Sex

1) Define pelvic cavity and review its boundaries Lesser/Greater Sciatic Foramen → gluteal region Obturator foramen → medial thigh Inguinal Ligament → anterior thigh Bladder – most anterior - abdominal and pelvic structure Uterus (female) Rectum – most posterior Pelvic Inlet = Pelvic Brim - Sacral Promontory - Margins of ala - Linea Terminalis - Arcuate line - Pectineal line - Pubic crest Layers - Bony Wall - Musculature - Nerves - Parietal Pelvic Fascia - Vessels - Arteries (medial) - Veins - Nerves (lateral) - Peritoneum Greater Sciatic Foramen - Superior Gluteal nerves/vessels ------Prirformis----------------------------------- Inferior Gluteal nerves/vessels - Sciatic Nerve - Posterior cutaneous nerve of thigh - Nerve to quadratus femoris - Pudendal nerve → exit pelvis – only sensory - Internal pudendal vessels → exit pelvis - Nerve to obturator internus → exit pelvis Lesser Sciatic Foramen - Obturator internus - Pudendal nerve → return into pelvis - Internal pudendal vessels → return into pelvis - Nerve to obturator internus → return into pelvis 2) Review blood supply and lymphatic drainage of the pelvis and perineum Arteries of Female Pelvis Internal Iliac a. (anterior branch) → Obturator a. ***may arise from external pudendal artery

→ Umbillical a. → Superior Vesicle a. → Uterine a. - similar to artery to ductus deferens in men - tortuous - ureter runs under – “water under the bridge” → Ascending branch → uterus → Descending branch → cervix and vagina → Vaginal a. → Inferior Vesicle a. → Middle Rectal a. → Internal Pudendal a. → Inferior Rectal a. → Inferior Gluteal a. – pass between S2 and S3 Internal Iliac a. (posterior branch) – parietal branches – supply posterior wall → Iliolumbar a. → Lateral Sacral a. → Superior Gluteal a. – pass between lumbar sacral trunk and S1 Arteries of Male Pelvis Internal Iliac a. (anterior branch) → Obturator a. ***may arise from external pudendal artery → Umbilical a. → Superior Vesicle a. → Artery of ductus deferens → Inferior Vesicle a. → Middle Rectal a. → Internal Pudendal a. → Inferior Rectal a. → Inferior Gluteal – pass between S2 and S3 Internal Iliac a. (posterior branch) – parietal branches – supply posterior wall → Iliolumbar a. → Lateral Sacral a. → Superior Gluteal a. – pass between lumbar sacral trunk and S1 Lymphatics Inferior Phrenic lymph nodes Lumbar lymph nodes - Pre-aortic – celiac, superior mesenteric, inferior mesenteric - Left Lateral Aortic - Right Lateral Aortic (Caval) - Retroaortic Iliac lymph nodes - Common Iliac - External Iliac - Internal Iliac Inguinal lymph nodes - Superficial – horizontal, vertical (T-shaped) - Deep

Sacral lymph nodes Collateral Circulation in Pelvis Lumbar a. ↔ Iliolumbar a. Median Sacral a. ↔ Lateral Sacral a. Superior Rectal a. ↔ Middle Rectal a. Inferior Gluteal a. ↔ Deep artery of the thigh Veins of Pelvis Pelvic Organs → Internal Vertebral (Batson’s) Venous Plexus - cancer can metastasize to brain and spinal cord - cancer can spread to heart and lungs Lymphatic Drainage - Fundus of Uterus near Round Ligament – superficial inguinal lymph nodes - Lower Uterine body, Cervix, and Bladder – internal and external iliac lymph nodes - Ovaries, Uterine Tubes, Upper Uterine Body, Testis – para-aortic lymph nodes - Glands Penis (Clitoris) and Labium minor – deep inguinal and external iliac lymph nodes - Prostate and Lower Rectum – internal iliac lymph nodes 3) Nerves of the pelvis (somatic, autonomic – SNS, PNS) Pelvic Nerves - Somatic – ventral rami → motor - Sacral Plexus – Lumbosacral trunk (L4, L5) + S1-S4 - Coccygeal Plexus – S4, S5 + Coccygeal nerves - Autonomic - Sacral Splanchnic (Sacral Plexus) – SNS – lower limb - Pudendal Nerve – S2, S3, S4 - Coccygeal Ganglion (Impar) - Periarterial Plexus – SNS – vasomotor - Hypogastric Plexus – pelvic organs - Superior Hypogastric plexus (SNS) - Right and Left Hypogastric Nerves (SNS) - Inferior Hypogastric plexus → join pelvic splanchnic (mixed – SNS/PNS) - Pelvic Splanchnic (Pelvic Plexus) – PNS - name changes depending on location (ex: prostatic plexus, vesicle plexus, etc.) - Cavernous nerve → supplies penis Innervation of Bladder - SNS (T11-L2) → contract internal sphincter → relax detrusor muscle - PNS (S2-S4) → relax internal sphincter → contract detrusor muscle - Pudendal → voluntary control of external sphincter

4) Concept of the pelvic pain line *Pelvic Pain Line – corresponds with inferior limit of peritoneum - Above – SNS (T12-L2) - Below – PNS (S2-S4) - Large Intestine pain does not correlate with peritoneum - pain line occurs in middle of sigmoid colon 5) Review the innervation of pelvic organs 6) Clinical Correlates *Suprapubic Cystostomy – drain bladder if urethra is obstructed (ex: enlarged prostate) or injured (torn urethra) *Pelvic Ultrasound – require full bladder to help sound waves travel better → better visualization of pelvic organs *Digital Rectal Exam - Females – palpate Rectouterine (Douglas) pouch - Males – palpate posterior lobe of prostate *Culdoscopy – insertion through posterior vaginal fornix to examine ovaries or uterine tubes *Culdocentesis – drainage of pelvic abscess, fluid, or blood through the posterior vaginal fornix *Anal Reflex – S4, S5 *Anesthesia for Childbirth - Spinal Anesthesia – lumbar puncture → anesthesia inferior to waist – cannot feel contractions - Caudal Epidural Block – catheter into sacral canal → feel contractions but not pain of childbirth - Pudendal Nerve Block – ischial spine landmark → S2-S4 dermatomes + ¼ of vagina *Benign Prostatic Hyperplasia – middle/intermediate lobe most commonly enlarged *Atonic Bladder – L2 injury → detrusor and external sphincter relax, internal sphincter contracted → urine dribble - usually present in early stages of spinal shock *Automatic Reflex Bladder – reflex contraction every 2-4 hours - loss of voluntary emptying of bladder *Autonomous Bladder – detrusor flaccid → bladder overfills → overflows

Bayesian Probability – Adjust a person’s prior risk, most often of being a carrier of a mutant gene - Conditional Risk – taking into account further information to lower the risk → posterior (modified) risk - ex: unaffected children, negative lab tests, etc.

Prior Risk Carrier = 1/2 Non-Carrier = 1/2 Conditional Risk – what is the patients risk of being normal? - Age 30 = 10% are clinically affected Carrier: 9/10 Non-Carrier = 10/10 Joint Risk – (Prior Risk) x (Conditional Risk) Carrier = (1/2) x (9/10) = 9/20 Non-Carrier = (1/2) x (10/10) = 10/20

Posterior Risk – (Joint Risk)/(Sum of Joint Probabilities) Carrier = (9/20)/(9/20 + 10/20) = (9/20)/(19/20) = 9/20 x 20/19 = 9/19 Non-Carrier = (10/20)/(9/20 + 10/20) = (10/20)/(19/20) = 10/20 x 20/19 = 10/19 Charlotte’s Risk of being a carrier = 9/19 - risk has decrease – originally 1/2, now it is 9/19 Charlotte’s Risk of being having a child with Huntington’s Disease 9/19 [risk of being a carrier] x 1/2 [passing on bad allle] x 99/100 [Penetrance] = 891/3800

Prior Risk – risk that both Stephan and Kim are carriers/non-carriers Carrier = 1/2 x 1/25 = 1/50 Non-Carrier = 1-1/50 = 49/50 Conditional Risk – what is the patients risk of being normal? - Both have already had 2 healthy children =  healthy children =  risk Carrier: 3/4 [child 1] x 3/4 [child 2] = 9/16 1/4 = chance of having homozygote recessive 3/4 = chance of being heterozygote or homozygote dominant = unaffected Non-Carrier = 4/4 - if both are not carriers, what is the risk of their children being affected? Joint Risk – (Prior Risk) x (Conditional Risk) Carrier = (1/50) x (9/16) = 9/800 Non-Carrier = (49/50) x (4/4) = 784/800 Posterior Risk – (Joint Risk)/(Sum of Joint Probabilities) Carrier = (9/800)/(9/800 + 784/800) = (9/800)/(793/800) = 9/800 x 800/793 = 9/793  1/88 Non-Carrier = (784/800)/(9/800 + 784/800) = (784/800)/(793/800) = 784/800 x 800/793 = 784/793 Stephan and Kim’s Risk of being carriers = 1/88 Charlotte’s Risk of being having a child with Huntington’s Disease 1/88 [risk of being a carrier] x 1/2 [Kim passing on bad allele] x 1/2 [Stephan passing on bad allele] = 1/352

