Crushing the CreogsCrushing the Creogs
Rapid PrimerRapid Primer
High YieldHigh Yield
AmenorrheaAmenorrhea
Abnormal puberty (delayed and Abnormal puberty (delayed and precocious)precocious)
EmbryologyEmbryology
Embryonic Sexual Embryonic Sexual DeterminationDetermination
Embryo bipotent at 5 Embryo bipotent at 5 wkswks
KaryotypeKaryotype– XY vs XXXY vs XX– SRY Gene (TDF)SRY Gene (TDF)
XX
No SRY
Normal female
Normal Male
XY
SRY
Embryonic Sexual Embryonic Sexual DeterminationDeterminationXX
XY (with SRY)
Ovary Testes at 6 weeks
Sertoli Leydig
Anti Mullerian Hormone
Testosterone DHT
Dev Ext Male
Ispilateral regressesionDev. Int. Male, ipsilaterally
““Default” pathwayDefault” pathway
MullerianDuct
UterineSeptum
Caudal tip ofMullerian Ducts
SinovaginalBulbs
(Vaginal plate)Urogenital Sinus
Lumen of uterus
Cervix
Fornix
Vagina
Hymen
Ovaries develop separately
Summary of Sex DeterminationSummary of Sex Determination
Embryo is bipotent at 5 weeks.Embryo is bipotent at 5 weeks.
If male (SRY, AMH, Testosterone/DHT) If male (SRY, AMH, Testosterone/DHT) starts male differentiation at 6 weeks.starts male differentiation at 6 weeks.
If no male differentiation If no male differentiation female is female is default pathway.default pathway.
Age
Gonadotropin
Prepubertal PhysiologyPrepubertal Physiology
+
-
Increasing weight, fat mass
Normal Puberty - Normal Puberty - GonadarcheGonadarche
Normal Puberty - Normal Puberty - GonadarcheGonadarche
Suppression of the gonadostat decreases.*Suppression of the gonadostat decreases.*
Nocturnal pulses in GnRH lead to:Nocturnal pulses in GnRH lead to:
Increasing FSH (then increasing LH) levels Increasing FSH (then increasing LH) levels lead to:lead to:
Increasing androgens and estrogen, leading Increasing androgens and estrogen, leading to:to:
– Everything we associate with puberty.Everything we associate with puberty.
Timing of puberty is largely geneticTiming of puberty is largely genetic
Estrogen Estrogen Breast Development and Breast Development and
Androgens Androgens Pubic Hair Pubic Hair
Bone Growth
Measurement of Puberty: Tanner Measurement of Puberty: Tanner StagesStages
Measurement of Puberty: Tanner Measurement of Puberty: Tanner StagesStages
Breast Pubic Hair
Stage 1 Elevation of papilla No pubic hair
Stage 2 Breast bud, areola enlarged
median age - 9.8 yrs
Sparse long pigmented hair, mostly labial
median age - 10.5 yrs (resident could count)
Stage 3 Further enlargement
median age - 11.2 yrs
Dark,coarse,curled hair, spread to mons
median age - 11.4 yrs (student could count)
Stage 4 Secondary mounding of areola
median age - 12.1 yrs
Adult type hair, abundant, limited to mons
median age - 12.0 yrs (to numerous to count)
Stage 5 Recession of 2° mound
median age - 14.6 yrs
Adult-type spread (thighs and abd)
median age - 13.7 yrs
There is NO stage Zero!
Order of Pubertal EventsOrder of Pubertal Events
Growth spurt / BreastsGrowth spurt / Breasts
Pubic hairPubic hair
Maximum growth velocityMaximum growth velocity
MensesMenses
aka “Boobs, pubes/pits and pads”aka “Boobs, pubes/pits and pads”
Normal Puberty - AdrenarcheNormal Puberty - AdrenarcheNormal Puberty - AdrenarcheNormal Puberty - Adrenarche
Independent of HPO axis. Independent of HPO axis.
Trigger unclearTrigger unclear
Generally precedes Generally precedes changes associated with changes associated with puberty.puberty.
Increase adrenal Increase adrenal androgens: DHEAS and androgens: DHEAS and A.A.
Mechanism: increased Mechanism: increased 17,20 lyase activity.17,20 lyase activity.
Appearance of Pubic Hair
The Menstrual CycleThe Menstrual CycleThe Menstrual CycleThe Menstrual Cycle
0
100
200
300
400
500
0
2
4
6
8
10
12
14
16
18
20
FSHFSHLHLHIU/LIU/L
2 4 6 8 10 2812 14 16 18 2420 22 260
1
2
3
4
5
6
7
8
9
10
PPng/mlng/ml
LHLH
FSHFSH
EE22
PP
OvulationMenses
EndocrinologyEndocrinologyEndocrinologyEndocrinology
Inh-BInh-BInh-AInh-A
Inh-Inh-AA//BBEEpg/mlpg/ml
22
ContinuousContinuous process process
Occurs in “waves”Occurs in “waves”
Stimulus/mechanism unknownStimulus/mechanism unknown
Independent of gonadotropinsIndependent of gonadotropins– Occurs in prepubertal ovaryOccurs in prepubertal ovary– Uninterupted by pregnancy, OCPUninterupted by pregnancy, OCP
Ends with follicular depletionEnds with follicular depletion
Preantral FolliclePreantral FollicleInitiation of Follicular GrowthInitiation of Follicular Growth
Preantral FolliclePreantral FollicleInitiation of Follicular GrowthInitiation of Follicular Growth
0
100
200
300
400
500
0
2
4
6
8
10
12
14
16
18
20
FSHFSHLHLHIU/LIU/L
EE22
pg/mlpg/ml
2 4 6 8 10 2812 14 16 18 2420 22 260
1
2
3
4
5
6
7
8
9
10
PPng/mlng/ml
LHLH
FSHFSH
EE22
PP
OvulationOvulationMensesMenses
GrowthGrowth AtresiaAtresia
Timely gonadotropin stimulation Timely gonadotropin stimulation can promote further growthcan promote further growth– Intercycle rise in FSH crucial Intercycle rise in FSH crucial
for continued development for continued development
Without gonadotropin support, Without gonadotropin support, doomed to atresiadoomed to atresia
Preantral FolliclePreantral FollicleIn Delicate BalanceIn Delicate BalancePreantral FolliclePreantral FollicleIn Delicate BalanceIn Delicate Balance
The “Two Cell, Two The “Two Cell, Two Gonadotropin Concept”Gonadotropin Concept”
The “Two Cell, Two The “Two Cell, Two Gonadotropin Concept”Gonadotropin Concept”
LH
LH Receptor
THECA CELLTHECA CELL
ATP cAMP
Androstenedione Testosterone
Cholesterol
Pregnenolone
GRANULOSA CELLGRANULOSA CELL
ATP
cAMP
Androstenedione Testosterone
FSH
Estrone Estradiol
Basement MembraneBasement Membrane
P450sccP450scc
P450c17P450c17
P450aromP450arom<< >>
Dominant FollicleDominant FollicleSelection MechanismsSelection MechanismsDominant FollicleDominant Follicle
Selection MechanismsSelection MechanismsNormal ovulatory quota = 1Normal ovulatory quota = 1
Rising estrogen levels Rising estrogen levels – positive feedback locallypositive feedback locally– negative feedback centrallynegative feedback centrally
