Endocrine Glands and Hormonal Control

Major Endocrine Glands

• Major endocrine glands operate in a chain of command to maintain bodily functions.

Hormonal Control

• Most cellular processes are regulated by effectors
• Effectors are regulated by the hypothalamus through the anterior and posterior pituitary glands.
• Hormonal control follows the path of HT → AP/PP → Target Tissue → Effector → Metabolic process.
• Insulin and glucagon secretion is not controlled by a master switch; they are secreted in response to blood glucose concentration.
• Epinephrine and norepinephrine from the adrenals are secreted in response to brain stimuli, independently from the anterior pituitary.

Hypothalamus

• The hypothalamus is the master key of the neuroendocrine system.
• It is the coordination center for the endocrine system, receiving and integrating messages from the CNS.
• Inputs from the CNS can be external, such as danger or internal, such as hunger, dietary intake, and blood pressure.
• A significant role include stimulation or inhibition of Heart rate, blood pressure, body temp, fluid and electrolyte balance, appetite, glandular secretions, substance production that influence horemone release and sleep cycles.
• The hypothalamus produces regulatory hormones (releasing and inhibiting hormones) in response to the CNS.
• These hormones travel to the nearby pituitary gland through blood vessels and neurons connecting the glands.
• The pituitary gland has two functionally distinct parts: an anterior and posterior pituitary.

Releasing Hormones

• Thyrotropin-releasing hormone (TRH or thyroliberin) triggers the pituitary to release thyrotropin (thyroid-stimulating hormone) and prolactin from the anterior pituitary
• Corticotropin-releasing hormone (CRH or corticoliberin) stimulates the pituitary to release corticotropin, which is involved in the stress response.
• Gonadotropin-releasing hormone (GnRH or gonadoliberin) prompts the pituitary to release gonadotropin.
• GnRH is a tropic peptide hormone synthesized and released from GnRH neurons.
• It's responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
• Growth hormone-releasing hormone (GHRH or somatoliberin) is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.
• GHRH appears in the human hypothalamus between 18 and 29 weeks of gestation, corresponding to the start of growth hormone production.

Inhibiting Hormones

• Somatostatin, or growth hormone-inhibiting hormone (GHIH), is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation.
• It interacts with G protein-coupled somatostatin receptors, inhibiting the release of numerous secondary hormones
• Somatostatin inhibits insulin and glucagon secretion.
• Various other inhibiting factors have tropic endocrine inhibition activity but are not always called hormones.
• Examples include dopamine, follistatin, and melanostatin.

Hypothalamic Disease/Disorder

• Diseases/disorders of the hypothalamus are hypothalamic diseases, with head injuries being a common cause of dysfunction.
• Hypothalamus disorders are hard to pinpoint since the hypothalamus affects so many systems.
• Conditions affecting both the hypothalamus and pituitary are termed hypothalamic-pituitary disorders, with hormone tests shedding light on the root cause.
• The hypothalamus is essential for alerting the pituitary gland to release hormones, ensuring internal processes are balanced.

Examples of Hypothalamic Disorders

• Hypothalamic obesity: rapid weight gain, excessive weight gain, and uncontrollable appetite.
• Functional hypothalamic amenorrhea: lack of sufficient energy from food causes high cortisol levels, dampening the hypothalamus-ovary connection, affecting ovulation and leading to absent periods.
• Central diabetes insipidus: rare autoimmune disorder where the immune system damages the hypothalamus, resulting in diabetes.
• Kallman syndrome: genetic condition leading to absent/delayed puberty and no sense of smell. Symptoms include no periods, undescended testicles, small penis, kidney/hearing problems, cleft lip/palate.
• Prader-Willi syndrome: genetic condition (chromosome 15) causing intellectual disabilities, poor growth, small genitals, obesity, an intense urge to eat, and other behavioral problems.
• Syndrome of inappropriate antidiuretic hormone (SIADH): causes high levels of antidiuretic hormone, leading to low electrolytes. Usually caused by stroke, infection or cancer that damages the hypothalamus. Too much of this hormone can cause low sodium levels and lead to weakness, vomiting, headaches, and brain fog.

Posterior Pituitary

• Contains the axonal endings of hypothalamic neurons
• These neurons produce oxytocin and vasopressin, which travels down the axon to nerve endings in the pituitary where they are stored for release.

