Unit 1 Flashcards
Peds Os Coxa (Innominate) - what features ensure us that the os coxa is pediatric and when does it fuse
Triradiate cartilage
fuse by 25 yo
what makes up SI joint
auricular surface of os coxa articulates with sacrum
pubic symphysis: Why is it this kind of joint?
only want movement during child birth (flex and expand)
sacrospinous lig
ischial spin to sacral spine
between sacrotuberous lig and sacrospinous exiting greater sciatic foramen
pudendal n and int. pudendal art. and vein
through gap in obturator membrane
obturator n, a, v (L2-L4) -> med compartment of thigh
what forms Pudendal n.
S2-S4
weak spot of pelvis and what does it effect?
pubic rami
will effect pelvic stability
could have laceration or rupture of internal organs (bladder)
Through pelvic inlet:
S1 of sacrum to sup pubic symphysis anteriorly
true pelvis
reproductive organ
sup. to pelvic inlet is:
false pelvis: inf. abdominal viscera
most post. muscle
coccygeus and overlying sacrospinous lig
levator ani fxn
supports and elevates ligament, fecal continence
tonically contracted
all posterior to rectum
innervation for levator ani
pudendal n.
other attachment of levator ani
attachment to tendinous arch (central thickening of fascia of internal obturator)
what grades are stretching and tearing of pelvic floor during pregnancy?
skin, fascia (grade 1)
levator ani components (grade 2)
consequences of tearing levator ani?
incontinence
urinary stress incontinence (sneeze, cough, sudden laugh/intra-abd pressure)
rectovesical pouch - clinical relevance?
collects fluid if standing up - most inf point of abd cavity (blood internal hemorrhage, pus from infxn, ascites)
what is migration of testes?
start sup. lumbar region and migrate down, and is guided by gubernaculum (fibrous tract) and connected to deep inguinal ring
diverticulum of peritoneum/porcessus vaginalis and fxns to:
push it’s way through abd layers and forming inguinal canal and pulls along abd wall to cover spermatic cord and scrotum
creates serous potential space that covers testes and forms tunica vaginalis - covers testes
Crytorchidsm
when testes don’t descend - usu along their natural migration
dartos fascia fxn and make up:
dartos muscle is within = smooth muscle
will crincle up skin of testes to elevate if temp cools
epididymis parts and fxn:
head = receives form
body
tail = convuluted and straightens and becomes continuous with ductus/vas deferens
ductus deferens what’s inside?
spermatic cord testicular artery (from abd aorta because testes move down) pampiniform venous plexus cremateric fascia and musc. internal and external spermatic fascia
drainage of testicular v
L testicular v = renal
R testicular v = IVC
testicular torsion causes and progression
usu. congenital abnl of processus vaginalis
twisting of spermatic cord
occlude pampiniform venous plexus -> back up of venous blood -> edema and swelling -> compress testicular artery
no anastomoses -> ischemia
variococele
more often on left side -> more acute angle, and more pressure -> valves may be more dysfxn
if pain -> could be cancer, tumor
ductus deferens, what does it join?
joins seminal gland/vesicles and secretes seminal fluid -> forms
trigone in bladder -> demarcated by?
openings of ureters and inf opening of urethra
male urethra - different parts?
intramural in neck of bladder
prostatic -> goes through prostate where it first receives semen, combines with seminal and prostatic fluid
short intermediate or membranous
penile or spongy urethra
prostatic urethra contains:
prostatic ducts + opening of ejaculatory duct
which ducts pass through perineal membrane?
bulbourethral glands
BPH (benign prostate hypertrophy)
central/middle part and impinges on prostatic urethra and can push up on neck of bladder and bladder
complications of BPH
dysuria
urgency
post and sup to bladder
uterus
anteverted (anteplex orientation) = most common
Female pouch/continuation of abd cavity
vesicouterine pouch (ant and smaller) rectouterine pouch (pouch of Douglas) -> lowest point
permetrium joins with
perineum
myometrium fxn:
contracts during childbirth
dilation of cervix
generate force to expel fetus
endometrium fxn:
grow new BV and where implantation occurs, and is shed during monthly cycle if no fetus
narrowing of uterus
isthmus
opening of uterus
internal os
what part of uterus atrophies post menopause
body of uterus
fxn of fimbrae
projects into ovary, guide egg as ovulated from ovary
fertilation usu in?
ampulla
where can ectopic pregnancy occur?
peritoneum cavity, uterine tube
Broad ligament
covering and surround uterine tube = mesosalpinx
mesentary = mesovarium
mesometrium = remaining
insertion of round ligament
labia majora (analagous to spermatic cord, remnant of gubernaculum also ligamen of ovary is remnant)
ligament of ovary fxn
tethers ovary
suspensory ligament
covers ovarian vessels (arteries and veins)
ovarian a. comes from?
abd aorta
ligaments
thickening of endopelvic fascia
tranverse cervical
uterosacral
primary support of uterus?
bladder
uterine artery relationship and where does it come from?
ant and sup to ureter
and from int iliac
so don’t clamp/cut ureter with historectomy
Uterine artery anastomoses
with ovarian
Vaginal artery anastomoses
with internal pudendal
Ischial tuberosity and pubic symphysis comprise what?
urogenital triangle
Ischial tuberosity and coccyx comprise what?
anal triangle (at an angle to urogeneital triangle, not flat)
contents of deep perineal pouch in females
urethra passes through
- urethral sphincter
- (transverse over sup. perineal memb) deep trans. perineal m.
Contents of Deep Perineal pouch in males
- bulbourethral gland
sup. pouch in females (DOUBLE CHEC?)
- bulbs of vestibule
- crus -> angle body and glans of clitoris
- ischiocavernosus
- bubospongiosus
sup. pouch in males
- crus of penis
- bulb of penis
- ischiocavernosus around the crus
- bulbospongiosus musc. around bulb of penis
- sup transverse per.
corpus spongiosum expands to form
glans penis
deep dorsal vein relationship
post to fascia and imp for erection
nerve blocks in female perineum
ilioinguinal n. block if still feeling pain
pudendal n. (esp. for tearing during childbirth -do near ischial spine for most prox)
what is Prader classification?
degrees of virilization where stage 0 is nl female and 5 is nl male
testing of virulization
FISH for Y (probes for SRY) and can get back within 48 hrs
karyotype and microarray takes a couple days
further work-up if SRY is present
imaging = US for presence of uterus
laparoscopy = best way to eval
46, XX DSD DDx?
