LC Unit 1 Flashcards
1
Q
2 functions and 2 compartments of gonads
A
produce mature gametes
produce hormones that determine the secondary sex characteristics
interstitial compartment:
leydig/thecal
gametogenic compartment:
sertoli/granulosa
2
Q
endocrine role of the gonads
A
interstitial cells:
leydig and thecal cells produce androgens (primarily testosterone in response to LH)
have LH receptors
supporting cells:
sertoli/granulosa cells
produce estrogens
proud inhibin (required for growth/dev of gametes)
nurture gametes
have FSH receptors
create a barrier between interstitial and seminiferous M or follicular F fluid and blood stream (protect gametes from potential external pathogens)
3
Q
anatomy of male genitalia:
A
seminiferous tubules:
formed by specialized epi made of sertoli cells w/ interspersed germ cells
-immature spermatogonia present at peripheral; mature closer to lumen
leydig cells lie between seminiferous tubules in the interstitial compartment
number of functioning sertoli cells determines max rate of sperm production
4
Q
sertoli cell only syndrome
A
germinal cell aplasia
5-10% of male infertility is attributable to this
small testes and azoospermia*
seminiferous tubules are lined by sertoli cells but no germ cells- no spermatozoa
leydig cells and testosterone are normal
sertoli cells producing a decreased production of inhibin which reduces neg feedback specific for FSH
–isolated increase in FSH
can be acquired- alcohol, toxic agents, etc
no effective tx’s
sperm extraction for IVF is possible if the lesions are focal
5
Q
androgen production in males
A
synthesized in leydig cells from cholesterol
P450 side chain cleavage 20,20 desmolase catalyzes the rate limiting step
- converts cholesterol to pregnenolone
- transport of cholesterol by STAR protein into mito may also be rate limiting
primary site for steroid hormone production is gonads
-other androgen sources:
adipose, skin, brain, adrenal cortex
testosterone
considered pro hormone that can be converted to other steroid hormones
6
Q
reversible conversion between testosterone and androstenedione enzyme
A
17beta-hydroxysteroid dehydrogenase
7
Q
testosterone to estradiol enzyme
A
aromatase
8
Q
testosterone to dihydrotestosterone DHT enzyme
A
5alpha reductase
9
Q
transportation of Testosterone in blood
A
most T and other steroid hormones bound to binding proteins in blood
45-60% bound to sex hormone binding globulin SHBG
rest is bound to serum albumin and corticosteroid binding globulin CBG
2% is present freely in serum
5% undergoes 5alpha reduction to make potent DHT
10
Q
testosterone binding and paths in the body
A
T binds directly to androgen receptors ARs on muscle, reproductive organs
T–> DHT via 5alpha reductase, which has higher affinity for ARs
-external genitalia, sebaceous glands, hair follicles
T–> estrogen via aromatase, binds to ER
-bone, adipose tissue, brain
T metabolized in liver
T excreted in kidney and feces
11
Q
how do males w/ 5 alpha reductase deficiency present
A
males w/ 5alpha reductase deficiency have ambiguous genitalia at birth
–can’t convert testosterone –> DHT to reach external genitalia, sebaceous glands, hair follicles
normal development of testes and wolffian ducts, epididymis, seminiferous tubules
–requires only testosterone and not affected by this
sertoli cells are still normally functioning
12
Q
MOA of androgens
A
membrane permeable
bind to intracellular nuclear or cytoplasmic ARs
AR is ligand inducible transcription factor
recruitment of coactivators/suppressors
regulation of transcription of target genes
13
Q
Hypothalamic-pituitary-gonadal axis w/ GnRH
A
GnRH:
10 AA peptide
gene located on chromosome 9
rapidly degraded in the plasma
synthesized in hypothalamus
synthesis influenced by light/dark cycles, pheromones, and stress
secretion modulated by sex steroids via feedback loops
travels to anterior pituitary
stimulates prod/secretion of gonadotropins LH and FSH
GnRH receptor:
GPCR
leads to activation of PKC
physiologic role:
pro fertility
pulsatile (M 8-14 /day; F variable w/ cycle)
-LH pulses follow GnRH pulses
-end result is gonadal development
-daily doses of long-lasting analog are inhibitory
14
Q
which hormones share subunits w/ LH and FSH
A
LH and FSH share alpha-subunit w/ TSH and hCG (pregnancy hormones)
-hCG frequently used as clinical substitute for LH
15
Q
gonadotropin info
A
LH and FSH
pulsatile secretion following GnRH, esp LH
-FSH pulses lower than LH
half life in plasma ~1hr
small amount secreted in urine
bind to GPCRs on target organs
act via cAMP and PKA
16
Q
function of LH
A
LH stimulates steroidogenesis in interstitial cells of ovary and testis
17
Q
function of FSH
A
FSH stimulates aromatase in sertoli and granulose cells to produce estrogen and promotes maturation of gametes
18
Q
gonadal peptides
inhibins and activins
A
inhibins: TGF beta family dimeric- alpha and beta subunit come in 2 flavors, A and B, depending on beta subunit Testis, beta B is major form ovary, both beta A and beta B inhibit FSH release (clear role)
Activins:
beta subunits only
stimulates FSH release (but endocrine role is unclear)
these and many related peptides play local role in gametogenesis that is poorly understood
19
Q
3 major components of sex determination and differentiation
A
chromosomal sex gonadal sex (testis or ovary or ovotestis) phenotypic or anatomic sex (internal and external)
–however none of these absolutely defines ones “sex” and psychological development
20
Q
bipotentiality of sex differentiation
A
undifferentiated structures can always develop in either F or M direction
current bio environment determines path taken at each stage
the same path doesn’t have to be taken at each stage- your can switch along the way
21
Q
chromosomal sex
A
describes the complement of sex chromosomes in an individual
22 pairs of autosomes
1 pair sex chromosomes
key to sexual dimorphism is on the Y chromosome!!!
presence of Y chromosome independent of number of X’s imparts male development
–SRY = Sex determining Region of Y
22
Q
SRY gene
A
sex determining region of Y- causes male development
located on YP11 (sort arm)
-right next to pseudoautosomal region
protein transcription factor which activates other transcription factors and initiates testicular differentiation from indifferent gonad
23
Q
gonadal development
A
undifferentiated gonads first appear at about 4-5 weeks gestation as paired genital ridges
genital ridges form in the posterior abdominal wall just MEDIAL to developing mesonephros (fetal kidney)
formed from proliferation of the epithelium and condensation of underlying mesenchyme
24
Q
transcription factors in genital ridge
A
Wilms tumor related gene (WT-1)
- -expressed in the developing genital ridge, kidney, and gonads
- -WT-1 deletions/mutations associated w/ gonadal dysgenesis and predilection for Wilms tumor and nephropathy
NR5A1 aka SF-1
- -regulates transcription of genes involved in gonadal and adrenal development, steroidogenesis, and reproduction
- -important to keep AMH levels up
- -deletions can cause gonadal dysgensis, adrenal failure, and persistent mullein structures
25
gonadal development
germ cells form in the yolk sac and migrate to genital ridge in 6th week
if germ cells fail to reach the ridges, the gonads do not develop
before the arrival of germ cells, gonads are indifferent
26
formation of primitive sex cords
6 week old embryo-
shortly before/during arrival of primordial germ cells, the genital ridge epithelium proliferates and penetrates underlying mesenchyme to form primitive sex cords
27
gonadal development determining the testis
expression of SRY at 6 weeks!!! leads to gonad differentiation into testes
- primitive sex cords continue to penetrate into medulla to form testis or medullary cords
- migration of mesonephric cells into developing testis
- differentiation of sertoli cells (from surface epithelium) and differentiation of leydig cells!!
at hilum, the testis cords form rete testis
a dense layer of fibrous CT (tunica albuginea) separates the testis cords from the surface epithelium
testis cords are now composed of PGC's and sertoli cells (supporting cells for germ cells)
leydig cells lie between testis cords and begin production of testosterone by 8th week
-necessary for further M development for testosterone to be developed by 8 weeks
28
transcription factors important for testicular differentiation
```
SOX-9
target of SRY
essential for normal testis formation
with SF-1, elevates AMH concentrations
-mutations = camptomelic dysplasia
--severe skeletal dysplasia!!!
-gonadal dysgenesis in 75% of pts (XY pts who can't make normal testes)
```
FGF9
29
transcription factors important for female development
WNT4 and RSPO1
-important in inhibiting testes development via activation of beta catenin pathway
DAX1 on X chromosome
2 copies inhibits testicular development
(gonadal dysgenesis in XXY pts)
FOXL2
30
gonadal development of ovaries
requires migration of primitive germ cells
presence of 2 functional X chromosomes and absent Y
cortex develops into ovaries and medulla fades away
31
phenotypic sex and internal ducts: initial
initially:
both mesonephric/Wolffian and paramesonephric/Mullerian ducts develop in both sexes
differentiation begins at 8 weeks
32
Male internal ducts
differentiation begins at 8 weeks
wolffian ducts become:
Epididymis
Vas deferens
Seminal vesicle
mesonephric tubules degenerate, except a few eventually become efferent ductules
process requires testicular secretions:
- high local conc's of T (from Leydig)
- AMH (from Sertoli)
- --induces mullerian duct regression
- --must be expressed before end of 8th week in human fetus
33
Female internal ducts
requires ABSENCE of local testosterone and AMH
paramesonephric/Mullerian ducts:
fallopian tables
midline uterus
UPPER portion of vagina
Wolffian ducts regress
34
Rokitansky syndrome
absent or underdeveloped mullerian structures in a 46 XX female
baby born like nl female
normal breast development (ovaries making estrogen)
--primary amenorrhea (no mullerian structures)
35
cause of persistent mullerian ducts in 46 XY male
defect in AMH synthesis or
defect in AMH receptor
babies born like nl males
unilateral hernia, taken to surgery to fix testis, then discovered
36
external genitalia and phenotypic sex development- 3 structures
develop from 3 initially indifferent structures:
genital tubercle
-glans penis or clitoris
urethral folds
-penile urethra or labia minora
labial-scrotal (genital) swellings
-scrotum or labia majora
37
Male external genitalia development
dependent on T and DHT
T converted to DHT by 5-alpha reductase
DHT has higher receptor affinity than T
Penile growth and formation of penile urethra is particularly dependent on DHT for development
in 1st trimester, placental HCG stimulates leydig cells to make T
after 1st trimester, hypothalamic-pituitary-testicular axis required for continued T production
male external genitalia complete by 13 weeks
-any defects before 13 weeks cannot be corrected by subsequent androgen exposure
38
excessive androgen exposure to female fetus
after 13 weeks, excessive exposure can cause clitoromegaly but CANNOT result in posterior labial fusion or penile urethra
exposure prior to 13 weeks can result in urogenital sinus and insertion of urethra into vagina
39
hypospadias
condition where urethra comes out of the penis
once 13 weeks goes by you can't fix this
before 13 weeks- androgens cause differentiation
after 13 weeks- androgens just cause growth
40
gonadal descent of testes timeline
testes reach inguinal region by 12 weeks
| scrotum by 33 weeks
41
cryptorchidism
failure of testes to reach scrotal sac (3%)
42
where gender-specific traits stem from
gender specific traits stem from:
- differences in sex chromosomes
- hormonal exposure
also influenced by social circumstances and family dynamics
43
3 components of psychosocial development
gender identity
gender role
sexual orientation
role of fetal exposure to androgens:
ex 46 XX female might have male gender role behavior in childhood
ex 46 XY male w/ cloacal extrophy (severe disorder where internal organs are exposed)
--raised as girls and have high rate of dysphoria
44
disorder/difference of sex development- DSD definition and criteria
congenital conditions where development of chromosomal, gonadal, or phenotypic sex is atypical
criteria:
-overt genital ambiguity
- apparent F genitalia w/ enlarged clitoris, posterior labial fusion, or an inguinal/labial mass (possibly testes)
- apparent M genitalia w/ bilateral undescended testes, micropenis, isolated perineal hypospadias, or mild hypospadias w/ undescended testes
- discordance between genital appearance and prenatal karyotype
- FHx of DSD
45
evaluation of DSD
palpable gonads?
position of urethral meatus (Prader stages)
degree of fusion
stretched penile length (>2.5cm)
clitoral length (<1 cm and diameter <0.6cm)
46
clinical evaluation/workup for DSD
FISH for Y (SRY)- fast
karyotype/microarray
US- evaluate for presence of uterus
laparascopy- best to define internal anatomy
47
classification of DSDs
46XX DSD (virilized XX)
46XY DSD (undervirilized XY)
48
46 XX DSD possible causes
95% have congenital adrenal hyperplasia CAH
46XX sex reversal (SRY translocation)- will look male
ovotesticular DSD
gestational hyperandrogegism
49
46 XY DSD possible causes
abnormal testicular development causes:
pure or partial gonadal dysgenesis
-lots of mutations, incl SRY, SOX9, WT1, etc
mixed gonadal dysgenesis (45X/46XY)
-mosaicism won't be same in every body compartment
testicular regression
leydig cell dysfunction
defects in adrenal and testicular steroidogenesis (various forms of CAH)
50
Smith-Lemli-Optiz syndrome
7-dehydrocholesterole reductase deficiency
causes 46 XY DSD- defect in adrenal and testicular steroidogenesis
51
5 enzymes that can cause defects in adrenal and testeicular steroidogenesis
StAR protein!!!
cholesterol--> pregnenolone
3beta-hydroxysteroid dehydrogenase
pregnenolone --> progesterone
(eventually to aldosterone)
17alpha-hydroxylase
pregnenolone --> 17-OH-prregnenolone
(eventually to cortisol or testosterone)
17,20, lyase
17-OH pregnenolone --> dehydroepiandroepiandrosterone
(eventually to testosterone)
17beta-HSD
androstenedione --> testosterone
52
5alpha reductase deficiency
causes 46 XY DSD- defects in T metabolism
-autosomal recessive
T doesn't --> DHT
external genitalia undervirilized (penis, penile urethra)
wolffian ducts differentiated
testes usually in inguinal canal or labial-scrotal folds
at puberty, spontaneous virilization occurs
high rate of M gender identity
53
androgen insensitivity syndrome
46 XY DSD- defects in androgen action
mutation in androgen receptor on X chromosome
probably most common DSD
```
complete and partial forms
XY:
testes develop
androgen produced, but body can't respond
wolffian ducts regress
AMH produced (no mullerian duct development)
external genitalia are F
feminizing puberty without menses
```
54
complete androgen insensitivity:
gonads intraabdominal or in inguinal canal
bilateral inguinal hernias common!!!!
at time of puberty, spontaneous breast development due to testosterone ---> estrogen
little or no pubic/axillary hair
F gender identity
55
3 zones and products of adrenal gland
zona Glomerulosa
mineralocorticoids (aldosterone)
Zona Fasciculata
Glucocorticoids (cortisol)
Zona Reticularis
Androgens
56
congenital adrenal hyperplasia
enzyme deficiency in one of the adrenal pathways that affects cortisol production
phenotype depends on which pathway is affected
95% are 21-hydroxylase
5% are 11beta-hydroxylase
tx: glucocorticoids
57
21-hydroxylase deficiency
CAH disorder- 95% of cases
aldosterone and cortisol pathways are blocked
progesterone and 17-OHprogesterone will be very high
androgen pathway is overstimulated
most prominent feature- virilization
F- virilization of external genitalia
M- no genital abnormalities
hyper pigmentation of skin (POMC --> high ACTH and MSH)
```
hyponatremia/hyperkalemia (aldo deficiency)
mild forms (nonclassical) may present later in life w/ early pubic hair, axillary hair, penile/clitoral enlargement
```
dx suspected in virilized XX or XY w/ hyponatremia and kyperkalemia
Dx confirmed by measuring 17-OH progesterone (newborn screen)
--false pos in stressed, premature, and low birthweight infants
tx:
surgery in F
replace deficient hormones and suppress ACTH overproduction
-hydrocortisone (replace cortisol)
-florinef (replace aldo) (also need salt supplements)
-IM or IV Solu-Cortef in acute adrenal insufficiency
Monitor:
labs (17OHprogesterone, androstenedione, T)
growth
skeletal maturation
58
11 beta hydroxylase deficiency
CAH disorder- 5% of cases
low aldosterone and cortisol
high 11-deoxycortiosterone
high 11-desoxycortisol
high androgens
virilization similar to 21-hydroxylase deficiency
NO salt wasting
11-deoxycorticosterone has mineralocorticoid activity
HTN is frequent finding
androgen pathway unaffected
59
StAR protein deficiency
CAH disorder- <1% of cases
AKA congenital Lipoid Hyperplasia (accumulation of cholesterol esters in adrenocorticoid tissue)
these babies don't make anything
- block initial cholesterol --> prenenolone conversion
- STaR protein involved in transfer of cholesterol from outer to inner mito membrane
die 2-3 weeks from salt wasting if not caught!!!
