5.+clinical+guidelines+for+evaluation+and+management+of+amenorrhea

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CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF AMENORRHEA www.Medixl.com

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Page 1: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF

AMENORRHEA

CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF

AMENORRHEA

www.Medixl.com

Page 2: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Definitions

Primary amenorrhea

Failure of menarche to occur when expected in relation to the onset of pubertal development.

No menarche by age 16 years with signs of pubertal development.

No onset of pubertal development by age 14 years.

Secondary amenorrhea

Absence of menstruation for 3 or more months in a

previously menstruating women of reproductive

age.

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CNS-Hypothalamus-PituitaryOvary-uterus Interaction

Neural control Chemical control

Dopamine (-)

Norepiniphrine (+)

Endorphines (-)

Hypothalamus

Gn-RH

Ant. pituitary

FSH, LH

Ovaries

Uterus

ProgesteroneEstrogen

Menses

–± ?

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Pathophysiology of Amenorrhea Inadequate hormonal stimulation of the endomerium

“Anovulatory amenorrhea” - Euestrogenic - Hypoestrogenic

Inability of endometrium to respond to hormones “Ovulatory amenorrhea”

- Uterine absence - Utero-vaginal agenesis - XY-Females ( e.g T.F.S) - Damaged endometrium ( e.g Asherman’s syndrome)

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Euestrogenic AnovulatoryAmenorrhea

Normal androgens Hypothalamic-pituitary

dysfunction (stress, weight loss or gain, exercise, pseudocyesis)

Hyperprolactinemia Feminizing ovarian tumour Non-gonadal endocrine

disease (thyroid, adrenal) Systemic illness

High androgens PCOS Musculinizing ovarian

tumour Cushing’s syndrome Congenital adrenal

hyperplasia (late onset)

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Hypoestrogenic AnovulatoryAmenorrhea

Normal androgens- Hypothalamic-pituitary failure - Severe dysfunction - Neoplastic,destructive, infiltrative, infectious & trumatic conditions involving hypothalamus or

pituitary- Ovarian failure - Gonadal dysgenesis - Premature ovarian failure - Enzyme defect - Resistant ovaries - Radiotherapy, chemotherapy

High androgens- Musculinizing ovarian tumour- Cushing’s syndrome- Congenital adrenal hyperplasia

(late onset)

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AMENORRHOEA AN APPROACH FOR DIAGNOSIS

• HISTORY• PHYSICAL EXAMINATION• ULTRASOUND EXAMINATION

Exclude PregnancyExclude Cryptomenorrhea

Page 8: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Cryptomenorrhea

Outflow obstruction to menstrual blood

- Imperforate hymen- Transverse Vaginal septum with functioning

uterus- Isolated Vaginal agenesis with functioning

uterus

- Isolated Cervical agenesis with functioning uterus

- Intermittent abdominal pain

- Possible difficulty with micturition- Possible lower abdominal swelling- Bulging bluish membrane at the introitus or

absent vagina (only dimple)

Page 9: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Imperforate hymen

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Once Pregnancy and cryptomenorrhea are excluded:

The patient is a bioassay for Endocrine abnormalities

Four categories of patients are identified 1. Amenorrhea with absent or

poor secondary sex Characters

2. Amenorrhea with normal 2ry sex characters3. Amenorrhea with signs of androgen excess

4. Amenorrhea with absent uterus and vagina

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AMENORRHEAAbsent or poor secondary sex Characteristics

FSH Serum level

Low / normal

High

Hypogonadotropichypogonadim

Gonadal dysgenesis

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AMENORRHEA

Normal secondary sex Characteristics

- FSH, LH, Prolactin, TSH- Provera 10 mg PO daily x 5 days

+ Bleeding No bleeing Prolactin TSH

FurtherWork-up(Endocrinologist)

- Mild hypothalamic dysfunction - PCO (LH/FSH) Review FSH result

And history (next slide)

