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Repro

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Repro Histo Quiz Study Guide
Histology of Male Organs of Reproduction (Cotter)
Histology of Testis
tunica vaginalis: outermost; single layer of simple epith ( ie, a visceral peritoneum)
tunica albuginea: thick capsule made of dense CT that surrounds testis
mediastinum testis: extension of tunica albuginea that contains rete testis
seminiferous tubules: long, coiled, & lined with stratified germinal epith where sperm produced
sperm immobile here so contractile myofibrocytes push them to epididymis where they mature
3 layers, ea layer the product of meiosis of previous layer: farthest from lumen (spermatogonia) vs.
middle layer (spermatocytes) vs. closest to lumen (spermatids spermatozoa)
Sertoli cells: lighter stained, oval nuclei, large nucleoli tight jx btwn them forms the 3 layers & the
blood testis barrier
o many fxs: secrete testicular fluid that baths sperm, nourishes developing sperm, phagocytosis of
residual bodies (excess cytoplasm shed by spermatids), etc.
o also secretes androgen binding protein (to keep local [T] high) & inhibin (to inhibit FSH release)
interstitium btwn tubules: collagen fibers, blood/lymphatic vessels, myofibroblasts also:
Leydig cells: largest cell in interstitium, acidophilic, round nuclei & lipofuscin pigment inside
o steroid producing cell thus, EM: lipid droplets, SER, & mitochondria with tubular cristae
o crystals of Reinke: refractive elongated acidophilic bodies large in Leydig cell tumors
Spermatocytogenesis 8 cell types seen inside seminiferous tubules:
dark type A spermatogonia: sits on basal lamina, darkly stained nuclei with peripheral nucleolus &
vacuole inside nucleus usu inactive
pale type A spermatogonia: same morphology as dark, just lighter stained self regenerates & gives rise
to Type B spermatogonia
type B spermatogonia: less uniformly stained nucleus with chromatin along periphery of nucleus
1 spermatocyte (4N): big nucleus, chromatin seen in cords
2 spermatocyte (2N): not easily IDed since rapidly progresses into spermatids
spermatid (1N): round cell with uniformly stained nucleus found in layer closest to lumen
spermatozoon: bullet-shaped head with thin tail
head (acrosomal cap, nucleus) vs. neck (centrioles) vs. middle piece (mitochondria)
sertoli cell: spermatozoa seen embedded in its luminal surface
Sperm Pathway
seminiferous tubule straight tubule rete testis efferent ductule epididymis vas deferens (aka
ductus deferens)
sperm only moves 1mm/min aided by muscular contractions of F repro organs & cilia in oviduct
efferent ductile: lined by pseudostratified epith of irregular, uneven thickness due to presence of tall
ciliated cells & short cells that absorb testicular fluid made by Sertolis
ductus epididymis: lined by regular, evenly-thick pseudostratified epith & stereocilia lining more
prominent
vas deferens: massive amt of muscle seen in its walls 3 layers: inner longitudinal, middle circular, outer
longitudinal

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Glands of Male Repro System
Cowpers bulbourethral gland & paraurethral glands of Littre both lubricate urethra
seminal vesicle: narrow sac-like twisted tube produces 2/3 of seminal fluid
folded, branched mucosa that projects into lumen allows surface area & expansion as lumen fills
with semen
only a few passageways (if any) can be traced from lumen to base of folds (unlike Fallopian tube where
its much easier to trace a path)
fxs of its secretions: solidifies semen, makes semen slightly alkaline (to protect sperm from acidic
vagina), provides fructose (for sperms energy source), adds prostaglandins (to alter thickness of mucus
at cervix allows sperm to pass thru more easily)
prostate: liquefies semen by producing fibrolysin, PSA (a Ser protease indicator of prostate ca if high),
prostate-specific acid phosphatase (PAP), etc.
produces 1/3 of seminal fluid
tissue hardness or nodules on DRE indicative of neoplasm (since should be soft)
look for: corpora amylacea (round, acidophilic objs) & urethra (since passes thru it)
order of secretion: bulbourethral/littre glands prostate gland vas deferens seminal vesicle
penis made of 3 columns of erectile tissue: 2 corpora cavernosa & 1 corpus spongiosum
Histology of the Female Organs of Reproduction (Cotter)
Vagina
stratified squamous nonkeratinized epith cells in this layer stim by E to make glycogen (which is
converted to lactic acid by bacteria there, creating the local acidic envt)
no glands lubricated by exudates of blood vessels in lamina propria & secretions from cervical/labial
glands during sex
elastic fibers in lamina propria allows for oragn expansion during childbirth
Cervix
connects vagina to uterus
ectocervix: sticks out in vaginal cavity, stratified squamous, no glands
endocervix: simple columnar glands present:
produce infertile mucus which plugs cervix to prevent sperm/bacteria from entering uterus
less active only at ovulation (mucus becomes more watery less barrier to sperm)
Ovary
unlike men: Fs not born with ability to produce unlimited supply of gametes all are developed in utero
& are 1 oocytes before birth
structure depends on age of F:
if reproductive age all possible structures seen:
o ovarian follicles: contains single egg
o corpora lutea: walls of follicle after egg released persists only if preg ensures
corpora albicans: CT that replaces corpora lutea if no preg
o atretic follicles: follicles not picked for ovulation look for: apoptosis, degeneration of zona
pellucida, hypertrophied glassy BM, &/or absent oocyte
corpus fibrosum: CT fibrous remains of follicles that have undergone atresia
if prepubescent age only small follicles seen

if menopausal age only corpora albicans remain

Ovarian Follicles
primordial follicle: small, oocyte still in prophase only single layer of simple squamous granulosa cells
seen
1 follicle: single layer of simple cuboidal granulosa cells seen & zona pellicuda forms (glycoprotein layer
seen unstained around oocyte)
2 follicle: 2/+ layers of granulosa cells & outer theca cell layer begins to form
(outer external shell, seen more flattened than granulosa cell layers)
early 3 follicle: theca fully developed, oocyte at full size, antrum
forms
(ie, cavity within follicle)
late 3 follicle (aka Graafian): granulosa layers seen
differentiated into:
corona radiata (surrounds oocyte), cumulus oophorus
(where it adheres to follicle wall; must be penetrated by
sperm for fertilization), & stratum granulosa (rim around
entire follicle)
Fallopian tube (aka oviduct)
often confused with small intestine (look for goblet cells) or seminal vesicle (so many folds that its difficult
to find a path from lumen to base of fold)
folds covered with simple epith made of 2 cells: ciliated vs. peg cells (secretory cells with rounded tops &
narrow stalks often appear as if they dont fit in epith layer)
influenced by ovarian cycle: follicular ( # of ciliated cells, active peg cells) vs. late luteal phase
(dedifferentiated, inactive)
egg path: ovary fimbria [infundibulum ampulla isthmus] uterus
Fertilization
occurs in ampulla of fallopian tube
acrosomal enzymes (hyaluronidase & acrosin) & hypermobility both help sperm get thru cumulus
oophorus surrounding egg
block to polyspermy: prevention of another sperm cell from entering oocyte once one sperm has penetrated
the eggs cell membrane
Ovarian Cycle
corpus hemorrhagicum: first structure formed by dominant follicle after oocyte released blood from
damaged vessels in theca fills antrum cavity
corpus luteum: large enough to be seen grossly, naturally yellow develops from remaining follicle walls
after oocyte released
2 cell types seen: granulosa lutein cells (from strata granulosa make E & P) & theca lutein cells
(from theca interna make androgen used by granulosa lutein cells to make E & also makes P itself)
o both steroid-producing cells: SER, lipid droplets, mitochrondria with tubular cristae
corpus albicans: atresic corpus luteum apoptosis & replaced by white collagen fibers (thus seen grossly
as white & pink if eosin stained)
forms if no preg or after 3rd months of preg once placenta can take over for it
Uterus body, fundus, & cervix

cavity lined by inner endometrium, middle myometrium, & outer adventitia/serosa

endometrium 2 layers:
functional: supplied by spiral aa, which become spastic once E/P when corpus luteum degenerates
after fertilization failed to occur layer dies & shed in menses
basal: wider glands, regenerates functional layer after menses, supplied by straight aa, which do not
become spastic once E/P & thus maintains survival throughout cycle
histo of menstrual cycle 3 phases:
menses: tattered surface, diminished in ht, dilated glands, disrupted CT btwn glands, blood
proliferative: glands long & straight with lots of CT in btwn
secretory: glands twisted & wider (esp deeper in endometrium) with less CT in btwn

Mammary Glands
an exocrine gland that releases its secretions into ducts & released onto external surface
compound branched alveolar gland with elaborate duct system 20 mammary glands/breast
stages: non-preg (inactive, mostly CT/fat cells) preg (proliferative, lots of lobules, alveoli formation)
lactating (resemble lung tissue; lobules expand & alveoli distend from milk) involuted (degeneration
& gradual reversion to inactive non-preg form)
2 types of secretion: apocrine (lipids released together with cytoplasm & fragments of membr seen as
blebs of cytoplasm bulging off cell) vs. merocrine (proteins released in secretory granules by exocytosis)

Repro FINAL the very LAST Study Guide

Sex Determination & Development (Hard)
The Y chromosome smaller & fewer genes than chr X

SRY: sex determining region on Y chr that encodes testis determining factor (TDF) which initiates male
gonad formation
general rule: if SRY is present on Y chr, the offspring will be male thus, XXY is still male
XX males possible if SRY gets translocated to an autosomal or X chr
XY females possible if SRY is abnormally absent from Y chr
PAR: region on each pole of the Y chr that is homologous to X chr so the 2 can still pair in meiosis

Meiosis Review
DNA replicated before cells enter meiosis thus, begin with 46 chrs made of 2 sister chromatids
after meiosis I (cells contain 23 double-structured chrs) vs. after meiosis II (23 single chrs)
prophase (homologous chrs get paired) metaphase (chrs align individually on metaphase plate)
anaphase (chrs separate & move to opposite sides of cell)
crossover: the interchanging of portions of homologous chromatids at the chiasma (ie, sites of exchange)
occurs during prophase I to create genetic variation
a translocation error of SRY here can cause an XX male & XY female
nondisjunction: failure of chrs to separate during anaphase forms gametes with 22 or 24 chrs
fertilization of these gametes with nl gametes monosomy (like Turners XO) or trisomy (like
Klinefelters XXY or Downs autosomal 21 trisomy)
Development of Reproductive System
human gestation: fertilization/fetal age (38 weeks) vs. obstetric age (40 weeks estimated age used
clinically since doctors dont exactly know when fertilization occurs)
week 1-6 (sexually indifferent stage) vs. week 7/+ (sex determined by presence/absence of SRY)
the gonad that SRY determines to form then dictates remaining devo of duct sys & ext genitalia
intermediate mesoderm ( stroma ie, supporting cells of testis/ovary) vs. primordial germ cells (PGCs
gametic cells ie, oogonia/spermatogonia)
PGCs must migrate along hindgut to the developing genital ridge, which forms in intermediate mesoderm
near mesonephros (functional primitive kidney) due to WT-1 & SF-1 gene expression to ultimately become
the gonads
fragilis/stella (2 genes uniquely expressed on PGCs) vs. mitogens (influence proliferation of PGCs during
its migration to genital ridge) all PGCs do not make it to genital ridge
indifferent gonad: ambiguous sex organ at week 6 made of primitive sex cords (solid tubes with PGCs
inside) has both cortex & medullary regions whose fates depend on if Chr Y is present:
if SRY (medullary cords develop as cortical cords degenerate & tunica albuginea thickens) vs. if Wnt-4
present (cortical cords develop as medullary cords degenerate & tunica albuginea is minimal)
2 sets of ducts present: mesonephric/Wolffian (proliferates in male becomes: epididymis, vas deferens,
seminal vesicles, etc.) vs. paramesonephric/Mullerian ducts (proliferates in female becomes: fallopian
tubes, uterus, upper vagina)
Male Sex Organ Development
testes require SRY (not PGCs) to induce medullary cord & tunica albuginea devo
medullary cords that are developing contain Sertoli cells which have 2 functions:
directly contact PGCs to inhibit their proliferation till puberty
SOX-9 induces production & release of mullerian inhibitory substance (MIS) to suppress further devo
of paramesonephric ducts
o prostatic utricle: remnant of paramesonephric duct in males

tunica albuginea that is developing contain Leydig cells which release testosterone (T), which stims
mesonephric duct prolif & accessory gland devo ie, prostate, seminal vesicle, etc.
testosterone dihydrotestosterone (stim ext genitalia devo) via 5 reductase
testicular feminizing syndrome: lack of T receptors
duct formation involves T interacting with mesenchymal tissue then activated mesenchyme interacts with
epithelium to form ducts

Female Sex Organ Development

ovaries require PGCs to develop thus, if absent or abnl, non-functional streak ovaries develop
cortical cords contain PGCs & then break up to form clusters in month 4 which differentiate into oogonia
that are permanently stuck in prophase I
ie, every egg a female will ever have is developed before shes even born
follicular cells then associate with oogonia primordial follicles
estrogen (from mom & fetal ovary) stim paramesonephric duct prolif & ext. genitalia
appendix of ovary: remnant of mesonephric duct in females
External Genitalia Development
indifferent stage: consists of genital tubercle ( phallus), genital swelling, & urogenital folds (with
urogenital sinus inside)
males: genital tubercle ( glans penis), genital swelling ( scrotal sac), & urogenital folds fuse together
( shaft) causing the urogenital sinus inside to become the walls of the urethra
scrotal & urethral raphe: site at which folds fuse together
o hypospodias: failure of folds to fuse urethra open along ventral surface
urethra within glans penis is the only part of the urethra derived from ectoderm
females: genital tubercle ( clitoris), genital swelling ( labia majora), & urogenital folds do not fuse all
the way to form the vaginal cavity
fused paramesonephric ducts ( uterus) vs. uterovaginal plate ( upper vagina) vs. urogenital sinus
( lower vagina)
Abnormalities of Sex Differentiation
from non-disjunction meiosis error:
Turners Syndrome (XO): PMGs degenerate after reaching gonads streak ovary & thus, presents at
puberty in girls with no menstrual period & no 2 sex characteristics develop
o also: short stature, web neck, brown nevi, constriction of aorta, etc.
Klinefelters Syndrome (XXY): extra X chr overwhelms single Y & thus feminine sex devo not further
suppressed breast devo, testicular atrophy, tall stature, osteoporosis, etc.
Multiple X Chromosomes: XXXY, XXYY, etc. all more severe forms of Klinefelters
true hermaphrodites: individual with both ovarian & testicular tissue (most XX mosaics)
ovotestis: ovary & testis tissue in same organ
pseudohermaphrodites: gonads & sex chrs of 1 sex but ext genitalia similar to the other sex due to: abnl
sex hormone levels or abnl receptors
spotted hyenas: females normally masculinized in this species fused scrotum, hypertrophied clit
(resembles penis, babies must be delivered thru it since no vaginal opening), etc.
o due to: high 17HSD ( T from androstenedione), high androgens, & low placental aromatase
( estrogens from androgens)
Genetic

Gonad

Ducts

External Genitalia

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No T receptor
T production
5-reductase
androgen production
Indifferent Structure
Genital Ridge
PGCs
Mesonephric ducts
Paramesonephric ducts
Lower Urogenital Sinus
Upper Urogenital Sinus
Genital Tubercle
Urogenital folds
Genital swellings

XY
XY
XY
XX

M
M
M
F

Male
Testis
Spermatozoa
Epididymis, vas deferens, seminal vesicle
Prostatic utricle
Penile urethra
Urethra, urinary bladder
Penis
Floor of penile urethra
Scrotum

