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• The Urinary System
• The Endocrine System
• The Reproductive System

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Kidney as an Endocrine Gland: Interstitial kidney cells, which do not participate in the filtration system.

• Renin: Secreted by kidney juxtaglomerular cells.
• Mild renal dysfunction can result in decreased blood flow ------> increased renal ------> hypertension reesulting from hypersecretion of renin.
• Erythropoietin: Secreted by interstitial cells in the cortex in a diffuse, non-specific manner.
• Bad kidneys are left in whenever possible so that erythropoietin can still be produced.
• Prostanoids: They are secrete in a diffuse, non-specific manner by interstitial cells in the medulla.

Nephrons: They come in two flavors in the kidney, cortical nephrons and juxtamedullary nephrons.

• Cortical Nephrons originate in the outer cortex and have relatively short loops of Henle and collecting tubules.
• Juxtamedullary Nephrons originate close to the cortico-medullary junction, and have very long loops of Henle and collecting tubules, extending almost down to the renal pelvis.

Renal Vasculature: Vessels are listed in order of blood flow.

• Renal Artery
• Interlobar Arteries: Descend between kidney lobules to the corticomedullary junction.
• Arcuate Arteries: They divide the kidney cortex from the medulla.
• Interlobular Arteries: Branch from the corticomedullary junction back outward toward the capsule.
• AFFERENT ARTERIOLES: Primary arterioles that provide incoming blood to the glomerulus.
• A major source of pressure drop in the kidney system. Kidney capillary pressure is around 50-60 mm Hg, whereas normal capillary pressure is around 20.
• EFFERENT ARTERIOLES: Primary arterioles that contain the remaining blood that was not filtered by the glomerulus.
• A major source of pressure drop in the kidney system. Kidney capillary pressure is around 50-60 mm Hg, whereas normal capillary pressure is around 20.
• VASA RECTA: The continuation of efferent arterioles, in the medulla
• They are virtually the only blood supply to the medulla.
• They run parallel to the collecting tubules in juxtamedullary nephrons.
• PERITUBULAR CAPILLARIES: The continuation of efferent arterioles, in the cortex.
• They have a high oncotic pressure due to high concentration of large blood proteins that didn't filter. They thus reabsorb a lot of the filtrate from the collecting tubules that run with them.
• Interlobular Veins
• Arcuate Veins
• Interlobar Veins
• Renal Vein

Tubular Systems: Tubules are listed in order of flow of tubular fluid.

• GLOMERULUS: Initial filtration of blood.
• Glomerular Structure: Layers of the glomerular filter, from blood-space to bowman's space.
• ENDOTHELIAL CELLS: Fenestrated cells of capillary wall.
• PODOCYTES: They extend Foot Processes onto the capillary wall, which can separate from each other when mesangial cells contract.
• Tight Junctions between foot processes are the primary barriers to filtration.
• MESANGIAL CELLS: They are interstitial cells in the glomerulus. When they contract, the foot processes spread out and the filtration slits become wider.
• GLOMERULAR BASEMENT MEMBRANE (GBM):
• Lamina Rara Externa: Facing the capillary space.
• Lamina Densa: Thick middle part.
• Lamina Rara Interna: Facing the tubular space.
• GBM Contents: The basement membrane has an overall negative charge. This negative charge makes the glomerulus repel large negative proteins in the blood so they don't filter.
• Proteoglycans: Heparan Sulfate, Chondroitin Sulfate, etc., with negative charge.
• Type IV Collagen
• BOWMAN'S SPACE
• Glomerular Structure: Polarity
• VASCULAR POLE: That part of the Glomerulus facing the afferent arteriole.
• URINARY POLE: That part of the glomerulus facing the collecting tubule as it is coming back up from the kidney medulla.
• Glomerular Filtration:
• Differential filtration of Dextrans:
• Neutral Dextran is filtered about 15%
• Dextran Sulfate is filtered only about 1% because it is negatively charged.
• Positively charged Dextran is filtered about 42% because positive charge can preferentially get through the Glomerular basement membrane.
• Glomerular pathologies:
• MEMBRANOUS GLOMERULOPATHY: Disease in which the glomerular filter is enlarged, such that albumin can get into the filtrate. This is bad!
• Results = Albuminuria and Hypoalbuminemia which leads to edema and hypertension.
• Foot processes are virtually gone in this disease.
• GLOMERULOSCLEROSIS: Proliferation of mesangial cells leading to reduced or no filtration.
• PROXIMAL TUBULE
• Histological Appearance:
• PROXIMAL CONVOLUTED TUBULE (PCT): Reabsorbs 70% of Na⁺ and water from filtrate.
• S1, S2 SEGMENTS: Classified according to Renal toxicity.
• Histological Structure: CUBOIDAL EPITHELIUM with modifications to make lots of surface area.
• Brush Border microvilli are present on the apical surface
• Basolateral Infoldings are present on the basal surface, with tons of mitochondria in between them, to run the Na/K-ATPases.
• Transport Proteins:
• Na/K-ATPase on basolateral membrane maintains gradient.
• Na⁺/Glucose Cotransporter, Na⁺ Cotransporters for specific amino acids.
• Apical Endocytic Vesicles endocytose tubular proteins and degrade them.
• PROXIMAL STRAIGHT TUBULE (PST, Thick Descending Limb):
• S3 SEGMENT: Classified according to renal toxicity.
• CISPLATIN = heavy metal platinum drug will wipe out the Proximal Straight Tubule. This is a chemotherapeutic agent and the renal toxicity is an undesirable (though often tolerable) side effect.
• GENTAMICIN: Broad-spectrum antibiotic that has renal toxicity.
• LOOP OF HENLE
• THIN DESCENDING / ASCENDING LIMB: Most of the limb is ascending.
• Location: This section of tubule is completely within the medulla.
• Outer (Cortical) Nephrons: Relatively short segment.
• Inner (Juxtamedullary) Nephrons: Very long segment.
• Histological Structure: SQUAMOUS EPITHELIUM
• Counter-Current Exchange: The epithelium of the Loop is adjacent to the Vasa Rectae, which is carrying blood in the opposite direction.
• DISTAL STRAIGHT TUBULE (DST, Thick Ascending Limb, TALH): Makes up the first portion of the Medullary Ray, heading back up to the cortex.
• Histological structure: CUBOIDAL EPITHELIUM.
• They do not have brush-border apical microvilli and can thus be distinguished from PCT.
• Basolateral Infoldings, with lots of mitochondria, are present.
• JUXTAGLOMERULAR APPARATUS: The juxtaposition of the DCT (macula densa cells) and afferent arteriole (JGA cells).
• MACULA DENSA: Forms the tubular part of the Juxtaglomerular Apparatus.
• The Macula Densa cells form part of the wall of the DCT.
• FNXN: They sense Na⁺ concentration in the tubular filtrate and feedback to the Juxtaglomerular Cells accordingly.
• LOW Na⁺ CONC indicates that GFR (and thus systemic blood pressure) is low. Thus Low Na⁺ concentration will lead to stimulation of JGA cells to release renin.
• JUXTAGLOMERULAR CELLS: Form the vascular part of the Juxtaglomerular Apparatus.
• The JGA cells form part of the wall of the Afferent Arteriole.
• The JGA cells secrete renin in response to input from the Macula Densa cells.
• In the bloodstream, Renin stimulates Angiotensinogen ------> Angiotensin I.
• In the lungs, ACE stimulates Angiotensin I ------> Angiotensin II, the active form.
• Glomerular Filtration Rate: Glomerular Filtration Rate is controlled by changing the vascular tone of the afferent and efferent arterioles.
• Constrict Afferent Arteriole ------> reduce renal blood flow ------> reduce GFR.
• Constrict Efferent Arteriole ------> reduce renal outflow ------> increase GFR.
• This is the primary point of control of GFR. Renin will ultimately lead to vasoconstriction of the efferent arteriole.
• DISTAL CONVOLUTED TUBULE (DCT): The distal tubule, in the kidney cortex.
• Transport: It uses a lot of energy (Na/K-ATPase) to drive even more Na⁺ out of the tubular fluid.
• It has more Na/K-ATPase transporters than the proximal tubule, because it requires more energy to maintain a strong enough gradient to keep driving Na⁺ out at this point.
• The result is that the tubular fluid is hypotonic at the end of the DCT-segment.
• CONNECTING TUBULE: In cortex, short tubule connecting the DCT to the Collecting Tubule.
• COLLECTING DUCTS: It receives generally hypotonic, dilute fluid from the DCT.
• CORTICAL (OUTER MEDULLARY) COLLECTING DUCT (OMCD):
• PRINCIPLE CELL:
• FNXN: It is involved in K⁺-secretion and is sensitive to ADH.
• ADH absent ------> insoluble to water ------> urine remains dilute and water is lost.
• ADH present ------> soluble to water ------> water is reabsorbed and urine becomes hypertonic.
• AQUAPORIN II and III: The names of the water channels, opened by ADH, in the principle cells.
• Histologically it appears light and is difficult to see in H&E
• INTERCALATED CELL:
• FNXN: They secrete H⁺, acid.
• Histologically it appears dark and visible.
• INNER MEDULLARY COLLECTING DUCT (IMCD): In juxtamedullary nephrons, they run parallel to the vasa recta.
• One cell types predominates in IMCD, and it is sensitive to ADH: Reabsorption of water continues in medulla, due to very strong concentration gradient with the ECF.
• MEDULLARY RAYS are formed histologically by the collecting ducts. The length of the collecting duct depends on the location of the nephron (juxtamedullary or cortical):
• Juxtamedullary Nephrons have long medullary rays, extending almost all the way down to the pelvis.
• Cortical Nephrons have short medullary rays.
• PAPILLARY DUCTS OF BELLINI: From individual kidney lobes, they lead into the Renal Pelvis.
• RENAL PELVIS: Empties into the ureter.

