70 Years of Levothyroxine

Preface
Contents
About the Editor and Contributors
	Editor
	Contributors
Therapeutic Use of Levothyroxine: A Historical Perspective
	1 Introduction
	2 Early Beginnings: Growing Understanding of the Thyroid
		2.1 Cretinism, Goitre, and the Recognition of the Importance of the Thyroid Gland
		2.2 An Endocrine Function for the Thyroid Gland
	3 Towards the Modern Era in the Management of Hypothyroidism
		3.1 Introduction of Chemically Synthesised Thyroid Hormones
		3.2 Monotherapy or Combination Therapy?
		3.3 Technological Advances: Better Assays of Thyroid Function
		3.4 Recent Developments in Levothyroxine Therapy
	4 Where We Stand Today
		4.1 A Fuller (But Incomplete) Understanding of Thyroid Hormone Homeostasis
		4.2 Unresolved Issues and Current Research Questions
	5 Conclusions
	References
Administration and Pharmacokinetics of Levothyroxine
	1 Introduction
	2 Absorption, Distribution, Metabolism, and Elimination of Levothyroxine
		2.1 Absorption and Distribution
		2.2 Metabolism and Elimination
	3 Factors That May Alter Exposure to an Oral Dose of Levothyroxine
		3.1 Factors That May Reduce Exposure to Levothyroxine
			3.1.1 Diurnal Variation
			3.1.2 Malabsorption of, and Suboptimal Adherence to, Levothyroxine
		3.2 Factors That May Alter the Measured Level of Thyrotropin
	4 Levothyroxine Tablets in a Changing Regulatory Environment
	5 Conclusions
	References
Pharmacodynamic and Therapeutic Actions of Levothyroxine
	1 Introduction
	2 Thyroid Hormone Homeostasis
		2.1 Conversion of T4 to T3
		2.2 Regulation of Deiodinases and Individual “Set Points” for Thyroid Function
		2.3 Thyroid Hormone Receptors (THRs)
		2.4 Regulation of TSH Release
	3 Clinical Pharmacodynamics of (Levo)Thyroxine
		3.1 Which Thyroid Hormones Are Important?
		3.2 Actions on Skeletal Muscle
			3.2.1 Mechanisms
			3.2.2 Clinical Studies of Interest
		3.3 Effects on Lipid Profiles
		3.4 Actions in Adipose Tissue
		3.5 Effects on Glucose Metabolism
		3.6 Actions on Mood and Affect
		3.7 Fatigue
		3.8 Actions on Inflammation and Haemostasis
		3.9 Effects in the Kidney
		3.10 Effects on the Heart and in Bone
	4 Evidence-Based Guidelines for the Management of Hypothyroidism
		4.1 Current Status of Evidence-Based Guidelines
		4.2 Levothyroxine Monotherapy, or Levothyroxine Plus Triiodothyronine, for Hypothyroidism
		4.3 Barriers to Optimal Care of Patients with Hypothyroidism
			4.3.1 The Impact of the Diagnosis Itself
			4.3.2 Avoiding over Diagnosis
	5 Conclusions
	References
Levothyroxine in Pregnancy
	1 Introduction
	2 Changes in Thyroid Function During Pregnancy
	3 Maternal and Foetal Outcomes in Women with Hypothyroidism
		3.1 Effects of Hypothyroidism on Fertility and Preterm Delivery
		3.2 LT4 Treatment and Pregnancy Outcomes: Importance of Thyroid Autoimmunity
		3.3 LT4 Treatment of Euthyroid Women with Thyroid Autoimmunity
		3.4 Thyroid Autoimmunity and Pregnancy Outcomes in Women Receiving Assisted Reproduction Technologies (ART)
		3.5 Effects on Offspring
	4 Summary of Current Major Guidelines
		4.1 Guidelines Considered Here
		4.2 Overt Hypothyroidism During Pregnancy and Postpartum
		4.3 Subclinical Hypothyroidism During Pregnancy and Postpartum
	5 Conclusions
	References
Levothyroxine in Children
	1 Introduction
	2 Overview of Hypothyroidism in Children
		2.1 Congenital Hypothyroidism
		2.2 Subclinical Hypothyroidism
			2.2.1 Prevalence and Clinical Course
			2.2.2 Outcomes in Children with Subclinical Hypothyroidism
		2.3 Other Causes of Hypothyroidism in Children
	3 Effects of Levothyroxine in Children with Hypothyroidism
		3.1 Congenital or Overt Hypothyroidism
		3.2 Subclinical Hypothyroidism
		3.3 Biochemically Euthyroid Children
	4 Conclusions
	References
Levothyroxine in the Older Patient
	1 Thyroid Homeostasis in Older Individuals
		1.1 Thyroid Homeostasis
		1.2 Thyroid Hormone Levels and Clinical Outcomes
	2 Therapeutic Use of Levothyroxine in Older Patients with Hypothyroidism
		2.1 Analyses from Randomised, Placebo-Controlled Trials
		2.2 Observational Studies of Levothyroxine in Older Patients with Hypothyroidism
		2.3 Managing Elderly Patients with Hypothyroidism: Implications of the SORTED 1 Trial
	3 Conclusions
	References
Levothyroxine and the Heart
	1 Introduction
	2 Overview of the Adverse Effects of Thyroid Dysfunction on the Heart
	3 Effects of Levothyroxine Replacement Therapy on the Cardiovascular System
		3.1 Effects on ECG Parameters
		3.2 Effects of l-Thyroxine on Cardiovascular Structure and Function
		3.3 Effects of LT4 on Major Adverse Cardiovascular Events
		3.4 Effects of LT4 in Patients with Heart Failure
	4 Conclusions
	References
Levothyroxine and Bone
	1 Overview of the Effects of Thyroid Hormones on the Skeleton
	2 Bone Health in Patients Receiving Treatment with Levothyroxine
		2.1 Patients with Congenital Hypothyroidism
		2.2 Adult Patients with Hypothyroidism
			2.2.1 Subclinical Hypothyroidism
			2.2.2 Overt Hypothyroidism
		2.3 Effects of Thyrotropin-Suppressive Doses of Levothyroxine
	3 Clinical Perspectives
	References
Levothyroxine and Cancer
	1 Introduction
		1.1 Overview of the Management of Differentiated Thyroid Cancer
		1.2 Scope of This Chapter
	2 Application of Thyrotropin-Suppressive Doses of Levothyroxine After Surgery and Radioactive Iodine for Well-Differentiated Thyroid Tumours
		2.1 Need for Suppression of Thyrotropin in Thyroid Cancer Survivors
		2.2 Long-Term Consequences of Thyroidectomy and Thyrotropin Suppression
			2.2.1 Bone
			2.2.2 The Cardiovascular System
			2.2.3 Patient-Reported Outcomes
	3 Thyroid Hormones and Cancer Risk
	4 Conclusions
	References
Practical Application of Levothyroxine-Based Therapy
	1 Introduction
	2 Safety and Tolerability of Levothyroxine
		2.1 Avoiding Symptoms of Thyroid Dysfunction
		2.2 Adverse Reactions to the LT4 Tablet Itself
	3 How to Prescribe and Take Levothyroxine
	4 Overview of Guidelines on the Management of Hypothyroidism
	5 Conclusions
	References