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 is the intermediate acting insulin drug?
NPH
What are the 2 long acting insulin drugs?
Glargine and Detemir.
What are the clinical uses of insulin therapy?
Types 1/2 diabetes mellitus. Gestational diabetes. Life-threatening hyperkalemia (pushes K+ into cells).
What oral drug is 1st line therapy for patients with type II diabetes mellitus? What are the pros and cons of using this drug?
Metformin, a biguanide. It inhibits gluconeogenesis in the liver, increases glycolysis and increases insulin sensitivity in peripheral tissues. This is a good drug because it does not cause hypoglycemia and can be used in patients with no islet cell function. The main adverse effect is lactic acidosis (because lactic acid is not utilized in gluconeogenesis), which is why it is contraindicated in patients with renal failure (because metformin AND lactic acid are not cleared well).
What drugs are used to treat type II diabetic patients but are useless in type I diabetic patients?
Sulfonylureas: Tolbutamide, Chlorpropamide, Glyburide, Glimepiride, Glipizide. These all close the K+ channel in beta cells, depolarizing them, opening Ca VGCs and increasing insulin release. This requires some islet cell function and hence are useless in type I diabetics.
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.
If a patient is on drug therapy for type II diabetes and becomes hypoglycemic from insulin, what drugs is he taking if you can only correct his hypoglycemia with glucose and not sucrose?
Alpha-glucosidase inhibitors: acarbose and miglitol. These inhibit the alpha-glucosidase in the intestinal brush border, delaying sugar hydrolysis and glucose reabsorption. This attenuates the postprandial hyperglycemia.
What drug is used to treat type I and II diabetes that slows gastric emptying and inhibits glucagon secretion?
Amylin analogue: pramlintide. Amylin is a normal product of the beta islet cells that works synergistically with insulin.
What drugs are used to treat type II diabetes that have strong stimulatory effects on insulin release from the beta cells and inhibitory effects on glucagon release from alpha cells? These drugs may also present with pancreatitis.
GLP-1 analogues: exenatide and liraglutide.
What drugs are used to treat type II diabetes that have strong stimulatory effects on insulin release from the beta cells and inhibitory effects on glucagon release from alpha cells? These drugs may also present with urinary infections.
DDP-4 inhibitors: linagliptin, saxagliptin, sitagliptin. These prevent breakdown of GLP-1 by the enzyme DDP-4, which increases insulin release from beta cells and inhibits glucagon release from alpha cells.
What endocrine drugs can present with side effects of tachycardia, heat intolerance, tremors and arrhythmias?
Lovothyroxine and triiodothyronine, these are for hypothyroidism and can cause overstimulation of the beta adrenergic receptors.
What drug could you use to treat Turner syndrome?
Growth Hormone is used to prevent short stature in Turner syndrome (45 X)
What drug do you use to treat acromegaly, carcinoid, gastinoma, glucagonaoma and esophageal varices?
Octreotide (somatostatin analogue).
What drug do you use to control uterine hemorrhage?
Oxytocin, in addition to stimulating milk let down it stimulates uterine contraction.
What drug do you use to treat central diabetes insipidus?
DDAVP
What drug do you use to treat SIADH?
Demeclocycline, and ADH antagonist
What drugs can be used in to treat Addison’s disease, inflammation and asthma?
Glucocorticoids: hydrocortisone, prednisone, triamcinolone, dexamethasone andbeclomethasone.
What are side effects of glucocorticoid use?
Iatrogenic Cushing’s: Corneal scarring, Ulcers, Skin thinning, HTN, Infection, Necrosis, Glycosuria, Osteoporosis, Immunosuppression, Diabetes. Also adrenal insufficiency occurs when the drug is stopped abruptly.
What symptoms do you see with DiGeorge syndrome?
DiGeorge syndrome is characterized by failure of the 3rd and 4th pharyngeal arches to develop. This results in T-cell deficiency from thymic aplasia (4th arch) and hypocalcemia from absent parathyroid glands (3rd and 4th arches)
What tumor syndrome is associated with RET1 mutation?