Prior Risk – risk that Amelia is a carrier/non-carrier Carrier = 2/3 Non-Carrier = 1/3 - risk of Amelia’s son being a isolated case (1/3) Conditional Risk 1 – what is the patients risk of being normal? - 70% of DMD carriers show normal CPK levels Carrier: 30% = 3/10 Non-Carrier = 10/10 Conditional Risk 2 – what is the patients risk of being normal? Carrier: 1/2 - for having a healthy boy Non-Carrier = 2/2 Joint Risk – (Prior Risk) x (Conditional Risk) Carrier = (2/3) x (3/10) x (1/2) = 6/60 Non-Carrier = (1/3) x (10/10) x (2/2) = 20/60 Posterior Risk – (Joint Risk)/(Sum of Joint Probabilities) Carrier = (6/60)/(6/60 + 20/60) = (6/60)/(26/60) = 6/60 x 60/26 = 6/26 Non-Carrier = (20/60)/(6/60 + 20/60) = (20/60)/(26/60) = 20/60 x 60/26 = 20/26 Amelia’s Risk of being carriers = 6/26 = 1/13 Amelia’s Risk of being having a child with Huntington’s Disease 1/13 [risk of being a carrier] x 1/2 [passing on bad allele] = 3/26 - if sex is unknown: 3/26 x ½ = 3/52

 

1) Describe the important features of the X chromosome, XIC, PAR region Lyon Hypothesis 1) A normal female will only have one X active, the other is inactivated - Barr Bodies – inactive X’s seen in the non-dividing cell - Dosage Compensation – “Balancing Out” – all X’s in excess of one are inactivated in females → male and females expresses similar doses of most genes on the X chromosome - ex: factor VIII - exception: steroid sulphatase; SHOX gene → all in greater amounts in women 2) X inactivation occurs early in embryogenesis 3) Choice of inactivation is random and independent in each cell 4) Inactivation is irreversible and all descendents will have the same X inactivated Manifesting Heterozygotes – A woman is a mosaic of clones with maternal or paternal X’s - ex: Calico cat – mosaic of black and orange due to X-inactivation Skewed X (Non-Random) Inactivation → not 50/50 inactivation - ex: inactivate abnormal X more often than normal X to ensure survival X Inactivation Center (XIC) – where inactivation begins → spread to short arm and rest of long arm Pseudoautosomal Region (PAR) - distal short arm regions on X and Y chromosomes - contain highly similar DNA sequences → allow for crossing-over to take place between X and Y PARs ***Recombination is higher in females than males → genetic map in female is longer than male - SRY is proximal to PAR1 in Y specific region - Unequal recombination → XX males (SRY) + XY females (no SRY) 2) Explain the principle of X inactivation X Inactivation: Molecular Aspects - X Inactivation Center (XIC) – where inactivation begins → spread to short arm and rest of long arm - Methylation – X Inactivation Specific Transcripts (XIST) → inactivation - XIST is only expressed in inactivated chromosome → spread inactivation methylation signal - Not all the X is inactivated if all X chromosome were inactivated → women would all be Turner’s Syndrome!! - Pseudo-autosomal region – gene in that remains active and escape XIST inactivation - Xp gene > Xq gene - deletions of Xp → more severe phenotype 3) Explain the consequences of X autosome translocations X Autosome Translocation Balanced Translocation → inactive normal X - derivative X contains important genes due to translocation and needs to be expressed Unbalanced Translocation → inactive derivative X - skewed X inactivation

Reciprocal Balance Translocations - exchange of genetic information between non-homologous chromosomes - exchange of genetic information between homologous chromosomes at different sites - Derivative (der) – abnormal chromosome - 70% of balanced translocations are inherited - reciprocal translocations are unique to a family - carriers are usually phenotypically normal but have reproductive problems → infertility; miscarriages; children w/abnormal phenotypes or unbalanced translocations - many female carriers of a balanced X-autosome translocation are infertile 4) Explain the genetic basis, molecular and clinical features of Duchenne muscular dystrophy

Duchenne Muscular Dystrophy (DMD) - X-linked progressive myopathy → muscle degeneration - most commonly inherited form of muscle disease (1:3500 in males) Pathogenesis: loss of dystrophin which stabilized smooth, cardiac, and skeletal muscle along with brain neurons - Dystrophin gene – large gene (3-78 exons) → high mutation rate → allelic heterogeneity - Allelic Heterogeneity – multiple types of mutations (for DMD gene) 60% = large deletion 5-10% = large duplication 25-35% = small deletions, insertions, point mutations - de novo mutations during Oogenesis and spermatogenesis Isolated Case – new mutation - 1/3 of DMD are due to new mutations *Becker Muscular Dystrophy (BMD) – allelic mutation → frame-shift mutations → shorter dystrophin protein Clinical Features Onset: childhood - difficulty standings, walking, sitting, climbing stairs (Gower’s maneuvers/sign) - pseudohypertrophy of calf muscles - IQ one standard deviation below the mean - DMD will involve heart muscle and respiratory system → death (age 18) Testing - Creatine Phosphokinase – elevated 10-20 times → indicate muscle damage - Stain for dystrophin protein Molecular Diagnosis - Multiplex PCR - Linkage Analysis Treatment: - No cure - Treatment objective = slow down disease progression and optimize cardiac/pulmonary function 5) Explain the basis of DMD expression in females X autosome translocation

6) Explain the principles of skewed X inactivation in relation to the expression of the DMD in females Duchenne Muscular Dystrophy Expression in Females - Age of onset + Severity depends upon degree of skewed X inactivation - ex: if X chromosome carrying DMD allele is active → female develop signs of DMD - 70% of female carriers will have slightly elevated serum creatine kinase - 20% of female carriers will have some muscle weakness - 10% of female carriers will have life-threatening cardiomyopathy

1) Explain characteristic features of trinucleotide repeat disorders (unstable mutation, anticipation, threshold, gender bias for expansion of the repeat) Classical Inheritance Identical inherited mutations – mutation for a genetic disorder is stable from one generation to the other

Trinucleotide Repeat Disorders – Triplet Repeat Disorders - most common type of unstable dynamic mutation - trinucleotide repeats  microsatellites (triplets which have no function) Mechanism – slippage mis-pairing - ex: replication strand detaches inappropriately from template - ex: replicating strands slips from proper alignment → mis-match - ex: extra repeat Dynamic Mutation – mutation which changes upon transmission - ex: Trinucleotide Repeat Disorders - expansion in increasing number of three nucleotide repeats - disease occurs when expansion surpasses a certain threshold - below threshold – repeat is stable in mitosis and meiosis - above threshold – repeat is unstable in mitosis and meiosis Anticipation - progressively earlier onset and increased severity in successive generations -  [repeats] → earlier onset + increased severity 2) Examples of disorders associated with trinucleotide expansion (myotonic dystrophy, Fragile X syndrome, Huntington’s Disease)

Myotonic Dystrophy – CTG - autosomal dominant - Threshold > 50 repeats - Gain of function - Maternal transmission -1:8000 – most common heritable neuromuscular disorder - CTG expansion 5’ end in non-coding region of dystrophy myotonic protein kinase (DMPK) - Extreme variability - Anticipation - Differential expansion in maternal and paternal allele - greater expansion if maternally inherited → congenital form almost always maternally inherited - congenital form rarely from paternal carrying CTG expansion Normal – 4-37 repeats – none Premutation – 38-49 repeats – none Protomutation – 50-80 repeats – asymptomatic with mild late onset (cataracts) Mutation – 200-500 repeats – associated with 3rd or 4th decade Mutation – 280-800 repeats – childhood onset Mutation – >1000 repeats – congenital - Testing

- EMB - Serum creatine kinase - Eye exam - Cannot release handshake

Fragile X Syndrome – CGG/GCC - X-linked recessive - Threshold > 200 repeats - Loss of function - Maternal transmission - 1:4000 (male); 1:8000 (females) – leading cause of inherited mental retardation - FRM1 – hypermethylation → loss of function due to expansion of CGG triplet → moderate retardation (males) – IQ 30-50 → mild retardation (females) – Skewed X inactivation - Onset: childhood - Pre-Puberty – large head - Post-Puberty – long head, large ear, prominent jaw, large testis - Somatic Mosaicism – patients can have a mixture of cells ranging from premutation to full mutation Normal – 6-44 repeats – normal Gray Zone – 45-58 repeats Premutation – 59-200 repeats – normal intellect Full Mutation – > 200 repeats **risk of expansion from premutation to full mutation increases with length of premutation - Full Mutations are mitotically unstable - Female carriers of premutation are at risk of premature ovarian failure - Male carriers of expanded, but unmethylated premuation at risk of Tremor/Ataxia Syndrome (FXTAS) - affect mostly men over 50 years old - Testing - Southern Blot Analysis

Huntington Disease – CAG - autosomal dominant - Threshold > 40 repeats - Gain of function - Paternal transmission - Voluntary and Involuntary movement – chorea (90%) - cognitive abnormalities - behavioral disturbances - Avg. age of presentation – 35-44 (25% developed after 50 years old) - Median age of survival – 15-18 years - CAG repeat in exon 1 coding for polyglutamine → toxic gene product - Anticipation –  expansion → earlier the onset - Differential expansion in maternal and paternal allele

- expansion > 36 repeats from paternal transmission (more common) Normal – < 26 Mutable – 27-35 – all patients inherit this allele from their father Reduce Penetrance – 36-39 Huntington Disease – > 40 - Anticipation

1) Understand the basis of genomic imprinting Genomic Imprinting - differential expression of alleles depending on parental origin → homologous chromosomes are not expression equally → diseases can result whether a gene is inherited from maternal or paternal origins → methylation – main mechanism by which expression is modified - Differentially Methylated Regions (DMR) – genes know to be imprinted - Imprinting Control Regions (ICR) – regulation of imprinting - occur during gametogenesis → maintained through embryogenesis and in somatic tissue - Epigenetic – heritable changes to gene expression that are not due to difference in genetic code - genomic imprinting is erased and reset in the germ line cells for the next generation

