Gastrointestinal, Endocrine, Reproductive and Exercise Physiology

The gut, the endocrine glands, the reproductive axes and the exercising body look like four separate subjects, but each one is a lesson in the same idea: signals released in one place change behavior somewhere else, and negative feedback keeps the whole system stable. The board rewards students who can trace a hormone from its source to its target and predict what happens when one link fails. In practice, these systems explain the fatigue, weight change, bone loss, menstrual change and exercise intolerance that patients bring to a chiropractic office long before anyone has named a diagnosis.

Section 1Gastrointestinal physiology

The enteric nervous system and its controls

The gut has its own nervous system. The myenteric (Auerbach) plexus lies between the circular and longitudinal muscle layers and mainly controls motility. The submucosal (Meissner) plexus lies in the submucosa and mainly controls secretion and local blood flow. Together they hold roughly as many neurons as the spinal cord and can run reflexes with no input from the brain. Extrinsic nerves modulate this system: parasympathetic fibers (vagus to the proximal colon, pelvic splanchnic nerves from S2 to S4 beyond that) generally increase motility and secretion, using acetylcholine, while sympathetic fibers (from T5 to L2 through the celiac, superior mesenteric and inferior mesenteric ganglia) slow motility, constrict sphincters and reduce blood flow, using norepinephrine.

Key enteric transmitters are acetylcholine and substance P (contraction) and VIP and nitric oxide (relaxation of smooth muscle and sphincters). Loss of inhibitory nitric oxide neurons explains two classic disorders: achalasia, where the lower esophageal sphincter fails to relax, and Hirschsprung disease, where absent ganglion cells in the distal colon leave a tonically contracted segment.

Motility

GI smooth muscle shows slow waves: rhythmic oscillations of membrane potential generated by the interstitial cells of Cajal, the gut pacemakers. Slow waves are not action potentials and do not by themselves cause contraction. When a slow wave carries the membrane above threshold, spike potentials fire (calcium entry), and the muscle contracts. Acetylcholine raises the plateau so more spikes ride each wave. Slow wave frequency sets the maximum contraction rate: about 3 per minute in the stomach, 12 per minute in the duodenum and about 8 to 9 per minute in the terminal ileum.

Swallowing has an oral (voluntary) phase, a pharyngeal phase coordinated by the swallowing center in the medulla (soft palate rises, larynx elevates, epiglottis tips, breathing pauses, upper esophageal sphincter relaxes) and an esophageal phase. Primary peristalsis follows the swallow; secondary peristalsis is triggered by distension if food remains. The lower esophageal sphincter relaxes ahead of the bolus by vagal inhibitory (VIP and nitric oxide) pathways, a process called receptive relaxation that also lets the fundus accommodate a meal.

The stomach stores, mixes and empties. The orad stomach relaxes; the caudad antrum grinds food against a closed pylorus (retropulsion) until particles are about 1 to 2 mm. Emptying is slowed by fat, acid, hyperosmolar contents and protein in the duodenum through the enterogastric reflex and the hormones CCK and GIP. Liquids empty faster than solids, and fats slowest.

In the small intestine, segmentation contractions mix chyme with secretions, and peristalsis (contraction above, relaxation below the bolus, the law of the intestine) propels it. Between meals, the migrating motor complex sweeps from stomach to ileum about every 90 minutes, clearing residue and limiting bacterial overgrowth; it is driven by motilin. In the colon, haustral contractions mix and slowly move contents, and mass movements one to three times a day push material into the rectum, often after a meal (the gastrocolic reflex). Rectal distension triggers the rectosphincteric reflex: the internal anal sphincter (smooth muscle, involuntary) relaxes, while the external anal sphincter (skeletal muscle, pudendal nerve, voluntary) holds until defecation is appropriate.

Vomiting is coordinated by the vomiting center in the medulla, which receives input from the chemoreceptor trigger zone in the area postrema (outside the blood brain barrier), the vestibular system, the pharynx and vagal afferents from the gut. Antiperistalsis starts in the small intestine, followed by forceful contraction of abdominal muscles against a relaxed stomach.

Secretions

About 7 to 9 liters of fluid enter the gut each day from saliva, gastric juice, bile, pancreatic juice and intestinal secretion, and nearly all is reabsorbed, most in the small intestine.

Saliva (1 to 1.5 L/day) contains salivary amylase (ptyalin), lingual lipase, mucus, lysozyme and IgA. Acinar cells make an isotonic primary fluid, and ductal cells reabsorb sodium and chloride and secrete potassium and bicarbonate, so final saliva is hypotonic, more so at low flow. Unusually, salivary secretion is stimulated by both parasympathetic (copious, watery) and sympathetic (small volume, protein rich) activity.