DIURETICS: They prevent water-reabsorption in the kidney, by multiple mechanisms, and are used to treat hypertension and edema.

• Carbonic-Anhydrase Inhibitor: Acetazolamide acts on the Proximal Tubule.
• Loop Diuretic: Furosemide acts on the Thick Ascending Limb of Loop of Henle.
• Thiazide acts on the Collecting Ducts, Na/H⁺ Antiport blocker.

TUBULAR NECROSIS:

• NON-OLIGURIC RENAL FAILURE: Renal failure involving a failure of reabsorption, and thus resulting in gallons of dilute, weak urine (and severe water-loss)
• Oliguria means little urine or deficiency of urine.
• Cisplatin destroys the microvilli on the proximal tubules. This leads to less Na⁺ reabsorption and thus less water reabsorption ------> polyuria.
• RENAL FAILURE:
• Creatinine and BUN are normally filtered by the kidneys. If blood levels of these go up, that indicates low filtration and thus kidney failure (Oliguric Kidney Failure (?))
• Gamma-Glutamyl Transferase is a brush border enzyme on the PCT.
• In Renal Failure: Blood Creatinine and BUN go up, while the gamma-Glutamyltransferase of the brush borders goes down.
• Killed tubules can heal and restore themselves eventually, within limits.
• Heart-Lung Bypass Machine can lead to secondary renal failure, as these machines don't supply as much as oxygen as the lungs themselves, and kidney demands for O₂ are high.

INTERSTITIAL FIBROSIS: This commonly occurs with progressive renal failure. When the kidneys don't work, the interstitium tends to become fibrotic.

URETER:

• It has a star-shaped lumen
• Transitional Epithelium
• Protein Plates on the apical surfaces of the epithelia, in order to protect the epithelia from the toxic urine.
• Two smooth muscle layers:
• Inner Longitudinal Layer
• Outer Circular Layer

POLYCYSTIC KIDNEY DISEASE (PKD):

• Simple Cysts:
• CYST: A fluid-filled sac with an epithelial monolayer lining. There are three requirements to make any cyst.
• Cell Proliferation is required for a cyst to form.
• ECM remodeling (proteases) must occur for the cyst to form.
• Fluid is inside: this distinguishes a cyst from a tumor. A cyst is fluid-filled and a tumor is solid.
• Simple cysts are the most common cystic abnormalities in humans, and they are harmless.
• AUTOSOMAL DOMINANT PKD (ADPKD): A very common form of PKD that does not manifest until mid-adulthood.
• Complications / Other systems are affected besides the kidneys:
• Liver Cysts are very common, about 50% of cases.
• Aneurysms: 10%
• Mitral Valve Prolapse: 25%
• Colonic Diverticula
• END-STAGE RENAL DISEASE: Renal failure only occurs in about 50% of cases. The kidneys can withstand an incredible number of cysts before function is compromised.
• TREATMENT: These patients are often otherwise healthy and are ideal candidates for dialysis and/or transplantation.
• GENETICS: Penetrance of the disease is 100%. If you have the gene, you're sick.
• Every time a PKD patient has a child, the child has a 50% of getting PKD. This should not stop them from having children since the disease won't affect them until their 50's.
• Chromosome 16 seems to have at least two loci that are involved with PKD. The expression of the gene is confined strictly to the kidney.
• DIAGNOSIS: CT-Scan is the best way to diagnose. Look for enlarged kidneys, cysts, or gross asymmetry between the two kidneys.
• SYMPTOMS:
• Nocturia is a common early symptom, from Non-Oliguric failure.
• Pain, due to bleeding infection, or rapid cyst growth.
• TREATMENT:
• Infection: It's tough to get antibiotic into the cyst. Lipophilic antibiotics are required, such as fluoroquinolones (trade name ciprofloxacin): These are new drugs that are a godsend for PKD. They get into the cysts well and are well absorbed orally.
• AUTOSOMAL RECESSIVE PKD (ARPKD):
• Etiology: As compared to ADPKD, the cysts arise primarily in the collecting ducts and are clustered into disparate groups.
• Three levels of the disease:
• FULL-BLOWN: Individual will die perinatally from respiratory failure, from pulmonary hypoplasia.
• INTERMEDIATE: Individual will die within 2 years if they don't get dialysis and a transplant.
• MILD: Will live to early adult years, where they will develop LIVER FAILURE, periportal fibrosis. They often die of portal hypertension in twenties.
• DIAGNOSIS: Sonography would be used because you are working with an infant, and infant's can't stay still for CT's and shouldn't be exposed to the radiation.
• COMPLICATIONS: Similar to before, except that pulmonary involvement is very significant.
• GENETICS: Standard recessive inheritance. If parents have had one baby with ARPKD, that would mean that they are both heterozygotes, and the likelihood of their having another ARPKD child is thus 25%.
• Incidence of disease = 1/6000 - 1/14000 live births.
• Note that for recessive diseases, the carrier-state for the disease is far more common than the incidence of the disease. This is not an uncommon disease.
• ACQUIRED PKD:
• AT RISK: People who already have chronic renal failure are at risk for developing acquired PKD.
• COMPLICATIONS:
• RENAL TUMORS are the most common complication. Renal tumors do not occur in the forms of PKD.
• Increased Hematocrit is often found, from excessive secretion of erythropoietin.