2) Know some evidence of imprinting in humans (partial vs. complete moles) Hydatidiform Moles - molar pregnancy derived from chorionic villi → burrow into uterus - rarely survives to term Partial Hydatidiform Mole - 68 chromosomes (46 from father + 23 mother) - Cause: dispermy or endoreduplication - fetus present but not viable Complete Hydatidiform Mole - 46 chromosomes (from father) - 46 XX (85%) - 46 XY (15%) - Cause: fertilization of an empty ovum by 2 sperm or single sperm undergoes endoreduplication - Risk: degeneration into choriocarcinoma (15-20%) - no fetus present Differential Expression Trophoblast vs. Embryoblast - Paternal nuclear genes: embryo fails to develop but trophoblast development proceeds unimpaired - Maternal nuclear genes: embryo will develop but trophoblast development is poor Conclusion: - Paternal derived genes essential for trophoblast development - Maternal derived genes essential for embryo development

3) Understand the clinical and molecular basis of and the mechanism of uniparental disomy (UPD) in Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS) Uniparental Disomy (UPD) - Non-disjunction @ Meiosis II → uniparental isodisomy (both chromosomes are the same and maternal) - Non-disjunction @ Meiosis I → uniparental heterodisomy (both chromosomes are different but maternal) - most often leads to PWS *Prader-Willi Syndrome (PWS) - Phenotypical Features - Infantile feeding difficulties - Childhood hyperphagia and obesity - Hypotonia - Cognitive impairment - Sterility - Dysmorphism – abnormal morphologic development - Mechanisms 1) Interstitial paternal deletion at long arm of chromosome 15 (70-75%) - 15q11-q13 - deletion cause: illegitimate recombination - Recurrence Risk: 50% = linkage < 50% = no linkage - Sib-Pair Analysis - only works if parents have both good and bad alleles (must be heterozygote) - chose family with at least 2 affected siblings - calculate allele sharing in each sib-pair - average all pairs - look at linkage Linkage – loci that are close enough that they segregate together through generations Association – events occur together more often than expected in a current generation Association in Genetics – a disease and a marker allele that occur together more often than expected Linkage Disequilibrium – occurrence of specific combination of alleles more frequently than expected by chance - bad allele is found together with a specific marker allele in nearly all people carrying the bad allele - only present if no crossovers happen - Association Study – look for marker frequency in affected group - Genome Wide Association Study 6) State the role of teratogens and intrauterine infections in the pathogenesis of congenital malformations 7) Describe the importance of identifiable single-gene effects in multifactorial disorders including autoimmune diseases, type 1 and 2 diabetes, Hirschsprung’s, and Alzheimer. *Hirschsprung’s Disease – “megacolon” due to failure of migration/differentiation of neural crest cells - male > females (4:1) - high heritability ( 100%) – polygenic - RET gene – implicated with dominant mutations - involved in tumors after activating mutations - involved in Hirschsprung’s Disease after inactivating mutation - involved in development and migration of neural-crest cells - Long Segmental Form - male  females - mutations of coding region → complete inactivation of RET - Short Segmental Form - male > female - Multifactorial – Chromosome 3, 10, 19 - mutations in enhancer → reduced penetrance → turn down expression of RET *Diabetes Mellitus – Type 1 (IDDM) - General Population = 0.3-0.5% - Sibling of affected = 6% - Affected Father = 4-6% - Affected Mother = 1-3% - Monozygotic Twins = 30-50% → not purely genetic!! - Genetic factors 1) Allele DR3 and DR4 on MHC >95% of all IDDM patients

2) Aspartic acid in position 57 of DQ = protective against IDDM → DR3/DR4 could serve as marker to non-aspartic acid in DQ region 3) Insulin gene → HLA alleles may not be presented well enough in thymus → auto-immunity - short repeat = increased risk - long repeat = increased insulin expression in thymus → better immune tolerance - Environmental factors - Viral infections → trigger immune reaction that cross-reacts with pancreas - ex: Coxsackie B, enterovirus - anti-Coxsackie B antibodies in 39% of children with IDDM *Diabetes Mellitus – Type 2 (NIDDM) 5-10 X more common than IDDM - Sibling of Affected = 15-40% - Monozygotic Twins = 90% → high heritability (concordance) → mostly genetic!! - Genetic Factors TCF7L2 – transcription factor → insulin secretion = 1.5X risk PPAR-γ – transcription factor → adipose/glucose metabolism = 1.25X risk KCNJ11 – potassium channel → insulin secretion = 1.2X risk - Environmental Factors - Obesity; low birth weight; diet, activity, etc. *Diabetes Mellitus – Maturity-Onset Diabetes of the Young (MODY) - autosomal dominant with 80-95% penetrance - 5% of all diabetes cases - multifactorial – 7 known genes (glucokinase) - often misdiagnosed as type I - Onset: < 25 years old - often not obese - metabolic syndrome is absent Obesity - major influence of environment - high concordance - Leptin; NPY; melanocortin 4-receptor *Alzheimer’s Disease - formation of amyloid plaques and neurofibrillary tangles - Genetic Factors 1) Amyloid Precursor Protein (APP) - cleavage by -secretase → Aβ40 and Aβ42 → overproduction → amyloid plaques and neurofibrillary tangles - Presenilin-1 and Presenilin-2 - regulation of -secretase

- mutations → increased cleavage →  [Aβ40 and Aβ42] 2) ApoE4 - Homozygote = 15X risk - Heterozygote = 3X risk 3) Interleukin-1 - overexpression of IL-1 correlated with plaque formation - involved in inflammation - Race - higher incidence in African American and Hispanic communities (genetic or environmental) *Down’s Syndrome - APP gene located on Chromosome 21 → mutations of APP →  [Aβ40 and Aβ42] - ABCG1 gene on Chromosome 21 also suspect *Cancer – best considered multifactorial with low heritability (majority) *Congenital Malformation - genetically heterogenous group - causes: - genetics (chromosomal abnormalities) - environment (drugs, infection, nutrition, maternal conditions, etc.) - single gene disorder *Pyloric Stenosis - Male > Females - Increased risk for sibling or children of affected female - for female to be affected, needs greater amount of defective genes *Mental Retardation - IQ < 70 - Global Developmental Delay – retardation < 5 years old - multifactorial (genetic and environmental) - Risk Factor: high maternal age, low education *Schizophrenia - Concordance = 60-85% for monozygotic twins - Risk Factor: high paternal age *Bipolar Affective Disorder - Concordance = 79% for monozygotic twins - no specific genes identified *Treatment of Coronary Heart Disease and Stroke - multifactorial - test for CYP2Cp and VKORC1 before starting treatment to improve accuracy of initial drug dosage 8) Describe the major/minor gene alleles have for risk assessment in disease where they occur and state examples of each in Hirschsprung’s and Alzheimer. Minor Genes – additive effects - observe multifactorial inheritance

Major Genes – act as a dominant allele which will confer  risk - observe Mendelian inheritance Additive Model – mixing of one gene between two different populations - looks similar to selective distribution - effects of each allele are co-dominant and have same level of influence on the trait Dominant Model – mixing of one gene between two different populations - 1 phenotype dominants and is expressed more often

1) State the criteria for a valid Hardy-Weinberg equation Rules: 1) Valid for population in equilibrium – allele frequency will stay the same in following generations 2) Mating must be random 3) Consanguinity (incest) – would not change allele frequencies - but proportion of homozygotes would increase 4) New mutations and selection offset each other 5) Population should be large - offset genetic drift - more genetic variability - decreased frequency of bad alleles 6) No gene flow (migration) 2) Use Hardy-Weinberg to predict allele frequency and frequency of different genotypes for single gene disorders if the disease incidence is known

Hardy-Weinberg Equation When having a number of actual people, could alleles instead of using Hardy-Weinberg!!

p2 + 2pq + q2 = 1 p2 = homozygote dominant 2pq = heterozygote frequency (carrier frequency) q2 = homozygote recessive (incidence) p = 1-q Review Semester 1 Pedigree ***In autosomal-recessive disorder - sibling of affected = 2/3 chance of passing on defective gene ***For X-linked recessive - males have a greater chance of being affected = multiply by ½ q = incidence in males q2 = X-linked recessive (affected females) 2pq = X-linked dominant (affected females) 3) Predict the effects of inbreeding and incest on the incidence of autosomal recessive and multifactorial disorders. State legal status of incest in related in part to these expected effects Effects of Small Interbreeding Population Autosomal Recessive: → increased frequency of homozygous affected for recessive diseases → increased selection against bad alleles (long-term effect) Multifactorial: → increased number of affected → decreased intelligence ***genetic drift may change allele frequency from one generation to the next

Monozygotic Twins = share 100% of alleles First degree Relatives = 50% of alleles (ex: siblings, offspring, parents, etc.) →  30% incidence of severe mortality and mortality Second degree Relatives = 25% of alleles (ex: half-siblings, uncles, grandparents, etc.) →  3% incidence of severe mortality and mortality Third degree Relatives = 12.5% of alleles (ex: first cousins, etc.) →  1% incidence of severe mortality and mortality Interbreeding Coefficient – percentage of gene loci that are homozygous as a result of interbreeding 4) Describe the expected effects of negative selection of allele frequencies of autosomal recessive and dominant diseases, and state that the lack of effects makes negative eugenetic unethical and scientifically wrong Complete Selection – when a person does not have viable offspring Even if implemented, it would not really work. It would take 10 generations to have 25% of the population having the gene and probably many more to get it to a smaller percentage. 5) Define the term stabilizing, disruptive, and directional selection. Give examples of each Selection Types - Stabilizing - extreme phenotypes do not perform as well → narrowing of distribution towards median - ex: blood pressure - Directional - one extreme of phenotypes performs better → movement of distribution towards one extreme - ex: higher education in women - Disruptive - extremes phenotypes do well, but average does not do well → split into two sub-populations - ex: birds at Galapagos Islands 6) Define heterozygote advantage, genetic drift, founder effect, assortative mating Founder Effect - can only include diseases with a low mutation rate - isolated population which descends from a small group of people who harbor an otherwise rare mutation → increased occurrence of a otherwise rare mutation within this isolated group - ex: Afrikaners (variegate Porphyria) - ex: Old Order Amish (Ellis-van Creveld syndrome), - ex: Pingelap islanders (Achromatopsia 3) Assortative mating – actively chosen mating Heterozygote Advantage – heterozygote genotype has a higher fitness than either homozygote dominant/recessive \ 7) State the effects of paternal age on rate of point mutations Mutations - Point Mutations increases with paternal age - Large deletions are more likely to arise in female meiosis (maternal age effect)

