1) Define pelvic cavity and review its boundaries Lesser/Greater Sciatic Foramen gluteal region Obturator foramen medial

al 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 (Batsons) 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 + 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 persons 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 Charlottes Risk of being a carrier = 9/19 - risk has decrease originally 1/2, now it is 9/19 Charlottes Risk of being having a child with Huntingtons 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 Kims Risk of being carriers = 1/88 Charlottes Risk of being having a child with Huntingtons 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 Amelias 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 Amelias Risk of being carriers = 6/26 = 1/13 Amelias Risk of being having a child with Huntingtons Disease 1/13 [risk of being a carrier] x 1/2 [passing on bad allele] = 3/26 - if sex is unknown: 3/26 x = 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 Xs seen in the non-dividing cell - Dosage Compensation Balancing Out all Xs 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 Xs - 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 Turners 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 (Gowers 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, Huntingtons 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: <1% 2) Maternal Uniparental Disomy (25%) functionally equivalent to a paternal deletion - associated with advance maternal age Maternal heterodisomy - Recurrence Risk: <1% 3) Chromosomal Abnormality (1%) - ex: parent with balance translocation child with unbalance karyotype 4) Imprinting Failure (2%) - ex: mutation of Imprinting Control Region fail to switch maternal imprints to paternal imprints fail to express active gene (paternal gene) - Recurrence Risk: 50% - Testing: FISH - Treat: Growth Hormone replacement to normalize height and improve lean body mass - Risk: for additional children with PWS depends on what is the molecular cause of the PWS *Angelman Syndrome (AS) - Phenotypical Features - Epilepsy - Severe learning disabilities - Unsteady gait - Happy face - Mechanisms 1) Interstitial maternal deletion at long arm of chromosome 15 (70-75%)

- 15q11-q13 - Recurrence Risk: <1% 2) Paternal Uniparental Disomy (5%) functionally equivalent to a maternal deletion - Parental isodisomy monosomy rescue - Recurrence Risk: <1% 3) Point Mutation UBE3A deletion (10%) ubiquitin gene expressed in the brain - Recurrence Risk: 50% 4) Imprinting Failure (5%) - ex: mutation of Imprinting Control Region fail to switch maternal imprints to paternal imprints fail to express active gene (maternal gene) - Recurrence Risk: 50% - Gonadal mosaicism some eggs may contain the mutation 5) Chromosomal Abnormality (rare) - ex: parent with balance translocation child with unbalance karyotype ***Majority of all imprinting disorders are sporadic and not familial!!

1) Understand molecule markers Locus particular location on the chromosome (loci) Allele particular form of a gene Genetic Markers - Biallelic marker RFLP genes encoding for proteins - Minisatellite VNTR - Microsatellite nucleotide repeats - Single Nucleotide Polymorphism (SNP) - Centromere tandem repeat sequences - Telomeres tandem repeat sequences Genetic Distance centiMorgan (cM) - 1 cM = 1% of recombination frequency ( = 0.01) - 1 cM = 1 million base pairs (human) 2) Understand polymorphism Polymorphism when multiple phenotypes exist in a population of species (ex: hair color) 3) Understand the difference between physical and genetic maps Physical Map number of bp Genetic Map number of recombinants 4) Understand how to determine the phase using the marker in coupling with the disease 5) Understand what is a recombinant and non-recombinant and be able to calculate () from a pedigree 6) Understand the basic concept of LOD score Genetic Linkage Linked 2 loci closely adjacent on the same chromosome are observed to be inherited together Coupling linked alleles on the same chromosome Repulsion alleles on opposite chromosomes Linkage Phase positioning of linked alleles in coupling and repulsion Haplotype groups of alleles that are coupled - markers should be numerous and highly polymorphic polymorphism increases probability that mating will be informative 1) How far are two loci apart? - estimate distance by recombination frequency ()

= (# recombinants)/(Total # of offspring)
2) How strong is the evidence for linkage vs. non-linkage? - estimate strength b calculating LOD-score - always take the maximal value of LOD LOD-Score = Log10 x (Linkage/No Linkage)

