Amenorrhea
Amy Byerly, D.O.
Contemporary OB/GYN
Definition
No period by age 14 in the absence of growth or development of secondary sexual characteristics
No period by the age of 16 regardless of the presence of normal growth and development with the appearance of secondary sexual characteristics
Absence of periods for a length of time equal to a total of at least 3 of the previous cycle intervals or 6 months of amenorrhea in a previously menstruating woman
Basic Principles in Menstrual Function
Need visible external evidence of menstrual flowNeed an intact outflow tract – patency of vagina
and the endocervix with the uterine cavityPresence of an endometrial liningIntact HPO axis (GnRH stimulating LH and FSH
stimulating estrogen and progesterone)Maximal number of eggs at 16-20 weeks (6-7
million)
HPO Axis (p.403)
d/o of CNS
d/o of ant.pit
d/o of ovary
d/o of outflowTract& uterus
Evaluation of Amenorrhea
H&PEmotional stress, apparent genetic anomalies,
nutritional status, abnormal growth and development, presence of a normal reproductive tract, evidence for CNS disease
Galactorrhea – nonpuerperal breast secretion; spontaneous or present only with expression; unilateral or bilateral, persistent or intermittent
Followed by a lab work-up
Step1: Initial Evaluation
HCG – to rule out pregnancyTSH – hypothyroidism; the longer the duration of
hypothyroidism, the higher the incidence of galactorrhea
PRL If associated with hypothyroidism, the value is <100
Progestational challenge – to assess the level of endogenous estrogen and the competence of the outflow tract
Lateral X-ray view of the sella turcica (for galactorrhea associated with amenorrhea)
Progestational Challenge
3 choices:Parenteral progesterone oil (200mg)Oral micronized progesterone (300mg) take hs to
avoid S.E.Oral medroxyprogesterone acetate (10mg) daily for
5 daysOCP not appropriate – not purely progesteronalWithin 2-7 days – bleed or not bleedIf bleeds – diagnosis is anovulation; intact
outflow tract; estrogen present; means minimal function of the ovary, pituitary and CNS
Anovulatory Patients
Require treatment; if untreated, unopposed estrogen can eventually lead to endometrial cancer
Minimal therapy:Provera 10mg po for the first 10 days of each
monthCan use OCPs if contraception is also desiredIf patient fails to have a withdrawal bleed after
progesterone, further work-up is needed
Polycystic Ovarian Syndrome
Insulin insensitivityIncreased risk for endometrial hyperplasiaDiagnosis
Glucose to insulin ratio 4:1Testosterone >40US not considered diagnostic
Step 2: Estrogen and Progesterone
If no withdrawal bleeding after progesterone only: Target organ outflow tract is not working Preliminary estrogen proliferation of the endometrium has not
occurredGive estrogen and progesterone
Premarin 0.3mg 30d Repeat Proesterone challenge
No bleeding: endometrium or outflow tract problem (due to aggressive curettage, infection, genetic anomaly);Compartment I d/o are rare
If bleeding: outflow tract and endometrium are working properly
AmenorrheaTSHPRLProg.challenge
GalactorrheaTSHPRL?MRI
TSH +withdrawBleed
-w/draw bleed
Hypothyroidism
NL PRLNL TSH
Anovulation
Estrogen &Progestin
cycle
-w/drawbleed
END ORGANPROBLEM!!