1) Age-dependence on infertility and specific causes Infertility – no pregnancy after trying for a minimum of 1 year - Prevalence: 40 = 11% Risks: multiple pregnancies (twins – 22%; triplets – 1.1%) Oocyte Donation: $4200 per egg

Cryopreservation - freezing can damage living cells (ex: osmotic stress, ice crystals piercing membranes) - only possible with small tissue sample (organs or bodies are impossible) - sperm can be frozen but insemination success is less than with fresh sperm - egg can be frozen without major risks - oocytes are difficult to freeze Technique: 1) Add antifreeze 2) Rapid freezing

Intracytoplasmic Sperm Injection (ICSI) Indication: - low sperm count - poor sperm quality - immotile sperm - post-vasectomy Procedure - sperm is immobilized → sucked into needle → injected directly into egg cytoplasm during IVF Risk: Slight increased risk of Beckwith-Wiedeman (overweight fetus) Slight increased risk of Angelman syndromes (imprinting error) 4) Principles, applications, and procedures of pre-implantation genetic diagnosis

Pre-Implantation Genetic Diagnosis - diagnosis of genetic diseases in early embryo Procedure - Make IVF - Grow embryo to 8-cell stage - Remove 1-2 cells for testing - Single-gene disorder: PCR - Aneuploidy: FISH - Shotgun screening – whole-genome amplification and DNA microassays 5) Major risks of procedures for assisted reproduction

Androgens - Replacement therapy in male hypogonadism - establish normal puberty and then support male secondary sex characteristics - induce fertility with gonadotropins - Not effectively administered orally - high rate of hepatic metabolism → insufficient testosterone levels - oral formulations are hepatotoxic - non-scrotal patch - scrotal skin – high rate of DHT conversion →  [DHT] →  BPH risk - Not effective for primary hypogonadism (problems with testes) - lipid solubility → depot preparation – few complications → gel preparation – applied daily with attention to bathing and possible contact with others → patch preparations – must be changed once or twice daily; possible skin irritation Testosterone 1) Begin with low dose → stimulate skeletal growth and secondary sex characteristic → avoid premature epiphyseal closure 2) Gradual increase until maturity achieved 3) Establish lifelong regimen Testosterone Enanthate – Testosterone Ester - fatty acid-esterification → increase lipid solubility - depot IM injection to bypass enterohepatic circulation 17-Alkylated Androgens - oral formulation of androgens - hepatotoxic

Drugs to Block Androgen Activity Flutamide – Receptor Inhibitors - used in conjunction with Leuprolide → prevent disease flare at initiation of leuprolide Finasteride – 5-Reductase Inhibitor - Use: androgen-dependent hyperplasia (BPH) → blocks formation of androgen that supports prostate growth and hyperplasia

Gonadotropin-Related Drugs Leuprolide – GnRH Agonist - down regulate GnRH receptor →  [androgens] - “chemical castration” - use in conjunction with flutamide Abarelix – GnRH Antagonist - GnRH receptor antagonist →  [androgens] - “chemical castration” - not as effective as leuprolide

Bromocriptine – dopamine agonist - inhibit prolactin → treat hyperprolactinemia

Treatments of Infertility Hypothalamic GnRH - not currently available - administration – pump → mimic in vivo pulsatility - lower incidence of multiple birth

Pituitary Menotropins (FSH + LH) hCG (LH) FSH LH - exogenous gonadotropins - suppress endogenous gonadotropins with GnRH - administer exogenous gonadotropins

Ovarian Clomiphene – anti-estrogen - block negative feedback that decreases hypothalamic pulsatility →  [LD] +  [FSH]

Contraception Adverse Effects - high doses of estrogen →  clotting factors - smoking → hypercoagulability - obesity →  risk of venous thrombosis Combined Oral Contraceptives - Smokers > 35 years old contraindicated

Estrogens Estradiol (17β-estradiol) - micronized for sufficient surface area for rapid absorption → highly absorbed through epithelial surfaces → cleared rapidly after oral administration Mestranol – metabolized to ethinyl estradiol Ethinyl Estradiol – more resistant to hepatic degradation

Progestins - rapid first-pass metabolism → poor bioavailability = give in high doses Norgestrel/Levonorgestrel; Norethindrone – 19-Nortestosterone Derivatives

- good oral activity - some androgenic actions Desogestrel – Gonanes - newer 19-Nortestosterone Derivative - less androgenic activity Medroxyprogesterone – C-21 - effects closer to progesterone Drospirenone – Spironolactone Derivative - C-21 derivative - mineralcorticoid antagonist

Selective Progesterone Receptor Modulator Mifepristone Ulipristal - emergency contraception - Use up to 5 days after intercourse - Best tolerated emergency contraceptive Progestin Actions: - suppression of LH → prevent ovulation - thicken cervical mucus → prevent sperm travel - decidualized endometrium → non-receptive to implantation - decreased fallopian tube motility

1) Be able to define pelvis, perineum, anal and urogenital triangles Anal Triangle - Ischiorectal (Ischioanal) Fossa 1) Rectum, anal canal 2) Pudendal Canal - Pudendal nerve – inferior rectal n. - Internal pudendal artery/vein – inferior rectal artery/vein - filled with fat - supportive packing - can be compressed or pushed for distention of fetus and feces - Anterior recess – extension into urogenital triangle - superior to perineal membrane and inferior to levator ani Rectum - Anal Crypt – ducts of glands - infections of glands → spreading into ischioanal fossa - Pectinate line Upper - Superior (Internal) Venous plexus - Visceral motor/sensory innervation - Internal iliac lymph nodes - Inferior Mesenteric Artery → superior rectal a. → drain to portal system Lower - Inferior (External) Venous plexus - Somatic motor/sensory innervation - Superficial inguinal lymph nodes - Internal Iliac a. → internal pudendal a. → inferior rectal a. → drain to caval system 2) Understand the structures of the pelvic floor Pelvic Diaphragm = obturator internus + levator ani Urogenital Diaphragm = perineal membrane 3) Be able to place the ischioanal fossa and its contents 4) Clinical relevance: anal fissure, perianal abscess, hemorrhoids, anorectal incontinence, episiotomy *Internal Hemorrhoids – dilation of internal rectal veins – painless - Factors: Pregnancy, Constipation, Portal Hypertension *External Hemorrhoids – dilation of external rectal venous plexus – puritis (itching) and painful - Factors: Pregnancy, Constipation, Portal Hypertension *Anal Fissures – mechanical tear in squamous epithelial mucosa of anal canal - if untreated → infection → abscess *Perianal Abscesses – collection of pus outside the anus - Location: Intersphincteric, Supra-levator, Ischiorectal, Perianal - Cause: Infection of anal fissures, infection of anal crypts - Treat: surgical drainage *Anorectal Fistulas – abnormal communication between anus and perianal skin - Location: Transsphincteric, Intersphincteric, Suprasphincteric, Extrasprincteric - Cause: Infection of anal fissures, infection of anal crypts - Treat: fistulotomy *Episiotomy – mediolateral cut to avoid tearing into external anal sphincter

1) Describe the bones, ligaments, and joints that compose the pelvic girdle Osteology Coxal (Hip) Bone - Sacroiliac Joint – synovial joint - Pubic Symphysis – cartilaginous joint - ASIS/AIIS - PSIS/PIIS - Greater Sciatic Notch - Lesser Sciatic Notch - Ischial spine - Ischial Tuberosity - Arcuate Line Sacrum - Lumbar-sacral joint - Anterior Sacral Foramina - Sacral Promontory Coccyx Greater Pelvis = False Pelvis = Pelvis Major Lesser Pelvis = True Pelvis = Pelvis Minor Pelvic Inlet – divide greater and lesser pelvis Ligaments Sacrotuberous – GSF – Sacrospinous + Sacrum Sacrospinous – LSF – Sacrospinous + Sacrotuberous 2) Why are the foramina of the pelvis important? Especially the greater and lesser sciatic foramina? 3) Understand the anatomical orientation of the pelvic girdle and the differences between the pelvic inlet and pelvic outlet and the clinical important ***Anatomical Position – pelvis at an angle where ASIS and pubic symphysis are one a vertical plane *Diagonal Conjugate – obstetric measurement of AP diameter of pelvic inlet (from sacral promontory to pubis) 4) Know the muscles related to the pelvic diaphragm, their orientations, apertures, and any important fascia

Muscles Related to the Pelvic Diaphragm Pubic Diaphragm’s Wall Piriformis – lateral rotation - form posterior wall of pelvic diaphragm - fibers travel out of GSF → attach to greater trochanter Obturator Internus – lateral rotation - forms lateral wall of pelvic diaphragm + lateral wall of perineum - fibers travel out of LSF → attach to greater trochanter - tendinous arch – thickening and lateral attachment site for levator ani Pubic Diaphragm Coccygeus Levator Ani – attach to tendinous arch (lateral) and anococcygeal ligament (medial) - Iliococcygeus