MEN 2A: pheochromocytoma, parathyroid hyperplasia and medullary thyroid cancer. This is because RET1 is associated with neural crest cell derivatives.
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 external genitalia and prostate but both male and female internal genitalia?
Sertoli cells are not producing Mullerian inhibitory factor.
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
What is the fibrous tissue that anchors testes within the scrotum?
Gubernaculum. Patients can get torsion if this is absent.
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 lymph nodes are likely to be enlarged in patients with advanced testicular cancer?
Para-aortic nodes.
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.
What cells in the testis are not affected by cryptorchidism or varicocele?
Both of these conditions increase the temperature inside of the testicle. The developing sperm cells cannot survive at body temperature and spermatogenesis decreases. Sertoli cells decrease secretion of inhibin with increased temperature. Leydig cells are unaffected and testosterone production continues as normal.
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.
Where are the most potent male androgens synthesized? The least potent?
DHT is the most potent and is synthesized in the Leydig cells along with testosterone. Androstenedione is least potent and is synthesized in the adrenal cortex zona reticularis.
What tissue is responsible for the generation of man boobs in fat people?
In adipose, the enzyme aromatase converts testosterone and androstenedione to estrogen which promotes growth of boobies. Note that the Leydig cells in the testis also have this enzyme, but when people gain adipose tissue as they do in obesity estrogen levels rise.
What are 5 functions of testosterone?
Differentiation of internal genitalia (except prostate), growth spurt (penis, seminal vesicles, sperm, muscle, RBCs), deepens voice, closing of epiphyseal plates (via testosterone conversion to estrogen by aromatase) and libido.
What are 4 functions of DHT?
Early on: differentiation of external genitalia + prostate. Later: prostate growth, male pattern baldness and sebaceous gland activity.
Why do people that abuse steroids have testicular atrophy?
Testosterone inhibits hypothalamic release of GnRH and pituitary release of LH. This decreases intratesticular testosterone levels and causes azoospermia.
Order the potency of the different estrogens
Estradiol (from ovary) > Estrone (adipose) > Estriol (placenta)
What are the Tanner stages of sexual development?
I) Child II) Pubarche (pubic hair appears) + Thelarche (breast buds form) III) Pubic hair darkens & curls, penis lengthens, breasts grow IV) Penis widens, scrotum darkens, glans develops, areolae raise V) Adult, areolae no longer raised
What drug can be used to treat precocious puberty or prostate cancer and works by down regulating GnRH receptors in the anterior pituitary?
Leuprolide. Bombarding the pituitary with GnRH analogue causes regression of GnRH receptors, limiting release of FSH/LH from the anterior pituitary and thus limiting androgen production which fuels these conditions.
What drugs can be used to treat hypogonadism and promotion of secondary sex characteristics in males?
Testosterone and methyltestosterone.
What drug can you give to a patient to treat his BPH and male pattern baldness?
Finasteride: This is a 5alpha-reductase inhibitor that prevents conversion of testosterone to DHT.
What drug is a competitive inhibitor of androgens at the testosterone receptor and are used to treat prostatic carcinoma?
Flutamide
What drug can be used to prevent hirsutism in females by inhibiting steroid synthesis?
Ketoconazole (inhibits 17.20-desmolase)
What drug can be used to prevent hirsutism in females by inhibiting steroid binding?
Spironolactone
What drug can you give patients with BPH that have normal blood pressure?
Tamsulosin, it antagonizes alpha-1a receptors on the prostate and leaves vascular alpha-1b receptors alone.
Drug that can cause life threatening hypotension if taken with nitrates?
Sildenafil and vardenafil
Drug that can be used to treat hereditary angioedema but comes with possible side effects of weight gain, edema, acne, hirsutism, masculinization, decreased HDL and hepatotoxicity.