Gastric secretion comes from oxyntic glands in the body and fundus and pyloric glands in the antrum.

The parietal cell secretes acid through the H+/K+ ATPase (proton pump) on its apical membrane. Inside the cell, carbonic anhydrase combines CO2 and water into carbonic acid, which splits into H+ (pumped into the lumen) and bicarbonate. Bicarbonate leaves across the basolateral membrane in exchange for chloride, and chloride then exits apically into the lumen. The bicarbonate entering the blood after a meal produces the alkaline tide. Three stimulants converge: acetylcholine (vagus, M3 receptors) and gastrin (CCK-B receptors) raise intracellular calcium, and histamine (H2 receptors) raises cAMP. They potentiate one another, which is why an H2 blocker reduces responses to all three. Proton pump inhibitors act at the final common step. Somatostatin and prostaglandins inhibit acid; low antral pH stimulates somatostatin, a built in brake.

Acid secretion runs in three phases: the cephalic phase (sight, smell, thought of food; vagal, about 30 percent), the gastric phase (distension and amino acids or peptides in the stomach; gastrin and local reflexes, about 60 percent) and the intestinal phase (small, and mostly inhibitory).

Pancreatic juice (about 1.5 L/day) has two parts. Ductal cells secrete a bicarbonate rich fluid in response to secretin, neutralizing acid in the duodenum. Acinar cells secrete enzymes in response to CCK and vagal acetylcholine. Proteases are secreted as inactive zymogens: duodenal enterokinase (enteropeptidase) converts trypsinogen to trypsin, and trypsin activates chymotrypsinogen, proelastase, procarboxypeptidases and more trypsinogen. Pancreatic amylase, lipase (with colipase) and phospholipase A2 complete the set. Trypsin inhibitor in the acinar cell guards against premature activation, whose failure is the core event in acute pancreatitis.

The GI hormones

Digestion and absorption

Carbohydrates. Starch is broken down by salivary and pancreatic α-amylase (which splits α-1,4 bonds) into maltose, maltotriose and α-limit dextrins. Brush border enzymes (maltase, isomaltase or α-dextrinase, sucrase and lactase) finish the job, producing monosaccharides. Only monosaccharides are absorbed. Glucose and galactose enter enterocytes by SGLT1, secondary active cotransport with sodium driven by the basolateral Na+/K+ ATPase. Fructose enters by facilitated diffusion through GLUT5. All three exit the basolateral side through GLUT2. Lactase deficiency leaves lactose in the lumen, where it draws water osmotically and is fermented by colonic bacteria into gas and short chain fatty acids, causing bloating and osmotic diarrhea. The SGLT1 mechanism is also why oral rehydration solutions contain both glucose and sodium.

Proteins. Pepsin begins digestion in the stomach (it is not essential). Pancreatic endopeptidases (trypsin, chymotrypsin, elastase) cut internal bonds; exopeptidases (carboxypeptidases A and B) remove terminal residues. Brush border peptidases make free amino acids, dipeptides and tripeptides. Free amino acids are absorbed by several sodium dependent cotransporters, while di- and tripeptides enter by PepT1, an H+ cotransporter, and are hydrolyzed inside the cell. Hartnup disease (neutral amino acid transporter defect) and cystinuria (dibasic amino acid transporter in gut and kidney) show that transporters, not enzymes, can be the weak link.

Fats. Lingual and gastric lipases start the process, but most triglyceride digestion happens in the duodenum. Bile salts emulsify large fat droplets, and pancreatic lipase, anchored by colipase, splits triglycerides into 2-monoglycerides and free fatty acids. Cholesterol esterase and phospholipase A2 act on their substrates. The products, with bile salts, form micelles, whose hydrophilic surface lets them cross the unstirred water layer to the brush border, where lipids diffuse into the enterocyte. Inside, triglycerides are re-esterified in the smooth endoplasmic reticulum, packaged with apoB-48 into chylomicrons, and exocytosed into the lacteals, reaching the blood through the thoracic duct. Short and medium chain fatty acids skip this and enter portal blood directly. The fat soluble vitamins (A, D, E, K) ride in micelles, so any cause of fat malabsorption (pancreatic insufficiency, bile salt loss, mucosal disease) can cause their deficiency and steatorrhea.

Water, electrolytes, vitamins and minerals. Water follows solute. Sodium is absorbed by cotransport with nutrients and by Na+/H+ exchange in the small intestine and through ENaC channels in the colon (aldosterone sensitive). Chloride is secreted by crypt cells through CFTR; cholera toxin permanently activates Gs, raises cAMP, and drives CFTR open, producing a secretory diarrhea of liters per day. Iron is absorbed as ferrous iron (Fe2+) in the duodenum, calcium mainly in the duodenum under the control of calcitriol, folate in the jejunum, and vitamin B12 (bound to intrinsic factor) and bile salts in the terminal ileum.