- Pubococcygeus - Puborectalis 5) Be familiar with the depth of the perineum and the two triangles that compose the perineum. Understand how the ischioanal fossa relates to the urogenital triangle and pelvic diaphragm

Perineum – diamond-shape structure containing two anatomical triangles – triangles are 90° to each other Anal Triangle - Anterior Recess – communication with urogenital triangle (deep perineal pouch) - potential space superior to perineal membrane - Ischioanal Fossa - filled with adipose tissue – pack and provide support to rectal structures - Pudendal Nerve (S2, S3, S4) Urogenital Triangle 6) Describe the origination, course, and termination of the pudendal nerve - Pudendal Nerve (S2, S3, S4) – lies on lateral wall in pudendal canal with pudendal vessels - Pathway - exits lumbar-sacral plexus → GSF - descends and runs laterally to Sacrospinous ligament → LSF - runs on wall of obturator internus → pudendal canal → into anal triangle - Branches - Inferior Rectal Nerve - Vessels - Internal Pudendal a. → Inferior Rectal a. 7) Why is the perineal body important? Why is an episiotomy? - Perineal Body – collagenous structure that serves as an attachment to many muscles - commonly torn during child birth *Episiotomy – mediolateral cut to avoid tearing into external anal sphincter 8) Know the perineum is composed of three pouches/spaces Urogenital Triangle 1) Inferior Fascia of Pelvic Diaphragm 2) Deep Perineal Pouch – pouch – communication with anterior recess of ischioanal fossa 3) Perineal Membrane 4) Superficial Perineal Pouch – pouch 5) Colles’ Fascia 6) Superficial Fascia – pouch 7) Skin 9) Know the contents of the three pouches for both male and females

Urogenital Triangle (Female) Skin Superficial Fascia - Labia major - Labia minor

- Vestibule - Round Ligament of Uterus Colles' Fascia Superficial Perineal Pouch Vestibular (Bartholin’s) Gland – secretion of fluids during sexual arousal Paraurethral (Skene’s) Glands – remnants of prostate gland Erectile Bodies: - Clitoris - Bulb of Vestibule Musculature - Ischiocavernosus - Superficial Transverse Perineal - Bulbospongiosus - Perineal Body – collagenous structure that serves as an attachment to many muscles - commonly torn during child birth Perineal Membrane Deep Perineal Pouch – communication with anterior recess of ischioanal fossa Urethral Sphincter Deep Transverse Perineal Dorsal Nerve of Clitoris Inferior Fascia of Pelvic Diaphragm

Urogenital Triangle (Male) Skin Superficial Fascia - Layers of scrotum + Testis, Epididymis, Ductus Deferens, etc. Colles’ Fascia Superficial Perineal Pouch Erectile Bodies - Corpus Cavernosa  2 crus - Corpus Spongiosum  bulb of penis → Glans Penis Buck’s Fascia Musculature - Superficial Transverse Perineal - Ischiocavernosus - Bulbospongiosus Perineal Membrane Deep Perineal Pouch Bulbourethral gland External urethral sphincter Deep Transverse Perineal Membranous urethra Dorsal Nerve of Penis Inferior Fascia of Pelvic Diaphragm

10) Understand the innervation and vasculature of the perineum Innervation - Posterior Femoral Cutaneous nerve (S2, S3) - Ilioinguinal nerve (L1) - Genital Branch of Genitofemoral nerve (L1) - Pudendal Nerve (S2, S3, S4) → Inferior Rectal nerve (main) → Perineal Nerve → Dorsal Nerve of Clitoris/Penis *Pudendal Nerve Block – palpate ischial spine Vasculature (Arterial) - Femoral Artery – superficial → Superficial External Pudendal Artery → Deep External Pudendal Artery - Internal Pudendal Artery (main) → Inferior Rectal a. → Perineal a. ---DEEP----------------------DEEP--→ Artery to Bulb → Dorsal Artery of Clitoris/Penis → Urethral a. Vasculature (Venous) – mostly follows arteries Exceptions: - Deep Dorsal Vein → Prostatic Venous Plexus - Superficial Dorsal Vein → Superficial External Pudendal v. → Femoral v. Lymphatics - Internal Iliac Nodes – deep parts of perineum - External Iliac Nodes – glans penis, glans clitoris, labia minor, distal end of vagina - Deep Inguinal Nodes – glans penis, glans clitoris, labia minor, distal end of vagina - Superficial Inguinal Nodes – scrotum, labia major, superficial tissue of penis/clitoris 11) Know the fascial layers and their clinical importance Fascia 1) Deep Fascia - External Oblique → External spermatic fascia → Buck’s fascia (male) → Fascia lata 2) Superficial Fascia - Deep Membranous – derived from Scarpa’s Fascia – fuse with fascia lata → Colles’ Fascia → Dartos Fascia (male) - Subcutaneous Fatty Layer – derived from Camper’s Fascia

12) Know the difference between a rupture of the spongy/penile urethra and membranous urethra *Rupture of Spongy/Penile Urethra – rupture of corpus Spongiosum and spongy urethra - fascia layers prevent fluid passing into the thighs and into the ischioanal fossa - ex: trauma or incorrect catheter insertion *Rupture of Membranous (Intermediate) Urethra – extravasation of urine and blood into deep perineal space - fluid may pass superiorly through urogenital hiatus and distribute around prostate and bladder - cause: fracture of pelvic girdle, separation of pubic symphysis and puboprostatic ligaments 13) Know the parts of the male urogenital system Male Urogenital System 1) Preprostatic Urethra 2) Prostatic Urethra 3) Intermediate (Membranous) Urethra 4) Spongy/Penile Urethra

Erection - Autonomic Innervation → relaxation of smooth muscle → allow blood to fill sinuses - Somatic Innervation – Bulbospongiosus and Ischiocavernosus → prevent outflow of blood - Perineal and Pudendal nerve Male Urogenital System - Emission – Testis → prostatic urethra - Ejaculation – prostatic urethra → external world - Semen – sperm + secretions Male Urogenital Vasculature Internal Iliac a. (anterior branch) → Obturator a. → Umbilical a. → Superior Vesicle a. → Artery of ductus deferens → Inferior Vesicle a. → Middle Rectal a. → Internal Pudendal a. → Inferior Rectal a. → Inferior Gluteal Internal Iliac a. (posterior branch) → Iliolumbar a. → Lateral Sacral a. → Superior Gluteal a. Female Urinary System - Sphincter Urethrae - Detrusor Muscle Female Reproductive System - Oviduct - Fimbria - Infundibulum - Ampulla - Isthmus - Uterus - Fundus - Body - Isthmus - Cervix - Internal Os - External Os - Fornix - Ligaments 1) Ligament of the Ovary 2) Round Ligament of the Uterus 3) Broad Ligament of the Uterus – double layered peritoneum; ovary located posteriorly

- Mesosalpinx - Mesovarium - Mesometrium 4) Suspensory Ligament of Ovary – ovarian vessels 5) Uterosacral Ligament 6) Cardinal (Transverse Cervical) Ligament – uterine vessels *Ectopic Pregnancy – pregnancy occurring outside of uterus - 90-95% occur in uterine tube Angles of Uterus and Vagina - Normal = anteflexion and anteversion - Flexion = angle between cervix and body of uterus - Version = angle between cervix and vagina *Vaginal and Uterine Prolapse – loss of tone; stretching of uterine ligaments - 1st, 2nd, 3rd (complete) prolapses Female Urogenital Vasculature Internal Iliac a. (anterior branch) → Obturator a. → Umbillical a. → Superior Vesicle a. → Uterine a. → Vaginal a. → Inferior Vesicle a. → Middle Rectal a. → Internal Pudendal a. → Inferior Rectal a. → Inferior Gluteal a. Internal Iliac a. (posterior branch) → Iliolumbar a. → Lateral Sacral a. → Superior Gluteal a. Rectum and Anal Canal Vasculature Inferior Mesenteric a. → Superior Rectal a. (Portal) Internal Iliac a. → Middle Rectal a. (Caval) Internal Pudendal a. → Inferior Rectal a. (Caval) Aorta → Median Sacral a. (Caval) Fascial Layers - Peritoneum - Parietal Fascia – continuous with transversalis fascia - Visceral Fascia - Rectovesicle pouch (male) - Vesicouterine + Rectouterine pouch (female) Innervation

Pelvic Splanchnics – PNS (S2-S4) Sacral Splanchnics – SNS (L1-L2) Testis/Ovaries - SNS – Lesser Splanchnic (T10-T11) - PNS – Vagus

Internal vs. External Genitalia Gender – roles assigned to them by society or themselves Biological Sex – chromosomal, gonadal, phenotypical

Transition to Puberty Negative Feedback in Pre-Puberty (GnRH) Inhibit: GABA, NPY, Endorphins, Testosterone, Estrogen (E2), Melatonin Stimulate: Glutamate Puberty:  [GABA], [Melatonin],  [NPY]  [Glutamate],  [Leptin] Pre-Puberty: [LH] < [FSH] Puberty:  [LH] >  [FSH] ***  fat =  [Leptin] - overweight children have greater chance of going into puberty at an earlier age Interaction between GH and LH/FSH GnRH →  LH/FSH +  GH - GH →  gonadal function → testosterone and estrogen →  GH →  IGF-1 → body growth +  gonadal function +  GnRH - LH/FSH →  gonadal function → testosterone and estrogen →  GH

