens and/or excessive glucocorticoids with potential programming of hypertension. Another possibility is inadequate mineralocorticoid treatment early in life in the late-diagnosed patient group. Prospective studies are now required to examine these hypotheses.

Context: Quality of life (QoL) has been variously reported as normal or impaired in adults with congenital adrenal hyperplasia (CAH). To explore the reasons for this discrepancy we investigated the relationship between QoL, glucocorticoid treatment and other health outcomes in CAH adults., Methods: Cross-sectional analysis of 151 adults with 21-hydroxylase deficiency aged 18-69 years in whom QoL (assessed using the Short Form Health Survey), glucocorticoid regimen, anthropometric and metabolic measures were recorded. Relationships were examined between QoL, type of glucocorticoid (hydrocortisone, prednisolone and dexamethasone) and dose of glucocorticoid expressed as prednisolone dose equivalent (PreDEq). QoL was expressed as z-scores calculated from matched controls (14,430 subjects from UK population). Principal components analysis (PCA) was undertaken to identify clusters of associated clinical and biochemical features and the principal component (PC) scores used in regression analysis as predictor of QoL., Results: QoL scores were associated with type of glucocorticoid treatment for vitality (P=0.002) and mental health (P=0.011), with higher z-scores indicating better QoL in patients on hydrocortisone monotherapy (P<0.05). QoL did not relate to PreDEq or mutation severity. PCA identified three PCs (PC1, disease control; PC2, adiposity and insulin resistance and PC3, blood pressure and mutations) that explained 61% of the variance in observed variables. Stepwise multiple regression analysis demonstrated that PC2, reflecting adiposity and insulin resistance (waist circumference, serum triglycerides, homeostasis model assessment of insulin resistance and HDL-cholesterol), related to QoL scores, specifically impaired physical functioning, bodily pain, general health, Physical Component Summary Score (P<0.001) and vitality (P=0.002)., Conclusions: Increased adiposity, insulin resistance and use of prednisolone or dexamethasone are associated with impaired QoL in adults with CAH. Intervention trials are required to establish whether choice of glucocorticoid treatment and/or weight loss can improve QoL in CAH adults.

Background: Adults with congenital adrenal hyperplasia (CAH) are treated with a wide variety of glucocorticoid treatment regimens., Objective, Design and Methods: To test whether drug dose and timing of glucocorticoid treatment regimen impacts on health outcomes. This was a cross-sectional study of 196 adult CAH patients in whom treatment and health outcomes were measured. Glucocorticoid dose was converted to prednisolone dose equivalent (PreDEq) using three published formulae. Associations between the type of glucocorticoid regimen and PreDEq with specific health outcome variables were tested using partial correlation and principal components analysis (PCA)., Results: Patients on dexamethasone had lower androgens and ACTH but greater insulin resistance compared with those receiving hydrocortisone or prednisolone. Dexamethasone dose and once daily administration were associated with insulin resistance. Partial correlation analysis adjusted for age and sex showed PreDEq weakly correlated (r < 0·2) with blood pressure and androstenedione. Mutation severity was associated with increased PreDEq (F(3,141)  = 4·4, P < 0·01). In PCA, 3 PCs were identified that explained 62% of the total variance (r(2) ) in observed variables. Regression analysis (age and sex adjusted) confirmed that PC2, reflecting disease control (androstenedione, 17-hydroxypregesterone and testosterone), and PC3, reflecting blood pressure and mutations (systolic and diastolic blood pressure and mutation severity), related directly to PreDEq (r(2)  = 23%, P < 0·001)., Conclusions: In adults with congenital adrenal hyperplasia, dexamethasone use was associated with lower androgens but greater insulin resistance, and increasing glucocorticoid dose associated with increased blood pressure, poor disease control and mutation severity., (© 2012 Blackwell Publishing Ltd.)

Context: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking., Objective: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH., Research Design and Methods: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort., Results: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups., Conclusions: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size., Objective: Our objective was to establish the health status of adults with CAH., Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom., Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18-69) years., Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts., Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised., Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.

