HPA 2022 Sum HP

**The HPA: Hypothalamic-Pituitary Axis** \ \ 1. Anatomy and mechanism: Chemical mediators are the mechanism for *inter*cellular communication. These chemicals are released from the afferent cell, move through body fluids to reach the efferent cell, and then bind to specific receptor proteins for them on or in the efferent cell. Binding of the chemical mediator to its receptor triggers a reaction in the efferent cell. 1. In the nervous system, the chemical mediators are called **neurotransmitters (NT).** 2. In the endocrine system, the chemical mediators are called **hormones** if they circulate widely in the blood (most common) or **parahormones** or **factors** if they only travel a few centimeters  from their release point to their targets. 2. Purpose: Endocrine and Nervous systems cooperate to regulate body functions. \ ***Sidebar: Afferent and efferent. Afferent and efferent are directional terms that always refer to a point of reference determined by the topic of discussion. “Afferent” refers to moving toward the point of reference – think “Ahhh!” when heading home after a long day. “Efferent” refers to moving away from the point of reference – think “EEEEeeee!” when running away from something. When the topic is communication between two cells, the point of reference is the spot right between them.***          2. **Differences in the structures of the nervous and endocrine systems reflect their different characteristics**. \ | Differences | Nervous | Endocrine | |----|----|----| | Structure | Discrete network of cellsthat communicate at synapses*Strength:*Allows discrete control of individual cells | Communicating cells are dispersed throughout the body*Strength*: Allows widespread responses to a single signal | | Long-distance travel | Electrical signals (APs) within long cells*Strengths:*Quick onset of response (msec). Short signal duration (msec) | Hormones circulate in body fluids*Strengths:*Slower onset (minutes to hours)Signal persists until hormone is cleared  (minutes to hours) | | Signal causes(generally) | Ion flow changes in efferent cell*Strengths:*Often results in motion: contraction, secretion | Enzyme alterations*Strengths:*Often results in biochemical changes in efferent cell | \         *A Question to Ponder, revisited:* Norepinephrine (NorE) is a neurotransmitter used in the short-term stress response; Epinephrine(Epi) is a hormone used in the short-term stress response. Being similar in shape, NorE and Epi activate many of the same receptors. Why would the symptoms of a brief fright wear off in two distinct sets? … The NorE wears off essentially immediately, since there are very few molecules needed and they travel only a few nanometers across the synapse. The epinephrine, being a hormone, starts to show effects after perhaps half a minute, and those symptoms fade over the next several minutes as the epinephrine molecules find their targets and/or are destroyed. **How the Systems Divide up the Job of controlling the body**                          1. Option one (rare): One system does one entire job *e.g*. Skeletal muscle contraction is entirely under the control of the somatic nervous system. 2. Option two (rare): Both systems play roles, but the two do not interact much.         *e.g.* low blood glucose Hypothalamus senses low blood glucose and initiates sympathetic activation. Endocrine pancreatic cells sense low blood glucose and release the hormone glucagon. 3. Option three (most common): Both systems play a role, with the nervous system directing endocrine activity. *e.g*. the short-term stress response: Nervous system activity includes a sympathetic response; these sympathetic nerves trigger adrenaline release. The adrenaline causes many of the stress responses. *e.g.* the Hypothalamic-pituitary axis         **Hypothalamic-Pituitary Axis (HPA) The HPA (synonym, hypothalamo-hypophyseal axis) is the best example of nervous system direction of endocrine action.** 1. **Parts of the system** 1. **Neurons in the hypothalamus are in charge of everything the pituitary gland does.** 2. **The posterior pituitary gland (synonym, *neurohypophysis*) is actually just an extension of the hypothalamus. The back half of the image below shows the posterior pituitary gland arrangement.** 1. **Neurons whose cell bodies are in nuclei in the hypothalamus stretch down to hang below the brain. The lump of tissue formed by the axon terminals of these neurons is called the posterior pituitary gland.** 2. **The *pituitary stalk* is a thin strand of tissue by which the pituitary gland dangles from the bottom of the brain. This stalk is actually composed of the axons of the hypothalamic neurons.