Factors affecting shared decision-making concerning menopausal hormone therapy.

Menopausal hormone therapy (MHT) is an effective treatment for menopause-related symptoms. Menopause management guidelines recommend a personalized approach to menopause care, including MHT use. Decision-making around menopause care is a complex, iterative process influenced by multiple factors framed by perspectives from both women and healthcare providers (HCPs). This narrative review aims to summarize evidence around factors affecting decision-making regarding menopause-related care. For HCPs, the provision of individualized risk estimates is challenging in practice given the number of potential benefits and risks to consider, and the complexity of the data available, especially within time-limited consultations. Women seeking menopause care have the difficult task of making sense of the benefit versus risk profiles to make choices in line with their decisional needs influenced by sociocultural/economic, educational, demographic, and personal characteristics. The press, social media, and influential celebrities also impact the perception of menopause and decision-making around it. Understanding these factors can lead to improved participation in shared decision-making, satisfaction with the decision and decision-making process, adherence to treatment, reduced decisional regret, efficient use of resources, and ultimately long-term satisfaction with care.

Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention.

In the early days of the first global wave of the COVID-19 pandemic, the potential for a postviral syndrome to manifest following COVID-19 infection was first recognized. Here, we present an analysis of a case series of the first 20 patients' data collected in clinical practice to evaluate the potential of a possible alternative treatment for Long COVID. Methods: Face-to-face treatment sessions with Perrin technique practitioners occurred weekly involving effleurage/other manual articulatory techniques. The individuals being treated also undertook daily self-massage along with gentle mobility exercises. Patients recorded symptom severity using the self-report 54-item profile of fatigue-related states (PFRS) before and after treatment. Results: The mean age of male patients was 41.8 years (range, 29-53 years), and for female patients, 39.3 years (range, 28-50 years). None of the participants had a prior diagnosis of chronic fatigue syndrome, and all were new attendees to the clinics at the time of initial assessment. The average number of treatment sessions was 9.7 in men and 9.4 in women. The reduction in PFRS scores was 45% in men and 52% in women. The highest subscale scores on average were for fatigue, with the lowest for somatic symptoms. All subscale scores showed, on average, a similar reduction of approximately 50% postintervention, with the reduction in score relating to a decrease in the severity of symptoms. Conclusion: Our findings suggest that a specific manual lymphatic drainage intervention may help to reduce fatigue symptoms related to Long COVID. Perhaps preventing acute symptoms through early intervention.

The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults.

The availability of recombinant human GH and somatostatin analogs has resulted in widespread treatment for adults with GH deficiency (GHD) and those with GH excess (acromegaly). Despite being at opposite ends of the spectrum in terms of their GH/IGF-I axis, both of these populations experience overlapping somatic impairments. Adults with untreated GHD have low circulating levels of IGF-I that manifest as altered body composition with increased fat and reduced lean body and skeletal muscle mass. At the other end of the spectrum, adults with GH excess, who have elevated levels of IGF-I, also have altered body composition. Impairments that result from disorders of either GHD or GH excess are both associated with increased functional limitations, such as reduced ability to walk quickly for prolonged periods, and poorer health-related quality of life (HR-QoL). Adults with untreated GHD and GH excess both commonly complain of excessive fatigue that seems to be associated more with impaired aerobic than muscular performance. Several studies have documented that administration of GH or somatostatin analogs to adults with GHD or GH excess, respectively, ameliorates abnormal biochemical profile and the associated somatic impairments. However, whether these improvements translate into improved physical function in adults with GHD or GH excess remains largely unknown, and their impact on HR-QoL controversial. Review of placebo-controlled trials to date suggests that GH and somatostatin analogs have greater effects on gas exchange and aerobic performance than as anabolic agents on skeletal muscle mass and function. Future investigations should include dose-response studies to establish the optimal combination of pharmacological agents plus exercise required to improve not only biochemical markers but also physical function and HR-QoL in adults with GHD or GH excess.

Immune function in hypopituitarism: time to reconsider?