F- normal genitalia
M- have F external genitalia
60
3 beta-hydroxysteroid deydrogenase deficiency
CAH disorder- <1% of cases
```
affects all 3 pathways
high pregnenolone
high 17-OH pregnenolone
high dehydroepiandrosterone
high cholesterol
```
F- virilization
M- undervirilization
salt wasting
61
17 alpha-hydroxylase 17,20 lyase deficiency
CAH disorder- <1% of cases
usually go together
super rare
blocks entire cortisol and testosterone pathway
high pregnenolone --> aldosterone pathway
F- virilization
--puberty: failure to develop 2ndary sex characteristics
M- born undervirilized
salt RETAINING
HTN 2/2 increased 11-deoxycorticosterone
hypokalemia
62
4 cardinal step sin mullerian development
elongation of mullerian structures/ducts
fusion of midline ducts
canalization from initially solid structures
septal resorption at the wall where they fuse
PLUS:
union of mullerian system w/ urogenital sinus to form lower 2/3 of vagina
63
3 important structures in the mullerian system
mesonephros- Wolffian ducts
just lateral- paramesonephros/mullerian structures
metanephros- primitive kidney; ultimately the full renal system
when you have a mullerian anomaly, >30% of the time you'll have renal anomaly too
(important to screen for the other when you find one congenital anomaly)
64
elongation phase of mullerian development
early on, so mesonephric/wolffian ducts are still prominent
65
fusion phase of mullerian development
mullerian ducts fuse in midline and subsequently fuse w/ urogenital sinus
tubes will ultimately become fallopian tubes
midline becomes uterus
Wolffian ducts regress
66
Cannulation phase of mullerian development
hollowing of mullerian ducts occurs
renal system is now fully fused w/ bladder
67
septal resorption and union w/ sinovaginal bulb phase of mullerian development
resorption of uterine septum occurs
sinovaginal bulb elongates (from bottom 1/3) and develops into full vagina
68
3 problems that can happen with vaginal obstruction
imperforate hymen
transverse vaginal septum
vaginal atresia
69
imperforate hymen
vaginal obstruction
failure of caudal end of sino-vaginal bulbs to canalize
present w/ primary amenorrhea and cyclic pain- classic pt!!
external exam: bulging w/ dark blood behind!
tx: surgery
- avoid urethra w/ volley catheter before you operate
- menstrual blood is evacuated
- thin membrane, easy to remove/repair
70
transverse vaginal septum
vaginal obstruction
failed canalization of the vaginal plate
present w/ primary amenorrhea and cyclic pain
external exam: vagina will end
no bulge, thick tissue 2/3 of the way up vagina
tx: can't just cut tissue -too thick
proximal and distal vagina need to be brought together, but pulling too much gives you pain the rest of your life
-DO NOT drain a thick septum w/ a needle- infection
surgery to open up and remove hymen; medically manage until then
71
vaginal atresia
vaginal obstruction
failure of canalization of urogenital sinus below vaginal plate
nothing there- no bulge, no connection
might have an obstructed uterus above
presents w/ amenorrhea and cyclic pain w/ no bulging
tx:
create a vagina
dilate when age appropriate across 3-6 months
surgical vaginoplasty (pull proximal vagina down) to ideally create a stretch 6-7cm long
72
Class 1 Mullerian anomalies
failed elongation causing segmental or complete agenesis
most severe = agenesis
blind ending vagina- NO UTERUS
AKA MRKH
present w/ primary amenorrhea- no uterus, no obstruction (no pain)
have ovaries and 2ndary sex characteristics regardless of Mullerian system
Type 1: classic (no mullerian structures); 90% of cases
Type 2: hypoplasia (sometimes a little bit of functional tissue --> pain from trapped blood)
73
class 2 mullerian anomalies
unicornuate uterus
from failure of one mullerian duct to elongate or reach urogenital sinus w/ contralateral duct
Type A: communicating
no pain, no obstruction
likely present w/ ectopic pregnancy or very pre-term delivery- outgrows cavity space
Type B: non-communicating
a lot of pain
functional endometrial lining w/o connection
no primary amenorrhea because the other horn is still open and menstruating
74
class 3 mullerian anomalies
uterine didelphys
from completely failed fusion in midline
reproductive system has completely duplicated- 2 of everything (but just 2 fallopian tubes)
75% of time- septum in vagina running down
usually not obstructive
pts may not present until try to use tampon or have painful sex
uterine didelphys w/ obstructed hemivagina:
OHVIRA
-obstructed hemivagina and ipsilateral renal agenesis
central septum is fused to one side
-often have absent kidney on same side as obstruction
-cyclic abdominal pain
normal menses (one side is working)
75
class 4 mullerian anomalies
Bicornuate
from failure to completely fuse down the midline
just 1 cervix (vs 2 in uterine didelphys)
Type A: complete (extends to os)
- pregnancy is going to run out of space
- extreme preterm delivery
Type B: partial (confined to fundus)
- late-preterm delivery
- less of an issue than A
76
class 5 mullerian anomalies
septate uterus
from failed septal resorption
most common mullerian anomaly- 55% of cases
usually asymptomatic
assoc w/ SAB and PTD
complete septum- runs all the way down the uterus, sometimes vagina
-preterm delivery/miscarriage
partial septum- not a huge problem
-higher risk for breached births
77
class 6 mullerian anomalies
arcurate uterus
near complete resorption of utero-vaginal septum
asymptomatic
normal external contour
no adverse reproductive outcomes
no surgical intervention
78
class 7 mullerian anomalies
DES drug related uterine anomaly
old drug used to tx 1st trimester hyperemesis
-69% of women w/ DES exposure have uterine anomalies
79
development of M reproductive tract w/ T and AMH levels
local production of AMH and T will give you testes
not having a high conc of AMH and T means you lack testes
-external genitalia will be normal- dependent on systemic T
80
default gonadal development pathway
Female is default pathway
involution of Wolffian ducts occurs in absence of T
differentiation of mullerian ducts occurs if no AMH
development of F ducts and external genitalia is independent of gonadal hormones-
estrogen is needed after differentiation to promote growth of uterus and external genitalia during puberty
81
function of leydig cells
produce androgen in response to LH (via GPCR)
95% of T comes from here
required for spermatogenesis
produce StAR protein and SCP protein
- transport cholesterol to mito side chain cleavage enzyme
- stimulate steroidogenesis
82
functions of sertoli cells
support/nurse cells for developing gametes/spermatozoa
secrete Androgen Binding Protein ABP
-maintains high local T levels
secrete inhibin and other GF's
make AMH
convert T to estrogen using aromatase
in response to FSH (via GPCR)
-most estrogen is produced here (unlike thecal cells)
form Blood-sperm barrier via tight junctions
protect developing gametes from bloodstream pathogens
prevent immune system from seeing spermatozoa in puberty as non-self
83
cross talk between Leydig and Sertoli cells
LH acts on Leydig cells to stimulate androgen production
-androgens (T) are substrates for estrogen production in Sertoli Cells
fSh acts on Sertoli cells to stimulate estrogen production
inhibitions released from sertoli cells in response to FSH act locally as GFs for Leydig cells
-if no functioning Sertoli cells, you won't get adequate leydig cell development either!!
FSH also induces other leydig GF release from Sertoli cells
via sertoli cells, FSH regulates proliferation and development of Leydig cells to provide adequate T for spermatogenesis
T synergizes with FSH to increase ABP production in Sertoli cells to maintain high local T conc's
84
Hypothalamic-Pituitary-Testicular HPT axis and negative feedback
GnRH stimulates production of FSH and LH from pituitary
LH acts on Leydig cells (8-14 pulses/day M)
- increased T
- increased StAR and SCP
fSh acts on Sertoli cells
- increased ABP
- increased aromatase expression
- increased GFs
- increased spermatogenesis
- increased inhibin production
Negative feedback:
androgens/T inhibit GnRH release from hypothalamus
androgens and estrogen inhibit LH and FSH release from pituitary
in response to FSH, sertoli cells make more inhibin to suppress FSH production from pituitary gonadotrophs (doesn't affect LH)
85
athlete with failed drug test scenario
high HCG in serum
-can tell whether is endogenous or synthetic based on its glycosylation
HCG closely resembles LH
could be taking HCG
LH would stimulate T production, but not enough to give him the results he wants, esp since it would be sustained vs pulsatile
Assume he's taking anabolic steroids
endogenous T would be shut down (completely suppress his own axis)
stops taking steroids for a drug test
-red flag of low T because testes haven't been making T for a long time
take HCG to try to kickstart his own testes/T production
dead give away in a drug test
86
menopause in a F- FSH and LH levels
high FSH and LH is diagnostic for menopause
they increase because the negative feedback is lost
87
sudden spiked increase in FSH in males
inhibin production from sertoli cells has decreased, which decreases the neg feedback on FSH
inhibin generally parallels spermatogenesis levels
-spike in FSH means you have a problem with spermatogenesis
infertility tx: sympathy and adoption
88
male pattern hair growth info
classically dependent on DHT
in scalp- females usually have less 5alpha reductase
differential expression and distribution of androgen receptors ARs in M and F
male pattern baldness:
hair follicles are growing faster but producing very fine/wispy hair that dies out
tx: 5alpha reductase inhibitor
vasodilator to improve blood flow (marginal hair help)
89
pubertal changes in males
prepubertal: FSH is higher than LH
switches at puberty: LH is higher than FSH
marked increase in T
-first maker of puberty = inc in testes size to >3mL
increased GH- growth spurt; avg 11"
(accounts for 4" height disparity w/ F)
pre-pubertal M and F have = body mass, skeletal mass, and body fat
```
post-pubertal males:
150% more muscle mass
150% more skeletal and lean body mass
200% more muscle cell number
50% of body fat
```
90
androgenic and anabolic effects on growth
androgenic effects:
growth and dev of M reproductive tract
2nday sex characteristics
behavioral responses
```
anabolic effects:
growth of somatic tissue
linear body growth (long bones)
nitrogen retention, protein synthesis
muscle development
```
effects mediated by same receptor- AR on X chromosome
responses are tissue/organ specific
interactions between steroids w/ IGF-1/ GH axis
91
interactions between steroids w/ IGF-1/GH and HPT axis
GH/IGF-1 stimulates gonadal function
to produce testosterone and estradiol
IGF-1 stimulates GnRH secretion
from hypothalamus
gives more LH/FSH
stimulates gonads to prod more T
T and estrogen stimulate GH secretion and growth
from liver
92
athletes and anti-estrogens
if you take a lot of T, you'll aromatize it to estradiol and drive estrogen production
elevated estrogen gives you gynecomastia
- -athletes are taking anti-estrogens to suppress aromatase inhibitors as well
- -now banning anti-estrogens for athletes
93
testosterone and estrogen w/ 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
when you add T, bone's aromatase converts T to estrogen locally
-stimulates bone growth but accelerates bone maturation and epiphyseal closure
estrogen stimulates growth and differentiation into more bone
- growth spurt but reduce window of growth
- plates will eventually close
- happens in F earlier (close sooner)
94
consequences of steroid abuse
infertility- decreased sperm production (testicular atrophy)
gynecomastia
baldness w/ excessive body hair (conversion to DHT)
tendon rupture, esp adolescent (develop muscle disproportionate to tendon)
bone fracture/abnormalities
MI, stroke (high BP; polycythemia from RBC production)
predisposes to liver cancer
magnified puberty- severe acne
roid rage
increased risk of blood borne infections from injections
-gateway drug of injections
addiction
95
define puberty
developmental events leading to the attainment of full sexual maturation and fertility capacity
requires intact hypothalamic-pituitary-gonadal axis
96
HPG axis times during development and puberty
active in fetal development (2nd trimester on)
continues to function in infancy "Mini puberty"
- boys lasts up to 6mo
- girls lasts up to 18mo
- if baby boy has low FSH and LH at this time, it's a hint that it will happen later in life too
after infancy, the axis enters quiescent state, referred to as juvenile pause
puberty- more of a reactivation than de-novo
- reemergence of GnRH secretion stimulating LH and FSH
- gonadal maturation
- gonadarche
97
Gonadarche
HPG axis reactivation
GnRH stimulating LH and FSH to bind to ovaries/testes causing gonadal maturation and production of sex steroids
KISS-1 peptin thought to be major player in stimulating GnRH secretion
98
GnRH pulses during puberty
initially at night- higher amplitude and frequency of GnRH pulses
-gives you a big LH surge- marker of puberty
eventually GnRH will pulse big throughout the day
-increased amplitude of LH pulses
99
how to lab test puberty evidence
random serum sample of LH/FSH is not that helpful, esp early in puberty, esp during the day
test by giving a GnRH analog and look at LH response levels:
mature axis: LH will go above 4-5
immature axis: more FSH response; LH will be 2-3
100
girl gonadarche changes
estrogen stimulated changes
```
breast development
genital growth (labia minor)
maturation of vaginal mucosa
uterine/endometrial growth
body composition/fat changes
menarche (estrogen and progesterone)- occurs mid-late puberty; 1.5-2 yrs after breast development
```
101
boy gonadarche changes
enlargement of testes (mediated by FSH and LH gonadotropins)
```
testosterone mediated:
scrotal changes
sexual hair
penile growth
prostatic/seminal vesicle growth
deepening of voice
increase in muscle mass
```
102
gonadarche changes in both sexes
linear growth acceleration
bone age advancement
- mediated by estrogen in both
- T is converted to estrogen via aromatase in boys
- estrogen produces GH
end of puberty- growth plates fuse and done growing
-mediated by estrogen in both
give aromatase inhibitor in pubertal boys to increase T but decrease estrogen so possibly slow growth plate fusion
-safe or ethical?