Rising inhibin levels Rising inhibin levels – further negative feedback further negative feedback
Declining FSH levelsDeclining FSH levels– withdraw growth support withdraw growth support – Atresia in lesser follicles atresiaAtresia in lesser follicles atresia
Dominant Follicle SelectionDominant Follicle Selection“Survival of the Fittest”“Survival of the Fittest”
Dominant Follicle SelectionDominant Follicle Selection“Survival of the Fittest”“Survival of the Fittest”
Selected follicleSelected follicle– More and larger cellsMore and larger cells
– more FSH receptor and greater sensitivity to falling more FSH receptor and greater sensitivity to falling FSHFSH
– more aromatasemore aromatase
Advanced vascular development provides Advanced vascular development provides preferential delivery of FSH and LDL substratepreferential delivery of FSH and LDL substrate
LHLH
FSHFSH
P Plasmin
Collagenase
PG
PB
Smooth MuscleSmooth MuscleFibersFibers
OvulationOvulation
OMI
PG
LI LH
LH stimulates meiosis, luteinization, and LH stimulates meiosis, luteinization, and PG productionPG production
P enhances proteolytic enzymes P enhances proteolytic enzymes
FSH stimulates expansion of cumulus and FSH stimulates expansion of cumulus and plasmin to stimulate collagenaseplasmin to stimulate collagenase
EstradiolEstradiol
ProgesteroneProgesterone
Corpus LuteumCorpus LuteumCorpus LuteumCorpus LuteumFollicle wall becomes convolutedFollicle wall becomes convoluted
Luteal cells enlarge, acquire lutein Luteal cells enlarge, acquire lutein pigment and lipidpigment and lipid
Capillary network penetrates granulosaCapillary network penetrates granulosa
Production of large amounts of both E & Production of large amounts of both E & PP
E & P act centrally and locally to E & P act centrally and locally to suppresses new follicular growthsuppresses new follicular growth
Corpus Luteum Corpus Luteum Requirements for Normal Luteal Requirements for Normal Luteal
FunctionFunction
Corpus Luteum Corpus Luteum Requirements for Normal Luteal Requirements for Normal Luteal
FunctionFunction
Optimal preovulatory follicular development - luteal cell massOptimal preovulatory follicular development - luteal cell mass– Adequate follicular phase FSHAdequate follicular phase FSH
Tonic LH stimulationTonic LH stimulation
LDL cholesterol substrateLDL cholesterol substrate
0
100
200
300
400
500
0
2
4
6
8
10
12
14
16
18
20
FSHFSHLHLHIU/LIU/L
EE22
pg/mlpg/ml
2 4 6 8 10 2812 14 16 18 2420 22 260
1
2
3
4
5
6
7
8
9
10
PPng/mlng/ml
LHLH
FSHFSH
EE22
PP
OvulationOvulationMensesMenses
Ovarian CycleOvarian CycleConceptionConception
Ovarian CycleOvarian CycleConceptionConception
hCGhCG
Normal mensesNormal menses
24-35 days24-35 days
2-7 days of flow2-7 days of flow
35ml (mean) <80 cc of non-clotting debris.35ml (mean) <80 cc of non-clotting debris.
Abnormal PubertyAbnormal Puberty
Terminology of Precocious PubertyTerminology of Precocious PubertyTerminology of Precocious PubertyTerminology of Precocious Puberty
GnRH - Dependent GnRH - Dependent aka aka True Precocious True Precocious Puberty Puberty aka Central Precocious Pubertyaka Central Precocious Puberty
GnRH - Independent GnRH - Independent aka aka Precocious Precocious Pseudopuberty Pseudopuberty aka Peripheral Precocious aka Peripheral Precocious PubertyPuberty
Isolated Precocious DevelopmentIsolated Precocious Development
Precocious PubertyPrecocious Puberty
Bone Age guides therapy.Bone Age guides therapy.
Bone age, bone age, bone ageBone age, bone age, bone age
Typically, once menses have started, Typically, once menses have started, growth is limited to 6 cm more. growth is limited to 6 cm more.
Mature Axis: GnRH stim test LH > FSH rise.
Prepubertal: GnRH stim test FSH > LH rise.
GnRH Dependent GnRH Dependent femalefemale male maleIdiopathicIdiopathic 74%74% 41%41%
CNS problemCNS problem 7%7% 26%26%
GnRH IndependentGnRH Independent Ovarian (cyst or tumor)Ovarian (cyst or tumor) 11%11% n/a n/a
TesticularTesticular n/an/a 10%10%
McCune-AlbrightMcCune-Albright 5%5% 1% 1%
Adrenal feminizingAdrenal feminizing 1%1% 0% 0%
Adrenal masculinizingAdrenal masculinizing 1%1% 22%22%
Ectopic gonadotropinEctopic gonadotropin 0.5%0.5% 0.5%0.5%
HypothyroidismHypothyroidism
Exogenous SteroidsExogenous Steroids
Etiologies of Precocious PubertyEtiologies of Precocious PubertyEtiologies of Precocious PubertyEtiologies of Precocious Puberty
1° Gonadotropin Elevation1° Gonadotropin ElevationCNS CausesCNS Causes– Hypothalamic TumorHypothalamic Tumor
Hamartoma (secretes GnRH), Hamartoma (secretes GnRH), Craniopharyngioma, Glioma, Ependymomas, Craniopharyngioma, Glioma, Ependymomas, NeurofibromaNeurofibroma
– Congenital malformation Congenital malformation Hydrocephalus, Rickett’s (skull malformation)Hydrocephalus, Rickett’s (skull malformation)
– Pineal tumorPineal tumor– Trauma (brain injury stims TGFTrauma (brain injury stims TGF which stims which stims
GnRH)GnRH)– EncephalitisEncephalitis
1° Steroid Elevation1° Steroid Elevation1° Steroid Elevation1° Steroid Elevation
TumorTumor– OvaryOvary
may produce estrogens, androgens, hCG - may produce estrogens, androgens, hCG - typically causing heavy irreg. bleedingtypically causing heavy irreg. bleeding
80% have palpable mass80% have palpable mass
granulosa, theca, gonadoblastomas, granulosa, theca, gonadoblastomas, teratomas, lipoid cell, cystadenomas, teratomas, lipoid cell, cystadenomas, epithelial cancerepithelial cancer
– Feminizing Adrenal TumorFeminizing Adrenal Tumorvery rare, usu. associated with very rare, usu. associated with DHA-S DHA-S
McCune Albright SyndromeMcCune Albright SyndromeMcCune Albright SyndromeMcCune Albright Syndromeaka polyostic fibrous dysplasiaaka polyostic fibrous dysplasiaMechanismMechanism:: – Activating mutation of GActivating mutation of Gss
resulting in unregulated cAMP resulting in unregulated cAMP formation.formation.
– Somatic mosaicSomatic mosaic mutation, therefore mutation, therefore not lethal and variable phenotype.not lethal and variable phenotype.