Liver and bile

The liver receives about 25 percent of cardiac output, roughly three quarters through the portal vein and one quarter through the hepatic artery. It handles carbohydrate (glycogen storage, gluconeogenesis), lipid (lipoprotein synthesis, fatty acid oxidation, ketone production), protein (plasma proteins such as albumin and clotting factors, the urea cycle), detoxification (cytochrome P450 phase I reactions and conjugation in phase II), storage (vitamins A, D, B12, iron, copper) and bile formation.

Bile contains bile salts, phospholipid (lecithin), cholesterol, bilirubin, water and electrolytes. Hepatocytes make primary bile acids (cholic and chenodeoxycholic acid) from cholesterol, the rate limiting enzyme being 7α-hydroxylase, and conjugate them with glycine or taurine to make bile salts that are more water soluble and stay in the lumen. Colonic bacteria convert some to secondary bile acids (deoxycholic and lithocholic acid). About 95 percent of bile salts are reabsorbed in the terminal ileum and return to the liver by the portal vein, the enterohepatic circulation; the pool cycles several times per day. Between meals, bile is concentrated in the gallbladder by sodium and water absorption. CCK contracts the gallbladder and relaxes the sphincter of Oddi; secretin increases bicarbonate rich ductal bile. When cholesterol exceeds the capacity of bile salts and lecithin to keep it in solution, cholesterol gallstones form.

Bilirubin comes mostly from the breakdown of hemoglobin heme in macrophages of the spleen: heme to biliverdin (heme oxygenase) to unconjugated bilirubin, which is lipid soluble, travels bound to albumin and cannot be filtered into urine. Hepatocytes conjugate it with glucuronic acid using UDP-glucuronosyltransferase, making water soluble conjugated bilirubin that is secreted into bile. Gut bacteria convert it to urobilinogen; some is reabsorbed and excreted in urine as urobilin (yellow color), and the rest becomes stercobilin (brown stool). Hemolysis and Gilbert syndrome raise unconjugated bilirubin; biliary obstruction raises conjugated bilirubin with dark urine, pale stools and pruritus.

Section 2Endocrine physiology I: hormone signaling and the hypothalamic pituitary axes

Hormone classes and how they act

A hormone is a chemical messenger released into the blood that acts on distant target cells bearing a specific receptor. Paracrine signals act on neighboring cells and autocrine signals on the secreting cell itself. Hormones fall into three chemical classes, and the class predicts almost everything about how the hormone behaves.

Membrane receptor pathways are worth knowing by hormone. Gs and cAMP: ACTH, TSH, LH, FSH, glucagon, PTH, calcitonin, CRH, ADH at V2 (kidney), and β receptors. Gq, IP3 and calcium: GnRH, TRH, GHRH (also cAMP), oxytocin, ADH at V1 (vascular), angiotensin II, gastrin and α1 receptors. Receptor tyrosine kinase: insulin and IGF-1. JAK-STAT (receptor associated tyrosine kinase): growth hormone, prolactin, erythropoietin and cytokines. cGMP: atrial natriuretic peptide and nitric oxide. A useful memory device for Gs hormones is that most anterior pituitary trophic hormones and calcium regulating peptides use cAMP.

Free hormone is the biologically active fraction. Changes in binding proteins change total but not free levels: pregnancy and oral estrogen raise TBG and total T4 while free T4 and the patient's thyroid status stay normal.

Feedback and the hypothalamic pituitary unit

Most endocrine systems are regulated by negative feedback: the end hormone (or the variable it controls) inhibits its own release, keeping levels within a range. Feedback can be long loop (target gland hormone back to the hypothalamus and pituitary), short loop (pituitary hormone back to the hypothalamus) or variable based (glucose controls insulin, calcium controls PTH). Positive feedback is rare: the LH surge driven by rising estradiol, oxytocin during labor and the milk ejection reflex.

The posterior pituitary (neurohypophysis) is neural tissue. Its hormones, ADH (vasopressin) and oxytocin, are made in the supraoptic and paraventricular nuclei of the hypothalamus, carried down axons bound to neurophysins, and released from nerve terminals. The anterior pituitary (adenohypophysis) is glandular tissue derived from Rathke pouch. Hypothalamic releasing and inhibiting hormones reach it through the hypothalamic hypophyseal portal system, a second capillary bed that delivers high concentrations of these peptides directly to pituitary cells.

Three anterior pituitary hormones (TSH, LH and FSH) share an identical α subunit with hCG; their β subunits confer specificity. This explains why very high hCG in pregnancy or molar disease can weakly stimulate the thyroid.