103
Adrenarche
adrenal component of puberty
maturation of zona reticularis- stim production of adrenal steroids
increased production of adrenal androgens (DHEA-S, androstenedione)
cause pubarche, the physical signs of pubic hair, axillary hair, body odor, and acne in both boys and girls
104
timing of puberty- girls across races
breast development
menarche
attainment of Tanner 2 breast development
White:
early 8
mean 10.4
black:
early 6.6
mean 9.5
Hispanic
early 6.5
mean 9.8
menarche
White
early 10.65
mean 12.55
black
early 9.7
mean 12.06
Hispanic:
early 10.05
mean 12.25
105
Tanner stages for females
pubic hair
Tanner 1- no hair
2- primarily just a labia or lower mons
3- covers most/whole mons, but still sparse
4- full coverage of mons
5- larger area, typically extension to thighs
breast
1- no breast dev; can't tell through shirt
2- little breast tube; small amount of tissue around areola
3- more tissue; more than 3cm diameter; round contour
4- double contour because areola is protruding; more areola development
5- single contour
106
timing of puberty for boys
no ethnicity difference
testes >3mL is first sign (orchidometer)
early: 9
mean 11.8
pubic hair 12
penile enlargement 13
peak height velocity 14
107
tanner stages in boys
pubic hair and genital stages, but genital stage is hard to assess and not really used
```
pubic hair:
1- nothing
2- base of penis or maybe just scrotum
3- covering more area just above penis
4- triangular area fully covered
5- diamond coming up to abdomen
```
108
delayed puberty
no pubertal signs by
13 in girls
14 in boys
low gonadotrophins-
hypogonadotropic (or central) hypogonadism
elevated gonadotrophins-
hypergonadotropic (or primary) hypogonadism
109
lack of pubertal progression
no menarche by 4 years after puberty starts
(after onset of breast development)
no completion of genital growth in boys after 5 yrs
more tricky- keep good records of puberty onset
110
bone age and puberty
onset of puberty is commensurate w/ childs biologic age (bone age)
girls start puberty at bone age of 10.5-11
boys start puberty at bone age of 11.5-12
111
hypogonadotropic hypogonadism
lack of puberty due to absence of GnRH and/or gonadotropin secretion from brain
low gonadotropins
may be complete or partial
may be temporary or permanent
112
constitutional growth delay
best example of temporary hypogonadism
deceleration of linear growth within first 2 yrs of life
nl linear growth after this w/ delayed bone age
onset and progression of puberty corresponds w/ bone age, not chronologic age!
growth continues after peers stop growing and genetic height potential is still achieved
FHx of "late bloomers"
```
tx:
reassurance if appropriate for bone age
can give boys short course of T
can give girls short course of estrogen
reevaluate in 4-6 months
```
113
congenital causes of hypogonadotropic hypogonadism
part of multiple hormone deficiencies
septa-optic-dysplasia
genetic syndromes- Prader Willi Syndrome
114
Idiopathic Hypogonadotropic Hypogonadism IHH
isolated defect in GnRH or gonadotropins in absence of any structural abnormalities of hypothalamus or pituitary
115
Kallman Syndrome
IHH plus anosmia/hyposmia
agenesis or hypoplasia of olfactory
assoc between IHH and impaired olfaction results from defect in shared developmental origins of GnRH and olfactory neurons
- olfactory nerves provide scaffolding for GnRH to travel to hypothalamus
- problems w/ neuron migration
116
acquired causes of hypogonadotropic hypogonadism
pituitary or hypothalamic tumor
cranial irradiation
CNS infection
infiltrative diseases
-histiocytosis, granulomatous disease, hemochromatosis
autoimmune hypophysitis
```
functional or reversible causes:
chronic illness
malnutrition
stress
excessive exercise
anorexia
hyperprolactinemia
hypothyroidism
```
117
HYPERgonadotropic hypogonadism
primary gonadal failure leads to decreased neg feedback and elevated LH and FSH
typically assoc w/ sex chromosome abnormalities
(girls w/ high LH and FSH- likely Turner)
118
causes of primary ovarian failure
Turner syndrome
XX or XY complete gonadal dysgenesis
galactosemia
radiation
chemo (alkylating agents)
autoimmune
119
Turner syndrome
45X0 karyotype in 50% of girls
rest are mosaics or structural abnormalities of X chromosome
may have no phenotypic characteristics except for short stature
```
short stature
ovarian failure
history of otitis
dysmorphic facies
cardiovascular
thyroiditis
```
120
causes of primary testicular failure
Klinefelter's syndrome
cryptorchidism
testicular regression syndrome
radiation
chemotherapy (alkylating agents)
121
Klinefelter's syndrome
47XXY genotypes (or additional X's)
hyalinization and fibrosis of seminiferous tubules
(no problem w/ leydig cells/T levels)
microphallus, small testes, learning disabilities, eunuchoid, delayed/arrested puberty, gynecomastia, infertility
122
evaluation of delayed puberty
Hx- ask about sense of smell
height and growth rate
bone age
labs: gonadotropins, T, estradiol
karyotype if elevated gonadotrpins
123
treat hypogonadism in M and F
M-
T 3-4 weeks initially low dose to gradually increase
F-
estrogen alone filled by cyclic therapy w/ estrogen and progesterone
try to mimic normal puberty
124
complete precocious puberty vs incomplete
early onset AND progression of physical development
<9 for boys
<8 for white girls; 6.5-7 for black/Hispanic
accelerated linear growth
advancement of skeletal age
central (GnRH dependent)
peripheral (GnRH independent)
incomplete:
benign thelarche
benign adrenarche
125
central precocious puberty
central- think brain
physical changes and testing are all consistent w/ progressive changes of HPG axis activation
5% of the time in girls caused by CNS abnormality; 50% of the time in boys
```
CNS causes:
hypothalamic hamartoma! (tx medically until they're ready to start puberty)
suprasellar tumor
hydrocephalus
previous CNS infection
major head trauma
cranial irradiation
```
126
causes of peripheral precocious puberty in girls and boys
NOT dependent on GnRH
both:
severe primary hypothyroidism
-MOA may be hormonal overlap (TSH is like FSH)
-key is delayed bone age and poor linear growth
```
girls: estrogen mediated symptoms
ovarian cysts- progression of ovarian follicles to form cysts as part of normal childhood
granulose cell tumor
exogenous estrogens
lavender products (breast dev in both)
```
boys:
adrenal tumor (low FSH and LH!)
leydig cell tumor (discrepancy in testis size)
hCG secreting tumor
McCune Albright syndrome
Late-onset congenital adrenal hyperplasia
familial testotoxicosis
127
McCune Albright Syndrome
activating mutation in the alpha subunit of stimulatory G-protein
triad of: precocious puberty, cafe-au-alit spots, polycystic fibrous dysplasia
can also have GH excess, hyperthyroidism, Cushing's syndrome
tx:
Aromatase inhibitor
128
Familial testotoxicosis
cause of peripheral precocious puberty in boys
mutation of LH receptor causing it to be constitutively activated
autonomous Leydig cell activity
testes enlarged but not to the extent expected for degree of virilization
boys are producing T at a very young age- significant penile enlargement, pubic hair, and only some testicular enlargement
tx:
aromatase inhibitor plus androgen blocker OR ketoconazole
129
evaluation of precocious puberty
random LH and FSH:
pubertal LH level --> central precocious puberty
cranial MRI
prepubertal LH --> GnRH stimulation test -->
recheck LH level
-if prepubertal LH --> peripheral precocious puberty
130
Tx of precocious puberty
attempt to reclaim loss of final height potential
also to halt pubertal progression and alleviate or prevent psychological stress
- psychosocial development corresponds w/ age, not physical maturity
- may see withdrawal, anxiety, depression
- may be victims of sexual encounters
central:
constant GnRH analog-
down regulates pituitary GnRH receptors
decreases gonadotropin secretion
Peripheral:
depends on cause
(ovarian cyst- watchful waiting w/ F/U US)
131
premature thelarche
incomplete pubertal development-
onset of breast development without other associated pubertal changes
no growth acceleration or bone age advancement
breast development progresses very slowly or waxes and wanes in size
under 2yo-
breast tissue usually caused by greater ovarian hormone production during infancy;
often regresses by 24 months
>2yo:
may be consequence of fluctuations of childhood HPG axis w/ temporary FSH-stimulated increases of ovarian steroid secretion
132
premature adrenarche
early development of pubic hair and/or axillary hair with or without increased body odor, oily skin, pimples
premature activation of adrenal androgen secretion
rare before 6yo
height and bone age generally normal or minimally advanced
generally timing of true puberty isn't affected and final height isn't compromised
15% of girls w/ premature adrenarche will develop PCOS
133
Testosterone pharmacology
most important androgen in muscle and liver
synthesized in testes 95% and adrenal 5%
98% bound to proteins (SHBG and albumin)- only the free hormone is active
concentrations fluctuate during the day but TOTAL daily secretion is constant
M 5-7 ng
F 0.25 ng
highest levels at 8-10am (500-700ng/dL)
--hypogonadal if <200
134
DHT pharmacology
synthesized from testosterone by 5alpha-reductase
2 forms of the enzyme have been ID'ed:
Type 1- non-genital skin, liver, bone
Type 2- urogenital tissue and hair follicles
DHT is predominant androgen mediator in
prostate and reproductive tissue
135
estrogen pharmacology
synthesized from testosterone via C19 aromatase, expressed in testes, bone, brain, and adipose tissue
actions in males are mediated by estrogen receptors
most significant actions occur in BONE
- closure of epiphyseal plate
- M's w/o aromatase or estrogen receptors don't fuse epiphyses and long bone growth continues
- these pts are also osteoporotic
136
androgen replacement therapy in hypogonadal men/boys
NOT controversial, esp <200
larger doses required if deficiency occurs prior to sexual maturation
osteoporosis
muscle wasting w/ AIDS pts
hormone replacement therapy in aging men IS controversial
137
androgen deficiency and pharmacology
androgen deficiency related symptoms:
low libido, decreased morning erections, small testes
low bone mineral density
gynecomastia
less specific:
fatigue, depression, anemia, reduced muscle strength, increased fat
Testosterone tx in AGING men ONLY who are distinctly subnormal T (<200-300) on multiple occasions and WITH symptoms
principle goal is to restore serum T conc to nl range
indicated only for testosterone deficiency- NOT impaired spermatogenesis
-T suppression of gonadotropin secretion would further impair spermatogenesis
138
steroid abuse in sports pharm
10-200x normal dose to increase strength and aggressiveness
huge doses increase lean body mass but MOA uncertain
all anabolic hormones also have androgenic side effects:
block of LH/FSH release
promotion of prostate growth
often used in patterns- cycling
also used in regimens- stacking
139
GH pharmacology
AKA somatropin
off-label uses- NOT FDA approved
used by athletes to increase muscle mass and improve performance
used by healthy elderly for "anti-aging"
oral prep's containing "stacked" AAs reportedly stimulate GH release- marketed as nutritional supplements
-lack of control trial validation
small changes in body composition
increased risk of adverse events:
edema, joint pain, muscle pain, carpal tunnel syndrome, skin numbness, tingling
may increase growth of pre-existing malignant cells and diabetes
hCG is exception among drugs in that off-label use has been deemed ILLEGAL
140
Testosterone preparations pharm
excellent oral abs, but rapid hepatic degradation makes it difficult to maintain nl serum T levels
Parenteral:
T ethane and T cypionate esters
-increased lipophilicity
-will initiate and maintain nl virilization in hypogonadal men given every 1-3 weeks
-trade-off between less frequent infections and greater fluctuations in serum T levels
---fluctuations in E, mood, and libido
oral:
methyl testosterone
reduced 1st pass metabolism BUT hepatic side effects- diminished use
Transdermal:
patch or gel
T in special formulation
chemicals increase T abs across non-genital skin
once daily normalized T levels in most men
severe skin rash necessitating discontinuance in up to 1/3 pts using patch
gel: major advantage-
- --maintains relatively stable T levels throughout the dosing period --> mood, E, and libido
- most expensive of T formulations
141
adverse androgen effects pharm
avoid androgens in infants and young
decreased spermatogenesis
- low LH/FSH release (neg feedback)
- conversion of androgens to estrogens
- return to nl func after discontinuation
reversible cholestatic jaundice
-higher w/ oral agents, hepatic carcinoma (17alpha-alkylated androgens)
edema--> weight gain
increased susceptibility to arterial thrombosis (low HDL, high HDL, and increased plt aggregation)
psych symptoms--> hypomania ("roid rage")
CVS risks- controversial data
BUT befits outweigh uncertain risks ONLY IN HYPOGONADAL MEN
142
GnRH pharmacodynamics
endogenous release from hypothalamus in hourly bursts
pulsatile agonist admin increases LH and FSH release from pituitary
Continuous agonist admin blocks release
-prior to desensitization, LH/FSH will transiently rise with a surge in T --> worsening of symptoms
continuous ANTAGONIST admin reduces T levels in 1 week without initial increase and flare-up symptoms
143
targets for androgen drug action
5 alpha reductase
inhibition of DHT synthesis by finasteride
androgen receptor
inhibition of androgen binding at its receptor by flutamide and spironolactone
144
Finasteride and Dutasteride pharm
5 alpha reductase inhibitors
Finasteride- blocks Type 2 (urogenital tissue and hair follicles- BPH, hair loss)
Dutasteride- blocks Type 1 and Type 2 (non-genital skin, liver, bone- BPH)
Adverse effects:
decreased libido
ejaculatory-erectile dysfunction
weakness
145
flutamide and bicalutamide pharm
androgen receptor antagonists- 1st generation
compete w/ agonists to block androgen binding to the AR's ligand binding domain
interferes w/ co-activator binding
adverse effects:
androgen deprivation effects:
loss of libido, gynecomastia,
Nausea, transient abnormal LFTs
146
Enzalutamide pharm
new generation anti-androgen
MOA-
inhibits nuclear translocation
inhibits co-activator recruitment
inhibits DNA binding of AR
no known partial agonist properties, which can be seen w/ first generation anti-androgens (Bicalutamide)
147
clinical uses of anti-androgens
```
prostate cancer
benign prostatic hyperplasia
androgenetic alopecia
precocious puberty in boys
Hirsutism of PCOS
```
148
prostate cancer pharm
GnRH agonists: Leuprolide, Histrelin
Flare symptoms: initial rise of T temporarily worsens bone pain, produces urinary tract symptoms
given w/ androgen receptor blockers to reduce symptoms (Bicalutamide, Enzalutamide)
-NO flare symptoms w/ antagonists
GnRH antagonists: Degarelix
given monthly is an option in advanced prostate cancer
149
BPH pharm
5 alpha-reductase inhibitors:
Finasteride and Dutasteride
Alpha-1 blockers: recommended initial therapy
150
androgenetic alopecia pharm
(male pattern baldness)
5 alpha reductase inhibitors:
Finasteride
-lower dose than for BPH
Minoxidil is option if non-systemic therapy is desired
therapy w/ each must be continued to maintain efficacy
151
precocious puberty in boys pharm
GnRH agonists
| Leuprolide
152
Hirsutism of PCOS pharm
androgen receptor antagonists:
Spironolactone
estrogen-progestin contraceptive is first choice
153
adverse effects of anti-androgens
Finasteride and Dutasteride:
decreased libido, ejaculatory-erectile dysfunction, weakness
154
Leuprolide pharm
GnRH agonist
used in precocious puberty in males
```
Adverse effects:
HA
nausea
injection site rxn
Hypogonadism w/ prolonged tx
```
155
spironolactone pharm
AR antagonist
Adverse effects:
hyperkalemia
gynecomastia
156
testes microanatomy
significant vol taken up by seminiferous tubules
meiosis: spermatogonia --> spermatozoa
spermatozoa then enter rete testes, which has CT to contract and move sperm through channels
then ductuli efferentes
then outside of testes- become highly coiled and called coni vasculosi
then fuse to single epididymus
then Vas deferens
then ejaculatory duct when it meets the seminal vesicle
joins prostatic urethra where the prostate is
157
seminiferous tubules microanatomy
outer basal lamina surrounded by myofibroblasts that can contract to propel spermatozoa
tissue between the tubules contains CT, leydig cells (make T), blood vessels, nerves
inside of tubules is avascular
spermatogenesis- production of male gametes
spermiogenesis- subsequent development of haploid gamete to motile spermatozoan
158
spermatogenesis microanatomy
spermatogenesis:
mitotic division of type A spermatogonia (2N)
outer region of seminiferous tubules
true stem cells that can divide mitotically to totipotent progenitors
some become Type B spermatogonia once committed to meiosis
these then become 4C (4 chromatids, officially, during crossover events during meiosis) ---called primary spermatocytes
-cells w/ large nuclei w/ clearly observable chromosomal components continuing development further towards center of tubule
complete meiosis 1
quickly complete meiosis 2 as secondary spermatocytes (2 hrs)
quickly become haploid spermatids
during entire meiosis process-
the cells derived from a given spermatogonium remain linked as a sanctum w/ connected cytoplasmic bridges
-believed to be important for RNA exchange
-interconnected cells are surrounded by supportive Sertoli cells
159
Sertoli cell microanatomy
form blood-testis border via tight junctions
(spermatogonia at base of seminiferous epi are not contained within the barrier, but all others are)
sertoli cells secrete androgen-binding protein ABP
-sequesters high levels of T required for spermatogenic process
sertoli cells have FSH receptors and produce inhibin to feedback to hypothalamus
provide nutrients to developing spermatocytes and spermatids
phagocytize residual bodies and degenerating cells
160
epididymus microanatomy
long convoluted tube w/ SM outside of basal lamina to help spermatozoa propulsion
tufts of long microvilli thought to involve fluid absorption
spermatozoa gain motility along the epididymus, but they're till not fully capacitated until they enter F reproductive tract
161
vas deferens microanatomy
conduits spermatozoa to ejaculatory duct by peristaltic contraction to expel into urethra
3 muscular layers:
inner longitudinal
medial circular
outer longitudinal
sympathetic innervation
162
M accessory gland microanatomy
seminal vesicle-
paired glands leading to a single vas deferens
unique glandular structure w/ highly irregular extensions of tissue
produces 80% of seminal fluid
prostate gland
where ejaculatory duct meets urethra
peripheral region- most of glandular tissue
empties into small ducts into urethra for semen fluid
hyperplasia incl glandular expansion and compression of prostatic urethra (urinary problems)
--most cases of carcinoma of prostate occur in peripheral glandular regions away from urethra!!!!
