Transcript Embryonic Sexual Determination 2007

Crushing the Creogs
Rapid Primer
High Yield
Amenorrhea
Abnormal puberty (delayed and
precocious)
Embryology
Embryonic Sexual
Determination
Embryo bipotent at 5
wks
Karyotype
XY
XX
SRY
No
SRY
– XY vs XX
– SRY Gene (TDF)
Normal
Male
Normal
female
Embryonic Sexual
Determination
XX
XY (with SRY)
Ovary
Testes at 6 weeks
Sertoli
Anti Mullerian Hormone
Ispilateral regressesion
Leydig
Testosterone
Dev. Int. Male,
ipsilaterally
DHT
Dev Ext
Male
“Default” pathway
Mullerian
Duct
Lumen of uterus
Cervix
Uterine
Septum
Caudal tip of
Mullerian Ducts
Sinovaginal
Bulbs
(Vaginal plate)
Urogenital Sinus
Fornix
Vagina
Hymen
Ovaries develop separately
Summary of Sex Determination
Embryo is bipotent at 5 weeks.
If male (SRY, AMH, Testosterone/DHT) 
starts male differentiation at 6 weeks.
If no male differentiation  female is
default pathway.
Prepubertal Physiology
G
o
n
a
d
o
t
r
o
p
i
n
+
Age
Increasing weight, fat
mass
Normal Puberty Gonadarche
Suppression of the gonadostat decreases.*
Nocturnal pulses in GnRH lead to:
Increasing FSH (then increasing LH) levels
lead to:
Increasing androgens and estrogen, leading
to:
– Everything we associate with puberty.
Timing of puberty is largely genetic
Estrogen  Breast Development and
Bone Growth
Androgens  Pubic Hair
Measurement of Puberty: Tanner
Stages
Breast
Pubic Hair
Stage 1
Elevation of papilla
No pubic hair
Stage 2
Breast bud, areola enlarged
Sparse long pigmented hair, mostly labial
median age - 9.8 yrs
median age - 10.5 yrs (resident could count)
Further enlargement
Dark,coarse,curled hair, spread to mons
median age - 11.2 yrs
median age - 11.4 yrs (student could count)
Secondary mounding of areola
Adult type hair, abundant, limited to mons
median age - 12.1 yrs
median age - 12.0 yrs (to numerous to count)
Recession of 2° mound
Adult-type spread (thighs and abd)
median age - 14.6 yrs
median age - 13.7 yrs
Stage 3
Stage 4
Stage 5
There is NO stage Zero!
Order of Pubertal Events
Growth spurt / Breasts
Pubic hair
Maximum growth velocity
Menses
aka “Boobs, pubes/pits and pads”
Normal Puberty - Adrenarche
Independent of HPO axis.
Trigger unclear
Generally precedes
changes associated with
puberty.
Increase adrenal
androgens: DHEAS and
A.
Mechanism: increased
17,20 lyase activity.