Reading primary and secondary disease

Feedback makes laboratory patterns predictable. In primary disease the target gland fails or overacts, so the pituitary hormone moves in the opposite direction from the end hormone. In secondary (pituitary) disease, the two move in the same direction. Primary hypothyroidism (Hashimoto thyroiditis): low free T4, high TSH. Secondary hypothyroidism: low free T4, low or inappropriately normal TSH. Graves disease: high T4, suppressed TSH because thyroid stimulating immunoglobulin, not TSH, drives the gland. Primary adrenal insufficiency (Addison disease): low cortisol, high ACTH, with hyperpigmentation because the POMC precursor also yields MSH, and with aldosterone loss (hyperkalemia, hyponatremia, hypotension). Secondary adrenal insufficiency: low ACTH, no hyperpigmentation, and aldosterone is largely spared because renin and angiotensin, not ACTH, control the zona glomerulosa.

Growth hormone

Growth hormone (somatotropin) is secreted in pulses, the largest during slow wave sleep. Release is stimulated by GHRH, ghrelin, hypoglycemia, fasting, amino acids (arginine), exercise, stress and deep sleep, and inhibited by somatostatin, IGF-1 (feedback), hyperglycemia, obesity and glucocorticoid excess. GH acts on the liver (and other tissues) through JAK-STAT to produce IGF-1 (somatomedin C), which mediates most growth effects: linear bone growth at the epiphyseal plates, protein synthesis and lean mass. GH itself has direct anti-insulin (diabetogenic) effects: it raises blood glucose, decreases glucose uptake, and increases lipolysis.

Excess GH before epiphyseal closure causes gigantism; after closure it causes acromegaly with enlarged hands and feet, coarse facial features, prognathism, organomegaly, insulin resistance, carpal tunnel syndrome and arthropathy. The best screening test is IGF-1, confirmed by failure of GH suppression after an oral glucose load. GH deficiency in children causes short stature; Laron dwarfism is GH receptor resistance with high GH and low IGF-1.

Prolactin

Prolactin is unique among anterior pituitary hormones because its dominant control is tonic inhibition by dopamine from the hypothalamus. Anything that cuts the pituitary stalk or blocks dopamine D2 receptors (antipsychotics, metoclopramide) raises prolactin. TRH, estrogen, suckling, sleep and stress also stimulate it. Prolactin promotes milk synthesis and breast development, and it inhibits GnRH, which is why breastfeeding suppresses ovulation and why a prolactinoma (the most common functioning pituitary adenoma) causes amenorrhea, galactorrhea and infertility in women and decreased libido and erectile dysfunction in men. Large adenomas compress the optic chiasm and cause bitemporal hemianopia. Dopamine agonists (cabergoline, bromocriptine) are first line therapy.

The thyroid axis

Thyroid follicular cells trap iodide with the sodium iodide symporter, move it into the colloid through pendrin, and oxidize it with thyroid peroxidase, which also iodinates tyrosine residues on thyroglobulin (organification) and couples them: MIT plus DIT forms T3, and DIT plus DIT forms T4. TSH stimulates every step, including endocytosis of colloid and release of hormone. The gland secretes mainly T4, but T3 is the active hormone, about four times more potent, formed in tissues by 5′-deiodinase. Reverse T3 is an inactive product that rises in severe illness and fasting.

Thyroid hormone acts on nuclear receptors and its effects follow from raising metabolic rate: increased Na+/K+ ATPase activity, oxygen consumption, heat production and basal metabolic rate; increased β1 receptor expression in the heart (raising heart rate, contractility and cardiac output); increased glycogenolysis, gluconeogenesis and lipolysis; and essential roles in brain development and bone growth (synergy with GH). Deficiency in infancy causes congenital hypothyroidism with intellectual disability and short stature, which is why newborns are screened. In adults, hypothyroidism causes fatigue, weight gain, cold intolerance, constipation, dry skin, bradycardia, delayed relaxation of deep tendon reflexes, myalgia and carpal tunnel syndrome; hyperthyroidism causes the reverse plus tremor, anxiety, heat intolerance, tachycardia or atrial fibrillation, and bone loss.

The adrenal axis and the stress response

The adrenal cortex has three zones, each with its own product and control. A simple memory device: "salt, sugar, sex" from outside in, matching "GFR" for glomerulosa, fasciculata, reticularis.

All adrenal steroids derive from cholesterol. The rate limiting step is transfer of cholesterol into mitochondria by the StAR protein and its conversion to pregnenolone by desmolase (side chain cleavage enzyme), which ACTH stimulates. The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency: cortisol and aldosterone cannot be made, ACTH rises, precursors are shunted into androgens, and the result is salt wasting, hypotension and hyperkalemia with virilization of female infants.