95% CAH
46, XX sex reversal (SRY translocation onto X)
Ovotesticular DSD (both ovarian and testicular tissue) -> most have xx karyotype, mom exposed or has high androgens
what makes SRY so easy to translocate
proximal pseudoautosomal region of Y
46, XY DSD pure gonadal dysgenesis
present with lack of puberty - no breast development or menstrual cycle because internal and external is female but no ovaries
mixed gonadal dysgenesis (45x/46,xy)
mosaic -> different karyotype in different cells
usu testes on one side and streak gonad on other side
testes is usu abnl
testicular regression
usu within first year
present with cryptorchidism
46, xy WT-1 mutation
present with bilateral wilm’s tumor before they did lots of genetic testing
androgen insensitivity was initial dx
46, xy, der(9)t(2;9)(p22.2;p24.3) underexpression of DMRT2
gonadal dysgenesis
female genetalia
mental delays
orig. dx of androgen insensitivity
46, xy DSD
any of these, not enough testosterone
under virulized xy
- 5alpha reductase
5 alpha reductase deficiency
undervirulized but degree varies
testes usu in inguinal canal or labial-scrotal folds (should be able to palpate gonads)
wollfian ducts differentiated
make AMA so don’t have mullerian structures
at puberty, spontaneous virilization occurs (at puberty type 1 is expressed and test. can be converted to DHT
Type 2 in newborn is deficient
Androgen insensitivity syndrome
mut in androgen receptor gene
complete -> picked up in childhood (hernia) or puberty with primary menorrhea
CAIS
XY - testes develop, can’t respond to testosterone though they are making, wollfian ducts mostly regress, testes make normal AMA so mullerian structures go away -> no internal duct system
External - very female, no clitoral megaly, nl labia, separate urethra/vagina openings
vagina ends into a wall -> no cervix or uterus
CAIS
gonads intra-abdominal or inguinal canal because testost. needed for descent
bilateral inguinal hernias common
at puberty, spontaneous breast development because such high testosterone from testes that is converted to estrogen
little or no pubic/axillary hair
female gender identity
what is management of CAIS?
avoid gender assignment before expert evaluation (esp at birth or before thorough eval)
center with experienced interdisciplinary team -> endo, urologist, gyn, psych, geneticist
communicate with pt/families, respect concerns and address in confidence
DSD Outcomes
gender dysphoria underestimated in past and gender counseling as well as sexual counseling should be part of multi-disciplinary service available to pt with DSD
try not to encourage surgery
what is precursor to all steroid hormones?
cholesterol
3 B HSD converts what to what?
pregnenolone to progesterone
17OHpreg -> 17OHprogesterone
dehydroepiandrosterone -> androstenedione
what happens when cortisol goes down
increased CRH and ACTH
CAH pathophys?
one of many enzyme def that leads to decreased cortisol, and increased CRH/ACTH
drives adrenal gland to make more hormones in pathways that aren’t affected by def.
CAH enzyme def
21-hydroxylase = 95% 11B-hydroxylase = ~5%
21 hydroxylase def hormone pattern?
decreased cort and aldo
increased androgens
most prominent feature = virilization
Clinical features of 21 OHase def?
female = virilization of external genitalia - clit megaly, GU sinus aka one opening (mullerian develops fine and no wollfian ducts develop) males = nl external genitalia
hyperpigmentation
- MSH and ACTH from POMC (more MSH and ACTH can bind to MSH receptor)
hypoNA, hyperK due to aldo def.
mild forms - present later with early pubic hair, axillary hair, penile/cliterol enlargement
KNOW THIS: Dx of 21 OHase def?
dx suspected in virilized XX infant or XY with hypoNA and hyperK and vomiting
measure 17OH progesterone -> now on newborn screen
KNOW THIS: Tx of 21 OHase def?
surgery in females
replace def hormones and suppress ACTH overproduction
Glucocort (hydrocortisone and increased for illness/stress), mineralcort (florinef and salt supplements) , acute adrenal insufficiency - IM/IV solu-cortef
11BOHas def
virilization similar to 21-OHase def
no salt wasting
HTN frequent finding
more of late dx
StAR protein clinical features
rare
3B HDD
virilization in girls = similar to 21 OHase def
undervirilization in boys = difference between 21 OHase def
17alpha OHase, 17,20 Lyase Def
decr. androgens
but no def. of aldo
HTN secondary to incr 11-deoxycorticosterone
hypoK
female failure to develop 2ry sex characteristics at puberty
male = undervirilized
Which def are salt wasting and which one arent?
Salt Wasting - 3B HDD - StAR protein Def No Salt Wasting 11B-OHase Def
Pathophys of StAR protein Def
Cholesterol stays in cholesterol ester -> fatty adrenal gland = lipoid in adrenocortical tissue
StAR involved in transfer of cholesterol from outer to inner mito membrane
KNOW THIS: Monitoring Tx of 21-OHase Def?
Lab: 17OHP, androstenedione, testosterone
Growth
Skeletal Maturation
what gives rise embryologically to all GU system?
intermediate mesoderm
what are cardinal steps in mullerian dev?
elongation fusion canalization septal resorption \+ union of mullerian (cephalad) with GU sinus (caudad)
cloaca divides into
anal and GU
sinovaginal bulbs
develop vagina from that
where mullerian system connects
upper vagina develops from?
paramesonephric duct (mullerian)
lower vagina develops from?
GU sinus (not skin) and migrates out
uterine tube migration
comes together to form fundus of uterus at top and bottom (septal/walls of tube) part has to resorb to form uterus
Obstructive lesions - sx depends on level of obstruction
Vagina obstruction
- imperforate Hymen - failure of caudal end of sino-vagninal bulbs to canalize
- transverse vaginal septum - Failed Canalization of the Vaginal Plate. this is where the Mullerian ducts meet Urogenital Sinus
- Vaginal atresia
Failure of Canalization of Urogenital Sinus Below Vaginal Plate
when is intervention probably not necessary?
If it doesn’t obstruct menstrual flow, affect fertility, or affect sexual function.
Imperforate Hymen Tx:
blue discoloration behind hymen - blood building up
- tx: surgery, very easily
transverse vaginal septum Tx:
more superior and thicker than hymen
excise
area is demuted and have to stitch close
Vaginal atresia Tx:
no vagina or uterus
incision posteriorly and skin graft is made and placed
bed rest so skin is re-vascularized
Failed cardinal steps of dev: elongation
mullerian agenesis
Unicornuate Uterus
Failed cardinal steps of dev: Fusion
uterine didelphys (2 cervix)
Failed cardinal steps of dev: septal reabsorption
septate uterus
2 uterus, 1 cervix, 1 vagina
Which chromosome is androgen receptor gene on?
x chromosome
what is default pathway for genitalia dev?