Appearance of Pubic Hair
The Menstrual Cycle
Endocrinology
FSH Inh-A/B
P
LH E2
IU/L pg/ml ng/ml
20
500
18
16
9
400
14
12
300
200
6
FSH
4
3
100
2
0
P
5
6
4
LH
8
7
10
8
10
2
Inh-A
Inh-B
E2
1
0
0
2
4
Menses
6
8
10 12 14 16 18 20 22 24 26 28
Ovulation
Preantral Follicle
Initiation of Follicular Growth
Continuous process
Occurs in “waves”
Stimulus/mechanism unknown
Independent of gonadotropins
– Occurs in prepubertal ovary
– Uninterupted by pregnancy,
OCP
Ends with follicular depletion
FSH
P
LH E2
IU/L pg/ml ng/ml
20
500
18
16
9
400
14
12
300
200
6
FSH
4
3
100
2
0
P
5
6
4
LH
8
7
10
8
10
E2
2
1
0
0
2
4
Menses
6
8
10 12 14 16 18 20 22 24 26 28
Ovulation
Preantral Follicle
In Delicate Balance
Growth
Atresia
Timely gonadotropin
stimulation can promote
further growth
– Intercycle rise in FSH
crucial for continued
development
Without gonadotropin
support, doomed to
atresia
The “Two Cell, Two
Gonadotropin Concept”
LH
THECA CELL
LH Receptor
ATP
Cholesterol
P450scc
cAMP
Pregnenolone
P450c17
Androstenedione Testosterone
Basement
Membrane
Androstenedione Testosterone
cAMP
< P450arom>
FSH
ATP
Estrone
Estradiol
GRANULOSA CELL
Dominant Follicle
Selection Mechanisms
Normal ovulatory quota = 1
Rising estrogen levels
– positive feedback locally
– negative feedback centrally
Rising inhibin levels
– further negative feedback
Declining FSH levels
– withdraw growth support
– Atresia in lesser follicles
atresia
Dominant Follicle Selection
“Survival of the Fittest”
Selected follicle
– More and larger cells
– more FSH receptor and greater
sensitivity to falling FSH
– more aromatase
Advanced vascular development
provides preferential delivery of
FSH and LDL substrate
Ovulation
LI
LH
PG
Smooth Muscle
Fibers
OMI
LH
PG
P
FSH
Plasmin
Collagenase
LH stimulates meiosis, luteinization,
and PG production
P enhances proteolytic enzymes
FSH stimulates expansion of
cumulus and plasmin to stimulate
collagenase
PB
Corpus Luteum
Follicle wall becomes
convoluted
Luteal cells enlarge, acquire
lutein pigment and lipid
Capillary network penetrates
granulosa
Production of large amounts
of both E & P
E & P act centrally and locally
to suppresses new follicular
growth
Estradiol
Progesterone
Corpus Luteum
Requirements for Normal Luteal
Function
Optimal preovulatory follicular
development - luteal cell mass
– Adequate follicular phase FSH
Tonic LH stimulation
LDL cholesterol substrate
Ovarian Cycle
FSH
P
LH E2
IU/L pg/ml ng/ml
20
500
18
16
400
300
200
hCG
6
FSH
4
3
100
2
0
P
5
6
4
LH
8
7
10
8
10
9
14
12
Conception
E2
2
1
0
0
2
4
Menses
6
8
10 12 14 16 18 20 22 24 26 28
Ovulation
Normal menses
24-35 days
2-7 days of flow
35ml (mean) <80 cc of non-clotting debris.
Abnormal Puberty
Terminology of Precocious Puberty
GnRH - Dependent aka True Precocious
Puberty aka Central Precocious Puberty
GnRH - Independent aka Precocious
Pseudopuberty aka Peripheral Precocious
Puberty
Isolated Precocious Development
Precocious Puberty
Bone Age guides therapy.
Bone age, bone age, bone age
Typically, once menses have started,
growth is limited to 6 cm more.
Mature Axis: GnRH stim test LH > FSH rise.
Prepubertal: GnRH stim test FSH > LH rise.
Etiologies of Precocious Puberty
GnRH Dependent
Idiopathic
CNS problem
female
male
74%
41%
7%
26%
11%
n/a
5%
1%
1%
0.5%
n/a
10%
1%
0%
22%
0.5%
GnRH Independent
Ovarian (cyst or tumor)
Testicular
McCune-Albright
Adrenal feminizing
Adrenal masculinizing
Ectopic gonadotropin
Hypothyroidism
Exogenous Steroids
1° Gonadotropin Elevation
CNS Causes
– Hypothalamic Tumor
Hamartoma (secretes GnRH),
Craniopharyngioma, Glioma, Ependymomas,
Neurofibroma
– Congenital malformation
Hydrocephalus, Rickett’s (skull malformation)
– Pineal tumor
– Trauma (brain injury stims TGF-a which stims
GnRH)
– Encephalitis
1° Steroid Elevation
Tumor
– Ovary
may produce estrogens, androgens, hCG typically causing heavy irreg. bleeding
80% have palpable mass
granulosa, theca, gonadoblastomas,
teratomas, lipoid cell, cystadenomas,
epithelial cancer
– Feminizing Adrenal Tumor
very rare, usu. associated with  DHA-S
McCune Albright Syndrome
aka polyostic fibrous dysplasia
Mechanism:
– Activating mutation of Gsa
resulting in unregulated cAMP
formation.
