Treating Obesity and Fertility in the Era of Glucagon-like Peptide 1 Receptor Agonists.

The objective of this narrative review is to advocate for improved comprehensive care of patients with obesity and infertility. Persons with elevated body mass index (BMI) have less successful reproductive outcomes, and recently, new medications to treat neuroendocrine hormone imbalances are producing meaningful weight loss akin to surgical interventions. For the first time, obesity is publicly being recognized as a disease, These medications contain the newest generation of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and deserve our attention for several reasons: 1) regardless of BMI, many patients will be using them, 2) it is necessary to understand the mode of action, side effects, and implications for anesthetic procedures and pregnancy, and 3) to evaluate when they could be used to improve health outcomes and/or access to fertility care.

Anti-obesity pharmacological agents for polycystic ovary syndrome: A systematic review and meta-analysis to inform the 2023 international evidence-based guideline.

This systematic review and meta-analysis evaluated the efficacy of anti-obesity agents for hormonal, reproductive, metabolic, and psychological outcomes in polycystic ovary syndrome (PCOS) to inform the 2023 update of the International Evidence-based Guideline on PCOS. We searched Medline, EMBASE, PsycInfo, and CINAHL until July 2022 with a 10-year limit to focus on newer agents. Eleven trials (545 and 451 participants in intervention and control arms respectively, 12 comparisons) were included. On descriptive analyses, most agents improved anthropometric outcomes; liraglutide, semaglutide and orlistat appeared superior to placebo for anthropometric outcomes. Meta-analyses were possible for two comparisons (exenatide vs. metformin and orlistat + combined oral contraceptive pill [COCP] vs. COCP alone). On meta-analysis, no differences were identified between exenatide versus metformin for anthropometric, biochemical hyperandrogenism, and metabolic outcomes, other than lower fasting blood glucose more with metformin than exenatide (MD: 0.10 mmol/L, CI 0.02-0.17, I2 = 18%, 2 trials). Orlistat + COCP did not improve metabolic outcomes compared with COCP alone (fasting insulin MD: -8.65 pmol/L, -33.55 to 16.26, I2 = 67%, 2 trials). Published data examining the effects of anti-obesity agents in women with PCOS are very limited. The role of these agents in PCOS should be a high priority for future research.

Navigating the Role of Anti-Obesity Agents Prior to Pregnancy: A Narrative Review.

Utilization of anti-obesity agents is rising in reproductive-age females with some planning for future pregnancy. Lifestyle-induced weight loss has been shown to increase spontaneous conception rate, improve rates of fertility intervention complications, and decrease pregnancy comorbidities. However, the definitive role of assisting weight loss with medication prior to pregnancy remains to be established. The implications of anti-obesity agent used prior to pregnancy are explored in this narrative review, considering benefits of weight loss as well as available evidence for use and risks of anti-obesity agents prior to pregnancy.

A Systematic Review and Meta-Analysis of Subsequent Malignant Neoplasm Risk After Radioactive Iodine Treatment of Thyroid Cancer.

Background: The potential risk of subsequent malignant neoplasms (SMNs) after radioactive iodine (RAI) treatment of thyroid cancer (TC) is an important concern. Methods: A systematic review was updated comparing the risk of SMNs in TC patients treated with RAI to TC patients without RAI. Six electronic databases were searched (up to March, 2018), supplemented with a hand search. Two reviewers independently screened citations, reviewed full-text papers, and critically appraised/abstracted data. Random-effects meta-analyses were conducted using crude data and data statistically adjusted for confounders. The outcomes were any SMN and specific SMNs for which sufficient data were available. Results: In total, 3506 unique electronic search citations and 93 full-text papers were examined, including 17 studies (3 systematic reviews and 14 original studies). Published knowledge syntheses were limited by inclusion of small numbers of studies, with two systematic reviews suggesting an increased risk of any SMN and one meta-analysis suggesting a reduced risk of breast SMN after RAI treatment. In a meta-analysis of crude data, the risk ratio of any SMN in RAI-treated TC patients was 0.98 ([confidence interval (CI) 0.76-1.27]; n = 10 studies of 65,539 individuals, heterogeneity Q = 64.26, degrees of freedom [df] = 9, p < 0.001, I2 = 85.99). The pooled risk ratio for any SMN, adjusted for confounders, was 1.16 ([CI 0.97-1.39]; n = 6 studies, data from at least 11,241 TC patients, Q = 10.86, df = 5, p = 0.054, I2 = 53.96). In secondary analyses examining specific SMNs, although relatively rare, the risk of subsequent leukemia was increased, but the risk of multiple myeloma was reduced in RAI-treated TC patients. There was no significant increased relative risk of breast cancer, salivary cancer, or combined hematologic malignancies according to RAI treatment status. Conclusions: The body of evidence on whether 131I treatment of thyroid cancer is associated with the primary outcome of any SMN is highly heterogeneous and complex. More research examining the long-term risk of specific SMNs after 131I treatment is needed.