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EMBRYOLOGY OF ENDOCRINE SYSTEM:

• ENDODERMAL: Glands that secrete peptide-derived hormones
• Thyroid
• Parathyroid
• Endocrine Pancreas
• MESODERM: Glands that secrete steroid hormones.
• Gonads
• Adrenal Cortex
• ECTODERMAL: Glands that secrete peptide and amino-acid derived hormones.
• Adrenal Medulla
• Anterior Pituitary
• Posterior Pituitary (Neuroectodermal)

HISTOLOGY OF SECRETORY TISSUES: Organelles tell you about the type and amount of secretory activity.

• The presence of Golgi Complex is the greatest indicator of whether a cell is currently active.
• Secretory Granules: Secretory granules are not a good indicator because secretory granules are stored.
• Lots of secretory granules tends to mean an inactive state, because the granules are being stored rather than exocytosed.
• Nucleolus: Prominent nucleolus indicates activity, as lots of ribosomes are being made from protein synthesis.
• Rough ER indicates synthetic activity of protein-derived hormones or secretory products.
• Smooth ER and Mitochondria indicate synthetic activity of steroid hormones or secretory products.
• Steroids are not stored in vesicles because they are lipid-soluble.
• Mitochondria that are specialized for steroid-synthesis have lots of tubular structures with in, and a much larger membrane surface area.

ADENOHYPOPHYSIS: Anterior Pituitary

• HYPOTHALAMIC RELEASING HORMONES: PARVOCELLULAR NEURONS of the hypothalamus secrete releasing hormones into the Superior Hypophyseal Arteries, where it travels to the Median Eminence, and thence to the Pars Distalis to elicit a response.
• PRECURSORS: The hypothalamic hormones are made from larger precursors.
• The precursors need to be 60-70 amino acids long before they can latch onto signal recognition particles and get put into the ER for eventual secretion.
• Disulfide Bonds require oxidation, and that only occurs in the lumen (either intracellular or extracellular) of the structure. The cytoplasm is too reducing an environment
• Releasing Hormones.
• Gonadotropin Releasing-Hormone: GnRH ------> FSH + LH
• Corticotropin Releasing Hormone: CRH ------> ACTH
• Thyrotropin Releasing Hormone: TRH ------> TSH
• Smallest peptide, only 3 a.a. long.
• Growth Hormone Releasing Hormone: GHRH ------> Growth Hormone
• Dopamine: the exception, tonically inhibits Prolactin release.
• Parvocellular Neurons are shorter than magnocellular neurons. They don't reach all the way down to the hypophysis, but stop short at the superior hypophyseal artery.
• PARS TUBULARIS: The Infundibulum, stalk of the anterior pituitary.
• Function is unsure
• PARS INTERMEDIA: The Median Eminence. It has only rudimentary functions in humans.
• Superior Hypophyseal Arteries form a capillary plexus in the median eminence.
• This plexus then perfuses the adenohypophysis, where it picks up all the pituitary hormones. All blood the adenohypophysis receives came directly from the hypothalamus.
• Portal Veins then leave the adenohypophysis ------> general circulation.
• BLOOD-BRAIN BARRIER: Compared to the hypothalamus, the median eminence has less of a blood-brain barrier than the hypothalamus.
• ARCUATE NUCLEUS of Hypothalamus has very THICK BASEMENT MEMBRANE facing the capillary endothelia. This prevents secretions into the blood there.
• MEDIAN EMINENCE has a thin basement membranes, and the hypothalamic neurons are right up against it, where it secretes releasing hormones into the capillary plexus.
• MELANOCYTE-STIMULATING HORMONE (MSH) is made in Median Eminence. This is more important in other animals, since in humans MSH is made in the Anterior Pituitary, too.
• PARS DISTALIS: The bulk of the anterior pituitary, containing synthetic cells.
• CHROMOPHILS: Active forms of the secretory pituitary cells. These cell types are indistinguishable histologically but can be distinguished by immunocytochemistry.
• SOMATOTROPHS: Growth Hormone -- ACIDOPHILIC
• 50% of the cells are somatotrophs.
• MAMMOTROPHS: Prolactin -- ACIDOPHILIC
• CORTICOTROPHS: ACTH -- BASOPHILIC (glycoprotein product)
• THYROTROPHS: TSH -- BASOPHILIC Cell (glycoprotein product)
• Smallest concentration of cells -- less than 10%
• GONADOTROPHS: FSH, LH -- BASOPHILIC (glycoprotein product)
• LH and FSH come from the same cell and can even be in the same secretory granules. They are secreted at the same time.
• CHROMOPHOBES: Pale-staining, inactive forms of the secretory pituitary cells.
• EMBRYOLOGY: RATHKE'S POUCH. All of the adenohypophysis is derived from Oral Ectoderm.

NEUROHYPOPHYSIS

• EMBRYOLOGY: NEUROENDOCRINE. The neurohypophysis is an extension of the hypothalamus and thus part of the brain.
• SECRETION: MAGNOCELLULAR NEURONS of the Hypothalamus send their axons down into Neurohypophysis.
• The magnocellular products (ADH + Oxytocin) are released, under neural control, into the inferior hypophyseal vein and on into the general circulation.
• This vein is fenestrated to allow passage of the neurosecretory products
• Magnocellular neurons have longer axons than the Parvocellular neurons, thus they reach all the way down to the neurohypophysis.
• BLOOD SUPPLY: The neurohypophysis receives its arterial blood from the inferior hypophyseal arteries, which did not come from the hypothalamus.
• HERRING BODIES are the names of dilated endings of the hypothalamic axons that contain ADH and Oxytocin.
• PITUICYTES are the names of the posterior pituitary glial cells that assist in debris-endocytosis, etc. These cells do not secrete any hormone.
• NEUROHYPOPHYSEAL HORMONES: These hormones are synthesized in and originate from the hypothalamus.
• OXYTOCIN: Produced in the PARAVENTRICULAR NUCLEUS of Hypothalamus, which surrounds third ventricle, and carried in Magnocellular neurons to the posterior pituitary.
• VASOPRESSIN (ADH): Produced in SUPRAOPTIC NUCLEUS of Hypothalamus and carried in Magnocellular neurons to the posterior pituitary.
• Diabetes Insipidus will result from damage to Supraoptic Nucleus.

PITUITARY ADENOMA: Pituitary tumor can lead to Giantism in early childhood, or Acromegaly in adolescence / adulthood.

• Tumor will lead to hypersecretion. The most common cells that hypersecrete:
• Growth Hormone: Leads to Giantism (childhood) or Acromegaly (adulthood)
• Prolactin: Hyperprolactinemia leads to infertility.
• ACTH: Secondary Cushing's Syndrome type symptoms.
• Tunnel Vision and blindness can result with large tumors because of proximity of optic chiasm.