Classic TriadClassic Triad::– cystic bone lesions causing easy cystic bone lesions causing easy
fracture - Tc bone scanfracture - Tc bone scan– cafe au lait spotscafe au lait spots– sexual precocitysexual precocity
Findings in Various DisordersFindings in Various Disorders
Gonadal Gonadal SizeSize
Basal FSH Basal FSH & LH& LH
E or T E or T LevelsLevels
DHEASDHEAS GnRH GnRH ResponseResponse
IdiopathicIdiopathic IncreasedIncreased IncreasedIncreased IncreasedIncreased IncreasedIncreased Pubertal Pubertal LH>FSHLH>FSH
CerebralCerebral IncreasedIncreased IncreasedIncreased IncreasedIncreased IncreasedIncreased Pubertal Pubertal LH>FSHLH>FSH
GonadalGonadal Unilat Unilat enlargedenlarged
DecreasedDecreased IncreasedIncreased IncreasedIncreased Flat*Flat*
McCune- McCune- AlbrightAlbright
IncreasedIncreased DecreasedDecreased IncreasedIncreased IncreasedIncreased Flat*Flat*
AdrenalAdrenal SmallSmall DecreasedDecreased IncreasedIncreased IncreasedIncreased Flat*Flat*
Isolated Premature Isolated Premature DevelopmentDevelopment
Isolated ThelarcheIsolated Thelarche– May be unilateral, may wax and waneMay be unilateral, may wax and wane– Normal growthNormal growth
Isolated Premature MenarcheIsolated Premature Menarche– VERY rare: suspect trauma or foreign body, VERY rare: suspect trauma or foreign body,
tumor.tumor.
Isolated Premature AdrenarcheIsolated Premature Adrenarche– Rule out CAHRule out CAH
Treatment ObjectivesTreatment ObjectivesTreatment ObjectivesTreatment Objectives
Dx and Rx any intracranial diseaseDx and Rx any intracranial diseaseDx and surgically treat peripheral Dx and surgically treat peripheral tumorstumorsArrest maturation until appropriate ageArrest maturation until appropriate ageLessen established precocious Lessen established precocious characteristicscharacteristicsMaximize adult heightMaximize adult heightAvoidance of abuse, treat emotional Avoidance of abuse, treat emotional problems, and consider contraceptionproblems, and consider contraception
Treatment of Central Precocious PubertyTreatment of Central Precocious PubertyTreatment of Central Precocious PubertyTreatment of Central Precocious Puberty
GnRHa therapy – GnRHa therapy – – monitor growth, 2° sexual characteristics, monitor growth, 2° sexual characteristics,
bone age, and keep E2 < 10 or maintain bone age, and keep E2 < 10 or maintain negative GnRH stim testnegative GnRH stim test
– GnRH may be used in the case of hamartomaGnRH may be used in the case of hamartoma
Delayed PubertyDelayed PubertyDelayed PubertyDelayed Puberty
Most girls in USA enter puberty by age 13Most girls in USA enter puberty by age 13
Workup whenWorkup when– no 2° sex characteristics by age 13no 2° sex characteristics by age 13– absence of menarche by age 16absence of menarche by age 16– 5 years between onset thelarche and 5 years between onset thelarche and
menarchemenarche
Delayed puberty is rare in girls and is Delayed puberty is rare in girls and is commonly associated with pathologycommonly associated with pathology
Delayed PubertyDelayed Puberty
Hypergonadotropic HypogonadismHypergonadotropic Hypogonadism 43%43%– Ovarian failure – abnormal karyotype (26%)Ovarian failure – abnormal karyotype (26%)
Turner’s SyndromeTurner’s Syndrome– Ovarian failure – normal karyotypeOvarian failure – normal karyotype
46XX (15%)46XX (15%)
46XY ( 2%)46XY ( 2%)– Other (rare)Other (rare)
1717 hydroxylase deficiency hydroxylase deficiency (HTN, sexual infantilism, (HTN, sexual infantilism, high P)high P)
Sickle Cells Disease, Torsion, Resistant Ovary Sickle Cells Disease, Torsion, Resistant Ovary SyndromeSyndrome
Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies
Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies
Hypogonadotropic HypogonadismHypogonadotropic Hypogonadism31%31% – Reversible (18%)Reversible (18%)
Physiologic delayPhysiologic delay 10%10%
Weight loss/anorexiaWeight loss/anorexia 3% 3%
ProlactinomaProlactinoma 1.5% 1.5%
1° hypothyroidism1° hypothyroidism 1% 1%
CAHCAH 1% 1%
Cushing’sCushing’s 0.5% 0.5%
Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies
Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies
Hypogonadotropic Hypogonadism Hypogonadotropic Hypogonadism 31%31%– Irreversible (13%)Irreversible (13%)
GnRH deficiencyGnRH deficiency 7%7%– Kallman’s, Prader WilliKallman’s, Prader Willi– GP54R, Leptin Receptor deficiencyGP54R, Leptin Receptor deficiency– Irradiation, infiltrating diseaseIrradiation, infiltrating disease
HypopituitarismHypopituitarism 3%3%CraniopharyngiomasCraniopharyngiomas 1%1%Congenital CNS defectsCongenital CNS defects 0.5% 0.5%pituitary adenomaspituitary adenomas 0.5% 0.5%Malignant pituitary tumorMalignant pituitary tumor 0.5% 0.5%
Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies
Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies
Eugonadism Eugonadism 26%26%
– Mullerian agenesisMullerian agenesis 14%14%– Inappropriate + feedback 7%Inappropriate + feedback 7%
(PCOS)(PCOS)– Vaginal septumVaginal septum 3% 3%– Androgen insensitivityAndrogen insensitivity 1% 1%– Imperforate hymenImperforate hymen 0.5% 0.5%
Three Cases of Amenorrhea Three Cases of Amenorrhea and Blind Pouchand Blind Pouch
MRKHMRKH– Normal pubic hair & breasts. No cyclic pain. Normal pubic hair & breasts. No cyclic pain.
AISAIS– Scant pubic hair, normal breast. No pain.Scant pubic hair, normal breast. No pain.– Androgen Receptor Defect (can’t respond to Androgen Receptor Defect (can’t respond to
Androgens, develop breasts because unopposed E, Androgens, develop breasts because unopposed E, have testes/AMH therefore don’t develop uterus.)have testes/AMH therefore don’t develop uterus.)
Transverse SeptumTransverse Septum– Normal pubic hair & breasts. Normal pubic hair & breasts. Cyclic Pain!Cyclic Pain!
Idiopathic Precocious PubertyIdiopathic Precocious Puberty
Spontaneous increase in GnRH.Spontaneous increase in GnRH.
Diagnosis of exclusion.Diagnosis of exclusion.
Treat with GnRH-agonist.Treat with GnRH-agonist.
Know for CREOGSKnow for CREOGSOrder of pubertal stages.Order of pubertal stages.
Genetics = #1 determinant of timing.Genetics = #1 determinant of timing.
