Male Repro, Genetics & Endocrine - First Aid Flashcards
What are three clinical manifestations supporting the manner in which the thyroid develops?
1) Foramen cecum 2) Pyramidal lobe of thyroid (persistent thyroglossal duct) 3) Thyroglossal duct cysts
What is the most common ectopic thyroid tissue?
Lingual thyroid
What endocrine abnormality might a fetus have that shows pulmonary hypoplasia and decreased lung surfactant?
The fetal adrenal gland consists of a dormant outer adult zone and an inner active fetal zone. The adult zone is dormant until late in gestation when CRH & ACTH from the fetal placenta & pituitary stimulate cortisol production. Cortisol is responsible for fetal lung maturation and surfactant production.
Most common tumor of the adrenal medulla in adults
Pheochromocytoma
Most common tumor of the adrenal medulla in children
Neuroblastoma
How to differentiate between a pheochromocytoma and a neuroblastoma?
Pheochromocytoma = paroxysms (episodic hypertension). Neuroblastoma does not have paroxysms.
What secretory products are released at each level of the adrenal gland?
Capsule = none. ATII -> Cortical zona glomerulosa = Aldosterone secretion. ACTH -> Cortical zona fasciculata = Cortisol + androgen secretion. ACTH -> Cortical zona reticularis = androgen secretion. Preganglionic sympathetic stimulation -> Adrenal medulla chromaffin cells -> Catecholamine secretion.
How does the venous drainage of the adrenal glands differ on each side?
Left adrenal vein -> left renal vein -> IVC. Right adrenal vein -> IVC…just like the gonadal veins.
Where do ADH and oxytocin come from?
Made in hypothalamus -> shipped down axons, carried by neurophysins -> Stored in posterior pituitary.
What are the different embryological origins of the pituitary gland?
Anterior: Rathke’s pouch, oral ectoderm. Posterior: neural ectoderm.
What hormones are secreted by what cells in the anterior pituitary?
B-FLAT: Basophils make FSH, LH, ACTH and TSH. GPA: Acidophils make GH and PRL.
What hormones released by the anterior pituitary may have some physiologic cross-over in less meticulous cells?
TSH, LH, FSH and hCG all share the same alpha subunits. The beta subunit is what determines hormone specificity.
What cells are present in this biopsy taken from the pancreas and what do they make?
Alpha cells make glucagon and are located peripherally. Beta cells make insulin and are located centrally. Delta cells make somatostatin and are interspersed throughout the islet of Langerhans.
What is the major regulator of insulin release?
Glucose. ATP generated from glucose metabolism closes K+ channels, causing beta cell membranes to depolarize. This opens Ca2+ VGCs and Ca2+ influx stimulates insulin secretion.
What tissues are independent of insulin when it comes to glucose uptake?
“BRICK L”: Brain, RBC, Intestine, Cornea, Kidney, Liver. Note that the brain and RBCs have GLUT-1 transporters that are insulin independent. Beta-islet cells, hepatocytes, kidney and the small intestine have GLUT-2 transporters that are bidirectional.
What tissues utilize GLUT-4 transporters?
Adipose and skeletal muscle: these are insulin-dependent glucose transporters.
What are the anabolic effects insulin has on the body?
Increased glucose uptake by skeletal muscle & fat. Increased glycogen synthesis. Increased fat synthesis. Increased Na+ retention. Increased protein synthesis. Increased uptake of K+ and amino acids. Decreased glucagon release.
3 things that will cause an increase in insulin release from beta cells
1) Hyperglycemia 2) Growth Hormone 3) Beta-2 antagonists
3 things that will cause a decrease in insulin release from beta cells
1) Hypoglycemia 2) Somatostatin 3) Alpha-2 agonists
By what mechanism does insulin allow for increased glucose uptake in fat and muscle?
Binding to alpha subunit -> Autophosphorylation of beta subunits -> Activation of Insulin receptor substrates (IRS) -> Phosphorylation of enzymes to induce fat synthesis, protein synthesis, glycogen synthesis, growth and GLUT-4 vesicle movement to the cell membrane.
Catabolic effects of glucagon
Glycogenolysis, gluconeogenesis, lipolysis and ketone production.
What are the hormones of the hypothalamus and what are their actions?
TRH -> +TSH/PRL. DA -> -PRL. CRH -> +ACTH/MSH/beta-endorphin. GHRH -> +GH. SST -> -GH/TSH. GnRH -> +FSH/LH.
What hormone is responsible for feedback inhibition of GnRH synthesis and release from the hypothalamus?
PRL. This is why PRL inhibits ovulation in females and spermatogenesis in males.
How is PRL release controlled at the level of they hypothalamus and pituitary?
