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Physiology Exam 4 — Study Guide

PAJ 5000 Graduate Physiology · Class of 2028

Endocrine Physiology I, II & III · Renal I & II · High-Yield Summary

1 · Endocrine Physiology I

Hormone Synthesis & Functions · Pituitary Hormones · Thyroid Hormones

Instructional Objectives

  1. Review the feedback system for the regulation of hormones.
  2. Describe the stimulus, synthesis, function, and controlling hormones of the pituitary gland.
  3. Describe the stimulus, synthesis, function, and controlling hormones of the thyroid gland.
  4. Compare and contrast the hormones of the adenohypophysis and the neurohypophysis and their function.
  5. Compare and contrast the hypothalamic hormones and their function.

1.1 General Principles of Hormones

A hormone is a chemical messenger secreted by an endocrine gland (or cell) directly into the blood, which carries it to distant target cells that possess specific receptors. Hormones are defined by their mode of action rather than their chemistry, and act at extremely low plasma concentrations (on the order of picograms to nanograms per mL).

The three hormone classes

  • Proteins & peptides (3–200 amino acids) — water-soluble, stored in secretory vesicles, and released by exocytosis. Bind surface (membrane) receptors. Includes all pituitary hormones (GH, ACTH, TSH, FSH/LH, ADH, oxytocin), insulin and glucagon (pancreas), and PTH (parathyroid).
  • Steroids — derived from cholesterol, lipid-soluble, made "on demand" with very little storage, and travel bound to plasma carrier proteins. Cross the cell membrane and bind intracellular (cytoplasmic/nuclear) receptors. Includes cortisol and aldosterone (adrenal cortex), estrogen/progesterone (ovary), testosterone (testis), and 1,25-dihydroxycholecalciferol (kidney).
  • Tyrosine derivatives (amines) — two subtypes that behave very differently: thyroid hormones (T3, T4) are lipid-soluble, carried on thyroxine-binding globulin, and act on nuclear receptors; catecholamines (epinephrine, norepinephrine) are water-soluble, stored in vesicles, and act on membrane receptors.

Receptors and second messengers

  • Membrane receptors — used by water-soluble hormones (peptides, catecholamines). Act through second-messenger systems: G-protein-coupled receptors (cAMP, IP3/Ca2+) and enzyme-linked receptors (tyrosine kinase, JAK/STAT). Fast responses (seconds–minutes).
  • Intracellular receptors — used by lipid-soluble hormones (steroids, thyroid hormone). The hormone–receptor complex binds a hormone-response element on DNA to alter gene transcription. Slow onset (hours) but long-lasting.
Figure 1.1
Figure 1.1. Mechanism of a lipid-soluble (intracellular-receptor) hormone — A lipophilic hormone diffuses straight through the plasma membrane into the target cell. Inside, it binds a cytoplasmic or nuclear receptor, forming a hormone–receptor complex. That complex enters the nucleus and binds a specific hormone-response element on DNA, switching transcription of target genes on (or off). The new mRNA is translated on ribosomes into proteins that produce the hormone’s effect. This is why steroid and thyroid hormone actions are slow to start but persist — they work by changing which proteins the cell makes.

Hormone clearance and plasma concentration

Plasma hormone concentration is a balance between secretion and clearance. Hormones are removed by (1) metabolic destruction in tissues, (2) binding to tissue receptors, (3) excretion by the liver into bile, and (4) excretion by the kidney into urine. Water-soluble hormones are cleared quickly; protein-bound (steroid, thyroid) hormones circulate far longer because only the free fraction is available for clearance.

Control of secretion — feedback (IO a)

  • Negative feedback — the most common control mechanism. The biological effect (or the downstream hormone) feeds back to inhibit the original endocrine cell, keeping the system near a set point. Example: cortisol inhibits both CRH (hypothalamus) and ACTH (pituitary).
  • Positive feedback — the response amplifies further secretion. Rarer and self-limited. Classic example: the estrogen surge that triggers the mid-cycle LH surge, and oxytocin during labor.
  • Cyclic variation — secretion overlaid with rhythms (e.g., cortisol’s circadian rhythm, the monthly menstrual cycle).

1.2 The Pituitary Gland & Hypothalamic Control (IO b, d, e)

The pituitary (hypophysis) sits in the sella turcica and has two functionally distinct lobes that arise from different tissues.

Figure 1.2
Figure 1.2. Gross anatomy of the pituitary — The pituitary hangs from the hypothalamus by the hypophysial stalk, just behind the optic chiasm and in front of the mammillary body. The anterior lobe (adenohypophysis) is glandular tissue derived from Rathke’s pouch (oral ectoderm); the posterior lobe (neurohypophysis) is neural tissue that is essentially an extension of the hypothalamus. The pars intermedia lies between them. Knowing this split explains why the two lobes are controlled in completely different ways.
Adenohypophysis (anterior)Neurohypophysis (posterior)
Glandular epithelium (from Rathke’s pouch)Neural tissue (extension of hypothalamus)
SYNTHESIZES its own hormonesOnly STORES/RELEASES hormones made in the hypothalamus
Controlled by hypothalamic releasing/inhibiting hormones via the portal bloodControlled directly by nerve axons (hypothalamic–hypophysial tract)
GH, ACTH, TSH, Prolactin, FSH, LH (+MSH)ADH (vasopressin) and Oxytocin
Figure 1.3
Figure 1.3. Hypothalamic–hypophysial portal system — This vascular link is how the hypothalamus commands the anterior pituitary. Hypothalamic neurons release regulatory (hypophysiotropic) hormones into a primary capillary plexus at the median eminence. Portal veins carry that blood down the stalk to a second capillary bed in the anterior lobe, delivering the releasing/inhibiting hormones in high concentration directly to their target cells. Because it is a portal (capillary→vein→capillary) system, tiny amounts of hypothalamic hormone reach the pituitary without being diluted in the whole circulation.

Hypothalamic (hypophysiotropic) hormones — IO e

  • GHRH — stimulates GH; Somatostatin (GHIH) — inhibits GH (and TSH).
  • TRH — stimulates TSH (and prolactin).
  • CRH — stimulates ACTH.
  • GnRH — stimulates FSH and LH.
  • Dopamine (PIH) — inhibits prolactin (prolactin is unique: under tonic inhibition).

1.3 Anterior Pituitary Hormones

  • Growth hormone (GH / somatotropin) — from somatotropes (~35% of the gland); acts on liver and peripheral tissues.
  • ACTH (corticotropin) — drives the adrenal cortex to make cortisol.
  • TSH (thyrotropin) — drives the thyroid.
  • Prolactin — milk synthesis; under tonic dopamine inhibition.
  • FSH & LH (gonadotropins) — drive the gonads.

Growth Hormone in detail

GH is a 191-amino-acid protein hormone and, unlike the other anterior pituitary hormones, it acts broadly on the body rather than on a single target gland. Its metabolic theme is to favor protein and shift fuel use toward fat, sparing glucose.

  • Protein — ↑ amino-acid transport, ↑ transcription and translation, ↓ protein catabolism (anabolic).
  • Fat — ↑ mobilization and oxidation of fatty acids for energy.
  • Carbohydrate — ↓ glucose uptake by muscle/fat and ↑ hepatic gluconeogenesis, raising blood glucose. This is the "diabetogenic" effect of GH.
  • Growth — stimulated largely indirectly through IGF-1 (somatomedin C) from the liver.
Figure 1.4
Figure 1.4. The GH receptor (JAK2/STAT signaling) — GH binds and dimerizes its membrane receptor, which activates the associated JAK2 tyrosine kinases. JAK2 phosphorylates STAT proteins, which then translocate to the nucleus and switch on target genes (driving the enzyme activation, translation and physiological effects of GH). SOCS proteins provide negative feedback by shutting the pathway off. This is an enzyme-linked (tyrosine-kinase-associated) receptor — a good contrast to the nuclear-receptor mechanism in Figure 1.1.
Figure 1.5
Figure 1.5. The somatomedin (IGF-1) hypothesis and GH axis — GHRH from the hypothalamus stimulates GH release; somatostatin (SST) inhibits it. GH acts on the liver to produce IGF-1 (somatomedin), and most of GH’s growth-promoting effect on muscle and bone is actually carried out by IGF-1. Note the direct GH effects too: in adipose it raises lipolysis and lowers glucose uptake, while in muscle and bone it drives amino-acid uptake, protein/DNA/RNA synthesis, collagen, and cell size and number. IGF-1 and GH both feed back to restrain the hypothalamus and pituitary.
  • Stimulate GH — deep sleep, exercise, stress, hypoglycemia, high blood amino acids (arginine), ghrelin, fasting.
  • Inhibit GH — high blood glucose/free fatty acids, obesity, aging, cortisol, and GH/IGF-1 feedback.
  • With age — GH falls (roughly 6 ng/mL in young adults down toward ~1.6 ng/mL by mid-adult life).

1.4 Posterior Pituitary Hormones

Figure 1.6
Figure 1.6. The posterior pituitary (neurohypophysis) — ADH and oxytocin are synthesized in hypothalamic cell bodies — ADH mainly in the supraoptic nucleus, oxytocin mainly in the paraventricular nucleus — and travel down axons of the hypothalamic–hypophysial tract (bound to carrier proteins called neurophysins) to nerve terminals in the posterior lobe, where they are stored and released into the blood on demand. The posterior pituitary makes no hormone of its own; the pituicytes are supporting glial cells.
  • ADH (vasopressin, AVP) — 9-amino-acid peptide from the supraoptic nucleus; acts on the kidney (collecting duct → inserts aquaporins → water reabsorption) and vasculature (vasoconstriction). Released by ↑ plasma osmolality and by ↓ blood volume/pressure.
  • Oxytocin — 9-amino-acid peptide from the paraventricular nucleus; causes milk let-down (contraction of breast myoepithelial cells) and uterine contraction. A classic positive-feedback hormone.