Average age of menarche is 12.8Average age of menarche is 12.8
Precocious puberty: prior to age 8Precocious puberty: prior to age 8
Delayed puberty: absence of 2Delayed puberty: absence of 2ndary ndary chars by age chars by age 1313
McCune-Albright SyndromeMcCune-Albright Syndrome
Clinical Differences between AIS, Transverse Clinical Differences between AIS, Transverse Septum and Mullerian AgenesisSeptum and Mullerian Agenesis
AmenorrheaAmenorrhea
Primary: Primary: – No menses by 16 in the presence normal No menses by 16 in the presence normal
growth and secondary sex characteristicsgrowth and secondary sex characteristics– No menses by 14 without secondary sex No menses by 14 without secondary sex
characteristicscharacteristics
Secondary:Secondary:– H/o previous menses. H/o previous menses. – No menses in for past three expected cycles No menses in for past three expected cycles
or past 6 months. or past 6 months.
Primary Amenorrhea PearlsPrimary Amenorrhea Pearls
Physical Exam is essential.Physical Exam is essential.– Breasts = Estrogen exposure.Breasts = Estrogen exposure.– Normal height = Estrogen exposure.Normal height = Estrogen exposure.– Uterus = Eliminates AIS, MRKH, Transverse Uterus = Eliminates AIS, MRKH, Transverse
Septum.Septum.
Broad DDxBroad DDx– Hypergonadotropic (ovarian failure)Hypergonadotropic (ovarian failure)– Hypogonadotropic (CNS, Pituitary issue)Hypogonadotropic (CNS, Pituitary issue)– Eugonadal (Secondary amenorrhea w/u)Eugonadal (Secondary amenorrhea w/u)
Primary AmenorrheaPrimary AmenorrheaIncreased FSHIncreased FSH
Gonadal FailureGonadal FailureMost common cause is Most common cause is geneticgenetic: XO or mosaic : XO or mosaic (XO/XX), or XY(XO/XX), or XY– Turners: Short stature, webbed neck, wide spaced Turners: Short stature, webbed neck, wide spaced
nipples, increased arm carrying angle, coarctation, nipples, increased arm carrying angle, coarctation, low posterior hair line, renal abnormalities, streak low posterior hair line, renal abnormalities, streak gonads.gonads.
GalactosemiaGalactosemia: failure to thrive, abnormal FSH : failure to thrive, abnormal FSH and LH and failure of germ cells to migrate to and LH and failure of germ cells to migrate to ovary.ovary.1717 hydroxylase deficiency hydroxylase deficiency (HTN, hypokalemia) (HTN, hypokalemia) with high 17-OHPwith high 17-OHP
Steroid SynthesisSteroid Synthesis
Start with cholesterol (27C)Start with cholesterol (27C)Rate limiting reaction is side chain cleavage 27C Rate limiting reaction is side chain cleavage 27C 21C 21C PregnenolonePregnenolone
21 Carbons21 Carbons: progestins, glucocorticoids, : progestins, glucocorticoids, mineralocorticoidsmineralocorticoids
19 Carbons19 Carbons: Androgens: Androgens
18 Carbons18 Carbons: Estrogens: Estrogens
Cortisol levels are Cortisol levels are regulated tightly, regulated tightly, others are not. others are not. – if cortisol synthesis is if cortisol synthesis is
limited, ACTH limited, ACTH increases to overcome increases to overcome blockage. blockage.
– precursors build upprecursors build up
Adrenal Steroid DisordersAdrenal Steroid Disorders
CAH (CAH ( nomal genitalia vs nomal genitalia vs ambiguous) ambiguous)– 21 hydroxylase deficiency (90% of cases)21 hydroxylase deficiency (90% of cases)– 1111 hydroxylase deficiency (5% of cases) hydroxylase deficiency (5% of cases)– 33 dehydrogenase deficiency (rare) dehydrogenase deficiency (rare)
Pubertal Disorders (Pubertal Disorders ()) vs Ambiguous vs Ambiguous Genitalia (Genitalia ())– 1717 hydroxylase deficiency hydroxylase deficiency – 1717 dehydrogenase deficiency dehydrogenase deficiency
CAH -- 21 Hydroxlase CAH -- 21 Hydroxlase
Most common enzyme deficiency leading Most common enzyme deficiency leading to congenital adrenal hyperplasia.to congenital adrenal hyperplasia.
Name is confusing: (named backwards)Name is confusing: (named backwards)– It adds on –OH group to C21It adds on –OH group to C21– Named this way because, scientists were Named this way because, scientists were
working back from cortisol and aldosterone. working back from cortisol and aldosterone.
The product names confuse people, for The product names confuse people, for the same reasons.the same reasons.
CAH – 11CAH – 11 hydroxylase hydroxylase deficiencydeficiency
Presentation more Presentation more variablevariable
HypertensionHypertension– Incr 11DOCIncr 11DOC
NaNa++ overload overload
Hypo KHypo K++
Female masculinizedFemale masculinized
Addisons possible Addisons possible with stresswith stress
1717 Hydroxylase Deficiency Hydroxylase Deficiency
Female pubertal delayFemale pubertal delayMale ambiguous genitaliaMale ambiguous genitaliaHTNHTN due to mineralocorticoid due to mineralocorticoid affect of 11-DOCaffect of 11-DOCHypokalemiaHypokalemia17-OHP is low.17-OHP is low.Renin low due to Na retension Renin low due to Na retension and water expansion.and water expansion.Aldosterone is also lowAldosterone is also lowLow urinary 17 keto-steroidsLow urinary 17 keto-steroids
CAH DiagnosisCAH Diagnosis
Screening Test is 17-Screening Test is 17-OHPOHP
Diagnosis made with Diagnosis made with ACTH stimulation ACTH stimulation test. test.
Measure cortisol and Measure cortisol and precursors before and precursors before and after. after.
CAH SummaryCAH Summary
The Cortisol, Aldo The Cortisol, Aldo enzymes are named enzymes are named backwards.backwards.21-hydroxylase def. is 21-hydroxylase def. is most common cause most common cause of CAH.of CAH.11-hydroxylase is 211-hydroxylase is 2ndnd Blockages lead to Blockages lead to buildup of precursors buildup of precursors and androgens.and androgens.
PCOSPCOS
Rotterdam Diagnostic CriteriaRotterdam Diagnostic CriteriaNeed two of threeNeed two of three
Chronic Oligo-Anovulation
Hyperandrogenism Polycystic Ovaries
Rule out other causes
Differential DiagnosisDifferential Diagnosis
Late-onset congenital adrenal hyperplasiaLate-onset congenital adrenal hyperplasia
Idiopathic (constitutional) hirsutismIdiopathic (constitutional) hirsutism
Hypothalamic amenorrheaHypothalamic amenorrhea
Premature ovarian failurePremature ovarian failure
ProlactinProlactin
ThyroidThyroid
Differential DiagnosisDifferential Diagnosis
Cushing’s SyndromeCushing’s Syndrome
Androgen producing tumorsAndrogen producing tumors
AcromegalyAcromegaly
Anabolic drugsAnabolic drugs
PathogenesisPathogenesis
Anovulation
Increasedandrogens
Acyclic, elevatedestrogen
Increased LHPCOS
Hirsutism
Amenorrhea
Polycystic ovaries
Insulinresistance& obesity
SHBG
FSH
Converted to DHT
‘‘Metabolic Syndrome’Metabolic Syndrome’
Insulin ResistanceAbdominal Obesity
Diabetesmellitus
Hypertension DyslipidemiaHigh triglycerides
Low HDL
Atherosclerosis PCOS
PCOS TreatmentPCOS Treatment
Management of mensesManagement of menses– OCP (35mcg EE), Mirena, Cyclic POCP (35mcg EE), Mirena, Cyclic P
Management of hirsuitismManagement of hirsuitism– OCP, Spironolactone, Finasteride, Vaniqa, LaserOCP, Spironolactone, Finasteride, Vaniqa, Laser
Management of insulin resistanceManagement of insulin resistance– Weight loss, metformin, exercise.Weight loss, metformin, exercise.– Metformin most useful if patient overweight.Metformin most useful if patient overweight.