Hypopituitarism is not currently considered as a potential cause of immune disruption in humans. Accumulating data from in vitro and animal models support a role for the pituitary gland in immune regulation. Furthermore, the increased mortality risk noted in patients with adult hypopituitarism remains poorly explained and immune dysfunction could conceivably contribute to this observation. In a recent issue of Clinical & Experimental Immunology, we presented new data relating to immune status in adults with treated, severe hypopituitarism. We observed humoral immune deficiency in a significant proportion, despite stable pituitary replacement, including growth hormone (GH). This was especially evident in those with low pretreatment IGF-I levels and appeared independent of anticonvulsant use or corticosteroid replacement. These observations require substantiation with future studies. In this short review, we summarize existing data relating to the effects of pituitary hormones on immune function and discuss potential clinical implications surrounding the hypothesis of immune dysregulation in severe hypopituitarism.

GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.

BACKGROUND: Females secrete 2-3 -fold greater amounts of GH compared with males despite maintaining similar IGF-I levels. IGF-I generation tests in healthy subjects suggest this discordancy results from relative resistance to GH in females. In GHD females the presumed relative insensitivity to GH is reflected by a lower basal IGF-I and the need for higher GH maintenance doses during replacement. Adults with severe GHD of childhood-onset (CO) have lower basal IGF-I SDS and require higher GH maintenance doses compared with adult-onset (AO) patients with GHD of equal severity. We hypothesised CO-GHD adults to be less sensitive to GH than AO-GHD patients. METHODOLOGY: In a single site study we analysed the incremental change in IGF-I (DeltaIGF-I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide DeltaIGF-I/mg GH because of slight variances in initial GH dose. RESULTS: Following GH replacement DeltaIGF-I was 230 +/- 245 and 356 +/- 278 ng/ml/mg GH in females and males, respectively (P = 0.01). In CO and AO patients DeltaIGF-I was 282 +/- 206 and 294 +/- 292 ng/ml/mg GH, respectively (P = 0.83). Further analysis after stratification by both gender and timing of onset of GHD showed DeltaIGF-I was 226 +/- 164, 324 +/- 228, 231 +/- 268, and 373 +/- 304 ng/ml/mg GH in the CO females, CO males, AO females, and AO males, respectively (AO males vs. AO females, P = 0.03; CO males vs. CO females, P = 0.17; AO males vs. CO males, P > 0.05; AO females vs. CO females, P > 0.05). Multiple linear regression with DeltaIGF-I as the dependent variable and age, gender, BMI, baseline IGF-I level, and timing of onset as independent variables showed DeltaIGF-I to be dependent on gender alone (R = 0.28, P = 0.004). Age (P = 0.44), BMI (P = 0.54), baseline IGF-I level (P = 0.63) and timing of onset (P = 0.61) had no effect on DeltaIGF-I. CONCLUSION: We have shown gender to have a significant impact on GH sensitivity in GHD adults, which, at least in part, explains differences in maintenance dosages during replacement. None of the additional variables impacted significantly on GH sensitivity. The lower basal IGF-I SDS and higher GH replacement requirement reported in CO compared with AO patients cannot be explained by differences in sensitivity to GH.

'They've all got to learn'. Medical students' learning from patients in ambulatory (outpatient and general practice) consultations.

BACKGROUND: The dynamics of effective teaching consultations need to be better understood. AIM: Find from medical students, patients and doctors how to optimize learning in ambulatory consultations. METHODS: Patients and students independently gave semi-structured exit interviews after 25 ambulatory teaching consultations during a clinical attachment set up experimentally to strengthen students' ambulatory learning. The results of an abbreviated grounded theory analysis were checked in three focus group discussions with teachers and students. RESULTS: Patients and students identified strongly with one another and benefited from teaching consultations in parallel ways yet defaulted to passive roles. Patients deferred to professional expertise whilst students were uncertain what was expected of them, feared harming patients and feared being showed up as ignorant. The educational value of consultations was determined by doctors' ability to promote student-patient interaction. CONCLUSIONS: In the most effective teaching consultations, doctors promoted a level of participation that realized patients' and students' mutual sense of responsibility by orientating them to one another, creating conditions for them to interact, promoting and regulating discourse, helping students to perform practical tasks and debriefing them afterwards. Those broad conclusions translate into 18 practical recommendations for supervising a medical student in an outpatient clinic or surgery.

Clinical diagnosis of Graves' or non-Graves' hyperthyroidism compared to TSH receptor antibody test.