ADRENAL GLANDS:

• EMBRYOLOGY: The fetal adrenals are almost as big as the fetal kidneys. They secrete incomplete steroids which then go onto the maternal placenta where their synthesis is completed.
• BLOOD SUPPLY: Superior, Middle, and Inferior Suprarenal Arteries supply the adrenals from various branches of Aorta (Renal Artery, etc.)
• The arterial blood trickles through the cortex before reaching the medulla, so that it is already full of cortical hormones (cortisol) before it even gets to the medulla.
• Some arteries in addition go directly to the medulla, so the medulla gets some freshly oxygenated blood.
• ZONES: The zones are determined by relative oxygen-tension in at each level of cortex. If you take Reticularis cells and put them in rich enough arterial blood, then they will behave like glomerulosa cells and secrete Aldosterone.
• ADRENAL CORTEX:
• STEROID SYNTHESIS: Whether you get Aldosterone or Cortisol depends on the final enzyme in the pathway, which is specific to either Glomerulosa (ACTH) or Fasciculata (Cortisol) cells.
• LDL is endocytosed into the glomerulosa cells.
• Cholesterol Ester Hydrolase first hydrolyzes the cholesterol.
• Cholesterol Ester Hydrolase is stimulated by ACTH ------> cAMP ------> Protein Kinase A
• The rest of synthesis requires shuffling back and forth between SER and mitochondria.
• Inner Mitochondrial Membrane: Cholesterol ------> Pregnenolone
• Smooth ER: Pregnenolone ------> 17-Hydroxypregnenolone
• Inner Mitochondrial Membrane: 17-Hydroxypregnenolone ------> 11-Deoxycortisol
• Smooth ER: 11-Deoxycortisol ------> Cortisol
• STEROID SECRETION / ACTIVITY LEVEL:
• Highly activated adrenal cell is indicated by:
• Large mitochondria
• Fewer Lipid droplets (they've been exocytosed)
• Enlarged Golgi
• If continual stimulation continues, the cells will hypertrophy.
• Pulsatile stimulation of the cells may occur in order to prevent hypertrophy.
• REGULATION: Steroid secretion is constitutive -- it is not stored in vesicles. Thus secretion is regulated at the synthetic level -- not the secretory level.
• ZONA GLOMERULOSA: Semi-acinar, smaller cells around outside.
• SECRETE: It secretes ALDOSTERONE. Aldosterone synthesis is not under the regulation of ACTH. It will be synthesized and secreted independent of ACTH.
• ZONA FASCICULATA: Arranged in cords, covering the majority of the cortex.
• Lipid Droplets of steroid product are common in these cells, giving the cells a "frothy" appearance.
• SECRETE: They secrete Cortisol
• An ACTH-Secreting Pituitary tumor will cause enormous hypertrophy of this layer.
• ZONA RETICULARIS: Nearest the medulla.
• SECRETE: They secrete Cortisol and weak androgens.
• ADRENAL MEDULLA:
• CHROMAFFIN CELLS: Adrenal Medullary cells. They are post-ganglionic neuroendocrine cells, innervated by pre-ganglionic sympathetics.
• PRE-GANGLIONIC sympathetics release Acetylcholine as a neurotransmitter onto these cells.
• SECRETION: These cells secrete 80% Epinephrine, 20% NorE, in secretory granules, into the bloodstream
• Cortisol stimulates the conversion of Norepinephrine ------> Epinephrine. The adrenal medulla receives cortisol directly from the cortex, via local arterioles.
• Thus, Epinephrine-secreting cells will be exposed to this cortical blood, while Norepinephrine-secreting cells are exposed to straight medullary arterial blood.
• Adrenal Pathologies:
• ADDISON'S DISEASE: Primary Adrenal Insufficiency
• Etiology: 80% of these cases are autoimmune. Most of the rest is by Tuberculosis.
• Both Cortisol and Aldosterone will be affected.
• Secondary Deficiency: Giving a patient too much glucocorticoid therapy can result in secondary deficiency (suppressed ACTH) when the therapy is stopped. Thus you have to wean them off the drugs.
• This problem does not affect Aldosterone, as Aldosterone is not stimulated by ACTH.
• CUSHING'S SYNDROME: Too much cortisol, either inherently, or by drugs, or by a pituitary tumor secreting excessive ACTH.
• PHEOCHROMOCYTOMA: Adrenal medulla hyperfunction, from a benign tumor, which can lead to hypertension and hyperglycemia.

THE THYROID:

• FOLLICLES: Contain Colloid material which contains Thyroglobulin
• THYROID FOLLICULAR CELLS: They line the follicles and secrete Thyroglobulin, a glycoprotein, into the follicles.
• THYROID SYNTHESIS and SECRETION:
• Thyroglobulin is synthesized in the Thyroid follicular cells and secreted into the lumen of the follicles.
• IODINATION:
• Iodide is taken into the thyroid follicular cells from the general circulation, and it is transcytosed to the apical membrane.
• This transport occurs by active Na⁺-Cotransport
• On the outside of the membrane, in the lumen, PEROXIDASE catalyzes the oxidation of iodide and its attachment to Thyroglobulin.
• Iodide is essentially for two or three tyrosines to fuse together, to form thyroid hormones.
• Iodide also cross-links several thyroglobulins together, and helps them form a 3D shape (similar to disulfide bonds).
• GOITER: Iodine-Deficiency leads to constant stimulation of the Thyroid by TSH, because of no Thyroxine feedback at the pituitary.
• Colloid is almost completely gone, as it is constantly being mobilized.
• No Thyroxine is being made because there is no iodide.
• Follicular cells hypertrophy creating the characteristic goiter thyroid gland.
• REABSORPTION / MOBILIZATION: TSH promotes the endocytosis and breakdown of the colloid. That is its primary mode of stimulating thyroid secretion.
• TSH works by a G-Protein / cAMP second messenger system.
• TSH promotes the reorganization of the cytoskeleton and the reaching out of the membrane, to begin endocytosis of the Thyroglobulin.
• Thyroglobulin is then endocytosed into the follicular cell, and those endosomes merge with internal lysosomes to form Phagolysosomes.
• Phagolysosomes then degrade the big thyroglobulin molecules into individual amino acids, and T₃ and T_4.
• The globulin components are resecreted back into the colloid lumen.
• T₃ and T₄ are lipophilic and thus are through to go out into the blood by simple diffusion.
• SECRETION:
• THYROXINE (T₄): The most common form of Thyroid released. It is less potent than T₃.
• TRIIODOTHYRONINE (T₃): T₄ is converted to T₃ in the bloodstream. T₃ is far more potent.
• Thyroid-Hormone Binding Globulin (THBG): Carries Thyroid hormone in the blood.
• At any given time, it has bound over 99.9% of T₃ and T₄ in the blood, leaving minute quantities (picograms, 10^-12) in their active forms.
• C-CELLS: CALCITONIN is synthesized directly into the blood, via the parafollicular cells between the follicles.
• Calcitonin secretion is stimulated by high blood Ca⁺² levels, and it stimulates the deposition of Ca⁺² into bone.
• Calcitonin could be used as a treatment for Osteoporosis, but it is expensive.
• Thyroid Pathologies:
• Hyperthyroidism (Grave's Disease): It is actually an auto-immune problem, but instead of destroying the TSH receptors, they activate them, leading to hypersecretion of thyroid hormone.
• Hypothyroidism

ENDOCRINE PANCREAS:

• Islets of Langerhorn: Endocrine part of pancreas has four different cells types
• BLOOD FLOW: The islets get relatively more blood than the exocrine pancreas.
• alpha-Cells: Glucagon: Eosinophilic, and generally lining the edge of the islets.
• beta-Cells: Insulin -- they make about 80% of the islets.
• GLUCOSE AFFINITY: beta-Cells have a very low affinity for Glucose. This allows them to increasingly respond to glucose concentrations at very high levels.
• Michaelis-Menton Constant of the GLUT2 Transporter 17.
• The Liver uses the same transporter and also has a very low glucose affinity.
• delta-Cells: Somatostatin: Somatostatin probably acts on the exocrine pancreas directly, in local pancreatic circulation.
• PP-Cells: Pancreatic Polypeptide
• FNXN has to do with digestion and secretion of bile.
• Gross Anatomy of Pancreas:
• DORSAL PANCREAS: Has high concentration of PP-Cells relative to the other endocrine cell types.
• ANTERIOR PANCREAS: Has high concentration of beta-Cells relative to the other cell-types.
• INSULIN:
• SYNTHESIS:
• Preproinsulin is the propeptide.
• Signal peptide is cleaved as the peptide passes through the ER, getting read for secretion.
• Proinsulin then goes through Golgi and into secretory vesicle.
• STRUCTURE:
• A-Chain: Amino terminus, connected to B-Chain by two disulfide bonds.
• B-Chain: Carboxy-Terminus, connected to A-Chain be two disulfide bonds.
• C-Chain: It is cleaved from Proinsulin to form active insulin.
• SECRETION: Biphasic release of insulin following a meal.
• The first phase is due to release of insulin-granules that are right up against the membrane, ready to go.
• The second phase occurs about ten minutes later -- it is not due to increased synthesis, but rather to mobilization of granules that are further within the cell.
• STIMULATION: It is not increased glucose per se, but an increased rate of glucose metabolism that causes the release of insulin.
• GLUCAGON:
• It is in high concentration in the blood between 0 - 5 mm glucose concentration -- at very low glucose levels.
• EXPT: Use insulin antibody and measure glucagon secretion in the pancreas.
• Anterograde Perfusion: Insulin antibody blocks insulin release ------> Glucagon levels went way up!
• Retrograde Perfusion: The antibody doesn't block the insulin release because of where the beta-cells are located relative to alpha-cells ------> Glucagon levels did not go up.
• CONC: Glucagon is inhibited by both glucose and by insulin in neighboring cells.
• BLOOD PERFUSION: In the islets, blood vessels perfuse the beta-cells before they perfuse alpha-cells.
• SOMATOSTATIN: Affects secretion in the exocrine pancreas

PARATHYROID GLANDS:

• CHIEF CELLS: They secrete PTH.
• They can be mistaken for lymphocytes.
• But, overall they are more eosinophilic.
• They have more cytoplasm than lymphocytes.
• They are arranged in semi-acinar structures while lymphocytes aren't.
• APICOLATERAL POLE: The surface of the chief cell that faces the bloodstream is called the Apicolateral pole.
• Chief Cells both take material from and secrete into the blood stream. Thus they have a functional "apicolateral surface" rather than basolateral surface, as enterocytes have.
• OXYPHIL CELLS: They are larger and extremely eosinophilic.
• Function is poorly understood.
• They are few in childhood but increase in number through adulthood.
• PARATHYROID HORMONE:
• SYNTHESIS: It is synthesized as a pre-pro-hormone, preproparathyroid hormone.
• Proparathyroid: Signal sequence is removed in the ER.
• Parathyroid: The pro-sequence is removed in the Golgi before active PTH is packaged into vesicles.
• STRUCTURE: 84 amino acids of pure protein (no sugar). That's why its eosinophilic.
• REGULATION: PTH releases Ca⁺² from bone and puts it into blood, raising the blood Ca⁺² level.
• CALCIUM: Standard homeostatic [Ca⁺²] concentration = 9.5 mg / dL. When the concentration gets below 9.5 mg / dL, chief cells are stimulated to release PTH.
• There are Ca⁺² receptors on the chief cells. It acts on a G-Protein, connected to cAMP and/or IP₃ pathway, both of which will lead to higher intracellular calcium.
• It is actually intracellular calcium that controls the rate of PTH secretion. But this, in turn, is controlled by extracellular calcium levels.
• MODE OF CONTROL: More PTH is always synthesized than is actually secreted. Some is wasted or recycled.
• Low cytoplasmic Ca⁺² ------> PTH vesicles go to the surface and get exocytosed.
• High cytoplasmic Ca⁺² ------> PTH vesicles go to lysosomes and get wasted.
• BASAL ACTIVITY: There is always some basal level of PTH secretion, even when Ca⁺² levels are sky high.
• Complete removal of PTH ------> tetany and cardiac arrest, presumably from hypocalcemia. This problem can be treated with Vitamin D supplements or other treatments.
• EPINEPHRINE causes release of PTH. Via beta2-receptors, Epinephrine will cause a spike of PTH release, as opposed to a smooth increase.
• Epi also acts by a G-Protein / cAMP mechanism (as it almost always does!).
• Probably reason for this is that PTH spike can cause release of lots of calcium, so it can go to your muscles and heart where it is needed for increased muscle activity.
• This helps to explain the incredible feats of strength that people can do under the influence of adrenaline.
• HYPERTROPHY: Hypocalcemia ------> parathyroid hypertrophy.

DIABETES:

• Type I / Type II: 50/50 Rule: At 50 years of age, about 50% of patients will have type I diabetes and 50% will have type II.
• Type I is more prevalent before that. Type II is vastly more prevalent in older age.
• ISLET TRANSPLANTATION WITHOUT IMMUNOSUPPRESSION: The current problem with transplantation really is immunosuppression.
• Dendritic Cells are present in the Islets, and are HLA-II+, which causes them to be rejected by the body's immunity. They are the primary barrier to successful Islets transplantation.
• EXPT: Purified islets in vitro (no dendritic cells) were successfully transplanted in rats, without immunosuppression.
• In humans, Type-I Diabetes means that HLA-II Antigens are present on the beta-Cells. Because of this, contamination by the fewest number of dendritic cells will initiate an immune response.
• THYMIC TRANSPLANTATION: Experimental stage; take islets and put them in the Thymus to give them immune-education, then transplant them later.
• ENCAPSULATED ISLETS: New idea for progress: encase the islets in an alginate (polymer) capsule, to protect them from auto-immunity. The encapsulated islets still retain their own feedback mechanism.