FertilityFertility– Ovulation induction: clomid, letrozole, metforminOvulation induction: clomid, letrozole, metformin
Clomid = anti estrogen (increases FSH)Clomid = anti estrogen (increases FSH)Letrozole = aromatase inhibitor (increases FSH)Letrozole = aromatase inhibitor (increases FSH)Require functioning hypothalmus/pituitary!!!Require functioning hypothalmus/pituitary!!!
HirsuitismHirsuitism
HirsuitimHirsuitim– Excess terminal hair in male pattern.Excess terminal hair in male pattern.
Midline chest, face, back, lower midline Midline chest, face, back, lower midline abdomen. Arm and leg hair get darker.abdomen. Arm and leg hair get darker.
VirilizationVirilization– Deepening voice, clitoromegally, breast Deepening voice, clitoromegally, breast
atrophy and loss of feminine contour. atrophy and loss of feminine contour.
Causes of HirsuitismCauses of Hirsuitism
EthnicityEthnicityIdiopathic (intrinsic 5a reductase activity)Idiopathic (intrinsic 5a reductase activity)Insulin stimulates pilosebaceous unit, ovarian Insulin stimulates pilosebaceous unit, ovarian androgen production and decreases SHBGandrogen production and decreases SHBGPCOSPCOSCAHCAHOvarian tumorOvarian tumorAdrenal tumorAdrenal tumorCushings, hyperprolactinemiaCushings, hyperprolactinemia
Hirsuitism WorkupHirsuitism Workup
Androgen assays not very reliable in women.Androgen assays not very reliable in women.
Rapid change associated with pathologyRapid change associated with pathology– Free T – most sensitive, rarely neededFree T – most sensitive, rarely needed..– Total T – used to rule out ovarian tumor, or follow Total T – used to rule out ovarian tumor, or follow
treatmenttreatment– DHEAS – used to rule out adrenal tumor DHEAS – used to rule out adrenal tumor – 17-OHP – screen for CAH17-OHP – screen for CAH– PRL – can lead to increased DHEASPRL – can lead to increased DHEAS
Consider Insulin Resistance, Cortisol, GHConsider Insulin Resistance, Cortisol, GH
Hirsuitism TreatmentsHirsuitism Treatments
Takes 6 months to arrest new hair growth. Takes 6 months to arrest new hair growth.
Lifestyle changes, as neededLifestyle changes, as needed
Cosmetic treatments:Cosmetic treatments:
Laser, ElectrolysisLaser, Electrolysis
Eflornithine (Vaniqa) – arrests new hair Eflornithine (Vaniqa) – arrests new hair growth – twice a day x 4 hours. 58% had growth – twice a day x 4 hours. 58% had overall improvement.overall improvement.
Hirsuitism TreatmentsHirsuitism Treatments
OCPs are off-label and no studies of adequate power to OCPs are off-label and no studies of adequate power to show benefit.show benefit.– Decrease LH (decrease androgens)Decrease LH (decrease androgens)– Increase SHBGIncrease SHBG
Spironolactone (Spironolactone (need contraceptionneed contraception))– Directly blocks androgen receptor and mildly inhibits 5a Directly blocks androgen receptor and mildly inhibits 5a
reductasereductase– Cheap and more affective than finasteride.Cheap and more affective than finasteride.– More side effects: polyuria, hypotension, fatique, hyperKMore side effects: polyuria, hypotension, fatique, hyperK
Finasteride (Finasteride (need contraceptionneed contraception))– 5a reductase inhibitor5a reductase inhibitor– Non-toxicNon-toxic
Flutamide (Flutamide (need contraceptionneed contraception))– Androgen receptor blocker, but Androgen receptor blocker, but liver toxliver tox limits use. limits use.
HyperprolactinemiaHyperprolactinemia
Elevated prolactin: Elevated prolactin:
May interfere with GnRH secretion to cause:May interfere with GnRH secretion to cause:– Short luteal phaseShort luteal phase– OligomenorrheaOligomenorrhea– AmenorrheaAmenorrhea
GalactorrheaGalactorrhea
HirsuitismHirsuitism
Bone lossBone loss
Decreased libido in menDecreased libido in men
HyperprolactinemiaHyperprolactinemia
InhibitorsInhibitors– Dopamine (primary Dopamine (primary
regulator via portal regulator via portal system)system)
– ProlactinProlactin
StimulatorsStimulators– TRHTRH– EstrogenEstrogen– VIP (food)VIP (food)– Oxytocin (sex, nipple Oxytocin (sex, nipple
stimulation)stimulation)– Many drugsMany drugs
HyperprolactinemiaHyperprolactinemia
Galactorrhea is bilateral and white. Galactorrhea is bilateral and white. May be seen with normal prolactin levels. May be seen with normal prolactin levels. – Assay does not reflect biologic activity.Assay does not reflect biologic activity.– May not detect nocturnal PRL secretion. May not detect nocturnal PRL secretion.
Fat seen on smear.Fat seen on smear.#1 cause of hyperprolactinemia is idiopathic. #1 cause of hyperprolactinemia is idiopathic. The higher the prolactin, the greater the chance The higher the prolactin, the greater the chance of having an adenoma. of having an adenoma. Renally and hepatically cleared, so increased Renally and hepatically cleared, so increased with renal failure and liver disease. with renal failure and liver disease.
HyperPRL – CNS IssuesHyperPRL – CNS Issues
Microadenoma <10mm, usually does not Microadenoma <10mm, usually does not grow.grow.Macroadenoma Macroadenoma >> 10mm (may secrete 10mm (may secrete GH, ACTH, TSH, FSH or nothing)GH, ACTH, TSH, FSH or nothing)Infiltrating disorders (sarcoid, TB)Infiltrating disorders (sarcoid, TB)RadiationRadiationEmpty Sella Syndrome (herniation of CNS Empty Sella Syndrome (herniation of CNS fluid into sella and compresses stalk)fluid into sella and compresses stalk)Rathke’s cyst or other stalk tumors.Rathke’s cyst or other stalk tumors.
