Optimal Hormone Replacement Therapy in Hypothyroidism - A Model Predictive Control Approach.
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ABSTRACT:
SUBMITTER: Wolff TM
PROVIDER: S-EPMC9263720 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.
| S-EPMC9145255 | biostudies-literature
Project description:Levothyroxine (LT4) is a safe, effective means of hormone replacement therapy for hypothyroidism. Here, we review the pharmaceutical, pathophysiological and behavioural factors influencing the absorption, distribution, metabolism and excretion of LT4. Any factor that alters the state of the epithelium in the stomach or small intestine will reduce and/or slow absorption of LT4; these include ulcerative colitis, coeliac disease, bariatric surgery, Helicobacter pylori infection, food intolerance, gastritis, mineral supplements, dietary fibre, resins, and various drugs. Once in the circulation, LT4 is almost fully bound to plasma proteins. Although free T4 (FT4) and liothyronine concentrations are extensively buffered, it is possible that drug- or disorder-induced changes in plasma proteins levels can modify free hormone levels. The data on the clinical significance of genetic variants in deiodinase genes are contradictory, and wide-scale genotyping of hypothyroid patients is not currently justified. We developed a decision tree for the physician faced with an abnormally high thyroid-stimulating hormone (TSH) level in a patient reporting adequate compliance with the recommended LT4 dose. The physician should review medications, the medical history and the serum FT4 level and check for acute adrenal insufficiency, heterophilic anti-TSH antibodies, antibodies against gastric and intestinal components (gastric parietal cells, endomysium, and tissue transglutaminase 2), and Helicobacter pylori infection. The next step is an LT4 pharmacodynamic absorption test; poor LT4 absorption should prompt a consultation with a gastroenterologist and (depending on the findings) an increase in the LT4 dose level. An in-depth etiological investigation can reveal visceral disorders and, especially, digestive tract disorders.
| S-EPMC8528480 | biostudies-literature
Project description:BACKGROUND:Although reversible in some patients, primary hypothyroidism is considered a permanent condition requiring lifelong hormone therapy. This study aimed to investigate the factors predicting the successful discontinuation of levothyroxine (L-T4) therapy in patients with primary hypothyroidism. METHODS:A retrospective study was performed in primary hypothyroidism patients who met inclusion criteria: patients who maintained stable L-T4 therapy for more than 1 year, following gradual dose reduction of L-T4 based on the clinical decision (L-T4 tapering); patients receiving either no L-T4 or a fixed minimum dose for more than 1 year after L-T4 tapering. Reduction in L-T4 dosage by 12.5-50 ?g within 3 months was considered as L-T4 tapering. Serum free T4, TSH, and clinical symptoms were evaluated before, during and after tapering. Logistic regression and decision tree analyses were performed to predict the successful discontinuation of L-T4. RESULTS:Among 382 patients, 22.5% and 58.4% showed successful discontinuation (T4-Discontinued) and dose reduction (T4-Reduced) of L-T4 therapy, while other did not obtained any reduction of L-T4 dose (T4-Unchanged). The median number of tapering visit was 1.0 (range, 1.0-4.0). In T4-Discontinued group, the TSH level and the positive rate of anti-thyroperoxidase at the time of L-T4 initiation were lower, the duration of L-T4 therapy was shorter, and the maintenance dose of L-T4 at the time of tapering was lower than those in the T4-Unchanged group. In ultrasonography, normal parenchyma was preserved in the T4-Discontinued group while others showed higher rates of heterogeneous or hypoechoic parenchymal changes. Among those different characteristics, the longer duration of L-T4 therapy and the higher maintenance dose of L-T4 at the time of tapering significantly predicted the failure of discontinuation of L-T4 in multivariate analysis. A decision tree showed that patients with a duration of L-T4 therapy >4.6 years had lower success rate of discontinuation. CONCLUSION:Shorter duration of L-T4 therapy and lower L-T4 dose at the time of tapering are the predictable factors for successful L-T4 tapering in stably maintained primary hypothyroidism patients.
