GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.

Gender disparity and the appropriateness of myocardial perfusion imaging.

BACKGROUND: Appropriate use criteria (AUC) were developed to guide the use of myocardial perfusion imaging (MPI). While MPI use has grown exponentially, women remain under tested. Given this bias in testing, we sought to determine if gender disparity exists in tests categorized by appropriateness and the role of referral bias. METHODS: The AUC were applied to 314 consecutive MPI. Analysis of variance and chi-squared tests were used for analysis. Gender disparity was assessed using correlation matrices comparing baseline to gender reversed data. RESULTS: Of the 314 studies, 263 were appropriate, 34 inappropriate, and 17 uncertain. Women had 68% of inappropriate studies, and 82% of uncertain studies (P < .01). Cardiologists ordered more appropriate studies than primary care physicians (PCPs) in women (86% vs 71%, P = .04). Among studies ordered by cardiologists and PCPs, a higher percentage of studies were appropriate in men vs women (96% vs 86%, P = 0.05 and 88% vs 71% P = .003), respectively. Gender reversal demonstrates disparity in the AUC tool with 46 (15%) not correlating (P < .00001). CONCLUSIONS: Comparing patient gender and ordering physician, the majority of inappropriate and uncertain studies were ordered in women by PCPs, indicating a continuing need for education among PCPs, particularly as the AUC apply to women.

Cardiac disease in pregnancy: value of echocardiography.

Cardiovascular disease in women during pregnancy poses particular challenges. It continues to be a leading cause of maternal mortality and contributes to significant morbidity. Echocardiography is essential in characterizing the extent and effects of heart disease prior to, during, and after pregnancy. By understanding the physiologic adaptation in pregnancy with increases in heart rate, blood volume, and cardiac output, and decrease in vascular resistance, one can anticipate and recognize the effects of these changes on various cardiac lesions. Cardiomyopathy, severe, obstructive valvular disease, aortic dilation due to Marfan's disease, and cyanotic congenital heart disease are poorly tolerated in pregnancy. These disorders can be readily distinguished from normal structural changes of pregnancy and their severity assessed by echocardiography. Cardiovascular disease in women of reproductive age requires careful, multidisciplinary management by obstetric and medical teams ideally beginning preconception and continuing through the postpartum period.

Risk Factors, Imaging Findings, and Sex Differences in Spontaneous Coronary Artery Dissection.

Spontaneous coronary artery dissection (SCAD) is increasingly being recognized. However, data supporting diagnosis and management are scarce. We analyze a contemporary and comprehensive SCAD registry to advance the understanding of SCAD risk factors, angiographic appearance, and gender differences. This is a retrospective analysis of a prospectively populated database of SCAD patients seen at the Massachusetts General Hospital (MGH) between June 2013 and October 2017. Core laboratory analysis of both coronary angiograms and computerized tomographic (CT) angiography of the extracoronary vessels was performed. Of the 113 patients, 87% were female and mean age was 47 ± 10 years. Traditional cardiovascular risk factors including hypertension, hyperlipidemia, and smoking were present in 27%, 14%, and 22% of patients. Among females, 14%, 8%, and 9% had a history of gestational hypertension, pre-eclampsia, and gestational diabetes, respectively. Fifteen percent had used fertility treatment and 47% of postmenopausal women had used hormone replacement therapy. Angiography showed multivessel SCAD in 42%, severe coronary artery tortuosity in 59%, and extracoronary vascular abnormalities in 100% of patients with complete CT angiographic imaging. Gender differences revealed a self-reported depression and anxiety prevalence of 20% and 32%, respectively, in women compared with 0% in men. Type 1 SCAD was more commonly diagnosed in men than women (71% vs 29%, p <0.01). In conclusion, we highlight under-recognized features of SCAD including (1) relation with pregnancy complications and exposure to hormonal therapy; (2) diffuse, multivessel process in tortuous coronaries on a background of extracoronary arterial abnormalities; and (3) gender differences highlighting the role of mental health as well as potential underdiagnoses in men.

Update on Valvular Heart Disease in Pregnancy.

OPINION STATEMENT: Valvular heart disease in women of childbearing age poses an increased risk of adverse maternal and fetal outcomes, and management in pregnancy can be challenging. Ideally, patients with suspected valvular disease should have preconception counseling by a multidisciplinary team including cardiologists with expertise in pregnancy and a maternal-fetal medicine specialist. Preconception planning should include a cardiac assessment of maternal risk, determination of frequency of surveillance, and a cardiovascular management plan during delivery. Women with valvular heart disease should be followed closely by a cardiologist and monitored for signs and symptoms of congestive heart failure and arrhythmias. In general, stenotic lesions may become more symptomatic in pregnancy, whereas regurgitant lesions are generally well tolerated. Left-sided valvular lesions have higher complication rates than right-sided lesions. For patients with asymptomatic valvular stenosis, medical management during pregnancy may include beta blockade and/or diuretics. Exercise stress testing prior to pregnancy in sedentary patients can be helpful to unmask symptoms and determine functional capacity. Patients with symptomatic, severe left-sided valvular obstruction have a high maternal risk of cardiovascular events during pregnancy, and percutaneous balloon valvuloplasty or surgery is recommended prior to pregnancy. The type of prosthetic valve (mechanical vs bioprosthetic) should be selected after a careful discussion with the patient. Invasive procedures are generally reserved for when medical management fails. The second trimester may be the optimal time for intervention as fetal organogenesis is complete and the cardiac positioning has not been affected by the gravid uterus.

Mitral valve disease in pregnancy: outcomes and management.

Young women may have asymptomatic mitral valve disease which becomes unmasked during the haemodynamic stress of pregnancy. Rheumatic mitral stenosis is the most common cardiac disease found in women during pregnancy. The typical increased volume and heart rate of pregnancy are not well tolerated in patients with more than mild stenosis. Maternal complications of atrial fibrillation and congestive heart failure can occur, and are increased in patients with poor functional class and severe pulmonary artery hypertension. Patients can be diagnosed by echocardiography and symptoms treated with beta-1 antagonists and cautious diuresis. Patients with heart failure unresponsive to treatment can undergo percutaneous balloon mitral valvuloplasty. Labour and delivery goals include reducing tachycardia by adequate pain control and minimized volume shifts. Mitral valve regurgitation, even when severe, is usually very well tolerated in pregnancy as the increase in volume is offset by a decrease in vascular resistance. On the other hand, patients with left ventricular dysfunction, moderate pulmonary hypertension or NYHA functional class III-IV are at increased risk for heart failure and arrhythmias. They may need cautious diuresis and limitations on physical activity during pregnancy, as well as invasive haemodynamic monitoring for labour and delivery. Vaginal delivery is preferred and caesarean section reserved for obstetric indications.