PRL and RxPRL and Rx
AntipsychoticsAntipsychotics
AntidepressantsAntidepressants
Opiates & CocaineOpiates & Cocaine
VerapamilVerapamil
MethyldopaMethyldopa
MetoclopramideMetoclopramide
H2 blockers ranitidine H2 blockers ranitidine and cimetidineand cimetidine
EstrogenEstrogen
DilantinDilantin
PRL levels usually return to normal within 2-4 days of stopping Rx
Prolactin VariantsProlactin Variants
PRL = normal bioactive formPRL = normal bioactive form
Big PRL (macro-PRL dimers which are Big PRL (macro-PRL dimers which are connected, can lyse and become connected, can lyse and become bioactive)bioactive)
Big-Big PRL (little bioactivity, but cross Big-Big PRL (little bioactivity, but cross react with assay)react with assay)
When to image for PRL?When to image for PRL?
Debatable. No clear answer.Debatable. No clear answer.– Some say any elevation is indication. Some say any elevation is indication. – Levels > Levels > 100 ng/ml100 ng/ml in absence of drug is in absence of drug is
universally accepted.universally accepted.– Antipsychotics my raise PRL into 300 range. Antipsychotics my raise PRL into 300 range.
(Still no one would fault you for imaging.) (Still no one would fault you for imaging.)
MRIMRI with and without contrast is image of with and without contrast is image of choice. choice.
HyperPRL TxHyperPRL Tx
Remove offending agentRemove offending agentBromocriptine (DA agonist) (FDA+)Bromocriptine (DA agonist) (FDA+)– Ergot deriv. Usually req 2-3x/day doseErgot deriv. Usually req 2-3x/day dose– 12% nausea, headache, syncope, dizziness and orthostatic 12% nausea, headache, syncope, dizziness and orthostatic
hypotensionhypotension– PO or PV route good. PO or PV route good.
Cabergoline (DA agonist) (Off label)Cabergoline (DA agonist) (Off label)– Long t 1/2 , give 2 x per weekLong t 1/2 , give 2 x per week– Few side effectsFew side effects
Both lead to tumor shrinkage.Both lead to tumor shrinkage.Except in cases of neurologic emergency, Rx therapy is Except in cases of neurologic emergency, Rx therapy is always first choice. always first choice.
MenopauseMenopause
Menopause DefinitionsMenopause Definitions
MenopauseMenopause: cessation of menses for 12 months due to : cessation of menses for 12 months due to loss of ovarian function.loss of ovarian function.– Average age 51Average age 51– Younger if smoker, Hispanic, African American.Younger if smoker, Hispanic, African American.
ClimactericClimacteric (perimenopause begins 5-6 years prior) (perimenopause begins 5-6 years prior) symptoms appear (vasomotor and irregular cycles.)symptoms appear (vasomotor and irregular cycles.)– Natural menopause: gradual decline, characterized by Natural menopause: gradual decline, characterized by
fluctuating E and FSH. fluctuating E and FSH. – Increase FSH due to loss of inhibin!Increase FSH due to loss of inhibin!
Premature ovarian failurePremature ovarian failure/menopause /menopause <<4040– Under 30 should get karyotypeUnder 30 should get karyotype to look for Y chromosome. to look for Y chromosome.– Consider Fragile X gene mutation testing (FMR1)Consider Fragile X gene mutation testing (FMR1)
Surgical menopauseSurgical menopause: sudden drop in E.: sudden drop in E.
Managing PerimenopauseManaging Perimenopause
Standard HRT doses Standard HRT doses will not prevent will not prevent pregnancypregnancy and should not be used as first and should not be used as first line agents unless a patient is surgically line agents unless a patient is surgically sterile or cannot take OCP.sterile or cannot take OCP. The patch:The patch:– Low dose patch 0.025 mg will reduce hot Low dose patch 0.025 mg will reduce hot
flashes by 85%. flashes by 85%. – If the patient has a uterus, you must give If the patient has a uterus, you must give
progestin therapyprogestin therapy for 14 days q monthfor 14 days q month..
Hot Flash Alternative ApproachesHot Flash Alternative Approaches
Lifestyle changes, cool environment Lifestyle changes, cool environment
BiofeedbackBiofeedback
Vitamin E, dong quai, and black cohoshVitamin E, dong quai, and black cohosh——no no difference compared with placebodifference compared with placebo
PhytoestrogensPhytoestrogens
Clonidine (patch or pill)Clonidine (patch or pill)
MegestrolMegestrol
SSRI/SNRI therapySSRI/SNRI therapy
Menopausal ChangesMenopausal Changes
SymptomsSymptoms: hot flashes (catecholamine : hot flashes (catecholamine mediated) hot and cold, night sweats, mood mediated) hot and cold, night sweats, mood changes, insomnia, vaginal atrophy, possibly changes, insomnia, vaginal atrophy, possibly skin changes.skin changes.
Bone lossBone loss (most in first 5 years), especially (most in first 5 years), especially trabecular bone. trabecular bone.
Increased Increased central obesitycentral obesity..
Lipid abnormalitiesLipid abnormalities..– Latter two increase Latter two increase HTN, CADHTN, CAD risk. risk.
ManagementManagement
Protect bone.Protect bone.
Protect against hyperplasia.Protect against hyperplasia.
Alleviate symptoms.Alleviate symptoms.
Promote healthy living.Promote healthy living.
Bone Mass by Age and SexBone Mass by Age and Sex
10 20 30 40 50 60 70 80
Bo
ne
Mas
s
Age (years)
Men Women
Menopause-AssociatedBone Loss
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.
OsteoporosisOsteoporosisDEXA scan = gold standard DEXA scan = gold standard (Dual Energy Xray Absorptiometry)(Dual Energy Xray Absorptiometry)
T scoreT score = StDev from healthy 30yo woman. = StDev from healthy 30yo woman.– Osteopenia = T -1 to -2.5Osteopenia = T -1 to -2.5– Osteoporosis = T < -2.5Osteoporosis = T < -2.5
Z scoreZ score = StDev from same age woman. = StDev from same age woman.– Used in premenopausal women.Used in premenopausal women.
T & Z scores correlate with fracture risk.T & Z scores correlate with fracture risk.– DEXA less reliable in Obese (artificially low T score) and DEXA less reliable in Obese (artificially low T score) and
osteoarthritis (artificially high T score) osteoarthritis (artificially high T score) Error range of DEXA = ~7% and repeat test not valid at <1 year, Error range of DEXA = ~7% and repeat test not valid at <1 year, more valid at 2 years.more valid at 2 years.Urinary and serum markers of bone turnover measure Urinary and serum markers of bone turnover measure cancellous bone. cancellous bone. (Telopeptides most commonly used, if at all)(Telopeptides most commonly used, if at all)
When to Measure BMD in When to Measure BMD in Postmenopausal WomenPostmenopausal Women
Non-ModifiableNon-ModifiableAge Age >> 65 65
Caucasian RaceCaucasian Race
FemaleFemale
Family historyFamily history
History of fractureHistory of fracture
History of fallsHistory of falls
Bad EyesightBad Eyesight
ModifiableModifiableSmoking CigarettesSmoking Cigarettes
Low Body WeightLow Body Weight
ETOHETOH
Not on HRT (low E)Not on HRT (low E)
HypothyroidismHypothyroidism
Immobility*Immobility*
Poor nutritionPoor nutrition
Medications (steroids Medications (steroids and heparin)and heparin)
One or more risk factors
Treatment OptionsTreatment Options
CalciumCalcium– 1500-2000mg daily1500-2000mg daily
Vit D supplementationVit D supplementation– SunshineSunshine– 400-800 IU/daily400-800 IU/daily
SERMs (raloxifene)SERMs (raloxifene)HRT (oral or patch)HRT (oral or patch)Bisphosphonates (Etidronate, Alendronate)Bisphosphonates (Etidronate, Alendronate)Weight bearing exerciseWeight bearing exercise
Affects of Various TreatmentsAffects of Various Treatments
Increases in Increases in BMD (%)BMD (%)††
Decreases Decreases Vertebral Vertebral Fracture Fracture RatesRates
ERT/HRT
Alendronate||
Risedronate||
Raloxifene||
Calcitonin
Yes§
Yes¶
Yes
No
No
5 - 6
5 - 8
5 - 6
1 - 2
1 - 2
Yes‡
Yes‡
Yes
Yes
Yes
MostMostCommon Common Side EffectSide Effect
Breakthrough bleeding
Gastric ulceration
Upper GI symptoms
Hot flushes
Nasal irritation
Decreases Hip Fracture Rates
WHI ResultsWHI Results
Absolute and Relative Risk or Benefit of HRT
Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.