Incomplete
Incomplete
M
F

F
Ambiguous
Ambiguous
Ambiguous

Female
Ovary
Ova
Appendix of Ovary
Fallopian tube, uterus, upper vagina
Lower vagina, vaginal vestibule, greater vestibular glands
Urethra, urinary bladder
Clitoris
Labia minora
Labia majora

Hypothalamic Pituitary Testes Axis (Gallant)

Male Gonad
seminiferous tubule: spermatogenesis takes place within its walls
spermatogonium (most primitive; farthest from lumen) 1 spermatocyte (4N) 2 spermatocyte
(2N from anaphase I) spermatid (1N from anaphase II) spermatozoon (most mature; closest to
lumen, head often embedded in luminal surface of sertoli cells)
blood testis barrier: tight junction btwn sertoli cells that separate Leydig cells/capillaries from
spermatogenic cells
sperm never contacts blood so any circulating toxins cannot affect spermatogenesis but this also
makes sperm act as an antigen in the body
Leydig cells: stimd by LH to make androgens: T (major product; intermediate potency some diffuses
into Sertoli cells to make estrogen), dihydrotestosterone (DHT strongest), DHEA / androstenedione
(weakest)
LH: induces StAR protein (to bring cholesterol in to make androgens) & CYP11Acscc
Sertoli cells: stimd by FSH to make androgen binding protein (allows for local accumulation of T as
needed to make sperm in testis), aromatase (aka CYP19; converts T to estrogen), MIS (to suppress
paramesonephric ducts), androgen receptors, etc.
found in seminiferous tubule walls to nourish growing sperm & maintain blood testis barrier
# of sertoli cells determine size of testes
also makes TGF superfamily proteins: activin (stims FSH production in pit.), follistatin
(binds/neutralizes activin), & inhibin (sequesters activin receptors to activin effects)
FSH: induces aromatase to make estrogens
both FSH & LH receptors are Gs-protein linked: cAMP PKA activation (which enters nucleus to affect
transcription)
Hypothalamic Pituitary Gonad Axis
GnRH: released by hypothalamus to stim FSH/LH release from ant pit
inhibited by (GABA) vs. stimulated by (glutamate, NE, NPY, kisspeptin)
released in pulses (to avoid down-regn of receptors) highest in morning
time btwn pulses of GnRH released determines whether LH or FSH is the predominant one made: if
short (more LH release relative to FSH) vs. if long (more FSH)
estrogen is the major player in neg feedback mechanism of this axis to LH/FSH thus, if you cant
convert T to estrogen (ex: aromatase deficiency), no neg feedback seen & T levels soar
inhibin (from Sertoli cells) also involved in neg feedback but only inhibits FSH (not LH)
FSH/LH: infancy (huge spike; FSH>LH) childhood (quiescent) puberty (2nd spike as pulse generator
for GnRH is initiated) adulthood (pulsatile spikes; LH>FSH)

completely dormant until puberty hits: testicular enlargement (1st sign)

adrenarche: maturation of adrenal cortex & release of androgens (distinct from puberty)
estrogens: cause growth spurt in both sexes
leptin: satiety hormone that prior to onset of puberty no puberty if mutated
kisspeptin: produced in AVPN & arcuate hypothalamic nuclei; thought to initiate puberty by stimulating
GnRH hypogonadotropic hypogonadism seen if mutated

Key Enzymes in Sex Hormone Synthesis

5 reductase: irreversibly converts T to DHT Type I (sebaceous glands) vs. Type II (genital skin, UG
tract) liver has both types
if deficient Imperato-McGinley syndrome male pseudohermaphroditism
17HSD: reversibly converts androstenedione / estrone (weak) to T / estradiol (strong)
CYP19 (aka aromatase): converts androgens to estrogens
Androgen Action
direct effects of T: Wolffian duct prolif (epididymis, vas deferens, seminal vesicles) & voice s (thickens &
elongates vocal cords; explains castration of boys to maintain their high opera voices)
also increases: RBC mass (explains higher Hb counts in Ms), muscle mass, upper body fat, LDL (while
HDL), etc.
indirect effects of T via DHT external genitalia devo (penis, scrotum, urethra, prostate)
also sebum formation (oil on skin acne), male pattern hair growth, 2 sex characteristics, etc.
excess DHT benign prostatic hypertrophy (BPH)
indirect effects of T via estrogen (E) skeletal maturation, growth spurts
T, DHT, & E all imprint sex drive/behr, sperm production, etc.
androgen receptor: a nuclear receptor once androgen ligand binds, heat shock proteins break off
receptor so it can enter nucleus & affect transcription
androgen insensitivity: X-linked mutn in androgen receptor

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Androgen Pharmacology (Bradford)
Androgen replacement therapy
for male hypogonadism (like in Klinefelters) also: andropause (androgen deficiency; male equivalent of
menopause), wasting syndrome in HIV, etc
never for muscle strength/endurance in athletes or anemia in kidney failure
testosterone alone can be given (as testoject) or it can be modified in 1 of 3 ways:
turn hydroxyl grp on C17 into ester ex: enanthate, cypionate
take methyl grp off C19 ex: nandrolone
add methyl grp to C17 ex: methyltestosterone, oxandrolone, stanazolol
o methyl grp causes ~100% oral efficacy (unlike the others above which must be injected) but!
causes hepatotoxicity: jaundice, hepatocellular carcinoma, liver enzs in serum
patches available for slower but continuous supply (unlike large spike seen when injected)
gels also available but preg women should not handle them since tetragenic
adverse effects: from DHT (acne, baldness, BPH, beard/axillary hair growth) vs. E (gynecomastia,
edema, salt retention, premature bone maturation) also: virilization in Fs
Androgen deprivation therapy tx of Prostate Cancer:
if stage III (beyond prostate capsule) or stage IV (metastatic), consider medical/surgical castration
androgen receptor antagonists flutamide, bicalutamide
often used with GnRH agonist (like leuprolide) for combined androgen blockade: chronic stims
release of LH/FSH down-regn of their receptors to nearly zero by 3 weeks
adverse affects: hot flashes, libido, osteopenia
high dose ketoconazole also used to androgen synthesis by inhib CYP11Acscc in adrenal gland
Treatment of BPH often just watchful waiting
5- reductase inhibitors finasteride, dutasteride (aka avodart): to DHT
also used at lower doses as tx for male pattern hair loss
1 blockers: relaxes smooth muscles in blood neck to allow for easier peeing
Male Reproductive Physiology (Sufrin)
GnRH neuron
the pulse generator that releases GnRH into portal system to stim release of FSH/LH from the same
basophil in ant. pit
originate in olfactory placode must migrate to periventricular & preoptic hypothalamic nuclei
anosmin: adhesion molecule encoded by Kal-1 gene on X chr to regulate its migration
GnRH is a peptide hormone made from series of cleavages: preproGnRH progNRH GnRH
neg feedback mechanism:
directly in pit: gonadotrophs have receptors that bind E/T/DHT to further FSH/LH release
indirectly in hypothalamus: no receptors that bind E/T/DHT on GnRH neurons, must bind to other
nuclei which release GABA which can directly inhib GnRH neuron

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The Testicle
4 compartments: spermatogenetic (44%; seminiferous tubules PGCs, spermatogonia, sertoli cells),
interstitial (38%; leydig cells, blood vessels/CT, myoid cells ie, smooth-muscle like contractile cells),
capsule (12%), & lumen (6%)
sperm maturation in 3 sub-compartments of seminiferous tubules takes ~90 days total
basal: spermatogonia on BM of tubule
intermediate: 1 spermatocytes
o tight junctions from adjacent sertoli cells form above and below to maintain blood testis barrier
(separates spermatogonia/1 from 2/spermatid)
once 1 becomes 2 spermatocyte, tight jx above degrades so it can enter adluminal
adluminal: 2 spermatocytes, spermatids (seen attached to sertoli cell till it fully matures & enters
lumen as a spermatozoon ready to fertilize some eggs)
spermatogenesis: early (FSH on sertoli cell maturation of spermatogonia & 1 spermatocyte) vs. late (LH
stim T to further sertoli cell maturation of 2 spermatocyte & spermatid)
Normal Ejaculate
seminal vesicles: supplies majority (70%) of fluid vol adds:
prostaglandins, fructose (to make ATP for sperm mobility), & semenogelin (which helps cum coagulate
after ejac after it is broken down into peptides by prostate specific antigen ie, PSA)
alkaline pH (buffers vaginal acidity)
prostate contributions: Ca/Zn/Mg, PSA, citric acid (hinders Ca from calcifying), spermine, & proteases
(which break down the ejaculated coagulum to allow sperm to move more freely inside)
Male Infertility
classified by semen analysis:
low vol: diabetes, duct obstr
azospermia (ie, no sperm): hypogonadotrophic hypogonadism, kallman syndrome, pituitary tumor, chr
abnormalities, spermatogenesis defects, gonadotoxins, etc.
oligospermia (ie, too few sperm): varicocele, cryptorchidism
asthenospermia (ie, sperm mobility): infection, sperm structural defects, prolonged abstinence
classified by 1 site of abnormality:
pre-testicular (hypothalamic or pituitary problem) vs. testicular vs. post-testicular (ejac dysfx, torsion
of spermatic cord, obstr, etc.)
More causes of Male infertility
endocrine hypogonadotrophic hypogonadism (HH): due to pit. prob or Kallman syndrome (olfactory
tract fails to develop & thus, GnRH neuron migration fails HH with anosmia)
impaired sperm mobility immotile cilia syndrome, duct obstr, etc.
cystic fibrosis: CFTR defect Wolffian ducts not appropriately lubricated, causing devo abnormalities
of vas deferens, seminal vesicles, & epididymis infertility
o semen analysis: vol, fructose, & acidic pH all due to absent seminal vesicles
chr abnormalities: Y chr microdeletion or Klinefelters (XXY presents as eunuchoid habitus: tall stature,
female pubic hair pattern, gynecomastia, atrophic testes, widened pelvis, etc.
also: Leydig hyperplasia & FSH/LH/E/T seen

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anatomic abnormalities:
varicocele: venous valve failure (usu in L testis) abnl dilation of pampiniform vv temp of testis
from blood flow oligospermia
cryptochidism: failure of testicular descent into scrotum spermatogenic arrest ( mature spermatozoa
seen in lumen)
hypospadias: abnl location of urethral meatus the farther from the glans penis, the more likely the
male will have infertility probs
testicular abnormalities ex: Sertoli Only Syndrome: only sertoli cells seen in seminephrous tubules (ie,
no spermatogenic cells seen at all thus, azospermia)

Case 1
Turner Syndrome (TS)
1/2500 F births but most TS fetus miscarriage (99%): causes 20% of all 1st trimester miscarriages
characteristic phenotype due to loss of p arm of X chr
diagnosis confirmed by karyotype usu XO but also: 46XY with SRY gene del or 46,X,i(Xq):
ie, an isochromosome is abnormally made: p arm is lost & replaced with exact copy of other q arm so X
chr is abnormally made with 2 q arms attached together
75% nondisjunction occurred in paternal X chr. explains why there is no risk of recurrence if parents
decide to have another child
cyst may be found on posterior neck prenatally on ultrasound resorbed by birth explaining the nuchal
thickness & neck webbing seen
also common: cupitus valgus (out-turned elbows), wide-spaced nipples, horseshoe kidneys, & bicuspid AV
valve / coarctation of aorta
short stature very common tx: GH ( anabolic steroids)
linked with DM, hypothyroidism, & osteoporosis
usu normal intelligence but impaired in visual-spatial coordination & math
amenorrhea & no breast devo from ovarian failure (streak ovaries seen) tx: estrogen (but dont give too
early since this can compromise adult height)
most infertile but have normal uterus so embryo transfer is often successful
Clinical Teratology (Robinson)
Teratology
if F did not know she was pregnant & was on teratogenic drugs, must calculate true extent of fetal
exposure:
consider fertilization to have occurred 14 days after last menstrual period
then primitive zygote is still not exposed to maternal blood till about 15 days after fertilization
thus, minimal risk of birth defects up to one month after last menstrual period
teratogen: any agent that acts during preg to risk of fetus expressing a pattern of malformation
variables to consider: dose/frequency (greater the dose, higher the risk), gestational timing (fetus most at
risk during 1st trimester), mechanism of action, route, maternal-fetal genetic interactions:
brain continues to mature throughout fetal devo & even after birth since alcohol is neurotoxic, preg
females should avoid it at all times & subsequently cede all their alcohol to their baby daddy

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Maternal teratogenic conditions
irradiation ex: microcephalic babies born to Fs preg when US dropped bomb on Hiroshima
maternal infection TORCH: Toxoplasmosis, Others (varicella, parvovirus, etc.), Rubella, CMV,
Herpes
PKU: deficiency of phenylalanine hydroxylase (used to convert Phe to Tyr) high Phe in maternal blood
is neurotoxic to fetus
diabetes: if mom is hyperglycemic, so is baby macrosomia (babies born with large birth wt)
often have delayed surfactant production ( RDS at birth) & hypoglycemia at birth (from residual high
insulin levels in fetus that were combating moms hyperglycemia in womb)
also: lumbosacral agenesis seen in the most poorly controlled diabetic pregnant Fs
Pharmacologic Teratogens
cocaine: displaces NTs & causes vasospasm ( fetal ischemia)
unlike other teratogens, cocaine will not cause birth defects till fetus is exposed during 3rd trimester
since no muscles in vessels yet in 1st trimester
retinoic acid: very teratogenic; once exposed, over 60% have problems (30% miscarriage)
important to consider in unplanned pregnant teens that use it to treat acne
thalidomide: anti-anxiety med that causes characteristic malformation of upper/lower extremities
warfarin: anticoagulant that risk of fetal hemorrhage
alcohol: causes fetal alcohol syndrome (depressed nasal bridge, midface hypoplasia (small nose &
cheeks), smooth philtrum above lip, thin upper lip, short palpebral fissue in eye, etc.)
sonic hedgehog (Shh): binds to membrane to orchestrate intracellular signaling for nl. brain devo
holoprosencephaly if mutated/absent (close eyes & severe midline defects)
alcohol down-regulates Shh explains midline defects seen in FAS
ADH2*3 polymorphism in mom actually protects against fetal alcohol syndrome)
phenytoin: causes tiny distal phalanges & nail hypoplasia also: MR, growth deficiency, midline defects,
cardiac defects, etc.
CYP450 enzyme polymorphisms alter risk of phenytoin since its metabolized by them
any folate pathway antagonist will risk of spina bifida thus, avoid: dihydrofolate reductase
antagonists (trimethoprime, aceptozolamide) & folic acid antagonists (aminopterin, valproic acid
carbamazepine)
aminopterin (calvarial (top of skull)/maxillary (jaw) hypoplasia, hypodactyly) vs. valproate (metopic
(forehead) ridging, thumb defects) both: growth deficiency, developmental delays
others: ACE inhibitors (causes fetal renal output oligohydramnios), trimethadoine, lithium
Non-Teratogens
any kind of paternal exposures will not cause birth defects
others: corticosteroids, amphetamine, lead, spermicides, etc.

