Bone mineral density in complete androgen insensitivity syndrome and the timing of gonadectomy.

OBJECTIVE: Low bone mineral density (BMD) has been reported in complete androgen insensitivity syndrome (CAIS), but the impact of timing of gonadectomy is not known. We aimed to assess the relationship between age of gonadectomy and BMD in women with CAIS. DESIGN: Retrospective analysis of pre- and post-gonadectomy parameters in women with CAIS attending an adult Disorders of Sex Development (DSD) clinic in a tertiary centre. PATIENTS: One hundred and thirteen women with CAIS. MEASUREMENTS: Dual-energy X-ray absorptiometry (DXA) before and after gonadectomy; and pre-gonadectomy hormone profile. RESULTS: Mean BMD was reduced (95% confidence interval); T-score -1.34 (-1.55 to -1.13; P<.001) at the lumbar spine and -0.3 (-0.49 to -0.12; P=.001) at the hip. There was no relationship between age of gonadectomy and BMD. Thirty-two subjects had BMD measured before or within 2 years of gonadectomy, and mean BMD was reduced (95% CI) at the lumbar spine; T-score: -1.05 (-1.54 to -0.57; P<.001), but was normal at the hip; T-score -0.04 (-0.35 to 0.28; P=.8). There was no relationship between BMD and history of hernia, testosterone, oestradiol or follicle stimulating hormone levels. Twelve subjects had DXA both before and after gonadectomy, and after 4.3 (1.7-12.8) years, there was no change in BMD. CONCLUSIONS: We found reduced BMD at the spine and hip in subjects with CAIS. We found no relationship between age of gonadectomy and BMD, and we also found no drop in BMD in subjects followed up after gonadectomy.

The Turner syndrome life course project: Karyotype-phenotype analyses across the lifespan.

INTRODUCTION: Turner syndrome (TS) is associated with a variety of morbidities affecting nearly every body system, some of which increase in prevalence in adult life. The severity of clinical features in TS is roughly in parallel with the magnitude of the deficit of X-chromosome material. The aim of this study was to extend the established karyotype-phenotype relationships using data from a large adult cohort. MATERIALS AND METHODS: Karyotypes were available in 656 women with TS. 611 of whom could be classified into five major groups within the cohort: 45,X; 45,X mosaicism (45,X/46,XX); isochromosome X (isochromosome Xq); mosaicism 45,X/46,XY and ring X. Continuous variables such as blood pressure and biochemical markers from clinic data were binarised allocating those in the upper quartile to represent at-risk individuals. With the exception of bone mineral density T-score for which the lower quartile was allocated as at risk. For comorbidities, initiation of formal treatment was recorded. RESULTS: 45,X/46,XX had considerably lower frequency of comorbidities compared to 45,X. The isochromosome group experienced similar outcomes to 45,X. Novel associations were found between the XY mosaic karyotype group and a decreased prevalence of thyroid disease and severe hearing loss. A previously unreported increased incidence of metabolic syndrome was noted within the ring chromosome subgroup. CONCLUSIONS: Karyotype may play an important factor against stratifying risk of comorbidity in TS and should be taken into consideration when managing adults with TS. Further investigations of the isochromosome (Xq) and ring groups are necessary to further clarify their associations with comorbidities.

Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency.

OBJECTIVE: Men with congenital adrenal hyperplasia (CAH) have impaired fertility. We aimed to assess fertility outcomes and the importance of hypogonadotropic hypogonadism, testicular failure and the presence of testicular adrenal rest tumours (TART). DESIGN: Retrospective analysis of men attending an adult CAH clinic in a tertiary centre. PATIENTS: Fifty men with CAH due to 21 hydroxylase deficiency were identified of whom 35 were salt wasting and 15 were non-salt-wasting. MEASUREMENTS: Review of fertility history and parameters including luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, 17-hydroxyprogesterone (17-OHP), semen analysis and the presence of testicular adrenal rest tissue (TART) on ultrasound. RESULTS: TART were detected by ultrasound in 21 (47%), and their presence was associated with an elevated FSH (P = 0·01). Severe oligospermia was present in 11 of 23 (48%), and this was associated with an elevated FSH (P = 0·02), suppressed LH (P < 0·01) and TART (P = 0·03) when compared to those with a sperm count >5 × 10(6) per ml. Of those that desired fertility, 10 of 17 (59%) required treatment intensification and four underwent in vitro fertilization. Intensification resulted in a rise in median LH (0·6-4·3 IU/l; P = 0·01). Live birth rate was 15 of 17 (88%) with a median (range) time to conception of 8 (0-38) months. CONCLUSIONS: Suppressed LH is a marker for subfertility and is often reversible. Testicular failure is closely associated with TART formation. If TART are detected, sperm cryopreservation should be offered given the risk of progression to irreversible testicular failure. Male fertility in CAH can be improved by intensified treatment and assisted reproductive technology.