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OVARIES:

• FOLLICLES:
• PRIMORDIAL FOLLICLE: Single layer of flattened epithelial cells.
• PRIMARY FOLLICLE: Multiple layers of cuboidal epithelia.
• SECONDARY (ANTRAL) FOLLICLE: Presence of an antrum.
• GRAAFIAN FOLLICLE: Presence of a large antrum and corona radiata.
• CORONA RADIATA:
• ZONA PELLUCIDA: The thin glycoprotein coat immediately surrounding the ovum. The sperm attaches to the zona pellucida to initiate fertilization.
• FOLLICULAR DEVELOPMENT:
• BIRTH: All follicles are in the primordial phase, arrested in Prophase I of meiosis.
• Meiosis of a follicle resumes when ovulation occurs.
• Several follicle undergo development at the same time. One of them dominates during each cycle and will be ovulated.
• ATRESIA: Atretic Follicle are degenerated follicles. A follicle can become atretic at any stage of development.
• FOLLICULAR CELLS:
• GRANULOSA CELLS: They immediately line the follicle.
• They contain Aromatase, which converts Androgens from the Theca cells into Estrogen.
• They secrete estrogen under the influence of FSH.
• THECAL CELLS: Outer layer of fibroblastic cells surrounding secondary and tertiary follicles. A basement membrane separates them from Granulosa cells.
• THECA INTERNA: These cells secrete androgens under the influence of LH.
• THECA EXTERNA: Mainly just structural.
• CORPUS LUTEUM: The body of tissue left over after ovulation.
• The Antral Cavity fills with blood after follicle ruptures.
• GRANULOSA LUTEAL CELLS: Transformed granulosa cells that secrete Progesterone and Estrogen
• THECA LUTEAL CELLS: Transformed thecal cells that secrete Estrogen under the influence of LH.
• CORPUS ALBICANS: The regressed corpus luteum, which will form at the end of the cycle if implantation does not occur.
• PREGNANCY: hCG keeps the Corpus Luteum active for about the first half of pregnancy, if implantation does occur. It will then continue to secrete Progesterone in huge amounts.
• OVARIAN CYCLE: About twenty follicles develop during each cycle, while one becomes dominant. The other 19 are thought to provide enough hormone for the cycle.
• FOLLICULAR PHASE (1-14): Development of the follicle under the influence of estrogen.
• OVULATION (14): Rupture of follicle.
• LUTEAL PHASE (15-28): Corpus Luteum and Corpus Albicans.
• Progesterone from the corpus luteum will feedback and strongly inhibit LH, which will ultimately lead to degradation of the Corpus Luteum.

OVIDUCT:

• Gross Anatomy:
• Infundibulum: Part nearest the ovaries, actually opened to the Peritoneal Cavity.
• Ampulla: Widened main part. Fertilization usually occurs here.
• Isthmus: Nearest the uterus.
• Layers:
• Outer Muscular Layer
• Inner Ciliated Epithelial Layer: Cilia beat toward the uterus in order to propel the egg forward.
• These cilia are lost during menopause.

UTERUS:

• Layers
• PERIMETRIUM:
• MYOMETRIUM: The straight and spiral arteries originate in this layer.
• ENDOMETRIUM:
• BASALIS: Basal stem cells.
• STRAIGHT ARTERIES (BRANCHES) supply the basalis region. These originate from myometrial layer.
• FUNCTIONALIS: Proliferates and is sloughed during menstruation.
• SPIRAL ARTERIES supply the functionalis. They are responsive to Progesterone and proliferate during the secretory phase.
• UTERINE CYCLE:
• MENSTRUAL PHASE (1-4):
• PROLIFERATIVE PHASE (5-14):
• Estrogen stimulates proliferation and thickening of Functionalis region.
• HISTOLOGY: Straight glands, mitotic figures.
• EARLY PROLIFERATIVE PHASE: Straight glands.
• LATE PROLIFERATIVE PHASE: Glands get a little wigglier.
• SECRETORY PHASE (15-28): It begins with Ovulation.
• HISTOLOGY: Convoluted glands, proliferation of spiral arteries.
• EARLY SECRETORY PHASE:
• LATE SECRETORY PHASE:
• PATHOLOGIES:
• UTERINE CANCER: Uterine and Cervical cancers are the most common cancers in women of reproductive age.
• Tamoxifen is successful in treating them. It is an estrogen-antagonist.
• ENDOMETRIOSIS: The endometrium continues to proliferate instead of being calmed back down during secretory phase.
• Complication = endometrium can proliferate in a retrograde fashion and attach to peritoneum. Not good.
• FIBROIDS: Common. Benign tumors in myometrial layer. No known treatment except hysterectomy.

CERVIX + VAGINA:

• EPITHELIUM:
• CERVIX: Similar to uterus. Tall secretory epithelium.
• VAGINA: Stratified Squamous.
• CERVICAL CANCER: Usually occurs at the transitional region, change in epithelium.
• Cervical junction is tested in a Pap-Smear.
• VAGINA:
• Secretes glycogen ------> lactic acid by bacterial metabolism. This serves a protective function in the vagina, to prevent proliferation of other pathogenic bacteria.
• Very heavily vascularized.
• MUSCULAR LAYER: The vagina will contract following intercourse to keep the sperm in.

FERTILIZATION / IMPLANTATION:

• FERTILIZATION:
• It usually occurs in ampulla of oviduct.
• Sperm reacts with zona pellucida of follicle, initiating the acrosomal reaction in which the sperm inserts its nuclei into the ovum.
• The continual sweeping of cilia in the oviduct are the only real things to prevent an ectopic pregnancy.
• IMPLANTATION: It occurs at the blastocyst stage of the fertilized egg.
• At this stage there is a recognizable trophectoderm and inner cell mass.
• The blastocyst burrows itself completely within the endometrium.
• hCG secretion will start as soon as implantation has occurred.

PLACENTA:

• FORMATION:
• Trophoblast cells invade the decidua cells of the endometrium.
• Spiral arteries then invade and form lacunae
• STRUCTURE: VILLI inside of Maternal Lacunae
• MATERNAL CELL LAYER: The Decidua makes up the maternal part of the placenta.
• FETAL CELL LAYERS:
• INNER CELL MASS will form the embryo
• TROPHECTODERM forms the placental barrier and consists of two layers
• Syncytiotrophoblast Cells: Multinucleated trophoblast cells around the outside of the extra-embryonic mesenchyme, facing the maternal blood space.
• NO BASEMENT MEMBRANE is in between the two trophoblast layers.
• Cytotrophoblast Cells: Inner single cell layer, facing the extra-embryonic mesenchyme.
• They are the progenitor cells for the syncytiotrophoblast cells.
• Migrating Trophoblast: These are found in placenta. They replace normal maternal endothelial cells, so the endothelia are no longer subject to the normal physiological process of vasoconstriction.
• Primary Villus: A villus that is solid and has not been invaded by maternal blood.
• Secondary Villus: A villus that has invaginations of maternal blood in it.
• EARLY GESTATION:
• Placental villi are relatively thick.
• Both cytotrophoblast and syncytiotrophoblast layers are present.
• LATE GESTATION:
• Villi become thinner and more finely branches
• This allows for larger surface area for diffusion, necessary for the larger embryo.
• Cytotrophoblast cells are gone, and syncytiotrophoblast layer is thinner.
• FIBRIN BAND forms between the placenta and mother. This band aids in parturition.
• IMMUNITY: The placenta transfers maternal antibodies to the fetus.
• Trophoblast cells protect the fetus against maternal immune responses:
• HLA Antigen expression in the placenta is regulated. Syncytiotrophoblast do not express the HLA antigen at all.
• Migrating trophoblasts express one type of HLA that is specific to them: HLA-G.
• Complement-Inactivating Proteins are expressed by trophoblasts in extremely high levels.
• Uterus secretes Prostaglandins and inhibitory cytokines during pregnancy.

