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Women's Health Reports (New Rochelle,... 2023Most women who are treated at fertilization (IVF) clinics have trouble conceiving due to ovarian failure (OF), which seems to be associated to short telomeres and...
BACKGROUND
Most women who are treated at fertilization (IVF) clinics have trouble conceiving due to ovarian failure (OF), which seems to be associated to short telomeres and reduced or absent telomerase activity in their granulosa cells. Indeed, telomere pathways are involved in organ dysfunction. However, sexual steroids can stimulate the expression of the telomerase gene and have been successfully used to prevent telomere attrition. Thus, a strategy to improve IVF outcomes in women with OF could be telomerase reactivation using sexual steroids.
METHODS
We conducted a double-blind, placebo-controlled study. Patients with diminished ovarian reserve were randomized to Danazol or placebo for 3 months. We included patients with normal ovarian reserve in the study as untreated controls. Patients and controls underwent several ovarian stimulations (OSs). Telomere and IVF parameters were assessed.
RESULTS
We found that the mean telomere length in blood and the percentage of short and long telomeres were similar throughout the 3 months of treatment with Danazol. Remarkably, while the number of cells with one telomeric repeat-containing RNA (TERRA) focus decreased ( = 0.04) after the first month of Danazol treatment, the number of cells with 2 to 4 TERRA foci increased ( = 0.02). Regarding fertility, no differences were found in the antral follicle count. Interestingly, in OS performed after the trial, all Danazol-treated patients had a better MII oocyte rate compared to OS performed before the pilot study.EudraCT number: 2018-004400-19.
CONCLUSIONS
Danazol treatment seemed to affect telomere maintenance, since both the number of TERRA foci and the ratio of MII oocytes changed. However, further research is needed to confirm these results.
PubMed: 37476605
DOI: 10.1089/whr.2023.0013 -
Asia Pacific Allergy Jun 2023Hereditary angioedema (HAE) is an uncommon disorder characterized clinically by recurrent episodes of nonitchy subcutaneous and/or submucosal swellings. The estimated...
Hereditary angioedema (HAE) is an uncommon disorder characterized clinically by recurrent episodes of nonitchy subcutaneous and/or submucosal swellings. The estimated prevalence of HAE is ~ 1: 10,000 to 1: 50,000. There are no prevalence data from India, however, estimates suggest that there are 27,000 to 135,000 patients with HAE in India at present. The majority of these, however, remain undiagnosed. Replacement of plasma-derived or recombinant C1-esterase inhibitor (C1-INH) protein, administered intravenously, is the treatment of choice during the management of acute episodes of angioedema (i.e., "on-demand treatment") and is also useful for short-term prophylaxis (STP) and long-term prophylaxis (LTP). This has been found to be effective and safe even in young children and during pregnancy. Until recently, none of the first-line treatment options were available for "on-demand treatment," STP or LTP in India. As a result, physicians had to use fresh frozen plasma for both "on-demand treatment" and STP. For LTP, attenuated androgens (danazol or stanozolol) and/or tranexamic acid were commonly used. These drugs have been reported to be useful for LTP but are associated with a significant risk of adverse effects. Intravenous pd-C1-INH, the first-line treatment option, is now available in India. However, because there is no universal health insurance, access to pd-C1-INH is a significant challenge. HAE Society of India has developed these consensus guidelines for India and other resource-constrained settings where plasma-derived C1-INH therapy is the only available first-line treatment option for the management of HAE and diagnostic facilities are limited. These guidelines have been developed because it may not be possible for all patients to access the recommended therapy and at the recommended doses as suggested by the international guidelines. Moreover, it may not be feasible to follow the evaluation algorithm suggested by the international guidelines.
PubMed: 37388810
DOI: 10.5415/apallergy.0000000000000100 -
The Cochrane Database of Systematic... Jun 2023Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment... (Review)
Review
BACKGROUND
Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decreased bone mineral density. In addition to assessing the effect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis who use GnRHas versus other treatment options.
OBJECTIVES
To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial registries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics, danazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents were also included in this review. DATA COLLECTION AND ANALYSIS: We used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in the most troublesome symptoms and patient satisfaction. Due to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk of selection bias. Sensitivity analysis including all studies was then performed.