** 3. **The *anterior pituitary* (synonym, *adenohypophysis*) is true gland tissue, in that it is composed of non-excitable cells that make and release hormones.** 4. **The anterior pituitary is plastered onto the front surface of the posterior pituitary, so the anterior and posterior together appear to be a single gland (called the pituitary, or hypophysis).** 5. **The hypothalamus communicates with the anterior pituitary through a special blood connection called the hypothalamic (synonym, hypophyseal) portal venules. The front part of the image below shows these blood connections.** 1. **Capillaries in the hypothalamus pick up chemical mediators (tropic factors, TFs) released by the hypothalamic neurons.** 2. **Venules drain the blood from the hypothalamic capillaries and carry it forward and down into the anterior pituitary. These vessels are the *hypophyseal portal venules* because a portal vessel connects two capillary beds along the same vascular circuit.** 3. **The blood drains directly into a second set of capillaries in the anterior pituitary gland.** 4. **The tropic factors exit the second capillary bed to affect the gland cells in the anterior pituitary and direct them to release hormones.** 5. **Hormones from the anterior pituitary cells enter the second capillary bed and drain through regular venules into the normal venous blood circulation. The hormones can now travel all around the body to find their targets.** 6. In all cases, the neurons of the hypothalamus integrate bodily information and determine the quantity of each pituitary hormone to be released. 7. The image below is thanks to OpenStax College, CC BY 3.0 , via Wikimedia Commons  \ \  \ \ 2. There are three patterns for how the hypothalamic-pituitary axis functions. Pattern 1:  **Hormones are released from the Posterior Pituitary gland.** 1. These are the steps of the mechanism by which posterior pituitary hormones act:The hypothalamus decides it’s time to release the hormones. 1. Action potentials travel down the axons of the hypothalamic neurons along the pituitary stalk and reach their axon terminals in the posterior pituitary gland. 2. When the action potentials arrive, previously prepared vesicles of the posterior pituitary hormone are released from the axon terminals. 3. The posterior pituitary hormones travel through the bloodstream until they reach their target organs and direct the appropriate responses. 2. ***Antidiuretic Hormone (ADH****,* synonym ***vasopressin)*** is the most important posterior pituitary hormone. It encourages water conservation and raises blood pressure. 1. Trigger: Low blood pressure and/or high blood osmolarity (both are signs of dehydration) are the signals that cause the hypothalamus to release ADH. 2. Target tissues: ADH has its most important action on the kidney tubules. Blood vessels are a secondary target. 3. Responses: ADH causes kidney tubules to increase water reabsorption and causes blood vessels to constrict. 3. ***Oxytocin*** is the second important posterior pituitary hormone. It causes the uterine contractions of childbirth and causes milk ejection. It also has some neurotransmitter actions in the brain (less well understood.) 1. Triggers: Being pregnant with a fetus that is at term (ready to be born) is one trigger that causes the hypothalamus to release oxytocin.  Having an infant suckling is another trigger that causes lactating women to release oxytocin. There are other triggers (including having sex); but they are not as biologically critical. 2. Target tissues: Oxytocin acts on the smooth muscle of the uterus, and on the milk glands. (It has additional, less understood actions in the brain.) 3. Responses: Oxytocin stimulates the uterine contractions of childbirth.  Oxytocin also causes contraction of milk glands which leads to the ejection of previously produced milk. 4. An example of the Posterior Pituitary Hormone pattern in action: 1. Blood pressure is low, so the hypothalamus decides to release ADH. 2. An action potential travels down the hypothalamic neurons through the pituitary stalk. 3. ADH is released from the axon terminals in the posterior pituitary gland into the bloodstream. 4. ADH travels through the bloodstream to reach the kidney tubules, where it stimulates the uptake of water from the fluid that will become urine. Thus the water is conserved in the body (which results in keeping the blood pressure from dropping more than it must). 