Carr and Hollins highlighted the paucity of research on the menopause in women with intellectual disabilities and, 10 years on, this area still remains poorly researched. Work exploring the age of onset of the menopause has suggested that the menopause is earlier in this group of women, but studies exploring what women with intellectual disabilities understand and experience during the menopause are limited. In this study 15 women with mild to moderate intellectual disabilities were interviewed using a semi-structured interview on a one-to-one basis about their knowledge and understanding of the menopause. Findings revealed limited accessible information about the menopause and a paucity in the women's knowledge and understanding about the menopause. This suggests a need for more accessible information, in order to increase understanding and awareness of the menopause in these women.

Collaborative learning is widely used in mainstream education but rarely utilized with children who have intellectual disabilities, possibly on the assumption that the metacognitive skills on which it capitalizes are less likely to be available. Effects of collaborative learning experience on a core cognitive skill, sorting by category, were investigated in three child groups: typically developing (TD) children, children with nonspecific intellectual disabilities (NSID) and children with Down syndrome (DS). Following collaboration, sorting performance improved significantly in lower ability partners in TD-TD pairings, with this pattern reversed in NSID-NSID pairings. Neither partner improved significantly in DS-NSID pairings, suggesting that the sociability attributed to children with DS did not necessarily support either their or their partner's learning in this social context.

Background: Interpreting emotional expressions is a socio-cognitive skill central to interpersonal interaction. Poor emotion recognition has been reported in autism but is less well understood in other kinds of intellectual disabilities (ID), with procedural differences making comparisons across studies and syndromes difficult. This study aimed to compare directly facial emotion recognition skills in children with fragile X syndrome (FXS), Down's syndrome (DS) and non-specific intellectual disability (NSID), contrasting ability and error profiles with those of typically developing (TD) children of equivalent cognitive and linguistic status., Methods: Sixty children participated in the study: 15 FXS, 15 DS, 15 NSID and 15 TD children. Standardised measures of cognitive, language and socialisation skills were collected for all children, along with measures of performance on two photo-matching tasks: an 'identity-matching' task (to control for basic face-processing ability) and an 'emotion-matching' task (happiness, sadness, anger, surprise, fear or disgust)., Results: Identity-matching ability did not differ across the four child groups. Only the DS group performed significantly more poorly on the emotion-matching task and only in comparison to the TD group, with fear recognition an area of particular difficulty., Conclusion: Findings support previous evidence of emotion recognition abilities commensurate with overall developmental level in children with FXS or NSID, but not DS. They also suggest, however, that syndrome-specific difficulties may be subtle and detectable, at least in smaller-scale studies, only in comparison with TD matches, and not always across syndromes. Implications for behavioural phenotype theory, educational interventions and future research are discussed.

The ability of children with Down syndrome to recognize expressions of emotion was compared to performance in typically developing and nonspecific intellectual disability groups matched on either MA or a performance-related measure. Our goal was to (a) resolve whether specific emotions present recognition difficulties; (b) investigate patterns of errors; and (c) explore the relationships among emotion-recognition ability and cognitive, linguistic, and adaptive behavior levels. Emotion-recognition ability in the Down syndrome group was significantly poorer than in the typically developing group overall, particularly for fearful expressions. Error patterns and relationships between task performance and assessment measures also differed across groups. Findings are consistent with a neurological explanation of specific deficits in sociocognitive functioning in children with Down syndrome.

Polycystic ovary syndrome is the most common cause of anovulatory infertility. Anovulation in polycystic ovary syndrome is characterized by the failure of selection of a dominant follicle with arrest of follicle development at the 5-10 mm stage. In an attempt to elucidate the mechanism of anovulation associated with this disorder we have investigated at what follicle size human granulosa cells from normal and polycystic ovaries respond to LH. Granulosa cells were isolated from individual follicles from unstimulated human ovaries and cultured in vitro in serum-free medium 199 in the presence of LH or FSH. At the end of a 48-h incubation period, estradiol (E2) and progesterone (P) were determined in the granulosa cell-conditioned medium by RIA. In ovulatory subjects (with either normal ovaries or polycystic ovaries), granulosa cells responded to LH once follicles reached 9.5/10 mm. In contrast, granulosa cells from anovulatory women with polycystic ovaries responded to LH in smaller follicles of 4 mm. Granulosa cells from anovulatory women with polycystic ovaries were significantly more responsive to LH than granulosa cells from ovulatory women with normal ovaries or polycystic ovaries (E2, P < 0.0003; P, P < 0.03). The median (and range) fold increase in estradiol and progesterone production in response to LH in granulosa cell cultures from size-matched follicles 8 mm or smaller were E2, 1.0 (0.5-3.9) and P, 1.0 (0.3-2.5) in ovulatory women and E2, 1.4 (0.7-25.4) and P, 1.3 (0.3-7.0) in anovulatory women. Granulosa cells from anovulatory (but not ovulatory) women with polycystic ovaries prematurely respond to LH; this may be important in the mechanism of anovulation in this common endocrinopathy.