HORMONE ACTIONS: Estrogen and progesterone act on uterine cells indirectly, by modulating the expression growth factors (CSF, TGF-beta, interleukins, IGF)

• ESTROGEN:
• UTERUS:
• Stimulates proliferation of the endometrium during PROLIFERATIVE PHASE.
• EXCITES myometrial contractility.
• CERVIX: Increases production of clear, penetrable mucous in order to facilitate passage of sperm through cervix.
• VAGINA: Stimulates proliferation and cornification.
• MAMMARY: Stimulates growth of ducts and deposition of fat.
• PROGESTERONE:
• UTERUS:
• Stimulates gland and vessel development during SECRETORY PHASE, but inhibits actual proliferation.
• INHIBITS myometrial contractility.
• It does this by inhibiting gap junction and oxytocin receptors.
• CERVIX: Promote production of thick, viscous mucous in order to protect the uterus during pregnancy.
• VAGINA: Reduces growth of vaginal epithelium.
• MAMMARY:
• Simulates ductal proliferation in alveoli. During pregnancy, when progesterone is high, the alveoli are developing, in preparation for lactation.
• Inhibits milk synthesis. During pregnancy, milk synthesis is inhibited. After birth, progester one levels drop sharply, and (prolactin-mediated) milk synthesis ensues.

MAMMARY GLANDS: Secretion occurs by two different mechanisms, both apocrine (lipophilic stuff) and exocytosis (casein).

TESTIS: They are retroperitoneal organs.

• DEVELOPMENT:
• Gubernaculum descend through Processus Vaginalis, which is part of peritoneum, creating a retroperitoneal organ.
• Tunica Albuginea: White hard covering. Visceral and parietal layers, with serous fluid in between.
• Tunica Vasculosa: Thickening of the tunica albuginea posteriorly to form the mediastinum.
• SEMINIFEROUS TUBULES:
• SPERMATOGENIC CELLS: Male germ cells, in the lumen of the seminiferous tubules.
• SERTOLI CELLS: They are huge, and may be in contact with 50 or 60 spermatogenic cells, as well as a few other Sertoli cells.
• STRUCTURE: Very big cells with tripartite nucleolus.
• They are in constant contact with lots of spermatogenic cells, and they send cytoplasmic processes to surround those cells.
• TIGHT JUNCTIONS allow the seminiferous tubules to be immunologically privileged.
• They have extensive cytoskeleton, so they can move spermatocytes along the tubules.
• They produce seminiferous fluid, which is later reabsorbed by the epididymis.
• This fluid is low in Na⁺ and Cl^-, and high in K⁺.
• The fluid has a lower protein content than plasma.
• They secrete lots of proteins into the seminiferous fluid:
• Androgen-Binding Protein (ABP): Binds testosterone and DHT. It is thought to deliver androgens to the head of the epididymis.
• It is essential for maintaining the differentiation of the Epididymis.
• Transferrin: Carries iron to spermatogenic cells.
• Plasminogen Activator: Breaks down the junctional connections that occur between Sertoli cells, to allow preleptotene sperm to pass through.
• Inhibin: Negative feedback to anterior pituitary to inhibit FSH.
• Mullerian Inhibiting Substance (MIS): Promotes regression of Mullerian (female) duct during embryonic development.
• Lactate: Nutrient essential for spermatogenic cells and sperm.
• P-MOD-S: It is essential for Sertoli cell differentiation.
• They are essential to the growth and survival of sperm.
• RESIDUAL BODIES are phagocytosed by Sertoli cells. This is residual cytoplasm of the spermatogenic cells.
• This process can fail, resulting in infertility and having the residual bodies remain in the final semen.
• BLOOD-TESTIS BARRIER: Formed by Sertoli cell tight junctions, they divide the tubules into two compartments.
• FNXN: The blood-testis barrier prevents auto-immune responses with the antigenically foreign haploid sperm.
• BASAL COMPARTMENT: Contain spermatogonia and pre-leptotene spermatocytes .
• ADLUMINAL COMPARTMENT: Contains sperm in later stages of development.
• INTERSTITIUM:
• PERITUBULAR MYELOID CELLS: Responsible for peristaltic contraction of tubules, to help move the immotile sperm.
• They have Oxytocin Receptors and contract in response to Oxytocin. This stimulus will peristaltically propel sperm forward.
• LEYDIG (INTERSTITIAL) CELLS: Respond to LH to secrete testosterone.
• Crystal of Reinke: Histological feature; unknown function.
• TESTICULAR VASCULATURE:
• PAMPINIFORM PLEXUS is at the head of the epididymis and surrounds the testicular arteries.
• It forms a counter-current heat exchanger with the Testicular Artery.
• Testicular capillaries are not fenestrated. There is a blood-testis barrier. Testosterone can still get through because it is lipophilic.
• SPERMATOGENESIS: Spermatogonia ------> 1 (Pre-Leptotene) Spermatocytes ------> 2 Spermatocytes ------> Spermmatids ------> Mature Sperm
• GENERAL STUFF:
• SPIRAL: Differentiation is thought to occur in a spiral in the seminiferous tubules.
• BASEMENT MEMBRANE: It is absolutely essential to the process.
• CYTOPLASMIC BRIDGES: For most of spermatogenesis, sperm form cytoplasmic bridges that connect cells together.
• This allows communication between sperm and transport of nutritive materials and gene products to all sperm.
• Even thought the sperm are all genetically different, they get common gene products through the cytoplasmic bridges.
• SPERMATOGONIA: Diploid. The stem cells. They rest on the basal lamina, in the basal compartment.
• TYPE-A
• TYPE-A DARK: Stem cells. They give rise to A-Pale. (Mitosis)
• TYPE-A PALE: They give rise to Type-B cells. (Mitosis)
• TYPE-B: They divide to form preleptotene spermatocytes. (Mitosis)
• PRELEPTOTENE SPERMATOCYTES: They migrate from the basal compartment to the adluminal compartment of the seminiferous tubules.
• They don't exactly go through the tight junctions. Instead, the tight junctions move with the migrating cell, and a new tight junction forms underneath.
• This process is controlled such that only the preleptotene spermatocytes can get through the Sertoli cells and change compartments. Normally other cells cannot get through.
• PRIMARY SPERMATOCYTES: The period during which meiosis is occurring.
• LEPTOTENE: Beginning of Prophase I of Meiosis. "Thin Ribbons"
• ZYGOTENE
• PACHYTENE: The longest period of meiosis (16 days), and the most frequently seen stage at any one time.
• Pachytene spermatocytes undergo genetic recombination and form chiasma.
• DIPLOTENE: Metaphase. The chromosomes separate and line up on the metaphase plates.
• DIAKINESIS
• SECONDARY SPERMATOCYTES: They then undergo Meiosis II to create spermatids.
• SPERMATIDS: They under go SPERMIOGENESIS, which can be arbitrarily divided into the following stages.
• GOLGI PHASE: Pro-acrosomal granule and vesicle develops out of Golgi Apparatus.
• ACROSIN is a serine protease found in the acrosome granules and later in the cap.
• CAP PHASE: Acrosomal cap develops from the granules.
• ACROSOMAL PHASE:
• MANCHETTE: Bundle of microtubules form and line up.
• MATURATION PHASE: Further condensation of nucleus, then sperm are released into the lumen by Sertoli cells. When they are released into the lumen, they are non-motile.
• Histones are kicked out of the genome and transition proteins are put in, which helps the genome become very condensed.
• Spermiation is the process of the Sertoli cells letting go of the sperm into the lumen.
• FLAGELLA arises out of a basal body opposite the cap.
• TESTICULAR PATHOLOGIES:
• HEAT: Testis are normally about 2 cooler than body temp. Elevated temperature causes tubular atrophy.
• Varicocele: Blood backup due to no valves in testicular veins.
• Cryptorchidism: Developmental failure for testes to descend.
• Hydrocele: Abnormal fluid collection in tunica vaginalis.
• It is the result of the fact that the peritoneum hadn't fully separated from the scrotum.
• Torsion: Twisted balls. ouch.
• Orchitis: Testicular inflammation. Can be caused by mumps or syphilis.
• TESTICULAR CANCER: Most common cancer in young adult males.
• HIV: Not in sperm per se, but in WBC's which enter semen in the prostate and seminal vesicles.