Cortisol follows a circadian rhythm, peaking just before waking and lowest near midnight. Its effects prepare the body for prolonged stress: it raises blood glucose by stimulating gluconeogenesis and reducing peripheral glucose uptake; mobilizes amino acids by protein catabolism in muscle; promotes lipolysis yet redistributes fat centrally; maintains vascular responsiveness to catecholamines (permissive action) and so blood pressure; suppresses inflammation and immunity (inhibiting phospholipase A2, IL-2 and histamine release, causing lymphopenia and eosinopenia with neutrophilia); inhibits bone formation and calcium absorption; and inhibits collagen synthesis and wound healing.

The stress response joins the HPA axis to the sympathetic nervous system. Physical or psychological stressors activate CRH neurons and the locus ceruleus. CRH (with ADH as a cofactor) raises ACTH and cortisol over minutes to hours, while sympathetic outflow and adrenal medullary epinephrine act in seconds. Chronic activation, with sustained cortisol, contributes to central adiposity, insulin resistance, hypertension, muscle wasting, osteoporosis, poor sleep and impaired immunity.

Section 3Endocrine physiology II: metabolic and calcium regulating hormones

Insulin

The islets of Langerhans hold β cells (insulin, about 65 to 80 percent, central), α cells (glucagon, peripheral), δ cells (somatostatin) and PP cells. Islet blood flows from the core outward, so insulin reaches α cells first and restrains glucagon. Insulin is made as preproinsulin, cleaved to proinsulin, then to insulin plus C-peptide in equal amounts. C-peptide is the marker of endogenous secretion: high with an insulinoma or a sulfonylurea, low when hypoglycemia comes from injected insulin.

Glucose stimulates insulin through a sequence worth memorizing: glucose enters the β cell by GLUT2, is phosphorylated by glucokinase, and is metabolized to ATP. Rising ATP closes ATP sensitive K+ channels, the cell depolarizes, voltage gated calcium channels open, and calcium triggers exocytosis of insulin granules. Sulfonylureas close the same K+ channel. Amino acids (arginine, leucine), incretins (GIP, GLP-1), vagal acetylcholine and glucagon also stimulate secretion; α2 adrenergic activity and somatostatin inhibit it, which is why stress and exercise lower insulin.

Insulin binds a receptor tyrosine kinase, which autophosphorylates and recruits IRS proteins, activating the PI3K and Akt pathway (metabolic effects) and the MAP kinase pathway (growth). In skeletal muscle and adipose tissue, insulin moves GLUT4 transporters to the membrane. Brain, red cells, liver, kidney and the intestinal mucosa do not need insulin for glucose uptake. Insulin is the hormone of plenty: it promotes glycogen synthesis, glycolysis, fatty acid and triglyceride synthesis, and protein synthesis; it inhibits glycogenolysis, gluconeogenesis, lipolysis (hormone sensitive lipase), ketogenesis and proteolysis. It also drives potassium into cells through the Na+/K+ ATPase, the basis for treating hyperkalemia with insulin and glucose.

Glucagon and the counterregulatory hormones

Glucagon is released by hypoglycemia, amino acids and sympathetic stimulation and suppressed by glucose and insulin. It acts mainly on the liver through Gs and cAMP to stimulate glycogenolysis, gluconeogenesis, fatty acid oxidation and ketogenesis. It has little effect on muscle glycogen, because muscle lacks glucagon receptors. Glucagon, epinephrine, cortisol and growth hormone are the counterregulatory hormones that defend blood glucose: glucagon and epinephrine act in minutes, cortisol and GH over hours.

Fed and fasted states

Red blood cells always depend on glucose (no mitochondria), and the brain depends on glucose unless ketones are high. In type 1 diabetes, autoimmune destruction of β cells leaves no insulin: unopposed glucagon drives hepatic glucose output and ketogenesis, producing diabetic ketoacidosis with hyperglycemia, an anion gap metabolic acidosis, Kussmaul breathing, dehydration from osmotic diuresis, and total body potassium depletion despite a normal or high serum potassium. In type 2 diabetes, insulin resistance comes first and β cell failure follows; enough insulin usually remains to prevent ketosis, so severe decompensation is the hyperosmolar hyperglycemic state.