14
Physiology of Erection, Ejaculation, & Male Orgasm (Sufrin)
The Penis
layers: skin Bucks fascia (outermost) tunica albuginea (outer longitudinal & inner circular)
dorsal a, v, & n of penis lie btwn Bucks fascia & tunica albuginea layers
corpus cavernosa: 2 of them separated by incomplete septum (allows blood to traverse btwn sides)
filled with small sinusoidal trabeculae (smooth m. lined by epith, involved in erection) & large
structural trabeculae (maintain penis structure)
glans penis: extension of corpus cavernosa
corpus spongiosum: 1 of them, supplied by bulbourethral a surrounds penile urethra
vasculature: internal pudendal penile a, which splits to form:
dorsal a. of penis glans
cavernosa a. helicine a. trabecular erectile tissue/sinusoids
trabecular sinusoids drained by sinusoidal venules ( subtunical v. emissionary v. circumflex v.)
deep dorsal v.
Physiology
limb (detumescence; contracted sinusoidal trabeculae, patent subtunical vv) hard (tumescence;
distended sinusoidal trabeculae, compressed subtunical vv)
parasympathetic nn release ACh (which binds to epith cells to stim NO release vascular smooth m
(SM) relaxes inside sinusoidal trabeculae a. blood inflow distended trabeculae compressed vv &
thus, venous drainage blood remains in penis to maintain erection
NO stim guanylate cyclase cGMP activates PKG intracellular Ca by closing L-type
Ca channel on membr & intracellular K by opening K channel SM relaxes
o phosphodiesterase-5: inactivates cGMP to GMP medicines like viagra inhibit this enz to prolong
cGMP effects & thus prolong erections
PG-E stim adenylate cyclase cAMP activates PKA intracellular Ca
cavernous n: parasympathetic n originating from intermediolateral column of sacral spinal cord involved
in erection since innervates both sinusoidal trabeculae & vascular smooth m in penis
has sympathetic fibers inside it as well (also originating from intermediolateral column but higher in
cord T11) thus, also involved in detumescence process
pudendal n: somatic n. that receives sensory info from dorsal n recognizes when penis is tactile
stimulated so an erection can be initiated
different types of erections: psychogenic (initiated by cortical stim when thinking about erotic things) vs.
reflex (initiated by spinal cord stim when penis is tactile stimulated) vs. nocturnal
thus, erections can still be elicited if spinal injury is above T10
Physiology of the Limb Dick
sympathetic neurons (also inside cavernous n) release NE, which binds to 1 receptors to initiate cleavage
of PIP into:
DAG ( PKC activation, which opens L-type Ca channel to intracellular Ca) & IP3 (which Ca
release from SR) SM contraction v compression in penis venous drainage
also caused by PG-F via same PKC-mediated mechanism
Hemodynamics inside penis during erection
Stage 1 (Latent): huge in pudendal a. flow (PAF) but no in intracorporeal pressure (ICP)

15

Stage 2 (Tumescence): PAF progressively as ICP steadily

Stage 3 (Full Erection): both PAF & ICP level off
Stage 4 (Rigid Erection): bulbocavernous mm compress urethra rapid ICP ejaculation
following ejac, penis temporary returns to stage 3, then progresses to the very short Stage 5 (Initial
Detumescence): small PAF & small ICP
Stage 6 (Slow Detumescence): gradual in PAF gradual in ICP
Stage 7 (Fast Detumescence): rapid in ICP as venous drainage capability fully returns

Physiology of Ejaculation
2 phases: emission (dumps semen into prostatic urethra) expulsion (ejects semen out meatus)
bladder neck contracts to prevent retrograde ejac distension of prostatic urethra (which elicits that
reflex when you must ejaculate & cant help it)
dorsal n. of penis ( pudendal n) senses distension & sends it to lumbar spinothalamic neurons:
found around central canal of spinal cord & together form spinal ejaculatory generator, which sends
axons to parvocellular subparafascicular thalamic nuclei, which sends axons to:
o reward centers in ventral tegmental area orgasm
serum PRL used as a marker for orgasm since levels are elevated after
can also occur independent of erection or ejaculation
o parasympathetic/sympathetic pregang neurons in spinal cord, which stim pudendal motoneurons
(only active during ejac not during fun activity proceeding it)
rhythmic bulbocavernosus/ischiocavernonsus m contraction pulsatile blasts of semen out meatus
latency (DA or 5HT) vs. latency (SSRIs)
thus, SSRIs used to tx rapid/premature ejac alternative tx: squeeze technique ( blue balls like much
like this unfortunate gingerbread man)
Pathology of the Male Reproductive System (Wild)
Possible congenital anomalies
failure of urethral canal/groove to close hypospadia (if ventral surface) vs. epispadia (if dorsal)
can cause recurrent UTIs, infertility (if located too proximally), & incontinence,
agenesis of vas deferens usu only in CF pts.
cryptochidism: failure of testes to descend into scrotum found in: inguinal canal/high scrotum
(commonest; androgen-controlled descent) or abdomen (MIS-controlled descent)
associated with impaired fertility & risk of intratubular testicular germ cell neoplasia (premalignant in-situ microscopic cell 50% develop invasive germ cell malign tumor)
tx: orchiopexy: surgical reposition of testis
hydrocele: scrotal mass caused by excess serous fluid in tunica vaginalis transilluminates (unlike solid
tumors which will not transmit light)

16
Inflammatory Disorders
bacterial epididymitis: usu occurs after UTI; heals with fibrous scarring ( infertility)
< 35y/o (chlamydia, gonorrhea) vs. > 35y/o (E.coli, pseudomonas)
prostatitis: diagnosed by clinical symptoms & labs (urine & prostate secretions) chronic bacterial (from
recurrent UTIs) vs. abacterial (no hx of recurrent UTIs & neg bacterial cultures)
granulomatous prostatitis: usu after topical BCG tx (bolis injected to stim immune response with the
intent to control bladder cancer)
Vascular Disorders
testicular torsion: twisted spermatic cord vascular supply hemorrhagic infarct
usu presents in adolescents with sudden severe scrotal pain/swelling surgical emergency
typically due to bilateral anatomic abnormality where tunica vaginalis reflects higher than it normally
does at the level of the spermatic cord, compressing arterial supply to testis
varicocele: dilated, twisted vv in spermatic cord nodular mass in lateral scrotum oligospermia
usu seen unilateral & on the left due to diff in testis venous drainage: R (drains into large IVC) vs. L
(drains into much smaller renal v)
Normal Prostate Histology
normally weighs 20g, no true capsule 4 functional zones:
transitional zone: site of BPH small zone that surrounds prostatic urethra ( explains urinary
problems seen)
peripheral zone: commonest site of prostatic cancer located posteriolateral & thus palpable in rectal
exam & far from urethra ( explains lack of urinary problems seen in cancer)
other zones: anterior fibromuscular stroma & central zones
made up of tubuloalveolar glands lined by secretory cells (inner, columnar, stain PSA+) & basal cells
(outer, cuboidal, stain HMW cytokeratin+)
basal cells are lost in prostate cancer thus, HMW cytokeratin stain used to ID basal cells, which
subsequently r/o cancer if present
Nodular Hyperplasia aka BPH
prolif of prostatic tissue prostate gland enlargement obstr to urine flow thru bladder outlet
due to DHT (causes GF release from both stromal cells where its made and epith cells where its acts
upon) & estrogen ( prostatic sensitivity to DHT since T in old age & blocks apoptosis)
all men have histological evidence of hyperplasia as they age: hyperplastic & cystically dilated acini lined
by double layer of proliferating epith cells 30% are actually symptomatic:
difficulty with urination: straining to void, weak stream, hesitancy, terminal dribbling incomplete
emptying stasis urine in bladder, which causes:
o 2 structural s to bladder ( freq/urgency & nocturia), obstructive kidney damage ( kidney
failure), bladder calculi, & recurrent UTIs
seen grossly as multiple circumscribed nodules surrounding urethral lumen in transitional zone ( focal
infarcts of various ages) no evidence BPH is precursor to prostate cancer
treatment: receptor blockers ( prostatic SM tone rapid relief) or 5-reductase inhibitors ( DHT
made from T, ultimately size of prostate long-term relief but libido/ED side effects)
TURP: send cystoscope up urethra, cut away strips of transitional zone prostate tissue & withdraw tissue
back out urethra
Adenocarcinoma of Prostate Gland

17

#1 cancer in men tumor of secretory cells (usu in peripheral zone) & thus tumor stains PSA+
due to polymorphisms in androgen receptor gene: if short CAG repeats seen, prostatic cells more sensitive
to androgens
blacks (shortest CAG repeats & thus highest risk of prostate cancer) vs. whites (intermediate length) vs.
Asians (longest CAG repeats & thus lowest risk of prostate cancer)
if immigrants from low-risk regions move to high-risk regions, risk suggests envt role
genetics: inactivated PTEN gene (tumor suppressor) also: inactivated GSTP1 gene:
normally encodes for GSTP, which protects prostatic epithelium thus, if inactivated:
o prostatic intraepithelial neoplasia (PIN): histological precursor to prostatic ca. prolif of
dysplastic secretory cells but! basal cell layer still intact (cancer when this layer is lost)
high-grade PIN often found next to invasive prostate ca & thus can be used as marker
Gleason grading system: well-differentiated (low grade scores 2-4; crowded, erratic sized glands)
poorly-differentiated (high grade scores 8-10; cribriform shaped glands, diffuse sheets of cells)
actual Gleason grade = dominant histo pattern + subdominant histo pattern
TNM stage: T1 (small, non-palpable often found incidentally in TURP specimen), T2 (palpable but
confined to prostate), T3 (local spread outside prostate), T4 (distant spread to bladder/rectum)
osteoblastic mets common (esp in ribs, vertebral column, & pelvic bones)
PSA levels seen in blood but many false positives/negs & thus must also consider: PSA
density/velocity, age-specific reference ranges, & free:bound PSA ratio
PSA screening: all man yearly once 50y/o (begin at 40y/o if 1st degree relative afflicted)
confirm diagnosis via sextant needle biopsies (6 prostatic biopsies from diff locations)

Testicular Tumors
commonest malignant tumor in 15-34y/o males presents as painless scrotal mass
stage I (confined to testis, epididymis, spermatic cord) stage II (mets to periaortic lymph nodes)
stage III (mets to lungs, liver, brain, bone)
types: germ cell tumors (90% usu malignant) vs. stromal sex-cord tumors (5% usu benign) vs.
metastatic (5%)
Germ Cell Testicular Tumors
nearly all inside testis but very rarely: extragonadal tumor in retroperitoneum midline
all share common precursor: intratubular testicular germ cell neoplasia
seminomas: most common, tumor cells resemble immature spermatogonia excellent cure rate since most
at low stage at diagnosis
large, bulky tumors that resorbs nearly all functional testicular tissue
multiple lobular nests with massive lymphocyte infiltration
nonseminomas: poorer cure rate since most at high stage at diagnosis (often present with met symptoms)
pure forms:
embryonal carcinoma: small tumor, does not resorb entire nl testis tissue unlike seminomas
teratomas: germ cell tumor that may contain several diff types of tissue (like hair, muscle, bone, etc);
usu in infants/young kids & often benign if adult, greater potential for malig.
choriocarcinoma: may not cause testicular enlargement, hemorrhage & necrosis common, mets form
bulky hemorrhagic lesions in lungs, liver, & brain

18
yolk sac carcinoma: pure form rare in adults but often found as a part of mixed histo cancers
o infantile yolk sac carcinoma: no precursor (unlike all other testicular tumors) tumor cells
organized in structures that resemble glomeruli (Schiller Duval bodies)
teratocarcinoma: commonest form of nonseminomas mix of all pure forms above
blood tests: -fetoprotein (indicates yolk sac carcinoma component present) & HCG (indicates
choriocarcinoma component present)

Stromal Sex Cord Tumors

Leydig cell tumors: hormonally active (secrete androgens, estrogens, or both) to make diagnosis: look
for Reinke crystals (pink rectangular cytoplasmic inclusions)
Sertoli cel tumors most benign & produce few symptoms
Other Cancers
penis cancer: squamous cell carcinoma presents as plaques on glans
scrotum cancer: also squamous cell carcinoma 1st documented neoplasm with envt-related etiology (
risk if prolonged exposure to hydrocarbons in dust/chimney soot)
Diseases of the Prostate (Sufrin)
Prostate
embryo: made from DHT action on urogenital sinus
epithelium (basal cells, columnar secretory cells, neuroendocrine cells) vs. stroma (smooth m cells,
fibroblasts, endothelium, ECM) gland made mostly of CT
components of prostatic secretions: citric acid, Zn/Ca/Mg ions, polyamines, proteases also:
PSA: a Ser protease made by from series of peptide cleavages works to degrade semenogelin
(released from seminal vesicles) to the peptides that mix with fibronectin to form seminal clot
o prostate specific but not disease specific
if puboprostatic ligament torn in trauma high riding, mobile prostate on DRE
BPH
multi-nodular neoplasm diagnosed by histopathology (not clinically) but pt. may present with LUTS
(lower urinary tract symptoms):
obstructive (hesitancy, weak stream, intermittent stopping during pee, straining to pee, dribbling all
due to bladder emptying d/o) & irritative voiding symptoms ( freq, urgency, & nocturia all due to
bladder storage d/o)
high detrusor m pressure & low urine flow suggests obstruction
if left untreated renal damage/failure, detrusor compensation ( unable to void overflow
incontinence), infections, bladder stones, acute urinary retention (a urologic emergency), etc.
begins as a single peri-urethral nodule in central/transitional zone multiple nodules develop
coalescence of nodules (benign adenoma)
tx: proscar / avodart (5 reductase inhibitors) vs. flomax / uroxotrol (1 receptor inhibitors to relax
prostatic smooth m) surgery if these fail: intraurethral or enucleation of adenoma

19
Prostate Cancer
histological prevalence with age regardless of where you live but clinical cancer differs by location:
Asians living in Asia (very low) vs. in America (high)
PSA is not diagnostic just helps to guide when diagnostic biopsy needs to be done
PSA is high in both BPH and cancer but less high in BPH since its a glandular epithelial prolif so
theres a lumen right there to release excess PSA made (unlike cancer found in peripheral)
histo: loss of basal cells (unlike BPH), glands seen butt up against ea. other with much less stroma
commonest sites for mets: pelvic lymph nodes & bone (usu causing osteoblastic lesions not osteolytic
lesions like most other cancers)
Gleason grade determines biologic aggressiveness
usu asymptomatic at time of diagnosis (typically found by abnl rectal exam or high PSA)
proscar, selenium, antioxidants all prophylactic measures
Treatment options for Prostate Cancer
radical prostatectomy includes removal of prostate, seminal vesicles, & lymph nodes
prostate & cavernous n. very close to ea other thus, ED & incontinence can result
deep dorsal venous complex also nearby thus, blood loss can result
brachytherapy (radioactive seeds implanted directly into prostate) vs. external beam radiation (better
option since high dose at once & now better accuracy extra-prostate damage)
cryotherapy (freezing prostate)
if cancer returns (due to unnoticed met) initiate androgen deprivation therapy (ADT):
inhib androgen synthesis aminoglutethimide (inhibits conversion of cholesterol to pregnenolone) vs.
ketoconazole (inhibits conversion of lanosterol to cholesterol & 17-OH pregnenolone to C19 steroids)
inhib androgen effects via androgen receptor blockers flutamide, bicalutamide
inhib GnRH & LH release estrogen (via neg feedback)
stim of GnRH release to down-regulate receptors leuprolide, goserelin (GnRH agonists)
inhib GnRH effects abarelix
osteoporosis, hot flashes, sex dysfx, depression, gynecomastia all possible side effects of ADT
Puberty (Egan)
Tanner Staging Females:
Breasts: 1 (preadolescent) 2 (small mound) 3 (enlarged mound) 4 (2 mound formed by
areola/papilla) 5 (sexually mature)
Pubes (same stages used for Ms): 1 (none) 2 (sparse, straight, lightly pigmented) 3 (more dense,
darker, some curls) 4 (coarse, curly, abundant but still less than adult) 5 (adult)
Tanner Staging Males:
Penis: 1 (childlike) 2 (slightly enlarged) 3 (longer) 4 (bigger head & girth) 5 (sexually mature)
Testes: 1 (preadolescent) 2 (enlarged, texture) 3 (larger) 4 (even larger & scrotum darkens) 5
(sexually mature)
Gender differences of puberty
Ms go thru puberty 1.5 yrs later than Fs: M (13.51) vs. F (121)
1 year later ( sexually mature: spermarche & menarche) vs. 2 years later ( adult form)