Oogenesis Oogenesis – takes 3 menstrual cycles to mature and ovulated Ovarian Follicle - maintain and nurtures resident oocyte - assists in fertilization - prepares lining of uterus to accept and implant a blastocyst - maintain hormonal support for the fetus until the placenta can take over - Most oocytes are produced by the 6th month of gestation – remain at diplotene (prophase I) - Birth = 2 million oocyte - Puberty = 400,000 oocytes Development of Ovarian Follicle - Stage 1 – Primordial follicle → primary follicle - Cells “turned on” to produce steroids - theca interna develop - granulosa cells begin to secrete fluid - Stage 2 – Primary Follicle → Multilayered state (Secondary follicle) - Stage 3 – Secondary Follicle → Graafian (Mature) follicle - liquor Folliculi - approximately 20 Graafian follicles are created at any one time

- Stage 4 - Single Graafian follicle achieves dominance → regression of cohort follicles - one Graafian follicle is more sensitive to FSH → controls/regulates FSH → regulates estrogen to its needs only!! - Dominant Graafian follicle matures → secondary oocytes (metaphase II) - Dominant Graafian follicle ovulated → retain zona pellucida and corona radiata - LH surge → ovulation Hormonal Regulation of Oogenesis - Hypothalamo-Pituitary-Ovarian Axis FSH: initially stimulate growth of granulosa cell and estradiol synthesis Follicular Phase FSH – affect aromatase in granulosa cell → estrogen LH – affect cholesterol desmolase in theca cell → androgen Luteal Phase/Pregnancy LH – affect theca-lutein cells → androgen hCG – affect theca-lutein cells → androgen LH – affect granulosa-lutein cells → progesterone hCG – affect granulosa-lutein cells → progesterone

Menstrual Cycle Follicular Phase - negative feedback – kill off cohort follicles - estrogen-mediated Ovulatory Phase - positive feedback –  estrogen →  LH >  FSH → drive ovulation - estrogen-mediated - LH receptors appear on granulosa cells → progesterone secretion

- estrogen levels fall 1 day before ovulation - LH surge → prostaglandin endoperoxidase synthase (granulosa cell) - pseudo-inflammatory → increased intrafollicular pressure - FSH surge → stimulate plasminogen activator → plasmin → break down follicular wall → break down cumulus oophorus prior to ovulation Luteal Phase - negative feedback - progesterone-mediated - progesterone indication that ovulation has occurred ***Ovum is viable for 72 hours after ovulation – fertilization is possible during this period Post-Ovulation Follicle - Corpus hemorrhagicum → corpus luteum - secrete progesterone - negative feedback – LH and FSH - inhibit uterine muscle contractions - 12-14 day lifespan unless stimulated by hCG during pregnancy - secrete steroid hormones until placenta assumes this role (during pregnancy) - Corpus luteum → corpus albicans (no pregnancy) - apoptosis begins by 8th day of ovulation

Uterine Cycle Proliferative Phase - driven by estradiol (estrogen) - proliferation of stromal and glandular epithelium Secretory Phase - driven by progesterone - increased vascularization + glandular function - cervical mucus ferning - uterine lining becomes filled with glycogen granules - secrete nutrients into lumen → supply nutrients to morula prior to implantation

Menstrual Phase  progesterone from corpus lueum - vasospasm of vessels → ischemia/necrosis → desquamation of uterine endometrium - first spotting is considered day 1 - max flow occurs on day 2

Estrogen and Progesterone Estrogen - 3 different steroids with the same effect but different affinity for the same estrogen receptor Progesterone → E1 (estrone); E2 (estradiol); E3 (estriol) Testosterone → E2 (estradiol); E3 (estriol) Effects: - kill cohort follicles - alter cervical mucus - affect fallopian tube →  contraction + ciliary movement → favor ovum and zygote movement - Uterus – stimulate cell proliferation +  uterine tube contractility - prepare endometrium for secretory phase - LH surge - secondary sexual characteristics Progesterone Secondary Sexual Characteristics - Uterus –  glandular function +  uterine contraction - Fallopian tube –  glandular secretions - Breast –  swelling + development of breast tissue + prepare for secretory function Menopause - exhaustion of functional primary oocytes -  plasma [estrogen] + [progestin] →  [LH]/[FSH] (loss of negative feedback) *Endometriosis – ectopically located endometrial tissue - response to cyclic variations of estrogen and progestions → proliferation → secretions → desquamation *Pelvic Inflammatory Disease (PID) – caused by numerous infectious organisms *Hypogonadism – lack of ovarian steroid hormones - causes: lack of gonads; enzyme malfunction; inadequate LH/FSH secretion *Amenorrhea – loss of menstruation - often related to cessation of LH/FSH secretion - ex: stress, low body weight, menopause

1) Define and describe 3 forms of sex (and 1 gender) in terms of differential embryonic development and the factors which controls this into the production of male or female tissues and organs 2) Outline the general features of biosynthesis of sex steroid hormones in males and identify the cell types in the testes that produces sex steroid hormones 3) List the primary and secondary sexual characteristics and the hormone responsible for each. 4) List major target organs or cell types of each steroid hormone and describe the effects of each 5) Define and describe the related process of spermatogenesis in males 6) Trace the development of sperm during spermatogenesis including the functions of Leydig and Sertoli cells and the interactions between these two cells 7) Describe the specific signal transduction pathways in males that mediate the actions of LH, FSH, GnRH, testosterone, DHT, estrogen, and progestins (include target tissue and receptor types) 8) Draw concept maps for feedback regulation of hypothalamic-pituitary-gonadal axis in males 9) Describe age-related changes in male reproductive system 10) List the sequence of four phases that constitute the sex act in males and the participation of neural, vascular, and endocrine factors in each face. Correlate these with the sequence of the five phases in erectile process Primary Reproductive Organs – Testes Accessory Reproductive Structures – scrotum, ducts, glands (seminal vesicles, prostate, Bulbourethral/Cowper’s) Defining Sex - Chromosomal - Gonadal - Phenotypical Sertoli Cells 1) Support maturation of spermatogonia 2) Growth factors 3) Androgen binding protein (ABP) 4) β-Estradiol 5) FSH receptors 6) Blood-testis barrier Leydig Cells 1) Synthesize testosterone 2) LH receptors Time Course of Male Differentiation

Negative Feedback in Pre-Puberty Male (GnRH) Inhibit: GABA, NPY, Endorphins, Testosterone, Estrogen (E2), Melatonin Stimulate: Glutamate Puberty:  [GABA], [Melatonin],  [NPY]  [Glutamate],  [Leptin] Pre-Puberty: [LH] < [FSH] Puberty:  [LH] >  [FSH] ***  fat =  [Leptin] - overweight children have greater chance of going into puberty at an earlier age  [GnRH] →  LH, FSH LH → proliferation of Leydig Cells →  testosterone → appearance of primary sexual characteristics → proliferation of seminiferous tubules FSH → onset of spermatogenesis → stimulate Sertoli cell function → Spermarchy (nocturnal emission of sperm) Spermatozoa - Spermatogenesis is constant – not accelerated by androgens or gonadotropins - Lifespan: 6 weeks (4 weeks functionally) - Head - Acrosome - Nucleus - Middle Piece - GLUT-5 – fructose transporter - Mitochondria - End Piece - Flagellum - Alkaline medium (semen) →  activity - Acidc Medium → death of sperm →  activity - High temperature →  activity →  metabolic rate →  lifespan (to 1-2 days) LH effects on Leydig Cell 1) Secretion of testosterone (cAMP)

- negative feedback from esterogen produced by Sertoli cells 2) Growth of Leydig Cell (trophic effect) 3) Prolactin assists – increase LH receptors 4) IGF-1 enhances testosterone synthesis 5) FSH facilitates LH action on Leydig Cells

Testosterone must be transported by Binding Proteins - ex: sex-hormone binding protein, albumin, corticosteroid-binding proteins

Testosterone sets the basal production rate of sperm – but it is augmented by FSH FSH effects on Sertoli Cell (via cAMP) 1) Stimulate Steroli Cell maturation of germ cells 2) Increase glucose metabolism of Sertoli Cells 3) FSH and Testosterone → peptide hormones (inhibin B, activin, growth factors)

Mechanism of Action of Androgens - in many cells, testosterone converted to DHT - both testosterone and DHT bind intracellular receptor → bind transcription factor regions → activate/repress expression of genes - actions can be regulated through [receptor]

Effects of Testosterone and other Sex Hormones

Male Sexual Functioning - process may be initiated by the brain - process may be initiated by afferent sensory impulses from the penis (pudendal nerve) Flaccid Phase - SNS tone dominates Tumescence Phase - NO and Prostaglandin E1 →  [cGMP] → relaxation of smooth muscle → vasodilation Full Erection Phase - output of blood from penis is decreased by pressure on veins from engorged Cavernosa Rigid Phase - Cavernosa pressure > systolic pressure → no blood flow!! - Ejaculation (SNS) - peristaltic contractions - closure of internal sphincter of bladder Resolution Phase SNS activity constricts arteries →  blood flow Male Sexual Act 1) Excitement – erection occurs 2) Plateau – variable time course 3) Orgasm – ejaculation (emission) - peristaltic contractions driven by SNS 4) Resolution – relaxation → refractory period *Kallmann Syndrome – GnRH producing cells do not migrate from olfactory placode during embryogenesis - hypogonadotropic hypogonadism – abnormally low LH and FSH - low plasma testosterone