Plasma Metanephrines Yield Fewer False-Positive Results Than Urine Metanephrines in Patients With Obstructive Sleep Apnea.

CONTEXT: Obstructive sleep apnea (OSA) is associated with increased nocturnal sympathetic activity. In OSA patients, elevations in metanephrines may lead to false-positive tests when evaluating for pheochromocytoma or paraganglioma (PPGL). OBJECTIVE: To evaluate whether morning plasma metanephrines would lead to fewer false-positive results than 24-hour urinary metanephrines in OSA patients. METHODS: Patients undergoing polysomnography for suspected OSA were recruited. Plasma free and 24-hour urinary metanephrines were measured by HPLC-MS/MS. Patients with elevated levels had repeat measurements, abdominal imaging, and follow-up to diagnose or exclude a PPGL. RESULTS: Seventy-six patients completed polysomnography and biochemical testing; 68 (89.5%) patients had OSA, of whom 19 (27.9%) had elevated plasma and/or urinary metanephrines. On follow-up, one patient had a bladder paraganglioma, while PPGL was excluded in the remaining patients. OSA patients had more false-positive urinary metanephrines (17 of 67, 25.4%) than plasma metanephrines (2 of 67, 3.0%), P < .01, and this was more common in severe OSA (13 of 34, 38.2%), compared to moderate/mild OSA (4 of 33, 12.1%), P < .01. Both plasma and urinary metanephrines decreased after treatment with continuous positive airway pressure. On multivariable analysis, severe OSA, obesity, and family history of hypertension were positive predictors for false-positive urinary metanephrines in patients with suspected OSA. CONCLUSION: In OSA patients, plasma metanephrines are less likely to yield false-positive results for the diagnosis of PPGL than 24-hour urinary metanephrines. In patients with suspected OSA, obesity, or a family history of hypertension, plasma metanephrines may be the preferred first-line test to avoid unnecessary anxiety or follow-up.

Improvement in quality of life and psychological symptoms after treatment for primary aldosteronism: Asian Cohort Study.

BACKGROUND: In addition to increased cardiovascular risk, patients with primary aldosteronism (PA) also suffer from impaired health-related quality of life (HRQoL) and psychological symptoms. We assessed for changes in HRQoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy. METHODS: Thirty-four patients with PA were prospectively recruited and completed questionnaires from 2017 to 2020. HRQoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms were assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment. RESULTS: At 1 year post-treatment, significant improvement was observed in both physical and mental summative scores of RAND-36, +3.65, P = 0.023, and +3.41, P = 0.033, respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional, and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (n = 21) had significant improvement in EQ-5D index score post-treatment and better EQ-5D outcomes compared to the medical group (n = 13) at 1 year post-treatment. 37.9, 41.6 and 58.6% of patients had symptoms in the cognitive, affective and somatic domains of BDI-II, respectively. There was a significant improvement in the affective domain of BDI-II at 1 year post-treatment. CONCLUSION: Both surgical and medical therapy improve HRQoL and psychological symptoms in patients with PA, with surgery providing better outcomes. This highlights the importance of early diagnosis, accurate subtyping and appropriate treatment of PA.

Bone mineral density and trabecular bone score in elderly type 2 diabetes Southeast Asian patients with severe osteoporotic hip fractures.