1.5 Thyroid Hormones (IO c)

Figure 1.7
Figure 1.7. Thyroid gland and follicle anatomy — The thyroid sits over the trachea below the larynx. Its functional units are follicles — spheres of cuboidal epithelial cells surrounding a central store of colloid (mostly thyroglobulin). This is unusual: the thyroid stores its hormone extracellularly, in the colloid, enough for weeks. The parafollicular (C) cells between follicles secrete calcitonin (covered in Lecture 2), not thyroid hormone.
Figure 1.8
Figure 1.8. Synthesis of thyroid hormone — Follow the steps in the follicular cell: (1) the Na+/I− symporter (NIS) actively traps iodide from blood (iodide "trapping"); (2) iodide moves to the apical membrane through pendrin into the colloid; (3) thyroid peroxidase oxidizes iodide and attaches it to tyrosine residues on thyroglobulin (organification), forming MIT and DIT; (4) peroxidase then couples these — DIT+DIT → T4 and MIT+DIT → T3 — still on thyroglobulin in the colloid. When stimulated by TSH, the cell takes colloid back in by pinocytosis; lysosomal proteases cleave thyroglobulin to release T4 and T3 into the blood (roughly 90% T4, 10% T3). Any MIT/DIT that is freed is deiodinated and its iodide recycled. Remember: T4 is the main secreted product, but T3 is the more active hormone at the receptor.

Transport and cellular action

  • Transport — ~99% of circulating thyroid hormone is protein-bound, mostly to thyroxine-binding globulin (TBG), with transthyretin and albumin as nonspecific carriers. Only the tiny free fraction is active. Binding distributes hormone through the body and buffers its levels.
  • Latency/half-life — T3 acts within 6–12 h; T4 within 2–3 days, with a half-life of ~6–7 days (activity persisting ~15 days). T3 has higher receptor affinity than T4.
Figure 1.9
Figure 1.9. Cellular action of T3 and T4 — Circulating T4 enters the cell and is largely converted to the more active T3 by deiodinase. T3 binds a nuclear thyroid-hormone receptor that is paired with the retinoid-X receptor (RXR) on a thyroid-hormone response element in DNA. This drives gene transcription and synthesis of new proteins — notably Na+/K+-ATPase and metabolic enzymes — which raises basal metabolic rate and oxygen consumption in almost every tissue (growth, CNS development, and cardiovascular and metabolic effects shown fanning out at the bottom).

Physiological effects of T3/T4

  • Metabolic — ↑ basal metabolic rate, ↑ O2 consumption and heat production, ↑ Na+/K+-ATPase activity.
  • Cardiovascular — ↑ heart rate, ↑ cardiac output and tissue blood flow, widened pulse pressure (mean pressure roughly unchanged).
  • Other — ↑ respiration, ↑ GI motility (diarrhea when high), ↑ CNS activity (anxiety, nervousness), and effects on muscle (slight ↑ strength; tremor when high).
  • Growth — needed for normal skeletal growth and, critically, CNS development in children (deficiency → impaired growth and cognition).
Figure 1.10
Figure 1.10. Control of thyroid hormone (the HPT axis) — Cold and stress (and low T3/T4) drive the hypothalamus to release TRH, which stimulates the anterior pituitary to release TSH (thyrotropin). TSH stimulates the thyroid to make and secrete T3 and T4, which raise metabolism. Circulating T3/T4 then exert negative feedback on both the pituitary and hypothalamus (dashed inhibitory arrows), closing the loop. This axis is the basis of thyroid lab interpretation — e.g., a high TSH with low T4 points to a failing thyroid (primary hypothyroidism).
Figure 1.11
Figure 1.11. Why "free vs. bound" matters — a clinical table — This table shows why total and free hormone levels can diverge. In hyperthyroidism both total and free T4/T3 are high and TSH is suppressed; in hypothyroidism both are low and TSH is high. But in pregnancy, estrogen raises binding proteins (TBG), so TOTAL T4/T3 rises while the FREE (active) hormone and TSH stay normal — the patient is clinically euthyroid. Liver disease lowers binding proteins, dropping total hormone while free hormone stays normal. Lesson: the free fraction, not the total, determines thyroid status.

2 · Endocrine Physiology II

Adrenal (Cortex & Medulla) · Pancreatic Hormones · Parathyroid & Calcium

Instructional Objectives

  1. Describe the stimulus, synthesis, and function of the parathyroid gland.
  2. Discuss the stimulus, synthesis, function, and controlling hormones of the adrenal cortex.
  3. Describe the synthesis and function of the adrenal medulla.
  4. Describe the stimulus, synthesis, and function of the endocrine pancreas and its hormones.

2.1 Adrenal Gland Overview

Figure 2.1
Figure 2.1. Zones of the adrenal gland — The adrenal has an outer cortex and an inner medulla, each functionally separate. The cortex has three zones, and a helpful mnemonic is "GFR → Salt, Sugar, Sex": zona Glomerulosa makes mineralocorticoids (aldosterone → salt); zona Fasciculata makes glucocorticoids (cortisol → sugar); zona Reticularis makes androgens (sex steroids). The medulla is really modified sympathetic tissue and secretes catecholamines (epinephrine, norepinephrine). Roughly: glomerulosa ~15% (aldosterone), fasciculata/reticularis ~75% (cortisol, corticosterone, androgens — under ACTH), and adrenal androgens ~10% (DHEA, androstenedione).
Figure 2.2
Figure 2.2. Adrenal steroid synthesis from cholesterol — All adrenal (and gonadal) steroids start from cholesterol. The first, rate-limiting step is cholesterol → pregnenolone by cholesterol desmolase (P450scc), the step ACTH stimulates. From pregnenolone, different enzymes in different zones steer the pathway: the glomerulosa route ends in aldosterone; the fasciculata route ends in cortisol; and the reticularis route makes androgens (DHEA, androstenedione). Because each zone expresses a different enzyme set, one gland makes three very different classes of hormone. (This same map is used in Endocrine III for the gonads.)

2.2 Aldosterone — the major mineralocorticoid

  • Made in — zona glomerulosa; acts on the renal collecting duct (principal cells).
  • Function — ↑ Na+ reabsorption and ↑ K+ and H+ secretion → expands ECF/blood volume and raises blood pressure.
  • Control (most important first) — ↑ plasma K+ and ↑ angiotensin II (RAAS) are the two main stimulators; ↑ ECF volume suppresses it; ACTH is permissive (needed for secretion but not a major regulator of the rate).
Figure 2.3
Figure 2.3. How aldosterone acts on the principal cell — Aldosterone is a steroid, so it diffuses into the principal cell and binds the intracellular mineralocorticoid receptor (MR). The complex enters the nucleus and increases transcription of proteins that reabsorb Na+ and secrete K+: the basolateral Na+/K+-ATPase (the pump that powers everything), the apical ENaC sodium channels, and ROMK potassium channels. Net effect: Na+ (and water) are pulled back into the blood while K+ is secreted into the urine. The blocked arrows show the drugs — spironolactone blocks the receptor, amiloride blocks ENaC.

Physiological effects of aldosterone (K+ is the theme)

High aldosteroneLow aldosterone
Hypokalemia (low K+)Hyperkalemia (high K+)
Muscle weakness; slow HR, arrhythmias↑ muscle excitability early → arrhythmias, V-fib
Metabolic alkalosis (H+ secreted)Metabolic acidosis
Na+/water retention → ↑ blood pressureNa+ loss → volume depletion, ↓ BP

2.3 Cortisol — the major glucocorticoid

  • Made in — zona fasciculata; acts on peripheral tissues broadly. ~90% travels bound to cortisol-binding globulin (CBG).
  • Carbohydrate — ↑ gluconeogenesis (induces liver enzymes, raises plasma amino acids, ↑ liver glycogen) and ↓ peripheral glucose use → raises blood glucose ("adrenal diabetes"). This is its best-known effect.
  • Protein — ↓ protein stores everywhere EXCEPT the liver (↑ catabolism, ↓ synthesis); liver protein and plasma proteins rise.
  • Fat — mobilizes fatty acids for energy (shift from glucose to fat fuel).
  • Anti-inflammatory / immunosuppressive — stabilizes lysosomes, blocks inflammatory mediators, and suppresses the immune response (the basis of steroid drugs). Also needed to withstand stress.
Figure 2.4
Figure 2.4. Cortisol vs. cortisone — 11β-HSD and the "aldosterone paradox" — Cortisol can actually bind the mineralocorticoid receptor, so how does aldosterone act specifically? The enzyme 11β-HSD2 (in kidney, colon, salivary/sweat glands) converts active cortisol into inactive cortisone, protecting the mineralocorticoid receptor so only true aldosterone activates it. Elsewhere (liver, adipose, CNS) 11β-HSD1 regenerates active cortisol. Clinically, licorice (glycyrrhetinic acid) blocks 11β-HSD2, so cortisol floods the mineralocorticoid receptor and mimics aldosterone excess (hypertension, hypokalemia) — "apparent mineralocorticoid excess."
Figure 2.5
Figure 2.5. Hypothalamic–pituitary–adrenal (HPA) axis — Stress (trauma, infection, surgery, cold, emotional stress) drives the hypothalamus to secrete CRH (CRF) into the portal system. CRH stimulates the anterior pituitary to release ACTH, which stimulates the adrenal cortex to make cortisol. Cortisol produces its effects (gluconeogenesis, protein/fat mobilization, lysosome stabilization) and then feeds back negatively on both the pituitary and hypothalamus (the two inhibitory arrows). This negative-feedback loop is why chronic steroid therapy suppresses the axis.
Figure 2.6
Figure 2.6. Cortisol’s circadian rhythm — Cortisol is not secreted evenly. It follows a strong daily (circadian) rhythm: levels peak in the early morning (around 6–8 AM, near waking) and fall to their lowest around midnight. This is why cortisol and ACTH must be interpreted relative to the time of day, and why an 8 AM value is the standard screening sample.