20
note: standard deviation denotes only 2/3 of popn thus, for ex: 1/3 of Fs have menarche when either
<11y/o or >14y/o
menarche at much younger age now (when compared to late 1800s) due to childhood illness
growth spurt correlates with pubertal s (not necessarily chronological age)
delayed puberty too short (if M) vs. too tall (if F)
bones mature at a rate that correlates to onset of puberty thus, bone age used to determine if delay in
puberty seen is nl for that pt. or if something is actually wrong
body composition s: M (substantial muscle mass & body fat) vs. F ( muscle mass but not as much as
men & body fat)
body fat in pubertal Fs risk of eating d/o, which is significant since bone mineralization peaks at
the same time (thus, if nutrient-deficient in puberty lifelong bone defects)
Ms have higher death rates than Fs at any stage of life but especially in puberty

Pubertal Development
what actually initiates puberty is unknown
neurokinin B receptor: located in hypothalamus; once stimulated, causes initiation of pulsatile release of
GnRH to start puberty if missing, no puberty
adrenarche due to androgen release from adrenals pubic hair
gametogenesis stimulated by LH/FSH release from ant. pit menarche/spermarche
wide range of gonadotropins seen at each Tanner stage thus, measuring their levels is not effective in
estimating pts pubertal devo
Disorders of Sexual Maturation
premature thelarchy: breast agenesis but no other long term effects
premature adrenarche: pubic hair seen from DHEA without any other signs of puberty
premature menarche: pt has period without any other signs of puberty
precocious puberty: onset of puberty seen too early (< 9y/o M & < 7y/o F) rare
causes: abnl GnRH (from CNS lesions), isosexual (gonad tumor), contrasexual (steroid secreting
tumor), etc.
delayed puberty: onset of puberty seen too late (>13y/o F & >14y/o M) common
causes: illness (usu renal failure), anorexia nervosa, high physical activity (only Fs), etc.
pubertal failure due to: high LH/FSH (a gonad problem hypergonadotropic hypogonadism) vs. low
LH/FSH (a hypothalamus/pituitary problem hypogonadotropic hypogonadism)
The Menstrual/Ovarian Cycle (Brownie)
Female repro overview
menstrual cycle begins in puberty kisspeptin binds to receptors on GnRH neurons to stim GnRH release,
which causes the FSH & LH secretion required for nl ovarian fx
2 functions of ovary: oogenesis (egg production) & hormone secretion
GnRH pulsatile release patterns:
early (pulse causes small spike in LH) vs. late follicular phase (pulse causes large spike in LH since
estrogen causes gonadotroph sensitivity to GnRH)

21
child (basal low) vs. puberty (pulsatile begins but only at night) vs. reproductive yrs (pulsatile release
day and night) vs. menopause (high pulsatile release day and night explains why FSH/LH levels
measured to determine if pt is in menopause)
GnRH receptor: linked to Gq ( PLC DAG PKC, which enters nucleus & transcription of
FSH/LH, which subsequently get released via IP3 (also from PLC) to intracellular Ca
LH / FSH / HCG all share same subunit (ea. has diff subunit that confers its specific action)
LH (controls ovulation & androgen/progesterone production in ovary) vs. FSH (controls follicle
development & estrogen made in granulosa cells)
inhibin: peptide dimer hormone made in ovary to inhibit FSH but not LH thus, must block
transcription of its subunit (explains why LH is higher in blood than FSH under nl conditions)
estrogen: made in ovary from androgens; involved in both positive (only in pre-ovulatory phase of cycle
LH surge ovulation) and negative feedback ( further FSH/LH/GnRH release)

Oogenesis
oogonia: primitive germ cells in ovary that develop into 1 oocytes within a developing female fetus during
intrauterine life
1 oocyte: held at prophase in ovary till puberty; enclosed by thin granulosa cell layer to form primodial
follicles # significantly to 400,000 by the time of menarche
early follicle devo does occur before puberty (independent of FSH/LH) but never matures enough to
Graafian follicle (ie, unable to achieve ovulation without FSH/LH)
Folliculogenesis stim by both FSH & LH
recruitment (multiple primodial follicles gather) selection (1 follicle deemed dominant, which is the
one that matures to release the ovum, while remaining follicles undergo atresia)
Ovarian Steroidogenesis
maturing follicle: includes 1 oocyte, thecal cells, & granulosa cells major source of hormone
production
theca cells: stimulated by LH to stim conversion of cholesterol to pregnenolone & make ultimately make
androstendione/T via CYP17 but no aromatase in these cells so no estrogen made
granulosa cells: stimulated by FSH to stim conversion of the androstenedione which cell picks up from
theca cells to make estrogen thus, aromatase but no CYP 17 in these cells
also be stimulated by LH during luteal phase pregnenolone, but still no CYP 17 inside so must
release that pregnenolone for theca cells to absorb & use toward supplying hormones to potentially
developing zygote till placenta can take over
Female Reproductive Cycles
endometrial cycle: proliferative (gradual thickening after menses) secretory (same thickness, able to
support fertilized egg if need be; begins to deteriorate if nothing implants onto posterior wall) menses
(shedding of endometrium)
ovarian cycle: follicular phase (LH > progesterone; events prior to & just including LH surge; includes
menses & proliferative phase) ovulation (immediately after LH surge) luteal phase (events following
release of ovum; progesterone > LH; includes secretory phase)
1 oocyte resumes meiosis begun during fetal devo & divides just before ovulation to form 2 oocyte &
nonfunctional 1st polar body
2 oocyte then begins meiosis II but held at metaphase till fertilization

22
dominant follicle then secretes estrogen positive feedback LH surge ovulation (release of ovum from
mature Graafian follicle)
plasminogen activator: released by granulosa cells (following stim by LH/FSH) & converted to
plasmin proteolytic enzyme that helps weaken follicular wall to allow ovum release
stigma: sit on dominant follicles surface where rupture occurs & 2 oocyte is expelled
oral contraceptives: GnRH/FSH/LH secretion suppression of folliculogenesis & ovulation
causes risk (ovarian/endometrial cancer, PID, benign breast disease, etc.) & risk (gallstones, HTN,
MI, stroke, DVT, pulmonary embolus, etc.)
remaining dominant follicle after ovulation corpus luteum (release hormones that drive the monthly s
to endometrium & the women into wackjobs)

Estrogen
stimulates: growth/blood flow in repro organs, uterine epith cells during follicular phase, uterine contractile
proteins, body s in pubertal girls, duct growth in breasts, granulosa cell growth
accelerates of linear body growth since epiphyses more sensitive to estrogen early closure
causes greater body fat, enlarged hips & bigger pelvic inlet
estrogen receptor: a nuclear hormone receptor 2 subtypes ( & ): same DNA binding domains but
different estrogen binding affinities
Progesterone
maintains endometrium but only after estrogen conditions it first & body temp at ovulation
counteracts estrogen effects on contractile proteins ie, myometrial cell excitability
CNS effects: appetite, depression, & sensitivity of resp centers to CO2
progesterone receptor: also a nuclear hormone receptor 2 subtypes (PR-A & PR-B)
Conception, Blastula Transport, & Implantation (Hard)
Oocyte
oocyte released by ovulation transports with immediate surrounding rim of zona pellucida plus follicular
cells of corona radiata
oocyte transport: ovary peritoneal cavity oviduct (infundibulum with fibriae ampulla isthmus
intramural) uterus
substantially decrease in mucosal folds seen from ampulla to intramural oviduct
fibriae: finger-like projections that contact ovary & sweep oocyte into oviduct but more importantly, keeps
egg inside oviduct to ensure it doesnt drop back into peritoneal cavity
even without fibriae, oocyte gets inside oviduct most of the time (90%)
ampulla: most common site of fertilization
posterior wall of uterine cavity: nl site of blastocyst implantantion
ectopic pregnancy: usu in oviduct most common in Fs with endometriosis or PID
Sperm
sperm transport: testis rete testis efferent ductules epididymis vas deferences prostatic
urethra membranous urethra penile urethra vagina cervix uterus oviduct (isthmus
ampulla)

23

sperm transport inside female an extremely traumatic event (99% die before ampulla reached):
upper vagina near cervix: very acidic pH (due to lactic acid from exclusive use anaerobic metabolism
by cells here) kills bacteria to protect against infection but also kills sperm
cervical mucous: highly neg-charged linear polymers stabilized by Ca bridges
o cycles btwn gel (so dense that allows no sperm passage) & hydrated forms (less dense so some
sperm pass but still most do not)
uterine crypts sperm get stuck inside & eventually die
structure:
head: contains nucleus (with compact DNA due to its binding to protoamines positive-charged
proteins) & acrosome (hydrolytic enzymes inside)
neck: contains centrioles important in cell division once it penetrates egg
midpiece: contains mitochondria (supplies energy to fuel locomotion)
axoneme (aka tail): the motor for locomotion
dynein: motor protein found in axoneme that converts chem. energy in ATP to mechanical energy of mvmt
lost in Kartageners syndrome (infertile Ms but Fs may not be since cilia in F repro tract backed up by
smooth m)
epididymis: site of sperm maturation modified by galactosyltransferase: can move but still cannot
fertilize
explains why sperm taken from a M will not fertilize egg in ext. envt (unlike starfish)
to be able to fertilize, mature sperm must undergo capacitation inside female repro tract: involves 2nd
modification by galactosyltransferase & acrosin-activated hypermotility

Fertilization
involves penetration of corona radiata & zona pellucida then fusion of oocyte & sperm membranes
zona pellucida: like steel wool, no sperm can pass thru it to enter egg structure:
ZP1 glycoprotein crosslinks the long, linear polymers made up of ZP2 & ZP3 glycoproteins
ZP3 receptor (found on sperm head): binds to carbohydrate residues of ZP3 in eggs zona pellucida
clustering of other ZP3 receptors on sperm head acrosome reaction (release of acrosin to digest a hole
thru the ZP)
if carbohydrate residues abnormally removed, no sperm-egg binding ( no fertilization)
ZP2 receptors on sperm bind to ZP2 on egg to keep sperm attached as ZP is being digested
this ZP interaction provides species specificity why animal sperm cant fertilize human eggs
izumo: sperm membr protein that binds to oocyte required for oocyte/sperm membrane fusion
binding triggers cortical reaction: Ca release of cortical granule enzymes modified ZP3 (to
prevent polyspermia) sperm enters egg
meiosis II follows female & male pronuclei form together inside egg (each haploid) pronuclei fuse &
mitosis begins 2 daughter cells with DNA of both mom & dad
possible problems:
too many sperm (if 2 enter egg, triploidy occurs usu spontaneously aborts), infertility, or bad timing
(ovulated egg cant be fertilized after 24hr & sperm only live 48hrs inside F repro tract)
Post-fertilization
blastula transport: ampulla of oviduct posterior uterine wall (fast stage of transport)
fast transport in oviduct: zygote 2-cell stage (after 1st mitosis) morula (30 cell stage)
size not increasing here: cells are just getting smaller with ea division (unique!)

24
cells form a central cavity blastocyst: embryoblast (inner cell mass bilaminar embryonic disc 3
germ layers) & trophoblast (outer cell mass implantation onto endometrium)
hatching: loss of ZP, allowing it to finally expand in size
embryonic pole: found on blastocyst that allows trophoblast attachment to endometrium
once attached, trophoblast cytotrophoblast (mitotically active to provide further cells to
syncytiotrophoblast) & syncytiotrophoblast (penetrates uterine epith & invades its CT to make synctium
with it many nuclei sharing 1 cytoplasm:
secrete HCG by day 14 what is detected by preg tests
lacunae eventually form inside: contain moms blood from ruptured capillaries in endometrium as
syncytiotrophoblast invaded primordial uteroplacental circulation:
o spiral aa (bring O2 to fetus) vs. uterine vv (take CO2 from fetus)
embryoblast epiblast (thick, columnar cells forms floor of amniotic cavity, continuous with amnion)
vs. hypoblast (thin, cuboidal cells forms roof of exocoelomic cavity, continuous with exocoelomic
membr)
1 yolk sac: formed by hypoblast & extraembryonic mesoderm
inner ( amnion & sac) vs. outer cell mass ( chorion & sac)
subsequent weeks: placenta (definitive connection btwn mom & fetus placental membr partially
separates circulations but viruses & most drugs can still pass in btwn) & umbilical cord forms (2 umbilical
aa & 1 umbilical v surrounded by protective Whartons jelly)

Uterine Menstrual Cycling & Abnormalities (Arroyo)

Secondary Amenorrhea
has had a period before but now has stopped for at least 3 months F is in Tanner 5
unlike 1 amenorrhea: never has had a period & F is inappropriately in Tanner 1
first measure FSH, PRL, & TSH levels
if TSH think 1 hypothyroidism
if PRL & nl TSH hyperprolactinemia (PRL >50): usu due to central-acting drugs
o think micro/macroadenomas if PRL is significantly high tx: bromocriptine
if FSH think gonadal failure (FSH high from no neg feedback by estrogen)
o due to idiopathic (commonest), chr. d/os (Turners), autoimmune all tx: replace estrogen
if above levels normal hirsuitism & virilization (states of hyperandrogenism)
if present measure T: if high (evaluate neoplasm) vs. if nl (think adult onset CAH)
if absent measure T: if slightly high (polycystic ovary) vs. if nl (functional hypothalamic amenorrhea)
functional hypothalamic amenorrhea is a diagnosis of exclusion must r/o all other causes
stress-induced, runners, etc. commonest cause of 2 amenorrhea (then polycystic ovary)
loss of nl GnRH pulsatile release LH/FSH amenorrhea (tx: estrogen (E) replacement)
can also be caused by any disruption in NTs that act on GnRH neurons: GABA, glutamate, NE, NPY,
opioids, etc.
1st day of period (day 1 of cycle) vs. ovulation from LH spike (day 14 of cycle)
Polycystic ovary syndrome
caused by LH pulsatility (due to disordered GnRH release usu induced from hyperinsulinemia)
ovarian androgen synthesis E inhib of FSH amenorrhea
hyperinsulemia also causes hepatic synthesis of sex-hormone binding protein further free E
to diagnose, use Rotterdam criteria (need 2/3):

25

abnl menstrual cycle (tx: oral contraceptive Yasmin best since also has anti-androgen effects)
o infertility results tx: agents that induce ovulation, like metformin (also helps with wt loss &
insulin resistance but watch GI side effects)
hyperandrogenism: seen as hirsuitism or asymptomatic with serum androgens
o tx: anti-androgens (like spironolactone)
polycystic ovaries: >10 follicles seen on ultrasound

Hormone Replacement Therapy (Wende)