INTRODUCTION: Studies show trabecular bone score (TBS) may provide information regarding bone quality independent of bone mineral density (BMD) in type 2 diabetes (DM2) patients. We analyzed our Southeast Asian severe osteoporotic hip fracture patients to study these differences. METHODS: We conducted a retrospective cross-sectional analysis of subjects admitted to Changi General Hospital, Singapore with severe osteoporotic hip fractures from 2014-2017 who had BMD performed. Electronic records were reviewed and subjects were classified as having diabetes according to the WHO 2019 criteria. DM2 patients were classified according to their HbA1c into well controlled (HbA1c < 7%) and poorly controlled (HbA1c ≥ 7%) DM2. RESULTS: Elderly patients with hip fractures present with average femur neck T scores at the osteoporotic range, however those with DM2 had higher BMD and TBS values compared to non DM2 patients. These differences were statistically significant in elderly women-poorly controlled elderly DM2 women with hip fracture had the highest total hip T-score (-2.57 ± 0.86) vs (-2.76 ± 0.96) in well controlled DM2 and (-3.09 ± 1.01) in non DM2 women with hip fracture, p < 0.001. In contrast, TBS scores were lower in poorly controlled DM2 women with hip fracture compared to well controlled DM2 women with hip fracture (1.22 ± 0.11) vs (1.24 ± 0.09), but these were still significantly higher compared to non DM2 women with hip fracture (1.19 ± 0.10), p < 0.001. In elderly men with hip fractures, univariate analysis showed no statistically significant differences in TBS or hip or LS BMD between those with poorly controlled DM2, well controlled DM2 and non DM2. The differences in TBS and BMD remained significant in all DM2 women with hip fractures even after adjustments for potential confounders. Differences in TBS and BMD in poorly controlled DM2 men with hip fractures only became significant after accounting for potential confounders. However, upon inclusion of LS BMD into the multivariate model these differences were attenuated and remained significant only between elderly women with well controlled DM2 and non DM2 women with hip fractures. CONCLUSIONS: Elderly patients with DM2 and severe osteoporosis present with hip fractures at a higher BMD and TBS values compared to non DM2 patients. These differences were significant after adjustment for confounders in all DM2 women and poorly controlled DM2 men with hip fractures, TBS differences were attenuated with the inclusion LS BMD. Further studies are needed to ascertain differences in BMD and TBS in older Southeast Asian DM2 patients with variable glycemic control and severe osteoporosis.

Effects of Estrogen Therapies on Outcomes in Turner Syndrome: Assessment of Induction of Puberty and Adult Estrogen Use.

CONTEXT: Turner syndrome (TS) is often associated with delayed puberty. To induce puberty, estrogen is administered in incremental doses at an age determined by age of presentation. After puberty, various types of maintenance estrogen replacement therapy (ERT) are used. OBJECTIVE: We sought associations between age of induction of puberty and type of ERT on adult health outcomes. DESIGN: Health surveillance data included blood profiles, bone density, and blood pressure. We assessed interactions between these data and age at first estrogen exposure in women with primary amenorrhea. We also assessed these data according to ERT subgroups [combined oral contraceptive pill (OCP), oral estrogen (OE), and transdermal estradiol (TE)] using data from each of 6679 clinic visits, controlling for age, body mass index, and height. SETTING: Adult TS clinic at University College London Hospital. PATIENTS: Of 799 women with TS, 624 had primary amenorrhea and 599 had accurate maintenance ERT data. MAIN OUTCOME MEASURES: Parameters of health surveillance derived from clinical guidelines. RESULTS: Estrogen start age was negatively correlated with adult bone density (spine: r = -0.20 and hip: r = -0.022; P ≤ 0.001). OCP users had higher blood pressure and an adverse lipid profile compared with other ERT subgroups. TE was associated with elevated liver enzymes and hemoglobin A1c compared with OE (P ≤ 0.01). CONCLUSIONS: An earlier age of induction of puberty may be beneficial for adult bone density. Given the high prevalence of hypertension in TS, the use of OCP for ERT should be limited. OE may be a benefit for steatohepatitis.

Managing polycystic ovary syndrome in primary care.

