Application of machine learning and artificial intelligence in the diagnosis and classification of polycystic ovarian syndrome: a systematic review.

Introduction: Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and remains widely underdiagnosed leading to significant morbidity. Artificial intelligence (AI) and machine learning (ML) hold promise in improving diagnostics. Thus, we performed a systematic review of literature to identify the utility of AI/ML in the diagnosis or classification of PCOS. Methods: We applied a search strategy using the following databases MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Web of Science, and the IEEE Xplore Digital Library using relevant keywords. Eligible studies were identified, and results were extracted for their synthesis from inception until January 1, 2022. Results: 135 studies were screened and ultimately, 31 studies were included in this study. Data sources used by the AI/ML interventions included clinical data, electronic health records, and genetic and proteomic data. Ten studies (32%) employed standardized criteria (NIH, Rotterdam, or Revised International PCOS classification), while 17 (55%) used clinical information with/without imaging. The most common AI techniques employed were support vector machine (42% studies), K-nearest neighbor (26%), and regression models (23%) were the commonest AI/ML. Receiver operating curves (ROC) were employed to compare AI/ML with clinical diagnosis. Area under the ROC ranged from 73% to 100% (n=7 studies), diagnostic accuracy from 89% to 100% (n=4 studies), sensitivity from 41% to 100% (n=10 studies), specificity from 75% to 100% (n=10 studies), positive predictive value (PPV) from 68% to 95% (n=4 studies), and negative predictive value (NPV) from 94% to 99% (n=2 studies). Conclusion: Artificial intelligence and machine learning provide a high diagnostic and classification performance in detecting PCOS, thereby providing an avenue for early diagnosis of this disorder. However, AI-based studies should use standardized PCOS diagnostic criteria to enhance the clinical applicability of AI/ML in PCOS and improve adherence to methodological and reporting guidelines for maximum diagnostic utility. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022295287.

The Thyroid Hormone Axis and Female Reproduction.

Thyroid function affects multiple sites of the female hypothalamic-pituitary gonadal (HPG) axis. Disruption of thyroid function has been linked to reproductive dysfunction in women and is associated with menstrual irregularity, infertility, poor pregnancy outcomes, and gynecological conditions such as premature ovarian insufficiency and polycystic ovarian syndrome. Thus, the complex molecular interplay between hormones involved in thyroid and reproductive functions is further compounded by the association of certain common autoimmune states with disorders of the thyroid and the HPG axes. Furthermore, in prepartum and intrapartum states, even relatively minor disruptions have been shown to adversely impact maternal and fetal outcomes, with some differences of opinion in the management of these conditions. In this review, we provide readers with a foundational understanding of the physiology and pathophysiology of thyroid hormone interactions with the female HPG axis. We also share clinical insights into the management of thyroid dysfunction in reproductive-aged women.

Scoping review of COVID-19-related systematic reviews and meta-analyses: can we really have confidence in their results?

AIM: The aim of this study was to systematically appraise the quality of a sample of COVID-19-related systematic reviews (SRs) and discuss internal validity threats affecting the COVID-19 body of evidence. DESIGN: We conducted a scoping review of the literature. SRs with or without meta-analysis (MA) that evaluated clinical data, outcomes or treatments for patients with COVID-19 were included. MAIN OUTCOME MEASURES: We extracted quality characteristics guided by A Measurement Tool to Assess Systematic Reviews-2 to calculate a qualitative score. Complementary evaluation of the most prominent published limitations affecting the COVID-19 body of evidence was performed. RESULTS: A total of 63 SRs were included. The majority were judged as a critically low methodological quality. Most of the studies were not guided by a pre-established protocol (39, 62%). More than half (39, 62%) failed to address risk of bias when interpreting their results. A comprehensive literature search strategy was reported in most SRs (54, 86%). Appropriate use of statistical methods was evident in nearly all SRs with MAs (39, 95%). Only 16 (33%) studies recognised heterogeneity in the definition of severe COVID-19 as a limitation of the study, and 15 (24%) recognised repeated patient populations as a limitation. CONCLUSION: The methodological and reporting quality of current COVID-19 SR is far from optimal. In addition, most of the current SRs fail to address relevant threats to their internal validity, including repeated patients and heterogeneity in the definition of severe COVID-19. Adherence to proper study design and peer-review practices must remain to mitigate current limitations.

Survivorship Issues in Adult Patients With Histiocytic Neoplasms.

Adult-onset histiocytoses (AOH), primarily Rosai-Dorfman disease (RDD), Erdheim-Chester Disease (ECD), and adult Langerhans cell histiocytosis (ALCH), are a group of related histiocytic neoplastic disorders featuring multisystemic manifestations. The disorders are largely incurable, and are essentially chronic neoplastic diseases with a variable prognosis. Prompt diagnosis and treatment is important to prevent debilitating and even life-threatening complications. Survivorship issues abound in AOH, due to their multisystemic manifestations and the sometimes recalcitrant chronic inflammation, which can lead to other debilitating complications such as fatigue, weakness, and pain. Because these disorders are rare, few healthcare professionals are proficient in their management; therefore the aim of these guidelines is to offer guidance on how to manage patients, and how to create survivorship care plans through the efforts of an interdisciplinary team.