Heart attacks
Strokes
Breast cancer
VTEs
Colorectal cancer
Hip fractures
Relative Riskvs Placeboat 5. Years
Increased Absolute Riskper 10,000Women/YrHealth Event
1.29
1.41
1.26
2.11
0.63
0.66
7
8
8
18
6
5
Increased Absolute Benefitper 10,000Women/Yr
WHI E-only ArmWHI E-only Arm
What’s differentWhat’s different– No increased CVD risk.No increased CVD risk.– No increased breast cancer risk.No increased breast cancer risk.
What’s the similarWhat’s the similar– Increased risk of DVTIncreased risk of DVT– Small increase risk of strokeSmall increase risk of stroke– Bone protection.Bone protection.
WHIWHI
Use HRT for shortest period of time needed, to Use HRT for shortest period of time needed, to treat symptoms.treat symptoms.HRT should not be continued or started to prevent HRT should not be continued or started to prevent heart diseaseheart diseaseDiscuss other methods of CVD prevention:Discuss other methods of CVD prevention:– lifestyle changeslifestyle changes– cholesterol- and blood pressure-lowering drugscholesterol- and blood pressure-lowering drugs
For osteoporosis prevention:For osteoporosis prevention:– weigh the benefits against their personal risks for heart weigh the benefits against their personal risks for heart
attack, stroke, blood clots, and breast cancer; alternate attack, stroke, blood clots, and breast cancer; alternate treatments are available to prevent osteoporosis and treatments are available to prevent osteoporosis and fractures.fractures.
NIH Recommendations
Endometriosis/AdenomyosisEndometriosis/Adenomyosis
Endometriosis = endometrial tissue outside the uterus.Endometriosis = endometrial tissue outside the uterus.Adenomyosis = endometrium within muscle.Adenomyosis = endometrium within muscle.Endometriosis Incidence: Endometriosis Incidence: – 3-10% of general population3-10% of general population– 30% of infertile population30% of infertile population– 50% of pelvic pain50% of pelvic pain– 70% of pelvic pain and infertility70% of pelvic pain and infertility
LEFTLEFT ovary is most common site of endometrioma. ovary is most common site of endometrioma. Disease stage correlates with ~fertility, but not pain.Disease stage correlates with ~fertility, but not pain.Genetic (7% of first degree relatives)Genetic (7% of first degree relatives)Etiology: genetic, environmental, autoimmune.Etiology: genetic, environmental, autoimmune.Tissue has abnormal regulation (altered responsiveness to Tissue has abnormal regulation (altered responsiveness to progesterone: resistant to apoptosis; excess aromatase.)progesterone: resistant to apoptosis; excess aromatase.)Also assoc with: premenstrual spotting, poor egg qualityAlso assoc with: premenstrual spotting, poor egg quality
Endometriosis TreatmentEndometriosis Treatment
InfertilityInfertilitySurgery benefits stage I-II disease.Surgery benefits stage I-II disease.– NNT = 12NNT = 12– More advanced disease, role of surgery mainly limited More advanced disease, role of surgery mainly limited
to diagnosis.to diagnosis.
GnRH-agonistGnRH-agonist– Modest benefit, if any for fertilityModest benefit, if any for fertility
All forms of fertility have decreased efficacy with All forms of fertility have decreased efficacy with endometriosis (IVF, COH/IUI)endometriosis (IVF, COH/IUI)– Likely related to poorer egg quality. Likely related to poorer egg quality.
Endometriosis TreatmentEndometriosis Treatment(pregnancy, pseudopregnancy or pseudomenopause)(pregnancy, pseudopregnancy or pseudomenopause)
OCPs (60-90% get relief in first year)OCPs (60-90% get relief in first year)– Promote decidualization (progestin effect), pseudopregnancyPromote decidualization (progestin effect), pseudopregnancy– 10% recurrence risk/year10% recurrence risk/year
Depo Provera/ProgestinsDepo Provera/Progestins– Promote decidualization (pseudopregnancy)Promote decidualization (pseudopregnancy)
Depot Lupron (75-90% get relief in first year)Depot Lupron (75-90% get relief in first year)– Decapeptide, long-acting GnRH promotes pseudomenopause by Decapeptide, long-acting GnRH promotes pseudomenopause by
decreasing ovarian E.decreasing ovarian E.– 50% recurrence upon stopping. 50% recurrence upon stopping. – Bone loss at 6 monthsBone loss at 6 months
Addback regimens: 25 ug E patch q week, 0.625 mg CEE QD, or Addback regimens: 25 ug E patch q week, 0.625 mg CEE QD, or norethindrone acetate 5mg QD.norethindrone acetate 5mg QD.
Levonorgestrel IUDLevonorgestrel IUD– Decrease severity of symptoms (pseudopregnancy).Decrease severity of symptoms (pseudopregnancy).
Danazol (95% relief)Danazol (95% relief)– Androgen side effects: hirsuitism, loss of female contour, liver toxAndrogen side effects: hirsuitism, loss of female contour, liver tox
Endometriosis SurgeryEndometriosis Surgery
Hysterectomy/BSOHysterectomy/BSO: 90% cure. : 90% cure.
Presacral neurectomyPresacral neurectomy: risks constipation, : risks constipation, helps midline pain.helps midline pain.
Laparoscopic Uterosacral Nerve AblationLaparoscopic Uterosacral Nerve Ablation (LUNA): no proven benefit. (LUNA): no proven benefit.
Cystectomy vs ablation of cyst wallCystectomy vs ablation of cyst wall– Both superior to simple drainage. Both superior to simple drainage.
InfertilityInfertility
No pregnancy after 1 year of adequate, No pregnancy after 1 year of adequate, unprotected intercourse. unprotected intercourse.
15% of all couples.15% of all couples.
Increases with age. Increases with age.
Roughly equal between male and female Roughly equal between male and female causes. causes.
20% of cases are isolated male factor.20% of cases are isolated male factor.
10% are unexplained.10% are unexplained.