+ w/draw bleed
FSH & LHASSAy
highnormalLo
MRI
HypothalamicAmenorrhea
Ovarianfailure
PRL >100
MRI
Step 3: Gonadotropin Assay
If bleeding occurred with estrogen and progesterone together, then there is a problem with the stimulation of estrogen production: follicular activity or gonadotropins
Assay the level of gonadotropins (must do this 2 weeks after the E/P challenge) – draw LH and FSH levels
Step 3 designed to determine if the lack of estrogen is a compartment II (follicle) or compartment III/IV (CNS-pituitary axis) issue
HPO Axis (p.403)
d/o of CNS
d/o of ant.pit
d/o of ovary
d/o of outflowTract& uterus
Gonadotrpins
High Gonadotropins
Causes: Castrate Postmenopausal Ovarian failure
Rare causes associated with ovaries that contain follicles:
1. Tumors (usually associated with lung cancer)2. Single gonadotropin deficiency (homozygous
mutations in the gonadotropin gene)3. Gonadotropin secreting pituitary adenomas
(associated with headache and vision changes, NOT assoc. w/ hypogonadism)
4. Perimenopausal period (rising FSH level)
High Gonadotropins
Rare causes associated with ovaries that contain follicles5. Resistant or insensitive ovary syndrome amenorrhea, normal growth and development, elevated
gonadotropins Ovarian follicles are unresponsive to stimulation Absent or defective gonadotropin receptors on the follicles Dx: laparotomy with full thickness ovarian biopsy6. Autoimmune disease – developing follicles are surrounded by
nests of lymphocytes and plasma cells; also evaluate for abnormal thyroid and adrenal function
7. Galactosemia – autosomal recessive; disorder of galactose metabolism due to galactose-1-phosphate uridyl transferase deficiency; irreversible premature ovarian failure
8. 17-hydroxylase deficiency – absent secondary sexual development, HTN, hypokalemia, high progesterone levels
High GonadotropinsChromosomal Evaluation
Ovarian failure, elevated gonadotropins and age under 30yo – need karyotype
Presence of mosaicism with a Y chromosome requires excision of the gonadal areas (highly malignant tumor formation ie. Dysgerminomas, yolk sac, gonadoblastoma) 30% do not develop virilization
Over 30yo do not need karyotype – premature menopause (most gonadal tumors will occur before 20yo)
Premature Ovarian FailureClinical Approach
Repeatedly elevated gonadotropin levels – ovarian failure – sterile
10-20% may resume normal function either spontaneously or with estrogen treatment, but this is RARE
Screen for autoimmune disorders every few years: calcium, phosphorous, fasting glucose, A.M. cortisol, free T4, TSH, thyroid antibodies, CBC, ESR, total protein, RF, ANA
If FSH:LH is <1.0 and estradiol is >50pg/ml, induction of ovulation can be considered
Recommend empiric treatment rather than official diagnosis with laparotomy and ovarian biopsy
Normal Gonadotropins
Negative progesterone challenge and normal LH and FSH
Causes:Gonadotropins have increases sialic acid in the
carbohydrate portion and are biologically inactive, the antibodies in the immunoassays recognize a portion of the molecule to return a normal answer (FSH/LH level)
Inherited disorder of gonadotropin synthesis -> production on immunologically active, but biologically inactive hormones
Evaluation: same as with low gonadotropins
Low Gonadotropins
Causes:PrepubertalHypothalamic dysfunctionPituitary dysfunction
Evaluation: in the past, coned down view of sella turcica via x-ray was done but now MRI is imaging of choice; diagnostic modality of choice is either thin section CT with IV contrast or MRI with gadolinium (more accurate)
Summary of Amenorrhea Work-up
Imaging of the Sella Turcica
Reasons to use CT or MRIAbnormal cone-downHeadache, visual disturbancesPRL >100 (associated with large tumors)
Reasons microadenomas are not significantMicroadenomas are very common They do not grow very rapidly during pregnancyRarely progress to macroadenomasHigh recurrence rate after surgeryNatural course is unaffected by dopamine agonist
treatmentNo contraindication to hormone therapy or OCPs
Evaluation of abnormal sella turcica and/or high prolactin
Refer to endocrinologist
Hypogonadotropic hypogonadism
+ amenorrhea- galactorrheaNL imaging of the pituitary
Mechanism of the amenorrhea is suppression of the pulsatile GnRH secretion below it’s critical range. This is diagnosis of exclusion. Identifiable causes are ie anorexia, stress, wght loss. However, there is NO test to manipulate or measure the hypothalamus to prove the dxn.