Pituitary Imaging Abnormalities and Related Endocrine Disorders in Erdheim-Chester Disease.

PURPOSE: We examined abnormal pituitary imaging (API) and associated endocrine dysfunction in subjects with ECD. METHODS: A cross-sectional descriptive examination of a natural history cohort study diagnosed with ECD was conducted at a clinical research center. Subjects underwent baseline endocrine tests of anterior and posterior pituitary function and dedicated pituitary gland MRI scans. We determined the frequency of various pituitary imaging abnormalities in ECD and assessed its relationships with age, sex, body mass index (BMI), BRAF V600E status, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), pituitary hormone deficits and number, diabetes insipidus (DI), and panhypopituitarism. RESULTS: Our cohort included 61 subjects with ECD [age (SD): 54.3 (10.9) y, 46 males/15 females]. API was present in 47.5% (29/61) of ECD subjects. Loss of the posterior pituitary bright spot (36.1%) followed by thickened pituitary stalk (24.6%), abnormal enhancement (18.0%), and pituitary atrophy (14.8%) were the most common abnormalities. DI and panhypopituitarism were more frequent in subjects with API without differences in age, sex distribution, hsCRP, ESR, and BRAF V600E status compared to normal pituitary imaging. CONCLUSIONS: We noted a high burden of API and endocrinopathies in ECD. API was highly associated with the presence of panhypopituitarism and DI. Therefore, a thorough assessment of hypothalamic-pituitary integrity should be considered in subjects with ECD.

The Hypothalamic Pituitary Thyroid Axis and Sleep.

Sleep has a bidirectional relationship with the hypothalamic-pituitary-thyroid (HPT) axis, and both these homeostatic processes are inter-dependent for robust physiological functioning. The quality and quantity of sleep influence the circadian pattern of TSH and thyroid hormone secretion. Short term sleep restriction significantly reduces the amplitude of nocturnal TSH secretion and may modulate active thyroid hormone secretion, likely through an increased sympathetic tone. Conversely, TSH and active thyroid hormone affect the quantity and architecture of sleep. For instance, low TSH values are permissive for slow wave sleep and maintenance of normal sleep architecture, while the hypo- or hyper-secretion of active thyroid hormones adversely affects the quality and quantity of sleep. Structural thyroid disorders may also be associated with an altered circadian clock - a phenomenon warranting further investigation. In this review, we aim to provide readers a comprehensive review on the associations between the HPT axis and sleep patterns.

The Hypothalamic-Pituitary-Thyroid Axis in Cushing Syndrome Before and After Curative Surgery.

BACKGROUND: We do not fully understand how hypercortisolism causes central hypothyroidism or what factors influence recovery of the hypothalamic-pituitary-thyroid axis. We evaluated thyroid function during and after cure of Cushing syndrome (CS). METHODS: We performed a retrospective cohort study of adult patients with CS seen from 2005 to 2018 (cohort 1, c1, n = 68) or 1985 to 1994 (cohort 2, c2, n = 55) at a clinical research center. Urine (UFC) and diurnal serum cortisol (F: ~8 am and ~midnight [pm]), morning 3,5,3'-triiodothyronine (T3), free thyroxine (FT4), and thyrotropin (TSH) (c1) or hourly TSH from 1500 to 1900 h (day) and 2400 to 04000 h (night) (c2), were measured before and after curative surgery. RESULTS: While hypercortisolemic, 53% of c1 had central hypothyroidism (low/low normal FT4 + unelevated TSH). Of those followed long term, 31% and 44% had initially subnormal FT4 and T3, respectively, which normalized 6 to 12 months after cure. Hypogonadism was more frequent in hypothyroid (69%) compared to euthyroid (13%) patients. Duration of symptoms, morning and midnight F, adrenocorticotropin, and UFC were inversely related to TSH, FT4, and/or T3 levels (r = -0.24 to -0.52, P < .001 to 0.02). In c2, the nocturnal surge of TSH (mIU/L) was subnormal before (day 1.00 ± 0.04 vs night 1.08 ± 0.05, P = .3) and normal at a mean of 8 months after cure (day 1.30 ± 0.14 vs night 2.17 ± 0.27, P = .01). UFC greater than or equal to 1000 µg/day was an independent adverse prognostic marker of time to thyroid hormone recovery. CONCLUSIONS: Abnormal thyroid function, likely mediated by subnormal nocturnal TSH, is prevalent in Cushing syndrome and is reversible after cure.

