Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.

Venous thromboembolism associated with medically assisted reproduction (MAR): British fertility society policy and practice guidance for assessment and prevention.

The association between Medically Assisted Reproduction (MAR) and thromboembolic complications has been reported widely in multiple published studies. Although venous thromboembolism (VTE) is not thought to be a common complication of MAR, it is associated with high morbidity and is often preventable. Since VTE usually occurs after completion of MAR treatment and is often managed outside of the treating fertility unit, these complications are likely to be underreported and there may be limited awareness of the risks among clinicians. As we continue to see a rise in the total number of MAR treatment cycles, particularly in women over 40 years of age, along with a steady increase in the number of fertility preservation cycles for both medical and social indications, it is likely that we will see an increase in absolute numbers of VTE complications. Currently, there is a lack of management guidance and reporting of VTE events associated with assisted conception treatment. The aim of this guidance is to provide clinicians with information on VTE risk factors, guidance on assessing VTE risk and the best practice recommendations on risk reducing strategies for individuals at risk of VTE undergoing ovarian stimulation and embryo transfer cycles.

Atopic Dermatitis: A Qualitative Study on the Burdens of Living with Itchiness.

Objective: We sought to understand the consequences itchiness has on daily life that may not be immediately obvious in clinical assessments for patients with atopic dermatitis (AD). Methods: Focus groups and interviews involving 21 patients with AD and 12 family members examined aspects of the effects of itchiness on health-related quality of life (HRQL). Investigators conducted a thematic analysis where two researchers independently coded the narratives and arrived at a consensus on major themes. Results: Five themes emerged from our discussions. 1) Miserable experience: Itchiness was difficult to control and cease. 2) Physical damage: Damage to skin and hair occurred from scratching to alleviate the itchiness. 3) Effects on daily activities: Itchiness could affect everything participants did, including how they dressed, used make-up, and slept. 4) Effects on social activities and relationships: The discomfort and embarrassment from scratching in public and others' reactions hindered participants' social lives. 5) Emotional consequences: Various emotional responses to itchiness were reported, including embarrassment, depression, and irritation. Limitations: Though qualitative research provides a level of detail not often found in quantitative analyses, this study design is limited by small sample size and generalizability. Conclusion: Understanding these challenges can help clinicians open deeper conversations with their patients to learn more about what patients need from their dermatologic care. While itchiness from AD is well-known, this study shows that its effects on HRQL are not minimal and that patients may need further care for the consequences of this symptom.

Quality of Life Among Family of Patients with Atopic Dermatitis and Psoriasis.

BACKGROUND: Chronic inflammatory skin diseases like atopic dermatitis (AD) and psoriasis can severely impact patients' quality of life (QOL). However, the effect of these diseases can diminish the QOL of patients' family members as well. The objective of this study was to understand the impact on QOL for family members of patients diagnosed with AD or psoriasis. METHODS: We conducted focus groups and interviews with 23 individuals; 12 had a family member with AD, and 11 had a family member with psoriasis. After investigators independently coded the transcripts, thematic analysis was conducted. RESULTS: Three major themes emerged: (1) lifestyle consequences-many daily activities for family members, including but not limited to leisure activities, sleep, and cleaning, were affected by AD or psoriasis; (2) emotional consequences-family members felt frustrated, worried, or embarrassed, among other concerns, because of their loved ones' AD or psoriasis; (3) relationships-relationships between family members and their loved ones with AD or psoriasis could become strained, and though family members might try to be sympathetic, doing so could be difficult because of their lack of understanding of how these diseases feel and personally affect their loved ones. CONCLUSIONS: This study highlights the impacts of AD and psoriasis on the whole family. Clinicians should be mindful of the effects on QOL not only for patients but also for family members who live with and care about these patients. Especially when family members assist with treatments, it is important to understand family members' experiences when making treatment decisions.

The effect of hormone replacement therapy on cognition and mood.