LOD > 1 = suggest two loci are linked

LOD < 1 = suggests two loci are unlinked LOD + 3 and above = proof of linkage LOD 2 and below = not linked
7) Apply genetic linkage in autosomal dominant/recessive and X-linked conditions Possible Problems - Do not always know the phase!! - ex: cannot establish phase in 2 generations = not enough information When Use Linkage? - if genes responsible for a disease is unknown or you cannot identify known mutations Linkage Disequilibrium significant deviation (more than by chance) from expected values Linkage Equilibrium haplotype has frequency of 0.25 in a population Examples:

= 0.05 chance of recombination (mutation that changes what is expected) - 5% normal - 95% affected - you would expect 1,2 to give you the disease

 = 0.05 chance of recombination (mutation that changes what is expected) - 5% affected - 95% normal - you would expect 2, 2 not give you the disease

Ovary
- 3cm long; 1cm thick; 1.3cm wide Tunica Albuginea dense connective tissue poorly vascularized Germinal Epithelium simple cuboidal - give rise to follicular cells - secrete OMI arrest development of primary oocyte (diplotene prophase I) Medullary Region (inner) - Content: blood vessels and connective tissue Cortical Region (outer) - Content: ovarian follicles, corpus luteum, corpus albicans Hormonal Overview GnRH pars distalis LH corpus luteum + ovulation + enhance maturation of follicle FSH maturation of follicle + ovulation Secondary + Mature Follicle Estrogen Corpus Luteum Progesterone receptive for blastocyst (implantation) Primary Follicle - Primary Oocyte (30m) - large nucleus 1 or more nucleoli + euchromatin - Balbiani Body concentrated collection of Golgi membranes, ER, mitochondria, and lysosomes - bursts release of organelles which multiply in number - Annulate Lamellae profiles of nuclear envelope (unknown function) - Cortical Granules locate beneath plasma membrane - enzymes alter plasma membrane prevent second fertilization Growth Primary Follicle not dependent upon FSH 1) Primordial follicle - Follicular (granulosa) cells surround follicle; on basal lamina; simple squamous Filopodia penetrate zona pellucida and contact oocyte via gap junctions - Zone pellucida composed of GAG and glycoproteins - Theca folliculi stomal connective tissue outside basal lamina 2) Unilaminar Primary Follicle Follicular (granulosa) cells simple cuboidal 3) Multilaminar Primary Follicle Follicular (granulosa) cells stratified cuboidal - Activin (primary oocyte) proliferation of follicular layer Granulosa layer stimulate FSH release - Granulosa layer not vascularized Secondary Follicle - characterized by fluid-filled cavities - Liquor folliculi = exudate of plasma (GAGs, proteoglycans, steroid-binding proteins, hormones) - Granulosa cells have FSH receptors [Granulosa cells] + intracellular spaces + [LH receptors]

- Theca Folliculi Differentiates - Theca interna inner layer cuboidal cells - Highly vascularized - LH receptors androstenedione (androgen) - LH receptor expression induced by FSH - many spaces for lipid droplets - separated from Granulosa layer via basement membrane - Theca externa outer layer - smooth muscle cells - collagen fibers Mature Graafian (Pre-ovulatory) Follicle - proliferation of granulosa cell and liquor folliculi single antrum space - Cumulus Oophorus granulosa cell projection of oocyte into antral space - Corona Radiata innermost layer of cumulus cells that surrounds oocyte

Summary
1) During Secondary and Mature follicle stage: LH stimulate theca interna cells secrete androstenedione (androgen) FSH stimulate granulosa cells convert androgen to estradiol (via aromatase) [estrogen] 2) [estrogen] negative feedback on FSH at pituitary gland LH surge resume of meiosis 1 secondary oocyte + 1st polar body - arrested at metaphase meiosis 2 ovulation (day 14 of 28 day cycle) formation of corpus luteum

Ovulation
- Surface of ovary loses blood stigma region (blanched, avascular region) degeneration of stigma region release of secondary oocyte at distal oviduct (fallopian tube) Corpus Luteum remnant of Graafian follicle - temporary endocrine organ - Corpus hemorrhagicum central blood clot - removal of clot by phagocytes under high LH levels Corpus Luteum - Corpus Luteum - basal lamina degenerates between granulosa layer and theca interna - highly vascularized vessels migrate to Granulosa layer vascularization of Granulosa layer! - Granulosa-Lutein cells (80%) modified granulosa cells - pale-staining (30-50m) - secrete progesterone with some estrogen - estrogen inhibit FSH prevent second ovulation - progesterone inhibit LH