| S-EPMC7259697 | biostudies-literature
Project description:BACKGROUND: Subclinical hypothyroidism (SCH) is not a rare condition in females, the elderly, or patients with chronic kidney disease (CKD). Even though previous studies have demonstrated that thyroid hormone replacement therapy (THRT) improves cardiac function and dyslipidemia in patients with SCH, it remains unclear as to whether THRT can improve renal function in CKD patients with SCH. This study investigated the impact of THRT on changes in estimated glomerular filtration rates (eGFR) in this patient population. METHODS: A total of 113 CKD patients with SCH who were treated with L-thyroxine and had eGFR available for at least 24 months before and after THRT were enrolled between January 2005 and December 2011. A linear mixed model was used to compare patients' clinical and biochemical parameters at various time points. The slope of the decline in eGFR over time, both before and after THRT, was also calculated and compared using a linear mixed model. RESULTS: The mean age of the study participants was 63.2±12.7 years, and 36 patients (31.9%) were men. The mean follow-up duration before and after THRT was 28.6±4.5 and 30.6±6.4 months respectively. After 24 months of THRT, serum thyrotropin (TSH) levels were significantly reduced-8.86±0.49 versus 1.41±0.73??IU/mL, p<0.001-but there were no significant changes in triiodothyronine and free thyroxine concentrations. Serum albumin, calcium, phosphate, cholesterol, and triglyceride levels were also comparable before and after THRT. The rates of decline in eGFR were significantly attenuated by THRT (-4.31±0.51 vs.-1.08±0.36 [mL/min]/[year·1.73 m²], p<0.001), even after adjustment for age, sex, diabetes, mean arterial pressure, and serum albumin, cholesterol, and triglyceride concentrations (p<0.001). CONCLUSION: THRT attenuated the rate of decline in renal function in CKD patients with SCH, suggesting that THRT may delay reaching end-stage renal disease in these patients.
| S-EPMC3675831 | biostudies-other
Project description:OBJECTIVE:To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. DESIGN:Retrospective cohort study. SETTING:The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. PARTICIPANTS:Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. EXPOSURE:TSH concentration in patients with hypothyroidism. MAIN OUTCOME MEASURES:Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. RESULTS:162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). CONCLUSIONS:In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.
| S-EPMC6719286 | biostudies-other
Project description:Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality. Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing's disease, or craniopharyngioma experience similar effects from GHRT as others. Arch Endocrinol Metab. 2019;63(6):592-600.
| S-EPMC10522239 | biostudies-literature
Project description:The American Women’s Health Initiative study published in July 2002 caused considerable concern among hormone replacement therapy (HRT) users and prescribers in many countries. This study is an exploratory research comparing the genome wide expression profile in whole blood samples according to HRT use. Within the Norwegian Women and Cancer study, 100 postmenopausal women (50 HRT users and 50 non-HRT users) born between 1943 and 1949 with normal to high body mass index and no other medication use were selected. After total RNA extraction, amplification and labelling, the samples were hybridized together with a common reference (Universal human reference RNA, Stratagen) to Agilent Human 1A oligoarrays (G4110b, Agilent Technologies, Palo Alto, CA) containing 20,173 unique genes. Differentially expressed genes were used to build a classifier using the nearest shrunken centroids method (PAM). Then, we tested the significant changes in single genes by different methods like t-test, Significance Analysis of Microarrays (SAM) and Bayesian ANOVA analysis (BAM). Results did not reveal any distinct gene list which predicted accurately HRT exposure (error rate = 0.45). Classifier performance slightly improved (error rate = 0.29) including only women who were using continuous combined HRT treatment. According to the small amplitude of expression alterations observed after HRT use in whole blood, large sample sizes are needed to identify significant single genes differentially expressed. However, significant enrichments in biologic process of genes with small changes after HRT use were observed (e.g. receptor and transporter activities, immune response, frizzled signalling pathway, actin filament organization, glycogen metabolism). Keywords: gene expression profile and exposure
2005-10-25 | GSE3492 | GEO
Project description:Predicting the movements, ground reaction forces and neuromuscular activity during gait can be a valuable asset to the clinical rehabilitation community, both to understand pathology, as well as to plan effective intervention. In this work we use an optimal control method to generate predictive simulations of pathological gait in the sagittal plane. We construct a patient-specific model corresponding to a 7-year old child with gait abnormalities and identify the optimal spring characteristics of an ankle-foot orthosis that minimizes muscle effort. Our simulations include the computation of foot-ground reaction forces, as well as the neuromuscular dynamics using computationally efficient muscle torque generators and excitation-activation equations. The optimal control problem (OCP) is solved with a direct multiple shooting method. The solution of this problem is physically consistent synthetic neural excitation commands, muscle activations and whole body motion. Our simulations produced similar changes to the gait characteristics as those recorded on the patient. The orthosis-equipped model was able to walk faster with more extended knees. Notably, our approach can be easily tuned to simulate weakened muscles, produces physiologically realistic ground reaction forces and smooth muscle activations and torques, and can be implemented on a standard workstation to produce results within a few hours. These results are an important contribution toward bridging the gap between research methods in computational neuromechanics and day-to-day clinical rehabilitation.