2.4 Adrenal Medulla (IO c)

  • Secretes — the catecholamines epinephrine (~80%) and norepinephrine, made from tyrosine and stored in vesicles (water-soluble amines that act on membrane adrenergic receptors).
  • Really modified sympathetic tissue — the chromaffin cells are like postganglionic sympathetic neurons without axons; preganglionic sympathetic fibers stimulate them directly.
  • Function — reinforce the "fight-or-flight" response: ↑ heart rate and contractility, ↑ blood glucose (glycogenolysis, gluconeogenesis), ↑ lipolysis, bronchodilation, and redirection of blood flow.

2.5 Endocrine Pancreas (IO d)

Figure 2.7
Figure 2.7. Islet of Langerhans — the cell types — The endocrine pancreas is the islets of Langerhans (scattered among the exocrine acini). Four cell types matter: alpha cells (~25%) make glucagon; beta cells (~60%, central) make insulin and amylin; delta cells (~10%) make somatostatin; and PP cells (~5%) make pancreatic polypeptide. Their arrangement lets them regulate each other by paracrine signaling.

Insulin — the storage/"fed-state" hormone

  • Made in — beta cells; a peptide with a 6-minute half-life, degraded by hepatic insulinase. C-peptide (cleaved from proinsulin) marks endogenous production.
  • Acts on — muscle, liver, and fat via an enzyme-linked (tyrosine-kinase) receptor.
  • Carbohydrate — ↑ glucose uptake into muscle and fat (GLUT4), and promotes hepatic glucose storage as glycogen. Note: insulin does NOT control glucose entry into the brain (GLUT1, insulin-independent).
  • Fat — promotes fat storage: ↑ glucose→triglyceride, ↑ lipoprotein lipase, ↓ hormone-sensitive lipase. Loss of insulin → unchecked lipolysis → ketoacids (DKA).
  • Protein — anabolic: ↑ amino-acid transport, ↑ transcription/translation, ↓ catabolism.
Figure 2.8
Figure 2.8. The insulin receptor — Insulin binds a receptor made of two extracellular α-subunits and two membrane-spanning β-subunits. Binding activates the β-subunit tyrosine kinase, which autophosphorylates and phosphorylates insulin-receptor substrates (IRS). This one signal branches into many effects: rapid GLUT4-mediated glucose transport, plus enzyme phosphorylation changes driving glycogen, fat and protein synthesis, and (over hours) altered gene expression and growth. It is the classic enzyme-linked receptor.
Figure 2.9
Figure 2.9. How glucose triggers insulin release — This is a high-yield mechanism. Glucose enters the beta cell through GLUT2 and is phosphorylated by glucokinase (the glucose "sensor"). Metabolism raises ATP, which closes the ATP-sensitive K+ channel. The cell depolarizes, opening voltage-gated Ca2+ channels; the Ca2+ influx triggers exocytosis of insulin. Sulfonylurea drugs work exactly here — they close the same K+ channel to force insulin release.
Figure 2.10
Figure 2.10. Insulin secretion vs. plasma glucose — Insulin secretion is tightly coupled to blood glucose. Below about 100 mg/dL there is little secretion; above that, insulin rises steeply and roughly proportionally until it plateaus at high glucose. This sigmoid relationship is what keeps fasting glucose near 80–90 mg/dL.

Glucagon, somatostatin, and glucose regulation

  • Glucagon — from alpha cells; acts on the liver to ↑ glycogenolysis and ↑ gluconeogenesis, raising blood glucose. Opposes insulin. Stimulated by hypoglycemia, amino acids, and fasting/exercise; inhibited by glucose, insulin, and somatostatin.
  • Somatostatin — from delta cells; a paracrine "brake" that inhibits both insulin and glucagon and slows GI activity to smooth out fuel absorption. (Also the hypothalamic GH-inhibiting hormone.)
  • Epinephrine & cortisol/GH — counter-regulatory: during hypoglycemia they mobilize glucose and fat.
  • Big picture — insulin lowers glucose after meals; glucagon (plus epinephrine, cortisol, GH) raises it during fasting; the liver is the buffer that stores and releases glucose.

2.6 Bone, Calcium & the Parathyroid (IO a)

Only ~0.1% of body calcium is in the ECF, yet it is tightly regulated (ionized Ca2+ is what matters for nerve/muscle) because bone is a vast calcium reservoir. Three hormones control calcium: PTH and 1,25-vitamin D raise plasma Ca2+; calcitonin lowers it.

Figure 2.11
Figure 2.11. Cortical vs. trabecular bone — Two bone types with different jobs: cortical (compact) bone forms the dense outer shell (the shaft/diaphysis) — strong, slow turnover. Trabecular (cancellous/spongy) bone is the internal lattice at the ends (epiphyses) — high surface area, fast turnover, and therefore the main site of rapid mineral (calcium) exchange. Marrow fills the spaces. When you need to mobilize calcium quickly, trabecular bone is where it comes from.
Figure 2.12
Figure 2.12. Activation of Vitamin D — Vitamin D must be activated in two steps. Skin makes cholecalciferol (D3) from 7-dehydrocholesterol under UV light (diet contributes too). The liver adds one hydroxyl → 25-hydroxycholecalciferol. The kidney adds another → 1,25-dihydroxycholecalciferol (calcitriol), the active hormone — and this final kidney step is stimulated by PTH. Active vitamin D then acts on the intestine (via calcium-binding protein/calbindin) to absorb calcium and phosphate. Note the feedback: the active form inhibits its own further production.
Figure 2.13
Figure 2.13. Parathyroid anatomy — Four small parathyroid glands sit on the posterior surface of the thyroid. Their chief cells sense plasma calcium and secrete PTH (a peptide); oxyphil cells are of uncertain function. PTH is synthesized as a preprohormone (110 aa) → prohormone (90 aa) → active PTH (84 aa).

Actions of PTH — raises plasma calcium

  • Bone — activates osteoblasts/osteocytes, which then recruit osteoclasts (osteoclasts have NO PTH receptor — they are turned on indirectly, e.g., via RANKL/OPGL) → bone resorption releases Ca2+ and phosphate.
  • Kidney — ↑ Ca2+ reabsorption (keeps calcium) but ↑ phosphate excretion (dumps phosphate), and stimulates the 1α-hydroxylase step that makes active vitamin D.
  • Intestine — indirect: via activated vitamin D, ↑ Ca2+ and phosphate absorption.
  • Control — low plasma Ca2+ stimulates PTH (via the calcium-sensing receptor); high Ca2+ suppresses it. Chronic low calcium causes parathyroid hypertrophy.
  • Calcitonin — from thyroid parafollicular (C) cells; released by HIGH plasma calcium; inhibits osteoclasts to lower calcium. A relatively minor, transient player in humans (opposes PTH).
Figure 2.14
Figure 2.14. Integrated control of plasma calcium — This ties calcium regulation together. A fall in plasma Ca2+ is sensed by the calcium-sensing receptor (CaSR) and triggers ↑ PTH. PTH then acts on three targets: bone (↑ resorption/Ca2+ efflux), kidney (↑ Ca2+ reabsorption, ↓ phosphate reabsorption, and ↑ 1,25-vitamin D synthesis), and — through vitamin D — intestine (↑ Ca2+ and phosphate absorption). All three arrows converge to restore plasma Ca2+. Calcitonin (not shown driving this loop) opposes PTH when calcium is high.

3 · Endocrine Physiology III

Reproductive & Hormonal Functions — Male, Female, Pregnancy, Lactation

Instructional Objectives

  1. Discuss the synthesis, function, and controlling hormones for testosterone.
  2. List the actions of testosterone and dihydrotestosterone.
  3. Describe the physiology of puberty.
  4. Compare and contrast the synthesis of estrogen and progesterone, including the controlling hormones.
  5. List the actions of estrogen and progesterone.
  6. Describe ovarian regulation.
  7. Describe the menstrual cycle.
  8. Describe the stages of pregnancy.
  9. Describe parturition and lactation.
  10. Review the target organs of hormones.