5. The ADH also causes constriction of blood vessels bodywide, raising blood pressure. \ 3. **Pattern 2:  Direct acting anterior pituitary hormones**  1. Here is the release mechanism: 1. The hypothalamus decides it’s time to release the hormone, and signals this by releasing the appropriate tropic factors (TF) into the first capillary bed of the hypophyseal portal system. 2. Hypophyseal portal venules carry the TF to the anterior pituitary gland. 3. The TF exits from the second capillary bed to reach the gland cells in the anterior pituitary. 4. The anterior pituitary gland cells respond to the TF by releasing their hormone into the second capillary bed. 5. The anterior pituitary hormone travels through the blood to the target tissues and directs the target tissues to respond. \ *Note*: The TFs are chemicals that direct the release of the anterior pituitary hormone. There are different TFs for each hormone system, but I’m not asking you to learn each one’s name. The anterior pituitary hormones themselves are completely different molecules (whose names you must learn). \ 2. Anterior pituitary direct action hormones include growth hormone, follicle stimulating hormone, and prolactin.         3. ***Growth hormone (GH)*** encourages growth and raises blood glucose. 1. Trigger: GH is released when the hypothalamic clock indicates it is time to grow, and when blood glucose gets low. 2. Target tissues: GH affects bones and ‘lean’ soft tissues such as muscle. 3. Responses: GH causes bones to increase in length and mass, encourages lean tissue growth, and triggers increases in blood glucose and fat breakdown. 4. ***Follicle Stimulating hormone (FSH)*** encourages germ cell production. 1. Trigger: FSH is released when the hypothalamic clock decides it’s time to make eggs or sperm. 2. Target tissue: FSH affects the gonads, either ovaries or testes. 3. Responses: FSH encourages germ cell, either egg or sperm, production. (Appropriate sex steroids are also required to make germ cells.) 5. ***Prolactin*** causes milk production and growth of the mammary glands. 1. Triggers: Prolactin is released during late-term pregnancy, and while a mother is breastfeeding. 2. Target tissues: Prolactin affects mammary glands. 3. Responses: Prolactin encourages breast development and milk production. 6. Example of the direct-acting anterior pituitary hormone system: 1. When a woman’s hypothalamic clock reaches the right time of the month, the hypothalamus releases the TF for FSH into the first capillary bed. 2. Hypophyseal portal venules carry the TF to the anterior pituitary. 3. The TF exits from the second capillary bed and directs the anterior pituitary to release the FSH. 4. Anterior pituitary cells release FSH, which enters the blood *via* the second capillary bed. 5. FSH travels the blood to the ovaries, where it stimulates egg development. \ 4. **Pattern 3:**  **Tropic anterior pituitary hormones** are an intermediary chemical signal between the hypothalamus and a distant gland.   1. Here is the mechanism for the tropic anterior pituitary hormone pattern: 1. The hypothalamus decides what must be done and releases the TF for the relevant anterior pituitary tropic hormone into the first capillary bed. 2. Hypophyseal portal venules take the TF to the second capillary bed in the anterior pituitary gland. 3. The anterior pituitary gland responds to the TF by releasing tropic *hormones* into the second capillary bed. 4. The blood carries the tropic hormone to the target gland. (Recall a hormone travels further to reach its target than a factor…so the tropic *factors* travel only from the hypothalamus to the anterior pituitary, while the entirely separate chemical that is the tropic *hormone* travels to wherever in the body the distant gland lies.) 5. The tropic hormone directs the target gland is to do two things:         1. grow, and 2. release its own (final) hormone 6. The final hormone from the target gland is carried by the blood to the target tissues, which have the intended response. 2. Tropic hormones from the anterior pituitary include luteinizing hormone, adrenocorticotropic hormone, and thyroid stimulating hormone. 3. ***Luteinizing Hormone (LH****)* causes production of sex steroids that create sex differences. 1. Trigger: LH is released when the hypothalamic clock indicates it’s time to develop/express sex differences. 2. Target gland: LH targets the gonads, either ovaries or testes. 3. Final hormone released: LH tells the gonads grow and to release sex steroids, either **estrogen and progesterone (from ovaries**) or **testosterone (from testes)**. 