– Somatic mosaic mutation,
therefore not lethal and variable
phenotype.
Classic Triad:
– cystic bone lesions causing easy
fracture - Tc bone scan
– cafe au lait spots
– sexual precocity
Findings in Various Disorders
Gonadal
Size
Basal FSH E or T
& LH
Levels
DHEAS
GnRH
Response
Idiopathic
Increased
Increased
Increased
Increased
Pubertal
LH>FSH
Cerebral
Increased
Increased
Increased
Increased
Pubertal
LH>FSH
Gonadal
Unilat
enlarged
Decreased Increased
Increased
Flat*
McCuneAlbright
Increased
Decreased Increased
Increased
Flat*
Adrenal
Small
Decreased Increased
Increased
Flat*
Isolated Premature
Development
Isolated Thelarche
– May be unilateral, may wax and wane
– Normal growth
Isolated Premature Menarche
– VERY rare: suspect trauma or foreign body,
tumor.
Isolated Premature Adrenarche
– Rule out CAH
Treatment Objectives
Dx and Rx any intracranial disease
Dx and surgically treat peripheral
tumors
Arrest maturation until appropriate
age
Lessen established precocious
characteristics
Maximize adult height
Avoidance of abuse, treat emotional
problems, and consider contraception
Treatment of Central Precocious Puberty
GnRHa therapy –
– monitor growth, 2° sexual characteristics,
bone age, and keep E2 < 10 or maintain
negative GnRH stim test
– GnRH may be used in the case of hamartoma
Delayed Puberty
Most girls in USA enter puberty by age 13
Workup when
– no 2° sex characteristics by age 13
– absence of menarche by age 16
– 5 years between onset thelarche and
menarche
Delayed puberty is rare in girls and is
commonly associated with pathology
Delayed Puberty
Hypergonadotropic Hypogonadism
43%
– Ovarian failure – abnormal karyotype (26%)
Turner’s Syndrome
– Ovarian failure – normal karyotype
46XX (15%)
46XY ( 2%)
– Other (rare)
17-a hydroxylase deficiency (HTN, sexual infantilism,
high P)
Sickle Cells Disease, Torsion, Resistant Ovary
Syndrome
Frequency of Delayed Puberty
Etiologies
Hypogonadotropic Hypogonadism
– Reversible (18%)
Physiologic delay
10%
Weight loss/anorexia
3%
Prolactinoma
1.5%
1° hypothyroidism
1%
CAH
1%
Cushing’s
0.5%
31%
Frequency of Delayed Puberty
Etiologies
Hypogonadotropic Hypogonadism
– Irreversible (13%)
GnRH deficiency
7%
– Kallman’s, Prader Willi
– GP54R, Leptin Receptor deficiency
– Irradiation, infiltrating disease
Hypopituitarism
Craniopharyngiomas
Congenital CNS defects
pituitary adenomas
Malignant pituitary tumor
3%
1%
0.5%
0.5%
0.5%
31%
Frequency of Delayed Puberty
Etiologies
Eugonadism
26%
– Mullerian agenesis
– Inappropriate + feedback
(PCOS)
– Vaginal septum
– Androgen insensitivity
– Imperforate hymen
14%
7%
3%
1%
0.5%
Three Cases of Amenorrhea and
Blind Pouch
MRKH
– Normal pubic hair & breasts. No cyclic pain.
AIS
– Scant pubic hair, normal breast. No pain.
– Androgen Receptor Defect (can’t respond to
Androgens, develop breasts because unopposed E,
have testes/AMH therefore don’t develop uterus.)
Transverse Septum
– Normal pubic hair & breasts. Cyclic Pain!
Idiopathic Precocious Puberty
Spontaneous increase in GnRH.
Diagnosis of exclusion.
Treat with GnRH-agonist.
Know for CREOGS
Order of pubertal stages.
Genetics = #1 determinant of timing.
