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