- Theca-Lutein cells (20%) modified theca interna cells - dark-staining (15m) - secrete progesterone with some estrogen - estrogen inhibit FSH prevent second ovulation - progesterone inhibit LH - Corpus Luteum of Menstruation - lasts 10-14 days - degenerated Corpus luteum if pregnancy does not occur invade by macrophages/fibroblasts fibrotic/ceasing of function (Corpus Albicans) - Corpus Luteum of Pregnancy - lasts 3-4 months - Human Chorionic Gonadotropin (hCG) secreted by syncytiotrophoblast

Summary
1) Pulsatile release of GnRH every 90 minutes from arcuate nucleus 2) Development of Follicles independent of FSH 3) Activin stimulates release of FSH proliferation/stimulation of granulosa cells 4) During Secondary and Mature follicle stage: LH stimulate theca interna cells secrete androstenedione (androgen) FSH stimulate granulosa cells convert androgen to estradiol (via aromatase) [estrogen] 5) [estrogen] negative feedback on FSH at pituitary gland LH surge resume of meiosis 1 secondary oocyte (arrested at metaphase meiosis 2) ovulation (day 14 of 28 day cycle) formation of corpus luteum 6) Corpus Luteum - progesterone inhibit LH - estrogen + inhibin inhibit FSH prevent second ovulation - all FSH-dependent follicles atresia

Oviducts (Fallopian/Uterine Tube)

- richly vascularized Infundibulum with fimbriae Ampulla where fertilization occurs Isthmus narrow portion Intramural region opening into uterus Layers - Mucosa extensive folds that project into lumen - Lamina Propria - Muscularis - inner circular smooth muscle - outer longitudinal smooth muscle - Serosa composed from mesothelium - Epithelium: 1) Non-ciliated columnar Peg or secretory cells - secrete nutritive material for ovum and facilitate capacitation 2) Ciliated columnar cells - beat towards uterus

Uterus (Fundus and Body)

Parts: Fundus, Body, Cervix Endometrium (inner) Functionalis layer thick superficial layer sloughed off during menstruation - Epithelium: simple columnar epithelium non-cilitated columnar secretory + ciliated columnar - Lamina Propria: tubular glands extending from basalis layer - Vascularized spiral arteries rich network of capillaries + blood-filled sinusoids Basalis narrow layer below functionalis layer - Regenerative layer regenerate sloughed-off funcionalis layer (glands and connective tissue) - Vascularized: straight arteries (via arcuate arteries in myometrium) Myometrium - Muscular Layers (3) smooth muscle Inner Longitudinal Outer Circular (Statum Vasculare) highly vascularized arcuate arteries Outer longitudinal - muscle amount diminished and is replaced by fibrous connective tissue as you approach cervix cervix composed of DCT w/elastic fibers and scattered smooth muscle cells - muscles hypertrophy during pregnancy along with connective tissue (50 500m) Perimetrium - Fundus + Posterior Body of Uterus = Serosa - Anterior Body of Uterus = adventitia

Cervix
- Epithelium: simple columnar epithelium mucus secreting Transformational Zone transform into stratified squamous non-keratinized epithelium

***development of cancer often starts in transformational zone ***epithelium similar to esophagus but no esophageal glands - Cervical Glands simple columnar epithelium cervical glands located below epithelium Ovulation secrete serous fluid allow sperm to enter Normally viscous secretions plug at cervix (via progesterone) - Mucosal Lining is not sloughed-off during menstruation - Relaxin destroy collagen cervical expansion (prior to parturition) - Nabothian Cysts obstructed endocervical glands

Menstrual Cycle
Ischemic Phase sometimes present depending on textbook!! - Spiral arteries permanently constrict 2 days before day 1 Menstrual (Bleeding) Phase Day 1 Day 4 - Spiral arteries permanently constrict 2 days before day 1 ischemia/necrosis + dilation of spiral arteries bursting of spiral arteries discharge of blood that removes functionalis layer - Functionalis layer is sloughed-off 35 mL blood loss Proliferative (Follicular) Phase Day 4 Day 14 - Renewal of epithelium of endometrium initiated by estrogen - functionalis layer 2-3 mm thick - Occurs during same time ovarian follicles are developing Secretory (Luteal) Phase - Functionalis layer continues to grow (5-6 mm) influenced by progesterone increased vascularity edema accumulation of glycogen secretions endometrial glands become convoluted and branched - Implantation - Stromal cells (C.T. surrounding glands) Decidual cells pale and glycogen rich - influenced by progesterone