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease.

Importance: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated. Objective: To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD. Design, Setting, and Participants: This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020. Exposure: Diagnosis of ECD. Main Outcomes and Measures: Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction. Results: A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050). Conclusions and Relevance: In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.

Insights into the Immunopathophysiology of Severe COVID-19 in Metabolic Disorders.

COVID-19 has affected millions of people across the world but disproportionately and severely affects persons with metabolic disorders such as obesity, diabetes mellitus and hypertension. In this brief review, we discuss the pathways of immune dysregulation that may lead to severe COVID-19 in persons with metabolic conditions.

Prevalence of Diabetes and Hypertension and Their Associated Risks for Poor Outcomes in Covid-19 Patients.

Coronavirus disease 2019 (Covid-19) has affected millions of people and may disproportionately affect those with hypertension and diabetes. Because of inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched databases from December 1, 2019, to April 6, 2020, and selected observational peer-reviewed studies in English of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence. We included 65 (15 794 participants) observational studies at moderate to high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% confidence interval [CI], 10-15; n = 12 870; I 2: 89%), and 17% (95% CI, 13-22; n = 12 709; I 2: 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI, 16-20; n = 1099; I 2: 0%) and 32% (95% CI, 16-54; n = 1078; I 2: 63%), respectively. Unadjusted relative risk for intensive care unit admission and mortality were 1.96 (95% CI, 1.19-3.22; n = 8890; I 2: 80%; P = .008) and 2.78 (95% CI, 1.39-5.58; n = 2058; I 2: 75%; P = .0004) for diabetics; and 2.95 (95% CI, 2.18-3.99; n = 1737; I 2: 0%; P < .001) and 2.39 (95% CI, 1.54-3.73; n = 3107; I 2: 66%; P < .001) for hypertensives. Neither diabetes (1.50; 95% CI, 0.90-2.50; n = 1991; I 2: 74%; P = .119) nor hypertension (1.48; 95% CI, 0.99-2.23; n = 2023; I 2: 69%; P = .058) was associated with severe Covid-19. In conclusion, the risk of intensive care unit admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared with those without these comorbidities. PROSPERO REGISTRATION NUMBER: CRD42020176582.

Doege-Potter syndrome presenting as 'end-stage renal disease-associated hypoglycaemia': a primary presentation of retroperitoneal sarcoma.

A middle-aged woman with end-stage renal disease (ESRD) due to obstructive nephropathy presented to the hospital for an episode of unresponsiveness and hypoglycaemia. Initially, she was diagnosed with hypoglycaemia associated with ESRD and was discharged. However, she returned to the hospital after experiencing tonic-clonic seizures and recurrent hypoglycaemia. Her hypoglycaemia workup revealed an elevated insulin-like growth factor 2 (IGF2) to IGF1 ratio consistent with paraneoplastic IGF2 secretion. Subsequently, a CT abdomen revealed a retroperitoneal mass, found to be a retroperitoneal sarcoma. Her hypoglycaemia was treated with glucocorticoids and growth hormone. Surgical debulking of her tumour was attempted, but she expired due to postoperative haemorrhagic shock. Doege-Potter syndrome is a rare cause of hypoglycaemia which should be suspected in any new-onset, worsening, inexplicable or refractory hypoglycaemia, particularly in non-diabetic ESRD. Here we present a report of retroperitoneal sarcoma presenting with hypoglycaemia in a patient with ESRD without diabetes.

Curative resection of an aldosteronoma causing primary aldosteronism in the second trimester of pregnancy.

SUMMARY: A 29-year-old primigravida woman with a known history of primary aldosteronism due to a right aldosteronoma presented with uncontrolled hypertension at 5 weeks of estimated gestation of a spontaneous pregnancy. Her hypertension was inadequately controlled with pharmacotherapy which lead to the consideration of surgical management for her primary aldosteronism. She underwent curative right unilateral adrenalectomy at 19 weeks of estimated gestational age. The procedure was uncomplicated, and her blood pressure normalized post-operatively. She did, however, have a preterm delivery by cesarean section due to intrauterine growth retardation with good neonatal outcome. She is normotensive to date. LEARNING POINTS: Primary aldosteronism is the most common etiology of secondary hypertension with an estimated prevalence of 5-10% in the hypertensive population. It is important to recognize the subtypes of primary aldosteronism given that certain forms can be treated surgically. Hypertension in pregnancy is associated with significantly higher maternal and fetal complications. Data regarding the treatment of primary aldosteronism in pregnancy are limited. Adrenalectomy can be considered during the second trimester of pregnancy if medical therapy fails to adequately control hypertension from primary aldosteronism.

A Novel Antigonadotropic Role of Thyroid Stimulating Hormone on Leydig Cell-Derived Mouse Leydig Tumor Cells-1 Line.