Amenorrhea Causes Compartment
Ioutflow tract/uterus
Asherman’s Syndrome
Mullerian anomalies
Mullerian Agenesis
Androgen insensitivity
7%
#2 primary cause
#3 primary cause
Compartment
IIOvary
Abnormal chromosomes
(Gonadal dysgensis)
Normal chromosomes
0.5%
10 %
#1 primary cause
Compartment
IIIAnterior pituitary
Prolactin tumors 7.5%
Compartment
IVCNS
Anovulation
Wgt loss/anorexia
Hypothalamic suppress
Hypothyroidism
28%
10%
10%
1%
Disorders of the Outflow Tract or Uterus (compartment I)
Asherman’s SyndromeMullerian AnomaliesMullerian AgenesisAndrogen Insensitivity (Testicular
Feminization)
Asherman’s Syndrome
Result of overzealous post partum curettage -> intrauterine scarringCan also occur after uterine surgery, IUD infections,
severe pelvic infections, tuberculosis in the uterus, uterine schistosomiasis
Diagnosis by Hysterogram or hysteroscopy: adhesions
Tx: hysteroscopic lysis of adhesionsFollowed by pediatric Foley catheter, antibiotics
Complications: infertility, miscarriages, dysmenorrhea
Mullerian Anomalies
Imperforate hymen, obliteration of the vaginal orifice, lapses in the vaginal continuity, presence or absence of uterus or cervix
Reestablishment of mullerian duct continuity usually can be achieved surgically
Dx: MRI delineate the anatomic abnormality
Mullerian AgenesisLack of Mullerian development:
Mayer-Rokitansky-Kuster-Hauser Syndrome Absence or hypoplasia of the internal vagina; may have
absence of uterus and fallopian tubesFemale karyotype, normal ovarian function, normal
growth and developmentOvaries are NOT mullerian structuresTx: vaginal dilators (Frank) or surgical (Vecchietti
procedure), neovagina w/ Creatsas modification of Willimas vaginoplasty
Additional studies: pelvic u/s or MRI assess anatomic structures
Look for other associated problems: urinary/renal tract abnormalities, skeletal (spine) anomalies
Androgen InsensitivityTesticular Feminization
Complete androgen insensitivity – no vagina, no uterus Incomplete androgen insensivity- clitoral
enlargement/phallus & axillary/pubic hair presentpresent, Male karyotype, female appearanceX-linked recessive transmissionNormal or elevated testosterone levelsMale pseudohermaphrodite (gonads opposite of genitalia)Suspect if: female child w/ inguinal hernias, primary
amenorrhea, no uterus, & absent body hairMay defer gonadectomy until after puberty 16-18 for
complete form (only exception to the rule that gonads w/ Y chromosome should be removed as soon as dxn is made)
Comparison of Mullerian Agenesis and Testicular Feminization
Disorders of the Ovary (Compartment II)
30-40% of primary amenorrhea cases have gonadal streaks due to abnormal development: gonadal dysgenesis50% 45X turner25% mosaics25% 46XX
Can also present as secondary amenorrhea46XX (most common), mosaics (45X/46XX), deletions
in X short and long arms, 47XXX, 45X
Disorders of the Ovary
1. Turner Syndrome (45X) Short stature, webbed neck, shield chest, increased carrying
angle at the elbow, hypergonadotropic hypoestrogenic amenorrhea
Lack of ovarian follicles, no gonadal sex hormone production, primary amenorrhea
Perform a karyotype R/O autoimmune d/o, CV & renal abnl
2. Mosaicism – multiple cell lines of varying sex chromosome composition Presence of a Y chromosome – required excision of gonadal
areas Short stature (<63 inches); early menopause
Disorders of the Ovary
3. XY gonadal dysgenesis Female pt with XY karyotype, palpable mullerian system,
normal female testosterone levels and lack of sexual development: SWYER’S SYNDROME
Remove gonadal streaks4. Gonadal atresia
May be due to viral and metabolic influences in early gestation or undiscovered genetic mutations
Female development Remove gonadal streaks
5. The Resistant Ovary Syndrome Rare; amenorrhea and normal growth and development;
elevated gonadotropins with unstimulated ovarian follicles; no evidence of autoimmune disease
Disorders of the Ovary
6. Premature Ovarian FailureEarly depletion of ovarian follicles1% of women will experience this before 40yoEtiology is unknown:
Genetic disordersChromosome anomaliesAutoimmune diseaseInfection: mumpsPhysical assault: chemotherapy or radiation
Age of presentation depends on how fast the follicles are lost
Disorders of the Ovary
7. The effect of chemotherapy and radiationRadiation – depends on dose used