Hormone Therapy (HT) in Women
recall in 1993, commonest in women: heart disease (#1 killer of women) then: fracture &
breast/colorectal ca
before Womens Health Initiative (WHI) observational studies findings about hormone therapy:
benefits ( CAD, lipids, colorectal ca, osteoporosis, fractures, dementia, hot flashes, night sweats, etc.)
vs. risks ( breast ca, PE/DVTs, stroke, etc.)
thus, top 3 reasons to give HT in 1996: menopause symptom relief, prevent/tx osteoporosis, & heart benefits
recall: observational studies include: cross-sectional (snap shot of 1 popn at 1 time) vs. cohort (following 1
popn over time) but! provide very weak scientific evidence
best study: RCT (since enrollment criteria creates a homogeneous popn & intervention is assumed to be
the only diff btwn them) but study popn may not reflect general popn
huge drop in HT use when estrogens found to endometrial ca but a decade later: progestin when used
with E was found to risk & thus, HT use began to climb again
post-menopausal E-progesterone intervention PEPI trial: showed HT LDL & HDL ( thus, risk of
CHD) but:
HERS trial (considered popn of post-menopausal Fs that already had established CHD to see if HT
helped): had to be stopped early since HT actually worsened their condition despite HT still LDL &
HDL
clearly more research needed to be done & thus, WHI came about to determine:
HT did risk of CHD & stroke when compared to placebo
o black box added to E products: should not be used to prevent CV disease (& if must used for other
purposes, should be prescribed at lowest doses)
o E-alone trial had to be stopped early due to risk of stroke (but no effect on heart disease)
HT did risk of breast cancer but! risk quickly returns to that of general popn after HT d/c
HT did risk of dementia
benefit: HT did risk of fracture
remaining unanswered questions: effects of other doses or other routes of administration for HT still not
known & effect of when HT is initiated
recent study suggests short term HT use in F close to menopause (ie, early tx) to be effective

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Pathology of Female Genital Tract I (Wild)
Symptomology of GYN lesions
abnl vaginal bleeding: menorrhagia (excessive bleeding during period) vs. metrorrhagia (bleeding btwn
period)
vaginal discharge: leukorrhea (thick white discharge suggests infection)
pelvic pain: dymenorrhea (painful menses) vs. dyspareunia (painful sex) vs. mittelschmerz (abdominal
cramp seen mid-cycle caused by peritoneal irritation following follicle rupture ovulation)
Congintal abnormalities of uterus
diethylstilbesterol (DES): synthetic E formerly used to prevent miscarriages found to cause:
adenosis: vaginal epith s from squamous to glandular (seen as more red grossly) risk to clear cell
adenocarcinoma of vagina
abnl mullerian duct morphogenesis:
fusion defects bicornuate uterus (heart-shaped with 2 cavities joined together instead of round with 1
central cavity) or uterine septum with double vagina
atretic defects: open ducts abnormally closed unilateral rudimentary uterine horn (oviduct on 1 side
is seen blocked)
Gartner duct cysts: persistent remnants of wolfian duct; can enlarge & fill with fluid; may bulge into
vaginal canal pain
Histo of Uterus
cervix: 2 parts: exocervix (nonkeratinized squamous) vs. endocervix (columnar mucous secreting
glandular)
squamocolumnar transition zone: seen btwn exocervix & endocervix whats looked at in PAP
smears since this is where most dysplasias arise
corpus 3 layers: parametrium (outer serosa layer) vs. myometrium (muscle layer) vs. endometrium
(inner layer that lines uterine cavity)
sublayers in endometrium: stratum basalis (germinative layer) vs. functionalis (what undergoes cyclic
s & is lost in menstruation each month)
menstrual cycle: preovulatory prolif (may vary in duration) vs. postovulatory secretory phase (usu
constant at 14 days; biopsy during this phase to date endometrium & determine when ovulation exactly
takes place helps with infertility & dysfunctional uterine bleeding issues)
Endometrium Pathology
endometritis rare unless cervix is breeched (like in childbirth or abortion)
presence of plasma cells indicates chronic episode
adenomyosis: endometrial glands inside myometrium in older reproductive aged Fs
endometriosis: endometrial glands outside uterus in younger reproductive aged Fs
catamenial: symptoms present with onset of menses (since hormonally active & thus hemorrhages in
its ectopic location as well)
usu seen in pelvic cavity: thought that endometrial fragment exits thru oviduct (but this does not explain
those seen in distant unusual sites; suggests lymph/blood involvement)
can cause scarring/distortion of pelvic organs (incl tubes/ovaries), dysmenorrhea, pelvic pain,
dyspareunia, intestinal disturbances, & mechanical infertility
chocolate cyst: an endometrioma in the ovary

27

dysfunctional uterine bleeding: commonest complaint seen by gynos due to hormone imbalance on
endometrium (does not include anatomic lesion)
endometrial hyperplasia (aka endometrial intraepithelial neoplasia): caused by sustained high levels of E
(usu around menopause) often due to inactivation of PTEN tumor suppressor
cystic/simple (swiss-cheese pattern, no cancer risk) vs. complex hyperplasia ( glands seen) vs.
complex hyperplasia plus nuclear atypia (many glands with abnl features inside nuclei huge in
endometrial adenocarcinoma risk)
endometrial adenocarcinoma 2 types:
Type I endometrial adenoca: commonest; due to prolonged unopposed E stim, present in early stage
& thus favorable prognosis
o can present as abnl post-menopausal vaginal spotting, low diagnostic yield on PAP smears
o stages: I (confined to corpus), II (spread to cervix), III (local mets), IV (distant mets)
Type II endometrial papillary serous / clear cell carcinomas: not due to E stim, present in later stage
& thus poorer prognosis
uterine corpus tumors:
endometrial polyp: fully benign but must excise it since thats only way determine not malig
fibroid leiomyoma of myometrium: commonest uterine tumor benign SM tumors
o submucosal (bulges into uterine wall) vs. intramural (inside uterine wall) vs. subserosal (bulges out
from uterus can compress bladder to cause urinary freq)
endometrial stromal tumors: benign nodule (circumscribed, no invasion) vs. low-grade sarcoma (well
differentiated nests, most recur) vs. high grade sarcoma (vascular invasion)

Menopause (Santhakumar)
Reproductive Aging
peri-menopause: from stage -2 to 12mo after FMP
menopausal transition: cycle begins to vary in length due to FSH: from stage -2 to final menstrual period
(FMP)
menopause: the 12 mo after FMP
post-menopause: anytime after FMP; stage 1+ (early after) vs. stage 2+ (5 yrs after FMP & on)
Menopause
natural event (genetically programmed loss of ovarian follicles) or induced (surgery, chemo, etc.)
avg age: 51y/o but diff age of onset seen due to genetic variations (in X chr & E receptor) & ethnicity:
(occurs earliest in Hispanics then: whites < Japanese)
menopause earlier if: cigarette smoker, childhood cancer survivor, nulliparity, T1DM, epilepsy,
antidepressant use, hx of heart disease, etc.
extent of alcohol consumed: no effect on onset
menopause later if: OCP use, many full-term preganancies, etc.

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Endocrinology of Menopause
nl repro cycle: follicular ( E FSH follicle matures E produced endometrial growth) vs.
periovulatory ( E LH surge ovum release & corpus luteum forms from residual follicle) vs. luteal
phase (E & P release from corpus luteum till it regresses menses)
estradiol: 1 E produced by ovary; maintains menstrual cycle via feedback mechanism
menopause transition: initiated by follicular atresia, inhibin B & anti-mullerian hormone, & s in CNS
control
more dramatic in FSH seen in follicular phase marks reproductive aging
steeper decline in follicle number & poor response to FSH/LH in remaining follicles
P often lower than nl but T levels do not (metabolism s due to age not menopause)
post-menopause: gradual in FSH/LH estrone becomes 1 estrogen produced
estradiol estrogen:androgen ratio ( possible hirsutism)
Clinical Issues of Menopause
a clinical diagnosis ( ie, no lab marker for menopause): amenorrhea for 1 year in >45y/o F
E never considered first line tx due to its other side effects
endometrial atrophy menstrual flow & freq s
possible tx: hysterectomy, D&C, low dose E (OC), etc.
hot flashes: often linked with perspiration/palpitations chills following
usu self-limited & thus no need to treat but if really bothersome: low dose E (most effective but risk of
DVT/breast ca) or SSRI (best choice in Fs not taking E)
E vaginal atrophy & vaginal pH ( risk for vaginitis) dyspareunia
tx: moisturizers & lubricants
urinary continence due to aging not menopause
long term effects: CV risk (from loss of Es cardio-protective effects) & bone mineral density loss (since
E cytokines osteoclast activity & thus more bone resorpted than formed)
colles fracture (wrist fracture, 1st sign of osteoporosis) vertebral & hip fractures seen later
tx: biphosphonates (1st line inhibs osteoclasts), VitD/Ca, avoid cigarettes (since lowers bone mass
even more), wt-bearing exercise, raloxifene (E agonist in bone but E antagonist elsewhere & thus can
worsen hot flashes)
other effects: wrinkled skin, impaired balance, atrophy of bone tooth sockets ( periodontitis & teeth loss),
etc.
Pharmacology of Estrogens, Progesterones, & Oral Contraception (Bradford)
Oral Contraceptives
are E &/or P that provides negative feedback to suppress FSH/LH release needed to ovulate
no endogenous sex hormone production seen (but nl levels maintained by tx)
used by 70% of US women, esp common in young Fs (sterilization more common in older Fs)
other administrations may be more effective since given continuous protection rather than peaks & troughs
seen in pill such as:
OrthoEvra (the patch) vs. Lunelle (monthly injection)
Depo-provera: injection more popular in young women who cant remember to take pill everyday
causes bone mineral density & thus should not be used for > 2 yrs
Nuva ring: inserted high in vagina to provide continuous hormone supply

29
Types of Oral Contraceptives
COC: combo oral contraceptive (ie, pill has both E&P inside)
made in fixed (like Loestrin) or triphasic doses (like Ortho-Novum)
o in triphasic doses, [E] remains constant but [P] gradually in ea phase to mimic nl. cycle
o pills in 4th phase contain nothing in them to allow for regular period to take place
ethinyl estradiol: synthetic E seen in nearly all COC preps (ethinyl grp makes it orally active)
when used, high FSH typically seen early in cycle to stim follicle growth is no longer seen ie, there is
mitosis thus, risk of ovarian/uterine cancer (but! risk of breast cancer)
yasmin: good pill since has additional anti-mineralocorticoid & anti-androgen effects also only drug
approved to treat emotional & physical premenstrual symptoms
seasonale: 91-day regimen so F only gets her period 4 times a year
lybrel: causes uterine lining to never undergo s needed for menses & thus, F gets no periods
ortho tri-cyclen: approved to treat moderate acne
side effects: thromboembolic d/o (esp if smoker), HTN, breast cancer, teratogenic effects
plan B: using COC at high doses to inhibit implantation the sooner its taken after unprotected sex,
the lesser the risk of pregnancy
some abx & drugs that induce P450 (like phenytoin) can decrease efficacy of COC
P-only OC: mini pills bad for bones since E levels from neg feedback & not replaced by tx
used only in: smokers (since risk of clot), migraines (since cause is linked to high E), nursing moms, or
prior hx of clot
Andrology, Fertilization, & Infertility (Burkman)
Requirements of Sperm that enable egg fertilization
hyperactivation: achieved by capacitation in F repro tract both tail & head of sperm begin moving very
vigorously in helical pattern
in artificial insemination or in vivo fertilization: sperm is washed with fluid from cervix/uterus to
capacitate them before they are implanted into egg
capacitation also involves metabolism/membr s, loss of cholesterol, acrosome, & zona binding
acrosome reaction: completed near egg surface releases enzymes that penetrate zona pellucida & expose
receptors inside it to allow for sperm binding
THC (from marijuana) & AM-356 (synthetic anandamide) both block acrosomal s
sperm must be able to bind to ZP receptors assessed by hemizona assay in infertility labs
5% of sperm must have normal morphology (ie, it is nl for 95% of mens sperm to look abnl)
Ab test: IgG beads will not stick to nl sperm if clumping seen, think groin injury/surgery
Fertility Issues
15% need medical assistance to have a baby but only <1% perform an advanced semen analysis able to
predict fertilizing potential
takes 74 days to make sperm from start to finish (but 1 spermatogonium can make 64 sperm)
once >50y/o, sperm count & quality seen

30

traditional blood labs have terrible semen analysis capabilities very subjective (done by eye)
only give sperm counts, % motility, & morphology these can all be nl in an infertile man
advanced semen testing only done in andrology labs but these are very sparse in US
more objective (use computer analysis) & excellent quality control
sperm analysis must be completed within 1 hour of collecting sample
fertility approaches: intrauterine insemination (tried 1st) in vivo fertilization intracytoplasmic sperm
injection into egg (tried last)

Pathobiology & Treatment of Failure to Conceive (Arroyo)

Differential for 1 amenorrhea
ie, has never had period & never went thru puberty Tanner 1 breasts/pubic hair
if >13y/o & F still hasnt had menarche check FSH levels
if high ovarian failure (commonest cause), must then karyotype to determine cause:
o if nl 46,XX ( autoimmune) vs. if 45X ( Turner syndrome)
if low must be pituitary/hypothalamus problem, must then consider growth pattern:
o if short for age think constitutional delay
o if nl growth but no growth spurt think Kallmans syndrome (if anosmia) or isolated gonadotropin
deficiency (if nl sense of smell)
o if late onset growth failure think CNS tumor (very rare)
if nl 2 sex characteristics but still never had menarche, must karyotype:
if nl ( think anatomic defect) vs. if 46,XY ( think androgen insensitivity syndrome: a genetic male
but defect in androgen receptors so never masculinated during devo)
o these females wont have uterus since anti-mullerian hormone still effectively released
Kallmans Syndrome (KS)
olfactory bulb/tract agenesis GnRH neuron cannot migrate down it to hypothalamus during devo as it
normally does thus, anosmia & amenorrhea seen
mutn in KAL-1, FGFR1, or PROK2 disrupts GnRH migration to also cause KS
normal ovaries so just give E replacement to elicit menarche
Isolated gonadotropin deficiency (IGD)
FSH/LH due to defect in gonadotrophs within pit. or GnRH neurons in hypothalamus but not due to
anatomic defect
often due to gene mutn (30%):
if amenorrhea with: adrenal insufficiency ( DAX1 mutn) vs. obesity ( leptin mutn)
kisspeptin: NT that acts on GPR54 receptor in brain to elicit GnRH release thus, if mutated: IGD with
abnl LH pulse profile
E may act on neurons that release kisspeptin in different hypothalamic nuclei: AVPV ( positive
feedback LH surge) or ARC ( negative feedback suppression of GnRH)
Infertility: 1 year of unprotected sex w/o conception approach:
if F is not menstruating, you already know anovulation (usu PCOS) causing the infertility
if F is menstruating, think tubal factor may be causing infertility tubes blocked preventing
fertilization/implantation from prior gonorrhea, PID, or IUD
also consider reduced ovarian reserve (ie, perimenopausal issues infertility)

31

look to the male as cause of infertility via advanced semen analysis once the above are r/o
intracytoplasmic sperm injection (1 single sperm injected into egg) if sperm count <5 mil/cc
endometriosis can cause mechanical infertility (scarring in pelvis forms physical barrier btwn released egg
& oviduct)
congenital anatomic defects preg is possible but may be harder to accomplish:
unicornuate uterus: risk of preterm labor (since smaller space) but requires no tx for infertility
uterine septum: incidence of recurrent miscarriages only defect that requires surgical tx