female
wollfian ducts will involute and die
without AMH -> mullerian ducts differentiate
dev of female ducts and external genetale is indep of gonadal hormones
If no gonads, female format
results
Leydig cells fxn
make testosterone (95%) which move into sertoli cells
- spermatogenesis
make StAR and SCP (sterol-carrier protein)
- Transport cholesterol to mitochondrial side chain
cleavage enzyme
- Stimulate steroidogenesis
Respond to LH through a G-protein coupled
receptor (GPCR)
sertoli cells fxn
FSH - stim aromatase to make estrogen
form blood testes barrier
- AI response to own sperm (don’t want) and want to protect from pathogens/toxins
nurture developing sperm
APB - conc. locally so right level for spermatogenesis
secrete inhibin and other growth factors - in response to FSH
respond to FSH through GPCR
Cross-talk between Leydig and Sertoli cells via FSH
- FSH also induces release of other Leydig cell growth factors from
Sertoli cells (TGFa, TGFB, IGF-1, FGF-2) - FSH (acting on Sertoli cells) regulates proliferation and
development of Leydig cells to provide adequate Testosterone for spermatogenesis - Testosterone from Leydig Cells synergizes with FSH to increase
Androgen binding protein (ABP) production in Sertoli cells to
maintain high local T concentrations
Hypothal-Pit-Testicular Axis
GnRH stimulates production of
FSH and LH from pituitary
LH acts on Leydig cells
Increased Testosterone
Increased StAR and SCP
FSH acts on Sertoli Cells Increased Androgen binding protein (ABP) Increased Aromatase Increased growth factors Increased spermatogenesis Increased inhibin
H-P-T Axis: Neg. Feedback
- Androgens (Testosterone) inhibit release of GnRH from
hypothalamus - Androgens (and Estrogen) inhibit LH and FSH release from pituitary
- Inhibin suppresses FSH production from pituitary gonadotrophs
hCG: role in doping in sports?
LH substitute -> stim testosterone release
- would have to be pulsatile because these hormones are
- stimulates fetal tissue to produce testosterone
- hCG can be produced from some cancers
what happens with aging in males with FSH/LH if gonadal fxn is compromised?
in males pituitary fxn starts to decline -> produce less LH/FSH even with loss of neg feedback with steroid hormones
decr spermatogenesis => decr. inhibin -> elevated FSH
FSH is sensitive marker of fertility in males
Actions of Androgens?
Differentiation and development of male internal and external
genitalia-T, DHT
Initiation and maintenance of Spermatogenesis-T,DHT, E
Development and maintenance of 2nd sex characteristics
Anabolic
Actions of Androgens specifically with dev. and maintenance 2ry sex characteristics?
Growth of external genitalia-T, DHT
Male pattern of hair growth-DHT (baldness) also beard growth
Sebaceous gland secretions-DHT
Inhibition of breast growth (mammillary gland) -T
Behavioral responses, Libido-T, E, DHT
Negative feedback at hypothalamus, pituitary-E, T
Stimulation of Androgen binding protein synthesis-T
Androgens action on Liver?
incr VLDL, LDL and decr HDL
Anabolic androgen action?
Muscle growth, strength
beer belly
bone growth - T -> E via aromatase
before puberty levels of LH/FSH?
FSH> LH
after puberty levels of LH/FSH?
LH> FSH
Male Pubertal Growth hormones?
Increased Growth Hormone
Increased Testosterone
growth spurt in females?
higher estrogen dampens growth and counters growth hormone
Male growth spurt?
Pubertal growth spurt
Average 28cm (11”)
Accounts for 10cm (4”) height disparity in males vs females
Post pubertal males comparison to females?
150% of female muscle mass
150% of female skeletal and lean body mass
200% of female muscle cell number
50% of female body fat
Effects of androgens mediated by?
ONE ANDROGEN Receptor
Hormone Dependent TF
- specific to organs or tissues though
-Effects mediated by same receptors and molecular
mechanisms
Interactions with Insulin-like growth factor (IGF-1)/
Growth Hormone (GH) axis
Androgens and Growth Androgenic Effects
Growth and development of male reproductive tract
Secondary sexual characteristics
Behavioural responses
Androgens and Growth
Anabolic Effects
Growth of somatic tissue
Linear body growth (long bones)
Nitrogen retention, protein synthesis
Muscle development
What happens with too much testosterone?
- converted to estrogen
- so want to prevent, Aromatase inhibitors etc.
Interaction of the GH/IGF-1 and HPT axes
GH/IGF-1 stimulate gonadal functional IGF-1 stimulates GnRH secretion Testosterone and Estrogen stimulate GH secretion and growth
GH effect on long bone growth?
GH causes balanced growth and ossification; bones continue to lengthen through childhood and pubertal ages under its influence in the absence of sex steroids.
sex steroids effect on long bone growth?
promote ossification epiphyses narrows and eventually closes • Stimulates bone growth • Accelerates bone maturation • Promotes epiphyseal closure • Dominant effect is to narrow growth window limiting long-bone growth • Growth ’levels off’ after puberty ( under control of GH/IGF-1 axis)
how does pre-pubertal abuse of steroids look?
grow faster then end up shorter
rapid rate of growth but end up shorter
(could be using because congenital anomaly causes need for steroids)
Consequences of Steroid Abuse? GU
Infertility-decreased sperm production
Gynecomastia- breast development
Testicular atrophy
Fluid retention, Kidney failure
Consequences of Steroid Abuse? CV
Increase LDL decreased HDL-atherosclerosis
High blood pressure
Heart attack and stroke
Enlargement of left ventricle
Consequences of Steroid Abuse? Psych and Drugs
Psychiatric disturbances- mania, delusions, rage & irritability -> anecdotal in humans and seen in animal models, insomnia
Gateway drug b/c injectable -> Increased risk of HIV or hepatitis and other infections
Consequences of Steroid Abuse? Hair/Bones/Liver/Skin
Baldness and excessive body hair
Short stature
Tendon rupture - disproportionate musc. dev.
Liver cancer, pelios hepatis (blood filled cysts)
Severe acne, cysts, oily scalp
hypogonadotropic hypogonadism
testes nl, baby is making plenty of testosterone in first trimester, penis is nl,
2nd phase of testicular dissent (b/c decr testosterone in 2nd and 3rd trimester)
- lack of puberty due to absence of GnRH and/or gonadotropin secretion from brain
- characterized by low gonadotropins
- complete or partial, temp. or permanent
puberty in fetus/infancy?
not de novo event (reactivation because active from 2nd trimester on)
- active in fetal development
- continues to fxn in infancy “mini-puberty” (boys only until 6 mo, 18 mo in girls -> gives idea of what is developing)
- after infancy, axis enters quiescent state, referred to as juvenile pause
In juvenile pause what NT is higher?
Gabba, more inhib
keeps pre-pubertal
indicator of puberty?
LH > FSH pulses at night
HPG axis during puberty?
process is gradual
GnRH increasing first at night and increased LH
pre-puberty hormones?
FSH> LH
Lab evidence of Puberty?