Can resume function laterPremature ovarian failure may occur laterNo increased risk of congenital anomalies if pregnancy
occursOvaries not affected if pelvis not involved; may transpose
ovaries to preserve fertilityChemotherapy
Alkylating agents pose the greatest riskMay have resumption of normal mensesMay present as premature ovarian failure
Harvesting and cryopreservation of oocytes prior to radiation/chemo to preserve fertility
Disorders of the Anterior Pituitary (Compartment III)
Pituitary tumors: most are benign; can grow and cause compression of the optic chiasm leading to visual changesOther rare causes: craniopharyngioma,
meningiomas, gliomas, metastatic tumors
Nonfunctioning adenomas (30-40% of pituitary tumors) – of gonadotroph originSecrete FSH, free alpha-subunit and rarely LHHave elevated PRL
Disorders of the Anterior Pituitary
Other causes of pituitary compressionCystsTuberculosisSarcoidosisFat depositsLymphocytic hypophysitis – autoimmune infiltration of
the pituitary; often occurs after pregnancy Internal carotid artery aneurysmObstruction of the aqueduct of Sylvius Ischemia and infarction secondary to obstetrical
hemorrhage – Sheehan’s syndrome
Treatment of Nonfunctioning Adenomas
Microadenoma (<10mm)No treatment neededF/U imaging every 1-2 years
Macroadenoma (>10mm) If symptomatic – surgical resectionHigh recurrence rate so radiation therapy is neededF/U imaging q6 mos for 1 year, then yearly for 3-5 yearsDopamine agonists and octreotide treatment has been
disappointing, but there have been some reductions in size, so keep this option open
Pituitary Prolactin-Secreting Adenomas
Most common pituitary tumorsAccount for 50% of all pituitary adenomasMicroadenomas range form 9-27% of pituitary tumors
found at autopsyAge 2-86yo; highest incidence 6th decade1/3rd of women with amenorrhea have elevated prolactin
levelPRL >1000 = invasive tumor; treated with dopamine
agonistsAmenorrhea associated with high PRL levels is due to
prolactin inhibition of the pulsatile secretion of GnRHTreatment that lowers the circulating levels of prolactin
restores ovarian responsiveness and menstrual function
Pituitary Prolactin-Secreting AdenomasResults with Surgery
Transsphenoidal neurosurgery – immediate resolution of hyperprolactinemia with resumption of cyclic menses in 30% of patients with macroadenomas and 70% with microadenomas
Recurrence rate high; long term cure rate 50%Complications: CSF leaks, meningitis, diabetes insipidus
(for <6 months)Best results when PRL level is 150-500ng (the higher the
PRL the lower the cure rate)Explanations for recurrence
Difficult to completely resect Tumor may be multifocal in origin Continuing abnormality of the hypothalamus -> chronic
stimulation of the lactotrophs
Pituitary Prolactin-Secreting AdenomasResults with Surgery
Management for patients who have had surgeryIf cyclic menses returns: periodic evaluation for
the problem of anovulationIf amenorrhea or oligomenorrhea and
hyperprolactinemia persist or recur: PRL level q6 mos and imaging yearly for 2 yearsThen image every 2 yearsIf tumor growth is evident – control of growth with a
dopamine agonist
Pituitary Prolactin-Secreting AdenomasResults with Radiation
Less satisfactory than with surgery; slow response
PRL levels take years to fallPanhypopituitarism can occur for 10 yearsFocused irradiation is better for small tumors or
a small residual tumor after surgeryCan be an adjunctive therapy for shrinking larger
tumors or for tumors unresponsive to medical therapy
Only a small number of women return to normal hormonal function
Pituitary Prolactin-Secreting AdenomasDopamine Agonist Treatment
Bromocriptine – dopamine agonist. Binds to dopamine R therefore mimicking dopamaine inhibition of pituitary prolactin secretion
Metabolized by liver; 28% absorbed by the GI tract Dose: start at 2.5mg daily to a maximum of 10mg daily Oral, IM and vaginal preparations; vaginal preparation has fewer
side effects and complete absorptio`n SE: nausea, headache, faintness (due to orthostatic hypotension),
dizziness, fatigue, nasal congestion, vomiting and abdominal cramps; 10% discontinue due to SE
For patients seeking pregnancy: 2.5mg BID until patient is pregnant 2.5mg BID during follicular phase, discontinue when temperature
indicates ovulation, resume when menses occurs
Pituitary Prolactin-Secreting AdenomasDopamine Agonist Treatment