BACKGROUND: TSH receptor antibody (TRAb) is considered the gold standard diagnostic test for the autoimmunity of Graves' disease (GD), which is commonly diagnosed clinically. AIM: To evaluate the true positive (sensitivity) and true negative (specificity) rates of clinical diagnosis of GD or non-GD hyperthyroidism compared to the TRAb test. SETTING: University teaching hospital in North West England. PARTICIPANTS: Patients in the Endocrinology service who had a TRAb measurement between December 2009 and October 2015. METHODS: Electronic patient records were studied retrospectively for a pre-TRAb clinical diagnosis of GD or non-GD hyperthyroidism. We examined descriptive statistics and binary classification tests; Fisher exact test was used to analyse contingency tables. RESULTS: We identified 316 patients with a mean age of 45 (range, 17-89) years; 247 (78%) were women. Compared to the TRAb result, clinical diagnosis had a sensitivity of 88%, specificity 66%, positive predictive value 72%, negative predictive value 84%, false negative rate 12%, false positive rate 34%, positive likelihood ratio 2.6 and negative likelihood ratio 0.2 (P < 0.0001). CONCLUSIONS: Clinicians were liable to both over- and under-diagnose GD. The TRAb test can help reduce the number of incorrect or unknown diagnoses in the initial clinical assessment of patients presenting with hyperthyroidism.

Can physical assessment techniques aid diagnosis in people with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study.

OBJECTIVE: To assess five physical signs to see whether they can assist in the screening of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and potentially lead to quicker treatment. METHODS: This was a diagnostic accuracy study with inter-rater agreement assessment. Participants recruited from two National Health Service hospitals, local CFS/ME support groups and the community were examined by three practitioners on the same day in a randomised order. Two allied health professionals (AHPs) performed independent examinations of physical signs including: postural/mechanical disturbances of the thoracic spine, breast varicosities, tender Perrin's point, tender coeliac plexus and dampened cranial flow. A physician conducted a standard clinical neurological and rheumatological assessment while looking for patterns of illness behaviour. Each examination lasted approximately 20 min. RESULTS: Ninety-four participants were assessed, 52 patients with CFS/ME and 42 non-CFS/ME controls, aged 18-60. Cohen's kappa revealed that agreement between the AHPs was substantial for presence of the tender coeliac plexus (κ=0.65, p<0.001) and moderate for postural/mechanical disturbance of the thoracic spine (κ=0.57, p<0.001) and Perrin's point (κ=0.56, p<0.001). A McNemar's test found no statistically significant bias in the diagnosis by the experienced AHP relative to actual diagnosis (p=1.0) and a marginally non-significant bias by the newly trained AHP (p=0.052). There was, however, a significant bias in the diagnosis made by the physician relative to actual diagnosis (p<0.001), indicating poor diagnostic utility of the clinical neurological and rheumatological assessment. CONCLUSIONS: Using the physical signs appears to improve the accuracy of identifying people with CFS/ME and shows agreement with current diagnostic techniques. However, the present study concludes that only two of these may be needed. Examining for physical signs is both quick and simple for the AHP and may be used as an efficient screening tool for CFS/ME. This is a small single-centre study, and therefore, further validation in other centres and larger populations is needed.

Interdependence of lean body mass and total body water, but not quality of life measures, during low dose GH replacement in GH-deficient adults.