Leuprolide = analoge of GnRH
look at response of LH
pubertal respons is > 5.6mlU/ml
if give and LH peaks at 2 or 3 -> pre-pubertal
physical changes of Gonadarche (girls) -> due to estrogen
breast dev. genital growth (labia minora) maturation of vaginal mucosa uterine/endometrial growth body comp changes (female fat distribution - hips) menarche (estrogen and progesterone)
Only change early on in boys for gonadarche?
enlargement of testes (mediated by FSH and LH) - @ 4-5 ml of testes -> can happen 6mo to yr before pubic hair
physical changes of Gonadarche (boys) -> due to testosterone from testes or adrenals
scrotal changes (thins) sexual hair (upper lip, chin, sideburns, axilla, pubic area) penile growth prostatic/seminal vesicle growth deepening of voice (late) incr muscle mass (late)
physical changes of Gonadarche (boys and girls)
linear growth acceleration
bone age advancement - mediate by estrogen in both boys and girls and testosterone is converted by aromatase enzyme in boys
Aromatase inhibitor to pubertal boy?
slows skeletal maturation
testosterone goes through the roof
Adrenarche what is it and what does it cause?
increased adrenal androgens (DHEA-S, androstenedione) which cause pubarche
girls - pubic hair, axillary hair, body odor, and acne -> because ovaries aren’t making
in boys - androgen is androgen
-> causes same changes but not specifically from adrenals
Timing of Puberty Tanner 2 Breast development - Girls
early age, mean
white - 8 yrs, 10.4 years
black - 6.6, 9.5
Hispanic - 6.8, 9.8
Menarche for caucasians?
between tanner 3 and 4 generally
menarche for girls?
early age, mean
white - 10.65 yrs, 12.55 years
black - 9.7, 12.06
Hispanic - 10.05, 12.25
Tanner stages- Breast
1 = pre-pubertal 2 = breast bud, just under or extended from areola
Tanner stages- Pubic
Stage 1: Prepubertal (can see velus hair similar to abdominal wall)
Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia
Stage 3: Darker, coarser and more curled hair, spreading sparsely over junction of pubes
Stage 4: Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs
Stage 5: Adult in type and quantity, with horizontal distribution (“feminine”)
Timing of Puberty - boys
testes > 3 ml = 11.8 yo (9-14)
pubic hair = 12 y0
penile enlargement = 13 yo
peak height velocity = 14 yo (mid to late puberty = fast growth) w/ more musc mass and deepening of voice
Tanner Stages boys
pubic hair and testicular volumes stages
genital stages- professor disregards
4 = triangular 5 = diamond shape
delayed puberty criteria for dx?
no pubertal signs by 13 yrs in girls and 14 yrs in boys
or lack of progression
- no menarche by 4 yrs after onset of breast development (puberty starts)
- no completion of genital growth in boys after 5 years
bone age and puberty?
onset of puberty is commensurate with child’s biologic age (bone age)
- girls start at bone age of 10.5 - 11
boys = 11.5-12
delayed puberty and hormones
- low gonadotropins = hypogonadotropic (or central hypogonadism)
- elevated gonadotropins = hypergonadotropic (or primary) hypogonadism
constitutional growth delay
- onset and progression of puberty corresponds with bone age
- growth continues later in life but reaches height potential
- FH of “late bloomers”
- decelaration of linear growth w/i first 2 yrs of life
- normal linear growth after this with delayed bone age
Tx of constitutional delay
reassurance
- for boys sometimes short course testosterone, for girls, short course of estrogen
- re-eval in 4-6 mo
difference between constitutional delay and hypogonadotropic hypogonadism
bone age (if older and no puberty might be hormones)
- presence/absence of adrenarche
- HGHG = boys and girls -> gonadarche and adrenarche is delayed
- adrenarche will start when it should
unicoid body habitus
arms and legs are longer than should
not going through puberty at right time
low upper to lower ratio
arm span bigger than hight
Congenital causes of HGHG
part of multiple hormone deficiencies - septo-optic dysplasia -> mult pit def from abnl brain development
- genetic syndromes = prader-willi syndrome (most common)
- hypotonia, wants to eat a lot
IHH = idiopathic hypogonadotropic hypogonadism
absence of any structural abnormalities of hypothalamus or pituitary
isolated defect in GnRH or gonadotropins
Kallman syndrome ?
IHH plus anosmia/hyposmia
- agenesis of hypoplasia of olfactory sulci and/or lobes
- association between from defect in shared developmental origins of GnRH and olfactory neurons -> migration of neurons
- genes assoc with IHH = Kal-1, FGFR1 … -> only accounts for 30% of cases
Fxn’l or revesible causes of HGHG
chronic illness, malnutrition
stress, excessive exercise (even in absence of low body wt)
anorexia, hyperprolactinemia(oma), hypothyroidism
Acquired Causes of HGHG?
pituitary or hypothalamic tumor, cranial irradiation, CNS infection, infiltrative diseases (histiocytosis, granulomatous disease, hemachromatosis), AI hypophysitis
HGHG
primary gonadal failure leads to decr. neg feedback
high LH and FSH - most common in girls = Turner Syndrome
Primary Ovarian Failure
- Turner Syndrome
- XX or XY complete gonadal dysgenesis (XY = SRY, no testes - not picked up until puberty because don’t start, will have adrenarche, nl internal and external genitalia, usu tall)
- galactosemia
- radiation
- chemotherapy (alkylating agents)
- AI
Turner Syndrome
- Frequent
- 45, X karyotype in 50% with the rest being moasaics or structural abnormalities of X chromosome
- may have no phenotypic characteristics except for short stature
Turner Syndrome phenotype percentages
100% short stature
94% ovarian failure
CV, thyroiditis, hx of otitis, dysmorphic facies = common
Primary Testicular Failure
- Klinefelter’s Syndrome
- cryptorchidism
- testicular regression syndrome
- radiation (usu ok testosterone but lower sperm)
- chemotherapy
Klinefelter’s Syndrome
most common, typically present with gynecomastia, smaller testes than expected for degree of virilization - tanner 4, usu don’t present with delayed puberty, miss because don’t check testes size
- 1/1000
47, xxy (or can have 3 or 4 x -> more X, more dev probs and behavioral probs)
- hyalinization and fibrosis of seminiferous tubules
phenotype Klinefelter’s Syndrome?
microphallus, infertil, small testes, learning disabilities, eunochoid, delayed or arrested puberty, gynecomastia, infertility
Eval of Delayed Puberty
bone age (growth delay, hypothyroid… why?