Treating strategy for infertility

clomiphene: E receptor blocker in brain neg feedback & thus FSH/LH ovulation induced
typically tried 1st since cheap & easy
if hyperinsulinemic (like in PCOS), may also try metformin since insulin acts directly on ovary to
inhibit ovulation
next try gonadotropins: direct injection of FSH given daily; must monitor with ultrasound regularly to
avoid potentially-fatal ovarian hyperstimulation syndrome much more expensive
if all else fails IVF (younger the mom, better the success)
no current limits on # of embryo transfers (problem with octomom), just recommendations: 2 if <
35y/o & 5 if >40y/o
Benign & Malignant Pathology of the Breast (Errick)
Boobies
modified sweat glands arise along milk line ridge starting at week 5 of gestation
puberty: elongation & branching of ducts & prolif of interstitial stromal tissue (to breast vol)
lining of ducts undergo cyclic s with menstrual cycle: secretions, sloughing, & regeneration
pregnancy: early (marked prolif) vs. late (differentiation into cells that secrete fat & protein)
colostrum: 1st secretion after delivery; thin, watery fluid containing many hormones / Abs
following colostrum secretion, acini become distended with milk
PRL (stim production of milk protein) vs. oxytocin (stim contraction of myoepith cells to move milk
along & help with release) both levels maintained by sucking reflex
Pathology of Breasts
amastia (no boob devo) vs. micromastia (underdevo) vs. macromastia (overdevo)
hypermastia (excessively enlarged) vs. hyperthelia (extra nipples)
acute mastitis: usu seen in nursing; staph or strep enters thru cracks in skin at nipple & causes abscess (
possible palpable scarring once resolved)
duct ectasia: usu seen in menopause; ducts dilate & rupture release of secretion into surrounding tissue
( inflammatory response)
galactocele: also seen in nursing blocked duct causes palpable mass of milk (can lead to mastitis or duct
ectasia)
fat necrosis: usu seen in trauma; nodular lesion from local destruction of fat cells
simple fibrocystic change: commonest, completely benign linked to caffeine blue domed cysts (since
filled with turbid, bloody fluid) & dense stromal fibrosis surrounding ducts
epith hyperplasia: due to higher than nl hormonal stim 2 types:
typical (small uniform nuclei) vs. atypical (bigger nuclei, mitoses risk of ca)

32

sclerosing adenosis: hyperplasia plus fibrosis

radial scar: sclerosing adenosis but in spoke-like pattern: looks just like ca but totally benign

Benign Breast Neoplasms

fibroadenomas: mid-aged Fs very well circumscribed & freely mobile (not very well connected to
stromal tissue so tumor nearly pops out once skin is cut open to remove it)
phyllodes tumor: a huge fibroadenoma uncontrollable in size can damage nl breast tissue
very unpredictable nature: some benign, some metastasize
intraductal papilloma: tumor of duct lining blood nipple discharge
gynecomastia: not a tumor but presents as a mass in women (unlike men: just diffusely enlarged)
Breast Carcinoma most arise from ductal cells
incidence (US > Japan) better prognosis if onset after menopause
risk (if child-bearer at early age) vs. risk (if obese, atypical hyperplasia, hx of other cancers)
extensive lymphatics spreading across breast substantially mets risk relative to other cancers
intraductal carcinoma (aka ductal carcinoma-in-situ): non-invasive & confined to ducts (but usu invasive
malig found elsewhere) found on mammogram since no palpable lumps present
cribriform (markedly enlarged ducts filled with tumor cells & spaces in btwn to give cribriform
appearance) vs. comedo type (necrosis, microcalcifications)
can coexist with: lobular carcinoma in situ (expanded lobules, uniform cells, small nuclei)
invasive ductal carcinoma: commonest; hard tumor (unlike rubbery fibrocystic diseases)
Pagets disease of nipple: occurs when tumor cells from coexisting ductal carcinoma invade epidermis of
nipple ( crusty nips)
rare types:
medullary carcinoma: lymphocytes react to tumor to tame its growth better prognosis
mucinous carcinoma: excessive mucin seen with mass
invasive lobular carcinoma: single file cells in rings around ducts bilateral risk
inflammatory carcinoma: misnomer since not inflammatory; poor prognosis
o tumor fills cutaneous lymphatics lymphedema of dermis puckering/dimpling of breast (ie,
orange peel appearance) seen on PE from tumor
Lab Eval of Breast Ca
use of fine needle aspiration (to inspect cytology if no palpable mass), core biopsy (via stereotactic guidance
to cause breast disfigurement), permanent section (for final diagnosis), & mammogram
lymph nodes dissected from axillary fat: if no signs of cancer in lymph node, 70% will have no recurrence
following lumpectomy
sentinel node testing: dye injected into breast & travels thru lymphatics 1st node that the dye reaches
would also be 1st node to receive mets (& thus this is the node selected to biopsy)
when tumor & some surrounding tissue excised, margins dipped in India ink: if no invasive tissue near
margin, surgeon can be ensured all invasive tissue had been appropriately removed
higher the tumor size, higher the likelihood of mets
immunohistochemical (IHC) methods used to detect receptors (via Ab vs. E/P receptors) & guide tx
strategy:
tamoxifen (blocks E receptor to block E-induced prolif of cancer cells) vs progesterone (has antiproliferative effects & thus useful as tx)

33
HER-2 status: product of oncogene found on cell surface involved in cell growth IHC used to detect its
precence & if seen overexpressed on cell, it must be proliferating
herceptin: monoclonal Ab vs. HER2 receptor to breast tumor growth
10% of cases are familial BRCA gene implicated & thus screening possible (but very costly)
follow-up early detection of recurrence via serum markers: CA15-3, CEA, & HER-2

Path Lab: GYN Pathology

Adenocarcinoma of Endometrium endometrioid type
E-related & thus risk in any condition with unopposed E stim (like PCOS, prolonged exogenous E
replacement, functional ovarian tumors, etc.)
atypical endometrial hyperplasia: precursor to endometrial adenocarcinoma
not reliably IDed by PAP smears thus, if vaginal bleeding, must obtain endometrial biopsy
Leiomyoma
benign neoplasms of smooth muscle usu seen in reproductive-aged Fs (unlike adenocarcinomas that usu
present around menopause)
more crowded than nl myometrium (but still much less dense than leiomyosarcomas), no nuclear atypia
& very low mitotic rate
pt most likely to bleed if submucosal leiomyoma (since found just beneath endometrium & bulge into
uterine cavity)
Serous Cystadenocarcina aka serous adenocarcinoma of ovary
commonest form of ovarian cancer tumor of ovarian epith with capsular invasion
ovarian epith tumor subtypes: serous (mimic oviduct epith), mucinous (mimic endocervix mucosa),
endometrioid (mimic endometrial glands), clear cell (mimic endometrial glands during preg cells high
in glycogen), & transitional cell tumors (mimic urinary bladder mucosa)
psammomma bodies (laminated calcified concretions) often seen
due to repeated episodes of disruption/repair of epith (thus more common in nulliparous Fs, esp if not on
OC) also risk if family hx, & use of feminine hygiene products
Endometriosis
abnl presence of endometrial tissue outside uterus responsive to hormones & thus undergoes periodic
bleeding in their ectopic locations pain (depending on site) & nodule formation:
red-blue (from recent bleed) vs. yellow-brown (from old bleed)
must distinguish from metastatic endometrial carcinoma: this has nl stromal cells (not fibrovascular stroma
induced by cancer) & nl epith cells lining glands
if intestinal endometriosis possible acute partial or complete bowel obstruction
laparoscopy with visual documentation of lesion: gold std for definitive diagnosis of endometriosis
Placental & Pregnancy Endocrinology (Gallant)
Luteal Phase (aka secretory phase of endometrial cycle)
occurs immediately following the LH surge & ovulation maintained by progesterone
if no preg occurs, corpus luteum degrades by the end of this phase & becomes corpus albicans

34

if blastocyst implants in preg, it will begin releasing hCG which temporarily delays corpus luteum
degradation till placenta develops enough to maintain developing fetus
17-OH-progesterone: made by corpus luteum can be measure to assess luteal fx

Development of Placenta
recall blastocyst: inner cell mass ( fetus) & outer trophoblast ( placenta)
from trophoblast, 2 cell types arise:
cytotrophoblasts: inner layer that secretes hypothalamic-like hormones (like GnRH which stim synctios
to release hCG) & also secretes hCG itself (but mainly in early preg)
synctiotrophoblasts: outer fused layer huge cell with many nuclei sharing one large cytoplasm
invades endometrium to obtain maternal blood supply for fetus
o encloses placental chorionic villi (which absorb moms blood & carries it to umbilical cord, which
supplies fetus) thus, synctios provide barrier btwn moms blood & fetal blood
umbilical cord: connects placenta to fetus made up of: 2 aa (carrying deoxygenated blood
from fetus) & 1 v (carrying moms oxygenated blood to fetus)
o GLUT-1 on its surface to obtain circulating glucose for fetus
o secretes pituitary-like hormones (like hCG) & steroids (E/P to take over corpus luteum)
flat but very dense structure weighs over 1 lb once fully mature
many fxs: supplies nutrients to fetus, gas exchange, protection, heat exchange, filter/remove waste &
protein/hormone production
Hormones released by Synctios
hCG: action to LH shares same subunit as LH, FSH, & TSH many fx:
rescues corpus luteum to maintain E, P, & relaxin synthesis till placental synctios become abundant &
developed enough to take over
detected on preg tests rapidly spikes after implantation, then declines to steady plateau
stimulates synthesis of: DHEA (in fetal adrenal; not stimulated by ACTH since HPA axis not developed
yet), early T (only if male critical for sex differentiation), & relaxin (in corpus luteum helps with
delivery to relax moms pelvic outlet & cervix)
if high hCG ( multiple fetuses, choriocarcinoma, hydatidiform mole) vs. if low hCG ( Downs, ectopic
preg, miscarriage)
human placental lactogen (HPL): action to GH & PRL
secreted to go into moms circulation to stim lipolysis & antagonize insulin FFA & glucose so that
nutrients go to fetus
also stimulates enzymes for milk production
progesterone: made from moms cholesterol synthesis begins at week 6 by synctios
maintains decidua (ie, uterine lining) & stimulates it to secrete nutrients for zygote
used by fetal adrenal to make cortisol & aldo
estrogen: levels progressively during preg to stim uterus growth
placenta has no CYP 17 thus, production stops at progesterone & cannot make androgens
but! has lots of aromatase to make E just needs DHEA from elsewhere (mostly from fetal adrenal
but also from mom)
no StAR to bring cholesterol in unique to placenta (ie, steroid synthesis not rate-limited)
16-OHase: seen in fetal liver; converts DHEA to 16-OH-DHEA (which is shipped to placenta to make
estriol not estone or estradiol; only significantly made in pregnancy)

35
Maternal Changes in Pregnancy
PRL rises during preg but lactation suppressed by high E/P
after childbirth, E/P levels drop, inhib is immediately lifted & mom begins to lactate
1st of preg (anabolic to build up fuels in prep for 2nd ) vs. 2nd (catabolic fuels available for
rapidly growing fetus; insulin resistance seen, explaining risk of hyperglycemia in preg diabetic moms)
parturition not very well understood:
protaglandins (which myometrial cell Ca) & oxytocin both stim uterine contraction
placental CRH ( ACTH release in fetus DHEA E) prostaglandin & oxytocin receptors
on uterus
Non-Endocrine Physiology & Pharmacology of Pregnancy (Egan)
CV Changes in Pregnancy
CO & bp suggests marked systemic vascular resistance
if cardiomyopathy or pHTN in mom high mortality rate & thus preg not advised in these Fs
but preg is safe for Fs: only 0.008% die (& of those, many die from causes other than preg)
total blood vol seen (in prep for obligatory blood loss during childbirth) explains HCT seen (mimics
anemia but a dilutional effect from vol not pathologic in preg)
Fe deficiency & hemolytic anemias both very compatible with preg
hemoglobinopathies: need aggressive prenatal care to avoid acute crises during preg but F<M so
fortunately not a common problem
if pre-existing HTN in mom 5x risk of pre-eclampsia (even if HTN treated before preg)
thrombocytopenia sometimes seen needs to be treated due to hemorrhage risk at birth
Renal Changes in Pregnancy
hydronephrosis & hydroureter: seen in nearly all Fs in late preg (75%)
due to obstruction by uterus explains risk of ascending UTIs in preg Fs
50% in GFR seen (unsure why)
GI Changes in Pregnancy
the smaller the BMI before preg, the greater the recommended wt. gain
only 15lb of wt gain recommended if high BMI very tough to do due to metabolic s seen:
fat stores (to prep for demand of lactation) striae gavidarum (stretch marks due to both physical
& hormonal factors on skins elastin fibers)
mom begins to use fat as 1 fuel so fetus can use CHO
morning sickness (N&V, usu resolves by week 20) hyperemesis gravidorum (malnourished state from
excessive vomiting)
constipation (from contraction of colon due to large uterus compressing it) & GERD
perianal pruritis & hemorrhoids (from venous pressure due to vessel compression by uterus)
melasma: characteristic skin rash on face in preg Fs or Fs on BC

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Diabetes in Pregnancy (Rodgers)
Diabetes in Pregnancy
recall: T1DM (absolute insulin deficient from autoimmune cell destruction, ketosis prone, early age of
onset) vs. T2DM (insulin resistance but not deficient, obesity, late age of onset)
diagnosed: >125 fasting glucose impaired tolerance if fasting glucose 100-125 (& thus at risk of
diabetes when preg)
gestational diabetes: glucose intolerance that first presents during preg, characterized by insulin resistance
(just like T2DM) clinical approach:
determine actual extent of disease in mom: nephropathy, retinopathy, peripheral/autonomic neuropathy,
HTN, hypoglycemic unawareness, etc.
determine viability of pregnancy via ultrasound: the more uncontrolled glucose is, the greater the risk
for miscarriage
determine risk of fetal anomaly: higher the glucose levels, high the risk for malformation
o use ultrasound, incl. fetal echo also measure MSAFP (seen high if anomaly present)
Glucose control in pregnancy
1st trimester: enhanced insulin sensitivity hypoglycemic risk
2nd/3rd trimester: counter-regulatory hormones (P, cortisol, HPL, etc.) seen since basal fetal needs (ie,
need more glucose from mom) insulin resistance insulin secretion & cell hypertrophy to maintain
normal glucose levels in mom
diabetic moms have poor cell reserve or pre-existing insulin resistance thus, unable to maintain
such nl glucose levels, leading to the problems
o explains rationale for insulin dosage when diabetics get preg
accelerated starvation of pregnancy: nl preg Fs have fasting glucose levels (since more being lost to
fetus) ketosis
explains why preg T1DM pts have substantial risk of developing diabetic ketoacidosis
large proteins cannot pass thru placenta & into fetus so maternal insulin/glucagon never enter fetus, but
maternal glucose (D-isomer) does via facilitated diffn inducing fetal insulin production
thus, if mom has hyperglycemia, so does the baby thus, fetal cell hypertrophy seen to maintain high
enough insulin to combat high influx of glucose
fetal hyperinsulinemia is what causes all problems in babies of diabetic moms:
macrosomnia (phenotypic marker) also: polycythemia ( RBC), jaundice, RDS, etc.
insulin fetal metabolic rates lesser amt of time tolerable without O2 during delivery hypoxia
( birth trauma & stillbirths)
hypoglycemia when born (since no longer has moms high glucose load to deal with but still has
residual hyperinsulinemia from its time in womb)
Diabetic Pregnancy Management
therapeutic end-pt: normalize moms glucose level to prevent fetal hyperinsulinema & need for C-section
(since baby will no longer be macrosomic)
2 end-pt (if maternal tx fails): optimize outcomes for the hyperinsulemic fetus
no restriction on caloric intake but frequent self-monitoring of blood glucose required:
very strict range of glucose levels for preg (A1C < 6%)
insulin (mainstay in tx for diabetic moms) also, oral hypoglycemics: glyburide (good choice since
enhances pancreatic production of insulin & does not cross placenta, unlike metformin)
measure insulin in amniotic fluid in fetus to determine if fetal hyperinsulinemia exists