3.1 Male Reproductive Physiology

Figure 3.1
Figure 3.1. Male reproductive anatomy — Trace the path of sperm: produced in the seminiferous tubules of the testis, they mature and are stored in the epididymis, then travel up the vas deferens. Accessory glands add fluid — the seminal vesicles contribute fructose-rich fluid (~60% of semen), the prostate a milky alkaline fluid (~30%), and the bulbourethral glands mucus. The testes hang in the scrotum because sperm need a temperature ~2 °C below core body temperature.
Figure 3.2
Figure 3.2. Spermatogenesis — Spermatogenesis begins at puberty and is continuous (a normal male makes up to ~120 million sperm/day). Diploid spermatogonia proliferate by mitosis, then a primary spermatocyte undergoes meiosis I → two secondary spermatocytes → meiosis II → four haploid spermatids, which differentiate (spermiogenesis) into mature spermatozoa. Note the timeline down the side — the full process takes roughly 64–74 days. Contrast this with oogenesis (Figure 3.5 area): one primary spermatocyte yields four sperm, whereas one oocyte yields a single ovum.
Figure 3.3
Figure 3.3. The seminiferous tubule — Sertoli and Leydig cells — Two key cells control sperm production. Leydig (interstitial) cells sit between the tubules and, under LH, secrete testosterone. Sertoli cells line the tubule and, under FSH, nurse the developing sperm and secrete inhibin (which feeds back to suppress FSH). Testosterone from the Leydig cells is essential for the germ-cell divisions occurring along the tubule wall.
Figure 3.4
Figure 3.4. Hypothalamic–pituitary–gonadal (HPG) axis in the male — The hypothalamus releases GnRH in pulses (every 1–3 hours). GnRH drives the anterior pituitary to release LH and FSH. LH → Leydig cells → testosterone; FSH → Sertoli cells → supports spermatogenesis and makes inhibin. Testosterone feeds back negatively on the hypothalamus and pituitary; inhibin selectively suppresses FSH. Pulsatile (not constant) GnRH is essential — continuous GnRH actually shuts the axis down.

Testosterone & DHT — actions (IO a, b)

  • Synthesis/transport — a steroid from cholesterol; ~98% travels bound to albumin and sex-hormone-binding globulin (only ~2% free). Converted to the more potent dihydrotestosterone (DHT) in target tissues by 5α-reductase; can also be aromatized to estrogen.
  • Fetal — the SRY gene → testis-determining factor → testosterone drives male internal ducts; DHT drives external genitalia and testicular descent.
  • Puberty/secondary sex characteristics — penis/scrotum/testis growth, body/facial hair, voice deepening (larynx), thicker/oilier skin (acne), ↑ muscle and bone, ↑ basal metabolic rate, and ↑ red blood cells.
  • Skeleton — ↑ bone thickness and calcium deposition; eventually closes the epiphyses (very high levels can reduce final height); broadens/strengthens bone.
  • DHT vs. testosterone — DHT is the main androgen for external genitalia, prostate, and male-pattern hair/balding; testosterone dominates for muscle, internal ducts, and libido.

3.2 Female Reproductive Physiology

The female axis uses the same players (GnRH → FSH/LH → ovarian estrogen/progesterone) but runs as a ~28-day cycle whose goal is to release one ovum and prepare the endometrium for implantation.

Figure 3.5
Figure 3.5. Folliculogenesis in the ovary — Follow a follicle around the ovary. A primordial follicle (oocyte + single granulosa layer) grows into a primary follicle (multiple granulosa layers + zona pellucida), then an antral (secondary) follicle as a fluid-filled antrum forms and the theca develops. FSH/LH accelerate 6–12 follicles each month, but usually only one becomes the mature (Graafian) follicle; the rest undergo atresia. At ovulation the ovum (with its corona radiata) is expelled, and the remnant becomes the corpus luteum — which, if there is no pregnancy, degenerates into the corpus albicans.
Figure 3.6
Figure 3.6. The two-cell (theca–granulosa) model of estrogen synthesis — Estrogen production is a collaboration. LH acts on theca cells to make androgens (from cholesterol) — but theca cells lack aromatase. Those androgens diffuse to the granulosa cells, where FSH has induced aromatase that converts them to estrogens. This "two-cell, two-gonadotropin" system is why both FSH and LH are needed for estrogen. In the luteal phase the corpus luteum makes so much progesterone that not all can be converted, so progesterone predominates.
Figure 3.7
Figure 3.7. The menstrual cycle — hormones, ovary, and endometrium together — This master figure lines up three things over 28 days. Top: the ovarian events (follicle maturing → ovulation at ~day 14 → corpus luteum). Middle: the hormone curves — estradiol rises through the follicular phase and peaks just before ovulation (triggering the LH surge), then progesterone dominates in the luteal phase. Bottom: the endometrium — the menstrual phase (shedding), the proliferative phase (estrogen rebuilds the lining), and the secretory phase (progesterone makes it glandular and ready for implantation). Key logic: estrogen’s pre-ovulatory PEAK flips from negative to POSITIVE feedback, causing the LH surge that triggers ovulation. If no pregnancy occurs, the corpus luteum dies (~day 26), estrogen and progesterone fall, and the lining is shed — starting the next cycle.

Regulation across the cycle (IO f, g)

  • Follicular phase — FSH/LH begin follicle growth; rising estrogen exerts negative feedback (keeps FSH/LH modest) and rebuilds the endometrium.
  • Pre-ovulatory (LH surge) — high estrogen switches to positive feedback → LH surge → ovulation.
  • Luteal phase — the corpus luteum makes estrogen + progesterone, which suppress GnRH/LH/FSH; the endometrium enters the secretory phase.
  • Menstruation — corpus luteum involutes → estrogen/progesterone fall → endometrial vasospasm, necrosis, and shedding (~40 mL blood).

Actions of estrogen vs. progesterone (IO e)

EstrogenProgesterone
Proliferates the endometrium; grows/matures sex organsSecretory changes in endometrium (prepares for implantation)
Breast: ductal growth, fat depositionBreast: lobule/alveolar development
Bone growth THEN epiphyseal closure; ↓ osteoclast activityReduces uterine contractility (quiets the uterus)
Female secondary sex characteristics; mild Na+/water retentionSlight ↑ body temperature; raises respiratory drive

Puberty, menarche, menopause (IO c)

  • Puberty — GnRH pulses gradually increase; onset ~11–16 years. Menarche (first menstruation) marks the start of cycles.
  • Menopause — ~51 years on average; ovaries become unresponsive, estrogen/progesterone fall, and FSH/LH rise (loss of feedback).

3.3 Pregnancy (IO h)

  • Fertilization — occurs in the ampulla of the fallopian tube; the ovum carries an X, sperm an X or Y. Capacitation prepares the sperm; the acrosome’s enzymes penetrate the ovum.
  • Transport & implantation — the fertilized ovum reaches the uterus in ~3–5 days as a blastocyst (~100 cells) and implants ~1–3 days later. Trophoblast cells invade the endometrium and become the placenta.
Figure 3.8
Figure 3.8. Structure of the placenta — The placenta is the maternal–fetal interface. Fetal placental villi (containing fetal capillaries) project into intervillous spaces bathed in maternal blood, so exchange occurs across a thin barrier without the two bloods mixing. Two umbilical arteries carry deoxygenated blood from fetus to placenta, and one umbilical vein returns oxygenated blood to the fetus. Gases cross by simple diffusion; glucose by facilitated transport (GLUT1); wastes (urea, creatinine) by diffusion.
Figure 3.9
Figure 3.9. Hormone profile of pregnancy — Three curves to know. hCG (from syncytiotrophoblast) rises first, peaking around 10–12 weeks — its job is to rescue the corpus luteum so it keeps making progesterone until the placenta can take over (and it is the basis of pregnancy tests). Progesterone and estrogen then climb steadily, produced increasingly by the placenta, and stay high to term. Progesterone quiets the uterus and maintains the pregnancy; estrogen enlarges the uterus/breasts and softens the pelvis.

3.4 Parturition & Lactation (IO i)

  • Parturition — a rising estrogen-to-progesterone ratio makes the uterus more excitable; oxytocin (with more uterine oxytocin receptors), fetal cortisol/prostaglandins, and cervical stretch drive labor. Cervical stretch → more oxytocin is the classic positive-feedback loop.
  • Stages of labor — (1) cervical dilation to 10 cm, (2) fetal expulsion, (3) placental delivery, (4) immediate postpartum uterine involution.
Figure 3.10
Figure 3.10. Breast structure for lactation — Milk is made in alveoli (clusters of milk-secreting epithelial cells) and drains through ducts to the nipple. Each alveolus is wrapped in myoepithelial cells that squeeze milk out during let-down. During pregnancy, estrogen grows the ducts and progesterone develops the lobules/alveoli, priming the breast — but high estrogen/progesterone block actual milk secretion until after delivery.
Figure 3.11
Figure 3.11. Prolactin and lactation after birth — After delivery, estrogen and progesterone fall sharply (removing their block on milk production), and prolactin from the anterior pituitary now drives milk synthesis. Prolactin is secreted in intermittent bursts triggered by suckling — each nursing episode causes a prolactin spike (the repeating red spikes). Suckling also releases oxytocin (milk let-down) and suppresses GnRH, which is why breastfeeding tends to suppress ovulation.

Estrogen & progesterone synthesis (IO d)

  • Estrogen — made by the two-cell model (Fig 3.6): LH drives theca cells to make androgens, which FSH-induced aromatase in the granulosa cells converts to estrogen — so both FSH and LH are required.
  • Progesterone — made chiefly by the corpus luteum (and the placenta in pregnancy) under LH; in the luteal phase so much is produced that it predominates over estrogen.

Target organs of hormones (IO j)

  • The reproductive hormones act on the gonads, reproductive tract, breasts, and bone, and feed back on the hypothalamus/pituitary. More broadly, each hormone in this unit has defined target organs — e.g., TSH→thyroid, ACTH→adrenal cortex, PTH→bone/kidney/gut, ADH→renal collecting ducts, insulin/glucagon→liver/muscle/fat.