Vagina
Mucosa - Epithelium non-keratinized stratified squamous epithelium (200m) - Langerhan cells - Estrogen stimulate synthesis and storage of glycogen - glycogen converted by bacteria to lactic acid as cells are sloughed-off pH anti-microbial - Lamina Propria - Loose Connective Tissue allow for expansion - highly vascularized - No glands lubrication from glands of cervix (differentiate from esophagus)

Muscularis - Inner Circular smooth muscle - Outer Longitudinal smooth muscle intermingles with inner circular layer - Sphincter of striated muscle at external opening of vagina Adventitia fibroelastic connective tissue

Mammary Glands
- Tubuloalveolar glands - Lobules Lobes Lactiferous duct Lactiferous sinus - Lactiferous Sinus dilated portion of lactiferous duct which stores milk - Milk Content: protein, lipids, lactose, lymphocytes, monocytes, antibodies, fat-soluble vitamins - Lipid Secretion: Apocrine (membrane budding) - Protein Secretion: Merocrine (exocytosis) Resting (Non-secreting) - sparse undeveloped alveoli + inactive duct elements - Epithelium - Duct: simple columnar epithelium - Lactiferous Duct/Sinus: stratified cuboidal epithelium Lactating (active) - developed alveoli + hypertrophy of breast via estrogen and progesterone - alveoli surround by myoepithelial cells influenced by oxytocin milk ejection - Colostrum protein-rich fluid; first milk released by mothers - Milk replaces colostrums a few days after birth production via prolactin

1) Use diagrams to show the fetal membranes and discuss the fate of each (amnion, chorion, yolk sac, and allantois) Primitive Umbillical Cord 1) Connecting Stalk Allantois + Umbillical Vessels 2) Yolk Stalk Vitelline Duct + vessels 3) Canal connect intraembryonic and extraembryonic cavities Amniotic Cavity - rapid enlargement envelopment of connecting stalk and yolk sac primitive umbillical cord - Amniotic fluid - absorb jolts - allows for fetal movement - prevent adherence - fluid replaces every 3 hours fetus swallows its own amniotic fluid 2) Describe the development of the placenta. Use diagrams to show features of placental structure and function

The Placenta
- Fetomaternal organ Fetal Portion chorion frondosum (villous chorion) Maternal Portion decidua basalis (functionalis layer of endometrium) Decidua - Decidua basalis forms maternal portion of placenta - Decidua capsularis overlies conceptus - Decidua parietalis remaining parts of decidua Tertiary Villus filled with capillaries and connective tissue Chorionic Villi - Growth of chorionic villi posteriorly compression and degeneration of decidua capsularis smooth chorion (chorion laeve) avascular bare area - Growth of chorionic villi anteriorly growth into decidua basalis Chorion frondosum (villous chorion) - 4th month decidua basalis replaced by frondosum Fetomaternal Junction - Cytoprophoblastic shell attach villous chorion to decidua basalis anchor to chorionic sac - endometrial vessels pass through shell open in intervillous (lacunar) spaces via gap junctions - Placenta Septa decidua basalis that erodes into intervillous spaces wedge shaped septa - divide placenta into incomplete cotyledons (compartments) - intervillous space lined by syncytiotrophoblast ( derived from synctiotrophoblasts) Amniochorionic Membrane fusion of amnion and smooth chorion - adhere to decidua parietalis ruptures during labor amniotic fluid escape through cervix and vagina 3) Illustrate the placental membrane barrier and discuss the transfer of materials between fetal and maternal blood Circulation of Placenta