Female Sex Act 1) Excitement phase – PNS 2) Plateau phase – maintenance of lubricated state 3) Orgasm – SNS → uterus changes position → more “open” → cervical opening becomes more patent 4) Resolution → cervical opening remains widely opened for 20-30 minutes Impregnation - only 50-100 sperm reach ampullary portion of fallopian tube - only one sperm successfully penetrates the external granulosa cells and zona pellucida Route of Spermatazoa - motility of spermatozoa aided by female-secreted oxytocin - motility of uterine tube aided by male-secreted prostaglandins in seminal fluid Capacitation - only occurs inside female reproductive tract after seminal fluid has been washed away - final maturation process of spermatozoa 1) Increase motility ( [Ca2+] influx into sperm + increase temperature) 2) Dissipation of inhibitory factors - Fertilization-Promoting Peptide (FPP) – inhibitory product of prostate gland - wash away FPP → activation of sperm 3) Loss of cholesterol → exposing acrosomal membrane → acrosomal reaction → enzyme release - Acrosomal Reaction - increase membrane fluidity - Ca2+ influx → hyaluronidase - facilitate penetration of zona pellucida Fertilization Process 1) Sperm reaches zona pellucida 2) Bind ZP3 receptor → bind sperm head to acrosomal membrane (species-specific!!) 3) Bind ZP2 receptor → release enzymes - some sperm do not have enough enzyme 4) Increase intracellular Ca2+ and flagella action 5) Penetration of ovum cell membrane 6) Polyspermy block – PLC →  [Ca2+] → cortical granules inactivate ZP3/ZP2 + harden zona pellucida Transport of Fertilized Ovum - Fertilized ovum enters uterine cavity and expands (morula → blastcyst) - Expansion → destruction of zona pellucida - Implantation 5-7 days - Uterus secrete fructose → food for blastocyst - Blastocyst secrete hCG → bind LH receptor → maintain corpus luteum - Chorion secrete hCG → bind LH receptor → maintain corpus luteum - Corpus Luteum secrete progesterone and estrogen → suppose decidualization of uterine endometrium - glandular structures - storage of lipids and glycogen

The Placenta - Transports molecules to and from the fetus - mother = open circulatory systems (open chambers = intervillous space) - fetus = closed circulatory system CO2 – simple diffusion Glucose – facilitated diffusion Lipids, Free Fatty Acids, Ions – simple diffusion Waste Products (Urea, Uric acid, Creatinine) – simple diffusion - Serve as: - Major endocrine gland - Fetal kidney - Fetal gut - Fetal lung – external respiration - handle low quantities of O2 - Maternal PaO2 = 50 mmHg - Fetal PaO2 = 30 mmHg - HbF – has higher affinity for oxygen than HbA - Increased ventilation ( 50%)– increased oxygen consumption - progesterone stimulates medullary respiratory centers

Hormones of Pregnancy Progesterone (major) - week 10 – placenta primary source - support endometrium (decidualization) - Progesterone block – suppress contractility of uterine smooth muscle - development of mammary glands → ductal and alveolar growth Human Chorionic Gonadotropin (hCG) - produced by synctiotrophoblasts - LH-like activity → rescue/sustain corpus luteum + growth factor + prepare endometrium for implantation Human Chorionic Somatomammotropin (hCS) – growth hormone - switch pregnancy metabolism from anabolic to catabolic phase Estrogen - stimulate growth of myometrium, uterus, breast, mammary ducts, external gentalia - development of mammary glands → ductal and alveolar growth - relaxation of pelvic ligaments - Estriol (E3) major product of placenta during pregnancy (Estradiol still in larger amounts) ***Progesterone and Estrogen released in multi-organ system → many points of control and regulation - synthesis is a coordinated effort of fetal, maternal, and maternal tissue 1) Maternal – produce cholesterol 2) Placenta – convert cholesterol to pregnenolone 3) Fetal Adrenal Gland – convert pregnenolone to androgens (DHEA) - Androgen – DHEA (fetal) – cannot convert to progesterone or estrogens (E1, E2, E3) → must transport androgen to placenta

- with assistance of maternal tissue → convert to estrogens and progesterone 4) Placenta – convert androgen (DHEA) to estrogen/progesterone Insulin - Early Pregnancy – sensitive - build energy stores for fetus (anabolic) - Late Pregnancy – insensitive - allow growing fetus to utilize energy stores (catabolic) Prolactin – produced by anterior pituitary Aldosterone – increased secretion to compensate “increased plasma volume” due to amniotic/fetal fluid Cortisol – increased levels due to increased estrogen-induced increases in cortisol-binding globulin Thyroxin – increased levels due to increased estrogen-induced increases in thyroid-binding globulin Calcitriol – increased to ensure adequate calcium absorption for fetal growth Maternal PTH – decreased by 50% to prevent demineralization of maternal bone

Metabolism of Pregnancy Anabolic Phase – first half - building up energy reserves - high insulin sensitivity Catabolic Phase – second half (particularly late second half) - accommodate growing needs of fetus - insulin resistance – low insulin sensitivity - increased maternal lipolysis

Most dramatic increase of blood/plasma volume and fetal weight = last 2 months Increased GFR and urine volume *Gestational Diabetes Mellitus (GDM) - Fasting Plasma Glucose > 126 mg/dL - Increase risk of developing type 2 diabetes (maternal)

- Risk Factors: family history, overweight babies, obesity, advanced maternal age - Fetal Effect: excessive weight gain, hyperglycemia, polyhydromnios, retardation, postnatal hypoglycemia *Preeclampsia – increased blood pressure during pregnancy - Risk: acute renal failure, hepatic failure, DIC, cerebral hemorrhage, edema

  1) Know embryonic origin of gonads and primordial germ cells Indifferent Gonads - developed from proliferation of epithelium and condensation of underlying mesenchyme - Week 4 – primordial germ cells (large, spherical) become visible – endoderm origin - Week 6 1) Primordial germ cells migrated to genital ridges → induce development of gonads 2) Primitive sex cords – invaginations of epithelium into the mesenchyme 3) Paramesonephric (Mullerian) Duct – invagination of coelomic epithelium 4) Mesonephric (Wolffian) Duct ***If Primordial germ cells fail to reach genital ridge by week 5 → gonads do not develop 2) Know the derivatives of mesonephric duct and paramesonephric ducts

Genital Ducts (Males) - Development of Mesonephric (Wolffian) Ducts 1) Appendix Epididymis – vestigial appendage from cranial mesonephric duct 2) Ductus Epididymis 3) Ductus Deferens - Development of Excretory Mesonephric Tubules 1) Paragenital tubules → Paradidymis – vestigial appendage from caudal excretory tubules 2) Epigenital Tubules → Ductuli efferentes - Development of Paramesonephric (Mullerian) Duct 1) Utriculus Prostaticus (Prostatic Utricle) – “little uterus” 2) Appendix testis - Primitive Urogenital Sinus (Paramesonephric/Mullerian Tubercle) → seminal colliculus

Genital Ducts (Female) - Development of Mesonephric (Wolffian) Ducts 1) Epoophoron – vestigial structure from cranial mesonephric duct + excretory ducts 2) Proophoron – vestigial structure from caudal excretory tubules 3) Gartner’s Cyst – vestigial structure from caudal mesonephric duct - Development of Paramesonephric (Mullerian) Duct 1) Fallopian Tubes (Oviduct) 2) Fusion of Paramesonephric Ducts → Uterine Canal → Body of Uterus - Broad Ligament of Uterus – separate Uterovesical pouch and Uterorecal pouch - Ovaries – upper border of Broad Ligament of uterus 3) Upper Part of Vagina - Primitive Urogenital Sinus (Paramesonephric/Mullerian Tubercle) Week 9 – two invaginations on lateral borders → Sinovaginal bulbs Month 3 – elongation of sinovaginal bulbs towards vaginal plate → elongation of vagina → hymen Month 5 – complete canalization

 

  Vagina – dual origins 1) Paramesonephric Duct 2) Primitive Urogenital Sinus (Sinovaginal Bulb)

Homologues Prostate Gland (male)  Prostatic Urethra → Urethral (Paraurethral) glands of Skene (female) Bulbourethral glands (male) Urogenital Sinus → Greater vestibular gland (of Bartholin) (female) Seminal Vesicle (male)  Mesonephric Duct 3) Know the structure and formation of indifferent gonads 4) Know the key factor for sex dimorphism Urogenital System – derived from intermediate mesoderm - male and females are virtually identical until the end of the 6th week - male development instigated by SRY on Y chromosome 5) Understand the formation of the testis or ovary from the indifferent gonads Testes 1) Mullerian Inhibiting Substance (MIS) (Anti-Mullerian) → suppress paramesonephric ducts 2) Testosterone (Leydig cells) → stimulate mesonephric duct + 5-reductase → dihydrotestosterone → stimulate external genitalia development Ovaries - Estrogen – also produced by placenta → Stimulate paramesonephric ducts → Stimulate development of external genitalia 6) Development of genitals External Genitalia (Indifferent Stage) Week 4 – Cloacal folds – derived from mesenchyme - Genital Tubercle – cranial union of cloacal folds Week 6 – Cloacal folds → Urethral and Anal Folds – caudal union of cloacal folds - Genital Swellings → scrotal swelling (male); labia major (female) Week 11 – female genital tubercle longer than males at this time External Genitalia Definitive Urogenital Sinus → penile urethra Urethral Fold → Corpus cavernousum surrounding penile urethra Genital Fold → scrotum - Phallus – rapid elongation of genital tubercle along with urethral folds under influence of androgen - fusion of urethal folds → corpus spongiosum surrounding penile urethra - Urethral Plate – line penile urethra – derived from distal urogenital sinus - Navicular Fossa – glandular part of urethra – derived from ectoderm - Prepuce – foreskin External Genitalia Genital Tubercle → clitoris Definitive Urogenital Sinus → vestibule Urethral fold → labia minor

 