Calcium, phosphate and the three regulating hormones

About 99 percent of body calcium sits in bone as hydroxyapatite. Plasma calcium (normal about 8.5 to 10.5 mg/dL) exists as roughly 45 percent free ionized calcium (the active fraction), 40 percent bound to albumin and 15 percent complexed with anions. Low albumin lowers total but not ionized calcium. Alkalosis increases binding of calcium to albumin and lowers ionized calcium, which is why hyperventilation causes perioral tingling and carpopedal spasm. Low ionized calcium increases neuronal excitability (it lowers the threshold for sodium channel opening), producing tetany, Chvostek sign (facial twitch on tapping the facial nerve) and Trousseau sign (carpal spasm with a blood pressure cuff).

Vitamin D is made in skin when UVB light converts 7-dehydrocholesterol to cholecalciferol (D3), or absorbed from diet (D2 or D3). The liver adds a hydroxyl at carbon 25 to form 25-hydroxyvitamin D (calcidiol), the main storage form and the best measure of vitamin D status. The kidney's 1α-hydroxylase forms active 1,25-dihydroxyvitamin D (calcitriol). Deficiency causes rickets in children (bowed legs, rachitic rosary, widened growth plates) and osteomalacia in adults (poorly mineralized osteoid, bone pain, proximal weakness, Looser zones). Chronic kidney disease loses 1α-hydroxylation and phosphate excretion, leading to secondary hyperparathyroidism and renal osteodystrophy. Granulomatous diseases such as sarcoidosis make calcitriol in macrophages and can cause hypercalcemia.

Bone remodeling

Bone is remodeled throughout life by basic multicellular units: osteoclasts resorb a pit over a few weeks, and osteoblasts fill it with new osteoid over a few months, which then mineralizes. Osteoblasts (from mesenchymal stem cells) make type I collagen and alkaline phosphatase, and they control osteoclasts. They express RANKL, which binds RANK on osteoclast precursors (monocyte macrophage lineage) and, with M-CSF, drives their maturation. Osteoblasts also secrete osteoprotegerin (OPG), a decoy receptor that binds RANKL and blocks resorption. The RANKL to OPG ratio is the dial: PTH, calcitriol, glucocorticoids and inflammatory cytokines (IL-1, IL-6, TNF-α) raise it; estrogen lowers it. Osteoclasts are multinucleated cells that seal onto bone, acidify the space with a proton pump and dissolve mineral, then digest collagen with cathepsin K.

Continuous high PTH favors resorption, but intermittent PTH (teriparatide) is anabolic. Peak bone mass is reached in the late twenties to early thirties. Weight bearing and resistance exercise strengthen bone by mechanical loading sensed by osteocytes, which normally restrain formation by secreting sclerostin. Serum calcium, phosphate and PTH are normal in osteoporosis, which helps distinguish it from osteomalacia (low calcium or phosphate, high alkaline phosphatase) and hyperparathyroidism (high calcium, low phosphate, high PTH).

The adrenal medulla

The adrenal medulla is a modified sympathetic ganglion: chromaffin cells, derived from neural crest, receive preganglionic sympathetic fibers that release acetylcholine onto nicotinic receptors. Catecholamines are made from tyrosine: tyrosine hydroxylase (rate limiting) forms DOPA, DOPA decarboxylase forms dopamine, dopamine β-hydroxylase forms norepinephrine, and PNMT methylates norepinephrine to epinephrine. Cortisol arriving through the intra-adrenal portal blood induces PNMT, linking the cortex and medulla. Catecholamines are degraded by MAO and COMT to metanephrines and vanillylmandelic acid (VMA), measured in the workup of a pheochromocytoma, which causes episodic headache, sweating, palpitations and hypertension.

Epinephrine raises heart rate and contractility (β1), dilates skeletal muscle arterioles and bronchioles (β2), constricts skin and splanchnic vessels (α1), raises blood glucose through glycogenolysis and gluconeogenesis, stimulates lipolysis (β3 and β1) and inhibits insulin release (α2). Together these effects make up the acute fight or flight metabolic response.

Section 4Reproductive physiology

The male axis and spermatogenesis

Pulsatile GnRH drives the anterior pituitary to release LH and FSH. Continuous GnRH (as with long acting agonists) paradoxically suppresses the axis. In the testis, LH acts on Leydig cells to make testosterone. FSH acts on Sertoli cells, which nurse developing sperm, form the blood testis barrier with tight junctions, secrete androgen binding protein (keeping local testosterone high), and make inhibin B, which selectively inhibits FSH. Testosterone feeds back on both the hypothalamus and pituitary, mainly suppressing LH.

Testosterone is converted in target tissues by 5α-reductase to the more potent dihydrotestosterone (DHT), and by aromatase to estradiol. Testosterone itself drives differentiation of the Wolffian ducts (epididymis, vas deferens, seminal vesicles), spermatogenesis, muscle growth, libido, deepening of the voice and growth of the penis at puberty. DHT drives the external genitalia and prostate in the fetus, and prostate growth, male pattern hair loss and acne in adults. Estrogen derived from testosterone is what closes the epiphyseal plates in males.