Tx purpose: pregnancy, suppression of bothersome galactorrhea, and reduction of tumor mass
Results of Treatment 80% have restored menses (average time 5.7 weeks) 50-60% have cessation of galactorrhea (12.7 wks) 75% have regression of breast secretions (6.4 wks) Cessation of galactorrhea is slower than restoration of
menses Discontinuation of bromocriptine
Amenorrhea recurs in 41% (4.4.weeks)Galactorrhea recurs in 69% (6.0 weeks)
Pituitary Prolactin-Secreting AdenomasDopamine Agonist Treatment
Regression of Tumors with BromocriptineMacroadenomas will regress with treatmentShrinkage occurs promptly (usually with 5-7mg) If fails to shrink with 10mg – do not go higher – no better
resultsReduction can take days to weeksThe most rapid reduction occurs during the first 3
monthsEven tumors with PRL >1000 have a good response to
bromocriptineMust be taken indefinitelyPRL levels will increase again with discontinuation
Pituitary Prolactin-Secreting AdenomasOther Dopamine Agonists
Pergolide: more potent, longer lasting, better toleratedSingle daily dose: 50-150mg
Lysuride, terguride, metergolineQuinagolide – 75-300mg qhs; good for tumors
resistant to bromocriptine; also has antidepressive effect
Cabergoline – weekly dose of 0.5-3mgLow rate of side effectsUnsure of fetal safety in patients trying to conceiveCan be given intravaginally
Summary: Treatment of Pituitary Prolactin-Secreting MacroadenomasDopamine agonist treatmentFollow PRL levels q3 mosWithdrawal of drug -> regrowth or reexpansion of the
tumorLong term treatment requiredMRI 1 year after treatment beganTranssphenoidal surgery if visual changes persistCan use short term treatment with a dopamine agonist
before surgery to help shrink the tumor10% do not respond to dopamine agonists; early surgery
is indicated
Summary: Treatment of Pituitary Prolactin-Secreting Microadenomas
Treat if patient has breast discomfort or infertility problems
Dopamine agonist – treatment of choiceHypoestrogenic amenorrhea – estrogen
therapy for bones; can use low dose OCPs if contraception is also needed
Summary of Treatment of Pituitary Prolactin Secreting Tumors
Pregnancy and Prolactin Adenomas
80% achieve pregnancy with dopamine agonist treatment
Breastfeeding can be doneSome women resume cyclic menses after
pregnancy (due to tumor infarction?)<2% have tumor growth evident by HA,
bitemporal hemianopsiaNo increase in miscarriage, perinatal M&MSurveillance as neededCan use bromocriptine during pregnancy
Empty Sella Syndrome
Congenital incompleteness of the sellar diaphragm; allows an extension of the subarachnoid space into the pituitary fossa
Coned down view is similar to a tumorFound in 5% of autopsies (Women>men)Elevated PRL, galactorrhea; annual
surveillance requiredBenign; does not progress to pituitary
failure
Sheehan’s Syndrome
Acute infarction and necrosis of the pituitary gland due to post partum hemorrhage and shock
See symptoms of hypopituitarism in the postpartum period
Failure of lactation, loss of pubic and axillary hair
Deficiencies of GH, LH and FSH are most common
CNS Disorders (Compartment IV)
Hypothalamic AmenorrheaWeight loss, anorexia and bulimiaExercise and AmenorrheaEating Disorders and PregnancyInherited Genetic DefectsPostpill AmenorrheaHormone Therapy
Hypothalamic Amenorrhea
Deficiency in GnRH pulsatile secretionOften a psychobiologic response to life events – stressful
situationsMild suppression: marginal effect on reproductionModerate suppression: anovulation with menstrual
irregularityProfound suppression: hypothalamic amenorrheaLow/normal LH and FSH, nl PRL, nl sella turcica;
evaluate annuallyStress increases secretion of CRH which can inhibit
gonadotropin secretionCan use induction of ovulation to achieve pregnancy
Weight loss, Anorexia, Bulimia
Acute weight loss can lead to the hypogonadotropic state
Diagnosis of anorexia nervosaOnset age 10-30yoWeight loss of 25% or weight 15% below normalDenial, distorted body image, unusual handling of foodLanugo, bradycardia, overactivity, overeating and
vomiting (bulimia)AmenorrheaNo medical or psychiatric illnessConstipation, low BP, hypercarotenemia, diabetes
insipidus
Weight loss, Anorexia, Bulimia
Occurs in 1% of womenUsually starts with a diet which brings a sense of
power and controlExcessive physical activityOverachievers and striversJudgmental; few friends due to high
expectationsDelayed psychosexual developmentMay having binging and purging - bulimia