Delaying Thyroxine Until Positive Beta-Human Chorionic Gonadotropin is Safe for Patients Receiving Fertility Therapy: Applying New ATA Guidelines to Subclinical Hypothyroidism.

OBJECTIVE: This study sought to examine the effect of changing TSH threshold recommendations from 2.5 to 4 mIU/L before fertility therapy on the prevalence of early gestational subclinical hypothyroidism (SCH) (TSH2 >2.5 mIU/L) and to evaluate implications on progression to clinical pregnancy (defined as detection of cardiac activity on ultrasound). METHODS: A retrospective chart review was performed in an academic fertility clinic on all patients with a measured pre-treatment TSH (TSH1) and positive beta-human chorionic gonadotropin following fertility treatment. The study assessed the effect of TSH2 on ongoing pregnancy, both in patients newly diagnosed with SCH and in patients previously receiving LT4, stratified by initial TSH. RESULTS: Of 482 women included in the study, baseline TSH (TSH1) was <2.5 mIU/L in 333 women (69%) and 2.5-4 mIU/L in 64 women (13.2%). Eighty-five women were taking LT4 at baseline (17.6%). Among women with a TSH1 between 2.5 and 4 mIU/L, the corresponding TSH in early pregnancy (TSH2) was <2.5 mIU/L in 35 women (55%). Overall, there was no difference in progression to clinical pregnancy between women with a TSH2 of 2.5-4 mIU/L compared with women with a TSH2 <2.5 mIU/L (OR 0.70; 95% CI 0.44-1.09). Similarly, when excluding women taking LT4 at baseline, there was no difference in progression to clinical pregnancy (OR 0.90; 95% CI 0.28-2.86). CONCLUSION: Rate of progression to clinical pregnancy was equivalent between women with an early pregnancy TSH (TSH2) <2.5 and women with a TSH2 of 2.5-4.0 mIU/L. Our findings support initiating LT4 in early pregnancy, as opposed to pre-pregnancy if the TSH remains above cut-off because there does not appear to be a difference in in early pregnancy outcomes if treatment is delayed.

Promoting resource stewardship: Reducing inappropriate free thyroid hormone testing.

RATIONALE: Free thyroxine (fT4) and free triiodothyronine (fT3) tests are often ordered when not clinically warranted. Preventing laboratory overuse by reducing inappropriate fT4 and fT3 testing is one strategy to promote resource stewardship. OBJECTIVES: (1) To characterize the frequency of inappropriate fT4 and fT3 testing and (2) to implement a quality improvement strategy aimed at reducing the number of these tests performed. METHODS: Quality improvement tools were used to create sequential change ideas: (1) education of physicians regarding appropriate indications for ordering fT4/fT3 and (2) implementation of a hospital-wide laboratory and forced-function system with a reflex fT4. This study was conducted at an academic ambulatory care hospital in Toronto, Canada. The main outcomes were the differences in weekly median number of thyroid-stimulating hormone, fT4, and fT3 tests performed during the preintervention, education, and reflex periods using the Kruskal-Wallis test and analysis for special cause variation with statistical process control charts. RESULTS: The median number of fT4/fT3 processed per week was significantly reduced from 90/39 at baseline to 78/34 posteducation and 59/14 postreflex (P < .0001). Comparing preintervention to the reflex period, there was 34% reduction in fT4 and 64% reduction in fT3. The number of processed thyroid-stimulating hormone tests was stable with only 2% variation. Statistical process control charts demonstrated special cause variation following implementation of the reflex system for both fT4 and fT3. CONCLUSIONS AND RELEVANCE: Inappropriate testing of free thyroid indices occurs frequently. The implementation of a reflex fT4 strategy after education was feasible in reducing overall testing by 49% and was effective in promoting resource stewardship.