InfertilityInfertilityBasic workupBasic workupOvulation?Ovulation?– Tests of ovulation: history, BBT (.5 degree rise), urinary LH detection, timed Tests of ovulation: history, BBT (.5 degree rise), urinary LH detection, timed
serum P.serum P.Sperm?Sperm?– Volume 2ml, concentration 20m/ml, motility 40%, morphology 14% (30% WHO Volume 2ml, concentration 20m/ml, motility 40%, morphology 14% (30% WHO
III)III)Anatomy?Anatomy?– HSG (pretty reliable if says tubes are patent 85% specific, only fair if tubes are HSG (pretty reliable if says tubes are patent 85% specific, only fair if tubes are
blocked 54% sensitive)blocked 54% sensitive)– Not the greatest test for endometriosis.Not the greatest test for endometriosis.
Ovarian reserve?Ovarian reserve?– Elevated CD3 FSH ( abnormal if >10 IUm/L)Elevated CD3 FSH ( abnormal if >10 IUm/L)– Elevated CD3 Estradiol (abnormal if >75 pg/ml)Elevated CD3 Estradiol (abnormal if >75 pg/ml)– Predicts outcomes with IVF, reliability not established for general public.Predicts outcomes with IVF, reliability not established for general public.
Post coital test.Post coital test.– Not predictive. Not predictive.
FertilityFertility
Septate uteri do not cause infertility.Septate uteri do not cause infertility.
Fibroids involving the cavity decrease Fibroids involving the cavity decrease fertility.fertility.
Polyps >2cm decrease fertilityPolyps >2cm decrease fertility
Endometriosis decreases fertility via egg Endometriosis decreases fertility via egg quality. quality.
Obesity and cigarette smoking decrease Obesity and cigarette smoking decrease fertility.fertility.
Normal fertilityNormal fertility
FecundityFecundity– approximately 20% per cycle during 20s and approximately 20% per cycle during 20s and
early 30s. early 30s. – Approximately 10% at age 40.Approximately 10% at age 40.– Most couples infertile by age 45.Most couples infertile by age 45.
– At age 44-45, age is more predictive of fertility At age 44-45, age is more predictive of fertility than is ovarian reserve. than is ovarian reserve.
RPLRPL
3 consecutive losses with same partner3 consecutive losses with same partner
If no prior livebirths:If no prior livebirths:– 70% chance of livebirth in next pregnancy.70% chance of livebirth in next pregnancy.– 40% livebirth after 4 losses.40% livebirth after 4 losses.
If prior livebirths:If prior livebirths:– 70% livebirth until 6 losses. 70% livebirth until 6 losses.
Increases risk of ectopic, neural tube Increases risk of ectopic, neural tube defectsdefects
RPL: GEISHARPL: GEISHA
GGenetic enetic 5% 5%
EEndocrinendocrine 20%20%
IInfectionsnfections 5% (controversial) 5% (controversial)
IImmunemmune 20%20%
SStructuraltructural 20%20%
AAnybody’s guess (unknown) 30%nybody’s guess (unknown) 30%
RPLRPL
ThrombophiliaThrombophilia
ACOG says the only definitive ones are ACOG says the only definitive ones are immune mediated:immune mediated:– Anticardiolipin antibodies and Lupus Anticardiolipin antibodies and Lupus
anticoagulant.anticoagulant.– These two are the best characterized.These two are the best characterized.
These are the only two, for which These are the only two, for which treatment has been demonstrated. treatment has been demonstrated.
RPL -- GeneticRPL -- Genetic
NormalNormal
RPL -- GeneticRPL -- Genetic
Robertsonian balanced Robertsonian balanced translocation account translocation account for 2/3 genetic for 2/3 genetic etiologies.etiologies.
6 possible gametes, only two can produce unaffected offspring.
RPL -- GeneticRPL -- Genetic
Balanced Balanced recipricol recipricol translocationtranslocation
Normal Abnormal Balanced Abnormal
Four possible combinations with two unaffected gametes
Endocrinology of PregnancyEndocrinology of Pregnancy
Maternal Recognition of PregnancyMaternal Recognition of Pregnancy– Progesterone is secreted by CL exclusively for 5-7 Progesterone is secreted by CL exclusively for 5-7
weeks, due to hCGweeks, due to hCG– After 6-7 weeks, placenta produces large amounts. After 6-7 weeks, placenta produces large amounts. – After 9th week, removal of ovaries has no effect on After 9th week, removal of ovaries has no effect on
pregnancypregnancy. . – Progesterone production peaks at termProgesterone production peaks at term. . – hCG quits doubling at 6-7 weeks gestation or at about hCG quits doubling at 6-7 weeks gestation or at about
10K10K– hCG peaks at 10 weekshCG peaks at 10 weeks
Endocrinology of PregnancyEndocrinology of Pregnancy
Function of P4 (summary)Function of P4 (summary)– Pregnancy maintenance.Pregnancy maintenance.– Uterine quiescenceUterine quiescence– Immune modulationImmune modulation
Is a fall in P associated with partuition?Is a fall in P associated with partuition?– No.No.
Does P have a role in partuition?Does P have a role in partuition?– YesYes
Explain:Explain:– Receptor changes cause decreased function of P.Receptor changes cause decreased function of P.
Endocrinology of PregnancyEndocrinology of Pregnancy
Placenta and steroid hormone productionPlacenta and steroid hormone productionWhat does the mother contribute to placental steroid What does the mother contribute to placental steroid production?production?– Cholesterol from LDL.Cholesterol from LDL.
What does the baby contribute? What does the baby contribute? – DHEASDHEAS
Which enzymes does placenta lack?Which enzymes does placenta lack?– 17hydroxylase/17,20lyase and 21 hydroxylase17hydroxylase/17,20lyase and 21 hydroxylase
ConsequenceConsequence– Placental steroid production stops at Placental steroid production stops at PP (No androgens or (No androgens or
cortisol)cortisol)– E3 is produced by conversion of DHEASE3 is produced by conversion of DHEAS
Endocrinology of PregnancyEndocrinology of Pregnancy
What is primary precursor for E?What is primary precursor for E? DHEAS from fetal adrenal.DHEAS from fetal adrenal.Primary E of pregnancy?Primary E of pregnancy? Estriol aka E3 (90%)Estriol aka E3 (90%)What organ makes E3?What organ makes E3? Placenta converts fetal Placenta converts fetal
precursors to E3precursors to E3Role of placental estrogens?Role of placental estrogens? Increase uteroplacental Increase uteroplacental
bloodflow.bloodflow.Are Es required for pregnancy maint?Are Es required for pregnancy maint? Does not seem so. E is Does not seem so. E is
mainly a sink to preventmainly a sink to preventexcess androgens.excess androgens.
Conditions associated with low E?Conditions associated with low E? AnencephallyAnencephallyCongenital adrenal lipoid Congenital adrenal lipoid
hyperplasiahyperplasiaAromatase and sulfatase Aromatase and sulfatase
deficienciesdeficienciesWhy has estriol been used as aWhy has estriol been used as a Indicates HPA axis in fetus.Indicates HPA axis in fetus.
marker of fetal well being?marker of fetal well being? b/c DHEAS b/c DHEAS Estriol Estriol