OBJECTIVES: To summarise the available data regarding the effect of hormone replacement therapy (HRT) on cognition and mood in women. BACKGROUND: Complaints of impaired cognition and mood are common in the peri-menopausal and menopausal period. There is debate as to whether HRT can ameliorate this phenomenon. DESIGN: A literature search of studies using electronic databases was conducted. Both randomised control trials and observational studies were included. PATIENTS: Perimenopausal and menopausal women. RESULTS: Due to the heterogenicity of results it is challenging to draw firm conclusions. The preparations used in many of the studies are older regimes no longer routinely used clinically. The notion of a 'critical window' for HRT is compelling, suggesting HRT has a positive impact on cognition when administered in the peri-menopausal or early postmenopausal period but may have negative effects on cognition in the older, postmenopausal woman. The evidence would seem to suggest importance of hormonal replacement in woman undergoing a surgical menopause, especially when young. It remains unclear for how long they ought to continue HRT though until at least the natural age of the menopause seems reasonable. Evidence for a positive effect of HRT on mood is more convincing, though possibly more efficacious in the younger age group. The effect of HRT on anxiety is less clear. CONCLUSIONS: Further study, particularly focusing on the more contemporaneous HRT preparations, is warranted before evidence-based conclusions can be drawn.

Transcriptomic recurrence score improves recurrence prediction for surgically treated patients with intermediate-risk clear cell kidney cancer.

BACKGROUND: Risk stratification of kidney cancer patients after nephrectomy may tailor surveillance intensity and selection for adjuvant therapy. Transcriptomic approaches are effective in predicting recurrence, but whether they add value to clinicopathologic models remains unclear. METHODS: Data from patients with clear cell renal cell carcinoma (ccRCC) was downloaded from The Cancer Genome Atlas. Clinicopathologic variables were used to calculate SSIGN (stage, size, grade, and necrosis) scores. The 16 gene recurrence score (RS) signature was generated using RNA-seq data. Transcriptomic risk groups were calculated using the original thresholds. SSIGN groups were divided into low, intermediate, and high risk. Disease-free status was the primary endpoint assessed. RESULTS: SSIGN and RS were calculated for 428 patients with non-metastatic ccRCC. SSIGN low-, intermediate-, and high-risk groups demonstrated 2.7%, 15.2%, and 27.5%, 3-year recurrence risk, respectively. On multivariable analysis, the RS was associated with disease-free status (sub-distribution hazard ratio (sHR) 1.43 per 25 RS [95% CI (1.00-1.43)], p = 0.05). By risk groups, RS further risk stratified the SSIGN intermediate-risk group (sHR 2.22 [95% CI 1.10-4.50], p = 0.03). SSIGN intermediate-risk patients with low and high RS had a 3-year recurrence rate of 8.0% and 25.2%, respectively. Within this risk group, the area under the curve (AUC) at 3 years was 0.69 for SSIGN, 0.74 for RS, and 0.78 for their combination. CONCLUSIONS: Transcriptomic recurrence scores improve risk prediction even when controlling for clinicopathologic factors. Utility may be best suited for intermediate-risk patients who have heterogeneous outcomes and further refinement for clinical utility is warranted.

The Disruptiveness of Itchiness from Psoriasis: A Qualitative Study of the Impact of a Single Symptom on Quality of Life.

BACKGROUND: Pruritus is the most common symptom of psoriasis, with a significant impact on patient quality of life. In spite of this, the severity, persistence, and overall impact of itchiness has only been rarely formally assessed during standard psoriasis clinic visits. Objectives: We sought to understand the far-reaching impacts of itchiness on the lives of those with psoriasis and their families. METHODS: We conducted a qualitative study with five focus groups and 10 semi-structured interviews from August 2018 to January 2019. We enrolled 25 individuals with a diagnosis of at least moderate plaque psoriasis and 11 family members (primarily significant others). Views and experiences were analyzed thematically via content analysis. RESULTS: Itchiness considerably impacts those with plaque psoriasis and their families. Our narrative analysis produced three main themes relating to itchiness: the triggers of itchiness, including climate, emotions, and behaviors; the physical consequences of itchiness, including disruption of emotional well-being, sleep disturbance, and daily activities; and the prevention and treatment strategies used to alleviate itchiness. CONCLUSION: Itchiness impacts the quality of life in those with psoriasis and their family members. We strongly urge clinicians to inquire about and monitor the severity and impact of itchiness in psoriasis patients.

Mechanisms of action of duodenal mucosal resurfacing in insulin resistant women with polycystic ovary syndrome.

BACKGROUND: Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans. METHODS: Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention. RESULTS: A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion. CONCLUSIONS: These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa.

Investigating the potential of clinical and biochemical markers to differentiate between functional hypothalamic amenorrhoea and polycystic ovarian syndrome: A retrospective observational study.