Oxytocin

• Oxytocin plays a role in social bonding, reproduction, childbirth, and the period after childbirth.
• It's an inactive precursor protein from the OXT gene, which includes the oxytocin carrier protein neurophysin I.
• The inactive precursor is progressively hydrolysed into smaller fragments by a series of enzymes.
• Also found in the corpus luteum, placenta, testicles, retina, adrenal medulla, thymus, and pancreas.

Vasopressin

• The main stimulus to vasopressin secretion is rising plasma osmolality.
• Significant reductions in arterial blood pressure and blood volume also stimulate vasopressin secretion.
• It has an antidiuretic action on the kidney, specifically in the collecting ducts.
• Vasopressin binds to V2 receptors on tubular cells, initiating a cascade that generates water channels (aquaporin-2.)
• Aquaporin-2 migrates to the luminal membrane of the tubule cells, reabsorbing water from the urine back into circulation.
• This leads to decreased renal free water clearance, concentrated urine, and reduced urine volume.
• Reabsorption of water normalizes plasma osmolality.

Anterior Pituitary

• Responds to hypothalamic hormones carried in the blood.
• It produces tropic hormones, "tropins," from the greek "tropos," causing a change or affecting.
• These hormones have other endocrine glands as their target
• Thyroid-stimulating hormone (TSH or thyrotropin) stimulates the thyroid gland to make and release thyroid hormone.
• Adrenocorticotropic hormone (ACTH or corticotropin) stimulates the adrenal cortex to release glucocorticoids.
• Luteinizing hormone (LH) stimulates the release of steroid hormones in the ovaries and testes.
• Follicle-stimulating hormone (FSH) stimulates the maturation of eggs and the production of sperm.

Hormonal Cascades

• Large amplifications of the original signal result, allowing fine-tuning by the final hormone.
• An example: electrical signal to the hypothalamus → release of nanograms of corticotropin-releasing hormone → release of micrograms corticotropin from the anterior pituitary → release of milligrams of cortisol from the adrenal cortex.
• Amplification can reach a million-fold.
• Negative feedback can inhibit earlier cascade steps.
• Elevated hormones inhibit the release of earlier hormones.

Mechanism of Hormonal Action: Steroid Hormones

• Steroid hormones have limited solubility in blood plasma and require a transport protein with a specific ligand-binding domain.
• The free hormone is active and is lipid soluble.
• It can freely cross the lipid bilayer.

Steroid Hormone Receptors

• Receptors are intracellular and initiate signal transduction for steroid hormones, leading to gene expression changes over hours to days.
• Binding can occur at the cytoplasmic or nuclear level.
• cytoplasmic receptors for mineralocorticoids/glucocorticoids/androgen
• Receptors in the nucleus primarily are for estrogen/thyroid hormone, vitamin D, and retinoic acid.

Steroid Hormone Receptors - Type 1 and 2

• There are two classes of receptors, depending on their mechanism and subcellular distribution.
• Receptors that bind steroid hormones are classified as type I.
• Type I receptors have a heat shock protein (HSP) associated with the inactive receptor, which is released when the receptor interacts with the ligand.
• Type I receptors can form homodimers or heterodimers located in the cytosol.
• Steroids enter the cell, interact with their receptor, dissociate heat shock protein, and translocate the receptor-ligand complex into the nucleus.
• Steroid receptors form dimers and act as a transcription factor on DNA
• Nuclear localization signal (NLS) facilitates uptake into the nucleus.
• Upon hormone binding, the receptor undergoes a conformational change, releasing HSP.
• Then the receptor with the bound hormone acts upon transcription.
• Type II receptors are located in the nucleus and have no HSP associated
• Ligands pass through the cell membrane and cytoplasm and enter the nucleus
• They activate the receptor without releasing HSP and initiate transcription the same way

Steroid Hormone Receptors - Types

• The best-studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3).
• They include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C).
• In the cytosol, a hormone forms a receptor complex which is then translocated to the nucleus or hormone, where it binds to a receptor.
• a small subset of chromatin is active and is different from cell to cell
• One can result in different responses as a function of each cells type.
• Cell surface receptors for certain steroid hormones: G protein-coupled receptors and ion channels.
• Progesterone modulates the activity of CatSper

Non-Genomic Actions

• Cell membrane aldosterone receptors increase the activity of basolateral Na/K ATPase, ENaC sodium channels, and ROMK potassium channels in the distal tubule/cortical collecting duct of nephrons, the large bowel, and sweat glands.
• Steroid hormone receptors can extend through lipid bilayer membranes and interact with hormones that remain outside cells.
• function outside the nucleus in cytoplasmic signal transduction.