PSA- used for screening prostate cancer
163
penis microanatomy
fibrocollagenous tube
2 dorsal cylinders of erectile tissue (corpus carvernosa)
1 ventral cylinder w/ urethra (corpus spongiosum)
interconnected vascular spaces fill w/ blood during erection; largely drained when flaccid
parasympathetic discharge- NO serves as one of the NTs, shunts allow blood to fill corpora
sympathetic input reopens shunts and allows detumescence
164
female oocyte microanatomy
oocytes are derived from population of primordial follicles
primordial germ cells divide mitotically up to 5 months gestation and enter meiosis 1 for years (DNA content 4C)
surrounded by flattened follicle cells in primordial follicles
--genomic DNA is not replicated during oocyte development in adult ovary
165
ovary microanatomy
oocytes grow and mature in ovaries
sex steroids are produced necessary for implantation-stage development of uterus endothelium
blood, nerves, and lymphatics enter/leave ovary via hilus
stroma contains fibroblast-like cells and thecal cells that participate in follicular development
166
follicle development in ovary microanatomy
in the fetus:
primordial germ cells divide to produce oogonia;
cease 5 months gestation; makes
primary oocytes arrested in meiosis 1 until ~6 months after birth
oocytes are surrounded by single layer flattened primordial follicle
(some become cuboidal- primary follicle)
primary follicle- acquire more than 1 layer of cells (granulosa cells) and are referred to as secondary (preantral) follicles
after puberty- some primary follicles develop to antral or advanced antral (Graafian) follicles under influence of FSH
--majority of these degenerate to form atretic follicles
after menarche:
primary/secndary follicles are stimulated to develop into antral follicles
granulose cells proliferate
thecal cells increase and enlarge
Graafian follicles have large fluid-filled antrum
1x/month one of the large Graafian follicles becomes dominant, greatly increasing in vol to ovulatory stage
few hrs prior to ovulation, meiosis 1 is completed and 1st polar body is released (oocyte still is not haploid yet though)
release of 2nd polar body only occurs after oocyte is penetrated by sperm
-loses one of its own haploid set of chromosomes but gains the male equivalent
during follicular development-
thecal and follicular granulose cells interact
thecal cells prod androstenedione, which is converted to estradiol by granulosa cells
167
corpus luteum microanatomy
corpus luteum- large endocrine group of cells from remodeled granulosa and thecal cells after an ovulatory follicle successfully releases an oocyte
occurs monthly
driven by LH production 12 days into cycle- called lutenization
cells distended by lipid
secrete progesterone and estrogen necessary for uterine endothelium for possible implantation
degenerates into corpus albicans (residual body) if implantation doesn't occur
enlarges if fertilization/implantation does occur, under the influence of chorionic gonadotropin
partly responsible for maintenance of pregnancy
168
oviducts/ fallopian tube microanatomy
fimbriae that embrace ovary during ovulation
conduct passage of egg to the uterus
3 zones:
infundibulum, ampullula, isthmus (then uterus)
muscular- inner circular and outer longitudinal SM layers
mucosa is highly labyrinthine and ciliated in infundibulum and less so as it goes
mucosal surface comprised of secretory and ciliated cells, and basal stem cells
estrogen sensitive
secretory cells release proteins, sugars, etc important for egg and sperm viability and fertilization, which typically occurs in ampulla
169
uterus microanatomy
3 main layers in to out:
endometrium (single layer of surface epi)
myometrium (thick muscular layer)
serosa (relatively elastic CT connected to broad ligaments)
cervical portion:
different from uterine body
endocervical canal is lined by single layer of tall epi cells that extend into deep slit-like invaginations along wall (endocervical mucus glands)
this ends at endocervix where transition occurs to stratified squamous more resembling integument
170
endometrium microanatomy
divided into 2 zones:
basalis
functionalis
- hormonally responsive
- cycles monthly from puberty to menopause
- coiled tubular glands lined by epi
beginning of cycle:
cellular proliferation as follicle develops in ovary
-EC stroma expands
```
secretory phase:
driven by progesterone
glands become highly coiled
secrete glycoproteins
become thicker
serial arteries develop in uterine stroma
```
when pregnancy does not occur:
functionalis enters menstrual phase
arteries contract and become kinked- ischemia and necrosis w/o adequate progesterone and estrogen
blood vessel rupture above kinked regions occurs w/ bleeding and deciduation
171
myometrium microanatomy
composed largely of bundles of SM
during pregnancy-
hypertrophy and hyperplasia occur
expanding size of uterus
benign fibroid tumors commonly develop in SM
hormone dependent, and typically regress w/ menopause
172
mammary gland microanatomy
typical non-lactating:
glandular tissue arranged as acini (AKA alveoli)
ducts leading to large ducts to nipple
acini lined w/ secretory-type epi cells w/ outer layer of flattened myoepithelial cells
lots of CT and adipose tissue are present
after childbirth:
prolactin stimulates milk production
extensive elaboration of glandular tissue w/ luminal spaces filling w/ milk
oxytocin tells myoepithelial cells to contract w/ propulsion of milk into lactiferous sinuses
protein components of milk enter acinar spaces via usual route- vesicles that fuse w/ plasma membrane
lipids enter by vesicular "budding" so lipid droplets are contained within a plasma membrane bilayer upon entering acinar spaces
173
where lesions drain
vulva
cervical
uterine corpus
vulva lesions drain into inguinal lymph nodes, then pelvic, then periaortic
cervical- first to pelvic (external/internal iliac), then periaortic
uterine corpus- pelvic, then periaortic
174
```
growth patterns and terms
endophytic
exophytic
pagetoid
adeno
myo
leio
rhabdo
oma
carcoma/sarcoma
eosinophilic
```
endoptytic- Down into the tissue
exOphytic- out from the surface
pagetoid- single cells/clusters percolating through the epithelium
```
adeno- gland forming
myo- muscle
leio- smooth
rhabdo- skeletal
oma- usually benign
carcinoma/sarcoma- malignant
eosinophilic- pink
```
175
most common malignancy in vulva
squamous cell carcinoma
| -firm yellow-white thickening of outer genitalia
176
herpes simplex virus
HSV2 is >70% of genital herpes
20% F will be seroposeivie by 40yo; 30% symptomatic
ultra painful red lesions 3-7 days after exposure
red papules - vesicles- coalescent ulcers
eosinophilic intranulcear inclusions
purulent exudate w/ viral cytopathic effect: multinuclear inclusions
never goes away
virus migrates to lumbosacral lymph nodes, est latent infection
biggest risk is transmission to newborn- indication for C section!!!!
177
molluscum contagiosum
found in both adults and children as an active infection
- adults- genital
- children- extremities (towels)
flesh colored, pearly skin lesions
painless
endophytic growth w/ eosinophilic inclusions (not multinucleated)
self-limited (no tx)
178
condyloma acuminatum
verrucous (cauliflower) growth pattern, multifocal
HPV6, 11 make up 90% of these
histo hallmark: koilocytes
-enlarged, raisinoid nucleus
hyperkeratosis and parakeratosis (esp papillae tips)
hypergranulosis and elongated rete ridges
cauliflower + koilocytes= condyloma
179
vulvar infections
trichomonas
candida
actinomyces
```
trichomonas
flagellated protozoan;
frothy yellow discharge
dysuria, dyspareunia
“strawberry cervix” on colposcopy!!
```
candida
normal, but can overgrow (diabetes, antibiotics, pregnancy)
curdlike discharge and pruritis
actinomyces
"sulfur granule" w/ clublike projections
assoc w/ non-copper IUD's
non-pathogenic, more incidental
180
vulvar intraepithelial neoplasia
low grade dysplasia- VIN 1
koilocyte
and lack of maturation
= dysplasia
1/8 as common as cervical cancer
HPV related- high risk types 16, 18
181
VIN 3- Squamous cell carcinoma in situ
increased mitoses, full thickness dysmaturity
- cells at surface look the same as those near base
- "in situ" means have not reached basement membrane
gross:
discrete white hyperkeratotic raised lesions
182
2 different pathways to Squamous cell carcinoma in women
```
HPV- associated SCC
90% HPV 16*, 18, 31
VIN is the classic precursor to this
10-20 yrs for progression
5 year survival is very different depending on lymph node involvement
risk factors:
smoking
immunosuppression
chronic inflammation
histo:
infiltrating nests of irregular malignant cells- desmoplastic stromal response
```
```
inflammatory- associated SCC
older population >70yo
HPV negative
Lichen sclerosus is precursor lesion
histo:
prominent keratin pearls!!! (hallmark for squamous neoplasm); increased mitoses; N/C ratio isn't as high as other invasive carcinomas
```
183
Lichen sclerosus
smooth white plaques/papules
-resembles parchment paper
```
RECOGNIZE ON AN IMAGE:******
superficial dermal fibrosis
-top, solid pink
perivascular mononulcear infiltrate
thinned epidermis w/:
loss of rete pegs
hydroponic degeneration of basal cells
superficial hyperkeratosis
```
most common symptoms:
itching
fissures/bleeding/pain
dyspareunia
increased risk for developing SCC
primary tx w/ steroid ointments/injections
184
extramammary paget disease
intraepithelial adenocarcinoma
believed to originate from toker cells
red, CRUSTED, sharply demarcated map-like area
histo:
marked hyperkeratosis and pale/white basal epidermis
tumor cells w/ a "halo" lie singly or in clusters (w/ occasional gland formation) in epidermis
185
malignant melanoma
<5% vulvar cancers
dismal 5 year survival
can histo look similar to Paget disease
but the melanoma will express S100 gene
brown pigment- think melanoma
186
embryonal rhabdomyosarcoma
grape-like protrusion!!!
- polypoid, rounded, bulky masses fill and protrude from vagina
- sarcoma botryoides
histo:
cambium layer
--dense zone of rhabdomyoblast present beneath the surface epithelium
small spindle-shaped cells w/ abundant mitoses
striations in elongated spindle cells w/ eosinophilic cyto: rhabdomyogenic (skeletal muscle) differentiation
187
adenosis
glandular tissue in vagina
may or may not be related to DES exposure
mucinous glandular epithelium
-red granular spots and patches
188
DES-associated clear cell carcinoma
looks like adenosis, but worse
multifocal, discontinuous- "kissing lesions"
histo:
tubulocystic pattern of growth w/ dense hyaline stroma
"clear" cytoplasm w/ bland nuclei
almost exclusively in women <30yo
189
cervix histology transformation
normal for cervix to undergo squamous metaplasia as a F ages
190
endocervical polyps
polls that can cause spotting
mostly benign
but can harbor dysplasia
composed of dilated glands, dense eosinophilic stroma
dilated mucus-secreting glands and inflammation
191
squamous cell carcinoma in cervix
cervical cancer is staged CLINICALLY- unique
majority treated w/ chemo, and then maybe a removal 2nd (usually reversed for other cancers)
increased mitoses, full thickness dysmaturity
infiltrating irregular nests of malignant squamous cells
desmoplastic stromal response
192
adenocarcinoma in situ AIS in cervix
```
histo:
hyperchromasia,
mucin depletion,
luminal mitoses
high N/C ratio
```
progresses to invasive
assoc w/ HPV 16, 18
193
days of cycle of menstrual cycle
proliferative
secretory
menstrual
194
proliferative phase
estrogen driven process
test tube glands!
presence of mitotic figures
nuclei are arranged in basal organization
195
secretory phase
increased progesterone
estrogen falls a little
this is the endometrium really getting ready to accept developing embryo
histo:
S shaped, tortuous, coiling glands
secretory activity
196
menstrual phase
w/o implantation
sharp drop off of estrogen and progesterone
-clumps of endometrium that get shed
acute inflammation
intravascular fibrin/thrombi
197
pregnancy endometrium response
progesterone, hCG
histo:
stromal decidualization
ARIAS-STELLA REACTION ASR!!!!