Spermatogenesis takes about 64 to 74 days in the seminiferous tubules: spermatogonia (diploid) divide by mitosis, primary spermatocytes enter meiosis I to become secondary spermatocytes, meiosis II yields haploid spermatids, and spermiogenesis remodels them into spermatozoa with an acrosome, condensed nucleus and flagellum. Sperm gain motility in the epididymis and capacitation in the female tract. The process requires a scrotal temperature about 2 °C below core, maintained by the pampiniform plexus countercurrent exchanger and the cremaster muscle. Exogenous anabolic steroids suppress LH and FSH, causing testicular atrophy and low sperm counts.

The female axis and the ovarian cycle

The ovary uses a two cell, two gonadotropin system. LH stimulates theca cells to make androgens (androstenedione) from cholesterol; FSH stimulates granulosa cells to express aromatase, converting those androgens to estradiol. Granulosa cells also make inhibin. After ovulation, the follicle becomes the corpus luteum, which secretes progesterone and estradiol under LH.

The cycle averages 28 days. In the follicular phase (variable length), FSH recruits a cohort of follicles; one dominant follicle with the most FSH receptors survives as estradiol and inhibin lower FSH. Low to moderate estradiol exerts negative feedback, but once estradiol stays above a threshold (about 200 pg/mL for roughly 2 days) feedback switches to positive, triggering the LH surge. Ovulation follows the surge by about 24 to 36 hours. The luteal phase is the constant one, about 14 days: progesterone and estradiol from the corpus luteum suppress GnRH. Without pregnancy, the corpus luteum regresses, progesterone and estrogen fall, and menstruation begins while FSH rises to start the next cycle.

The menstrual (uterine) cycle

The endometrium tracks the ovarian hormones. During the proliferative phase, estradiol rebuilds the functional layer, lengthens glands and spiral arteries, induces progesterone receptors and produces thin, stretchy cervical mucus that sperm can penetrate. During the secretory phase, progesterone makes glands coiled and glycogen rich, stabilizes the endometrium for implantation, thickens cervical mucus and raises basal body temperature by about 0.3 to 0.5 °C, a sign that ovulation has occurred. Withdrawal of progesterone causes spiral artery constriction, ischemia and shedding of the functional layer (menses, days 1 to 5); prostaglandins mediate the cramping of dysmenorrhea.

Pregnancy, parturition and lactation

Fertilization occurs in the ampulla of the uterine tube, and the blastocyst implants about 6 days later. The syncytiotrophoblast secretes hCG, structurally similar to LH, which rescues the corpus luteum so progesterone continues; hCG is the basis of pregnancy tests, detectable in blood about 8 days after fertilization, and peaks near 8 to 10 weeks. By the end of the first trimester the placenta takes over progesterone and estrogen production (the luteal placental shift). Estriol synthesis needs fetal adrenal DHEA-S, so it reflects fetal wellbeing. Human placental lactogen (hPL) causes maternal insulin resistance, sparing glucose for the fetus and contributing to gestational diabetes. Pregnancy also raises blood volume (about 40 to 50 percent), cardiac output, GFR and tidal volume, and relaxin and hormonal changes loosen pelvic ligaments.

Parturition involves rising estrogen to progesterone ratio, more oxytocin receptors and gap junctions in the myometrium, and prostaglandins that soften the cervix. Stretch of the cervix sends signals to the hypothalamus that release more oxytocin, which strengthens contractions, a positive feedback loop (the Ferguson reflex) that ends with delivery.

Lactation: during pregnancy, estrogen, progesterone, prolactin and hPL develop the breast, but high estrogen and progesterone block milk production. After delivery of the placenta these fall, and prolactin initiates milk synthesis. Suckling maintains prolactin (by inhibiting dopamine) and releases oxytocin, which contracts myoepithelial cells for milk ejection; oxytocin release can also be conditioned by a crying infant.

Menopause

Menopause is defined as 12 months without menses, at an average age of about 51, caused by depletion of ovarian follicles. With fewer follicles, estradiol and inhibin fall, so FSH rises (the best lab marker) along with LH. Effects include vasomotor symptoms (hot flashes), vaginal atrophy, sleep and mood change, an atherogenic shift in lipids and accelerated bone loss, fastest in the first five or so years, because estrogen no longer restrains RANKL.