In experimental animal models, insulin-like growth factors (IGFs) have been found to be more potent stimulators of ovarian function than insulin. In human theca cells, however, insulin, IGF-I, and IGF-II have similar effects on androgen production. The relative effects of insulin and IGFs on human granulosa cell steroidogenesis is unknown. Furthermore, it is unclear whether effects of IGF-II on steroidogenesis are mediated by the type-I or type-II IGF receptor. The effects of insulin, IGF-I, and IGF-II on human granulosa cell steroidogenesis were compared in vitro. As expected, insulin, IGF-I, and IGF-II enhanced steroidogenesis. Previously, IGF-II has been shown to enhance granulosa cell steroid production after insulin preincubation. In this study, an effect of IGF-II, independent of insulin priming, also was observed. In granulosa cell cultures from small antral follicles (< or = 13 mm), insulin and IGF-I stimulated steroid production to a similar degree, whereas IGF-II was less effective. In contrast, IGFs were more effective than insulin (IGF-I > IGF-II > insulin) in granulosa cells isolated from preovulatory follicles. IGF-I and IGF-II actions were mediated via the type-1 IGF receptor. The increased responsiveness of mature granulosa cells to IGFs may be an important mechanism by which granulosa cells increase their steroidogenic output in the preovulatory follicle.

This study analysed the effect of oestradiol on basal and LH-stimulated production of androstenedione and progesterone by human theca cells in monolayer culture. Incubations were carried out for either 2 days (seven experiments) or 4 days (four experiments), in the presence or absence of luteinizing hormone (LH), oestradiol (10(-9)-10(-6) M) or inhibin. Medium collected at 48 and 96 h was stored until radioimmunoassay for steroid content. Theca pooled from small follicles (<10 mm) was used in all but two experiments; in these, ovaries were obtained from ovulatory women in the mid-follicular phase of their cycle and theca from small and large follicles was pooled. Oestradiol inhibited progesterone production in a dose-dependent manner in all experiments, irrespective of follicle size, ovulatory status and ovarian morphology, with maximum effect at 10(-6) M. At this dose, oestradiol had no effect on androstenedione production by theca from four anovulatory women with polycystic ovaries but produced a significant augmentation of both basal and LH-stimulated androstenedione production in theca from five of the seven ovulatory women, with maximal response in theca from the two pre-ovulatory subjects. During the 48-96 h period of incubation, oestradiol augmented androstenedione production in all four experiments and had a greater stimulatory effect than the physiological dose of inhibin (10 ng/ml). This is the first report of oestradiol regulating human theca cell steroidogenesis in a dose-dependent manner.

The adverse effects of obesity on reproductive function in women are well recognized, but women with polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, seem particularly vulnerable to the effects of excessive intake of calories. Polycystic ovary syndrome is associated with hyperinsulinaemia and insulin resistance, the causes of which remain unclear. These metabolic abnormalities are, in turn, related to a disorder of energy expenditure, characterized by reduced post-prandial thermogenesis. It is proposed that these closely interlinked phenomena that, particularly in overweight subjects, are associated with anovulation, may confer a biological advantage for women with PCOS at times of food deprivation, when such women may reproduce more successfully than those without PCOS. A possible causal link between hyperinsulinaemia and ovulation is explored by reference to the interaction of insulin and LH in granulosa cells.