198
menopause endometrium
>6 months w/o menstruation
thin endometrium w/o mitoses
decreased cervical mucous and glycogenation
cystic atrophy
199
abnormal uterine bleeding
irregularity in menstrual cycle
amenorrhea- lack of menstruation
menorrhagia- heavy or prolonged
metrorrhagia- irregular (metronome)
dysfunctional- no pathological cause identified
the older a woman gets, the higher the suspicion for cancer
200
endometrial polyps
analogous to cervical polyps
dense pink stroma, hapardazly arranged glands
cystic dilation, hormonally unresponsive
201
endometritis
clinically PID
acute
increased polyps in stroma and glands
curettage curative
chronic
plasma cells
infertility
202
adenomyosis/endometriosis
synonymous, depending on location
endometrial glands and stroma in abnormal location
in uterine wall = adenomyosis
extrauterine = endometriosis
infertility, dysmenorrhea
activated inflammatory cascade
know ADENOMYOSIS IS ENDOMETRIAL GLANDS AND STROMA WITHIN THE ENDOMETRIUM WALL
203
leiomyoma in uterus
can arise in subserosal, submucosal, or intramural in myometrium or endometrial lining
"white, whorled" classic description
well circumscribed!!!!! (benign)
spherical, firm
single or multiple
histo:
"cigar shaped" nuclei
whorled bundles of bland smooth muscle cells
hormonally responsive
most common uterine tumor
menometrorrhagia, infertility, mass
```
tx:
surgery
embolization
GnRH agonist
nothing
```
NO MALIGNANT POTENTIAL
204
Leiomyocarcoma
arise de-novo (not from leiomyoma)
malignant SM tumor
-infiltrating, polypoid mass
-high grade
hemorrhage, necrosis
most common uterine sarcoma
-not good prognosis
behavior
rapid increase in size
metastasizes to lungs
histo:
hypercellular, mitoses, pleomorphic, enlarge nuclei
205
type 1 endometrial cancer
pre-menopausal
background hyperplasia w/ increased gland/stroma ratio
minimal invasion
ER/PR positive (estrogen and progesterone receptors)
risk factors:
unopposed estrogen!!! (PCOS, obesity, meds)
genetics
tx:
ER/PR antagonists
genetics:
PTEN, KRAS, beta-catenin, sporadic MLH1
more women w/ Lynch syndrome will present with endometrial tumors than colon tumors
```
inherited risk factors:
HNPCC: mutated mismatch repair genes- micro satellite instability
-MLH1, MSH2, PMS2, MSH6
Men present w/ colon cancer
F present w/ endometrial cancer
```
206
endometrial hyperplasia
physiologic response to unopposed estrogen --> polyclonal
EIN--> clonal proliferation (PTEN mutation)
AUB or asymptomatic
tx:
hormonal
curettage
surgery
207
endometrial hyperplasia
```
simple hyperplasia:
moderate hyperplasia
thickened "fluffy" endometrium
increased gland/stroma ratio
rarely progresses to cancer
tx: progestins
```
complex hyperplasia:
increased risk for progression to carcinoma
w/ or w/o cytologic atypica
glandular crowding and architectural complexity
diffuse involvement of endometrial cavity
208
endometrial carcinoma
usually PMB, but many asymptomatic
peak in 5-6th decades
85% endometriod
-resembles endometrial glands
209
endometrial adenocarcinoma
grade 1 = <5% solid growth
exophytic (protruding) mass of tightly packed glands without intervening stroma
squamous metaplasia
grade 2-3
less well differentiated
less able to resemble its normal histo
210
prognosis of endometrial cancers
depends on STAGE- extent of spread
stage 1- 96% 5yr survive
stage 3- 23% 5yr survival
```
tx:
surgery
radiation
-vaginal brachy
-whole pelvis
chemo
```
211
type 2 endometrial cancer
post-menopausal
aggressive
P53 MUTATION RELATED
10-20% endometrial cancers
serous carcinoma- type 2 cancer; hallmark cancer
papillary growth, atypia
disseminated at presentation
histo:
elongated papillae w/ fibrovascular stromal cores
intravascular tumor
malignant mixed mullerian tumor (carcinosarcoma)
biphasic tumor- epithelial (carcinoma) and mesenchymal (sarcoma) components
neoplasm in lung
homologous (sarcoma/mesenchymal) = cell types normally found in uterus (SM, fibroblasts)
heterologous = cell types NOT normally found in uterus (cartilage, fat, bone, Skeletal muscle)
212
take home vulvar messages
Vulvar itching
-common complaint
skin biopsy is maybe helpful, but tx may be empirical w/ steroids
most dysplasia in urogenital tract is HPV-related
-can progress to cancer
most important lesions to remember in a pt w/ abnl bleeding:
polyps
adenomyosis
leiomyomas
hyperplasia
carcinoma
--most cases of abnl bleeding are not due to lesions- HPO axis miscommunication
GRADE- degree of differentiation
STAGE- spread
Type 1 endometrial cancers-
younger women
estrogen-dependent
generally good prognosis
Type 2 endometrial cancers-
older women
higher grade histology
poorer prognosis
213
pregnancy numbers in US
6.3 million pregnancies/yr
51% intended
49% unintended
- --22% birth
- --20% abortion
- --7% fetal loss
214
overview of conception
sperm production
male production- spermatogenesis
sperm transport
entry into cervix
thin cervical mucus during ovulation
patent fallopian tube
ovulation
female production- oogenesis
zygote transport and implantation
patent fallopian tube
receptive (thick) endometrial lining
215
ovulation overview
follicular phase
estrogen dominates
follicle grows
uterine lining grows (proliferative phase)
```
luteal phase-
progesterone dominates
always constant- always 2 weeks long
corpus luteum
uterine lining matures (Secretory phase) in order to allow for implantation
beginning of ovulation
basal body temp increases by a degree
```
216
how to prevent conception
stop testosterone production in M
- male hormonal contraception (not available yet)
- vasectomy
- --is not immediately effective- need so many ejaculations before it works; need semen analyses at urologist
stop entry of sperm into/past cervix
male condom
Female barrier methods
- -female condom
- -diaphragm
- -cervical cap
- -sponge
- -spermicide needed w/ the insertion methods
- -copper intrauterine device
```
thicken cervical mucus (to block sperm)
-hormonal methods, specifically progestin
pills
depot medroxyprogesterone acetate
implant
progestin IUD
```
ligate/occlude/remove fallopian tubes- female sterilization
ligate (tubal ligation)
occlusion
removal- salpingectomy
```
prevent ovulation- trick the body w/ feedback mech's
suppress secretion of FSH and LH
--Progestin alone
progestin only pills
depot medroxyprogesterone acetate
implant
progestin IUD
--Estrogen and Progestin
oral contraceptive pills
transdermal patch
transvaginal ring
```
```
avoid intercourse when ovulating
-billings ovulation method- recognize signs of fertility
-symptothermal method- basal body temp rise after ovulation
-LH predictor kits
----concerns
sperm can last 3-6 days
variable cycles
often retrospective
```
avoid implantation w/ thin endometrium
progestin- thins endometrium
estrogen- stabilizes endometrium = less bleeding
217
progestin effects as a contraceptive
inhibits ovulation by suppressing function of HPO axis
modifies mid-cycle surges of LH and FSH
diminishes ovarian hormone production
reduces activity of cilia
produces endometrial changes unfavorable to embryo implantation
thickens cervical mucus to impede sperm transit
218
effects of estrogen as a contraceptive
contraceptive benefit:
helps stabilize uterine lining- less breakthrough bleeding
added suppression of FSH- less follicle development
non contraceptive benefit:
increases SHBG--> less male effects (acne, PCOS)
reduces ovarian cancer, endometrial, colon cancer risks
physiologic risks of estrogen:
estrogen increases clotting factors 2,7,10,12, factor 8, and fibrinogen
shifts towards thrombus formation and prevention of clot dissolution
leads to greater risk of venous (and arterial) clot formation
higher estrogen--> more production of clotting factors
219
who should avoid contraception with estrogen (combined hormonal)?
smoker over 35
CAD or heart disease
H/O or risk of clots (DVT, pulm embolism)
uncontrolled HTN
diabetes w/ vascular changes
migraines w/ aura
active liver/gallbladder problems
breast cancer (estrogen dependent cancers)
major surgery w/ prolonged immobilization
220
failure rates w/ contraceptives
lower failure rate ---- less user dependent
higher failure rate --- more user dependent
IUD > OCP > condom > fertility awareness
221
progestin-only methods of contraception
Pills
all are active pills-
take every day to thicken cervical mucus
does an ok job at inhibiting ovulation, but some still get periods
plasma Norethindrone drops quickly, but thickening of cervical mucus lasts about 27 ours
miss pill >3 hours puts woman at risk
most commonly used postpartum period (estrogen will increase the clot risk!)
```
Depo Provera injection
-huge dose every 3 months
inhibits ovulation (amenorrhea)
```
progestin-only implant:
inhibits ovulation
thickens cervical mucus
222
Levonorgestrel IUD
mainly works to thicken cervical mucus
kind of inhibits ovulation
223
combined hormonal contraception
pill, patch, ring
good job at inhibiting ovulation
thickens mucus some too
varying times of effectiveness
224
Copper IUD
acts as a spermicide in the cervix
| creates an inflammatory rxn
225
emergency contraception
prevents pregnancy after sex
MOA is same as other methods, but higher
not the same as abortion pill
Ypzpe method (combined OCPs)- sick
Plan B- levonorgesterol
Copper IUD
Ella- ulipristal acetate = progesterone receptor modulator
226
1. Name the two major epithelial cell types of the cervix and identify them on a cervical cytology specimen interpreted as normal.
squamous epi
columnar epi
227
2. Name the types of human papilloma virus associated with cervical warts, cervical dysplasia, and cervical carcinoma.
cervical warts: HPV 6, 11
cervical dysplasia: HPV 6, 11
cervical carcinoma: 16 (squamous dominant), 18 (adeno dominant), 31, 33, etc.
majority of infections will clear
228
3. Diagram the changes in the squamous epithelial layer accompanying progressive levels of cervical dysplasia and carcinoma.
key to progression- infection of basal layer and host DNA
229
4. Identify the most common histologic types of invasive cervical carcinoma and recognize the cytologic and histologic features of these lesions and their associated premalignant lesions (CIN 1-3 and AIS).
squamous cancer is most common cancer of epithelial origin
| adenocarcinomas- tend to be younger pts, more aggressive
230
8. Describe 2012-13 recommendations for cervical cancer screening and summarize recent trends in the changes made to such national recommendations in recent years.
<21 no screening
21-29 cytology (pap test) every 3 yrs
30-65 HPV and cytology every 5 yrs or cytology every 3 yrs
>65 no screening necessary after adequate neg prior screening
total hysterectomy: no screening is necessary
vaccinated against HPV: follow age recommendations above
hrHPV testing for primary screening is not adequate enough yet to replace co-testing with cytology-based screening
a negative hrHPV test provides greater reassurance of low CIN3+ risk than a negative cytology result
231
which viruses lead to CIN3
16 and 18 are predominant viruses that lead to CIN3
232
squamous and glandular cell abnormalities
```
squamous cell abnormalities:
atypical squamous cells ASC
suspicious for:
low grade squamous intraepithelial lesion LSIL
high grade HSIL
```
glandular cell abnormalities
atypical glandular cells of undetermined significance AGUS
adenocarcinoma in situ AIS
233
cytology vs histology
detect via colposcopy or pap
if you get dysplasia:
tx w/ CKC or LEEP to try to remove dysplastic cells
cytology SIL and histology CIN
LSIL = CIN1 - mild dysplasia
HSIL = CIN2- moderate dysplasia; cells are more pleomorphic and atypical
HSIL = CIN3- full thickness; severe dysplasia; carcinoma in situ
invasive SCC- invasive through the basement
234
cytology vs histology
detect via colposcopy or pap
if you get dysplasia:
tx w/ CKC or LEEP to try to remove dysplastic cells
cytology SIL and histology CIN
LSIL = CIN1 - mild dysplasia
HSIL = CIN2- moderate dysplasia; cells are more pleomorphic and atypical
HSIL = CIN3- full thickness; severe dysplasia; carcinoma in situ
invasive SCC- invasive through the basement
235
cytology vs histology
detect via colposcopy or pap
if you get dysplasia:
tx w/ CKC or LEEP to try to remove dysplastic cells
cytology SIL and histology CIN
LSIL = CIN1 - mild dysplasia
HSIL = CIN2- moderate dysplasia; cells are more pleomorphic and atypical
HSIL = CIN3- full thickness; severe dysplasia; carcinoma in situ
invasive SCC- invasive through the basement
236
cervical carcinoma staging
stage based CLINICAL evaluation!!!
```
acceptable staging tools:
clinical exam/colpo/biopsies- can be done anywhere; majority
CXR
IVP
cystoscopy
sigmoidoscopy
barium enema
```
cannot use: CT, PET, MRI
237
vaccination for primary cervical cancer prevention
Guardasil: quadrivalent
6,11,16,18
cervarix-
16,18
guardasil 9:
6,11,16,18,31,33,45,52,58
6 and 11 are warts
efficacy when given before infection at a young age nears 100%
chance that we'll need boosters in the future
238
medical model of sexual dysfunction
sex is a physiologic process
sexual dysfunctions result from alterations in physiology
alterations come from "blocks" or interruptions in sexual response cycle
emotional responses may alter or stop response cycle
239
sex concepts
sex is a natural function
- like other physiologic processes, cannot teach or learn sexual physiology
- not under voluntary control
- can identify "blocks" and remove them
most of sexual behavior is learned
behaviors are under voluntary control and can be modified
sex therapy is a learning process and a behavioral modification
240
sexual response cycle
```
Masters 4 phases:
excitement
plateau
orgasm
resolution
```
others say "bi-phasic"
desire phase-
innate and global
no measurable physiologic changes
desire for intercourse- innate, similar to other desires
can be augmented or inhibited by learned responses and experiences
desire for sex is DIFFERENT than attraction
at least partially under hormonal influence (estrogen testosterone)
disorders of desire phase are almost always due to performance anxiety or aversion
```
arousal/excitement phase
physiologic changes- tachycardia and tachypnea
shifts blood to pelvis and genitalia
-erection in men
-clitoral engorgement, vaginal expansion and lubrication, uterine elevation in women
shifts blood flow to skin
--"flush", feeling warm, sweating
nipple erection
```
plateau
-heightened state of arousal
physiologic changes are stable
orgasm-
series of rhythmic contractions of perineal muscles occurring every 0.8 seconds
M- accompanied by 3 to 7 ejaculatory spurts of seminal fluid
F- accompanied by elevation of "orgasmic platform"- posterior vaginal wall- elevator and and pubococcygeus
both- involuntary contractions of skeletal muscles and EEG changes
resolution
M- obligatory resolution phase in which physiologic changes return to baseline and further stimulation cannot produce excitement
-varies w/ age
F- resolution not always obligatory; may return to plateau and repeat orgasm w/o resolution
241
attraction
everyone has an "attraction template"
template appears to be modifiable over time and experience, but some elements may be constant
modifiable- age, body habitus, personality/maturity
constant elements- gender, "type"
242
erection
caused by increased penile blood flow from relaxation of penile arteries and corpus carveronsal SM
mediated by release of NO from nerve terminals and endothelial cells
stimulates the synthesis of cyclic GMP in SM cells
cyclic GMP causes SM relaxation and increased blood flow into the corpus cavernosum
243
innate desire
common early in relationships
sometimes cyclical in younger F
typically missed w/ medical disruptions of sexual physiology
may endure for decades in the same relationship
244
3 ROS questions
are you in a sexual relationship?
How often do you have intercourse?
F-
Do you have pain w/ intercourse?
How often do you have orgasm w/ intercourse?
M-
Do you have problems getting or keeping an erection?
Do you ejaculate before you want?
245
desire phase disorders
low libido-
---Hypoactive Sexual Desire Disorder
usually assoc w/ chronic disease, depression, hypoestrogenic states (hypogonadism, high prolactin)
inhibited sexual desire-
---Sexual Aversion Disorder
result of pain or other dysfunction
sexual aversion and HSDD are a continuum
246
arousal/excitement phase disorders
```
male erectile disorder
female sexual arousal disorder
premature ejaculation
dyspareunia
vaginismus
```
247
erectile disorder
most of the time:
-marked difficulty in obtaining an erection, or maintaining one until completion of sex, or marked decrease of erectile rigidity
symptoms persist for at least 6 months
symptoms cause clinically significant distress
sexual dysfunction not better explained by something else
248
delayed ejaculation
most of the time:
marked delay in ejaculation, or marked infrequency or absence of ejaculation
symptoms at least 6 months
significant distress in the individual
dysfunction not explained by nonsexual mental disorders/ other stressors
249
Vaginismus
involuntary spasm of muscles around the outer third of the vagina
may make penetration impossible
causes:
pain
religious orthodoxy
severe negative parental attitudes
pts may be hyper-feminine
often bizarre images of genitals
usually have a partner who supports dysfunction
primary- occurs w/ 1st attempt at intercourse
secondary- occurs after some event
250
dyspareunia
pain w/ intercourse
sites of pain:
introital
vaginal
deep
may be reproduced on exam
251
premature ejaculation
failure of excitement-
persistent ejaculation w/ minimal sexual stimulation before, on, or shortly after penetration and before person wishes it
pt's internal there is they get too excited too fast
often develop mechanisms to prevent excitement
252
plateau phase disorders
female orgasmic disorder
delayed ejaculation/ male orgasmic disorder
253
changes from DSM 4 to DSM 5
There are now only three female dysfunctions and four male dysfunctions, as opposed to five and six in DSM 4
Female hypoactive desire disorder and Female arousal disorder Merged into Female sexual interest/arousal disorder
Genito-pelvic pain/penetration disorder combines vaginismus and dyspareunia
Sexual aversion disorder was deleted
Sexual dysfunctions (except substance-/medication-induced sexual dysfunction) now require a duration of approximately 6 months and more exact severity criteria
Gender Dysphoria (DSM5) is similar to (but not identical to) gender identity disorder (DSM4)
Male hypoactive sexual desire disorder now has a separate entry
Male orgasmic disorder was changed to delayed ejaculation
254
DSM 5 criteria
specify whether:
lifelong or acquired
generalized or situational
mild, moderate, or severe
255
Male Hypoactive Sexual Desire Disorder
deficient sexual/erotic thoughts or fantasies and desire for sexual activity
6 months
causes significant distress
not better explained by something else
256
Premature (Early) Ejaculation
pattern of ejaculation within 1 minute of penetration and before pt wishes
6 months
causes significant distress
not better explained by something else
257
Female Orgasmic Disorder
presence of either symptom in almost all occasions of sexual activity:
- marked delay in, marked infrequency of, or absence of orgasm
- reduced intensity of orgasmic sensations
6 months
causes significant distress
not better explained by something else
258
Female Sexual Interest/Arousal Disorder
lack of, or significantly reduced, sexual interest/arousal, as manifested by at least 3:
little interest in sex
few thoughts related to sex
decreased start and increased rejecting of sex
little pleasure during sex most of the time
decreased interest in sex even when exposed to erotic stimuli
little genital sensations during sex most of the time
6 months
causes significant distress
not better explained by something else
259
Genito-pelvic Pain/penetration disorder
difficulties with at least 1:
vaginal penetration during intercourse
marked vulvovaginal or pelvic pain in anticipation or result of vaginal penetration
tensing or tightening of the pelvic floor muscles during vaginal penetration
6 months
causes significant distress
not better explained by something else
260
female orgasmic disorder
Male orgasmic disorder
delay in, or absence of orgasm following normal sexual excitement phase
women exhibit wide variability in the type or intensity of stimulation that triggers orgasm
causes distress
not better explained by something else
261
sex therapy options
sensate focus exercises
bibliotherapy
marital therapy
pharmacotherapy
262
sensate focus exercises
```
series of defined behaviors/exercises
focus on sensations and emotions
"I" language
recognize that the same stimulus does not always give the same response
recognize your response
"spectating"
"what's wrong with me?"