OBJECTIVES: Functional hypothalamic amenorrhoea (FHA) is a common cause of amenorrhoea, but diagnosis can be challenging. The aim of this study was to investigate the clinical and biochemical features of FHA, compared to that of polycystic ovarian syndrome (PCOS) and assess the diagnostic performance of the different parameters for differentiating the two conditions. DESIGN AND PATIENTS: This was a retrospective observational study. We analysed clinical and biochemical parameters of women diagnosed with FHA and PCOS following specialist assessment at the reproductive endocrine gynaecology clinic, St Mary's Hospital. RESULTS: Compared with PCOS, women with FHA had significantly lower body mass index (BMI; 20.1 ± 2.9 vs. 31.1 ± 7.8 kg/m2 ; p< .0001) and a thinner endometrium (3.75 ± 2.23 vs. 6.82 ± 3.32 mm; p< .0001). Women with FHA had significantly lower luteinising hormone (LH; 3.46 ± 7.31 vs. 8.79 ± 4.98 IU/L; p< .0001), and lower LH to follicle-stimulating hormone (FSH) ratio, estradiol, thyroid-stimulating hormone, free thyroxine and prolactin levels; there was no significant difference in FSH levels. BMI had the greatest predictive performance for FHA (area under the curve [AUC]: 0.93; p< .001), followed by estradiol (AUC: 0.89; p< .001), LH (AUC: 0.88; p< .001) and LH:FSH ratio (AUC: 0.86; p< .001). CONCLUSIONS: Our data provides quantification for diagnostic accuracy of clinical parameters to differentiate FHA from PCOS, namely low BMI, estradiol, LH and LH:FSH ratio. These data could help clinicians more reliably diagnose FHA in women with secondary amenorrhoea.

Effects of Pain From Atopic Dermatitis: Interview and Focus Group Study With Patients and Their Families.

BACKGROUND: Pain is an underappreciated symptom of atopic dermatitis that can affect the health-related quality of life (HRQL) of patients. OBJECTIVE: The aim of this study is to understand the effect of pain on patients with atopic dermatitis and their family members and to recognize how this symptom affects HRQL. METHODS: We conducted focus groups and interviews with patients with atopic dermatitis and their family members. Researchers independently coded the transcripts and reached a consensus on the major themes. RESULTS: A total of 33 adult participants, consisting of 21 patients with atopic dermatitis (median age 47 years, range 22-77) and 12 family members (median age 50, range 22-72), attended either focus groups (23/33, 70%) or interviews (10/33, 30%), where we assessed their experiences of pain. Four themes emerged in our study. Itchiness and pain can be intertwined: pain was often caused by or otherwise associated with itchiness and could result from open sores and excoriated skin. Characteristics of pain: pain was most often described as burning. Other descriptors included mild, persistent discomfort; stinging; and stabbing. Effects of pain: pain negatively affected various aspects of daily life, including choice of clothing, sleep, social activities, and relationships. The location of painful areas could also limit physical activity, including sex. Pain management: pain from atopic dermatitis could be managed to varying degrees with different over-the-counter and prescription treatments. Systemic agents that cleared the skin also resolved the pain associated with atopic dermatitis. CONCLUSIONS: Pain can be a significant factor in the HRQL of patients with atopic dermatitis and should be considered by clinicians when caring for patients with atopic dermatitis.

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders.

BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.

Current understanding of hypothalamic amenorrhoea.

Hypothalamic amenorrhoea (HA) accounts for approximately 30% of cases of secondary amenorrhoea in women of reproductive age. It is caused by deficient secretion of hypothalamic gonadotrophin-releasing hormone, which in turn leads to failure of pituitary gonadotrophin and gonadal steroid release. Functional HA (FHA) is defined as HA occurring in the absence of a structural lesion and is predominantly caused by significant weight loss, intense exercise or stress. Treatment of FHA is crucial in avoiding the long-term health consequences on fertility and bone health, in addition to reducing psychological morbidity. This article summarises our understanding of the mechanisms underlying FHA, the evidence base for its clinical management and emerging therapies.

A Randomized Trial of Endometrial Scratching before In Vitro Fertilization.