4. Target tissues: Every tissue that differs between men and women is a target for sex steroids: The gonads and reproductive tract structures, but also structures present in both sexes but expressed differently, such as bones and muscle. 5. Responses: Sex steroids promote and maintain primary and secondary sexual characteristics: basically everything different between the sexes *other than* the presence of ovaries *vs.* testes. 1. Appropriate sex steroids (along with FSH) are necessary to produce eggs and sperm cells.   2. Appropriate sex steroids also are required for reproductive tract structures to maintain their size and activity. They also promote sex differences produced by bone, muscle, fat tissue, *etc*. by affecting the development of these structures. 4. ***Adrenocorticotropic Hormone (ACTH)*** directs the *long term stress response*, which helps you deal with a chronic stressor. It doesn’t *take away* the stress, rather it adapts your body to succeed in stressful situations. 1. Trigger: ACTH is released when stress is perceived (but doesn’t have noticeable effect unless the stress lasts for longer than a few minutes; the long-term stress response) 2. Target gland: ACTH directs the adrenal cortex (the outer shell of the adrenal glands) to grow and release its hormones. 3. Final hormone released: The adrenal cortex responds to ACTH by producing glucocorticoid hormones, primarily ***cortisol.*** 4. Target tissues: Many tissues are affected by cortisol, most notably the liver, blood vessels, and fat tissue. 5. Responses: When cortisol is received, the liver releases more blood glucose, blood vessels constrict to raise blood pressure, the immune system is suppressed, muscle tissue breaks down to release amino acids to blood, *etc.* Cortisol acts synergistically with Sym activation to some extent. 5. ***Thyroid Stimulating Hormone (TSH****)* raises basal metabolic rate and promotes nervous system development and activity. 1. Trigger: TSH is released when the metabolic rate is too low. 2. Target gland: TSH affects the thyroid gland. 3. Final hormone released: TSH causes the thyroid gland to grow and release **thyroid hormone** (synonyms ***thyroxine,* TH, T3** and **T4** which are triiodothyronine and tetraiodothyronine, respectively). 4. Target tissues: TH affects almost all tissues, but especially the nervous system. 5. Responses: All tissues increase metabolic rate (increase their ‘idling speed’ of cellular metabolism) in response to TH. The nervous system is also stimulated to develop more fully and act more energetically. 6. Example of a mechanism involving tropic hormones of the anterior pituitary: 1. When someone is overtraining, she becomes physically stressed. The hypothalamus responds by releasing the tropic factor for ACTH into the first capillary bed. 2. The hypophyseal portal venules carry the TF to the anterior pituitary. 3. The TF exits from the second capillary bed to direct the anterior pituitary cells to release ACTH. 4. ACTH enters the second capillary bed and is carried through the bloodstream to the adrenal cortex. 5. The adrenal cortex responds by growing and releasing cortisol and other glucocorticoids into the blood. 6. The cortisol travels through the blood and finds many target tissues. 7. In response to cortisol, the liver increases blood glucose release, the muscle tissue breaks down to raise blood amino acids, blood vessels constrict so blood pressure rises, *etc.* Since she’s releasing so much cortisol, she loses strength (from muscle breakdown), gets high blood pressure, tends to build abdominal fat, is at greater risk for diabetes mellitus (from the high blood glucose), and is likely to become temporarily infertile (from suppression of FSH and LH release). 7. [Click here](https://www.google.com/url?q=https://www.youtube.com/watch?v%3DVae5CcaPN_8%26feature%3Drelated&sa=D&source=editors&ust=1663275832123264&usg=AOvVaw1ZmMUmilCv7ZG1OIaUzw4Q) for an animation that shows the TSH system is available at [https://www.youtube.com/watch?v=Vae5CcaPN_8&feature=related](https://www.google.com/url?q=https://www.youtube.com/watch?v%3DVae5CcaPN_8%26feature%3Drelated&sa=D&source=editors&ust=1663275832123593&usg=AOvVaw07a5o3tIuVKgw7HL4d7UMZ) The ‘thyrotropin releasing hormone’ he mentions is the TF for TSH. He also brings up the negative feedback loop for controlling TSH; as described below. \ 5. How does the hypothalamus decide how much hormone is required? 1. Presence of specific triggers for each hormone (as listed above) induces the hypothalamus to direct an increase of the hormone’s release. These triggers are related to the perceived need for the hormone. 