"Sex is work!"
"act for your own enjoyment"
```
typically 12-16 visits
involves behavioral modification
involves marital therapy
must be trained in technique
263
bibliotherapy exercises
assign reading to pt for sex therapy
most successful in (female) orgasmic dysfunction
264
pharmacotherapy effects on sex
primary tx of dysfunctions
management of medication side effects
side effects of commonly used meds:
contraceptives (depo-provera hypoestrogenic)
anti-hypertensives
anti-epileptics
psycho-active drugs
illicit/recreational drugs (alcohol, marijuana opioid)
---difficult to determine sexual effects of common drugs- definitions, ambiguity, sexual effects not tested for in randomized trials---
265
drug therapy of sexual dysfunction
```
PDE5 inhibitors
estrogen
Flibanserin
Testosterone
Antidepressants
Other drugs
```
266
PDE5 inhibitors
Male-
highly effective for erectile dysfunction
PDE5 is an enzyme that accepts cGMP and breaks it down; NO causes release of cGMP which relaxes muscles; inhibiting PDE5 leads to relaxation and filling of penis/blood
-originally developed as anti-angina drug
```
side effects:
HA
dizziness, flushing, dyspepsia, nasal congestion
sudden hearing loss
anterior optic neuropathy
```
Sildenafil and Vardenafil- half life approx 4 hr
Tadalafil has half life of 17.5 hrs
Female-
healthy- variable correlation between objective increase in congestion and subjective sexual arousal
arousal disorder- disconnect between objective measures and subjective measures of arousal
conditioned neg response
drug therapy doesn't work well
267
estrogen therapy
high correlation between serum estradiol levels and sexual function in women
also helps w/ vaginal dryness and dyspareunia and other sexual problems
268
Flibanserin
post-synaptic 5HT1A receptor agonist and 5HT2A receptor antagonist
lowers 5-HT and raises dopamine and Noradrenaline in prefrontal cortex
"little pink pill"
originally created as anti-depressant, decreasing serotonin and increasing dopamine effects, but ineffective
approved for sexual dysfunction, but minimal effect on HSDD
must be taken every day
-approx $10k per year
```
significant side effects:
hypotension!, potentiated by alcohol
Nervous system- dizziness, somnolence, sedation, fatigue, vertigo
Nausea
accidental injury
```
269
anti-depressant therapy
bupropion has been reported to improve hypoactive sexual desire assoc w/ SSRI use
may have beneficial effect on desire and orgasm in some women but it's not clear which women, and if the effect is independent of the antidepressant effect
270
apomorphine and Yohimbine therapy
some evidence of some minimal increased excitement
don't really work
271
role of testosterone in female inhibited sexual desire
effective in tx hypoactive sexual disorder, but effect is small
not FDA approved for this
no role for measuring serum androgens in women with HSDD or other dysfunctions
do not give them
272
treat vaginismus
dilators:
purpose is NOT to dilate vagina
learn to have something in the vagina
learn to confront fears and feelings around penetration
MUST involve partner
273
orgasmic dysfunction
etiologies:
boredom
performance anxiety
fear of loss of control
address stimulation
address performance anxiety
address spectatoring
274
PLISSIT model
Permission giving
Limited Information
Specific Suggestions
Intensive Therapy
275
Identify the four categories of primary ovarian tumors based on the cell type they originate from.
KNOW THESE
```
surface epithelial ovarian cancer
65-70% overall frequency
90% of malignancies
>20 yo
origin: fimbirated end of fallopian tube
types:
serous tumor
mutinous tumor
endometrioid tumor
clear cell tumor
Brenner tumor
Cystadenofibroma
```
Germ cell tumor
276
List the common presenting symptoms for epithelial ovarian tumors.
bloating
pelvic/abdominal pain
early satiety
urinary symptoms
(others: fatigue, dyspareunia, constipation, metrorrhagia)
>12 times/month or persistent symptoms new to pt --> visit doctor
ovarian cancer has a much different 5yr survival rate than endometrial (45%)
```
RISK FACTORS:
infertility
unopposed estrogen >10yrs
2nd degree FHx
1st degree FHx!!!
inherited risk factors: BRCA1 and BRCA2 (DNA repair genes, syndrome incl CA of breast and ovary)--pts usually die from ovarian CA; HIGH GRADE SEROUS CARCINOMA
```
```
Protective factors:
oral contraceptives
full-term pregnancy
gynecologic surgery
breast feeding
```
277
Explain how lesions of presumed gynecologic origin spread throughout the peritoneum.
```
benign lesion:
well circumscribed
cannot metastasize but may be life threatening
tx usually surgical
80% of ovarian tumors
```
```
borderline lesions:
intermediate bio phenotype
low malignant potential
often assoc w/ long term survival
low proliferative rate- so not responsive to radiotherapy or chemotherapy
```
```
malignant lesions-
heterogenous (solid and cystic; hemorrhagic and necrosis)
may have vaginal bleeding
increased abdominal girth
high risk for dissemination
```
278
PCOS
young female w/ infertility, oligomenorrhea, obesity, and hirsutism
pathophysiology:
persistent an ovulation due to asynchronous release of FSH and LH
excess androgens w/ peripheral conversion to E2
--disrupted Hypothalamic/pituitary control
tx:
early intervention
metformin
risk:
unopposed E2 risk for endometrial carcinoma
279
Hereditary Breast and Ovarian Cancer Syndrome HBOC
increased predisposition to one or both with auto dominant transmission
(BRCA in minority of families)
- many have no identifiable pathogenic mutation
RRSO decreases risk by 80% in BRCA carriers
280
Hereditary Breast and Ovarian Cancer Syndrome HBOC
increased predisposition to one or both with auto dominant transmission
(BRCA in minority of families)
- many have no identifiable pathogenic mutation
RRSO decreases risk by 80% in BRCA carriers
281
screening for ovarian cancer
none
```
blood test: CA-125 (non specific)
pelvic exam (not sensitive)
transvaginal US (invasive, mixed sensitivity)
```
282
surface epithelial cell ovarian cancer
can be benign, borderline, or malignant
type 1 tumors: more benign, can progress
type 2: sporadic/de-novo development
283
serous neoplasms
surface epithelial tumor
(most frequent; resemble tubal epithelium, but do NOT have cilia)
classic histo feature: epithelial tufting
cyst adenoma: no cytologic atypia or mitoses
borderline tumor: asymptomatic, large cystic or solid mass w/ soft papillary projections or surface excrescences
histo hallmark: Hierarchial branching!!!! w/ complex papillae and epithelial tufting
no stromal invasion
PSammoma bodies!!! (calcifications)
carcinoma
solid, cystic, mixed
friable w/ hemorrhage and necrosis
cysts contain "straw like" proteinaceous fluid
histo: Stromal Invasion present!!!
marked cyto atypia:
pleomorphism, mitoses, glandular or solid
284
serous neoplasms of ovarian cancer
surface epithelial tumor
(most frequent; resemble tubal epithelium, but do NOT have cilia)
classic histo feature: epithelial tufting
cyst adenoma: no cytologic atypia or mitoses
borderline tumor: asymptomatic, large cystic or solid mass w/ soft papillary projections or surface excrescences
histo hallmark: Hierarchial branching!!!! w/ complex papillae and epithelial tufting
no stromal invasion
PSammoma bodies!!! (calcifications)
carcinoma
solid, cystic, mixed
friable w/ hemorrhage and necrosis
cysts contain "straw like" proteinaceous fluid
histo: Stromal Invasion present!!!
marked cyto atypia:
pleomorphism, mitoses, glandular or solid
285
Mucinous tumors
multiloculated cystic mass w/ STICKY mucoid contents
very age dependent w/ malignancy
cyst adenoma:
simple glandular epi w/ small basal nuclei and abdunant blue (mucinous) apical cytoplasm
borderline tumor:
stratified epi w/ atypia and scattered mitoses
histo: GOBLET CELLS!!! (intestinal type)
carcinoma:
RARE compared to serous carcinomas
unilateral 80% of time
2 types of invasion: destructive and expansile
destruction- infiltration of irregular glands into stroma; desmoplastic response; more likely to recur
expansile- hard to tell the border invasion
286
Mucinous tumors of ovarian cancer
multiloculated cystic mass w/ STICKY mucoid contents
very age dependent w/ malignancy
cyst adenoma:
simple glandular epi w/ small basal nuclei and abdunant blue (mucinous) apical cytoplasm
borderline tumor:
stratified epi w/ atypia and scattered mitoses
histo: GOBLET CELLS!!! (intestinal type)
carcinoma:
RARE compared to serous carcinomas
unilateral 80% of time
2 types of invasion: destructive and expansile
destruction- infiltration of irregular glands into stroma; desmoplastic response; more likely to recur
expansile- hard to tell the border invasion
287
endometrioid tumor of ovarian cancer
resembles uterine adenocarcinoma
-always exclude metastasis from uterine tumor
synchronous primary endometrial carcinoma in 15-30%
20% of all ovarian CA
40% bilateral
288
clear cell carcinoma of ovarian cancer
very rare, but may be aggressive
exclue metastases from other organs
many growth patterns
associated w/ ENDOMETRIOSIS
"Hobnail cell"!!!! - nuclei bulging into cystic space w/o apparent cytoplasm
289
histology cues for ovarian cancers
serous neoplasms
HIERARCHIE BRANCHING
PSAMMOMA BODIES
minimal cytoplasm, variably pleomorphic nuclei
Mucinous tumors
GOBLET CELLS
basal small nuclei and apical blue/pink cytoplasm
Endometrioid tumors
resemble normal endometrial glands
Clear cell lesions
HOBNAIL CELLS
assoc w/ ENDOMETRIOSIS
290
female germ cell tumors
20% of all ovarian neoplasia
95% are benign cystic mature teratomas, 5% malignant
UNLIKE MALES: Mature cystic teratoma in any age woman is BENIGN
UNLIKE MALES: Mixed relatively rare (10-15% in ovaries vs 32-60% in testes)
291
mature cystic teratoma (dermoid cyst)
commonest ovarian tumor (some w/ teeth!)
most asymptomatic
15% bilateral
can have hair
adult-type tissues representing all 3 germ layers:
ectodermal
mesodermal
endodermal
NMDAR encephalopathy
affects young women
presents w/ psychosis, memory deficits, seizures
freq assoc w/ underlying neoplasm, most often teratoma
292
immature teratoma in female
tightly packed small dark cells w/ lots of mitoses
always a neoplasm in a female
293
dysgerminoma
50% of malignant germ cell tumors
female counterpart to seminoma
bilateral in 20%
can have extra ovarian spread
excellent prognosis, even w/ widespread metastases
-highly sensitive to radiation and chemo (high mitoses)
10yr survival >90%
sheets and nests of cells w/ large central nuclei and prominent nucleoli
"squared off" nuclear contour
clear cytoplasm 2/2 glycogen
isochromosome 12p
294
yolk sac tumor in female
AKA endometrial sinus tumor
usually 10-30yo
produces alpha-fetoprotein AFP (serum tumor marker
SCHILLER-DUVAL BODY: glomeruloid structure w/ central body vessel surrounded by neoplastic cells
295
sex cord stromal tumors in female
granulosa cell tumor:
adult
-assoc w/ endometrial neoplasia (estrogenic manifestation in 2/3)
-serum inhibin to monitor recurrence (late recurrence)
----CALL EXNER BODIES resembles primitive follicle; central space w/ secretions
----prominent nuclear grooves
juvenile
thecoma-fibroma
cellular fibroma
sertoli-leydig cell:
heterogeneous elements
296
fibroma/thecoma in female
almost all benign, but 1/5 have concurrent endometrial carcinoma
hormone secreting in some- abnormal bleeding as presenting symptom
MEIG'S SYNDROME: fibroma + ascites + hydrothorax
thecoma:
post-menopausal women
plumper cells w/ more abundant clear cytoplasm
abundant reticulin fibers
297
Sertoli Leydig cell tumor in female
recapitulates developing testis
clinical outcome based on stage and grade
avg age 25 yo
298
primary vs metastatic lesions of ovary
```
primary:
unilateral
no surface growth
absence of modularity
larger >10cm
```
```
metastatic:
bilateral
surface and hilar involvement
nodular growth pattern
infiltrative growth w/ desmoplastic stroma
smaller <10cm
```
```
both:
cyst formation
necrosis
low grade areas
stromal luteinization
```
299
2 metastatic tumors we need to know for ovarian cancer
Krukenberg tumor:
metastatic gastric carcinoma (70%)
SIGNET RING CELL morphology
```
Pseudomyxoma Peritoneii
"Jelly belly"
mucin throughout abdomen
some have neoplastic epithelium
appendices origin
---anytime you suspect this, also evaluate for appendicitis
```
300
tubal intraepithelial carcinoma TIC
lesion arising from fimbriated end of fallopian tube
putative precursor to most ovarian high grade serous carcinomas!!!
P53 mutation (type 2 pathway)
```
histology-
same as high grade serous carcinoma anywhere else
nuclear enlargement
pleomorphism
>=1 mitosis
stratification
```
301
primary amenorrhea without hirsutism/acne labs
```
get a beta hCG to exclude pregnancy
prolactin
LH, FSH, and estradiol: TIMED day 1-5
thyroid func tests: TSH th abs, fT4
pituitary labs: cortisol, IFG-1
```
302
hypothalamic amenorrhea
Low LH, FSH, E!!!!!!!
messing up the GnRH pulse generator
amorrhea, esp with heavy exercise
headaches
no change in vision
congenital: GnRH deficiency
---KAL1 and many genes
Tumor: craniopharyngioma or Rathke's cleft cyst
cranial irradiation
Acquired GnRH deficiency
----ANOREXIA NERVOSA
----functional amenorrhea/Athlete's triad- excessive exercise, eating disorders, stress
303
pituitary cause of low estrogen and amenorrhea
low/normal FSH, LH, with low E
Prolactinoma!
other pituitary hormone: GH, ACTH, gonadotrope/null cell (LH, FSH)
infiltrative disease:
hemochromatosis, sarcoidosis, lymphocytic hypophysitis, anti-T cell targeted therapies
304
treatment of hypothalamic and pituitary defects
GnRH pulse generator defect:
treat w/ physiologic hormones or OCPs
Prolactin elevation:
if tumor, give Dopamine agonist (Bromocryptine or cabergoline)
--if meds can change or give OCPs
pregnancy desired:
fertility drugs: clomiphene, gonadtropins, pulsatile GnRH
305
ovarian causes of low estrogen and high FSH and LH
ovarian: high FSH, LH, and low E
congenital: gonadal dysgenesis (Turner's syndrome X0)
screen for other congenital defects:
cardiac- coarctation, renal duplication
Risks: HTN, metabolic
lifestyle intervention
new guidelines are hormone therapy
306
premature ovarian insufficiency
avg age of menopause is 51 in US
premature menopause- cessation of menses before 40
-surgical, autoimmune, genetic
autoimmune third disease (Hashimoto's or Graves)
pernicious anemia (B12 deficiency)
Addison's: adrenal insufficiency
other: celiac sprue, RA, lupus, myasthenia gravis
other genetic: Fragile X w/ FHx
```
tx:
OCPs
cyclic E and Progestin
glucocorticoids?