BACKGROUND: Endometrial scratching (with the use of a pipelle biopsy) is a technique proposed to facilitate embryo implantation and increase the probability of pregnancy in women undergoing in vitro fertilization (IVF). METHODS: We conducted a pragmatic, multicenter, open-label, randomized, controlled trial. Eligible women were undergoing IVF (fresh-embryo or frozen-embryo transfer), with no recent exposure to disruptive intrauterine instrumentation (e.g., hysteroscopy). Participants were randomly assigned in a 1:1 ratio to either endometrial scratching (by pipelle biopsy between day 3 of the cycle preceding the embryo-transfer cycle and day 3 of the embryo-transfer cycle) or no intervention. The primary outcome was live birth. RESULTS: A total of 1364 women underwent randomization. The frequency of live birth was 180 of 690 women (26.1%) in the endometrial-scratch group and 176 of 674 women (26.1%) in the control group (adjusted odds ratio, 1.00; 95% confidence interval, 0.78 to 1.27). There were no significant between-group differences in the rates of ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, or miscarriage. The median score for pain from endometrial scratching (on a scale of 0 to 10, with higher scores indicating worse pain) was 3.5 (interquartile range, 1.9 to 6.0). CONCLUSIONS: Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF. (Funded by the University of Auckland and others; PIP Australian New Zealand Clinical Trials Registry number, ACTRN12614000626662 .).

Fertility preservation for medical reasons in girls and women: British fertility society policy and practice guideline.

Fertility preservation in the female poses several challenges due to the invasive nature of the techniques available to achieve it. The guideline aims to bring together the evidence available for the measures for fertility preservation and their outcome. The guideline addresses fertility preservation for medical reasons and includes both oncological and non-oncological causes. The techniques that the guideline considers are: (i) embryo and oocyte cryopreservation; (ii) ovarian tissue cryopreservation; (iii) GnRH agonist suppression and (iv) ovarian transposition. Although ovarian tissue cryopreservation is still considered experimental, the availability of this technique is gaining momentum as more live births from auto-transplanted tissue are reported. The guideline also highlights use of current treatment modalities for benign and malignant conditions that have a better fertility sparing profile. The guideline recommends a multidisciplinary approach in counselling women and girls about the risk to their fertility and available techniques. The role of psychological support in assisting women and girls with decision-making is highlighted. The guideline also highlights the risks associated with these techniques. Women need to be medically fit to undergo invasive procedures. Fertility preservation techniques are appropriate when treatment has curative intent. Fertility preservation is a subject of on-going research on outcomes of different techniques and at the time of publication, studies are still likely to emerge adding to the available literature.

HRT for women with premature ovarian insufficiency: a comprehensive review.

BACKGROUND: Premature ovarian insufficiency (POI), often and misleadingly referred to as 'premature menopause', is defined as a loss of ovarian activity before the age of 40 years and is characterized by irregular or absent periods and reduced fertility. Symptoms include those associated with the natural menopause (night sweats and vaginal dryness), and with the long-term adverse effects of estrogen deficiency (osteoporosis and cardiovascular disease): the latter is believed to explain the shorter life expectancy associated with POI. OBJECTIVE AND RATIONALE: The objective of the current review was to collect all relevant studies supporting recommendations on the indications, treatment options, and risks of hormone replacement therapy (HRT) (estrogen, progestogens and androgens) for women with POI. SEARCH METHODS: The current review was written based on the best available evidence on the topic collected for the recently published ESHRE guideline on the management of women with POI. PUBMED/MEDLINE and the Cochrane library were searched in a stepwise approach. Relevant references were summarized in evidence tables, with assessment of the quality. OUTCOMES: HRT is strongly recommended for women with POI, mainly for vasomotor and genito-urinary symptom relief. In addition, HRT has been shown to have a role in bone protection and probably also in primary prevention of cardiovascular disease. There is little evidence on the optimal type, regimen and dose of HRT; patient preference for route and method of administration of each component of HRT must be considered when prescribing, as should contraceptive needs. In women with POI, physiological replacement of estrogen (and progesterone) is essential for their health, and the controversies that surround the use of HRT in postmenopausal women do not apply. LIMITATIONS REASONS FOR CAUTION: N/A. WIDER IMPLICATIONS: New areas of study on HRT for women with POI should focus on life expectancy, quality of life and neurological function. Furthermore, randomized controlled trials comparing transdermal estradiol with oral estrogens with regard to efficacy, patient satisfaction and side effects are urgently needed. STUDY FUNDING/COMPETING INTERESTS: The authors received no funding for the review. The costs for the development of the ESHRE guideline were covered by ESHRE. The authors have no conflicts of interest to disclose.