Weight loss, Anorexia, Bulimia
Dysfunction of body mechanisms regulated by the hypothalamus: appetite, thirst and water conservation, temperature, sleep, autonomic balance and endocrine secretion
Low FSH and LH; elevated cortisol; normal PRL, TSH and T4; low T3 and high reverse T3 (relative hypothyroidism)
Response of GnRH is regained at 15% below the ideal weight -> resumption of normal menses
No specific therapy
Exercise and Amenorrhea
2 major influences on normal menses Critical level of body fat Effect of stress
Women who weigh less than 115 pounds and lose more than 10 pounds while exercising are the women who develop problems
Critical weight hypothesis: the onset and regularity of menstrual function necessitate maintaining weight above a critical level and therefore above a critical amount of body fat
10th %ile at 16yo ~ 22% body fat – minimum for maintaining menstruation
10th %ile at 13yo ~ 17% body fat – minimum for menarche A loss of body weight of 10-15% of normal may result in abnormal
menstrual function
Exercise and Amenorrhea
Stress and energy expenditure appear to play an independent role Ovarian activity can also be affected by seasonal variation (more
problems in the fall and winter) Acute exercise decreases gonadotropins and increases PRL, GH,
testosterone, ACTH, adrenal steroids and endorphins Endogenous opiates inhibit gonadotropin secretion by suppressing
GnRH Naltrexone (opioid receptor blocker) restores menstrual function
when given to women with amenorrhea associated with weight loss CRH also inhibits GnRH secretion Prognosis: excellent with weight gain and decrease in exercise
Can give hormone therapy for bone protection in women who do not quit exercising
Can use ovulation induction in women who want to become pregnant Recommend weight gain and decrease in exercise in women desiring
conception
Eating Disorders and Pregnancy
Typical pregnancy requires 300 extra calories a dayWeight gain in an average weight person: 22-26 poundsWeight gain in an underweight person: 26-33 poundsLinear relationship between birth weight and maternal
weight gainAs prepregnancy weight increases, the importance of
maternal weight gain diminishesWeight gain during pregnancy in underweight women
can bring an infant into the normal range for birth weightUnderweight status before pregnancy and inadequate
weight gain during the second half of pregnancy increase the risk of preterm birth
Eating Disorders and Pregnancy
Women who have been treated for anorexia or bulimia and are in remission gained more weight and had higher birth weights
Women with active disease had worsening symptoms and psychological problems during pregnancy and smaller birth weights
Rate of preterm labor and delivery in patients with eating disorders is twice the normal incidence
Recommend treatment for eating disorders before getting pregnant
Expert consultation for pregnant women with a current or previous history of an eating disorder
Careful monitoring of maternal and fetal growth
Inherited Genetic Defects
Kallmann’s Syndrome Congenital hypogonadotropic hypogonadism due to deficient
secretion of GnRH; anosmia Primary amenorrhea, infantile sexual development, low
gonadotropins, normal female karyotype, inability to perceive odors
X linked, autosomal dominant, autosomal recessiveMolecular Explanations – isolated deficiency of GnRH
secretion Autosomal mode of transmission; only pursue this in patients
with a family historyAdrenal Hypoplasia – X-linked inherited disorder that
results in adrenal insufficiency Hypogonadotropic hypogonadism Mutation in DAX-1 gene
Postpill Amenorrhea
Investigation should be pursued if patient is amenorrheic:6 months after discontinuing OCPs12 months after last injection of Depo-Provera
Hormonal Therapy and Amenorrhea
Any patient who is hypoestrogenic needs hormone therapy to maintain bone density
Standard therapy: 0.625mg conjugated estrogens or 1mg estradiol daily with 5mg
medroxyprogesterone acetate for 2 weeks every month Menstruation generally occurs 3 days after last progestin
medicationFor patients not wanting menstruation
0.625mg conjugated estrogens and 2.5mg medroxyprogesterone acetate given daily without a break
For patients refusing hormone therapy: 1000-1500mg calcium daily
The end
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