FSH/LH, and hCG
donor eggs w/ in-vitro fertilization
```
307
hyperandrogenic anovulation
irregular menses w/ hirsutism and acne
```
Congenital adrenal hyperplasia
ovarian or adrenal tumor
PCOS
obesity-induced hyperandrogenic an ovulation
other: prolactinoma, Cushing's
```
LABS:
LSH/FSH ratio TIMED in first 5 days post-menses
T
DHEAS (adrenal androgen marker)
Prolactin
urniary free cortisol and Cr or Dex suppression test
17-OH-progesterone 30 min after ACTH stim
beta hCG to exclude pregnancy
308
nonclassical congenital adrenal hyperplasia : NCCAH
uncommon
Hx of early pubarche, hirsutism, irregular menses
FHx and ethnic predisposition
basal >200 or stimulated >1000 17-OH-progestin
309
Hyperandrogenic anovulation tumors
rare
RAPID onset of symptoms and signs in a F w/ previously normal menses
Location of hirsutism: upper back and chet and abdomen
Virilization: temporal recession, anabolic phenotype, loss of breast tissue, clitoromegaly
ovarian tumors:
testosterone in M range (very high at >200)
adrenal tumors
DHEAS very high at >8-900
310
PCOS
genetic predisposition to excess ovarian androgen secretion
high testosterone levels
high LH levels (3:1 LH:FSH)
insulin resistance and hyperinsulinaemia
hirsutism
anovulation
```
risks:
infertility
obesity: 60%
metabolic syndrome (insulin resistance, central obesity, abnl lipids w/ low HDL and high triglycerides, glucose intolerance)
obstructive sleep apnea
nonalcoholic liver disease NASH
cardiovascular?
```
tx:
when no pregnancy is desired:
regularize menses- OCPs w/ constant, nonadrogenic progestin, or cycli progesterone
--tx hirsutism:
antiandrogen, spironolactone, electrolysis
--insulin sensitizer: metformin
when pregnancy is desired:
clomiphene citrate (SERM) alone or w/ insulin sensitizer
Letrozole (aromatase inhibitor) more effective than clomiphene but initial reports of congenital defects?
Stop spironolactone 3mo before attempting conception (anti-androgen effects on fetus)
311
obesity induced hyperandrogenism
common
history of nl menarche, regular menses
progressive weight gain w/o problems
then surpass "threshold weight" with onset of irregular menses, hirsutism, and acne
cysts on ovaries due to anovulation
successful weight loss reverse phenotype
312
estrogen pharm agonists and antagonists
MOA:
majority of agonist actions are mediated via binding to estrogen receptors ERalpha or ERbeta
demerization
recruit co-activators, and initiate transcription
Antagonists of ERs:
dimerization, but different conformational change
recruit co-repressors and reduces transcription
concept of ligand-mediate changes in ER conformation is central to action of agonists, antagonists, and SERMs
313
physiologic effects of estrogen
breast growth (cancer post-puberty)
endometrium growth (cancer post-puberty)
bone (decrease osteoclasts)- closes epiphyses of long bones
promote urogenital function
promote vasomotor function
decrease LDL and increase LDL (cardioprotective)
increase synthesis of binding globulins- SHBG (increased total levels of hormones, but decreases free T)
alter bile composition- increased cholesterol saturation (increased gallstone incidence, but decreases colon cancer??)
increase clotting factors** (VTE risk)
decrease LH/FSH (hypothalamus/pituitary)
continuous estrogen en exposure leads to endometrial hyperplasia usually assoc w/ irregular bleeding
increased hepatic effects when estrogens are given orally- 1st pass + enterohepatic recirculation
314
clinical uses of estrogen pharm
menopausal hormonal therapy MHT- symptomatic
estrogen is most effective if symptoms are moderate to severe
use lowest effect dose and for shortest duration
-risk of endometrial cancer is reduced if given w/ progestin
vasomotor symptoms: thermoregularity instability (hot flashes and night sweats)
-systemic tx needed
vulvovaginal and urogenital complaints:
vaginal dryness/pruritis, postcoital bleeding
-vaginal products preferred
315
non-hormonal treatments of Menopausal hormonal therapy MHT pharm
varying efficacies
clonidine, antidepressants (SSRIs, SNRIs), gabapentin
OTC treatments incl Vit E, phytoestrogens (in soy) and black cohosh
non-estrogen treatments are marginally better than placebo
316
prophylaxis of MHT pharm
prevention of osteoporosis:
only consider if pt is at sig risk of osteoporosis: thin, white, inactive, low Ca intake, FHx
risks: increased invasive breast cancer risk, MIs, VTE
role of SERMs in osteoporosis:
Raloxifene
retain agonist actiivty on bone receptors and liver receptors
lack activity in uterine and breast tissue
---retain increased risk of thromboembolic disorders via increase in hepatic synthesis of clotting proteins
prevention of CVD:
no longer approved for heart disease prevention
(increased risk of MI and stroke)
317
physiologic replacement to prevent hypoestrogenic menopausal symptoms pharm
ethinyl estradiol (equivalent to estradiol or conjugated estrogens
pharmacologic suppression of ovulation:
ethinyl estradiol in oral contraceptives
318
contraindications to use estrogen in MHT pharm
adverse rxns
Hx of breast or endometrial cancer
vaginal bleeding
acute liver disease
active thrombosis
```
adverse rxns:
postmenopausal bleeding
nausea, breast tenderness
anorexia, vomiting, diarrhea
HTN, reversible
increased migraine HA frequency
gallstones
```
319
synthetic progestins pharm
medroxyprogesterone and megestrol
-megestrol has less effect on pituitary gonadotropin release- mainly peripheral actions (enodmetiral tissue)
OCP progestins incl 19-nortestosterone analogs -> androgenic and anabolic effects
Norethindrone (1st gen)- in "minimill"
Levonorgestrel (2nd gen)- decreased VTE risk
but increased androgenic actions
Desogestrel, norethynodrel, norgestimate (3rd gen)- lower androgenic activity-
slightly higher VTE risk
Drospirenone (4th gen)- antimineralocorticoid and antiandrogenic activity;
increased VTE risk
used as contraception
and menopausal hormonal therapy WITH estrogen
produces anovulation/amenorrhea in:
dysmenorrhea, endometriosis, bleeding disorders, hirsutism---- dosage-timing is critical in these indications
obstructive sleep apnea
anorexia/; weight loss of AIDS
```
adverse rxns:
CNS: depression, somnolence, HA
breast enlargement, tenderness
Nausea
elevated BP, edema, weight gain
```
320
hormonal contraception pharm
combined OC formulations:
estrogen + progestin
ethinyl estradiol
monophonic: single dose of progestin
multiphase: varying dose of 1 or both hormones during cycle
many have lower total hormone dose per cycle
note: no evidence for advantage monophonic pills- choice of progestin probably more important
severe effects--> discontinue use
thromboembolic disorders- estrogen implicated
increases coagulation pathways and fibrinolytic activity
overall minimal effect on healthy non-smokers (MI or cerebrovascular disease minimal)
increase in risk in COC users is LOWER than risk of VTE associated w/ pregnancy
increased (but still small) risk of breast cancer
cervical cancer ONLY in long term users w/ persistent HPV
reduced risk of endometrial and cervical cancer, possibly colorectal cancer
GI disorders
Depression
drug interactions:
drugs that induce or enhance estrogen metabolism leading to a reduction in contraceptive effect
--Rifampin (CYP450 inducer!!!), anticonvulsants (phenytoin, carbamazepine, phenobarbital), griseofulvin
--now thought that oral antibiotics do NOT decrease effectiveness of OCPs
321
spermatogenesis process
process by which a spermatogonial stem cell gives rise to a spermatozoon
- starting point: spermatogonia
- end point: spermatozoa
1. proliferative phase
- spermatogonia proliferate and give rise to spermatocyte
- maintain their number by self-renewal
- 2 types of spermatogonia: Type A (A dark and A pale) and Type B
- Type A divide by mitosis-->Type B; or Type A--> Type A by self-renewal (chromosome number does NOT change; diploid; 46C)
- Type B --> primary spermatocyte
- -> meiotic phase
2. Meiotic phase
- spermatocyte undergoes 2 rounds of meiosis (reduces chromosome number by half)
- 1st round: primary spermatocyte (double the DNA, but same # chromosomes; genetic exchange between non-sister chromatids) --> 2 secondary spermatocytes (homologous chromosomes are separated; 1/2 chromosome #; haploid; the "XX" have separated into different cells w/ just "X")
- 2nd round: each secondary spermatocyte --> 2 spermatids (sister chromatids are separated; the individual "X" separates into "> +
322
spermiogenesis process
complex maturational process by which a haploid spermatid differentiates into a mature spermatid, or spermatozoa
-no change in terms of chromosome number or DNA amount
4 rough phases:
- Golgi phase (elaborates acrosomal vesicle to one end of nucleus; centrioles move opposite)
- Cap phase (acrosomal vesicle eventually becomes cap)
- Acrosomal phase (cytoplasm pulled away from nucleus; mito sequestered at base of tail)
- Maturation phase (excess cytoplasm cast off from cell)
spermiation: final stage of spermiogenesis
- mature spermatozoa are released and deposited to lumen by sertoli cells
Epididymis:
- post-testicular sperm maturation location
- spermatozoa develop their motility, capability to fertilize, and final maturational process (called capacitation)
- head (caput epididymis): concentration
- body (corpus epididymis): maturation
- tail (cauda epididymis): storage
entire cycle takes ~64 days
323
Leydig and Sertoli cell function
Leydig cells:
- found between seminiferous tubules
- produce T
- receives LH signal from pituitary
Sertoli cells:
- provide unique supporting matrix for spermatogenesis
- provide movement and release of germ cells
- tight junctions form blood-testis barrier (prevents proteins/toxins from accessing gametes)
- secretory function (tubule fluid; ABP; Inhibin)
324
hormonal control of spermatogenesis
Leydig cells:
- receive LH signal from pituitary to produce T
- T has neg feedback to control release of LH
Sertoli cells:
- receive FSH signal from pituitary
- produce ABP, which has high affinity for T (ensure high conc of T in seminiferous tubules)
- produce Inhibin, which has neg feedback on pituitary control/release of FSH
high conc of T is critical for spermatogenesis
325
anatomy and physiology of M reproductive axis
T levels are dependent on sex hormone bonding globulin SHBG levels
- higher SHBG makes T look high
- lower SHBG makes T look low
326
general approach to disorders of H-P-G axis for M
Hypogonadism:
-failure of testes to produce T (androgen deficiency) and normal # spermatozoa due to disruption of 1 or more levels of H-P-G axis
clinical manifestations:
- Physical (low BMD, muscle mass/strength, gynecomastia, anemia, frailty, body fat/BMI, fatigue)
- psychological (depressed mood, low E, sense of vitality, or well-begin; impaired cognition)
- Sexual (low libido, ED, difficult orgasm, decreased performance)
Hypogonadism can be:
-mechanical or hormonal AND congenital or acquired
Most common cause of T being just slightly low: obstructive sleep apnea
- ED: decreased NO in carvernosal muscle, decrease in cGMP
- slight impairment of GnRH pulse generator (often T isn't actually low)
- Tx: CPAP, lifestyle (T meds worsen untreated OSA)
Men's T level decreases as they age- "andropause" (late-onset hypogonadism)
- some can have low T w/o symptoms
- some can have nl T w/ symptoms
- weight loss/diet/lifestyle changes increase T and SHBG levels
Real hypogonadism:
-symptoms and low T w/ a cause
327
hypo- vs hyper- gonadotropic hypogonadism in M
HYPOGONADOTROPIC HYPOGONADISM:
- AKA pituitary hypogonadism
- low LH and FSH
- low T
HYPERGONADOTROPIC HYPOGONADISM:
- AKA primary hypogonadism
- high FSH (loss of inhibin; FSH goes up before LH)
- high GnRH
- low T
328
etiologies of M hypo-gonadotropic hypogonadism
AKA pituitary hypogonadism
- low LH and FSH
- low T
- Prolactinoma or meds increasing PRL
- Tumors/mass effects (craniopharyngioma, Rathke's cleft cyst; pituitary tumor (GH, ACTH, some gonadtrope); metastasis)
- infiltrative disorders (hemochromatosis- Fe deposition in gonads; liver dz; bronze skin)
- inflammatory (lymphocytic hypophysitis)
329
etiologies of M hyper-gonadotropic hypogonadism
AKA primary hypogonadism
- high FSH (loss of inhibin; FSH goes up before LH)
- high GnRH
- low T
Congenital:
Klinefelter Syndrome
- XXY
- delayed puberty, eunuchoid body habitus, gynecomastia
- low inhibin levels
- progressive tubular fibrosis, azoospermia
- eventual need for T replacement
- need for mammograms
- risk of DVT/PE?
- new options for fertility w/ hCG and sperm harvest
also undescended testes or orchiectomy
Acquired:
- injury
- mumps orchitis
- alcohol: direct testicular toxin
- diabetes
- radiation/chemotherapy
- autoimmune testicular failure (check for other autoimmune diseases)
- pituitary tumor (high FSH/LH; low T)
330
treatment of M hypo-gonadism
hypogonadism due to aging:
-tx: lifestyle/diet/weight loss increases T and SHBG levels
T therapy:
- assoc w/ CVD events in elderly men
- low T or high T assoc w/ death
- stimulation of prostate growth (monitor PSA levels)
- risk of bladder outlet symptoms (from prostate vol)
- edema in pts w/ preexisting cardiac, renal, or hepatic dysfunc
- gynecomastia
- erythrocytosis; polycythemia
- ppt of sleep apnea
- increased CVD events?