- Endometrial arteries maternal blood flows into intervillous spaces toward chorionic plate - blood flows slowly over branch villi gas/nutrient/metabolic product exchange - Endometrial veins return blood to maternal circulation Fetal Circulation - Arterio-Capillary-Venous System brings fetal venous blood close to maternal blood - Placental Membrane/Barrier separates maternal and fetal blood no mixing of blood!! - Pre-week 20 4 layers 1) Syncytiotrophoblast 2) Cytotrophoblast 3) Connective tissue in villous core extraembryonic mesoderm 4) Endothelium of fetal capillaries - Post-week 20 2 layers faster exchange 1) Syncytiotrophoblast 2) Endothelium of fetal capillaries 4) List the main activities of the placenta and explain their role in maintaining pregnancy and promoting embryonic development Function of Placenta 1) Metabolism - Synthesis: glycogen, fatty acids, cholesterol 2) Transport (simple diffusion, facilitated diffusion, active transport, pinocytosis) - gases, nutrients, electrolytes - maternal antibodies (week 14) IgG passive immunity - newborns reach adult levels at age 3 3) Endocrine Secretion - Syncytiotrophoblast proteins and steroids - Human Chorionic Gonadotropin (hCG) maintain corpus luteum - measured to determine pregnancy - Human Chorionic Somatomammotropin (hCS) give fetus priority on maternal glucose - Thyrotropin (hCT) - Corticotropin (hCACTH) - Progesterone maintain corpus luteum - Estriol stimulate uterine growth and development of mammary glands - max levels just before end of pregnancy ***Protein hormones do not cross placenta except T4, T3 and Unconjugated steroids ***Drugs can cross placenta via simple diffusion 5) Discuss the effects of drugs, viruses, and microorganisms that can cross the placental barrier *Alcohol *Organic Mercury *Thalidomide *Diethystilbestrol synthetic estrogen cross placenta carcinoma of vagina + abnormal testis *Treponema pallidum syphilis cross placenta *Toxoplasma gondii toxoplasmosis cross placenta damage to eye and brain

6) Use diagrams to show the gross and microscopic features of the placenta and umbilical cord 7) Discuss the embryological basis on twins Dizygotic Twins fraternal twins 2 eggs + 2 sperm Monozygotic Twins paternal (identical) twins 1 eggs + 1 sperm

Telomere Structure - Telomere repeats sequence = AGGGTT = GGTTAG = TTAGGG - always have one repeat unit that is single stranded at the tip of the 3 strand - triple helix loop stabilized by proteins protection from degradation Mosaicism mitotic error two cells that differ in content or expression Chimerism inclusion of cells originating in two different zygotes Euploidy normal chromosome count Aneuploidy abnormal chromosome count Polyploidy extra copies of ALL chromosomes not viable Trisomy excess of one chromosome only Trisomy 13, 18, 21, X, Y are viable - trisomy 16 is most common spontaneous abortion - size and amount of genes on chromosome determines severity - mutation in 18 and 13 more severe - 80% of trisomy 21 die in utero Monosomy lack of one chromosome only Monosomy X is viable - 99% of monosomy X die in utero Non-disjunctions primary or secondary meiotic non-disjunctions - primary (maternal) trisomy - 2 cells with 1 of each type trisomy (ex: 1, 3, 7) - 2 cells with nothing monosomy - secondary (paternal) monosomy - 1 cell with 2 of 1 type trisomy (ex: 1, 3, 3) - 2 cells with 1 of 1 type normal - 1 cell with nothing monosomy *Quantitative Marker Analysis measure with quantitative marker and compare peaks (ex: 1, 3, 3 vs. 1, 3, 7) Turner Syndrome (Monosomy X) Diagnosis: - normal intelligence - short stature - widely-spaced nipples - webbed neck - missing development of secondary sexual characteristic - infertile Incidence: 1/2500 to 1/5000 females - defect in paternal meiosis or mitotic error Complication: Heart Defect (30%); Renal defect (30%); hypertension; and rarely others Ultrasound Findings: Nuchal translucency + heart/renal defects + cystic hygroma - severe defects spontaneous abortion (99% occurrence) - Nuchal translucency space between soft issue of spine and skin - abnormally large (> 95 percentile) indicates abnormality - invisible nasal bone indicates abnormality