4 · Renal I

Fluid Regulation · Glomerular Filtration · Urinary System

Instructional Objectives

  1. Describe the micturition reflex.
  2. Identify bladder innervation.
  3. Describe glomerular filtration.
  4. Calculate glomerular filtration rate (GFR).
  5. Identify mechanisms that regulate GFR.

4.1 Bladder Innervation (IO b)

The bladder wall is the detrusor muscle — smooth muscle whose cells are electrically coupled, so an action potential spreads through the whole bladder and it contracts as a unit. Two sphincters guard the outlet: an internal sphincter (smooth muscle of the bladder neck, involuntary) and an external sphincter (skeletal muscle, voluntary).

Figure 4.1
Figure 4.1. Innervation of the bladder — Three nerves control the bladder. Parasympathetic pelvic nerves (S2–S4) are the motor supply that CONTRACTS the detrusor and empties the bladder — they also carry the sensory stretch fibers. Sympathetic hypogastric nerves (from L1–L2) mainly relax the detrusor/tighten the neck to STORE urine. The somatic pudendal nerve controls the voluntary external sphincter. Memory aid: parasympathetic = "P" = Pee (empties); sympathetic = Storage.

4.2 Micturition Reflex (IO a)

  • The setup — urine flows essentially unchanged from the collecting ducts through calyces and ureters to the bladder, which fills progressively until wall tension crosses a threshold.
  • The reflex — an autonomic spinal-cord reflex: stretch receptors → pelvic nerve afferents → sacral cord → parasympathetic efferents back to the detrusor → contraction (bladder pressure rises to 40–60 mmHg).
  • Self-regenerative — each contraction stretches the bladder more, recruiting more sensory firing and stronger contraction, until the bladder empties or the reflex fatigues and resets.
  • Voluntary control — higher centers (pons facilitates; cerebral cortex is mainly inhibitory) keep the reflex suppressed and hold the external sphincter closed until it is convenient. To void, the cortex facilitates the sacral center and relaxes the external sphincter. Normally only 5–10 mL residual urine remains.
Figure 4.2
Figure 4.2. The cystometrogram — A cystometrogram plots bladder pressure against volume. At first, adding volume barely raises pressure (the bladder relaxes to accommodate — the flat "basal" part). Once threshold is reached, the sharp dashed spikes are micturition-reflex contractions. It visually captures both the bladder’s compliance during filling and the reflex pressure waves that drive emptying.

Summary chain: Bladder stretch → pelvic afferents (S2–S4) → sacral micturition center → parasympathetic efferents → detrusor contraction + internal sphincter relaxation → urination.

4.3 Glomerular Filtration (IO c)

Glomerular filtration is the first step in urine formation: plasma is filtered from the glomerular capillaries into Bowman’s capsule. The filtrate is essentially protein-free and cell-free plasma — it contains water, salts, glucose, amino acids, and small organic molecules, but normally almost no protein and no cells. The glomerulus filters ~180 L/day (GFR ≈ 125 mL/min).

Figure 4.3
Figure 4.3. The glomerular filtration barrier — Filtrate crosses three layers. (1) The capillary endothelium is fenestrated (full of pores) and coated with a negatively charged glycocalyx. (2) The basement membrane is a meshwork of collagen and negatively charged proteoglycans. (3) Podocytes wrap the capillary with foot processes (pedicels) whose filtration slits are bridged by a thin diaphragm (nephrin/podocin). Together they permit rapid filtration of water and small solutes but block cells and plasma proteins — by both size and negative charge.
Figure 4.4
Figure 4.4. Filterability by size and charge — This plots how freely molecules filter as they get larger. Filterability falls as molecular radius rises. Critically, at any given size the polycationic (positive) molecule filters best and the polyanionic (negative) filters worst, with neutral in between — because the barrier’s fixed negative charges repel anions. This is why albumin (only ~6 nm, smaller than the ~8 nm pores) is still held back: it is negatively charged and electrostatically repelled.

4.4 Calculating GFR (IO d)

  • GFR — the volume of plasma filtered into Bowman’s capsule per minute; normal ≈ 125 mL/min (≈ 180 L/day).
  • Clearance — the volume of plasma cleared of a substance per minute: C = (U × V) / P, where U = urine concentration, V = urine flow rate, P = plasma concentration.
  • Inulin — the gold standard: freely filtered, not reabsorbed or secreted, so its clearance equals GFR exactly.
  • Creatinine — the practical clinical marker: made by muscle, freely filtered, only minimally secreted, so creatinine clearance slightly OVERestimates true GFR but is convenient. Labs report an eGFR from serum creatinine + patient characteristics.
  • Filtration fraction — FF = GFR / renal plasma flow ≈ 125/650 ≈ 0.2 (about 20% of plasma entering the glomerulus is filtered). GFR is ~10% lower in women and declines with normal aging.

4.5 Regulation of GFR (IO e)

GFR is governed by the Starling forces across the glomerular capillary:

GFR = Kf × (PG − PB − πG + πB)

Figure 4.5
Figure 4.5. Net filtration pressure — Four forces act across the glomerular capillary. Glomerular hydrostatic pressure (PG ≈ 60 mmHg) pushes fluid OUT (favors filtration). Opposing it are Bowman’s capsule hydrostatic pressure (PB ≈ 18 mmHg) and glomerular colloid osmotic pressure (πG ≈ 32 mmHg, from plasma proteins). The net filtration pressure = 60 − 18 − 32 ≈ 10 mmHg outward. Because PG is the force most easily changed, it is the main lever the body uses to regulate GFR.
Figure 4.6
Figure 4.6. Afferent vs. efferent arteriolar resistance — The two arterioles feeding/draining the glomerulus control PG in opposite directions. Constricting the AFFERENT arteriole (top: ↑RA) reduces blood entering the glomerulus → ↓PG, ↓renal blood flow, and ↓GFR. Constricting the EFFERENT arteriole (bottom: ↑RE) dams blood inside the glomerulus → ↑PG and ↑GFR (while renal blood flow still falls). Caveat: if the efferent constricts too much, filtration fraction and πG rise so high that GFR eventually falls again. This is exactly how angiotensin II (efferent constrictor) preserves GFR when perfusion is low.

Autoregulation, RBF, and hormones

  • Myogenic mechanism — ↑ arterial pressure stretches the afferent arteriole, which reflexively contracts, keeping PG (and GFR) stable.
  • Tubuloglomerular feedback — the macula densa (in the juxtaglomerular apparatus) senses NaCl delivery. High GFR → more NaCl → adenosine/ATP constrict the afferent arteriole → GFR back down. Low GFR → less NaCl → renin release → angiotensin II preserves GFR. Together these hold GFR/RBF nearly constant over arterial pressures of ~80–180 mmHg.
  • Hormonal/neural — angiotensin II (constricts efferent, preserves GFR), ANP (raises GFR/promotes natriuresis), sympathetic nerves (constrict, ↓GFR in stress), and renal prostaglandins (protective vasodilators).
  • Renal blood flow — the kidneys get ~22% of cardiac output; RBF = ΔP / total renal vascular resistance (Ra + Re + Rv). Much of renal O2 use goes to tubular Na+ reabsorption.

5 · Renal II

Tubular Reabsorption & Secretion · Urine Concentration/Dilution · Regulation of Ions

Instructional Objectives

  1. Describe how hormones regulate kidney function.
  2. Explain renal function in relation to Na+, K+, H+, and HCO3−.
  3. Discuss the functions of the segments that compose the nephron.
  4. Describe the countercurrent multiplier system.
  5. Describe the roles of the collecting ducts and ADH on urine formation.
  6. Review the renin–angiotensin–aldosterone (RAAS) pathway.

5.1 The Nephron and Its Segments (IO 3)

Figure 5.1
Figure 5.1. The kidney and urinary system — Orientation figure: the kidney has an outer cortex and inner medulla (organized into pyramids). Urine formed in the nephrons drains from the papillae into the minor and major calyces, collects in the renal pelvis, and leaves via the ureter to the bladder and urethra. The cortico-medullary organization matters because the medulla holds the salt gradient that concentrates urine.
Figure 5.2
Figure 5.2. Nephron tubular segments — The nephron in order: blood is filtered at the glomerulus (in Bowman’s capsule) → proximal tubule (bulk reabsorption) → loop of Henle (descending thin, ascending thin, thick ascending — builds the medullary gradient) → distal tubule → collecting duct → to the pelvis. The juxtaglomerular apparatus sits where the distal tubule touches its own glomerulus. Peritubular capillaries wrap the tubules to reclaim reabsorbed fluid.
Figure 5.3
Figure 5.3. Cortical vs. juxtamedullary nephrons — Two nephron types. Cortical nephrons (majority) have short loops that barely dip into the medulla. Juxtamedullary nephrons have long loops of Henle that plunge deep into the medulla and are paralleled by long vasa recta — these are the nephrons that generate and use the deep medullary osmotic gradient, making concentrated urine possible.