Average age of menarche is 12.8
Precocious puberty: prior to age 8
Delayed puberty: absence of 2ndary chars
by age 13
McCune-Albright Syndrome
Clinical Differences between AIS,
Transverse Septum and Mullerian
Agenesis
Amenorrhea
Primary:
– No menses by 16 in the presence normal
growth and secondary sex characteristics
– No menses by 14 without secondary sex
characteristics
Secondary:
– H/o previous menses.
– No menses in for past three expected cycles
or past 6 months.
Primary Amenorrhea Pearls
Physical Exam is essential.
– Breasts = Estrogen exposure.
– Normal height = Estrogen exposure.
– Uterus = Eliminates AIS, MRKH, Transverse
Septum.
Broad DDx
– Hypergonadotropic (ovarian failure)
– Hypogonadotropic (CNS, Pituitary issue)
– Eugonadal (Secondary amenorrhea w/u)
Primary Amenorrhea
Increased FSH
Gonadal Failure
Most common cause is genetic: XO or mosaic
(XO/XX), or XY
– Turners: Short stature, webbed neck, wide spaced
nipples, increased arm carrying angle, coarctation,
low posterior hair line, renal abnormalities, streak
gonads.
Galactosemia: failure to thrive, abnormal FSH
and LH and failure of germ cells to migrate to
ovary.
17a hydroxylase deficiency (HTN, hypokalemia)
with high 17-OHP
Steroid Synthesis
Start with cholesterol (27C)
Rate limiting reaction is side chain cleavage 27C
 21C Pregnenolone
21 Carbons: progestins, glucocorticoids,
mineralocorticoids
19 Carbons: Androgens
18 Carbons: Estrogens
Cortisol levels are
regulated tightly,
others are not.
– if cortisol synthesis is
limited, ACTH
increases to overcome
blockage.
– precursors build up
Adrenal Steroid Disorders
CAH (% nomal genitalia vs & ambiguous)
– 21 hydroxylase deficiency (90% of cases)
– 11b hydroxylase deficiency (5% of cases)
– 3b dehydrogenase deficiency (rare)
Pubertal Disorders (&) vs Ambiguous
Genitalia (%)
– 17a hydroxylase deficiency
– 17b dehydrogenase deficiency
CAH -- 21 Hydroxlase
Most common enzyme deficiency leading
to congenital adrenal hyperplasia.
Name is confusing: (named backwards)
– It adds on –OH group to C21
– Named this way because, scientists were
working back from cortisol and aldosterone.
The product names confuse people, for
the same reasons.
CAH – 11b hydroxylase
deficiency
Presentation more
variable
Hypertension
– Incr 11DOC
Na+ overload
Hypo K+
Female masculinized
Addisons possible
with stress
17a Hydroxylase Deficiency
Female pubertal delay
Male ambiguous genitalia
HTN due to mineralocorticoid
affect of 11-DOC
Hypokalemia
17-OHP is low.
Renin low due to Na retension
and water expansion.
Aldosterone is also low
Low urinary 17 keto-steroids
CAH Diagnosis
Screening Test is 17OHP
Diagnosis made with
ACTH stimulation
test.
Measure cortisol and
precursors before and
after.
CAH Summary
The Cortisol, Aldo
enzymes are named
backwards.
21-hydroxylase def. is
most common cause
of CAH.
11-hydroxylase is 2nd
Blockages lead to
buildup of precursors
and androgens.
PCOS
Rotterdam Diagnostic Criteria
Need two of three
Chronic Oligo-Anovulation
Hyperandrogenism
Polycystic Ovaries
Rule out other causes
Differential Diagnosis
Late-onset congenital adrenal hyperplasia
Idiopathic (constitutional) hirsutism
Hypothalamic amenorrhea
Premature ovarian failure
Prolactin
Thyroid
Differential Diagnosis
Cushing’s Syndrome
Androgen producing tumors
Acromegaly
Anabolic drugs
Pathogenesis
iSHBG
Hirsutism
Insulin
resistance
& obesity
iFSH
Increased
androgens
Increased LH
PCOS
Acyclic, elevated
estrogen
Amenorrhea
Converted
to DHT
Anovulation
Polycystic
ovaries
‘Metabolic Syndrome’
Diabetes
mellitus
Hypertension
Dyslipidemia
Atherosclerosis
High triglycerides
Low HDL
Insulin Resistance
Abdominal Obesity
PCOS
PCOS Treatment
Management of menses
– OCP (35mcg EE), Mirena, Cyclic P
Management of hirsuitism
– OCP, Spironolactone, Finasteride, Vaniqa, Laser
Management of insulin resistance
– Weight loss, metformin, exercise.