37

also do fetal ultrasound to ID any growth abnormalities:

macrosomnia: abdominal growth relative to head seen due to effects of insulin on tissues that are
particularly responsive to insulin ie, fetal liver & adipose tissue
intrauterine growth restriction: rare; only in diabetic moms with vascular disease
stillbirth: most often due to maternal hyperglycemia during 3rd trimester
prevented by electively delivering baby as soon as lungs mature (as evident by presence of surfactant in
amniotic fluid)

Thyroid Disease & Pregnancy (Rodgers)

Recall: Thyroid Metabolism
iodine obtained by diet 80% (even more in preg since GFR is ) excreted by kidney & 20% made into
TH by thyroid gland
most of the active T3 is made from T4 in periphery via action of deiodinases:
Type I (liver, kidney, thyroid, pit) & Type II (CNS, brown fat, thyroid, placenta)
Type III in placenta (also CNS) makes rT3 (the inactive form of T3) from T4
Thyroid metabolism in pregnancy
E in preg TBG & thus, in order to maintain free TH levels, preg Fs must total TH made
thus, typical TFTs in preg: nl free TH, total TH, & rT3 (from placental Type III deiodinase)
o radioactive iodine uptake test is contraindicated in preg (but would be )
iodine loss & TBG both risk of hypothyroidism in preg
pregnancy goiter: formed from iodine deficiency (hyperplasia of thyroid seen in attempt to compensate for
TH in preg) thus, iodine in diet required in preg Fs
maternal TH does cross placenta fetus needs it for nl. CNS devo (esp in 1st & 2nd trimesters since fetal
thyroid not fully developed till week 20) & bone maturation
deiodinase activity in fetus: Type I (low) & Type III (high) both of which active TH in fetus
but! Type II deiodinase is particularly high (to maintain critical CNS T3 levels)
thus, a relatively hypothyroid fetal envt established to allow for an anabolic fetal state while
maintaining essential active TH levels in brain (via high Type II activity)
hCG: released by placenta to weakly stimulate moms thyroid gland to ensure nl fetal CNS devo
recall: hCG very similar to TSH shares same subunit & acts on homologous receptor
important to screen moms thyroid status to prevent maternal sub-clinical hypothyroidism (high TSH but
nl free T4 so mom asymptomatic fetal IQ) & cretinism (MR in fetus from congenital deficiency of TH
or prolonged iodine deficiency from diet)
can inject levothyroxine right into amniotic fluid if mom found to be hypothyroid
Pregnant females with pre-existing hypothyroidism
recall: due to autoimmune (Hashimotos), iatrogenic (for prior tx of Graves or thyroid ca), iodine deficiency
(only in 3rd world countries now that we have iodine in our salt), or drug induced
hypothyroidism disguised by typical symptoms of preg: wt gain, fluid retained, depression, etc.
possible complications: miscarriage/infertility or postpartum thyroiditis both from TPO Abs
also: anemia, pre-eclampsia, fetal IQ, fetal death, preterm labor, fetal growth restriction, etc.
thus, these Fs need to levothyroxine dose due to hypothyroid-like conditions of preg: TBC, HCG
thyroid stim, vol of distribution, iodine loss from GFR, etc.
Pregnant females with pre-existing hyperthyroidism

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transient subclinical hyperthyroidism: free T4 in upper range of nl & low TSH

seen in many asymptomatic preg Fs during 1st trimester due to transient exaggerated effects of HCG &
requires no tx
transient gestational thyrotoxicosis: an extreme form of subclinical hyperthyroidism (since free T4 is
actually high with low TSH) due to abnormally high HCG:
may indicate multiple gestation or molar preg (placental trophoblast neoplasm without a fetus)
causes severe nausea & emesis wt. loss, dehydration, & electrolyte imbalance (cause of 50% of Fs
with hyperemesis gravidarum)
Graves Disease: mediated by thyroid-stim Igs (TSIs ie, Abs that chronically stim the TSH receptor)
commonest cause of hyperthyroidism in preg
signs disguised by typical symptoms of preg: fatigue, palpitations, heat intolerance, HR but! wt.
loss seen often incites diagnosis
high free T4, very low TSH, TSI Abs present, thyroid goiter (with bruit)
can cause congenital hyperthyroidism in fetus since Igs can cross placenta (usu a good thing to boost
fetal immune response but bad here since TSIs can also cross)
o important to consider in thryoidectomized preg moms: mom asymptomatic but TSIs still circulating
in her to affect fetus fetal tachycardia (1st sign seen)
o craniosynostosis seen (ie, premature closure of fontanels from TH effects on fetal bones)
tx goal: control maternal hyperthyroidism with lowest possible antithyroid meds to avoid
hypothyroidism in fetus
o thionamides (usu PTU since less crosses into placenta than methimazole): inhibits peripheral
conversion of T4 into active T3

Pathology of Female Genital Tract II (Wild)

Neoplasia of the cervix
squamous metaplasia: prolif of endocervical reserve cells which replace the simple epith of endocervix
with stratified squamous occurs at cervical transformation zone
condyloma acuminatum: warty growth due to infection of the low grade strains of HPV that do not cause
cancer (Types 6 or 11)
cervical intraepith neoplasm (aka squamous dysplasia or carcinoma in situ): caused by high grade strains
of HPV (Types 16, 18, 31, 33, 35 able to integrate into host nucleus, drive cell prolif & inactivate tumor
suppressor genes via E6/E7 oncoproteins)
non-invasive but pre-cancerous lesions: screened for on PAP smear if found, can remove lesion &
thus prevent invasive form of cervical ca
dysplasia: block in nl squamous cell differentiation prolif of abnl cell popn
squamous carcinoma of cervix (90% of cervical cancers):
most important prognostic factor: stage at time of diagnosis: 0 (in situ) I (confined to cervix) II
(beyond cervix) III (into lower vagina/pelvic wall) IV (beyond pelvis, distant mets)
cause of death: cancer spreads around bladder/ureter obstr death from uremia & sepsis
Vulvar Squamous Cell Carcinoma
rare; most large, outward-growing tumor masses stage I (<2 cm) vs. stage II (>2 cm)
precursor lesion: vulvar intraepith neoplasia (also associated with HPV infection)
Fallopian Tube (Oviduct) Pathology

39
salpingitis: inflammation of oviduct usu from infection that began in cervix/uterine wall & ascended up
gonorrhea, chlamydia, mycoplasma, & E.coli
acute pyosalpix (obstructive abscess filled with pus inside oviduct) or tubo-ovarian absecess
chronic hydrosalpinx (obstructive accumulation of water-like fluid inside oviduct)
ectopic preg: 95% inside oviduct usu due to PID or endometriosis (since both cause adhesions in
oviduct which block passage of embryo into uterus)

Cystic Lesions of Ovary

follicle cyst: thin wall fluid cavities lined by granulosa & theca interna cells
corpus luteum cyst: central cavity of follicle fills with blood to delayed involution seen with bright
yellow wall & eventually involutes (& thus self-limited)
polycystic ovary disease: excess androgen secretion ( hirsuitism, follicle atresia, etc.), persistent
anovulation ( infertility) & multiple cysts
androgens E in peripheral adipose tissue risk of endometrial ca
corpora lutera & albicantia usu absent in ovary
Cancer of ovary
2nd commonest (endometrial ca is #1) but higher mortality than all other F genital ca combined
most present in high stage at diagnosis
arise from surface epith cells (commonest) also: germ cells, sex cord/stromal, & mets
Krukenburg tumor: met from GI tract ca seen as solid bilateral tumors ovarian with signet ring
cells (mucin fills cell so much that nucleus displaces to periphery)
Ovarian tumors of surface epithelium
due to repeated injury & repair of ovarian cortex thus, risk in nulliparous Fs or those on long-term BC
pills
most present w/ non-specific sx (usu abdominal pain/fullness) at Stage III (into abdominal cavity)
once thru ovarian capsule transcoelomic pattern of spread (seeds the peritoneal cavity with
implants)
non-functional hormonally but serum glycoprotein CA-125 measured (used as tumor marker to monitor pts
following tx)
serous tumors: cytic tumors, mimic oviduct epith, often bilateral 3 types (75% of which are low malig
potential LMP):
benign serous cystadenoma (no malig potential), borderline serous tumor (LMP, often bilateral), or
malig serous cystadenocarcinoma (commonest ovarian cancer most bilateral)
mucinous: typically huge tumors, mimic endocervix mucosa 3 types:
mucinous cystadenoma, borderline mucinous tumor, & malig mucinous cystadenocarcinoma
unlike serous: rarely bilateral thus, if mucinous tumor & bilateral, think metastases, esp:
o pseudomyxoma peritonei (metastatic mucin-producing adenocarcinoma of appendix)
others: endometrioid/clear cell tumors (mimic endometrial glands) vs. Brenner tumor (mimic transitional
epith of bladder)
Ovarian Stromal / Sex Cord Tumors
most are hormonally functional (unlike surface epith ovarian tumors) but most also benign
granulosa cell tumor (look for Call-Exner bodies ie, structures resembling immature follicles filled with
pink material) vs. thecoma both produce estrogen levels

40

Sertoli-Leydig cell tumors (aka arrhenoblastoma or androblastoma) produce androgen levels

Ovarian Germ Cell Tumors

commonest type in kids rare after menopause
mature cystic teratoma (aka dermoid cyst): commonest germ cell tumor contains skin, hair, bone/teeth
(& thus can be diagnosed with XR), muscle, brain, etc.
immature malignant terotoma: solid tumors that look like immature embryonal tissues
momodermal specialized terotoma: made up of only 1 type of tissue ex: struma ovarii (made up of
mature thyroid tissue hyperthyroidism)
yolk sac tumor: very malignant; look for Schiller-Duval bodies (glomerulus-like str with central blood
vessel convered by primitive cells)
Hydratidiform mole
trophoblastic prolif with avascular villi that have undergone hydropic (ie, become cystic, swollen,
edematous) to form translucent grape-like structures molar pregnancy
2 types: complete (X sperm & Y sperm enter an empty follicle with no egg diploid but no embryonic
devo) vs. partial (nl egg fertilized by 2 sperm triploid & some embryonic devo)
can cause choriocarcinoma: extremely hemorrhagic germ cell tumor of trophoblastic cells
mimics epith covering placental villi & no longer fatal with good prognosis since highly sensitive to
chemo
Breast Cancer Risk & Treatment (Edge)
Breast Cancer (BCa)
gross: often star-like, irreg mass that infiltrates thru breasts adipose tissue
precursor lesion: atypical ductal hyperplasia often undetectable till after >5 yrs of slow growth
age: most important risk factor gradual in incidence beginning at 30y/o & peaking at 79y/o
if the inherited genetic mutn (BRCA1) is detected, that pt is at highest risk for developing BCa but
accounts for only 10% of cases
s in lifestyle causes no risk
Treating Breast Cancer
tamoxifen: competitive inhib of E receptor ( E effects tumor growth)
given prophylactically to high risk pts, it rate of developing BCa in all age grps by 50%
but! acts as E agonist in other locations (like endometrium) & thus can risk of endometrial ca
no survival seen btwn mastectomy (entire breast removed) & lumpectomy (only lump removed)
radiation: local recurrence but does not survival
chemo: low risk (no benefit) vs. high risk (dramatic benefit)
studies show it does not matter when you get chemotherapy relative to surgery (ie, no survival seen
btwn pre & post-op chemo tx)

41

thus, standard tx of BCa: lympectomy plus radiation then adjuvant therapy:

if tumor is hormone-receptor positive: tamoxifen (if pre-menopausal) or anastrazole (if postmenopausal; aromatase inhibitor that E synthesis)
o use hormone therapy for 5 years (no further benefit seen in using drug for more than that)
if tumor is HER2 positive: traztuzumab (aka herceptin; Ab vs. HER2 cell surface proteins)
if tumor is hormone receptor negative: chemotherapy
o killed them with kindness: no benefit to chemo if pt is treated with < full dose
important to determine what type of BCa youre dealing with using molecular markers & more recently,
genomic profiling to better define prognosis & tx strategy
tumor can be positive or negative for E receptors, P receptors, HER2, etc. also consider basaloid (ie,
triple negative: tumor that is ER-, PR-, & HER2-)

Case 4
Lobular Carcinoma of the Breast
web-like; often fails to form distinct mass explains why often missed on mammograms
tumor cells seen in lines as they invade tissue (single file invasion pattern) & rings of cells around benign
breast ducts
initial tx: lumpectomy then radiation (to local recurrence)
give chemo post-operatively if high risk, then start 5 yrs of tamoxifen or anastrazole depending on if
menopausal
Pre-eclampsia (Lee)
Biological Effects of Gestation important to know when caring for preg Fs
immune recognition of fetus: if not recognized, mom unable to see dissimilarity of implanted fetus & thus
her body fails to make s needs to maintain preg spontaneous abortion
tough since humans are least genetically diverse primates
condoms risk of pre-eclampsia since mom more nave to sperm & paternal antigens
also explains why risk of pre-eclampsia is seen in 1st preg & why risk is the same when a MILF gets
pregnant by another man
thus, risk (1st pregs, pregs with different partners, barrier contraceptive use, IVF, trophoblastic mass, etc.)
vs. risk of pre-eclampsia (pregs with same partner, previous abortion, frequent semen exposure, previous
blood transfusion, etc)
altered taste/smell (can trigger N&V, which may be a good thing since associated with less complications
later ie, premature births & risk of pre-eclampsia) & altered BO (pets may not recognize preg owners)
others: clotting factors, blood vol ( GFR), albumin, altered carbohydrate metabolism, etc.