- if bone age is older -> check labs
- Labs: gonadotropins, test in boys and estradiol in girls, may consider TSH, T4, Prolactin, CBC, ESR, BMP
- karyotype if elevated gonadotropins
Tx of hypogonadism
- Boys
testosterone Q3-4 wks initially low dose to gradually incr (gels are annoying) - Girls
estrogen alone followed by cyclic therapy with estrogen and progesterone (add if have uterus like in Turner)
Complete Precocious Puberty Signs
onset and progression of changes - accel linear growth - advancement of skeletal age Can be: - Central (GnRH dependent) OR - Peripheral (GnRH independent)
Incomplete Precocious Puberty
benign thelarche benign adrenarche Defn: boys - dev prior to 9 yrs of age girls - dev prior to 8 yr in caucasian, 6.5-7 in AA and hispanic
Central Precocious Puberty
same physical ∆ and lab testing are consistent with progressive ∆ of HPG axis activation
- 5% in girls = CNS abnormality
- 50% of time in boys is caused by CNS abnormality - lower threshold to image boys because more common
Central Precocious Puberty Causes
- Hypothalamic Hamartoma (present in first 2-3 yrs of life)
- treat medically
anything that disrupts inhibition of HPG axis
- suprasellar tumor
- hydrocephalus
- previous CNS infection
- major head trauma
- cranial irradiation
Causes of Peripheral Puberty
Girls: Estrogen mediated
Ovarian cysts
granulosa cell tumor
exogenous estrogens
lavender or tea tree oil products
Ovarian cysts
ovarian follicles form cysts (prepubertal FSH stimulation, can secrete estrogen for breast development but usu present with vaginal bleeding)
- areola gets dark as estrogen increases but as estrogen goes down - causes bleeding
- trans-abdominal US to assess and do it at that time
- assoc with McCune- Albright Syndrome
McCune-Albright Syndrome
lethal if mutation in all cells
- constituative activation in alpha subunit of stim G-protein
- triad of precocious puberty, cafe-au-lait spots (doesn’t cross midline usu or follows dermatome), polyostotic fibrous dysplasia (MOST COMMON)
- can also have GH excess, hyperthyroidism, Cushing’s syndrome
Peripheral Precocious Puberty Boys
Adrenal tumor
Leydig cell tumor
hCG secreting tumor (LH like, stims Leydig cells to make testosterone)
McCune-Albright Syndrome (rare)
Late-onset congenital adrenal hyperplasia
presentation of adrenal tumor and late-onset congenital adrenal hyperplasia
pubic hair maybe axillary hair maybe some growth acceleration testes = small (no LH/FSH) bone age advancement
LABS differentiate between the two
hCG secreting tumor
- testes a little bit enlarged but not as large as central precocious puberty
- more virilization compared to how big testes are
Familial testotoxicosis
Periph precocious puberty in boys
- testes somewhat enlarged from leydig hyperplasia
- high testost from early on
- sign. penile growth
- mutation of LH receptor - activated
- AD with only male penetrance
- Autonomous Leydig cell activity
- more virilization compared to how big testes are
severe primary hypothyroidism
TSH > 500 and close to 1000
- both sexes
- mechanism may be hormonal overlap - TSH is like FSH
- girls can present with ovarian cysts, high estrogen, vaginal bleeding
- boys - stim of sertoli cells, no testosterone so no leg hair etc. don’t have stim of leydig cell = macro-orchidism
- delayed bone age and poor linear growth
Eval of precocious puberty
hx
- growth pattern (nl or accel)
- BONE AGE
- tanner staging, size and symmetry of testes, cafe au lait, neuro findings
- GnRH stim test or random gonadotropins
NL ranges for LH for Tanner stages and labs values to test for puberty
tanner 1 = .02-.18
tanner 2 = .02-4.7
so if do random LH and is above .18 then it is dx of precocious puberty but if below then have to do GnRH stim and if LH is above 5 then diagnostic
eval of precocious puberty in girls
estradiol and pelvic US
eval of precocious puberty in boys
testosterone, androstenedione, DHEA-S, 17-OH progesterone, hCG
- adrenal/testicular US based on lab results -> not first line
ovarian cyst eval
high estradiol but GnRH stim test is pre-pubertal -> do US
Tx of precocious puberty Central
GnRH analogue (Lupron/Supprelin) - down regulates pit GnRH receptors supprelin suppresses better and just have implant so easier decr gonadotropin secretion
Peripheral Precocious Puberty TX?
Cyst = watchful waiting
- If large enough, ovaries can have torsion around cyst -> monitor for pain
McCune - Aromatase inhibitor (letrozole)
Familial Testotoxicosis: aromatse inhibito to block bone age but then testoterone gets high -> androgen blocker OR ketoconazole (SE)
CAH - Glucocorticoids
Incomplete Pubertal Development causes?
Premature Thelarche
Premature Thelarche defn:
- onset of breast development w/o other assoc pubertal ∆
- no growth acceleration or bone age advancement
- breast development progresses very slowly or waxes and wanes in size
GnRH
Continuous = suppression Pulsatile = increased
Exogenous Testosterone effects (Pharm)
Positive peripheral aspects but shuts down axis testicular atrophy (give hCG) and decr. spermatogenesis
Testosterone most important androgen in?
muscle and liver
what actions in males mediated by estrogen receptors?
Bone
- closure of epiphyseal plate, if doesn’t then long bone growth continues -> osteoporotic
HRT used in aging men?
testosterone levels below normal (below 200-300) and with symptoms
- low libido - decreased morning erections - small testes
- low bone mineral density
- gynecomastia
FSH or gonadotropins for spermatogenesis
ONLY for testosterone def.
- inc inappropriate use b/c ads for non specific sx encouraging men
Symptoms related specifically to androgen def in aging males
LOW LIBIDO and Low Bone mineral density
Testosterone abuse in sports
all anabolic hormones (testost. analogs) also have androgenic SE
- block of LH-FSH release
- promotion of prostate growth
- trying cycling and stacking to reduce androgenic SE
Testosterone administration and most stable chemical form?
infrequent administration and most stable
make it ester and inject IM
half life clock doesn’t start until in plasma
so this formulation extends half life
Oral testosterone = methyltestosterone pharmacokinetics and ADR:
alkylated to reduce first pass metabolism but has Hepatic side effects
Transdermal ADR and reasons for:
severe skin rash
sustained delivery over 24 hr pd (normalizes T levels)
- has a peak
Transdermal gel pros and cons:
$$, best at maintaining stable levels
ADR of Testosterone
AVOID androgens in infants and young - decr spermatogeneis (androgenic) reversible cholestatic jaundice (hepatotoxicity) - incr PLT aggregation, arterial thrombosis - roid rage - concerns of stroke, MI, mortality - no info on PSA, prostate enlargement - gynecomastia
USE of testosterone where benefits outweigh risks:
HYPOGONADAL MEN (not just low T men)
pulsatile agonist
increases LH and FSH
Continuous agonist
blocks release - prior to desensitization -> LH/FSH will transiently rise and exacerbate
Finasteride = efficacy in prevention of male pattern baldness by virtue of its ability to:
reduce production of DHT
5 alpha reductase inhibitor
anti androgens flare sx?
no flare symptoms with antagonists
clinical uses of anti-androgens
BPH, Androgenetic alopecia (male pattern baldness), precocious puberty in boys, Hirsutism (PCOS)
first choice in hirsutism
estrogen-progestin contraceptive
synth of androgens is not controlled -> increase binding globulin so free levels go down
ADR of anti androgens
leuprolide = hypogonadism finasteride = decr libido
what size of testes will you know the male has gone through puberty?