– Metformin most useful if patient overweight.
Fertility
– Ovulation induction: clomid, letrozole, metformin
Clomid = anti estrogen (increases FSH)
Letrozole = aromatase inhibitor (increases FSH)
Require functioning hypothalmus/pituitary!!!
Hirsuitism
Hirsuitim
– Excess terminal hair in male pattern.
Midline chest, face, back, lower midline
abdomen. Arm and leg hair get darker.
Virilization
– Deepening voice, clitoromegally, breast
atrophy and loss of feminine contour.
Causes of Hirsuitism
Ethnicity
Idiopathic (intrinsic 5a reductase activity)
Insulin stimulates pilosebaceous unit, ovarian
androgen production and decreases SHBG
PCOS
CAH
Ovarian tumor
Adrenal tumor
Cushings, hyperprolactinemia
Hirsuitism Workup
Androgen assays not very reliable in women.
Rapid change associated with pathology
– Free T – most sensitive, rarely needed.
– Total T – used to rule out ovarian tumor, or follow
treatment
– DHEAS – used to rule out adrenal tumor
– 17-OHP – screen for CAH
– PRL – can lead to increased DHEAS
Consider Insulin Resistance, Cortisol, GH
Hirsuitism Treatments
Takes 6 months to arrest new hair growth.
Lifestyle changes, as needed
Cosmetic treatments:
Laser, Electrolysis
Eflornithine (Vaniqa) – arrests new hair
growth – twice a day x 4 hours. 58% had
overall improvement.
Hirsuitism Treatments
OCPs are off-label and no studies of adequate power to
show benefit.
– Decrease LH (decrease androgens)
– Increase SHBG
Spironolactone (need contraception)
– Directly blocks androgen receptor and mildly inhibits 5a
reductase
– Cheap and more affective than finasteride.
– More side effects: polyuria, hypotension, fatique, hyperK
Finasteride (need contraception)
– 5a reductase inhibitor
– Non-toxic
Flutamide (need contraception)
– Androgen receptor blocker, but liver tox limits use.
Hyperprolactinemia
Elevated prolactin:
May interfere with GnRH secretion to cause:
– Short luteal phase
– Oligomenorrhea
– Amenorrhea
Galactorrhea
Hirsuitism
Bone loss
Decreased libido in men
Hyperprolactinemia
Inhibitors
– Dopamine (primary
regulator via portal
system)
– Prolactin
Stimulators
–
–
–
–
TRH
Estrogen
VIP (food)
Oxytocin (sex, nipple
stimulation)
– Many drugs
Hyperprolactinemia
Galactorrhea is bilateral and white.
May be seen with normal prolactin levels.
– Assay does not reflect biologic activity.
– May not detect nocturnal PRL secretion.
Fat seen on smear.
#1 cause of hyperprolactinemia is idiopathic.
The higher the prolactin, the greater the chance
of having an adenoma.
Renally and hepatically cleared, so increased
with renal failure and liver disease.
HyperPRL – CNS Issues
Microadenoma <10mm, usually does not
grow.
Macroadenoma > 10mm (may secrete GH,
ACTH, TSH, FSH or nothing)
Infiltrating disorders (sarcoid, TB)
Radiation
Empty Sella Syndrome (herniation of CNS
fluid into sella and compresses stalk)
Rathke’s cyst or other stalk tumors.