The underlying cause of anovulation in polycystic ovary syndrome is unknown. Circulating levels of immuno- and bioactive FSH are within the normal range, and the follicles contain measurable levels of bioactive FSH. The aim of this study was to compare estradiol (E2) production in response to FSH by granulosa cells from normal ovaries with those from polycystic ovaries derived from both anovulatory (anovPCO) and ovulatory subjects (ovPCO). Intrafollicular levels of immunoactive FSH, E2, and androstenedione in follicles of less than 12 mm were also measured. Follicular fluid steroid concentrations were obtained from 41 pairs of normal ovaries and 23 pairs of polycystic ovaries (8 anovPCO and 15 ovPCO). In size-matched follicles from each group there were no significant differences in follicular fluid FSH or E2 concentrations, but androstenedione levels were significantly higher in 5- to 11-mm follicles from ovPCO than in corresponding follicles from normal ovaries. Dose responses to FSH were determined in granulosa cells derived from 9 pairs of normal ovaries, 7 anovPCO, and 8 ovPCO. Cells from anovPCO produced 6- to 10-fold more E2 in response to FSH than normal cells, although there was no significant difference in the ED50 values. The response in cells from ovPCO was reduced compared to normal, but this difference did not reach significance. In summary, as judged by their FSH and E2 contents, polycystic ovaries do not have a higher proportion of atretic follicles than normal. Indeed, cells from anovPCO are hyperesponsive to FSH in vitro. This could be explained by stimulation of aromatase in vivo by either paracrine or, more probably, by endocrine factors, of which insulin is an arguable candidate.

The aim of this study was to examine the hypothesis that hypersecretion of ovarian androgens in polycystic ovary syndrome results from an intrinsic abnormality of androgen biosynthesis by thecal cells. Steroid accumulation by human thecal cells from normal and polycystic ovaries (PCO-theca) was examined under basal and LH-stimulated conditions. A method for dispersing and culturing human thecal cells as primary monolayers in serum-free medium was developed. LH increased androstenedione (A), progesterone (P), 17 alpha-hydroxyprogesterone, dehydroepiandrosterone, and estradiol accumulation in the overlying medium in a dose-dependent manner at a maximum effective dose of 2.5 ng/mL. The principal variables affecting the magnitude of steroid accumulation were plating density, duration of incubation, and follicle size. Using only theca from follicles less than 10 mm and keeping plating density constant, 48-h steroid production by theca from five normal ovaries was compared to that from nine polycystic ovaries isolated from both anovulatory and ovulatory women. There was a significant increase in both basal (median, 32.1 pmol/1000 cells.48 h; range, 18.7-250) and LH-stimulated (56 pmol/1000 cells; range, 40.7-406) A accumulation by PCO-theca compared to basal (1.7 pmol/1000 cells; range, 1.1-4.3) and LH-stimulated (2.8 pmol/1000 cells; range, 2.0-8.1) A accumulation by normal theca, with no overlap in values between the two. Although P production was also increased in the PCO-theca, the A to P ratios under both basal and LH-stimulated conditions were significantly higher in the PCO-theca [A/P ratio normal; PCO basal, 0.1 and 0.53 (P < 0.01); LH-stimulated, 0.04 and 0.65 (P < 0.001)], suggesting increased conversion of P to A. The steroid response to LH was similar in both groups. This is the first report of a difference in thecal androgen production between normal and polycystic ovaries and supports the hypothesis that there is a primary abnormality in the regulation of androgen production in PCOS.

Although abundant mRNA for IGF-II has been detected in the human ovary, a role for IGF-II in steroidogenesis has not yet been established. In rat adipocytes, incubation with insulin greatly increases cell-surface IGF-II receptor (5-fold) and the receptor is rapidly internalised in the absence of insulin. We have therefore investigated the effects of insulin preincubation on the response of granulosa cells from unstimulated ovaries to a range of doses of IGF-II. In the absence of insulin, IGF-II stimulated steroidogenesis in only one of three experiments. After incubation with 10 ng/ml insulin, there was a dose-dependent response to IGF-II in all experiments. Cells incubated with insulin produced 5-10 fold more estradiol in response to IGF-II than those incubated without. In contrast, insulin produced only a small increase of estradiol in response to IGF-I. These results demonstrate a synergistic interaction of insulin with IGF-II in human granulosa cells and suggest that there is an important role for IGF-II in human ovarian steroidogenesis.