| S-EPMC5390028 | biostudies-literature
Project description:PurposeA decline in breast cancer incidence has been attributed to the reduction in hormone replacement therapy (HRT) prescriptions since the publication of the landmark WHIT paper in 2003. Concurrently, a relationship between HRT and cerebrovascular disease incidence has also been suggested. No generalized analysis of HRT prescription rates and breast cancer incidence rates that included more than seven years of data. We hypothesized that detailed analysis of SEER data would clarify the relationship between HRT use and breast cancer incidence. Given the large decline in HRT prescription rates uncovered, analyses of potential complications were also conducted, with the understanding that a small effect or one limited to a subpopulation, such as a single race, might not be detected.MethodsIncidence rates (per 100,000 women) and standard errors for ductal and lobular breast carcinomas, and endometrioid /endometrial carcinomas in women over 50 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database 1992-2012. From the Medical Expenditure Panel Survey 1996-2012 weighted counts and standard errors of hormone replacement therapy (HRT) prescriptions for women over 50 years were obtained. Using the National Hospital Discharge Survey (NHDS), 1996-2010 weighted counts and standard errors of femoral neck fractures, total hip replacements, acute myocardial infarctions, and cerebral infarctions were obtained for 50+ year men and women. Weighted counts and standard errors were divided by US census figures and multiplied by 100,000. Joinpoint regression was used to analyze rates.Main resultsBeginning 2001, HRT prescription rates dropped dramatically, 2001-2012 AAPC -14.9 (95% CI -17.4, -12.4). Breast cancer rates, which began to decline in 1999, increased after 2003; 2012 rates were similar to those seen in 2001 for both ductal, AAPC 0.1 (-0.4, 0.6) and lobular, AAPC 0.5 (-0.4, 1.5), carcinoma. Endometrial carcinoma rates increased, 2001-2012 AAPC 3.5 (3.1, 3.8), arguing against a negative effect of HRT discontinuation of endometrial carcinoma. Tests for parallelism failed to detect APC differences among genders for femoral neck fractures (P = 0.24), for total hip replacements (P = 0.11), for myocardial infarctions (P = 0.10), or for cerebral infarctions (P = 0.19), precluding any assignment of general effect on these disorders by HRT.ConclusionsUsing SEER data, we demonstrated that changes in breast cancer rates cannot be explained by HRT prescription rate changes.
| S-EPMC4575090 | biostudies-literature
Project description:ObjectivesHormone replacement therapy (HRT) had been the gold standard for the treatment of menopausal symptoms until the publication of the World Health Initiative (WHI) study. After the WHI study, the use of HRT changed among the physicians and patients all over the world despite newer more reassuring data. This study aimed to investigate the knowledge and attitudes of women towards HRT and the factors affecting it for better counseling. Study design. A clinic-based cross-sectional study using a survey was offered to women aged 40 years and above coming to the women's health center at the American University of Beirut Medical Center (AUBMC) from October 1st, 2017, till March 31st, 2018. The questionnaire included questions about demographics and menopausal symptoms in addition to knowledge and attitudes towards menopause and HRT. Main outcome measures. Our main hypothesis was that women would be aware of HRT as a treatment modality; however, the majority would have a negative attitude towards its usage.ResultsThe response rate was 87.8%. Seventy-three percent of the respondents had already heard about HRT with 57.9% supporting the use of HRT; however, 47.9% did not know when to use it. The significant predictor for having heard about HRT and a positive attitude towards HRT were having HRT prescribed as a part of treatment and employment status, respectively.ConclusionsLebanese women are aware of HRT as a treatment option; however, a lack of both proper information and positive attitude towards HRT use was noted.
| S-EPMC7315264 | biostudies-literature