> 10-12 mls
low testosterone with hypogonadism
if at hypothalamus LH and FSH = nl or low
if at testes LH and FSH is high and testosterone is low
Acquired central hypogonadism
GnRH pulse generator defect
Narcotics
Glucocorticoids - usu steroid injections
Supplements
what can cause GnRH pulse generators defects?
stress, severe illness, abnormal wt loss, low body fat
what other meds besides narcotics can cause hypogonadism?
opioids, other pain meds, synthetic marijauna
What supplements can cause central hypogonadism and what should you do about it?
prohormones, anabolic steroids - major cuase if undetectable LH, FSH
Take them all out since not FDA approved and then add them back one at a time
what do you do to recover from exogenous androgen supppression of hpt
time, data is weak to show any faster recover with clomiphene, hCG
how do we measure testosterone?
testosterone bound to protein, assays aren’t good for free testosterone
why could total testosterone be incorrect?
because testosterone binding protein can change with age and reflect a false low
cause of borderline low testosterone in colorado?
obstructive sleep apnea
- cortisol and catecholamines from hypoxia
- decreased NO in cavernosal musc, decrease in cGMP
slight impairment of GnRH pulse generator
tx sleep apnea
low LH and FSH, low T, what is DDX? (pituitary hypogonadism)
prolactinoma, craniopharyngioma, rathke’s cleft cyst, pituitary tumor (GH, ACTH, some gonadotrope), metastasis, hemachromatosis, inflammatory: lymphocytic hypophysitis
headache and blurred vision might be clues
hypogonadism (8ml bilateral), nl testosterone, high FSH and nl LH, no sperm
something went wrong with puberty (small testes)
LH and FSH shoul be equal and should be about 10-12
FSH higher than LH -> loss of inhibin which inhibits FSH
probably congenital due to no sperm and small testes -> hypergonadotropic hypogonadism (high FSHH +/- LH, low T)
congenital causes of hypergonadotropic hypogonadism
congenital anorchia
klinefelter’s
klinefelter’s syndrome
delayed puberty, low inhibin, azospermis, eventual need for T replacement, mammogram, progressive tubular fibrosis, gynecomastia, if prime testes with hCG and sometimes harvest sperm, don’t know if risk for DVT/PE
acquired causes of hypergonadotropic hypogonadism:
trauma/torsion
mumps orchitis
etoh: direct testicular toxin
dm
radiation/chemo
AI testicular failure: check for others (TSH, glucose, B12, vit D)
pituitary tumor gonadotrope (secreting FSH, nl LH and nl T)
late onset hypogonadism
Rare only 3-5% of men
seen with comorbidities (dz), incr wt, increase with age
and T levels increase with wt loss
tx of late onset hypogonadism
diet, lifestyle, wt loss
- improve CV health, OSA, metabolic fitness, testosterone levels, sometimes improves ED
CAD events with Testosterone?
risk of event correlated with higher testosterone levels
potential mechanisms for cardiac risk?
induction or worsening of polycythemia
Worsening obstructive sleep apnea
Stimulation of platelet aggregation via Thromboxane A2 receptor density
Decrease in HDL levels
Salt and water retention
? Dose, type of T administration - high testosterones correlated with IM testosterone but too low is bad too
potential risks of testosterone tx? everything but CV
CHECK PSA, if rises more than 1.5 in 1 yr -> work up
Stimulation of prostate growth in previously undiagnosed prostate cancer (PSA rise 1.5/12mo w/u)
Risk of bladder outlet symptoms due to increase in prostate volume
Gynecomastia
Precipitation or worsening of sleep apnea
potential risks of testosterone tx? CV
Erythrocytosis, Edema in patients with pre-existing cardiac, renal, or hepatic disease, Increased cardiovascular events
Real hypogonadism with low LH, FSH, testosterone
Low LH, FSH, testosterone
- Genetic rare
- Acquired: narcotics, glucocorticoids, hemochromatosis, tumor, XRT, stress, illness
Not Real hypogonadism
OSA, T assay (effects of SHBG)
Real hypogonadism with High FSH, LH, low testosterone
Primary testicular failure (XXY, trauma, other)
Gonadotrope pituitary tumor
tx testosterone indicated for what?
chronic narcotics -> testosterone
pituitary tumors and radiation -> hypopit
GnRH def
Klinefelter’s
if want to try and figure it out but know at incr risk for CV
good at physiological levels but pharmacological levels is less good.
as testes distends they:
pulls peritoneum with it -> peritoneal pouch goes into scrotum -> can become traumatized/infxn
histology of testes: leydig cells, tunica albuguinea etc.
tunica albuguinea = white coat around outside - protect from abrasion
leydig cells -> testosterone -> driving force for spermatogenesis
blue elastic fibers of BM -> hold spermatogoonia
development of sperm
spermatogonium -> primary spermatocyte -> secondary -> spermatids -> spermiogenesis -> late spermatids
without BTB
made by: tight jxn between sertoli cells -> AI towards self (granulomatous inflam) -> can cause infertility
Congenital abnormalities of testis
maldescent, absence, fusion, cysts
maldescent of testis
cryptorchidism -> not found it’s way properly into scrotum
can be found: abdominal, superficial or deep inguinal canal, opposite thigh, perineum, root of penis
Most in superficial inguinal canal
testes maldescent, reason why:
lots of ligamentous attachments (the one the doesn’t degrade becomes high that pulls testes along)
cryptorchidism complications and facts:
easily traumatized
unilateral (75%) and mostly idiopathic
atrophy as early as 2 yo
contralateral testis may also regress
2 degrees cooler than body for optimal sperm development
5x increased risk of malignancy (in cryptorchid testis and contralateral testis)
when you tx cryptorchidism
the earlier the better
reduce risk of malignancy and atrophy of contralateral testis
cryptorchidism histology at 2 yrs
∆ within tubules themselves
leydig cells almost vanished
cryptorchidism histology at puberty
disorganized
cryptorchidism histology at adulthood
atrophy
anaplasia and dysplasia
testicular atrophy
cryptorchidism athersclerosis and DM - affect blood stream (big role in US) worldwide = inflam and malnutrition hypopit hormone tx (prostate cancer) klinefelter's syndrome
histology of testicular atrophy
layers of spermatocytes etc = thinner
can completely lose all germ cells - just sertoli cells are left (usu hard to see)
interstitium devoid of leydig
klinfelter’s sclerosing tubular degeneration
tubular sclerosis
leydig cell hyperplasia (hormones) b/c elevated FSH/LH
decreased testosterone (no feedback on FSH/LH)
no elastic fibers
atrophy loss of hypertrophy of leydig
depends on etiology
varicocele anatomy and common causes
def abnormal dilatation of tortuosity of veins in pampiniform plexus
- venous valve insufficiency
- LS more common only 10% bilateral
varicocele assoc with infertility when:
bilateral,
possible thermal effect
Maturation arrest, hypospermatogenesis, abnormal sperm morphology
Possible epiphenomenon
twisting/ torsion -> infertility
how does this cause?