Lean body mass (LBM) and total body water (TBW) are reduced in GH-deficient (GHD) adults and alter with GH replacement. Whether these parameters are interdependent and whether alterations in their homeostasis contribute to the perceived quality of life (QOL) deficit in GHD remains unclear. In this study, IGF-I, body composition by whole-body dual-energy X-ray absorptiometry, TBW by deuterium dilution (D(2)O) and two validated QOL instruments - psychological general well-being schedule (PGWB, generic, 6 domains; lower score worse QOL) and assessment of GH deficiency in adults (AGHDA, disease orientated; higher score worse QOL) were studied at baseline and after 3 and 6 months of GH replacement in thirty GHD adults. Patients with diabetes insipidus, and cardiac and renal failure were excluded. Median age-adjusted IGF-I standard deviation score increased from -3.40 (-6.40 to -1.60) to -0.2 (-1.88 to 0.78) (P < 0.0001) at a median daily GH dose of 0.4 mg. During treatment, LBM increased from 47.4 +/- 10.7 kg at baseline to 49.5 +/- 10.8 kg at 6 months (P = 0.0008), and fat mass decreased from 28.0 +/- 12.1 kg at baseline to 27.2 +/- 12.6 kg at 6 months (P = 0.0004). A non-significant trend towards an increase in TBW was observed (mean 1.7 kg, P = 0.08). The PGWB score increased from 62.9 +/- 20.6 to 73.7 +/- 21.7 (P = 0.0006). The AGHDA score decreased from 13.7 +/- 7.3 to 8.75 +/- 7.75 (P = 0.0002). At each time point, a linear correlation between LBM and TBW was demonstrated, defined by TBW = (0.972 x LBM)-10.6. However, only a weakly positive correlation existed between the percentage changes in these variables (R = 0.40, P = 0.04). No correlations were demonstrated between QOL measures and body composition. The change in LBM with physiological GH replacement correlates weakly with change in TBW, therefore factors other than TBW may also contribute to the LBM changes. Improved QOL with GH replacement is not explained by favourable changes in body composition.

Seeking the optimal target range for insulin-like growth factor I during the treatment of adult growth hormone disorders.

Impaired GH activity at target tissues, occurring when GH action is blocked or during suboptimal GH replacement therapy, may result in a pathological state associated with lowering of IGF-I, but not GH levels. Such a state represents functional but not necessarily actual GH deficiency (GHD). The aim of this study was to identify a range of IGF-I values commensurate with GHD, which could be used to determine the risk of functional GHD during the treatment of adult GH disorders. Centrally measured baseline IGF-I data from the Kabi International Metabolic Study European GHD database were analyzed. Inclusion criteria were adult-onset GHD and two or more additional anterior pituitary hormone deficits. Adults with childhood-onset GHD and cured acromegaly were excluded. The cohort was stratified into six gender-based age ranges. Baseline IGF-I measurements from 376 females (median age, 48 yr; range, 21-77 yr) and 434 males (median age 52 yr; range 21-80 yr) were analyzed. Data were not normally distributed and are presented as medians (quartiles). The median serum IGF-I and IGF-I SDS in males were 94.0 microg/liter (64 and 141) and -1.52 (-2.53 and -0.456; n = 434). Both were significantly greater than the equivalent values of females, which were 73 microg/liter (46 and 103.5) and -2.30 (-3.28 and -1.328; n = 376; P < 0.0001 for both). Age and gender-related 90th and 95th percentiles for IGF-I SDS were determined to generate risk estimates for functional GHD, which, in conjunction with the clinical status of the patient, may be used to aid dose titration during treatment of GH disorders in adulthood.

Skeletal requirements for optimal growth hormone replacement in the transitional years.

In addition to its well-established effects on linear growth in childhood and adolescence, growth hormone (GH) has both direct and indirect actions on bone remodelling and homeostasis. In this review, the discussion begins with the influence of childhood-onset growth hormone deficiency (CO-GHD) on bone mineral accretion. The limitations of methods of assessing bone mineral density (BMD) are highlighted and specific influential factors, which affect peak bone mass achievement and therefore skeletal health in later life, are evaluated.

Pharmacological treatment of hypercortisolism.

PURPOSE OF REVIEW: To consider the current status and types of drug therapy aimed at restoring eucortisolaemia in patients with Cushing's syndrome. RECENT FINDINGS: Advances such as laparoscopic adrenalectomy modify the exact placing of drug therapy among the wide variety of therapies available to treat patients with Cushing's syndrome because of different causes; nonetheless, it is now clear that hypercortisolism, per se, if present for any length of time, modifies the future prognosis of the patient, even after cure of the Cushing's syndrome. Thus, early diagnosis and restoration of eucortisolsm are critical. There are three main types of drug therapy: steroidogenesis inhibitors, glucocorticoid antagonists and neuromodulatory compounds. Currently, steroidogenesis inhibitors such as metyrapone and ketaconazole are most commonly the first choice if drug therapy is to be used, but at least for the most common form of Cushing's syndrome, Cushing's disease, the neuromodulatory compounds such as cabergoline show potential. SUMMARY: Pharmacological therapy for Cushing's syndrome remains critically important for normalizing cortisol levels while awaiting the impact of more definitive treatment.

Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors.