What each segment does

  • Proximal tubule — reabsorbs the bulk (~65%) of filtered Na+, water, glucose, amino acids, and HCO3−; freely water-permeable.
  • Thin descending limb — water-permeable, solute-impermeable: water leaves, filtrate concentrates.
  • Thick ascending limb — the "diluting segment": actively reabsorbs Na+, K+, Cl− (Na-K-2Cl) but is water-IMPERMEABLE, so it dilutes the filtrate and loads the medulla with salt.
  • Early distal tubule — active NaCl reabsorption (~5%), water-impermeable; contains the macula densa; major site of Ca2+ reabsorption (TRPV5, enhanced by PTH).
  • Late distal tubule & collecting duct — water permeability depends on ADH; site of aldosterone-controlled Na+/K+ handling and acid-base fine-tuning.

5.2 Hormonal Regulation of the Kidney (IO 1, 5)

Figure 5.4
Figure 5.4. ADH — synthesis, release, and action — ADH (vasopressin, AVP) is made in hypothalamic magnocellular neurons (supraoptic/paraventricular), stored in the posterior pituitary, and released when osmoreceptors sense high plasma osmolality or baroreceptors sense low volume/pressure. It acts on principal cells of the late distal tubule and collecting duct: binding V2 receptors inserts aquaporin-2 water channels into the apical membrane, so water is reabsorbed and urine becomes low-volume and concentrated. No ADH → water stays in the tubule → dilute urine.

The other regulatory hormones

  • Aldosterone — acts on principal cells (late distal/collecting): ↑ Na+ reabsorption and ↑ K+ secretion (via Na+/K+-ATPase, ENaC, ROMK); on intercalated cells ↑ H+ secretion. Increased by angiotensin II and high K+; decreased by ANP and high Na+.
  • Angiotensin II — stimulates aldosterone, directly ↑ Na+ reabsorption along the tubule, and constricts the efferent arteriole to preserve GFR and drive Na+/water retention.
  • ANP (atrial natriuretic peptide) — released when blood volume rises; dilates the afferent and constricts the efferent to ↑ GFR, and promotes Na+ and water excretion (natriuresis/diuresis) → lowers volume/pressure. The counter-regulator to RAAS.
  • PTH — ↑ Ca2+ reabsorption (distal tubule) and ↓ phosphate reabsorption (proximal tubule).

Mnemonic: ADH Adds water · Aldosterone Adds sodium · Angiotensin II Assists Na+/water retention · ANP Allows Na+/water to leave · PTH Preserves calcium, Tosses phosphate.

5.3 The RAAS Pathway (IO 6)

Figure 5.5
Figure 5.5. RAAS at the nephron — The juxtaglomerular apparatus is the control center. Its granular (JG) cells in the afferent arteriole release renin, and the macula densa in the early distal tubule senses NaCl. Renin release is triggered by three things: low perfusion pressure (afferent baroreceptors), low NaCl delivery (macula densa), and sympathetic β1 stimulation. Renin then launches the cascade that ends in aldosterone-driven Na+ reabsorption.

The RAAS sequence

  • Angiotensinogen (from the liver) is cleaved by renin → Angiotensin I.
  • Angiotensin I is converted by ACE (mainly in the lungs) → Angiotensin II.
  • Angiotensin II → constricts efferent arterioles, directly ↑ Na+ reabsorption, ↑ ADH, ↑ thirst, and stimulates the adrenal cortex to release aldosterone.
  • Aldosterone → ↑ Na+ reabsorption (water follows) in the distal nephron.
  • Net result — Na+ and water retention → ↑ blood volume and ↑ blood pressure (restoring the low pressure/volume that started the cascade).

5.4 Urine Formation & the Countercurrent System (IO 4, 5)

  • Four basic processes — Excretion = Filtration − Reabsorption + Secretion. Filtration at the glomerulus; reabsorption (water, glucose, amino acids, Na+, Cl−, HCO3−) mainly in the PCT; secretion (H+, K+, NH4+, drugs/toxins) in proximal and distal segments/collecting ducts.
Figure 5.6
Figure 5.6. The countercurrent multiplier — This is how the kidney builds the medullary salt gradient that lets ADH concentrate urine. It runs as two repeating steps. The SINGLE EFFECT: the water-impermeable ascending limb actively pumps Na+/Cl− OUT into the interstitium, making the interstitium ~200 mOsm more concentrated than the tubular fluid. FLUID DISPLACEMENT: new filtrate flows in, and because the descending limb IS water-permeable, water is drawn out into the now-salty interstitium, concentrating the fluid inside the descending limb. Repeating these steps as fluid keeps flowing "multiplies" a small 200-mOsm difference into a large cortex-to-papilla gradient (isosmotic ~300 in the cortex up to ~1200 mOsm deep in the medulla). The vasa recta act as a countercurrent EXCHANGER that supplies the medulla with blood while preserving this gradient rather than washing it out.

When ADH is present, the collecting duct becomes water-permeable and water is drawn out into this hyperosmotic medulla → concentrated urine. When ADH is absent, the duct stays impermeable and the dilute fluid is excreted → dilute urine.

5.5 Renal Handling of Ions & Acid–Base (IO 2)

Figure 5.7
Figure 5.7. Where sodium is reabsorbed — Sodium reabsorption is distributed along the nephron: the proximal tubule reclaims the majority (~65%), the thick ascending loop of Henle ~25%, the distal tubule ~5%, and the collecting system ~3% (the finely regulated, aldosterone-controlled fraction). Even though the collecting duct handles only a few percent, that is the part that is hormonally tuned to match Na+ excretion to the body’s needs.
Figure 5.8
Figure 5.8. Primary active transport — the Na+/K+-ATPase — Every bit of sodium reabsorption is ultimately powered here. The basolateral Na+/K+-ATPase pumps Na+ out of the tubular cell into the peritubular blood (and K+ in), keeping intracellular Na+ low and the cell interior negative (~−70 mV). That electrochemical gradient then pulls Na+ from the tubular lumen across the apical membrane (via channels/cotransporters), so glucose, amino acids, and other solutes can ride along. Note the tight junctions and brush border (luminal membrane) that define the transcellular route.

Potassium, hydrogen, and bicarbonate

  • K+ — reabsorbed proximally; finely SECRETED by principal cells in the collecting duct under aldosterone. Because the same pump moves Na+ in and K+ out, "when Na+ is reabsorbed, K+ is secreted."
  • Acid–base — the proximal tubule reabsorbs ~80–90% of filtered HCO3− (needs carbonic anhydrase). Type A intercalated cells in the collecting duct secrete H+ (via H+-ATPase / H+/K+-ATPase) and reabsorb/generate new HCO3−; type B cells can secrete HCO3−.
  • Ammonium buffer — the tubule makes NH3, which binds secreted H+ (NH3 + H+ → NH4+) to excrete acid and regenerate bicarbonate — a major way the kidney handles a chronic acid load.

6 · Bone & Muscle Physiology

Skeletal & Smooth Muscle Contraction · Bone Cells · Bone Metabolism & Calcium

Instructional Objectives

  1. Describe the neuromuscular junction.
  2. Discuss excitation–contraction coupling of skeletal muscle.
  3. Compare and contrast the composition and function of smooth and striated muscles.
  4. Review bone histology and the types of bone cells.
  5. Describe the physiology of bone metabolism and bone cells.

6.1 Skeletal Muscle Organization

Skeletal muscle is built from progressively smaller units. Each muscle fiber is a single, multinucleated cell wrapped by the sarcolemma (its plasma membrane). Inside, the cytoplasm (sarcoplasm) is packed with myofibrils — the contractile rods — with mitochondria and sarcoplasmic reticulum tucked between them. Each myofibril is a chain of sarcomeres, the smallest contractile unit of muscle.

Figure 6.1
Figure 6.1. Levels of muscle organization — A whole muscle is bundles of muscle fibers; each fiber (one long multinucleated cell) contains many myofibrils; each myofibril is a repeating series of sarcomeres. The take-home hierarchy is muscle → fiber (cell) → myofibril → sarcomere, and only the sarcomere is the actual force-generating unit.

6.2 The Neuromuscular Junction (IO a)

The neuromuscular junction is the specialized synapse between a motor neuron and a muscle fiber, occurring at the motor end plate (usually just one per fiber). The nerve terminal sits in a synaptic trough; the synaptic cleft (20–30 nanometers wide) is loaded with acetylcholinesterase, and subneural clefts fold the muscle membrane to increase surface area — acetylcholine receptors sit at the tops of these folds and voltage-gated sodium channels line the bottom halves.

Figure 6.2
Figure 6.2. The neuromuscular junction — The motor neuron terminal contains ~300,000 synaptic vesicles, each holding ~10,000 molecules of acetylcholine. When the action potential arrives, local depolarization opens voltage-gated Ca²⁺ channels clustered along "dense bars"; the Ca²⁺ influx triggers ~125 vesicles to fuse and release acetylcholine by exocytosis. Random single-vesicle fusion at rest produces miniature end-plate potentials, which are too small to cause contraction.

From acetylcholine to muscle action potential

  • Receptor — the nicotinic acetylcholine receptor is a nonselective cation channel: it lets Na⁺, K⁺, and Ca²⁺ through, but the net driving force produces an inward movement of positive charge (mostly Na⁺). Its combined equilibrium potential is ~0 millivolts.
  • End-plate potential — this inward current depolarizes the end plate. If it spreads far enough to open the neighboring voltage-gated sodium channels, a full muscle action potential fires and propagates along the fiber.
  • Termination — acetylcholinesterase in the cleft rapidly hydrolyzes acetylcholine, ending the signal so each nerve impulse produces exactly one muscle response.