block venous first- engorges with blood
- > hemorrhagic infarction because arterial pressure -> congestion of interstitium
- > pressure necrosis of testes parenchyma
- > PAINFUL (dramatic)
infertility with sperm specifically
dynein arms needed
if missing -> infertility
inflam dz of testis and epididymis
Nonspecific epididymitis & orchitis Mumps orchitis Tuberculous orchitis Syphilis Granulomatous (autoimmune) orchitis
Nonspecific Epididymitis/Orchitis - causes in children through elderly?
children - rare but use assoc with UT malformation (Gm neg rods)
Sexually active adults – C. trachomatis, N. gonorrhoeae
Elderly - Enterobacteria
Direct extension from urinary tract
histology and pathogenesis of nonspecific epididymitis/orchitis
see pus
infxn in this area -> acts like abscess -> necrosis quickly because disturb vascular flow
mumps orchitis
usu parotid infxn
1 - 2 wks after parotid involvement = mumps orchitis
painful/pressure
infertility uncommon because mumps is usu unilateral 70% of time
- shrunken and white scarring
what two disease of testes mimic eachother
TB and syphilis
TB orchitis
Epididymis → Testis
Usually part of systemic disease
Caseating granulomas- giant cells (look just like lung)
syphilius orchitis
gumma = coag necrosis that extend along blind ended arteries Testis → Epididymis Congenital or acquired Plasma cells, lymphs Obliterative endarteritis
Testicular Tumors
Germ cell tumors (95%)
- Seminoma
- Spermatocytic seminoma
- Embryonal
- Yolk sac
- Choriocarcinoma
- Teratoma
- Mixed
Germ cell tumors
- most are pure or mixed
- metastases can vary from primary
- tend to occur in young men (15-30)
Painless testicular enlargement
Predisposing factors: cryptochidism (5X), genetic factors (family history-5X), dysgenesis (50X)
Environmental factors?
Chromosomal changes: +12p
GERM CELL NEOPLASMS flow chart KNOW!
totipotential germ cell -> seminoma or can go to embryonal carcinoma
totipotential germ cell -> most primitive form
seminoma
embryonal carcinoma can go on to make what?
extra embryonic (Yolk sac, choriocarcinoma) or embryonic (teratoma)
Testis seminoma
Most common (50%) Fourth decade Radiosensitive and chemosensitive Good prognosis Serum markers often negative - so primitive don't really have - late stage = efface the testis fish flesh tumor
histology of seminoma
- biphasic appearance = fried eggs
- benign lymphocytes that go along with BV
Spermatocytic Seminoma
1-2% of GCT’s
Older age (>50 yrs)
Good prognosis - no report of metastasis
Serum markers negative
Spermatocytic Seminoma histology
biphasic appearance
all different sized nuclei
some stuck in spermatid (phenotypically)
mixoid, gelatinous structure
Embryonal Carcinoma
Pure – rare (3%)
Mixed – common (85%)
Third decade
Chemosensitive
Higher likelihood of extratesticular spread
Recurrences common
Markers variable: PLAP (placental alkaline phosphatase), placental lactogen, hCG
Embryonal Carcinoma histology (immature phase carcinoma)
destructive lots of areas of necrosis, hemorrhage cells = more anaplastic big dark nuclei more atypia mitotic figures some structure - primitive tubular arrangements
Teratoma
40% of testis tumors in infants
2-3% pure in adults
Mixed ~45%
Mature vs. Immature
Malignant transformation -> every part that is mature can undergo this
Chemoresistent – slow to progress but may undergo “malignant” change - surgically remove the rest
Malignant transformation of teratoma
if mature sq cell can get squamous cell carcinoma
has seen pancreatic carcinoma from it
histology of teratoma
cysts - lined by mature tissues
Elements -> can have cartilage, epithelial lined surface, can be epidermis, respiratory epithelium, colon epithelium, pancreas with acinar, skeletal muscle, nervous tissue
the more immature, the more likely to progrees to metastasis
Yolk Sac Tumor
Pure common in children (80% of testicular tumors)
Part of mixed tumor in adults (40-50%)
Prognosis relatively good
Produces alpha-fetoprotein (AFP)
histology of yolk sac tumor
AFP globules
AFP on IHC
Choriocarcinoma
Pure (0.3% of GCT’s) Mixed (10%) Aggressive – often metastasizes - often dx metastasis before finding primary tumor Chemosensitive, but worse prognosis Produces hCG functional- functions like placenta
histology of choriocarcinoma
hemorrhagic
destructive
sinsitial trophoblast and cytotrophoblasts
most common cancer in testes in adults?
mixed tumor
Testis Cancer Staging
I - confined to testis
II - retroperitoneal nodes or below diaphragm
III - outside retroperitoneal nodes or above diaphragm
Testis Cancer Serum Markers
AFP
hCG
Placental-like Alkaline Phosphatase (PLAP)
Human placental lactogen
Testicular Tumors (5% that aren’t germ cell)
Sex-cord/stromal tumors Leydig cell Sertoli cell Granulosa cell Mixed Lymphoma
Leydig Cell Tumors
2% of all testicular neoplasms
90% benign
10% malignant
Often masculinizing, some feminizing (because produce testosterone and sometimes can be converted via aromatase)
sertoli cell tumor
more rare, more serious
very malignant
metastasize early
seminiferous tubules gone bad -> more sertoli, more invasive -> go into blood stream
most common testicular tumor in men over age of 60
remember not GERM CELL
Lymphoma is answer!