OBJECTIVE: Systematic collections of neuroimaging data are nonexistent in brain tumour survivors treated with adult growth hormone replacement therapy (AGHRT). We present our surveillance data. DESIGN: In 1993, our unit implemented a policy of performing brain scans on every brain tumour survivor before starting AGHRT, with repeat neuroimaging at least once after 12-18 months' treatment. Reports for baseline scans and most recent scans were analysed for this retrospective study. PATIENTS: All brain tumour survivors who received AGHRT (60 patients) were included in the analysis. MEASUREMENTS: Evidence and extent of residual tumour, tumour progression, tumour recurrence, and secondary neoplasms (SN) on baseline scan and latest follow-up scan. RESULTS: All patients had baseline scans performed. Follow-up scans were available in 41/45 (91%) patients who received AGHRT for more than 1 year (mean duration +/- SD of GHRT was 6.7 +/- 3.6 years). Sixteen patients had residual tumours, and SNs (all meningiomas) were demonstrated in three patients on baseline scans. Appearances remained stable in 34 (83%) patients during follow-up (extending to 17.4 +/- 8.3 years after tumour diagnosis). Of the 16 residual primary tumours, an incurable ependymoma continued to grow, and one meningioma progressed slightly in size over 7.7 years. Follow-up scans also revealed continued growth of the SNs detected at baseline, and five additional meningiomas (two in patients with a previous SN, confirming an excess risk in this subgroup, P = 0.02). All SNs occurred on average 22.8 (range 17-37) years after radiotherapy. CONCLUSIONS: Our data do not suggest an increased rate of recurrence or progression of childhood brain tumours during AGHRT. Nonetheless, vigilance and long-term surveillance are needed in these patients in order to detect and monitor SNs, in particular in patients with a previous history of a SN. We endorse a proactive neuroimaging policy, preferably as part of a larger, controlled trial in the future.

A new sustained-release preparation of human growth hormone and its pharmacokinetic, pharmacodynamic and safety profile.

OBJECTIVE: Adult GH replacement is currently given by daily subcutaneous (sc) injections. Recently, sustained-release (SR) preparations of GH have been developed, the preparations being characterized by a dominant early release, resulting in supraphysiological early GH peaks, and a rapid decline thereafter. We present data on a new SR GH preparation. DESIGN: Phase I/II study of hGH-Biosphere(R) (SkyePharma AB, Malmo, Sweden), a new SR preparation of recombinant human GH in amylopectin microspheres coated with polylactide-coglycolide. PATIENTS: Eight adults with severe, untreated GH deficiency (stimulated GH peaks between < 1 and 1.7 microg/l), aged 36.1 years (range 22-49 years) in good general health. MEASUREMENTS: Pharmacokinetic (PK), pharmacodynamic (PD) and safety data over a period of 28 days. RESULTS: The systemic and local tolerability of the drug was satisfactory, and no serious adverse events occurred. PK analysis showed a smaller early serum hGH peak followed by a broad sustained second peak of hGH (C(max) 1.20 microg/l at 7.2 days), and hGH levels were maintained above baseline for at least 14 days. The mean GH level never exceeded 1.1 microg/l, making the GH fluctuations comparable to continuous sc infusion. Resultant IGF-I concentrations were characterized by sustained elevation at a level near C(max) of 103 microg/l (at t(max) of 9.7 days), equal to an SD score of +0.8. IGF-I generation per administered GH was more efficient compared with reports of other SR preparations. CONCLUSION: hGH-Biosphere(R) is a well-tolerated SR GH preparation with superior efficacy in achieving target IGF-I levels without causing supraphysiological GH concentrations. Our data suggest the suitability of this preparation for longer-term trials in adults with injection frequencies of no more than once every 2-3 weeks.

Growth hormone replacement therapy (GHRT) in children and adolescents: skeletal impact.

In addition to its well-established effects on linear growth in childhood and adolescence, growth hormone has both direct and indirect actions on bone remodelling and homeostasis. In this review the limitations of methods of assessment of bone mineral density are highlighted. The influence of growth hormone deficiency of childhood-onset, on bone mineral accretion and, the specific skeletal implications of GHD in long-term survivors of childhood cancers, are discussed. Specific influential factors, which affect peak bone mass achievement and therefore skeletal health in later life, are evaluated.