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Pre-eclampsia
complicates 10% of 1st pregs & usu presents in the 2nd half of pregnancy
risk if: old age, preexisting HTN, diabetes, renal dz, SLE, obesity
spiral aa: remodeled & enlarged by synctios during its endometrial invasion to maximize fetal blood supply
such remodeling is diminished in pre-eclampsia & thus, fetal blood flow seen
the earlier the HTN seen, the more severe the pre-eclampsia will be
characterized by HTN, proteinuria, & edema (but dont need all 3) no bp dictates pre-eclampsia (can
even be pre-eclamptic with nl bp)
all pregs have some degree of edema thus, need regular urinanalyses to check for proteinuria to hint
possible pre-eclampsia
gradually resolves once baby is delivered (but possible long term effects on CV system)
when diagnosed, baby should be delivered as soon as lungs mature to avoid any dire consequences
may wish to give Mg sulfate (anticonvulsant but mom can stop breathing if OD & cant be used
long-term: basically used to buy some time while mom in hospital) & minimize fluids
if umbilical blood flow deliver baby immediately (no matter how far along it is)
3 degrees of severity all characterized by diffuse vasospasm ( HTN & endothelial damage):
mild (pregnancy-induced HTN): no organ injury, edema
COUPON!
moderate (pre-eclampsia): organ ischemia possible organ dysfx: proteinuria, visual probs, headache,
serum liver enzyme, thrombocytopenia, etc.
severe (eclampsia): organ injury, severe HTN severe brain/kidney/liver injury
HELLP syndrome: hemolytic anemia, elevated liver enzymes & low platelets
can be fatal to mom: seizures, cerebral hemorrhage, renal/liver failure, etc.
can be fatal to fetus: amniotic fluid, placental abruption, fetal growth, etc.
Physiology of Labor & Delivery (Egan)
Uterus during Gestation & Delivery
infant (cervix > body) vs. young virgin (cervix = body) vs. multipara (body > cervix)
E & P corpus hyperplasia & new muscle created with continuous SM hypertrophy throughout all of
preg (ie, myometrial cells become longer & wider)
cervical ripening: softens (from water & collagen) & dilates once labor begins
prostaglandin E2: used to ripen cervix for elective induction of labor
lower uterine segment (btwn anatomical & histological internal os): not used in contraction
uterine quiescence: what makes uterus unique usu SM hollow organs contract when dilated but uterus
remains inactive
uteroplacental circulation: a low resistance shunt allows maternal blood flow to preferentially perfuse
uterus/placenta (explains why O2 level in moms blood is well in excess of fetal needs)
uterine blood blow progressively during gestation (& peaks once at term) but! during labor:
during intermittent uterine contractions, this blood flow is completely cut off what makes human
delivery so much more serious than other animals
the longer the cervix, the greater the risk of C-section

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Labor
involves both: uterine contractions plus cervical dilation/effacement
false labor: vigorous uterine contractions without the cervical s
still unknown what initiates it in humans
in sheep: cortisol but cant be in humans since anencephalic fetuses still have spontaneous labor (ie,
no pituitary but still go into labor so it cant be cortisol in humans)
in rats: P release but cant be in humans since no in maternal steroid hormones seen
labor in 2 phases:
1st stage latent phase (cervix effaces (ie, thins) but no dilation; contractions 5 mins apart) vs. active
phase (rapid cervical dilation, contractions get more frequent)
o fetus does not begin its descent into birth canal till cervix is nearly completely dilated
2nd stage pressure is so high & contractions so frequent that the blood supply cut off in the process
cannot get resupplied (where fetal hypoxia becomes an issue)
during labor, uterine myometrial cells form physical connections or bridges with ea other (via connexin,
prostaglandin & Ca action) synchronous contractions
trigger unknown but oxytocin & prostaglandin Rs seen & Ca activates myocin kinases
indications to induce labor: pre-eclampsia, fetal death, chorioamnionitis, post-mature (> 42 weeks)
use oxytocin since very short life & thus more easily controlled than prostaglandins
Preterm labor: premature loss of uterine quiescence seen 100% of the time if triplets
can be caused by incompetent cervix, spontaneous rupture of membranes, etc.
can give tocolytics (-adrenergic or SM depressants to prolong labor long enough to load fetus with steroids
to induce early surfactant production to mature lungs)
premature birth poses many risks to babys future health: special ed, disabled, or death but if >1500g,
most (85%) are completely fine
post-mature birth (> 42 weeks) may be just as bad as premature birth:
usu due to limited nutrition failure of fetus to put on appropriate fat prolonged preg
can cause aspiration of meconium (fetuss first poop) perinatal asphyxia ( gas exchange) still
birth & labor complications
thus, elective C-section given once preg persists into week 43
Complications of Labor
post-partum hemorrhage (due to uterine injury or preexisting coagulopathy) death within mins if left
untreated since such a rapid, massive bleed
fetal distress: acute hypoxia in fetus as suggested by fetal HR tracing
shoulder dystocia: usu in macrosomnic babies; head no longer biggest part of fetus & shoulder gets stuck in
birth canal during the most hypoxic part of delivery
major injury from immediate need to get baby out (n. damage, maternal anal fissures) explains why
macrosomnia is an indication for C-section
prolapse of umbilical cord: fetal head cuts off cord a medical emergency
placenta previa: placenta implants over cervix blocking fetus from entering into birth canal
failure to progress: prolonged active labor with either failure of cervical dilation or substandard uterine
contraction
cephalopelvic disproportion: fetal head fails to descend despite dilated cervix & contractions
abruption: separation of part or all placenta from uterine lining gas exchange (emergency)

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if previous C-section risk of uterine rupture (from weak, old scars from prior operation)
explains why always get C-sections in subsequent births once youve had one
malposition: feet or butt first instead of head indication of C-section

Endometriosis Case
Endometriosis
caused by retrograde menstruation: some cells of endometrial functional layer shed during menses end up
leaving oviduct & into peritoneal cavity rather than out cervix
occurs in all Fs suggests additional factors involved (genetics, blood spread, etc.)
improved or even cured by pregnancy since:
P seen ovarian anovulation estradiol (which is what stims endometriosis to grow)
estriol synthesis seen in preg, which competitively blocks estradiol at E receptor
goserelin: a GnRH agonist down-regn of GnRH receptors LH/FSH amenorrhea
but very intolerable side effects induces a medical menopause: hot flashes, wt gain, bone loss,
depression, hair loss, etc.
oral BC often given instead since P cause endometrial atrophy (when endometrium is not first prepped by
E) menstrual flow, anovulation, & progression of disease
Coitus (Egan)
Humans vs. Primates
harems (seen in gorillas): Ms must compete for solo access to all Fs small balls & semen since their
genetic material doesnt need to compete with others in popn to produce offspring
promiscuous (seen in chimps): Ms & Fs both have multiple partners huge balls & semen since need
to have the better sperm over the others to produce offspring
non-lactating breasts: humans (prominent) vs. primates (flat)
sexually receptive: humans (anytime) vs. primates (estrous only)
androgens ( libido in Fs but not in Ms with nl T levels) vs. androgen blockers ( libido in both
Ms & Fs)
thus, T might benefit Fs with sexual dysfx but very subjective results
estrous: humans (undetectable) vs. gorillas (olfactory but not visible) vs. chimps (visible)
orgasm: humans (sometimes present) vs. primates (absent)
PRL levels seen after female orgasm (just like Ms)
Masters & Johnson studies on human sex response: very weak findings since cannot be reversible

45
Drips, Bumps, & Sores (Sellick)
Drips & Discharges
predominantly from gonorrhea & chlamydia (detected by urine screening)
in Ms, due to urethritis:
if caused by chlamydia: whites, high SES & usu students, 1-3 week incubation period, gradual onset,
scant amt of thin white discharge
o tx: doxycycline plus azithromycin if untreated: Reiters syndrome (reactive arthritis)
if caused by gonorrhea: GN diplococci, non-whites & low SES, 3-7 day incubation period, sudden onset,
abundant amt of yellow discharge
o tx: ceftriaxone plus doxy/azithro (to cover chlamydia often present with it)
if recurrent, possibly due to trichomonas vaginalis (tx: azithro plus metronidazole/tinidazole)
in Fs, can be due to:
urethritis: dysuria (pain when peeing) & pyuria (WBCs in urine) often neg bacteria cultures seen
(since fastidious growth requirements for chlamydia)
mucopurulent cervicitis: marker of upper tract disease ex: PID (caused by ascent of chlamydia or
gonorrhea into oviduct)
trichomonas vaginitis: itching, frothy yellow malodorous discharge with erythemic vaginal wall &
strawberry cervix tx: metronidazole or tinidazole
bacterial vaginosis: white malodorous discharge due to prolif of anaerobes which replace nl H2O2producing lactobacillus species; no WBCs or erythema look for clue cells
o can cause adverse preg outcomes: rupture of membr, premature birth, endometritis, etc.
o tx: metronidazole or clindamycin
vulvo-vaginal candidiasis: curdlike adherent material with red base soreness & dyspareunia
o tx: topical azole or fluconazole
diagnosis via gram-stained smear/culture, wet preps, or NAAT (nucleic acid amplification test like PCR
used to determine if the microbes DNA is present most sensitive)
Bumps & Raised Lesions
Genital herpes usu HSV2; initial infection can be asymptomatic, can also get sores with this
if pt presents as clusters of vesicular blisters on red base think herpes till proven otherwise
can cause whitlow (infection on finger) then can rub eyes to cause keratitis (inflamed cornea)
diagnosed: tissue culture (done 1st to prove presence of virus & what type) also: Tzanck prep (to look
for giant cells but not specific) or gG assay (tests for G glycopeptide, only for HSV2)
tx: acyclovir to help severity & recurrences but no cure
Venereal warts: due to HPV usu Types 6/11: will not grow in culture; no link to cervical ca
outward growth pattern (rather than the typical plantar wart with deep base under skin)
if Types 16/18/31/33/35 no warts seen but risk to cervical ca
Moluscum contagiosum poxvirus; totally benign, causes no sequelae (just ugly)
Scabies (itch mite): spread by close contact (often sex but not always)
often have many bumps from bites but only few organisms actually on body thus, must scrap
burrows where eggs are found to accurately diagnose
if pt presents with nodules on genitals think scabies till proven otherwise
tx: permethrin cream
Sores & Ulcers
syphilis: due to Treponema pallidum (thin, coiled spirochete)

46
3-90 days, single, painless sore with indurated edges (ie, heaped up) & clean base, painless adenopathy,
& nonsuppurative (ie, no pus formed)
1 (usu unnoticed) vs. 2 (skin lesions) vs. 3 (CNS, heart, bone)
diagnosed via rapid plasma reagin (RPR but if positive, only actually have it 50% of time) or
fluorescent treponemal antibody (FTA more specific)
tx: benzathine penicillin G (benzathine causes very thick motor-oil soln for prolonged release of PCN
given IM)
chancroid: due to H. ducreyi
4-7 days, multiple, painful sores with necrotic base & non-indurated edges, painful adenopathy & may
be suppurative
herpes: due to HSV-2 (or 1)
begin as painful, superficial vesicles (which eventually coalesce) with erythematous base, painful
adenopathy & nonsuppurative

Crabs
characterized by intense itching (due to bites of pediculosis pubis) spread by close contact
tx: permethrin, pyrethrin, & lindane shampoo
Lactation (Egan)
Breast Anatomy
at puberty ductal growth stimd & fat deposition (via ovarian steroid action)
milk produced in alveolar acinar cells found in lobules of breast
myoepithelial cells surrounding lobules which contract to expel milk into ducts that converge at the nipple
many plasma cells surround lobules explains Igs found in breast milk
Lactation
during preg: lactogenesis I (acinar cells ready to make milk but production suppressed by E) vs.
lactogenesis II (full milk production once E levels at birth maintained by regular emptying)
PRL: essential for milk production induces galactosyl transferase & lactalbumin to make lactose,
which are secreted into milk via vesicles
oxytocin: stim myoepith cell contraction shortened/widened milk ducts
suckling stim elicits spinal signal that inhibs DA release in hypothalamus, which:
negates the DA inhib on PRL release thus, PRL throughout preg
inhibits GnRH neurons GnRH levels anovulation (explains why you usu cant get preg while
lactating)
suckling stim also elicits another separate spinal signal that stim release of oxytocin
Contents of Human Milk
whey (ie, protein & CHO), cell debris, casein pellet (ie, lactoferrin to efficacy of Fe absorption & Igs to
boost newborns immune response) & creamy fats
protein content often less than optimal for newborn found at levels in formula

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fats secreted into milk by budding off cell membr thus, fats are membrane-bound in milk:
o provides source of phospholipids for new membrane formation in newborn & prevents lipid globules
from making large aggregates
osmotics present in breast milk: lactose, Na, Cl, & K
humans have lactose relative to other animals: explains in electrolytes in human milk (to maintain
osmolarity equal to that of plasma)
colostrum: secreted the 1st 4 days after birth thinner, low calorie, high protein, high Igs

Breast Feeding
current recommendation: breast milk until 6 mo old but breastfeeding more or less optional for Fs in US
since no significant success seen btwn breast-fed & formula-fed babies
most drug []s low in breast milk & thus still encouraged to breast feed when on most drugs, except:
chemo/radiopharmaceuticals, major psychotropics, or drug abuse
strongly advised in undeveloped countries since H2O contaminated & milk provides sterile meal
possible complications:
engorgement: gradual, bilateral, generalized heat/swelling/pain, no fever or systemic sx
plugged duct: gradual, unilateral, localized pain, no fever or systemic sx
mastitis: sudden, unilateral, localized, hot, significant fever/pain, flu-like sx
HIV (Lesse)
Risk Factors of HIV
sexual activity (homo and heterosexual) #1 risk factor
Ms much more likely to infect Fs than vice versa b/c semen has enormous [HIV]
also risk if M is uncircumsized
substantially higher in blacks than any other race, esp young, sexually active black Fs
also spread by blood contact always consider in IVDAs
occupational exposure in medical field from needle stick is low (esp if non-hollow needle like suture
needles) but still post-exposure prophylaxis given
infant can become infected from mom but only during delivery (not while in utero)
fetal risk related to moms viral load (ie, amt of active virus in body) at time of delivery
zidovudine: show to rate of transmission in preg HIV+ moms
risk if STD present since genital ulcers provide an extra route for transmission always treat STDs with
single dose observed therapy (to avoid non-compliance)
older you are, the poorer your chances for survival
do not even know theyre infected & this grp causes an equal amt of new infection than the much larger
grp that do know they have it emphasizes worth of HIV testing:
rapid tests: very sensitive & highly reliable if +, must confirm with ELISA & Western blot
HIV ELISA: high risk of false positive in low-risk (despite having great sensitivity & specificity) if
positive, must run Western blot to confirm diagnosis

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Progression of HIV Disease
acute retroviral syndrome: acute illness seen after initial infection before clinical latency
almost always confused for mononucleosis or CMV since such common sx: fever, rash
lymphadenopathy, & pharyngitis
clinical latency: asymptomatic stage of 10 yrs
defined as gradual in CD4 ( lesser immune response) gradual in viral load
the higher the HIV RNA levels, the faster the rate of progression to symptomatic disease
the higher the viral load & the lower the CD4 count, the faster the disease progression
o viral load determined by: PCR (target amplification) or bDNA (signal amplification no risk of
cross contamination in lab unlike PCR) both equally effective
AIDS: occurs after clinical latency when viral load overcomes immune sys: CD4 count <200
officially deemed immunodeficient & thus at risk of opportunistic infections explains why routinely
tested for the following when diagnosed with HIV by ELISA/Western blot:
o VDRL ( syphilis), anti-toxoplasma Ab titer, CMV Ab, & PPD skin test/CXR ( TB)
o look for IgG Abs since that indicates past infection if +, must treat prophylactically so recurrence
of infection is not seen once immunodeficient:
1 prophylaxis: prevention of the 1st episode TB (at any CD4+ count if +PPD 5mm instead of
15mm in nl. pts) vs. toxoplasmosis (if CD4+ count <100 & IgG + for toxo)
HIV Life Cycle Drug Treatments
HIV must bind to a surface protein on CD4+ T-cell & also to a chemokine coreceptor (CCR5 &/or CXCR4)
to enter cell
maraviroc: blocks CCR5 only thus, not effective in HIV infections that bind to CXCR4 or both types
of chemokine coreceptors
Fusion of virus with CD4 cell membrane (via Leu-zipper mechanism)
enfuvirtide: inhibits fusion must be given SQ 2x/day (compliance problems)
enters cytoplasm & releases its RNA & enzymes that help with its replication process:
HIV reverse transcriptase (RT) reverse transcribes the HIV-RNA into dsDNA
o has low fidelity (ie, bad accuracy & causes many mistakes (ie, single nucleotide s) while making
DNA) such mistakes can actually help virus become resistant to RT inhibitors:
M184 mutn ( rapid resistance to lamuvudine/emtricitabine) vs. K103mutn ( rapid
resistance to efavirenz)
o nucleoside RT inhibitors lamuvudine & emtricitabine (SLE)
all lack 3-OH grp needed for next base to be added to DNA strand chain termination
o non-nucleoside RT inhibitors efavirenz: only needs to be given 1/day, but causes variable effects
on P450 activity & CNS side effects, incl sleepiness & thus given at night
o nucleotide RT inhibitors tenofovir
HIV integrase: integrates HIV-dsDNA into host genome
o raltegravir: inhibits integrase among the newest tx options (along with maraviroc)
HIV protease: cleaves the viral polypeptides made (gag & gag-pol) into functioning proteins
o lopinavir-ritonavir: most potent currently available fixed combo therapy:
ritonavir (inhibits P450 to prolong lopinavir activity so pt only needs to take it 2/day; given at
very low dose since causes GI upset) vs. lopinavir (inhibits HIV protease)
HIV pts typically given 3 drugs to resistance now found that early initiation of therapy (when
CD<500) causes marked improvement of survival

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