Polycystic ovary syndrome (PCOS) presents with a spectrum of conditions resulting from androgen excess, anovulation and metabolic syndrome. Patients with PCOS may see their primary care physicians for various presentations, including hirsutism, acne, menstrual irregularities, infertility, obesity, and psychiatric disorders such as anxiety and depression. Management of these patients should include screening for Type 2 diabetes mellitus, dyslipidaemia and hypertension. Treatment should be targeted to each patient's phenotype and personal expectations such as desire for pregnancy. Psychological well-being due to the effects on physical appearance is also an important consideration. Diet and exercise are major components in the management of patients with PCOS and obesity. The first-line therapy for fertility and metabolic syndrome in PCOS is lifestyle modification with diet and exercise, followed by pharmacological therapy.

Hormone replacement treatment choices in complete androgen insensitivity syndrome: an audit of an adult clinic.

OBJECTIVE: To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. DESIGN: Retrospective review. PATIENTS: Women with CAIS identified from our database. RESULTS: The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1-53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. CONCLUSIONS: In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone.

High prevalence of missed opportunities for secondary fracture prevention in a regional general hospital setting in Singapore.

This study aims at assessing the gap in secondary fracture prevention at a regional general hospital setting in Singapore. Male patients have significantly lower rate of being investigated and treated for osteoporosis than their female counterparts. Vitamin D deficiency is prevalent in our population. PURPOSE: Secondary fracture prevention services are not routine in Singapore; we seek to assess the treatment gap that exists in the lack of diagnosis and treatment of osteoporosis in fragility fracture patients. METHODS: We performed a retrospective analysis of all admissions for fragility fractures between December 2013 and December 2014. Demographic data, rates of BMD performance, serum vitamin D investigation and calcium and vitamin D supplementation as well as antiresorptive initiation 1 year post admission were analysed. RESULTS: There were 125 fragility fractures in patients below 65 and 615 fractures in older patients. There was a slightly higher proportion of males in the younger population, whereas females predominated in the older population. Median vitamin D levels were low in both younger (19.1 µg/L) and older (22.0 µg/L) groups, but supplementation was lower in younger patients (4.8 versus 16.6%, p = 0.003). Rate of BMD performance was lower in younger patients (34.4 versus 64.6%, p < 0.01); there was a significant difference of BMD performance between male and female patients in the younger population (19.1 versus 52.8%, p < 0.01) which was not present in the older age group. Antiresportive initiation was significantly lower in the younger age group versus older (10.4 versus 31.5%, p < 0.01); male patients in the younger and older age groups had significantly lower antiresorptive initiation rate compared to the females. CONCLUSION: There is a significant treatment gap in diagnosis and treatment of osteoporosis in fragility fracture patients in a regional hospital setting in Singapore. Male osteoporosis remains inadequately investigated and treated in both age groups.

Swyer syndrome.

PURPOSE OF REVIEW: This review focuses on the pathogenesis, diagnosis, management and long-term outcomes of disorders of sex development, specifically women with Swyer syndrome (46,XY complete gonadal dysgenesis). RECENT FINDINGS: Recent discoveries have broadened our understanding of the complex pathways involved in normal and abnormal sex development. In 46,XY gonadal dysgenesis, lack of testis development may be triggered by sex determining region Y, NR5A1, DHH or testis-determining gene loss-of-function mutations, DAX1 or WNT4 duplication or MAP3K1 gain-of-function mutations. The diagnosis and management of patients with Swyer syndrome is complex, and optimal care requires an experienced multidisciplinary team. Early diagnosis is vital because of the significant risk of germ cell tumour, and bilateral gonadectomy should be performed. Furthermore, early sex hormone treatment is necessary to induce and maintain typical pubertal development and to achieve optimal bone mineral accumulation. Pregnancy is possible via ova donation, and outcomes are similar to women with 46,XX ovarian failure. SUMMARY: Further pathogenic gene mutations are likely to be identified, and the function, interaction and phenotypic effects of new and existing mutations will be further defined. Patients require long-term follow-up in specialist centres.

Endothelial progenitor cells and cardiovascular disease.