PRL and Rx
Antipsychotics
Antidepressants
Opiates & Cocaine
Verapamil
Methyldopa
Metoclopramide
H2 blockers ranitidine
and cimetidine
Estrogen
Dilantin
PRL levels usually return to normal within 2-4 days of stopping Rx
Prolactin Variants
PRL = normal bioactive form
Big PRL (macro-PRL dimers which are
connected, can lyse and become
bioactive)
Big-Big PRL (little bioactivity, but cross
react with assay)
When to image for PRL?
Debatable. No clear answer.
– Some say any elevation is indication.
– Levels > 100 ng/ml in absence of drug is
universally accepted.
– Antipsychotics my raise PRL into 300 range.
(Still no one would fault you for imaging.)
MRI with and without contrast is image of
choice.
HyperPRL Tx
Remove offending agent
Bromocriptine (DA agonist) (FDA+)
– Ergot deriv. Usually req 2-3x/day dose
– 12% nausea, headache, syncope, dizziness and orthostatic
hypotension
– PO or PV route good.
Cabergoline (DA agonist) (Off label)
– Long t 1/2 , give 2 x per week
– Few side effects
Both lead to tumor shrinkage.
Except in cases of neurologic emergency, Rx therapy is
always first choice.
Menopause
Menopause Definitions
Menopause: cessation of menses for 12 months due to
loss of ovarian function.
– Average age 51
– Younger if smoker, Hispanic, African American.
Climacteric (perimenopause begins 5-6 years prior)
symptoms appear (vasomotor and irregular cycles.)
– Natural menopause: gradual decline, characterized by
fluctuating E and FSH.
– Increase FSH due to loss of inhibin!
Premature ovarian failure/menopause <40
– Under 30 should get karyotype to look for Y chromosome.
– Consider Fragile X gene mutation testing (FMR1)
Surgical menopause: sudden drop in E.
Managing Perimenopause
Standard HRT doses will not prevent
pregnancy and should not be used as first
line agents unless a patient is surgically
sterile or cannot take OCP.
The patch:
– Low dose patch 0.025 mg will reduce hot
flashes by 85%.
– If the patient has a uterus, you must give
progestin therapy for 14 days q month.
Hot Flash Alternative Approaches
Lifestyle changes, cool environment
Biofeedback
Vitamin E, dong quai, and black cohosh—no
difference compared with placebo
Phytoestrogens
Clonidine (patch or pill)
Megestrol
SSRI/SNRI therapy
Menopausal Changes
Symptoms: hot flashes (catecholamine
mediated) hot and cold, night sweats, mood
changes, insomnia, vaginal atrophy, possibly
skin changes.
Bone loss (most in first 5 years), especially
trabecular bone.
Increased central obesity.
Lipid abnormalities.
– Latter two increase HTN, CAD risk.
Management
Protect bone.
Protect against hyperplasia.
Alleviate symptoms.
Promote healthy living.
Bone Mass by Age and Sex
Bone Mass
Men
Women
Menopause-Associated
Bone Loss
10
20
30
40
50
60
70
Age (years)
Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999;1366-73.
Riggs BL, Melton LJ III. N Engl J Med. 1986;314:1676-86.
80
Osteoporosis
DEXA scan = gold standard (Dual Energy Xray
Absorptiometry)
T score = StDev from healthy 30yo woman.
– Osteopenia = T -1 to -2.5
– Osteoporosis = T < -2.5
Z score = StDev from same age woman.
– Used in premenopausal women.
T & Z scores correlate with fracture risk.
– DEXA less reliable in Obese (artificially low T
score) and osteoarthritis (artificially high T score)
Error range of DEXA = ~7% and repeat test not valid
at <1 year, more valid at 2 years.