T therapy regimens:
- Injections (Depotestosterone) IM q 2-3 weeks
- T gel daily
- T patch daily
- Injection (Testosterone undecanoate) ABUSE IM q 3mo (NOT recommended)
- Testosterone pellets (Testopel) (NOT recommended)
- Aromatase inhibitors to block gynecomastia
331
pathophysiology of gynecomastia
sometimes develops in pts on T therapy
- often persists
- some pts take aromatase inhibitors to block gynecomastia from high T levels
332
basic anatomy and histology of testis
tunica vaginalis:
- pancake over testes
- injury can cause it to fill w/ fluid and cause testes to grow
seminiferous tubules:
- epithelium called Sertoli cells
- germ cells (most primitive on outside)
Interstitial/Leydig cells w/ granules
-T production
development of testes:
- occurs in abdominal cavity
- courses through inguinal canal to scrotum
- can be held up at various points along the pathway
- Gubernaculum that dominates is the one that goes through inguinal canal and descend into scrotum
- -if another dominates, then you could cross midline or end up in thigh (trauma risk and too hot temp)
333
causes of testicular atrophy and male infertility
Problems with Testes:
- most do not causes issues w/ fertility or longevity of life
- maldescent (causes problems)
- absence
- fusion
- cysts
causes of testicular atrophy:
- cryptorchidism
- atherosclerosis (seminiferous tubules are blind-end; if you get atherosclerosis they'll die)
- inflammation
- malnutrition
- hypopituitarism (not making hormones and not driving androgen production)
- hormone therapy (prostate cancer)
- Klinefelter's syndrome
Cryptorchidism (maldescended testes)
- 75% unilateral
- contralateral testis may also regress; both testes are at risk (crosstalk)
- most are idiopathic; but 5x increased risk of malignancy
- atrophy evident as early as 2 yo
- best tx: surgery to lower testis into scrotum long before puberty
Klinkefelter syndrome
- sclerosing tubular degeneration
- no elastic fibers (no help propelling down a tube)
- leydig cell hyperplasia (profound)
- elevated FSH/LH
- decreased T
- no germ cells in tubules
334
Inflammatory diseases of testes (organisms and morphology)
Varicocele:
- deficient/abnormal dilation and tortuosity of veins in pampiniform plexus
- venous valve insufficiency
- left side alone 90%; bilateral 10%
- assoc w/ infertility (possible epiphenomenon; thermal effect; maturation arrest; hypo spermatogenesis; abnl sperm morphology)
Torsion:
- twisting spermatic cord
- compromising vascular/venous flow
- not pumping blood out (painful)
- eventually causes hemorrhagic necrosis of testes
Nonspecific epididymitis and orchitis
- most common form of inflammatory processes that affects testis
- direct extension from urinary tract
- children: assoc w/ UT malformation (GN rods)
- sexually active adults: (C trachomatis, N gonorrhoeae)
- Elderly (enterobacteria)
Mumps orchitis
- pubertal or adult M
- 1 week after parotid involvement
- 70% unilateral
- infertility is uncommon
Tuberculus orchitis
- affects epididymis, then testes
- usually part of systemic disease
- caseating granulomas
syphilis
- affects testis first, then epididymis
- congenital or acquired
- plasma cells, lymphocytes
- obliterative endarteritis
- Gummas
granulomatous (autoimmune) orchitis
335
```
testicular tumors:
epidemiology, markers
classification (germ cell tumors and sex-cord-stromal tumors)
major morphologic findings
staging
treatment
```
Germ cell tumors (95%)
- painless testicular enlargement
- pure or mixed
- metastases can vary from primary type
- tends to be 15-30yo
- predisposing factors: cryptorchidism, genetic/FHx, dysgenesis
- chromosomal changes: +12p
- occurs when totipotent germ cell becomes malignant
Types of Germ cell tumors:
-Mixed
- seminoma (when totipotent cell stays in its primitive form; most common 50% of GCTs; 30yo; radiosensitive/chemosensitive; good prognosis; serum markers often neg because of immaturity; "fish flesh tumor")
- Spermatocytic seminoma (1-2% of GCTs; >50yo; good prognosis; serum markers neg; some degree of differentiation still within germ cell line)
- Embryonal carcinoma (branches to the next 2; pure is rare 3%; mixed is common 85%; 20yo; chemosensitive; higher likelihood of spread; common recurrences; variable markers: PLAP, placental lactogen, hCG)
- Extraembryonic (Yolk sac- pure is common in children 80%; ~good prognosis; AFP serum marker; tend to make Schiller-Duval bodies) (choriocarcinoma- rarest and most aggressive; often metastasizes; chemosensitive, but worse prognosis; hCG in large amounts- positive pregnancy test)
- Embryonic (teratoma; 40% of testis tumors in infants; mature or immature; MALIGNANT transformation in M; chemoresistant- slow to progress but may undergo malignant change)
(listed above were all germ cell tumors)
Sex cord/stromal tumors:
- supporting structures of testes
- Mixed
- Leydig cell (90% benign; often masculinizing; some feminizing if aromatizing happens)
- Sertoli cell (try to form nestlike cels to reflect seminiferous tubules; aggressive; metastasize)
- Granulosa cell
Lymphoma:
- most common testicular tumor in men >60yo
- painless enlargement of testicle
- not germ-related
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neoplastic conditions of penis
skin ends up being most pathological
Condyloma acuminatum
- genital warts caused by HPV
- warty projections of squamous epithelium
- characteristic coital holocytes w/ scrunched up raisenoid nuclei
Verrucous carcinoma
- also warts caused by HPV
- locally destructive
- can invade downward, but low malignancy
carcinoma in situ
- red velvety crust
- full thickness dysplasia of keratinizing and non-keratinizing cells
- start to pile up and skin gets thicker (Still bound by basement membrane)
- Bowen's disease (occurs in keratinizing disease)
- Erythroplasia of Queyrat (carcinoma in situ of non-circumsized pts)
Squamous cell carcinoma
- when lesions break through the basement membrane
- 95% of epithelial malignancies (and epithelial malignancies make up 95% of all penile malignancies)
- "chimney sweeps disease"
- precursor lesion: carcinoma in situ
- others are: melanoma, basal cell, and urethral TCC
other malignancies:
- Mesenchymal make up 5% of penile malignancies
- mesenchymal incl:
- -leiomyosarcoma, fibrosarcoma, Rhabdomyosarcoma, Kaposi's sarcoma, Angiocarcinoma, hemangioendothelioma
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basic zonal anatomy of prostate w/ relationship to urethra and ejaculatory ducts
dura montana:
-where urethra and ejaculatory ducts meet
transition zone:
- tissues that surround urethra before joining
- where BPH occurs!
central zone:
- coveres ejaculatory duct until joining
- tends to be relatively resistant to path
peripheral site:
-tends to be primary site of prostate cancer
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acute vs chronic prostatitis
etiology
histology
normal to have prostate atrophy w/ aging
-can also get prostatic concretions (hard/calcified secretions)
prostatic diseases:
- can be asymptomatic until advanced
- symptoms usually incl urethral obstruction or irritation
- inflammation:
- --acute or chronic prostatitis
acute prostatitis:
- focal or diffuse PMN inflammation
- Enterobacter (E coli), Staph aureus most common
- direct extension from UT
- can be iatrogenic (w/ foley catheter)
chronic prostatitis
-mononuclear cell inflammation
-often assoc w/ atrophy
-unclear etiology
-histologic chronic inflammation much more common than clinical prostatitis
-granulomatous form (eroded corpora amylacea; Tuberculosis)
(bacterial
("abacterial"- cannot culture; most common)
(granulomatous
- hyperplasia
- neoplasia
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hyperplasia of prostate vs adenocarcinoma of prostate
prevalence
age distribution
characteristic anatomic location
gross features
microscopic features
clinical symptoms and findings
complications
prognosis
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Benign prostatic hyperplasia:
- benign nodular enlargement of prostate
- most common proliferative prostate disease
- Histologic BPH: "rule of 10s"
- clinical BPH<< Histological BPH
- symptomatic BPH usually incl lower UT symptoms (voiding, and esp storage affect QOL)
- various classifications based on: epithelium, fibroblasts/stroma, and/or SM
- natural history: L UT symptoms most common; complications (acute urinary retention, recurrent UTIs, renal failure, incontinence)
- management: medical (5alpha-reductae inhibitors to attack stromal/epi elements), minimally invasive therapy, surgery (TURP- often left pts bloody and incontinent; not common anymore)
prostatic carcinoma:
- most common non-skin cancer of adult M
- 2nd leading cause of M cancer deaths
- more die WITH PCa than OF it
- risk factors: age, race, genetics, possibly Western lifestyle
- affects peripheral zone
- screening: PSA- controversial usefulness; DRE
- blind "random" biopsies still gold standard for Dx (50% sensitive; many ca's detected will never be life threatening)
- "rarely balls and typically claws"- irregular shape and borders
- tumor vol were biggest in prostate w/ 1 tumor (smaller tumors grew together; heterogeneity of grade patterns and mutations)
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importance of grade and stage for prognosis of prostatic carcinoma
Prognostic factors:
- grade is based on histology (important)
- stage is based on location (super important)
- tumor volume (PSA)
- molecular markers (research in progress)
Gleason Grading:
- morphologic resemblance to normal prostate
- degree of invasiveness
- score = most common + 2nd most common
- higher the number = worse prognosis
Staging:
-best to remove prostate and tumor comes with it before the tumor becomes invasive
Risk of progression at 5 yrs:
- 95% pelvic lymph nodes
- 85% seminal vesicles
- 48% established capsular penetration
- 33% focal capsular penetration
- 10% organ confined
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diagnostic approaches and treatment options for prostatic carcinoma
Prostatic adenocarcinoma diagnostic criteria:
- uniform round glands
- infiltrative pattern
- single cell layer (loss of basal cells)
- nuclear enlargement (prominent nucleoli)
- perineural invasion
Treatment options:
- surgery (radical prostatectomy)
- external beam radiation
- brachytherapy (radioactive "seeds")
- cryotherapy
- hormone ablation (mainline tx for advanced metastatic PCa)
- chemotherapy
- new concepts (expectant management; targeted focal therapy)
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importance of prostatic intraepithelial neoplasia
development
diagnosis
PIN: prostatic intraepithelial neoplasia:
- believed to be noninvasive precursor to some prostatic Ca's
- genetic and molec changes similar to PCa
- 30-50% of prostates w/ PIN harbor prostate cancer- look harder for a real cancer
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oogenesis (vs spermatogenesis)
oogenesis: development of mature ovum/egg cell from a primary oocyte
-germ cell = oocyte
-location = ovary
-germ cells will eventually assoc w/ somatic cells around them
-end production is ovarian follicles (his specialty!!)
-ovarian follicles = fundamental unit; ability to produce egg and key steroid hormones to drive menstrual cycle forward (contains oocyte and soma (granulosa and theca cells)); need this for maturation but also endocrine driving function
-menopause = when you run out of follicles; if your ovaries aren't working, you're not making endocrine hormones
-primary oocyte (4n) --> meiosis 1 --> 2n secondary oocyte (w/ sister chromatids; this is ovulated) + 1 polar body
--> fertilization --> meiosis 2 (during ovulation) -->
fertilized oocyte (1n) + 3 polar bodies
(uneven segregation so oocyte can have room for other stuff to drive embryogenesis)
-meiosis starts during fetal life
-arrest at prophase meiosis 1 until puberty
-somatic cells will invade and surround individual germ cells
-half of germ cells will die
-left w/ granulosa (somatic) cells surrounding a single oocyte (follicle arrest; granulosa cells are flat and do not divide)
-primordial follicle = primary oocyte + granulosa cell (do not grow until puberty)
-hormone production by ovary follicles is dependent upon growth activation of puberty
-follicle = oocyte surrounded by granulosa cells
-primordial follicle = oocyte + pregranulosa cells (between 1 and 5 granulosa cells)
-growing follicle = all stages after primordial = oocyte + granulosa cells + theca cells
spermatogenesis:
- germ cell = spermatozoa
- location = testis
- SRY gene for male reproductive tract at the expense of the F reproductive tract
- testis cords develop into seminiferous tubules
- contents incl prospermatogonia, sertoli, and leydig cells
- duplicating chromosomes w/o dividing, then meiosis 1/2 (dividing 2x to get 4 haploid progeny cells from original single diploid cell; 4n--> 4x 1n)
- cords fill w/ more mature sperm cells; eventually dump into tubules and into epidermis where sperm maturation can occur
- pre-puberty: arrested in spermatogonial stage (no meiosis)
- puberty reactivates meiotic regression
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functional and histologic changes which occur in ovarian follicle and corpus luteum
cumulous granulosa cells:
- cloud-like appearance after ovulation
- in a shiny matrix of hyluranic acid
adult ovary:
- everything is mixed up and going on at once in every part of ovary
- has a proper cortex and medulla, but all follicles are mixed up and can be found anywhere
development of corpus luteum from a follicle:
- follicle is organized into distinct layers before ovulation
- Antrum: fluid filled lumen surrounded by granulosal layer
- granulosal layer and oocyte separated from rest of follicle by basement membrane
- outside basement membrane: theca interna and theca externa layers of the follicle
- capillaries of vascular wreath surrounding follicles are present in theca layers but not past basement membrane (barrier)
- LH causes breakdown of follicular wall and release of oocyte at ovulation
- after ovulation, cells of theca interna and its assoc capillaries cross degraded BM and invade granulosal layer as follicular tissue develops into the corpus luteum
- corpus luteum contains hetero population of cells that incl large steroidogenic luteal cells (luteinized granulosal cells) and small steroidogenic luteal cells (luteinized thecal cells)
- abundance of capillaries is indicative of high degree of vascularization of the corpus luteum
- when not fertilized, corpus luteum degenerates
Granulosa Layer, Theca interna, and theca externa are the 3 steroid hormone producing cells of the follicle
2 follicular cell types:
- granulosa
- theca
large growing follicles containing eggs are needed to produce estradiol
if conception and ongoing pregnancy occur, the remaining cells of the ovulated ovarian follicle form the corpus luteum
- and pregnancy (placental production of hCG) stabilized the corpus luteum and therefore progesterone production
- pregnancy feeds back to corpus luteum and stabilizes it via hCG
low and high density lipoproteins (LDL/HDL) make progesterone
-or you can use cholesterol within cell using StAR
zona granulosa cells:
-begin to secrete progesterone (granulosa lutein cells)
corpus luteum secretes:
- oestrogen (which inhibits FSH)
- Relaxin (relaxes fibrocartilage of pubic symphysis)
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structure, functions, and MOAs of hormones involved in H-P-G axis in F
HPG axis in F:
- hypothalamus prod GnRH
- stimulates pituitary for FSH and LH
- FSH and LH enter bloodstream
- impact follicle development/survival in ovary
- mature follicles produce progesterone and some estrogen
- those steroid hormones feed back to down regulate GnRH
- basis of cyclic nature of menstrual cycle
- GnRH is pulsatile
- pattern is required to keep LH/FSH high during correct times of cycle
when FSH is present:
- follicles grow
- fosters granulosa proliferation
- FSH is a little higher during follicular phase (highest during this phase)
- FSH is lower during luteal phase
- (estradiol produced by granulosa cells negatively regulates FSH production at distant pituitary)
LH:
- fosters granulosa lutenization (transition to luteal cells)
- LH receptor comes on when the structure is competent to lutenize
vast majority of follicles die (random selection)
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autocrine and paracrine function examples that modulate follicular development
need specific growth factors to make the granulosa cells grow so the oocyte can grow
-endocrine and paracrine signaling molecs help prime a follicle that's ready to continue w/ meiosis
meiotic resumption is due to local and systemic endocrine factors
inside the oocyte there's cell cycle molecs that keep it arrested
-stimulation and release of cAMP and intracellular Ca stores can cause physiologic meiosis to resume
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emergence of dominant follicle
atreitic follicle:
- granulosa cells and sometimes the oocyte die via apoptosis
- entire structure involutes and disappears
women only ovulate 1 egg/month, but there's a bunch of follicles that are ready around the same time (~5-7)
selection of dominant follicle:
- one will produce the most estrogen, the most FSH and LH receptors, express the highest level of enzymes that convert precursors to our final steroid products
- NO direct evidence that shows the dominant follicle suppresses the growth of its neighbors (not neg selection process)
- it's just the most competent to ovulate
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2-cell therapy of sex steroid production
k
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gonadal cells responsible for sex steroid production in F
thecal cells:
- controlled by LH
- induce androgen production
Granulosa cells:
-converts androgen --> estradiol
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label a diagram of ovarian/menstrual cycle
1- Follicular phase:
- GnRH pulsatile secretion is more frequent, but smaller in amplitude
- LH and FSH levels are equal early on
- increase in GnRH pulsatility = circulating LH and FSH levels reach peak just prior to ovulation
- inhibin enhances LH stimulation of androgen synthesis in theca cells (providing more substrate for estrogen synthesis in granulosa cell)--> estrogen peak, and subsequent LH surge is possible
- LH surge --> ovulation
Ovulation
2- Luteal Phase:
- increasing progesterone levels slow LH pulses to every 3-4 hrs
- progesterone falls at end of luteal phase, so LH pulse frequency increases 4-fold
- FSH is secreted preferentially over LH
- circulating FSH increases 3-fold
- circulating LH increases 2-fold
Sequence of ideal 28 day cycle:
Estradiol peak
o Onset of LH surge (most reliable indicator of impending ovulation, about 36 hours before ovulation – the basis for urinary LH ovulation predictor kits)
o LH peak (14 ‐ 24 hours after the estradiol peak) – Day 14
o Completion of meiosis I with extrusion of the first polar body
o Ovulation (10 – 12 hours after the LH peak) – Day 15
o Oocyte transport to the ampulla of the fallopian tube (2 – 3 minutes)
o Fertilization in the ampulla (12 – 24 hours after ovulation) – Day 16‐ 17
o Cellular division and transport to the endometrial cavity (80 hours) – Day 18 – 20 o Endometrial receptivity – Days 20 ‐ 24
o Implantation – Day 20 ‐ 21