A Systematic Review of Unmet Information and Psychosocial Support Needs of Adults Diagnosed with Thyroid Cancer.

BACKGROUND: Patient education and psychosocial support to patients are important elements of comprehensive cancer care, but the needs of thyroid cancer survivors are not well understood. METHODS: The published English-language quantitative literature on (i) unmet medical information and (ii) psychosocial support needs of thyroid cancer survivors was systematically reviewed. A librarian information specialist searched seven electronic databases and a hand search was conducted. Two reviewers independently screened citations from the electronic search and reviewed relevant full-text papers. There was consensus between reviewers on the included papers, and duplicate independent abstraction was performed. The results were summarized descriptively. RESULTS: A total of 1984 unique electronic citations were screened, and 51 full-text studies were reviewed (three from the hand search). Seven cross-sectional, single-arm, survey studies were included, containing data from 6215 thyroid cancer survivor respondents. The respective study sizes ranged from 57 to 2398 subjects. All of the studies had some methodological limitations. Unmet information needs were variable relating to the disease, diagnostic tests, treatments, and co-ordination of medical care. There were relatively high unmet information needs related to aftercare (especially long-term effects of the disease or its treatment and its management) and psychosocial concerns (including practical and financial matters). Psychosocial support needs were incompletely met. Patient information on complementary and alternative medicine was very limited. CONCLUSIONS: In conclusion, thyroid cancer survivors perceive many unmet information needs, and these needs extend to aftercare. Psychosocial information and supportive care needs may be insufficiently met in this population. More work is needed to improve knowledge translation and psychosocial support for thyroid cancer survivors.

A systematic review of randomized controlled trials for management of persistent post-treatment fatigue in thyroid cancer survivors.

BACKGROUND: Fatigue that persists post-treatment is commonly reported by thyroid cancer (TC) survivors. METHODS: A systematic review of published English language randomized controlled trials (RCTs) on interventions for management of persistent post-treatment fatigue in TC was conducted. This review excluded studies on short-term interventions used in preparation for radioactive iodine diagnostic scans or treatment. An electronic search was executed in six databases and supplemented by a hand search. Two reviewers independently reviewed all citations from the electronic search and relevant full-text studies. Two abstractors independently critically appraised included studies and abstracted the data. The data were qualitatively summarized. RESULTS: A total of 1086 unique citations and 25 full-text studies were reviewed. Four studies summarizing the results of three RCTs were included. The interventions included: combination triiodothyronine with levothyroxine (L-T4) therapy compared to L-T4 alone (one RCT), reduction in degree of thyrotropin (TSH) suppression using L-T4 compared to maintenance of TSH suppression (one RCT), and supervised exercise compared to inactivity (two RCTs examining different fatigue outcomes in same population). Trial duration ranged from 10 weeks to six months. All trials had limitations, and the number of TC survivors included in respective RCTs ranged from 15 to 36. Hormonal treatment RCTs had mixed fatigue outcome results within respective trials. However, multiple measures suggesting improvement in fatigue were reported following the exercise intervention. CONCLUSIONS: There is paucity of RCTs to guide evidence-based management of persistent post-treatment fatigue in TC survivors. RCTs of interventions for prevention or treatment of fatigue in TC survivors are needed.

A pediatric patient with Cushing syndrome caused by ectopic ACTH syndrome and concomitant pituitary incidentalomas.