6.3 Excitation–Contraction Coupling (IO b)

Excitation–contraction coupling is how the electrical action potential is converted into a mechanical contraction. Two membrane systems make it possible: transverse (T) tubules — invaginations of the sarcolemma filled with extracellular fluid that carry the action potential deep into the fiber — and the sarcoplasmic reticulum, the intracellular Ca²⁺ store whose swollen terminal cisternae sit against the T-tubules.

Figure 6.3
Figure 6.3. The triad — A "triad" is the junction of one T-tubule flanked by two terminal cisternae of the sarcoplasmic reticulum. On the T-tubule sits the dihydropyridine receptor (a voltage sensor); directly across sits the ryanodine receptor (the sarcoplasmic reticulum's Ca²⁺-release channel). This physical pairing is what lets a membrane voltage change open a calcium gate.
Figure 6.4
Figure 6.4. Excitation–contraction coupling, step by step — (1) The action potential travels down the T-tubule. (2) The voltage change is sensed by the dihydropyridine receptor, which (3) mechanically opens the ryanodine receptor, dumping Ca²⁺ from the sarcoplasmic reticulum. (4) Ca²⁺ enables actin–myosin cross-bridging → contraction. (5) A Ca²⁺ pump returns Ca²⁺ to the sarcoplasmic reticulum, where calsequestrin buffers it for storage, and contraction ends.
Skeletal vs. cardiac coupling — the key difference. In skeletal muscle the trigger is voltage: the dihydropyridine receptor mechanically tugs the ryanodine receptor open (Voltage-Activated Calcium Release) — no outside calcium is needed. In cardiac muscle the trigger is calcium: the dihydropyridine receptor is itself a Ca²⁺ channel that lets a little Ca²⁺ in, which then opens the ryanodine receptor (Calcium-Activated Calcium Release), so cardiac contraction depends on extracellular calcium.

6.4 The Sarcomere & Sliding Filaments

The sarcomere runs from one Z disc to the next. Thin filaments (actin) anchor at the Z discs; thick filaments (myosin) sit in the center; the giant elastic protein titin tethers myosin to the Z disc and provides passive recoil. Contraction is the sliding-filament mechanism: the filaments slide past each other, shortening the sarcomere without the filaments themselves changing length.

Figure 6.5
Figure 6.5. Sarcomere banding — The A band is the full length of the thick filament (dark); the I band is thin filament only (light); the H zone is thick filament with no overlap; the M line anchors myosin at center. During contraction the I band and H zone narrow while the A band stays constant — the visual signature that filaments slide rather than shorten.
Figure 6.6
Figure 6.6. The thin (actin) filament — F-actin is a double helix of polymerized G-actin, each carrying a myosin-binding active site. Tropomyosin lies over these sites to block myosin at rest. The troponin complex regulates access: troponin I binds actin, troponin T binds tropomyosin, and troponin C binds Ca²⁺ — when Ca²⁺ binds troponin C, tropomyosin shifts and uncovers the active sites.
Figure 6.7
Figure 6.7. The myosin molecule and "walk-along" — Myosin has two heavy chains and four light chains; the head region carries the ATPase. In the walk-along (cross-bridge) cycle the energized head binds an actin active site, pivots in a power stroke that pulls the thin filament toward the sarcomere center, then binds fresh ATP to detach and re-cock. Repeated cycles "walk" the filaments past each other.

6.5 Muscle Mechanics & Fiber Types

Figure 6.8
Figure 6.8. The length–tension relationship — Active tension is greatest at an intermediate sarcomere length where thick- and thin-filament overlap is optimal (maximum cross-bridges). Overstretched, the filaments barely overlap and tension falls; overly shortened, the filaments collide and tension also falls. This is why there is an ideal muscle length for force.

Isometric vs. isotonic: an isometric contraction develops force at constant length (the muscle does not shorten — pushing against an immovable load), whereas an isotonic contraction shortens against a constant load. Stretching a muscle first lengthens the sarcomeres, then loads the connective-tissue collagen, realigning fibers along the line of force — the basis for rehabilitating scarred tissue.

Figure 6.9
Figure 6.9. Fast vs. slow fibers — Contraction speed is set by the Vmax of myosin ATPase. Slow (Type I, red) fibers are oxidative — high myoglobin, many mitochondria, high capillary density, fatigue-resistant, small diameter. Fast (Type II, white) fibers are glycolytic — low myoglobin, few mitochondria, large diameter, powerful but quick to fatigue. All fibers in a given motor unit are the same type.
Figure 6.10
Figure 6.10. The motor unit — A motor unit is all the muscle fibers innervated by one motor neuron. Small units (e.g., extraocular, larynx — as few as ~10 fibers) give precise, rapid control; large units (e.g., quadriceps — up to ~1000 fibers) give coarse, powerful control. Slow motor units are recruited first for everyday contractions; fast units are added when more force is needed.
Remodeling. Hypertrophy (common, over weeks) adds actin/myosin in response to near-maximal force (weight lifting) → more force, no change in shortening velocity. Hyperplasia (rare) forms new fibers. Lengthening occurs with normal growth → more shortening capacity and velocity. Atrophy (denervation, casting, bed rest, spaceflight) degrades contractile proteins → less force and velocity; fibers lost for 1–2 years are very hard to replace. Loss of nerve supply also abolishes muscle tone, leaving the muscle flaccid.

6.6 Smooth Muscle (IO c)

Smooth muscle has mononucleate cells with no striations and forms the walls of hollow organs (gut, airways, blood vessels, urogenital tract). It comes in two organizations: unitary (visceral) — sheets of electrically coupled cells joined by gap junctions that contract as a unit (a functional syncytium), often spontaneously active; and multiunit — discrete, densely innervated bundles that contract only when stimulated (e.g., iris, vas deferens, piloerector muscles).

Multi-unit versus unitary smooth muscle organization
Multi-unit (A) vs. unitary (B) smooth muscle. Multi-unit fibers are separate, individually innervated cells that contract independently (iris, vas deferens, piloerector muscles). Unitary (visceral) smooth muscle — here in a small artery's medial layer — is a sheet of gap-junction–coupled cells that contract together as a syncytium, the arrangement found in the walls of the gut, airways, and blood vessels.
What makes smooth muscle special. It can shorten over a huge range (60–75%), is extraordinarily energy-efficient (oxygen use ~1% of skeletal muscle at the same tension), and can hold force for hours to days via the latch state. It has a poorly developed sarcoplasmic reticulum, so Ca²⁺ entering through membrane channels is a major calcium source, and it uses dense bodies (analogous to Z discs) anchored by intermediate filaments. Its neuromuscular junctions are "diffuse junctions" — autonomic varicosities release transmitter into the interstitium rather than onto a discrete end plate.

Contraction is myosin-based, not actin-based. Smooth muscle uses the same sliding-filament actin–myosin interaction, but troponin is absent; the Ca²⁺-sensor is calmodulin. Myosin cannot act until its regulatory light chain is phosphorylated by myosin light chain kinase, which is active only when bound to Ca²⁺–calmodulin.

Figure 6.11
Figure 6.11. The contraction–relaxation switch — Ca²⁺ (from extracellular fluid or sarcoplasmic reticulum) binds calmodulin; the Ca²⁺–calmodulin–myosin light chain kinase complex phosphorylates the myosin light chain (costs one ATP), so the myosin head binds actin and the power stroke proceeds automatically. A second ATP detaches the head. Myosin light chain phosphatase removes the phosphate to relax the muscle — and because its activity is regulated, it sets the muscle's calcium sensitivity.
Figure 6.12
Figure 6.12. Diverse control of smooth muscle — Unlike skeletal muscle (one motor nerve), smooth muscle integrates many inputs: endocrine (epinephrine, angiotensin II, antidiuretic hormone), paracrine/local (histamine, nitric oxide, CO₂, adenosine, extracellular K⁺), the enteric nervous system, and the autonomic nervous system. The same transmitter (norepinephrine or acetylcholine) can contract one tissue and relax another depending on the receptor present.

6.7 Bone Cells & Ossification (IO d)

Ossification is the calcification of a collagen scaffold. Osteoblasts secrete type I collagen (which requires ascorbic acid, vitamin C, as a cofactor for lysyl hydroxylase) plus bone matrix proteins, forming unmineralized osteoid. Hydroxyapatite crystals then precipitate onto the collagen, and calcium–phosphate salts deposit within them to harden the bone (~70% of bone is inorganic salt).

The three bone cells

  • Osteoblast — a versatile secretory cell (relative of the fibroblast) that still divides. It makes type I collagen (90% of bone protein) and matrix proteins including osteocalcin and osteonectin (calcium-binding), bone sialoproteins, osteopontin, and alkaline phosphatase. Osteocalcin bonds hydroxyapatite to collagen, and vitamin K helps it do that job.
  • Osteocyte — a mature osteoblast that became trapped in the matrix it secreted, now living in a lacuna and communicating through canaliculi. Osteocytes sense mechanical load (piezoelectric signaling) and maintain the bone matrix, participating in both synthesis and degradation to keep calcium homeostasis.
  • Osteoclast — a large, multinucleated cell derived from the fusion of hemopoietic granulocyte/macrophage progenitor cells. It resorbs bone from a pit called Howship's lacuna, releasing protons and lysosomal enzymes (cathepsin K and matrix metalloproteinases) into the sealed space to dissolve mineral and digest collagen.
Figure 6.13
Figure 6.13. Bone-cell lineages — Osteoblasts and osteocytes arise from mesenchymal (osteoprogenitor) cells, while osteoclasts come from a completely different source — the fusion of blood-derived monocyte/macrophage progenitors. This separate origin matters because bone-building and bone-removing cells are regulated independently, letting the body balance formation against resorption.
Figure 6.14
Figure 6.14. The osteocyte in its lacuna — A mature osteocyte sits in its lacuna with cytoplasmic processes reaching through canaliculi to neighboring cells. This network is how osteocytes communicate load signals and coordinate remodeling deep within mineralized bone where diffusion alone cannot reach.

