Hypothalamic – Pituitary – Thyroid Axis (HPT) AKA: Hypothyroidism Secondary to Pituitary Hypofunction
Another more appropriate name for the Hypothalamic – Pituitiary – Thyroid (HPT) Axis is Hypothyroidism Secondary to Decreased Pituitary Output. This is the label used in Dr. Kharrazian’s book Why Do I Still Have Thyroid Symptoms When My Lab Tests Are Normal.
The pituitary gland is often portrayed as the “Master Gland” of the body. Such praise is justified in the sense that the anterior and posterior pituitary secrete a battery of hormones that collectively influence all cells and affect virtually all physiologic processes.
The pituitary gland may be king, but the power behind the throne is clearly the hypothalamus. Some of the neurons within the hypothalamus – neurosecretory neurons – secrete hormones that strictly control secretion of hormones from the anterior pituitary. The hypothalamic hormones are referred to as releasing hormones and inhibiting hormones, reflecting their influence on anterior pituitary hormones.
T3 and T4 regulation
The production of thyroxine (T4) and triiodothyronine (T3) is regulated by thyroid-stimulating hormone (TSH), released by the anterior pituitary. The thyroid and thyrotropes (cells in the anterior pituitary) form a negative feedback loop: TSH production is suppressed when the T4 levels are high, and vice versa. The TSH production itself is modulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold (in which an accelerated metabolism would generate more heat).
Thyroid Hormones Pass Through Blood – Brain -Barrier
Thyroid hormones and neuroendocrine transmitters have important influences upon the hypothalamus, and to do so they must pass through the blood–brain barrier. The hypothalamus is bounded in part by specialized brain regions that lack an effective blood–brain barrier; the capillaries at these sites has perforations to allow free passage of hormones and even large proteins and other molecules. At these sites, the hypothalamus samples the hormone composition of the blood. Some of these sites are the sites of neurosecretion, where signals are sent from the nerve cells of the hypothalamus to the posterior pituitary. The hypothalamus secretes substances known as neurohormones that start and stop the secretion of anterior pituitary hormones.
The neurons are in intimate contact with both blood and Cerebrospinal Fluid (CSF). These structures are densely vascularized, and contain receptive neurons that control hormones, regulation of fluid and electrolyte balance.
The hypothalamic-pituitary-thyroid axis (HPT axis) is a neuroendocrine system that regulates metabolism. When the hypothalamus senses low circulating levels of the hormones T3 and T4 in the blood, it signals to the pituitary by releasing Thyroid Releasing Hormone (TRH) into the capillaries traveling to the anterior pituitary, which secretes Thyroid Stimulating Hormone (TSH) into the veins. The veins carry the TSH to the thyroid signaling the thyroid gland to release T3 and T4. T4 normally is converted to the more active T3, but T4 can also be converted to reverse T3 (rT3). Reverse T3 antagonizes the T3 receptor, so high levels can be detrimental.
Hypothalamic Sampling Requires Blood Flow
Sampling of hormones (including the sex hormones) by the hypothalamus requires consistent blood flow. In the body, blood carries hormones released by endocrine glands and carries them to body parts that need them.
In parasympathetic withdrawal, diagnosis is usually considered adrenal fatigue. The volume of blood shifts from the muscles and brain to the central abdominal compartment. The blood flow to the brain is not stopped when this occurs. The flow is reduced and Poiseuille’s Laws come into play.
The circulatory system provides many examples of Poiseuille’s law in action—with blood flow regulated by changes in vessel size and blood pressure. Blood vessels are not rigid but elastic. Adjustments to blood flow are primarily made by varying the size of the vessels, since the resistance is so sensitive to the radius. This is done by the Abdominal Brain through the release of NeuroEndocrine transmitters.
A 19% decrease in flow is caused by a 5% decrease in radius of the blood vessels. The body may compensate by increasing blood pressure by 19%, but this presents hazards to the heart and any vessel that has weakened walls.
This decrease in radius is surprisingly small for this situation. To restore the blood flow in spite of this buildup would require an increase in the pressure difference of a factor of two, with subsequent strain on the heart.
ISCHEMIC PENUMBRA OF PARASYMPATHETIC DOMINANCE
In severe and/or chronic illness, profound changes occur in the hypothalamic-pituitary-thyroid axis. Ischemia and inflammation disrupt the porous Blood-Brain-Barrier surrounding the hypothalamus. The observed decrease in serum concentration of both thyroid hormones and thyrotropin (TSH) are not compatible with a negative feedback loop.
Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive, healthy and functioning properly). Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue or organs. It also means local anemia in a given part of a body sometimes resulting from congestion (such as vasoconstriction, red blood cell aggregation due to insulin resistance/diabetes). Ischemia comprises not only insufficiency of oxygen, but also reduced availability of nutrients and inadequate removal of metabolic wastes.
Parasympathetic Withdrawal (vasodilation) with blood pooling in the Abdominal Compartment makes the Movement Compartment and Brain/Spinal Cord Ischemic. At the periphery of the ischemic region, the so-called ischemic penumbra, neuronal damage throughout the body develops more slowly because blood flow arising from adjacent vascular territories (collateral flow) keeps blood perfusion above the threshold for immediate cell death. In the ischemic core, the major mechanism of cell death is energy failure caused by Oxygen/Glucose Deprivation (O2/GD). The hypothalamus and midbrain are most vulnerable to ischemia.
Neurons in the most vulnerable areas cease to respond or show only faint responses and develop irreversible ischemic or post-ischemic damage. The hypothalamus responds to ischemic insults rigorously without having irreversible ischemic or post-ischemic damage.
The thalamus-hypothalamus interface represents a discrete boundary where neuronal vulnerability to ischemia is high in thalamus (like more rostral neocortex, striatum, hippocampus). In contrast hypothalamic neurons are comparatively resistant, generating weaker and recoverable anoxic depolarization similar to brainstem neurons, possibly the result of a Na/K pump that better functions during ischemia.
There is a well recognized but poorly understood caudal-to rostral increase in the brain`s vulnerability to neuronal injury caused by metabolic stress (insulin resistance).
Several brain regions, including the caudate, hippocampus, and hypothalamus, are vulnerable to hypoxic–ischemic brain injury. During O2/GD, hypothalamic neurons gradually depolarized during ischemic exposure. The O2/glucose deprivation (O2/GD) response induces failure of the Na+/K+ pump. The recovery is slow with chronic ischemic penumbrance
Without oxygen and glucose, neurons cannot generate the ATP needed to fuel the ionic pumps that maintain the ionic gradient across the neuronal membrane, mainly the Na+−K+ ATPase.
In the ischemic penumbra, the flow reduction is not sufficient to cause energy failure, and neurons remain viable for a prolonged period of time after the insult, but the neurons are stressed and critically vulnerable to pathogenic events that may tip their fragile metabolic balance. Excessive extracellular accumulation of glutamate is a major factor contributing to production of cytotoxic nitric oxide, free radicals and arachidonic acid metabolites. These events lead to necrosis or programmed cell death depending on the intensity of the insult and the metabolic state of the neurons. Injured and dying cells have a key role in post-ischemic inflammation because they release danger signals that activate the immune system.
Neurons that demonstrate particular vulnerability to ischemic challenges have been termed “selectively vulnerable neurons”. Of the entire forebrain, the neurons of the hippocampus are the most vulnerable.
Summary: Parasympathetic Dominance causes Ischemia to the Hippocampus, Hypothalamus, and Pituitary producing alterations in the HPA, HPT, HPD and HPG axis.
During illness, profound changes may occur in the hypothalamic-pituitary-thyroid (HPT) axis. The most consistent change is a decrease in serum tri-iodothyronine (T3) level, but in severe illness, serum thyroxine (T4) may also decrease. The persistence of a normal or even decreased serum level of thyrotropin (TSH) in the face of decreased serum thyroid hormone concentrations implies there is not an adequate concentration of T3 or T4 reaching the hypothalamus for sampling.
Since these abnormalities of thyroid hormone concentration usually occur without any evidence of thyroid disease and disappear with recovery, they have been referred to as the `sick euthyroid syndrome’ or the `euthyroid sick syndrome’.
The downregulation at all levels of the HPT axis (decreased thyrotropin-releasing hormone (TRH) and TSH at the hypothalamic-pituitary level, and a decreased production of T3 at the peripheral extra-thyroidal level) in Non-Thyroid Illness is part of the neuroendocrine adaptation to Parasympathetic Withdrawal. In this view, attempts to restore thyroid hormone levels are detrimental and should not be undertaken.
There is a neuroendocrine component in the pathogenesis of the decreased activity of the HPT and somatotropic axes in prolonged critical illness. T3 can stimulate dendritic cell (DC) maturation, leading to DC-induced T cell proliferation and IFN-γ release. The cytokines IL-1β, TNF-α, IFN-γ, and IL-6 can inhibit the conversion of T4 to T3, thereby shunting T4 towards the production of the potentially detrimental rT3.