TRH stimulates PRL release. PRL increases DA synthesis and secretion from hypothalamus. DA inhibits synthesis and secretion of PRL from anterior pituitary.
What drug can be used to treat patients with a prolactinoma?
Bromocriptine (DA agonist) inhibits secretion of PRL.
What drugs stimulate PRL secretion?
Antipsychotics (DA andtagonists) and estrogens
Why do people with acromegaly or gigantism have huge bones and diabetes?
GH stimulates linear growth and muscle mass by stimulating IGF-1/somatomedin secretion. It also increases insulin resistance and causes diabetes.
What activates and what inhibits secretion of growth hormone?
Exercise and sleep activate GH secretion. Glucose and somatostatin inhibit secretion of GH.
A mother brings in her 5 year old twins. They both have hypertension and hypokalemia. The boy has undescended testes and ambiguous genitalia. The girl has a normal female phenotype. U/S reveals bilaterally enlarged adrenal glands. What is causing their condition?
Congenital adrenal hyperplasia due to 17alpha-hydroxylase deficiency. When 17alpha-hydroxylase is deficient, prenenolone and progesterone cannot go on to form cortisol or androgens (DHT & estradiol). Consequently, all cholesterol in the adrenal cortex is shunted toward aldosterone production, hence the hypertension and hypokalemia. The male has ambiguous genitalia because DHT and testosterone do not promote Wolffian duct or external genitalia formation. The female is okay for now, but in the future lack of estradiol will preventer her from developing secondary sex characteristics. Finally, the decrease in cortisol is responsible for adrenal enlargement due to no feedback by cortisol and increased ACTH secretions.
A mother brings in her 5 year old twins. They both have hypotension and hyperkalemia. The boy has precocious puberty. The girl has masculinization and pseudohermaphroditism. U/S reveals bilaterally enlarged adrenal glands. What is causing their condition?
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the most common form of CAH. Absence of 21-hydroxylase prevents movement of progesterone down the mineralocorticoid and glucocorticoid pathways. Instead, all of the intermediates are shuttled toward androgen biosynthesis, which explains the precocious puberty in the boy and virilization in the girl. Decreased aldosterone secretion causes hypotension and hyperkalemia. Decreased cortisol secretion causes adrenal hyperplasia.
A mother brings in her 5 year old twins. They both have hypertension. The boy has precocious puberty. The girl has masculinization and pseudohermaphroditism. U/S reveals bilaterally enlarged adrenal glands. What is causing their condition?
CAH due to 11beta-hydroxylase deficiency. Since 11-deoxycorticosterone is a mineralocorticoid excreted in excess it causes hypertension despite a decrease in aldosterone. Cortisol levels will still be decreased and contribute to adrenal hyperplasia. Shunting of pregnenalone intermediates towards androgen synthesis accounts for the precocious puberty and virilization.
Why do people with cortisol deficiency due to CAH sometimes have trouble maintaining their blood pressure?
Cortisol upregulates alpha-1 receptors on arterioles, increasing sensitivity to NE, EPI and allowing for vasoconstriction.
What are the mechanisms by which cortisol inhibits the immune system?
Inhibits phospholipase A2 and COX-2, which prevents production of leukotrienes and prostaglandins. It inhibits leukocyte adhesion and causes neutrophilia. It blocks histamine release from mast cells. It reduces the number of eosinophils. It blocks the production of IL-2 and thus blocks T-cell differentiation.
What effect does cortisol have on metabolism?
Increased insulin resistance, gluconeogenesis, lipolysis and proteolysis.
Why do people with Cushing’s syndrome get striae?
Fibroblasts are inhibited by cortisol and blood vessels get weak.
Cortisol in the blood is active when it is in its free state. What is it bound to when it is inactive?
Corticosteroid-binding globulin (CBG)
What is the feedback cycle of cortisol secretion?
Hypothalamic CRH release -> Anterior pituitary ACTH release -> Zona fasciculata glucocorticoid release -> glucocorticoid feedback inhibits ACTH at pituitary and CRH at hypothalamus
How does the parathyroid gland respond to a drop in serum calcium?
Chief cells sense the drop and release PTH. PTH increases bone resorption of Ca and PO4, increases renal reabsorption of Ca in distal tubule/collecting duct and increases excretion of PO4 in the proximal tubule. It also increases stimulation of renal 1alpha-hydroxylase and 1,25-(OH)2D3 (Calcitriol) production. Calcitriol stimulates reabsorption of Ca and PO4 from the gut. Finally, increased Ca2+ and Calcitriol feedback inhibit PTH release from the parathyroids
What is the mechanism behind PTH-mediated bone resorption?
Increased production of M-CSF and RANK-L in osteoblasts stimulates the osteoclasts.
What two ions play a large role in regulation of PTH secretion by the parathyroid glands?