Treatment: - estrogen induce secondary sexual characteristics - growth hormone increase height - remove gonads if virilization occurs Kleinfelter Syndrome (47, XXY) Diagnosis - intelligence ranges from normal to mental retardation - developmental delays - learning disabilities - social maladjustment OR - Small testis [testosterone] - infertility - Gynecomastia (55%) ***Test for pituitary gonadotrophins (feedback) Incidence: 1/1000 males - 56% extra maternal X - 44% extra paternal X - 15% mosaics Complications: obesity, diabetes, thyroid problems, pulmonary disease Treatment: androgens improve virilization, bone density but worsen gynecomastia XXX (47, XXX) Diagnosis: - no abnormalities to slight mental deficiency - mental retardation with 48, XXXX or 49, XXXXX Incidence: 1/1000 females - maternal age effect XYY Diagnosis: - Increased height - Slightly decreased IQ - Behavioral abnormalities (hyperactivity, ADD, learning disabilities) Incidence: 1/1000 males Downs syndrome (Trisomy 21) Diagnosis: - mental retardation - specific head, hand, feet shapes - heart malformation (40%) - hypothyroidism - aging: early senility; Alzheimers disease (APP gene) 95% = trisomy 21 3-4% = have a translocation of trisomy 21 (usually Robertsonian)

- ex: 14-21 translocation, 21-21 translocation 1% = mosaic - 60% are spontaneously aborted + 20% still born = 80% die in utero - ex: 14-21 translocation carrier - 10% chance of having offspring with Downs syndrome *Single incidences occur often maternal age effect *Robertsonian translocations can lead to multiple cases in a family of Downs syndrome Edwards Syndrome (47 XX/XY + 18) most die within first year Diagnosis: - Prominent occiput - Malformed ears - Small chin - Heart Defects - Mental retardation - Hypertonicity clenched fingers Incidence: 1/8000 (80% females) - maternal age effect Patau Syndrome (47 XX/XY + 13) most die within first year Diagnosis: - Sloping forehead - Forebrain defect - Eye abnormalities - Cleft lip and palate - Polydactyly - Heart defect (88%) - Mental retardation - Deafness Incidence: 1/20000 - maternal age effect Cri-du-Chat Syndrome (spontaneous deletion of several genes chromosome 5) good survival into 30s (Italy) Diagnosis - distinctive, cat-like cry in babies - low birth weight - failure to thrive - severe retardation - characteristic faces Incidence: 1/20000 to 1/50000 - among severely retarded = 1/100 (1%) - deletions variable - deletions mental retardation

- mostly spontaneous - 10% - reciprocal translocation of parent DiGeorge Syndrome (CATCH-22 or VeloCardioFacial Syndrome) - many have deletion in chromosome 22 - development problems with 3rd and 4th brachial arch defects in aortic area of heart hypoparathyroidism hypocalcemia reduced immune function (thymus hypoplasia) increased risk of psychiatric disease *Fluorescence in situ Hybridization (FISH) - use labeled single probe only works if you know what youre looking for - must use control probe to flag desired chromosome - use chromosome paint cannot detect inversions and small deletions *Comparative Genome Hybridization (CGH) - map out genome and hybridize with patient DNA - measure hybridization signal detect variation in concentration of genome in a patient (deletions, etc.) - polymorphic copy number variation variation within genome concentration in normal population

Chromosomes in Cancer
- many cancers show unstable chromosomes during later profession - ex: non-disjunction; structural changes; de novo translocations - accumulation of mutations allow for faster cell replication/division - Visible as: - Aneuploidy - Homogenously staining regions genetically identical regions due to cancerous cell replication - Double minutes excised cancerous regions continue to replicate on its own after removal - Karyotype useful for prognosis and treatment Philadelphia Chromosome Chronic Myelogenous Leukemia (CML) - BCR chromosome 9 - ABL chromosome 22 - BCR-ABL fusion BCR product is now under control of an upstream ABL promoter overproduction of WBCs (lymphocytes) low grade fever, fatigue, night sweats enlarged spleen sternal tenderness (bone pain) Treatment: - bone marrow transplant (only cure) - hydroxyurea can alleviate symptoms - tyrosine kinase inhibitor (imatinib mesylate glivec/gleevec) - ABL gene is normally tyrosine kinase receptor inhibit ABL stop overproduction ***Diagnosis is made by finding the BCR-ABL fusion gene