Section 5Exercise and sports physiology

Acute cardiovascular and respiratory responses

Cardiac output (heart rate times stroke volume) rises from about 5 L/min at rest to 20 to 25 L/min in an untrained adult and 35 L/min or more in an elite endurance athlete. Heart rate climbs roughly linearly with workload toward a maximum (estimated as 220 minus age). Stroke volume rises through greater venous return (muscle and respiratory pumps, venoconstriction) and sympathetic contractility, and plateaus at about 40 to 60 percent of VO2 max in untrained people. Blood flow is redistributed: local metabolites (K+, adenosine, CO2, H+, lactate, nitric oxide) dilate active muscle arterioles, while sympathetic vasoconstriction reduces flow to the gut and kidneys. Total peripheral resistance falls, so systolic pressure rises while diastolic pressure stays the same or falls slightly during dynamic exercise; heavy isometric or resistance exercise raises both sharply.

Minute ventilation rises from about 6 L/min at rest to over 100 L/min. At the onset, ventilation jumps abruptly (a neural feedforward drive from the motor cortex and joint and muscle receptors), then rises more gradually. Arterial PO2 and PCO2 change little in moderate exercise; the mixed venous PO2 falls because muscle extracts more oxygen. The oxygen dissociation curve shifts right in working muscle (higher CO2, H+, temperature and 2,3-BPG), unloading more oxygen. Ventilation is rarely the limit to performance in healthy people.

VO2 max and the lactate threshold

VO2 max is the highest rate of oxygen consumption a person can reach, the best single measure of aerobic fitness. By the Fick principle, VO2 = cardiac output × (arterial minus mixed venous O2 content). In healthy people VO2 max is limited mainly by maximal cardiac output (central delivery), not by the lungs. Typical values are about 35 to 45 mL/kg/min in untrained young adults and 70 to 85 mL/kg/min in elite endurance athletes; it is largely genetic, trainable by about 15 to 25 percent, and declines about 10 percent per decade after age 30 without training. One MET equals 3.5 mL O2/kg/min.

The lactate threshold is the intensity at which blood lactate begins to rise above resting levels because production exceeds clearance, typically 50 to 60 percent of VO2 max untrained and 70 to 85 percent in trained endurance athletes. Lactate is not a waste product: the heart, liver (Cori cycle) and oxidative muscle fibers use it as fuel. The accompanying H+ is buffered by bicarbonate, producing extra CO2 that drives ventilation up disproportionately (the ventilatory threshold). The respiratory exchange ratio (VCO2/VO2) is about 0.7 when burning fat and 1.0 with carbohydrate, and exceeds 1.0 above the threshold. Lactate threshold predicts endurance performance better than VO2 max.

After exercise, oxygen consumption stays high (EPOC, the old oxygen debt) to restore phosphocreatine, reoxygenate myoglobin, clear lactate and pay for elevated temperature and hormones.

Energy systems in sport

As intensity rises, fuel shifts from fat toward carbohydrate (the crossover concept). Muscle glycogen depletion causes fatigue ("hitting the wall") in prolonged events, which is why carbohydrate loading and carbohydrate intake during long events help. Type I (slow oxidative) fibers suit endurance; type IIx (fast glycolytic) fibers suit power.

Training adaptations

Endurance training raises VO2 max mainly by increasing stroke volume (larger left ventricular cavity, eccentric hypertrophy, more plasma volume), so resting and submaximal heart rates fall (athletic bradycardia from increased vagal tone); maximal heart rate barely changes. In muscle it increases mitochondrial density, oxidative enzymes, capillary density, myoglobin and fat oxidation, shifting the lactate threshold to a higher percentage of VO2 max. Resistance training produces early strength gains through neural adaptation (better motor unit recruitment and synchronization, less co-contraction), within the first 6 to 8 weeks, followed by hypertrophy of fibers (mainly type II) through mTOR driven protein synthesis, with mild concentric thickening of the left ventricle wall. Detraining reverses aerobic gains within weeks.

Thermoregulation and hydration

Only about 20 to 25 percent of the energy of contraction does mechanical work; the rest is heat. The preoptic anterior hypothalamus responds to rising core temperature with cutaneous vasodilation and sweating. Evaporation is the main route of heat loss during exercise, and it fails in high humidity; radiation, conduction and convection work only when skin is warmer than the surroundings. Sweat is hypotonic, and losses can exceed 1 to 2 L/hour. Plasma volume falls, skin and muscle compete for cardiac output, and heart rate rises at a fixed workload (cardiovascular drift). Losing 2 percent of body mass impairs performance. Heat acclimatization over about 10 to 14 days brings earlier, more profuse and more dilute sweating (aldosterone conserves sodium), expanded plasma volume, and lower heart rate and core temperature at a given workload.

Replace fluids by thirst and by weight change (about 1.25 to 1.5 L for every kilogram lost). Overdrinking plain water in long events can cause exercise associated hyponatremia, with confusion, nausea and seizures.

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