Subclinical hypothyroid men characterized by a rise in only thyroid stimulating hormone (TSH) levels and normal thyroid hormone levels showed a fall in their serum progesterone and testosterone levels. This suggested a role of TSH in regulating Leydig cell steroidogenesis. Therefore, we investigated the direct role of TSH on steroid production and secretion using a mouse Leydig tumour cell line, MLTC-1. MLTC-1 cells were treated with different doses of TSH isolated from porcine pituitary as well as recombinant TSH. Steroid secretion was measured by radioimmunoassay. The mRNA levels of steroidogenic enzymes were quantitated by real time PCR whereas the corresponding protein levels were determined by Western blot. In MLTC-1 cells, pituitary TSH as well as recombinant TSH inhibited progesterone and testosterone secretion in a dose dependent manner. The inhibitory action of TSH on steroid secretion was unique and not mimicked by other anterior pituitary hormones including FSH and ACTH. Recombinant TSH showed no effect on StAR and CYP11A1, the enzymes catalysing the non-steroidogenic and steroidogenic rate-limiting steps of steroid synthesis respectively. Recombinant TSH was shown to inhibit steroidogenesis in MLTC-1 cells by inhibiting the 3ß hydroxy steroid dehydrogenase mRNA and protein levels, the enzyme that catalyses the conversion of pregnenolone to progesterone. This inhibitory effect of TSH is probably direct as both mRNA and protein of the TSH receptor were shown to be present in the MLTC-1 cells.

Endocrine Conditions and COVID-19.

COVID-19 was declared a global pandemic by the WHO and has affected millions of patients around the world. COVID-19 disproportionately affects persons with endocrine conditions, thus putting them at an increased risk for severe disease. We discuss the mechanisms that place persons with endocrine conditions at an additional risk for severe COVID-19 and review the evidence. We also suggest precautions and management of endocrine conditions in the setting of global curfews being imposed and offer practical tips for uninterrupted endocrine care.

Adrenocortical carcinoma and pulmonary embolism from tumoral extension.

SUMMARY: Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice. LEARNING POINTS: ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

Quality of Life in Patients with Coronary Artery Disease and Panic Disorder: A Comparative Study.

OBJECTIVES: The quality of life (QOL) of patients with coronary artery disease (CAD) is known to be impaired. Non-cardiac chest pain referrals are often under-diagnosed and untreated, and there are hardly any studies comparing the QOL of CAD and panic disorder related (non-cardiac) chest pain referrals (PDRC). METHODS: We assessed the psychiatric morbidity and QOL of patients newly diagnosed with CAD (n = 40) at baseline and six weeks post-treatment and compared their QOL with patients with PDRC (n = 40) and age- and gender-matched healthy controls (n = 57). Psychiatric morbidity in the CAD group was assessed using the General Health Questionnaire (GHQ12) item, Hamilton Anxiety Scores (HAM-A), and Hamilton Depression Scores (HAMD). QOL measures were determined by the World Health Organization QOL questionnaire (brief) and Seattle Angina Questionnaire. The CAD group was treated with anti-ischemic drugs (nitrates, betablockers), antiplatelet drugs (acetylsalicylsalicylic acid), anticoagulants (low molecular weight heparin, clopidogrel), and managed for risk factors. The PDRC group was treated with selective serotonin reuptake inhibitors and anxiolytics. RESULTS: Patients with panic disorder had a worse QOL than those with CAD and healthy controls in the physical domain and psychological domain (PDRC vs. CAD vs. healthy controls, p < 0.001). In the CAD group, smoking was associated with change in angina stability (p = 0.049) whereas other tobacco products were associated with change in angina frequency (p = 0.044). Psychiatric morbidity was present in 40.0% of patients with CAD. In the PDRC group, a significant correlation of HAM-A scores was noted in the physical (p = 0.000), psychological (p = 0.001), social (p = 0.006), and environment (p = 0.001) domains of QOL. Patients with panic disorder had a significant improvement in anxiety scores after treatment compared to baseline (HAM-A scores difference 21.0 [16.5-25.6]; p < 0.001). CONCLUSIONS: Patients in the PDRC group had a worse QOL than those in the CAD and healthy control groups. This highlights the need for careful diagnosis and prompt treatment of panic disorder in these patients to improve their QOL. Additionally, smoking, the use of other tobacco products, and hypercholesterolemia were associated with angina symptoms in patients with CAD.

Thyroid and male reproduction.

Male reproduction is governed by the classical hypothalamo-hypophyseal testicular axis: Hypothalamic gonadotropin releasing hormone (GnRH), pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) and the gonadal steroid, principally, testosterone. Thyroid hormones have been shown to exert a modulatory influence on this axis and consequently the sexual and spermatogenic function of man. This review will examine the modulatory influence of thyroid hormones on male reproduction.