  Genital swelling → labia major 7) Know the embryonic origin of the Sertoli cells, Leydig cell, and follicular cell SRY gene → Testis Determining Factor (transcription factor) → stimulate differentiation of Sertoli/Leydig cells Primitive Sex Cord - continue proliferation and elongation → medullary cord → Rete testis → Seminiferous tubule – horseshoe-shaped testis cords (canalize at puberty) - Primordial Germ cells → spermatogonia - Surface Epithelium of Celom → Sertoli cells - Mesenchyme of Genital Ridge → Leydig cells - Excretory Mesonephric Tubules → Ductuli Efferentes - Mesonephric Duct → Ductus Deferens Primitive Sex Cord 1) Continue proliferation and elongation → medullary cords 2) Degeneration of medullary cords 3) Replacement of medullary cords by ovarian medulla Week 7 – 2nd generation of cords from surface epithelium – Cortical Cords Month 4 – Cortical Cords split into cell clusters – Follicular Cells → primordial follicular cell → oogonia 8) Know the mechanism of developmental abnormalities *Klinefelter Syndrome (47 XXY/XXXY) – males – infertility, Gynecomastia, impaired sexual development *Swyer Syndrome (XY Female Gonadal Dysgenesis) – point mutation or deletions of SRY gene - oocyte absent - externally female but no menstruation or secondary female characteristic *Turner Syndrome (45 X) – female – gonadal dysgenesis, short, webbed neck, cardiac/renal abnormalities *True Hermaphrodites – both testicular and ovarian tissue *Pseudohermaphrodites – genotypic sex is masked by phenotypic sexual appearance - Female (46 XX) - ovary present - ex: Congenital Adrenal Hyperplasia (CAH); consumption of androgenic agents during pregnancy - Male (46 XY) - testis present - ex: androgen insensitivity syndrome; reduced production of androgen and MIS *Hypospadias – incomplete fusion of urethral folds → abnormal openings of urethra along ventral (inferior) border *Epispadias – urethral opening found on dorsal (superior) aspect of penis *Micropenis – insufficient androgen stimulation - Primary – Hypogonadism - Secondary – hypothalamic or pituitary dysfunction *Bifid/Double Penis – genital tubercle splits *Hydrocele *Indirect Inguinal Hernia *Cryptorchidism – undescended testis →  risk for sterility, malignancy 3% of male newborns 30% of premature Treat: corrective surgery > 1 year

 

  *Imperforated Hymen – birth defect → hymen complete tissue plate → accumulation of fluids Hydrometrocolpos – accumulation of menstrual blood *Duplication of Uterus – lack of fusion of paramesonephric ducts - Uterus Didelphys – double vagina – sinovaginal bulbs fail to fuse - Uterus Arcuatus – least severe – indentation of upper border of uterus - Uterus Bicornis – most common – partial fusion of paramesonephric duct - Uterus Bicornis Unicollis – complete or partial atresia of one of the paramesonephric ducts *Atresia of Cervix – atresia of both paramesonephric ducts *Atresia of Vagina – sinovaginal bulbs fail to develop 9) Know the mechanism of the descent of testis and ovaries Descent of Testis - descent mediated by shortening of gubernaculums → pulls testis down toward scrotum Week 12 – inguinal region Week 28 – inguinal canal Week 33 – scrotum Descent of Ovaries Gubernaculum → ovarian ligament + round ligament of the uterus

 

Primary Reproductive Organs – Testes Accessory Reproductive Structures – scrotum, ducts, glands (seminal vesicles, prostate, Bulbourethral/Cowper’s)

Testes Tunica vaginalis – remnant of process vaginalis – does not extend posteriorly Tunica albuginea – thick connective tissue capsule 1-4 seminiferous tubules per lobule → straight tubules → retes testis (in mediastinum testis) → efferent ductules → ductus epididymis → ductus deferens → ampulla + seminal vesicle → ejaculatory duct (distal ductus deferens) → membranous urethra + bulbo-urethral gland → penile urethra Function – Spermatogenesis - highly sensitive process - temperature must be 2-3 centigrade below normal body temperature - pampiniform plexus surrounds testicular artery → decrease arterial blood temperature 1) Infections – Mumps → mumps orchitis → possible loss of stem cells 2) Radiation 3) Drugs – diethylstilbestrol (DES) – synthetic estrogen used during cancer treatment or pregnancy → birth defects → increased risk of genital related cancers + sterility in males 4) Hormonal Imbalance – excessive androgen use 5) Cryptochordism (Undescended testis) –  temperature in undescended testis → no spermatogenesis Seminiferous Tubules Interstitium Leydig (Interstitial) Cells – production of testosterone Myoid Cells – contractile Fibroblast Cells Seminiferous Epithelium Spermatogenic Cells Sertoli (Sustentacular) Cells Spermatogenesis - approx. 64 days - not synchronized process → constant production and supply of sperm Spermatogonia (Spermatocyte → Spermatid) → Type A – true stem – maintain population of stem cells → produce more spermatogona → Type B – progenitor cell → primary spermatocytes (2n, 4N) → Meiosis I - rest at basal aspect – larger cell - simple cuboidal appearance - characteristic condensed chromosomes → secondary spermatocyte (1n, 2N) → Meiosis II - short-lived → Spermatid (1n, 1N) – with fertilization, normal diploid number is attained - early spermatid

- late spermatid – attached to luminal aspect of sertoli cells Spermiogenesis (Spermatid → Spermatozoa) - newly formed spermatozoa are immotile – will mature will traveling through the ductile system 1) Golgi Phase - Golgi complex → acrosomal vesicles 2) Cap Phase - Acrosomal vesicles → acrosomal cap - Centrioles → developing acrosomal complex - Mitochondria migrate towards middle-piece 3) Acrosome Phase - Manchette (microtubules) – condensation and elongation of the nucleus 4) Maturation Phase - Residual body *Immotile Cilia Syndrome – immotile spermatozoa due to lack of dynein or other proteins → infertility - associated with chronic respiratory infections

Know how to recognize cells in each phase of spermatogenesis - differentiate by location and by morphology Sertoli Cells - under control of FSH - inhibin + activin modulate FSH release - columnar in shape - Function: - Support, protection, nutritional regulation - Phagocytosis of residual bodies - Secretion of fluid for sperm transport - Production of Androgen Binding Protein (ABP) – transport testosterone to seminiferous tubule - Production of Anti-Mullerian Hormone - Blood-Testis Barrier = Sertoli-Sertoli junctional complex – bound together by occluding junctions - blood-testis barrier prevents exposure to immune system → Basal Compartment – stem cells (spermatogonia) → Adluminal (Luminal) Comparment – maturation of spermatocytes and successive generations Leydig Cell - under control of LH - secretion of testosterone - irregular shaped; acidophilic; filled with lipid droplets → foamy appearance

The Duct System Intratesticular Genital Ducts Straight Tubules – lined with sertoli cells (abruptly join retes testis → abruptly becomes simple cuboidal) Retes testis – lined with simple cuboidal cells Proximal ductuli efferentes – lined with tall columnar ciliated cells and shorter non-ciliated cells → scalloped appearance

- ciliated cells helps transport sperm - non-ciliated cells absorb testicular fluid - thin circular layer of smooth muscle outside basal lamina → peristalsis Excretory Genital Ducts Distal ductuli efferentes – lined with tall columnar ciliated cells and shorter non-ciliated cells → scalloped appearance - ciliated cells helps transport sperm - non-ciliated cells absorb testicular fluid - thin circular layer of smooth muscle outside basal lamina → peristalsis Ductus epididymis – lined with pseudostratified columnar with stereocilia - main storage site of sperm - sperm mature → motile at distal part of ductus epididymis - Principal Cell – with stereocilia, tall, columnar - Basal Cell – stem cell - circular muscular layer → peristalsis Ductus deferens – lined with pseudostratified columnar with stereocilia - Muscular Layers – very muscular → narrow lumen - Inner longitudinal - Middle circular - Outer longitudinal Ejaculatory duct – lined with simple or pseudostratified columnar epithelium without muscular layers - segment leaving prostate - formed by junction of ductus deferens (ampulla) and seminal vesicle Urethra *Vasectomy – cut through ductus deferens - due to thicker walls and easily “seen” through scrotal skin + easy to access and identify

Accessory Genital Glands Seminal Vesicle - outgrowth of ductus deferens – lined with pseudostratified or simple columnar epithelium - two highly tortuous tubes (15 cm) → honeycomb appearance (highly secretory epithelium) - secretions = 70% of ejaculation - contain sperm-activating substances (fructose, citrate, prostaglandins, etc.) - three layers: 1) Mucosa 2) Muscularis (inner circular, outer longitudinal) 3) Adventitia rich in elastic fiber Prostate Gland - lined with simple columnar though cuboidal, squamous, or pseudostratified epithelium may be visible - aggregation of many glands - largest accessory organ - Prostatic Concretions (corpora amylacea) – calcified glycoproteins in lumen of glands

Peripheral Zone (70%) - outer (main) glands - major site for prostate cancer Transitional Zone (5%) - submucosal glands - site where BPH usually originates Central Zone (25%) - mucosal gland *Benign Prostatic Hyperplasia – 40-50% of men → obstruction of urethra *Malignant Prostatic Tumor – second most common cancer in men and third leading cause of cancer deaths - prostatic-specific antigen (PSA) – elevated during malignancy Bulbourethral (Cowper’s) Glands - lined by simple cuboidal epithelium - two pea-sized structures - clear viscous secretions → lubricating function prior to ejaculation

Penis - consist of three parallel cavernous bodies - Flaccid: shunt between deep artery and deep dorsal vein remains open - Rection: shunt is closed due to expansion of erectile tissue → closure of deep dorsal vein Erection – PNS Ejaculation – SNS *Sildenafil (Viagra) – block phosphodiesterase (PDE) → prevent breakdown of cGMP → continual vasodilation → erection