The effects of recombinant human follicle stimulating hormone (rFSH; Org 32489) have been examined in human granulosa cells from ovaries obtained from women with spontaneous menses. In the first series of experiments the actions of rFSH on production of oestradiol and progesterone were compared with those of urinary-derived gonadotrophins. Recombinant FSH induced dose-dependent increases in production of both oestradiol and progesterone which were similar to the effects of 'pure' FSH (Metrodin) and the International Standard IS 71/223. In further studies, the actions of rFSH on oestradiol production by individual preovulatory follicles were investigated; rFSH increased oestradiol accumulation from cells obtained from follicles before the luteinizing hormone (LH) surge. In contrast, rFSH inhibited oestradiol production by granulosa cells derived from a follicle after the onset of the LH surge, whereas the gonadotrophic action of growth hormone was maintained. Following preliminary reports of the in-vivo effects of rFSH in women, these findings provide further validation of the efficacy of rFSH in the human ovary. The results of studies of the preovulatory follicle illustrate the experimental importance of the availability of recombinant preparations of pure gonadotrophins, produced by recombinant technology, in the understanding of human ovarian function.

Objectives: To establish a normal range for urinary growth hormone in adults and to investigate the urinary growth hormone levels in patients with acromegaly, comparing these with the serum growth hormone results of a glucose tolerance test. We also studied the molecular identity of the growth hormone recognized by our assay method., Design: Overnight urine samples and, in some cases, timed urine samples taken during the day were obtained from healthy volunteers and acromegalic patients. A standard glucose tolerance test with serum growth hormone measurements was performed on the acromegalic patients., Patients: One hundred and thirty-five normal adults and 33 acromegalic patients were studied., Measurements: Urinary growth hormone was measured using a sensitive and precise assay developed previously., Results: In healthy volunteers overnight urinary growth hormone values fell gradually with increasing age, but there was no significant difference between men and women in any decade or between smokers and non-smokers. Sexual intercourse had no detectable effect on the values, but there was a large increase following strenuous exercise. Studies of the diurnal patterns in normal and abnormal adults suggested that it might be possible to diagnose acromegaly on a random urine sample. Gel filtration studies on a urine sample from an acromegalic patient showed a single peak of molecular weight 22,000. Using overnight collections there was clear discrimination between the values given by the normal adults and the acromegalic patients and an excellent correlation between urinary growth hormone levels in acromegalic patients and the mean serum growth hormone in a glucose tolerance test., Conclusions: In contrast to some other groups we conclude that urinary growth hormone provides a useful, non-invasive screening test for acromegaly, but this conclusion depends crucially on the assay being sensitive and precise at low values.

As a result of performing pressure standardised lumbar discography, in vivo pressure measurements within lumbar discs have been recorded. Our results support the theory that for normal discs, the internal pressure within the nucleus pulposus increases when the subject changes from lying prone to standing and thence to sitting. However, when comparing our results with other published data, we consistently show a reduction in the absolute values recorded. We discuss the possible reasons for this discrepancy. Arguments have been advanced in the literature both for and against the nucleus in a normal disc behaving hydrostatically. An hypothesis which occupies the middle ground between these two concepts is proposed which could well be consistent with all the published data including our own.

By observing the variation of intradiscal pressure occurring at different body postures, it is possible to infer a functional hydrostatic behavior of a lumbar disc. Results from such observations on normal discs are already available. However, observations on degenerate discs are largely restricted to in vitro studies. The authors are now able to report a series of recordings taken from discographically degenerate lumbar discs in patients presenting with low-back pain. In this study of twenty patients, pressure observations were made on 21 normal and 19 abnormal discs. From the results that the authors have obtained, they can reaffirm that normal discs behave predictably and as previously described. The abnormal discs, however, did not behave as a single group. They showed patterns of pressure changes in different postures often dissimilar from that shown by the normal discs both in the absolute values recorded and the sequential changes that occur during the postural change. Unfortunately, the authors were unable to correlate either the extent or character of disc degeneration with the observed variation in pressure changes.