2. Homeostatic set-points exist for many pituitary hormone actions. A certain level of hormone release is maintained by negative feedback loops         involving hypothalamic perception of the action of the hormone. Some of these negative feedback loops can impact the pituitary directly (for example, make the anterior pituitary less sensitive to hypothalamic stimulation); but the hypothalamus itself remains the foremost controller. *e.g.* Body temperature is one measure of metabolic rate. If body temperature is below its set-point, the hypothalamus will increase thyroid hormone release to get the metabolic rate back where it belongs. 3. Timing is often a factor. Hormone release may change with age, time of month, time of day, *etc.* The hypothalamus is part of the bodily ‘clock’ that measures time and adjusts responses appropriately. *e.g.* Testosterone is allowed to remain very low throughout childhood. Hypothalamic up-regulation of testosterone release is the foremost driving factor in male puberty.                         \ **Summary of Pituitary Hormones** \ | **Hormone** | **From** | **Trigger** | **Targets** | **Actions** | |----|----|----|----|----| | Oxytocin | Post. Pit. | Suckling,Infant at term | Mammaries,uterus | Milk letdown,Contraction | | ADH, synonymVasopressin | Post. Pit. | Dehydration, high osM,low bp | Kidneys,blood vessels | Retain water by reabsorbing more before the urine is released,Constrict blood vessels | | Growth H | Ant. Pit. | Timing,Low blood glu | Manyliver | Lean tissue growthRaise blood glucose | | FSH | Ant. Pit. | Timing, neg. feedback | Ovaries and testes | Eggs or sperm cells made | | Prolactin | Ant. Pit. | Breastfeeding,Pregnant | Mammaries | Grow, make milk | | LH | Ant. Pit. | Timing,neg. feedback | Ovaries and testes | Grow, release sex steroidsSex steroids (testosterone in males, estrogen and progesterone in females) cause almost all sex differences | | ACTH | Ant. Pit. | Stress (long-term) | Adrenal glands | Grow, release cortisolCortisol raises bp and blood glu, encourages other stress responses | | TSH | Ant. Pit. | Low MR | Thyroid gland | Grow, release Thyroid HormoneTH raises MR and promotes NS development and activity | \ Test yourself:  For any of these hormones, describe a trigger that would initiate the system and tell in order of action which structures would release what chemical mediators in what sequence, and how the target tissues would respond. \ **Summary of key points on the HPA** \ 1. The nervous and endocrine systems both contribute to controlling body systems. Both systems use chemical messengers as the ultimate intercellular signal. The nervous system is faster and more precisely targeted, but less persistent due to its use of cellular networks and APs for long-distance communication. It often causes movement of various descriptions. The endocrine system is slower but has more widespread and persistent effects due to its use of blood-borne chemicals messengers. It is most likely to effect biochemical shifts. 2. The most common approach is for the nervous system to direct endocrine activity.  The hypothalamic-pituitary axis is the foremost example of this. 3. Posterior pituitary hormones are produced by hypothalamic neurons but released from their axon terminals in the posterior pituitary. They include ADH and oxytocin. 4. Direct acting posterior pituitary hormones are released when the hypothalamic neurons send signals in the form of tropic factors through the hypophyseal portal venules to tell the anterior pituitary cells to release their hormones. They include follicle stimulating hormone, growth hormone, and prolactin. 5. Tropic pituitary hormone mechanisms are similar to direct acting, except the hormone from the anterior pituitary finds some other gland elsewhere in the body and makes it release one more hormone, which actually directs the tissues. Tropic hormones include luteinizing, adrenocorticotropic, and thyroid stimulating hormones. 6. You do need to know the triggers, target glands (for tropic hormones), final hormones (for tropic hormones), target tissues, and responses for each of the hormones named. You’ll need to be able to use this information to develop mechanisms for any of the hormones, similar to the examples given at the end of the section that described each pattern. \  LadyofHats \[Public domain\], via Wikimedia Commons Kindly released this image which shows the sources of various chemical mediators from the hypothalamic-pituitary axis.  Test yourself:  Which of these are you to know for this class, and what trigger would cause each to be released? \ \