MALE GENITAL DUCT:

• TUBULI RECTAE: Short straight tubes that connect the seminiferous tubules to the Rete Testis.
• Lined by Simple Columnar Epithelium, which have true cilia to aid movement of sperm.
• RETE TESTIS: Posterior to seminiferous tubules, in the mediastinum.
• All Tubuli Rectae converge on the Rete Testis.
• Rete Testis is lined by a simple cuboidal epithelium, which resemble Sertoli Cells.
• EFFERENT DUCTULES: Connects Rete Testis to Epididymis.
• EPITHELIUM: Unique.
• Both ciliated and non-ciliated, and of differing height.
• FNXN: Lots of absorption of the seminiferous fluid takes place here.
• EPIDIDYMIS:
• CAPUT EPIDIDYMIS (HEAD):
• Sperm MATURATION occurs
• ABSORPTION of most testicular fluid
• SECRETION of other proteins essential to sperm maturation
• Sperm in the head are not yet capable of fertilizing an egg/.
• CORPUS EPIDIDYMIS (BODY): Sperm reach maturity here, and become capable of fertilization.
• CAUDA EPIDIDYMIS (TAIL):
• Sperm STORAGE occurs in tail -- about 70% of sperm are stored here.
• SPERM DISPOSAL: Over 50% of sperm degenerate in the tail of the epididymis, especially after prolonged abstinence. Prolonged abstinence decreases the count of viable sperm, not increases it.
• Androgen-Binding Protein Receptors are throughout the Epididymis. They absorb ABP throughout the tract.
• EPITHELIAL STRUCTURE:
• Stereocilia, long microvilli with actin filaments, which serves to increase absorptive / secretory surface area.
• Pseudostratified Columnar Epithelium with basal cells beneath.
• The amount of basal epithelium decreases, and the amount of musculature increases, as you move forward in the epididymis.
• VAS (DUCTUS) DEFERENS: Muscular tube, pseudostratified columnar.
• Three layers of smooth muscle: Inner Longitudinal, Middle Circular, Outer Longitudinal
• VASECTOMY: Vas Deferens cut as it come into the Inguinal Canal.
• VASOVASOSTOMY: Vasectomy reversal.
• SEMINAL VESICLES: Secretes the majority of seminal fluid.
• Secretions:
• Fructose, essential for sperm nutrition.
• Prostaglandins (originally thought to be secreted from Prostate, but that was wrong): It may stimulate smooth muscle contraction in female reproductive tract.
• Proteins responsible for semen coagulation.
• Ascorbic Acid.
• SYMPATHETICS cause seminal vesicles to contract and release contents.
• PROSTATE: Responsible for a good deal of seminal fluid.
• EMBRYOLOGY: Two different origins
• Part of the Prostate + the Ejaculatory Ducts are derived from the mesonephric duct.
• The remainder of the Prostate comes form the Urogenital Ridge
• EPITHELIA: Pseudostratified Columnar with basal cells.
• CENTRAL ZONE: Immediately surrounding urethra.
• BENIGN PROSTATIC HYPERTROPHY often occurs here or in Transitional Zone.
• TRANSITION ZONE: Surrounds the central zone.
• It also surrounds the ejaculatory ducts which are directly posterior to the urethra.
• PERIPHERAL ZONE: The majority of the prostate.
• PROSTATE CANCER occurs here.
• SECRETIONS:
• Acid Phosphatase:
• Spermine: Responsible for sperm odor.
• Fibrinolysin: Responsible for liquidization of semen.
• Amylase
• Zinc
• Pathologies:
• PROSTATE CANCER: Occurs in peripheral zone.
• Adenocarcinoma occurs as a proliferation of the epithelial layer.
• Prostate-Specific Antigen (PSA) Test: Has a high sensitivity but not a high specificity.
• PSA will be in the blood anyway, for a lot of reasons other than cancer.
• MOre than 4 ng / mL of PSA is considered a positive test and merits further testing.
• TREATMENT:
• Prostatectomy is most common. Unwanted side effects are impotence and incontinence.
• Most recent procedures allow them to spare the cavernous plexus of nerves, potentially preventing impotence, in a lot of cases.
• Alternative Tx: Insert radioactive rods to achieve targeted radiation therapy.
• BENIGN PROSTATIC HYPERTROPHY (BPH): Occurs in Central Zone.
• Hypertrophy occurs of the stroma and the glands -- not necessarily the epithelial layer.
• TREATMENT: Transurethral resection; use sharp tools to carve out lower part of bladder and upper part of prostate to restore urine flow.
• New balloon insert can be put into the prostatic urethra to blow it up and enlarge it without damaging the UG musculature.
• PROSTATITIS: Prostate inflammation.
• PROSTATIC CONCRETIONS: Proteinaceous secretions that can calcify and may block the prostate ducts. Occur in 20-30% of older men.
• BULBOURETHRAL GLANDS: Located within the UG-Diaphragm. Simple-columnar epithelia secrete pre-ejaculate into urethra.
• PENIS: Pseudostratified columnar and stratified squamous at the end.

SEMEN / SPERM STRUCTURE:

• CAPACITATION: The process of making sperm capable of fertilization in the female reproductive tract. Sperm are not capable of fertilization until about 1 hr in female tract.
• ACROSOME REACTION: Sperm interaction with Zona Pellucida, to release proteolytic contents into egg and allow sperm nucleus to enter egg.
• SPERM STRUCTURE:
• HEAD
• Acrosomal Cap
• Post-Acrosomal region
• MID-PIECE: Has lots of mitochondria.
• PRINCIPLE COMPONENT: 9+2 microtubules and dense fibers, with a surrounding sheath.
• END-PIECE: Just the 9+2 microtubules and plasma membrane.
• SEMEN:
• VOLUME: 2-3 mL, or up to 6 mL
• Seminal Vesicles can secrete 2-3 mL all by itself.
• Prostate can secrete another 0.5 or so mL
• Vas Deferens secretes the final 0.5 mL or so.
• CONTENTS:
• Normal sperm Concentration: 43 million / mL
• Any sperm count under 20 million / mL is considered infertile.
• Only about 50% of sperm have motility.
• White Blood Cells: about 1 million. Higher than 1 million needs to followed for possible infection.
• Sperms Terms:
• Normospermia
• Oligospermia: Low sperm count, less than 20 million / mL
• Azoospermia: No sperm, as in vasectomy, ideally.
• Aspermia: Inability to ejaculate.

SEXUAL ACTIVITY:

• ERECTION: Parasympathetic vasodilation in corpus cavernosum.
• EMISSION: Sympathetic contraction of vas deferens and seminal vesicles to move fluid into urethra.
• EJACULATION: Contraction of bulbospongiosus muscle (skeletal).
• Sperm and Prostate contents are in first portion of ejaculate.
• Seminal Vesicle contents are in later part of ejaculate.
• DETUMESCENCE: Sympathetic reduction of blood flow to corpus cavernosum to aid losing erection.
• SEVERED SPINAL CORD: There still remains an ability to produce an erection with mechanical stimulation due to a reflex. Ejaculation won't occur, however.

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