1) Explain why multifactorial traits usually show a bell-shaped phenotypic distribution Bell Curve bell curve distribution observed in quantitative traits - Regression Towards the Mean offspring of extreme values tend to deviate back towards the average - extreme values usually caused by unusual environmental effects are arent likely to be repeated 2) Define the term heritability and state its limitations of analyzing the nature-nurture problem Heritability total variance that is caused by genes - data comes from comparing: - monozygotic vs. dizygotic twins - twins that were adopted - siblings raised together vs. siblings adopted - siblings vs. general population Concordance values are similar based upon relatedness (family, monozygotic vs. dizygotic twin, etc.) Correlation value of one is associated with a change in the value or the expectation of the other Look at notes to observe graph vs. table to measure heritability 3) Make semi-quantitative guestimate about the heritability of some multifactorial traits based on prior knowledge or data presented Multifactorial Inheritance a trait influenced by both genes (plural) and environmental factors Polygenic Trait trait determined by more than one gene but no environmental factors Liability combination of good and bad alleles + environment Threshold Trait when liability is above a threshold value the person will have the disease Observations 1) Siblings of affected have a higher risk than the general population affected individuals in a family = risk of being affected Rule-of-Thumb Risk for those closely related (1st degree) - risk for sibling of an affect = square root of population risk 2) Siblings of an affected person belonging to a more rarely affect sex higher risk - if affected person belongs to a more rarely affect sex, person must have more bad alleles - since siblings share 50% of their alleles, these siblings will have higher risk 3) More severe the symptoms more bad genes/environment higher risk for siblings 4) Risk decreases rapidly if relationship is less close Example: Pigmentation - determined by several (>5) genes show additive effects - show strong signatures of selection - ex: SLC24A5 in Africans vs. Europeans 4) Specify the typical effects of the number of affected relatives and of the severity of the disease in an affected relative on the risk of multifactorial disorders 5) Apply the multifactorial threshold model to predict the relative risk to first-degree relatives of patients with a sex-influenced multifactorial disorder Allele Sharing (look at notes!!)

> 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, Hirschsprungs, and Alzheimer. *Hirschsprungs 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 Hirschsprungs 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- 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 *Alzheimers Disease - formation of amyloid plaques and neurofibrillary tangles - Genetic Factors 1) Amyloid Precursor Protein (APP) - cleavage by -secretase A40 and A42 overproduction amyloid plaques and neurofibrillary tangles - Presenilin-1 and Presenilin-2 - regulation of -secretase

- mutations increased cleavage [A40 and A42] 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) *Downs Syndrome - APP gene located on Chromosome 21 mutations of APP [A40 and A42] - 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 Hirschsprungs 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 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: <10% of young couples; more common with increased age - Cause: Males: infections, autoimmune, Klinefelter, single gene, Y-chromosome microdeletions; age Female: age; polycystic ovaries, endometriosis, tubal obstructions - peak fertility at age 22 Female Fertility normally 20-25% change of pregnancy in 1 cycle Major Risk: multiple pregnancies

2) Principles, applications, and procedures of sperm banking and donor insemination

Donor Insemination
Indication - infertile husband - genetic disease - rhesus incompatibility - career women Procedure: sperm bank select donor order frozen sperm thaw inseminate Sperm Banks - Analyze sperm: quality, infectious disease - Educational/psycho-history of donor - Family history of donor - Carrier tests 3) Principles, applications, and procedures of IVF and ICSI

Intravenous Fertilization (IVF)

Indication: tubal disease (obstruction), or other causes of infertility Procedure: - done in specialized clinics 1) Induce superovulation gonadotropins, clomiphene, aromatase inhibitors 2) Harvest eggs 3) Add sperm 4) Incubate 2-3 days 5) Implant 2-6 embryos - implantation dependent upon age of female age = quality of egg implantation amount age = quality of egg implantation amount Outcome - Success dependent upon age of mother or oocyte donor < 38 = 36% > 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 (17-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 Diaphragms 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 (Bartholins) Gland secretion of fluids during sexual arousal Paraurethral (Skenes) 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 Bucks 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 Bucks fascia (male) Fascia lata 2) Superficial Fascia - Deep Membranous derived from Scarpas Fascia fuse with fascia lata Colles Fascia Dartos Fascia (male) - Subcutaneous Fatty Layer derived from Campers 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/Cowpers) Defining Sex - Chromosomal - Gonadal - Phenotypical Sertoli Cells 1) Support maturation of spermatogonia 2) Growth factors 3) Androgen binding protein (ABP) 4) -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) Gartners 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/Cowpers)

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 (Cowpers) 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