Endothelial Progenitor Cells (EPCs) are bone-marrow derived stem cells that are postulated to contribute to post-natal vasculogenesis and to repair of damaged endothelium by incorporation into the vessel wall, secretion of paracrine hormones and stimulation of angiogenesis. Since the first description of the putative EPCs in 1997, and the role of these cells in neovascularisation of mouse and rabbit ischaemic limbs was originally described, there has been an explosion of research into the role of EPCs in human cardiovascular disease. There is now a large body of direct and indirect evidence to support an important role for EPCs in cardiovascular disease processes. This book chapter explores the following: 1. Correlation between EPCs and other cardiovascular risk markers 2. EPCs in patients with established cardiovascular disease 3. Reversible defects in EPC number and function in patients with an increased cardiovascular risk 4. Statins and EPC biology 5. The effect on EPCs of other interventions known to reduce cardiovascular risk - EPCs and treatment of diabetes, hypertension, subclinical hypothyroidism 6. Beneficial effects of EPC-based therapies animal models of ischaemia 7. Human Studies of EPC-based therapies A lower level of circulating EPCs and reduced EPC function in vitro are associated with an increased cardiovascular risk. The accumulated evidence suggests that a balance between the damaging effects of conventional cardiovascular risk factors and the ability of circulating EPCs to affect endothelial repair determines this cardiovascular risk.

Endothelial progenitor cells in mothers of low-birthweight infants: a link between defective placental vascularization and increased cardiovascular risk?

CONTEXT: Offspring birthweight is inversely associated with future maternal cardiovascular mortality, a relationship that has yet to be fully elucidated. Endothelial progenitor cells (EPCs) are thought to play a key role in vasculogenesis, and EPC numbers reflect cardiovascular risk. OBJECTIVE: Our objective was to ascertain whether EPC number or function was reduced in mothers of low-birthweight infants. DESIGN AND SETTING: This was a prospective cohort study in a general antenatal department of a university maternity hospital. PARTICIPANTS: Twenty-three mothers of small for gestational age (SGA) infants (birthweight < 10th centile) and 23 mothers of appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile) were recruited. MAIN OUTCOME MEASURES: Maternal EPC number and function, conventional cardiovascular risk markers, and cord blood adiponectin were measured. RESULTS: Median EPC count was lower (294 vs. 367, P = 0.005) and EPC migration was reduced (0.91 vs. 1.59, P < 0.001) in SGA compared with AGA infants, with no difference in EPC adhesion (0.221 vs. 0.284 fluorescence units, P = 0.257). Maternal triglyceride levels were higher in SGA than AGA infants (0.98 vs. 0.78 mmol/liter, P = 0.006), but there was no difference in cholesterol, glucose, insulin, glycosylated hemoglobin, adiponectin, or blood pressure. There was a moderate monotone (increasing) relationship between birthweight and umbilical cord blood adiponectin (r = 0.475, P = 0.005). CONCLUSION: Giving birth to an SGA infant was associated with lower maternal EPC number and reduced migratory function. Cord blood adiponectin was significantly correlated with birthweight.

Long-term outcome of idiopathic hypogonadotropic hypogonadism.

PURPOSE OF REVIEW: This review focuses on the presentation, treatment and long-term outcomes of men with idiopathic hypogonadotropic hypogonadism (IHH). RECENT FINDINGS: The traditional view that IHH is a simple monogenic disorder has now been revised, with some cases having an oliogenic basis involving mutations in more than one locus in each affected individual. The majority of IHH men respond well to induction of spermatogenesis with gonadotropins or pulsatile gonadotropin-releasing hormone. Favourable prognostic factors include larger testicular size, prior gonadotropin therapy, no previous androgen therapy, absence of cryptorchidism and pretreatment inhibin B levels more than 60  pg/ml. Genetic factors influence response to therapy and patients with KAL1 mutations tend to have less favourable outcomes as they may have defects in multiple levels of the hypothalamic-pituitary-gonadal axis.Androgen replacement is warranted in all IHH patients after usual chronological age of puberty, and poor treatment compliance is associated with lower bone mineral density and higher fat mass. However, 10% of patients display sustained reversal so a brief treatment interruption should be considered. SUMMARY: IHH is a heterogeneous disorder. The complex genetics and interaction with environmental factors likely underlie the variable expressivity of the reproductive and nonreproductive phenotypes. The demonstration of reversibility, the impact of inadequate testosterone replacement and the good response to induction of spermatogenesis confirm the need for specialist care and long-term follow-up.