Danazol, partial androgen receptor agonist. It can stimulate the liver to synthesize hepatic esterase inhibitor to treat hereditary angioedema.
A nonsense mutation and a deletion in the OTC gene both cause lethal neonatal hyperammonemia due to absence of OTC, an important hepatic enzyme in the urea cycle. What genetic term best describes this concept?
Allelic heterogeneity: different mutations within the same gene cause the same disease.
Retinitis pigmentosa, a form of retinal degeneration, occurs in autosomal and X-linked forms. What genetic term best describes this concept?
Locus heterogeneity: different mutations on different genes cause the same disease
What are 4 mechanisms a female can have an X-linked recessive disease like Hemophilia A.
1) X-inactivation 2) Homozygous for diseased X 3) Turner syndrome (45 X) 4) X translocation that inactivates good chromosome
Pathogenic mechanism of Huntington disease? Fragile X? Myotonic dystrophy?
Huntington: trinucleotide repeats = gain of function toxic protein. Fragile X: trinucleotide repeats = hypermethylation, FMR1 silenced and loss of function. Myotonic dystrophy: trinucleotide repeats = mRNA unstable.
Hardy-Weinberg equation for 3 alleles?
p = A, q= B, r = O. p^2 + 2pq + q^2 + 2pr + 2qr + r^2
When would you use percutaneous umbilical blood sampling (cordocentesis)?
If a suspected enzyme defect were in the WBCs.
Triple screen for Down Syndrome
Does not confirm diagnosis: Estriol (low), maternal serum AFP (low) and beta-hCG levels (high) means Down syndrome. If all are low it is associated with Trisomy 18.
What genetic diseases are often associated with deficient enzyme activity?
Autosomal recessive
What type of genetic inheritance is expressed in Marfan’s syndrome?
AR
What type of genetic inheritance pattern is expressed in retinitis pigmentosa?
AR
What type of genetic inheritance pattern is expressed in osteogenesis imperfecta?
AD
What is the most likely explanation of two offspring of normal parents to have an autosomal dominant disease?
Germinal mosaicism in one parent
Two parents are both affected with albinism (203100, 203200) but have a normal child. What genetic term describes this situation?
Locus heterogeneity. Albinism is an AR disease and the parents have mutations on different genes that cause the same disease. This is why the kid didn’t get it.
PKU is an AR disease that causes mental retardation of untreated 2 normal parents are told by the geneticist that their third child has PKU. What is the risk that their 1st child is a carrier of PKU?
Since it is AR, both parents are heterozygotes and the 1st child is unaffected, there are 3 possibilities for the 1st child: AA, Aa and Aa. Thus, his chance is 2/3.
A couple requests repeat DNA studies on their newborn because he was found to be positive for CF at two mutations on the CF gene. The couple is confused about how this occurred because the 3 year old child is unaffected. What genetic concept best explains this situation?
Mendelial gene segregation.
A couple is screened for Tay-Sachs. Their hexA activities are 40 and 45%. If they have a child, what is there risk the child has of possessing one or more alleles of the Tay-Sachs mutation?
Activity in both parents is moderately reduced, indicating heterozygosity. Since the options in the Punnet square are: AA, Aa, Aa, aa, there is a 3/4 chance the child will have one of the alleles.
In some patients, not all features of WAGR syndrome are seen. In others, features of the syndrome can be inherited separately in a Mendelian fashion. Finally, some features also present in patients without visible chromosome deletions. What is the most likely mechanism for this finding?
Contiguous gene syndrome
How do the different pancreatic tumors present?
*
An African American couple wants to know the chance that their child has sickle cell anemia. The incidence of sickle cell trait in African Americans is 1/8. What is the risk of the child?
Risk of mom = 1/8. Risk of dad = 1/8. Risk of child = 1/8. 1/8 x 1/8 x 1/8 = 1/256.