Urinary and serum markers of bone turnover
measure cancellous bone. (Telopeptides most commonly
used, if at all)
When to Measure BMD in
Postmenopausal Women
One or more risk factors
Non-Modifiable
Modifiable
Age > 65
Caucasian Race
Female
Family history
History of fracture
History of falls
Bad Eyesight
Smoking Cigarettes
Low Body Weight
ETOH
Not on HRT (low E)
Hypothyroidism
Immobility*
Poor nutrition
Medications (steroids
and heparin)
Treatment Options
Calcium
– 1500-2000mg daily
Vit D supplementation
– Sunshine
– 400-800 IU/daily
SERMs (raloxifene)
HRT (oral or patch)
Bisphosphonates (Etidronate, Alendronate)
Weight bearing exercise
Affects of Various Treatments
Decreases
Vertebral
Fracture
Rates
Decreases
Hip
Fracture
Rates
Increases in
BMD (%)†
Most
Common
Side Effect
ERT/HRT
Yes‡
Yes§
5-6
Breakthrough bleeding
Alendronate||
Yes‡
Yes¶
5-8
Gastric ulceration
Risedronate||
Yes
Yes
5-6
Upper GI symptoms
Raloxifene||
Yes
No
1-2
Hot flushes
Calcitonin
Yes
No
1-2
Nasal irritation
WHI Results
Absolute and Relative Risk or Benefit of HRT
Health Event
Increased
Relative Risk Absolute Risk
vs Placebo
per 10,000
at 5. Years
Women/Yr
Heart attacks
Strokes
Breast cancer
VTEs
Colorectal cancer
Hip fractures
1.29
1.41
1.26
2.11
0.63
0.66
Increased
Absolute Benefit
per 10,000
Women/Yr
7
8
8
18
Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.
6
5
WHI E-only Arm
What’s different
– No increased CVD risk.
– No increased breast cancer risk.
What’s the similar
– Increased risk of DVT
– Small increase risk of stroke
– Bone protection.
WHI
NIH Recommendations
Use HRT for shortest period of time needed, to
treat symptoms.
HRT should not be continued or started to
prevent heart disease
Discuss other methods of CVD prevention:
– lifestyle changes
– cholesterol- and blood pressure-lowering drugs
For osteoporosis prevention:
– weigh the benefits against their personal risks for
heart attack, stroke, blood clots, and breast cancer;
alternate treatments are available to prevent
osteoporosis and fractures.
Endometriosis/Adenomyosis
Endometriosis = endometrial tissue outside the uterus.
Adenomyosis = endometrium within muscle.
Endometriosis Incidence:
–
–
–
–
3-10% of general population
30% of infertile population
50% of pelvic pain
70% of pelvic pain and infertility
LEFT ovary is most common site of endometrioma.
Disease stage correlates with ~fertility, but not pain.
Genetic (7% of first degree relatives)
Etiology: genetic, environmental, autoimmune.
Tissue has abnormal regulation (altered responsiveness to
progesterone: resistant to apoptosis; excess aromatase.)
Also assoc with: premenstrual spotting, poor egg quality
Endometriosis Treatment
Infertility
Surgery benefits stage I-II disease.
– NNT = 12
– More advanced disease, role of surgery mainly limited
to diagnosis.
GnRH-agonist
– Modest benefit, if any for fertility
All forms of fertility have decreased efficacy with
endometriosis (IVF, COH/IUI)
– Likely related to poorer egg quality.
Endometriosis Treatment
(pregnancy, pseudopregnancy or pseudomenopause)
OCPs (60-90% get relief in first year)
– Promote decidualization (progestin effect), pseudopregnancy
– 10% recurrence risk/year
Depo Provera/Progestins
– Promote decidualization (pseudopregnancy)
Depot Lupron (75-90% get relief in first year)
– Decapeptide, long-acting GnRH promotes pseudomenopause by
decreasing ovarian E.
– 50% recurrence upon stopping.
– Bone loss at 6 months
Addback regimens: 25 ug E patch q week, 0.625 mg CEE QD, or
norethindrone acetate 5mg QD.
Levonorgestrel IUD
– Decrease severity of symptoms (pseudopregnancy).
Danazol (95% relief)
– Androgen side effects: hirsuitism, loss of female contour, liver tox
Endometriosis Surgery
Hysterectomy/BSO: 90% cure.
Presacral neurectomy: risks constipation,
helps midline pain.
Laparoscopic Uterosacral Nerve Ablation
(LUNA): no proven benefit.
Cystectomy vs ablation of cyst wall
– Both superior to simple drainage.
Infertility
No pregnancy after 1 year of adequate,
unprotected intercourse.
15% of all couples.
Increases with age.
Roughly equal between male and female
causes.