Ca2+ (low = increased secretion, high = decreased secretion) and Mg2+ (low = decreased secretion).
What are common causes of low PTH levels due to low Mg2+?
Diarrhea, aminoglycosides, diuretics and alcohol abuse.
How does the body respond in the setting of hypophosphatemia?
1alpha-hydroxylase in the kidney is stimulated to form additional 1,25-(OH)2-D3 (calcitriol). This increases intestinal absorption of phosphate and increases release of phosphate from bone matrix.
What type of vitamin D comes from sun exposure in the skin and what type comes from eating plants?
D3 = sun. D2 = plants. In a normal healthy person both of these are converted to calcidiol (25-(OH)-D) in the liver and calcitriol (1,25-(OH)2-D) in the kidney.
What is the inactive form of vitamin D?
Hydroxylation at the 24 position = 24,25-(OH)2-D.
What 3 things regulate vitamin D?
PTH, low serum Ca and low serum PO4 increase 1,25-(OH)2-D3 production. 1,25(OH)2D3 feedback inhibits its own production.
What cells are important in opposing the actions of PTH?
Parafollicular (C) cells of the thyroid. These secrete calcitonin in response to high serum Ca and decrease bone resorption.
Which hormones utilize the Gs protein for cellular signaling?
Gs -> Adenylyl cyclase -> cAMP -> PKA -> Phosphorylation of transcription factors -> Turns genes on. This pathway is utilized by FSH, LH, ACTH, TSH, CRH, hCH, ADH, MSH, PTH, calcitonin, GHRH and glucagon. “FLAT CHAMP”
Which hormones utilize cGMP for cell signaling?
Vasodilators (ANP, NO)
What hormones utilizes PLC/PI3-K for intracellular signaling?
Hormone binds -> tyrosine kinase autophosphorylates and activates PLC -> PIP2 goes to DAG + IP3 -> IP3 increases Ca influx and PKC phosphorylates transcription factors and turns genes on. This pathway is utilized by GnRH, GHRH, Oxytocin, ADH, TRH, histamine, angiotensin II and gastrin “GGOAT”
What hormones bypass the cellular membrane and go straight to a steroid receptor in the cytosol or nucleus?
“VETTT CAP” Vitamin D, Estrogen, Testosterone, T3, T4, Cortisol, Aldosterone and Progesterone.
What hormones utilize tyrosine kinase receptors?
MAP-kinase pathway. Growth factors: insulin, IFG-1, FGF, PDGF, EGF.
What hormones utilize the receptor-associated tyrosine kinases for intracellular signaling?
JAK/STAT pathway is utilized by acidophils and cytokines: PRL, Immunomodulators (IL-2, IL-6, IL-8, IFN) and GH. “PIG”.
Because sex hormones are lipophilic they must bind to globulins in circulation to increase their solubility. With this in mind, what might cause gynecomastia in men and hirsutism in women? How does this process change in pregnancy?
Gynecomastia in men: increase in sex hormone-binding globulin (SHBG) lowers free testosterone levels. Hirsutism in women: decreased SHBG raises free testosterone levels. In pregnancy, SHBG levels rise, lowering levels of testosterone.
4 B’s of T3 function
Brain maturation, Bone growth (synergistic w/GH), Beta-adrendergic (increased CO, HR, SV, contractility), Basal metabolic rate (increased Na/K ATPase -> increased O2 consumption, RR and body temperature)
Why might some patients with liver failure experience hyperthyroidism while others who are pregnant or taking oral contraceptives experience hypothyroidism?
Liver failure = decrease thyroxine-binding globulin (TBG) = increased free active T3/T4. Pregnancy/OCP = increased estrogen = increased TBG = decreased free active T3/T4.
Where is most of the T3 made in the body?
Peripheral tissues have the enzyme 5’-deiodinase that converts T4 to T3.
What does propylthiouracil do?
Inhibits organification of iodide and coupling of MIT & DIT by inhibiting thyroid peroxidase. It also inhibits actions of T3 in peripheral tissues by inhibiting 5’-deiodinase.
What does methimazole do?
Inhibits organification of iodide and coupling of MIT & DIT by inhibiting thyroid peroxidase.
What effects does T3 have on metabolism?
Increased glycogenolysis, gluconeogenesis and lipolysis
What regulates the synthesis and release of thyroid hormone?
Hypothalamic TRH -> Pituitary TSH -> Thyroid TSH receptor -> cAMP turns on TPO -> Colloid breakdown -> Lysosomal degradation -> Release of T3/T4 -> T3/T4 feedback inhibit the pituitary and hypothalamus
When do you see TSIs?
Thyroid stimulating immunoglobulins are seen in Grave’s disease and stimulate follicular cell release of T3/T4.