In Minnesota, African American screening for A globin allele is 7/8 and S is 1/8. A companion surgery of 6400 of their ancestors shows AA: 4,600, AS: 1,600 and SS: 200. If all SS individuals were sterilized, the SS genotype frequency in the next generation would be?
About the same.
The frequency of glactosemia is 1/40,000 live births. What is the frequency of the carrier state?
q = sqrt(1/40,000) = 1/200. p =1. Carrier frequency = 2pq = 2(1)(1/200) = 1/100.
Mode of prenatal testing for hemophilia A?
Chorionic villus sampling with DNA analysis for factor VIII mutations
Mode of prenatal testing for spina bifida and anencephaly?
Maternal serum alpha-fetoprotein (+ if elevated) and ultrasound
What phenotype will a 46, XY child have who does not have Sertoli cells?
Male external genitalia and female + male internal genitalia. Although MIS is gone, testosterone is still present and able to differentiate the Wolffian ducts.
One of the most common causes of an elevated AFP
Underestimation of gestational age
Where does rT3 come from?
T4. T3 cannot be converted to rT3 or T4 at all.
Drug you give prior to removal of a pheochromocytoma
Phenoxybenzamine
Why might a patient with a testicular tumor presents with hyperthyroidism?
hCG can be very high in patients with choriocarcinoma testicular cancer. The alpha subunit of hCG is similar to FSH, LH and TSH and can stimulate TSH receptors on the thyroid to cause hyperthyroidism.
Increased PLAP
Seminoma
Increased AFP
Yolk sack tumor
Why might a diabetic mother have a child with transient hypoglycemia once it is born?
Diffuse hyperplasia of the neonatal islet cells due to high maternal glucose levels. This causes transient hypoglycemia when the fetus has to rely on its own blood glucose.
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.
Nests of polygonal cells with Congo red deposits + a pheochromocytoma. What is the mutation?
MEN2A = RET mutation.
Medullary carcinoma of thyroid, pheochromocytoma, oral/intestinal mucosa tumors and Marfinoid habitus? Mutation?
MEN2B = RET mutation
Acute hemorrhage in pituitary gland, headache, bitemporal hemianopsia and decreased libido.
PRL-secreting pituitary adenoma
Medication that causes hypercalcemia
Thiazides
Permanent central diabetes insipidus
Damage to hypothalamic nuclei. Transient central DI is from damage to the posterior pituitary.
MEN1
Pituitary, parathyroid and pancreatic tumors
Where are the T3 receptors located?
Nucleus. Thyroid hormone starts as a peptide, but acts on peripheral cells like a steroid.
High 17-hydroxyprogesterone is diagnostic for?
21-hydroxylase deficiency -> CAH
How does a prolactinoma affect GnRH, LH and testosterone levels?
Decreases them all because PRL inhibits GnRH at the top of the GnRH, LH, testosterone axis.
Enzyme responsible for glucose toxicity in tissues not regulated by insulin
Aldose reductase takes glucose to sorbitol
What conditions present with increased creatine kinase?
Hypothyroidism, autoimmune and muscular dystrophies.
What pituitary hormone levels would you expect to see in a patient with Klinefelter’s syndrome & small, firm testicles?
Low testosterone production from testis -> Increased serum GnRH -> Increased FSH & LH.
Low plasma sodium and osmolality, inappropriately concentrated urine, increased urinary sodium and normal body fluid volume w/a mass in the lungs.
SIADH. Note that ANP is secreted and contributes to the normal volume load.
Why might you see an increase in the total T4 pool in a pregnant woman without any change in TSH levels?
Estrogen (from pregnancy or oral contraceptives) increases TBG (thryoid binding globulin) levels. Although estrogen increases T4 production in the thyroid, T4 is increasingly bound and inactivated by TBG and won’t stimulate increased TSH release from the pituitary. Note that liver failure will cause decreased TBG levels and can cause hyperthyroidism.
Identify the genetic term that corresponds with each of the following diseases:
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