LC Unit 1 Flashcards
2 functions and 2 compartments of gonads
produce mature gametes
produce hormones that determine the secondary sex characteristics
interstitial compartment:
leydig/thecal
gametogenic compartment:
sertoli/granulosa
endocrine role of the gonads
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)
anatomy of male genitalia:
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
sertoli cell only syndrome
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
androgen production in males
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
reversible conversion between testosterone and androstenedione enzyme
17beta-hydroxysteroid dehydrogenase
testosterone to estradiol enzyme
aromatase
testosterone to dihydrotestosterone DHT enzyme
5alpha reductase
transportation of Testosterone in blood
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
testosterone binding and paths in the body
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
how do males w/ 5 alpha reductase deficiency present
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
MOA of androgens
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
Hypothalamic-pituitary-gonadal axis w/ GnRH
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
which hormones share subunits w/ LH and FSH
LH and FSH share alpha-subunit w/ TSH and hCG (pregnancy hormones)
-hCG frequently used as clinical substitute for LH
gonadotropin info
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
function of LH
LH stimulates steroidogenesis in interstitial cells of ovary and testis
function of FSH
FSH stimulates aromatase in sertoli and granulose cells to produce estrogen and promotes maturation of gametes
gonadal peptides
inhibins and activins
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
3 major components of sex determination and differentiation
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
bipotentiality of sex differentiation
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
chromosomal sex
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
SRY gene
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
gonadal development
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
transcription factors in genital ridge
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
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
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
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
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
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
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
phenotypic sex and internal ducts: initial
initially:
both mesonephric/Wolffian and paramesonephric/Mullerian ducts develop in both sexes
differentiation begins at 8 weeks
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
Female internal ducts
requires ABSENCE of local testosterone and AMH
paramesonephric/Mullerian ducts:
fallopian tables
midline uterus
UPPER portion of vagina
Wolffian ducts regress
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)
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
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
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
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
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
gonadal descent of testes timeline
testes reach inguinal region by 12 weeks
scrotum by 33 weeks
cryptorchidism
failure of testes to reach scrotal sac (3%)
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
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
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
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)
clinical evaluation/workup for DSD
FISH for Y (SRY)- fast
karyotype/microarray
US- evaluate for presence of uterus
laparascopy- best to define internal anatomy
classification of DSDs
46XX DSD (virilized XX)
46XY DSD (undervirilized XY)
46 XX DSD possible causes
95% have congenital adrenal hyperplasia CAH
46XX sex reversal (SRY translocation)- will look male
ovotesticular DSD
gestational hyperandrogegism
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)
Smith-Lemli-Optiz syndrome
7-dehydrocholesterole reductase deficiency
causes 46 XY DSD- defect in adrenal and testicular steroidogenesis
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
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
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
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
3 zones and products of adrenal gland
zona Glomerulosa
mineralocorticoids (aldosterone)
Zona Fasciculata
Glucocorticoids (cortisol)
Zona Reticularis
Androgens
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
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
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
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
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
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
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
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)
elongation phase of mullerian development
early on, so mesonephric/wolffian ducts are still prominent
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
Cannulation phase of mullerian development
hollowing of mullerian ducts occurs
renal system is now fully fused w/ bladder
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
3 problems that can happen with vaginal obstruction
imperforate hymen
transverse vaginal septum
vaginal atresia
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
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
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
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)
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
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)
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
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
class 6 mullerian anomalies
arcurate uterus
near complete resorption of utero-vaginal septum
asymptomatic
normal external contour
no adverse reproductive outcomes
no surgical intervention
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
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
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
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
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
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
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)
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
menopause in a F- FSH and LH levels
high FSH and LH is diagnostic for menopause
they increase because the negative feedback is lost
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
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)
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
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
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
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
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)
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
define puberty
developmental events leading to the attainment of full sexual maturation and fertility capacity
requires intact hypothalamic-pituitary-gonadal axis
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
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
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
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
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
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
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?
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
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
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
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
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
delayed puberty
no pubertal signs by
13 in girls
14 in boys
low gonadotrophins-
hypogonadotropic (or central) hypogonadism
elevated gonadotrophins-
hypergonadotropic (or primary) hypogonadism
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
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
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
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
congenital causes of hypogonadotropic hypogonadism
part of multiple hormone deficiencies
septa-optic-dysplasia
genetic syndromes- Prader Willi Syndrome
Idiopathic Hypogonadotropic Hypogonadism IHH
isolated defect in GnRH or gonadotropins in absence of any structural abnormalities of hypothalamus or pituitary
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
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
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)
causes of primary ovarian failure
Turner syndrome
XX or XY complete gonadal dysgenesis
galactosemia
radiation
chemo (alkylating agents)
autoimmune
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
causes of primary testicular failure
Klinefelter’s syndrome
cryptorchidism
testicular regression syndrome
radiation
chemotherapy (alkylating agents)
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
evaluation of delayed puberty
Hx- ask about sense of smell
height and growth rate
bone age
labs: gonadotropins, T, estradiol
karyotype if elevated gonadotrpins
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