Ectopic ACTH syndrome is a rare but important cause of pediatric Cushing syndrome, for which management by a multidisciplinary team is required. Although diagnostic evaluation is similar to that in adults, the variation in epidemiology may sway investigations, leading to inappropriate and/or incomplete diagnostic interventions. We present a case of 15-year-old girl with symptoms of severe ACTH-dependent Cushing syndrome and two pituitary adenomas. The ectopic source of ACTH production was confirmed after petrosal venous sampling was performed. Diagnostics and perioperative management of a pulmonary carcinoid tumor producing ectopic ACTH is reviewed. In pediatric patients, as in adult patients, a pituitary lesion <6 mm on MRI is not sufficient confirmation of Cushing's disease, and appropriate diagnostic work-up should be performed to assess the source of the ACTH overproduction.

Ciprofloxacin and rifampin have opposite effects on levothyroxine absorption.

BACKGROUND: Levothyroxine (L-T4) absorption varies between individuals, and can be affected by various concomitantly administered drugs. Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose. METHODS: The effects of two antibiotics on T4 absorption were prospectively assessed in a double-blind, randomized, crossover fashion. Eight healthy volunteers received 1000 µg L-T4 combined with placebo, ciprofloxacin 750 mg, or rifampin 600 mg as single doses. We measured total plasma thyroxine (T4) concentrations over a 6-hour period after dosing using liquid chromatography-tandem mass spectrometry. For each study arm, areas under the T4 plasma concentration-time curve (T4 AUCs) were compared. RESULTS: Coadministration of ciprofloxacin significantly decreased the T4 AUC by 39% (p = 0.035), while, surprisingly, rifampin significantly increased T4 AUC by 25% (p = 0.003). CONCLUSION: Intestinal absorption of L-T4 is differentially affected by acute coadministration of ciprofloxacin or rifampin. Mechanistic studies focused on intestinal and possibly hepatic thyroid hormone transporters are required to explain the observed drug interactions with L-T4.

Efficacy and plasma drug concentrations with nondaily dosing of rosuvastatin.

BACKGROUND: Nondaily statin dosing is an alternative for patients unable to tolerate daily dosing. The higher potency and longer half-life of rosuvastatin lends itself to this regimen. The basis of this improved tolerability is not understood, but might be related to lower plasma drug concentrations. We examined the efficacy of nondaily rosuvastatin in previously statin-intolerant patients and determined plasma drug concentrations at various dose regimens. METHODS: A retrospective analysis at a specialty lipid clinic identified 58 patients eligible for evaluation after therapy with nondaily rosuvastatin. Plasma rosuvastatin levels were measured by liquid chromatography-mass spectrometry in 12 patients taking 10 mg nondaily rosuvastatin and in 11 and 12 age- and sex-matched patients taking 10 mg and 5 mg rosuvastatin daily, respectively. Whole body cholesterol synthesis was estimated from serum lathosterol measured by liquid chromatography-mass spectrometry. RESULTS: In patients with a previous history of statin intolerance, nondaily rosuvastatin (average of 29.4 mg per week) lowered low-density lipoprotein cholesterol by 34.4 ± 21.3% (P < 0.001). Serum lathosterol levels were significantly higher in patients on nondaily regimens, as expected. However, mean plasma rosuvastatin levels of patients taking 10 mg nondaily did not significantly differ from those taking 10 mg daily. CONCLUSIONS: In statin intolerant patients, nondaily rosuvastatin resulted in clinically relevant reductions in low-density lipoprotein cholesterol levels, with improved compliance. Whole body cholesterol synthesis was higher in patients taking nondaily rosuvastatin, but no differences in plasma drug concentrations were observed, suggesting that the improved tolerability was independent of plasma rosuvastatin levels.

Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib.