MAIN RESULTS
Seventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies were serious risk of bias due to poor reporting of study methods, and serious imprecision. Trials comparing GnRHas versus no treatment We did not identify any studies. Trials comparing GnRHas versus placebo There may be a decrease in overall pain, reported as pelvic pain scores (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87, low-certainty evidence), dysmenorrhoea scores (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 85, low-certainty evidence), dyspareunia scores (RR 2.21; 95% CI 1.39 to 3.54, 1 RCT, n = 59, low-certainty evidence), and pelvic tenderness scores (RR 2.28; 95% CI 1.48 to 3.50, 1 RCT, n = 85, low-certainty evidence) after three months of treatment. We are uncertain of the effect for pelvic induration, based on the results found after three months of treatment (RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81, low-certainty evidence). Besides, treatment with GnRHas may be associated with a greater incidence of hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to 5.01, 1 RCT, n = 100, low-certainty evidence). Trials comparing GnRHas versus danazol For overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. We are uncertain about the effect on relief of overall pain, when a subdivision was made for overall pain (MD -0.30; 95% CI -1.66 to 1.06, 1 RCT, n = 41, very low-certainty evidence), pelvic pain (MD 0.20; 95% CI -0.26 to 0.66, 1 RCT, n = 41, very low-certainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20; 95% CI -0.77 to 0.37, 1 RCT, n = 41, very low-certainty evidence), pelvic induration (MD -0.10; 95% CI -0.59 to 0.39, 1 RCT, n = 41, very low-certainty evidence), and pelvic tenderness (MD -0.20; 95% CI -0.78 to 0.38, 1 RCT, n = 41, very low-certainty evidence) after three months of treatment. For pelvic pain (MD 0.50; 95% CI 0.10 to 0.90, 1 RCT, n = 41, very low-certainty evidence) and pelvic induration (MD 0.70; 95% CI 0.21 to 1.19, 1 RCT, n = 41, very low-certainty evidence), the complaints may decrease slightly after treatment with GnRHas, compared to danazol, for six months of treatment. Trials comparing GnRHas versus analgesics We did not identify any studies. Trials comparing GnRHas versus intra-uterine progestogens We did not identify any low risk of bias studies. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents There may be a slight decrease in bone mineral density (BMD) after 12 months treatment with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents for anterior-posterior spine (MD -7.00; 95% CI -7.53 to -6.47, 1 RCT, n = 41, very low-certainty evidence) and lateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence). AUTHORS' CONCLUSIONS: For relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD, there may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in favour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. Due to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement instruments, the results should be interpreted with caution.
Topics: Female; Humans; Endometriosis; Danazol; Progestins; Gestrinone; Dysmenorrhea; Calcium; Dyspareunia; Pelvic Pain; Calcium, Dietary; Drug-Related Side Effects and Adverse Reactions; Gonadotropin-Releasing Hormone
PubMed: 37341141
DOI: 10.1002/14651858.CD014788.pub2 -
European Review For Medical and... Jun 2023The aim of this study is to investigate the temporal relationship between the first occurrence of thromboembolic events (TEE) and the timing of myeloproliferative...
OBJECTIVE
The aim of this study is to investigate the temporal relationship between the first occurrence of thromboembolic events (TEE) and the timing of myeloproliferative neoplasm (MPN) diagnosis and to determine risk factors for TEE-related mortality in MPN.
PATIENTS AND METHODS
A total of 138 BCR-ABL-negative MPN patients with TEE, diagnosed from January 2010 to December 2019, were included in this retrospective cohort. Patients were compared according to mortality and subjects were classified into three groups with respect to having suffered index TEE before, during, or after MPN diagnosis.
RESULTS
The mean age of surviving patients was 57.5±13.8, while those who had died had a mean age of 72.0±9.0 (p<0.001). Males represented 56.5% of patients with mortality and 60.9% of those without mortality (p=0.876). TEE was detected in 26.0% of MPN patients, and TEE-related mortality rate was 16.7%. There was no relationship between mortality and the classification of patients according to index TEE (p =0.884). High age (p<0.001) and danazol use (p=0.014) were independently associated with TEE-related mortality.
CONCLUSIONS
The temporal relationship between TEE and MPN diagnosis was not found to influence mortality. Older patients and danazol recipients should be considered to have a higher risk of TEE-related mortality.
Topics: Male; Humans; Middle Aged; Aged; Aged, 80 and over; Retrospective Studies; Danazol; Neoplasms; Myeloproliferative Disorders; Thromboembolism
PubMed: 37318468
DOI: 10.26355/eurrev_202306_32611 -
Allergy, Asthma, and Clinical... May 2023Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, recurring subcutaneous or submucosal swelling. Without effective therapy, HAE can...
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, recurring subcutaneous or submucosal swelling. Without effective therapy, HAE can negatively impact patients' quality of life. Management of HAE includes on-demand treatment of attacks and short- and long-term prophylaxis (LTP) to prevent attacks. Newer therapies may be more tolerable and effective in managing HAE; however, therapies such as androgens are still widely used in some countries owing to their relative ease of access and adequate disease control for some patients. This study evaluated the characteristics, treatment patterns, clinical outcomes, and healthcare resource utilization of a multinational cohort of patients with HAE, with a focus on understanding reasons for recommending or discontinuing available therapies.
METHODS
A retrospective chart review was conducted at 12 centers in six countries and included data from patients with HAE type 1 or 2 who were ≥ 12 years of age at their first clinical visit. The relationship between LTP use and attack rates was evaluated using a multivariable Poisson regression model. Data were collected between March 2018 and July 2019.