6.8 Bone Metabolism & Calcium Regulation (IO e)

Bone is regulated by mechanical force but even more by hormones. The two primary calcium hormones are parathyroid hormone (from the parathyroid glands) which raises blood calcium, and calcitonin (from thyroid C-cells / parafollicular cells) which lowers it. During growth, growth hormone drives osteoprogenitor division, and epiphyseal growth-plate chondrocytes respond to liver-derived insulin-like growth factor I.

Parathyroid hormone — the master calcium regulator

  • Trigger — calcium-sensing receptors in the parathyroid gland detect a fall in serum calcium and release parathyroid hormone. In plasma, ~40% of calcium is protein-bound and ~60% is free/filterable; only free ionized calcium is biologically active.
  • Bone — parathyroid hormone binds osteoblasts, driving them to express RANKL (receptor activator of nuclear factor kappa-B ligand) and release macrophage colony-stimulating factor. RANKL and this factor push preosteoclasts to mature into bone-resorbing osteoclasts. Parathyroid hormone also lowers osteoprotegerin, a decoy that normally binds RANKL to block osteoclast formation.
  • Kidney — increases renal calcium reabsorption (distal tubule), inhibits phosphate reabsorption in the proximal tubule (so phosphate is excreted), and stimulates active vitamin D production, which raises intestinal calcium absorption. Vitamin D deficiency can cause secondary hyperparathyroidism.
Figure 6.15
Figure 6.15. The calcium–phosphate inverse relationship — Calcium and phosphate move in opposite directions: as one rises the other tends to fall. This is why parathyroid hormone, while raising blood calcium, simultaneously dumps phosphate in the urine — keeping the calcium × phosphate product from precipitating in tissues.
Calcitonin — the counter-regulator. Released by thyroid C-cells in response to hypercalcemia, calcitonin inhibits osteoclasts to slow bone resorption and, with prolonged high calcium, reduces the formation of new osteoclasts. It has only minor effects on the kidney and intestine — the mirror image of parathyroid hormone.

7 · High-Yield Summary — Rapid Review

Cover the right side and quiz yourself. These are the points most likely to be tested.

Endocrine I — Hormones, Pituitary, Thyroid

  • Three hormone classes — peptides & catecholamines: water-soluble, membrane receptors, fast. Steroids & thyroid hormone: lipid-soluble, intracellular receptors, slow gene effects.
  • Anterior pituitary — makes its own hormones (GH, ACTH, TSH, PRL, FSH, LH); controlled by hypothalamic releasing hormones via the portal system.
  • Posterior pituitary — only stores ADH (supraoptic) and oxytocin (paraventricular) made in the hypothalamus; controlled by nerves.
  • GH — anabolic for protein, mobilizes fat, "diabetogenic" (raises glucose); acts largely via IGF-1 from the liver.
  • Thyroid — iodide trapped by NIS, organified by peroxidase onto thyroglobulin (MIT/DIT → T3/T4), stored in colloid. T4 is main product; T3 is more active. Raises BMR. HPT axis: TRH → TSH → T3/T4 → negative feedback.
  • Free vs. bound — only free hormone is active; pregnancy raises TBG (↑ total, normal free/TSH = euthyroid).

Endocrine II — Adrenal, Pancreas, Calcium

  • Adrenal cortex — GFR = Salt (aldosterone/glomerulosa), Sugar (cortisol/fasciculata), Sex (androgens/reticularis). Medulla = catecholamines.
  • Aldosterone — ↑ Na+ reabsorption, ↑ K+/H+ secretion (collecting duct). Driven by ↑ K+ and angiotensin II.
  • Cortisol — ↑ gluconeogenesis/blood glucose, protein catabolism (spares liver), anti-inflammatory. HPA axis with circadian peak in the morning. 11β-HSD2 protects the mineralocorticoid receptor (licorice blocks it).
  • Insulin (beta cells) — fed-state storage hormone; glucose→GLUT2→glucokinase→ATP→closes K+ channel→depolarize→Ca2+→exocytosis. Sulfonylureas act here.
  • Glucagon (alpha) — raises glucose via glycogenolysis/gluconeogenesis. Somatostatin (delta) inhibits both.
  • Calcium — PTH raises Ca2+ (bone resorption via osteoblasts→osteoclasts, renal Ca2+ reabsorption, ↑ active vitamin D, ↑ phosphate excretion). Vitamin D: skin→liver(25)→kidney(1,25, PTH-driven)→gut Ca2+ absorption. Calcitonin lowers Ca2+.

Endocrine III — Reproduction

  • Male — LH → Leydig cells → testosterone; FSH → Sertoli cells → spermatogenesis + inhibin. Pulsatile GnRH is essential. DHT (5α-reductase) for external genitalia/prostate/hair.
  • Female — two-cell model: LH→theca→androgens; FSH→granulosa→aromatase→estrogen. Estrogen’s pre-ovulatory peak flips to positive feedback → LH surge → ovulation (~day 14).
  • Endometrium — proliferative (estrogen) then secretory (progesterone); corpus luteum death → menses.
  • Pregnancy — hCG rescues the corpus luteum (peaks ~10–12 wk); placenta then makes estrogen/progesterone. Progesterone quiets the uterus.
  • Lactation — prolactin drives milk synthesis (suckling → prolactin spikes); oxytocin drives let-down; suckling suppresses GnRH.

Renal I — Filtration & GFR

  • Bladder — parasympathetic pelvic (S2–S4) empties (detrusor); sympathetic (L1–L2) stores; pudendal = voluntary external sphincter.
  • Filtration barrier — fenestrated endothelium + basement membrane + podocyte slits; blocks by size AND negative charge (albumin repelled).
  • GFR ≈ 125 mL/min (180 L/day). GFR = Kf × (PG − PB − πG). Net filtration pressure ≈ 10 mmHg. Inulin = gold standard; creatinine clearance slightly overestimates GFR.
  • Regulation — PG is the main lever. ↑ afferent resistance ↓ GFR; ↑ efferent resistance ↑ GFR. Autoregulation = myogenic + tubuloglomerular feedback (macula densa) over ~80–180 mmHg.

Renal II — Tubules, Concentration, Ions

  • Segments — PCT reabsorbs ~65% Na+/bulk; thick ascending limb = diluting segment (Na-K-2Cl, water-impermeable, loads medulla with salt); collecting duct = ADH-controlled water, aldosterone-controlled Na+/K+.
  • ADH — V2 receptor → aquaporin-2 → water reabsorption → concentrated urine. No ADH → dilute urine.
  • Countercurrent multiplier — single effect (ascending limb pumps NaCl out) + fluid displacement (water leaves descending limb) build the medullary gradient (~300 cortex → ~1200 papilla). Vasa recta preserve it.
  • RAAS — low pressure/low NaCl/sympathetic → renin → angiotensinogen → AngI →(ACE)→ AngII → efferent constriction + aldosterone + ADH + thirst → Na+/water retention → ↑ BP. ANP opposes it.
  • Acid–base — PCT reabsorbs ~80–90% HCO3−; type A intercalated cells secrete H+ and generate new HCO3−; ammonium (NH3+H+→NH4+) excretes acid.

Bone & Muscle — Contraction, Bone & Calcium

  • Neuromuscular junction — action potential → voltage-gated Ca²⁺ opens → ~125 vesicles release acetylcholine → nicotinic cation channel → end-plate potential → muscle action potential. Acetylcholinesterase terminates it.
  • Excitation–contraction coupling — action potential down T-tubule → dihydropyridine receptor (voltage sensor) mechanically opens ryanodine receptor → Ca²⁺ out of sarcoplasmic reticulum. Skeletal = voltage-triggered (VACR, no outside Ca²⁺); cardiac = calcium-triggered (CACR, needs extracellular Ca²⁺).
  • Sliding filament — Ca²⁺ binds troponin C → tropomyosin uncovers actin → myosin "walk-along" power stroke. A band constant, I band/H zone narrow.
  • Fiber types — set by myosin ATPase Vmax. Slow (Type I, red) = oxidative, fatigue-resistant, recruited first; Fast (Type II, white) = glycolytic, powerful, fatigable. Motor unit = one neuron + its fibers (all same type).
  • Smooth muscle — no troponin; Ca²⁺→calmodulin→myosin light chain kinase phosphorylates myosin (myosin-based); myosin light chain phosphatase relaxes it. Latch state, 60–75% shortening, very energy-efficient.
  • Bone cells — osteoblast (secretes type I collagen = 90% of bone protein + osteocalcin; needs vitamin C/K) → osteocyte (in lacuna, senses load via canaliculi) ; osteoclast (blood-derived, multinucleated, resorbs via cathepsin K in Howship's lacuna).
  • Calcium — PTH raises Ca²⁺ (osteoblast RANKL → osteoclasts, ↑renal Ca²⁺ reabsorption, ↓phosphate reabsorption, ↑vitamin D). Calcitonin lowers Ca²⁺ (inhibits osteoclasts). Only free ionized calcium is active; calcium and phosphate move inversely.