Among the noteworthy recent stories in the management and prevention of atherosclerotic cardiovascular disease (CVD) is the saga of the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP). Inhibiting CETP significantly raises plasma concentrations of high-density lipoprotein cholesterol, which has long been considered a marker of reduced CVD risk. However, the first CETP inhibitor, torcetrapib, showed a surprising increase in CVD events, despite a dramatic increase in high-density lipoprotein cholesterol levels. This paradox was explained by putative off-target effects not related to CETP inhibition that were specific to torcetrapib. Subsequently, three newer CETP inhibitors, namely dalcetrapib, anacetrapib, and evacetrapib, were at various phases of clinical development in 2012. Each of these had encouraging biochemical efficacy and safety profiles. Dalcetrapib even had human arterial imaging results that tended to look favorable. However, the dalcetrapib development program was recently terminated, presumably because interim analysis of a large CVD outcome trial indicated no benefit. These events raise important questions regarding the validity of the mechanism of CETP inhibition and the broader issue of whether pharmacological raising of high-density lipoprotein cholesterol itself is a useful strategy for CVD risk reduction.

Severe hypertriglyceridemia in pregnancy.

CONTEXT: Pregnancy-related hypertriglyceridemia is rare, but it can be life threatening in some patients with genetic susceptibility. Complications can include acute pancreatitis, hyperviscosity syndrome, and possibly preeclampsia. We present a case of successful management of recurrent gestational chylomicronemia due to compound heterozygous mutations in the LPL gene. EVIDENCE ACQUISITION: To outline advances in clinical management of this condition, we searched English language publications in PubMed, EMBASE, and ISI Web of Science (search terms: pregnancy, pregnancy complications, pregnan*, hyperlipoproteinemia, hypertriglyceridemia, chylomicrons, chylomicronemia) and reference lists of relevant published articles from 2002 to 2011. We identified eight case reports. EVIDENCE SYNTHESIS: Interventions reported in those cases are reviewed including: 1) low-fat diet; 2) nutritional supplements; 3) oral prescription medications; 4) parenteral heparin; 5) insulin infusion in the context of hyperglycemia; and 6) therapeutic plasma exchange. CONCLUSIONS: Overall, our recommendations are to monitor for pregnancy-related hypertriglyceridemia in those with prepregnancy fasting triglyceride level greater than 4 mmol/liter and to institute therapy when triglyceride level increases to more than 10 mmol/liter. Therapy should include a multidisciplinary team to address dietary fat restriction, appropriate supplements, and possible medications when needed. Admission to hospital is recommended in severe cases. We conclude that complications are preventable with appropriate and timely intervention.

Measurements of aneurysm morphology determined by 3-d micro-ultrasound imaging as potential quantitative biomarkers in a mouse aneurysm model.

Aneurysms remain a significant medical problem and our current understanding of aneurysm formation and developmental stages remains incomplete. Noninvasive 3-D micro-ultrasound (3-D micro-US) imaging technologies designed for noninvasive evaluation of small laboratory animals diminish risks associated with invasive examination and provide in-situ (live) analysis of vascular morphological changes, which enables quantitative measurements of live biological specimens. We demonstrate here that aneurysm morphology can be quantified using 3-D micro-US, and we validate this methodology through comparison of geometric measures with those obtained from 3-D serial histologic records in a mouse model of accelerated aneurysm formation. Aneurysms were induced in Balb/C mice after C57Bl/6 mouse aortic transplant with injections of a pro-inflammatory viral serpin with a mutated reactive site. Aortic transplant segments were imaged 28 days after transplant using 3-D micro-US. Upon sacrifice, the aortas were excised and histology sections (5-microm thick) were digitized, co-registered using mutual information and stacked to form 3-D images. Surfaces of the mouse aorta and aneurysm were manually segmented from the 3-D micro-US and histology images. Comparisons with 3-D histology images demonstrated that 3-D micro-US allowed in-vivo analysis of aneurysm morphology, including total aneurysm area, plaque growth and lumen size. Linear regression of 3-D US-derived aneurysm and plaque volumes vs. 3-D histology-derived volumes resulted in slopes of 1.30 (R(2) = 0.96) and 1.20 (R(2) = 0.98), respectively, demonstrating that 3-D micro-US measurements can be used to track aneurysm growth in a mouse aortic transplant model.