RESULTS
Data from 225 patients were collected (62.7% female, 86.2% White, 90.2% type 1); 64.4% of patients had their first HAE-related visit to the center prior to or during 2014. Treatment patterns varied between countries. Overall, 85.8% of patients were prescribed on-demand treatment and 53.8% were prescribed LTP, most commonly the androgen danazol (53.7% of patients who used LTP). Plasma-derived C1 inhibitor (Cinryze) was used by 29.8% of patients for LTP. Patients who received LTP had a significantly lower rate of HAE attacks than patients who did not receive any LTP (incidence rate ratio (95% confidence interval) 0.90 (0.84-0.96)). Androgens were the most commonly discontinued therapy (51.3%), with low tolerability cited as the most frequent reason for discontinuation (50.0%).
CONCLUSIONS
Overall, findings from this study support the use of LTP in the prevention of HAE attacks; a lower rate of attacks was observed with LTP compared with no LTP. However, the type of LTP used varied between countries, with tolerability and accessibility to specific treatments playing important roles in management decision-making.
PubMed: 37248521
DOI: 10.1186/s13223-023-00795-2 -
F&S Reports Jun 2023The development of highly potent gonadotropin-releasing hormone agonists (GnRHa) allowed for a significant addition to options for the medical management of symptomatic...
The development of highly potent gonadotropin-releasing hormone agonists (GnRHa) allowed for a significant addition to options for the medical management of symptomatic endometriosis. Pituitary GnRH receptor down-regulation leads to a hypogonadotropic and secondary hypoestrogenic state resulting in lesion regression and symptom improvement. There may be an additional effect of these agents on the inflammatory processes associated with endometriosis as well. This is a review of critical milestones in the clinical application of these agents. Most initial trials of various GnRHa employed danazol as a control and demonstrated general equivalence in reducing symptoms and extent of lesions but without hyperandrogenic side effects and adverse metabolic changes induced by the latter. Short-acting GnRHa is administered intranasally or subcutaneously. Longer-acting preparations are administered intramuscularly or as subcutaneous implants. GnRHa also decrease symptom recurrence rates after surgical management. The hypoestrogenic side effects, including bone mineral density loss and vasomotor symptoms, have limited the duration of use of these agents alone to six months. The use of an appropriate add-back allows for the mitigation of side effects while maintaining efficacy and allowing extension of use for up to 12 months. There is a limited amount of data regarding the use of GnRHa in adolescents out of concern for the effect on developing bone. These agents should be used with caution in this group. The lack of dose flexibility, need for parental administration, and side effect profiles represent drawbacks to GnRHa use. The development of oral GnRH antagonists with short half-lives, variable dosing, and decreased side effects represents an exciting alternative.
PubMed: 37223763
DOI: 10.1016/j.xfre.2022.11.009 -
The Journal of Allergy and Clinical... Aug 2023Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better...
BACKGROUND
Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care.
OBJECTIVE
To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients.
METHODS
A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data.
RESULTS
The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home.
CONCLUSIONS
Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.
Topics: Humans; Female; Male; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Danazol; United Kingdom; Surveys and Questionnaires
PubMed: 37146882
DOI: 10.1016/j.jaip.2023.04.035 -
Cureus Apr 2023Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is a common gynecological disorder. The prevalence of pelvic endometriosis... (Review)
Review
Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is a common gynecological disorder. The prevalence of pelvic endometriosis approaches 6%-10% in the general female population, and in women with pain, infertility, or both, the frequency is 35%-50%. The gold standard recommended process for diagnosing endometriosis is laparoscopy, an invasive surgical procedure, with or without histologic verification. The currently available nonsurgical treatments include oral contraceptives (estrogen-progestogen preparations), progestogen preparations (containing progesterone derivatives), androgenic hormones (danazol), and gonadotropin-releasing hormone (GnRH) agonists and antagonists. Two GnRH types have been discovered in mammals, GnRH I and GnRH II. In particular, GnRH I is released by the hypothalamus; however, it can be present in various tissues and organs of the body, including neural tissue, where it exerts neuroendocrine, autocrine, and paracrine actions in the peripheral and central nervous system (CNS). Interestingly, another GnRH isoform, GnRH III, has been identified, which has 60% similarity with GnRH I from which it varies by four amino acids. This peptide has been shown to have a significant role in reproduction, specifically in gametogenesis and steroidogenesis. Further research is needed to identify innovative treatment options for endometriosis, such as the therapeutic exogenous administration of GnRH II or antagonists of the GnRH I receptor. In this review, we examined the role of GnRH in endometriosis, outlining the specific actions of GnRH and GnRH receptors (GnRHRs). The innovative use of GnRH analogs and antagonists in the treatment of endometriosis is also discussed.
PubMed: 37122983
DOI: 10.7759/cureus.38136 -
Blood Advances Jul 2023Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and...
Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Anemia; Thrombocytopenia
PubMed: 37042865
DOI: 10.1182/bloodadvances.2022009311