Wolff-Chaikoff effect
Excess iodine temporarily inhibits thyroid peroxidase -> decreased iodine organification -> decreased T3/T4 production
What is the treatment strategy for patients with type I diabetes mellitus?
Low sugar diet + insulin replacement
What is the treatment strategy for patients with type II diabetes mellitus?
Diet + exercise + oral hypoglycemics + insulin
What are the 4 fast acting insulin drugs?
Lispro, Aspart, Glulisine, Regular
What drugs are used to treat type II diabetic patients that specifically increase insulin sensitivity in target tissues? Why can these patients become fat?
Glitazones/thiazolidinediones: Pioglitazone and Rosiglitazone. These bind the PPAR-gamma nuclear transcription regulator and up regulate GLUT-4 expression on cell surface as well as promote anabolic events within the cell. These patients can become fat because fatty acid storage is increased and adiposity increases.
How does a 46 XY fetus develop into a male?
SRY gene on Y chromosome codes for testis determining factor (TDF) -> Stimulates Sertoli cells to produce Mullerian Inhibiting Factor (MIF) & MIF causes degeneration of the Mullerian (paramesonephric) ducts. TDF also stimulates testosterone production by Lydig cells which initiates development of the Wolffian duct (internal genitalia except prostate) -> Testosterone is converted to DHT to initiate differentiation of the genital tubercle/urogenital sinus into external male genitalia/prostate.
What congenital defect occurred if a child is born with male internal genitalia and ambiguous external genitalia until puberty?
5alpha-reducatse deficiency inhibits conversion of testosterone to DHT, which prohibits formation of the external male genitalia and prostate.
Congenital abnormality due to failure of urethral folds to close?
Hypospadias, opening on ventral penis
Congenital abnormality due to faulty positioning of genital tubercle? Associated with what other condition?
Epispadias, opening on dorsal penis, associated with bladder extrophy
Which side of the scrotum are varicoceles more likely to be found?
Left. The left gonadal vein makes a 90 degree turn into the renal vein which then empties into the IVC. The right gonadal vein empties straight into the IVC and has less risk for back up.
What is the pathway sperm follows on its way out?
Seminiferous tubules -> Straight testis -> Rete testis -> Efferent ductules -> Head of epididymis -> Tail of epididymis -> Vas deferens -> Ejaculatory ducts -> Urethra
Why can’t sildenafil and vardenafil help stimulate ejaculation?
They help with erection. ACh binds M3 -> NOS activated -> NO produced -> Guanylyl cyclase activated -> cGMP induces smooth muscle relaxation, vasodilation and erection. These drugs inhibit PDE5, which normally breaks down cGMP. Ejaculation is stimulated by the sympathetic nervous system. Release of NE causes and increase in intracellular Ca2+ which contracts smooth muscle, vasoconstricts and the erection goes away.
Where in the testis are the spermatogonia located?
They are the germ cells that produce the primary spermatocytes and line the walls of the seminiferous tubules.
What substances are produced by the Sertoli cells and what is the result of their secretion?
Inhibin -> Inhibits FSH. Androgen Binding Protein (ABP) -> Maintains local testosterone levels. Mullerian Inhibiting Substance -> Causes regression of Mullerian tubes in fetus.
What cells are responsible for protecting the primary spermatocytes from autoimmune attack?
Sertoli cells. They form the testis-blood barrier. Note how the spermatogonium are located just outside of the barrier.
How does spermatogenesis occur?
Spermatogonium (Diploid, 2N, 2C) crosses blood-testis barrier and replicates to become a primary spermatocyte (Diploid, 2N, 4C) -> Meiosis I splits the primary spermatocyte into a secondary spermatocyte (Haploid, 1N, 2C) -> Meiosis II makes haploid spermatids (23, 1N, 1C) -> Spermiogenesis develops the spermatids into mature spermatozoon with an acrosomal head, nucleus and tail.
How is spermatogenesis regulated?
Hypothalamus secretes GnRH -> Anterior Pituitary releases FSH/LH -> FSH stimulates Sertoli cells to produce ABP/Inhibin. LH stimulates Leydig cells to produce testosterone. Inhibin feedback inhibits FSH release from the pituitary. Testosterone feedback inhibits LH release from the pituitary and GnRH release from the hypothalamus.
How do the different pancreatic tumors present?
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Why do people with hyperaldosteronism have normal serum Na, hypokalemia and metabolic alkalosis?
ANP increases secretion of Na into the tubules. Aldosterone causes excretion of K+ and hypokalemia and excretion of H+ and metabolic alkalosis.
High 17-hydroxyprogesterone is diagnostic for?
21-hydroxylase deficiency -> CAH
Identify the genetic term that corresponds with each of the following diseases:
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