20% of cases are isolated male factor.
10% are unexplained.
Infertility
Basic workup
Ovulation?
– Tests of ovulation: history, BBT (.5 degree rise), urinary LH detection, timed
serum P.
Sperm?
– Volume 2ml, concentration 20m/ml, motility 40%, morphology 14% (30% WHO
III)
Anatomy?
– HSG (pretty reliable if says tubes are patent 85% specific, only fair if tubes are
blocked 54% sensitive)
– Not the greatest test for endometriosis.
Ovarian reserve?
– Elevated CD3 FSH ( abnormal if >10 IUm/L)
– Elevated CD3 Estradiol (abnormal if >75 pg/ml)
– Predicts outcomes with IVF, reliability not established for general public.
Post coital test.
– Not predictive.
Fertility
Septate uteri do not cause infertility.
Fibroids involving the cavity decrease
fertility.
Polyps >2cm decrease fertility
Endometriosis decreases fertility via egg
quality.
Obesity and cigarette smoking decrease
fertility.
Normal fertility
Fecundity
– approximately 20% per cycle during 20s and
early 30s.
– Approximately 10% at age 40.
– Most couples infertile by age 45.
– At age 44-45, age is more predictive of fertility
than is ovarian reserve.
RPL
3 consecutive losses with same partner
If no prior livebirths:
– 70% chance of livebirth in next pregnancy.
– 40% livebirth after 4 losses.
If prior livebirths:
– 70% livebirth until 6 losses.
Increases risk of ectopic, neural tube
defects
RPL: GEISHA
Genetic
5%
Endocrine 20%
Infections
5% (controversial)
Immune
20%
Structural
20%
Anybody’s guess (unknown) 30%
RPL
Thrombophilia
ACOG says the only definitive ones are
immune mediated:
– Anticardiolipin antibodies and Lupus
anticoagulant.
– These two are the best characterized.
These are the only two, for which
treatment has been demonstrated.
RPL -- Genetic
Normal
RPL -- Genetic
Robertsonian
balanced translocation
account for 2/3 genetic
etiologies.
6 possible gametes, only two can produce unaffected offspring.
RPL -- Genetic
Balanced
recipricol
translocation
Normal
Abnormal
Balanced
Abnormal
Four possible combinations with two unaffected gametes
Endocrinology of Pregnancy
Maternal Recognition of Pregnancy
– Progesterone is secreted by CL exclusively for 5-7
weeks, due to hCG
– After 6-7 weeks, placenta produces large amounts.
– After 9th week, removal of ovaries has no effect on
pregnancy.
– Progesterone production peaks at term.
– hCG quits doubling at 6-7 weeks gestation or at about
10K
– hCG peaks at 10 weeks
Endocrinology of Pregnancy
Function of P4 (summary)
– Pregnancy maintenance.
– Uterine quiescence
– Immune modulation
Is a fall in P associated with partuition?
– No.
Does P have a role in partuition?
– Yes
Explain:
– Receptor changes cause decreased function of P.
Endocrinology of Pregnancy
Placenta and steroid hormone production
What does the mother contribute to placental steroid
production?
– Cholesterol from LDL.
What does the baby contribute?
– DHEAS
Which enzymes does placenta lack?
– 17hydroxylase/17,20lyase and 21 hydroxylase
Consequence
– Placental steroid production stops at P (No androgens or
cortisol)
– E3 is produced by conversion of DHEAS
Endocrinology of Pregnancy
What is primary precursor for E?
Primary E of pregnancy?
What organ makes E3?
Role of placental estrogens?
Are Es required for pregnancy maint?
Conditions associated with low E?
Why has estriol been used as a
marker of fetal well being?
DHEAS from fetal adrenal.
Estriol aka E3 (90%)
Placenta converts fetal
precursors to E3
Increase uteroplacental
bloodflow.
Does not seem so. E is
mainly a sink to prevent
excess androgens.
Anencephally
Congenital adrenal lipoid
hyperplasia
Aromatase and sulfatase
deficiencies
Indicates HPA axis in fetus.
b/c DHEAS  Estriol