Penile Lesions
Condyloma Acuminatum Verrucous carcinoma Carcinoma in situ - Bowen’s disease - Erythroplasia of Queyrat Squamous cell carcinoma Other malignancies
Genital warts
HPV- papillary outgrowths atypia in squamous cells koilocytosis = big hollow cells (clear cytopasm) with wrinkled raison like nucleus virus filled cells 16,18, 30-33 -> high risk
limited lesions of penis
Verrucous carcinoma (wart like, large wart, keritinizing, local destruction without metastasizing)
Carcinoma in situ
- Bowen’s disease
- Erythroplasia of Queyrat (mucosa of uncircumsized male)
Carcinoma in situ
full thickness dysplasia of squamous epithelium
Penile malignancies epithelial
Epithelial (95%) Squamous cell carcinoma (95%) Melanoma (1%) Basal cell carcinoma (1%) Urethral TCC (2%)
Penile malignancies mesenchymal
Mesenchymal (5%) Leimyosarcoma Fibrosarcoma Rhabdomyosarcoma Kaposi’s sarcoma Angiosarcoma Hemangioendothelioma
Penile Squamous Carcinoma
0.3-0.6% of male cancers
0.5-1.0 per 100,000
60-80 years of age
African American:Caucasian 2:1
“Chimney sweeps disease”
Precursor lesion: carcinoma in situ
Penile Squamous Carcinoma gross findings and histology
ulcerative lesions, destructive
pointlike downward lesions of skin -> then become glandlike
- invasion doesn’t have to be too far to get to blood -> dissemination
most cancers effect what of prostate?
peripheral zone
BPH effects what of prostate?
transitional zone
cell layers of tubular alveolar gland
2 cell layers tall columnar = secretory
Basal or stem cell
Malignancies lose 2 cell morphology
Prostatic Diseases
Inflammation
Hyperplasia
Neoplasia
Prostatic dz: sx?
Can be asymptomatic until advanced
Symptoms, when present, are usually those of urethral obstruction or irritation while urinating
inflammation of prostate
Acute Prostatitis Chronic Prostatitis - Bacterial = rare - “abacterial” = more common - granulomatous
Acute Prostatitis
Focal or diffuse polymorphonuclear inflammation
Enterobacter (E. coli), S. aureus most common, also think about STI bugs
Direct extension from urinary tract
Can be iatrogenic
iatrogenic causes?
prostatitis
miss 45 degree angle and damage prostate
Chronic Prostatitis
Mononuclear cell inflammation
Often associated with atrophy
Unclear etiology - ? Response to occult infection, dietary
Histologic chronic inflammation much more common than clinical prostatitis
Granulomatous form
Granulomatous form of chronic prostatitis
Granulomatous form
Eroded corpora amylacea
Tuberculosis
Chronic Prostatitis on histology
inflam infiltrate
around and into epithelium
atrophic changes
columnar cells have regressed
BPH
Benign nodular enlargement of prostate
Most common proliferative disease of prostate
Blacks>Whites>Asians -> reflects same trend as cancer
Histologic BPH: Rule of “10’s”
Clinical BPH age 60
Lower urinary tract symptoms (LUTS)
NOT PREMALIGNANT
LUTS voiding
voiding symptoms - hesitancy, poor urine flow, dribbling, incomplete bladder emptying
LUTS storage
increased frequency >7x/day
nocturia
urgency
urge incontinence
histology of BPH
transitional zone near urethra
large nodules confined to transitional zone
classification of BPH nodules
3 major components that can be in any combo
epithelium, fibroblasts/stroma, smooth muscle
BPH nodules - more stroma
worse it is symptomatically and more refractory to tx
BPH natural hx complications:
LUTS most common – quality of life impact Complications: Acute urinary retention Recurrent UTI/ pyelonephritis Renal failure Incontinence
BPH natural hx management
Management:
Medical - recently is main tx
Minimally invasive therapy (ex. Microwave thermotherapy)
Surgery (TURP) - lot of morbidity (incontinence)
Prostatic Carcinoma
Most common non-skin cancer of adult males (~20% of all male cancers)
~200,000 new cases per year
Second leading cause of male cancer deaths (~27,000 per year)
More men die with PCa than of it
- US sees most because if you screen for it you’ll find it
- Asians = low risk
Prostatic Cancer Risk Factors
Age - older, more likely
Race - AA more likely
Genetics - father had it, 4x more likely
Diet - thought to because asians living in Japan who move here adopt our risk of prostate cancer
DM - might effect mortality of prostate cancer
Prostatic Carcinoma screening problems:
Effects peripheral zone > transition zone
Screening:
Serum prostate specific antigen (PSA) - not prostate or cancer specific
Digital rectal exam - only see posterior part of prostate 10% sensitive
Blind “random” biopsies still gold standard for diagnosis
- Only ~ 50% sensitive
- Many cancers detected will never be life threatening-
grade progression of prostate carcinoma
thought prostate goes from low grade to high grade
can start as high grade -> this progression doesn’t always occur
- multifocal disease
multiple grades
2 tumors within prostate = different grades
Relationship of PIN and PCa
Believed to represent noninvasive precursor to some prostate cancers
Genetic and molecular changes similar to PCa
Increases with age, peak prevalence 5-10 yrs before PCa [Sakr 1993]
30-50% of prostates with PIN harbor prostate cancer
Prostatic adeno dx criteria
Uniform round glands Infiltrative pattern Single cell layer (loss of basal cells) Nuclear enlargement -prominent nucleoli Perineural invasion
Prognostic factors of prostate cancer
Grade most important
Stage
Tumor volume (PSA) - monitoring tool, larger = more likely to metastasize
Molecular markers – research in progress
gleason grading of prostate
degree of invasiveness is in architecture = GLEASON SCORE
= ragged sheets vs. morphologic resemblance to nl prostate
Score = most + 2nd most
most informative about eventual mortality
high grade malignancy in gleason score
lack of glandular formation
metastasis of prostate cancer
lymph or hematologic spread of prostate cancer
can get into spain -> pathologic fracture and pain
survival of prostate cancer
Pelvic lymph nodes 95% Seminal vesicles 85% Established capsular penetration 48% Focal capsular penetration 33% Organ confined 10% organ confined doesn't mean you're out of woods
random biopsy of prostate
might miss cancer or a high grade tumor because of multiple focality
combining epigenetic and genetic might be more
genomics of prostate cancer
genes tell us more than grade - could determine prognosis by genes (deletions, amplifications)
Prostate CancerTreatment Options
Surgery – radical prostatectomy External beam radiation Brachytherapy (radioactive “seeds”) Cryotherapy Hormone ablation – mainline therapy for advanced metastatic PCa - eventually fails Chemotherapy
new concept TX of prostate cancer
New concepts:
Expectant management
Targeted focal therapy
BOTTOM LINE OF PROSTATE CANCER
~200,000 new cases expected
3/4 receive localized treatment (~150,000)
40% will experience PSA recurrence (60,000/yr)
~27,000 deaths expected
Autopsy: 30% of men > 50 years have PCa
SOOOOOO MANY MEN ARENT DYING OF PROSTATE CANCER THAT ARE BEING TREATED BUT WE’RE NOT CATCHING THE ONES THAT NEED TO BE TREATED
new theories on how to tx/cure prostate cancer
need improved imaging and biomarkers to better assess tumor burden and aggressiveness
want to treat the people that will die of prostate cancer but not find and treat the ones that will die of other causes (not their prostate cancer)
haven’t done a good job of separating sleeping giants and mean mice