Variation in antral follicle counts at different times in the menstrual cycle: does it matter?

Antral follicle count (AFC) variation was examined across the menstural cycle and its effect on clinical management assessed. In 79 women, AFC was documented in early (iAFC) and late follicular phase (sAFC). Absolute agreement between iAFC and sAFC and agreement for classification into categories of risk of extremes of ovarian response were examined. Ovarian stimulation protocols designed with iAFC and sAFC, and the predictive value of iAFC and sAFC for extremes of ovarian response, were compared in women undergoing ovarian stimulation. Significant differences were found between iAFC and sAFC (16 [IQR 9-24] versus 13 [IQR 7- 21]; P = 0.001), with moderate agreement for the classification into at risk of extremes of response (k = 0.525). Agreement for protocol selection based on either AFC (k = 0.750) and starting gonadotrophin dose was good (concordance correlation coefficient 0.970 [95% CI 0.951 to 0.982]). Predictive value for iAFC and sAFC was maintained for poor ovarian response and risk of ovarian hyperstimulation syndrome (OR 0.634 [0.427 to 0.920], 0.467 [0.233 to 0.935]) and (OR 1.049 [0.974 to 1.131], 1.140 [1.011 to 1.285]). Across the cycle, AFC varies but does not significantly affect ovarian stimulation protocol design and prediction of extreme ovarian response.

Role of Insulin-like growth factors in initiation of follicle growth in normal and polycystic human ovaries.

CONTEXT: Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by disordered follicle development including increased activation and accelerated growth of preantral follicles. Data from experimental animals and preliminary results from studies of human ovarian tissue suggest that IGFs affect preantral follicle development. OBJECTIVE: Our objectives were to investigate the expression of the type-1 IGF receptor (IGFR-1) in the human ovary and to determine whether IGFs are involved in stimulating the transition of follicles from primordial to primary stage in normal and polycystic ovaries. DESIGN: We used archived ovarian tissue for protein expression studies and small cortical biopsies for follicle isolation and for tissue culture. SETTING: This was a laboratory-based study, using clinical tissue samples. PATIENTS: A total of 54 women, 33 with normal ovaries and 21 with polycystic ovaries, were classified by reference to menstrual cycle history and ultrasonography. MAIN OUTCOME MEASURES: We evaluated expression of IGFR-1 mRNA in isolated preantral follicles and of IGFR-1 protein in archived ovarian tissue samples from normal and polycystic ovaries and effects of exogenous IGF-1 on preantral follicle development and survival in cultured fragments of normal and polycystic ovaries. RESULTS: IGFR-1 mRNA and protein was expressed in preantral follicles at all stages of development and enhanced expression was noted in PCOS follicles during early preantral development. IGF-1 stimulated initiation of follicle growth in normal tissue but had little effect on preantral follicle growth in polycystic ovaries in which, characteristically, there was a higher proportion of follicles that had entered the growing phase even before culture. CONCLUSIONS: IGFs are plausible candidates in regulation of initiation of human follicle growth, and accelerated preantral follicle growth in PCOS may be due to increased activity of endogenous IGFs.

Determinants of dyslipidaemia in probands with polycystic ovary syndrome and their sisters.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with dyslipidaemia and obesity. It is not clear whether the dyslipidaemia of PCOS is attributable to PCOS itself, obesity, or a combination of both. Our objective was to assess the importance of familial dyslipidaemia in PCOS by comparing fasting lipids between probands and their (affected and nonaffected) sisters. DESIGN: Retrospective data set analyses. PATIENTS: Family study; 157 probands, 214 sisters and 76 control women (normal ovaries and regular cycles). All probands had PCOS, defined by symptoms of anovulation and/or hyperandrogenism with polycystic ovaries on ultrasound. Affected or unaffected status of sisters was defined by ovarian morphology. MEASUREMENTS: Serum concentrations of triglycerides, total cholesterol, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol. RESULTS: Triglyceride levels and body mass index (BMI) were higher and HDL cholesterol levels were lower in the probands than affected sisters, unaffected sisters and controls. These differences in lipid profiles between the groups disappeared after adjustment for BMI. No differences in lipids were seen between affected and unaffected sisters. CONCLUSIONS: These data are consistent with heritability of lipid levels in sisters but strongly suggest that the predominant influence on the manifestation of dyslipidaemia in PCOS is body weight.

Rituximab versus cyclophosphamide for ANCA-associated vasculitis.

BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)