Page 13: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

FSH

Low / normalHigh

Hypothalamic-pituitaryFailure

Ovarian failure

If < 25 yrs or primary amenorrhea karyoptype If < 35 yrs R/O autoimmune disease

?? Ovarian biopsy

head CT- scan or MRI

- Severe hypothalamicdysfunction

- Intracranial pathology

Page 14: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Amenorrhea Utero-vaginal absence

Karyotype

46-XX

Mullerian Agenesis

(MRKH syndrome)

Andogen Insenitivity

(TSF syndrome)

. Gonadal regressioon. Testocular enzyme defenciecy. Leydig cell agenisis

46-XY

Normal breasts& sexual hair

Normal breasts& absent sexual

hairAbsent breasts& sexual hair

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Normal FSH, LH; -ve bleedinghistory is suggestive of amenorrhea trumatica

Asherman’s syndrome History of pregnancy associated D&C Rarely after CS , myomectomy T.B

endometritis, bilharzia Diagnosis : HSG or hysterescopy Treatment : lysis of adhesions; D&C or

hysterescopy + estrogen therapy ( ? IUCD or catheter)

Some will prescribe a cycle of Estrogen and

Progesterone challenge Before HSG or Hysterescopy

Page 16: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Asherman’s syndrome

Page 17: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

AmenorrheaSigns of androgen excess

Testosterone, DHEAS, FSH, and LH

DHEAS 500-700 mug/dL DHEAS >700 mug/dLTEST. >200 ng/dL

Serum 17-OHProgesterone level

Late CAH Adrenal hyperfunction

U/S ? MRI or CT

OvarianOr adrenal

tumor

Lower elevations PCOS (High LH / FSH)

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Amenorrhea

PRIMARY AMENORRHEA

. Ovarian failure 36%

. Hypogonadotrophic 34% Hypogonadism.. PCOS 17%. Congenital lesions (other than dysgenesis) 4%. Hypopituitarism 3%. Hyperprolactinaemia 3%. Weight related 3%

SECONDARY AMENORRHEA

. Polycystic ovary syndrome 30%

. Premature ovarian failure 29%

. Weight related amenorrhoea 19%

. Hyperprolactinaemia 14%

. Exercise related amenorrhoea 2%

. Hypopituitarism 2%

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Gonadal dysgeneis

Chromosomally incompetent - Classic turner’s syndrome (45XO) - Turner variants (45XO/46XX),(46X-abnormal X) - Mixed gonadal dygenesis (45XO/46XY) Chromosomally competent - 46XX (Pure gonadal dysgeneis) - 46XY (Swyer’s syndrome)

Page 20: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Gonadal dysgenesisClassic Turner’s

TurnerVariant

True gonadal Dysgenesis

MixedDysgenesis

phenotype Female Female Female Ambiguous

Gonad Streak Streak Streak - Streak - Testes

Hight Short - Short - Normal

Tall Short

Somatic stigmata

Classical ± Nil ±

karyotype XO XX/XO or abnormal X

46-XX(Pure)46-XY (Swyer)

XO/XY

Page 21: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Turner’s syndrome

• Sexual infantilism and short stature.• Associated abnormalities, webbed

neck,coarctation of the aorta,high-arched pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low hairline on the neck, short metacarpal bones and renal anomalies.

• High FSH and LH levels.• Bilateral streaked gonads.• Karyotype - 80 % 45, X0 - 20% mosaic forms (46XX/45X0)• Treatment: HRT

Page 22: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Mosaic (46-XX / 45-XO) (Classic 45-XO)

Turner’s syndrome

Page 23: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Ovarian dysgenesis

Page 24: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

None-dysgenesis ovarian failure

Steroidogenic enzyme defects (17-hydroxylase)

Ovarian resistance syndrome Autoimmune oophoritis Postinfection (eg. Mumps) Postoopherectomy Postradiation Postchemotherapy

Page 25: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Premature ovarian failure

Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions

10% of secondary amenorrhea Few cases reported, where high dose estrogen

or HMG therapy resulted in ovulation Sometimes immuno therapy may reverse

autoimmue ovarian failure Rarely spont. ovulation (resistant ovaries) Treatment: HRT (osteoporosis, atherogenesis)

Page 26: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Polycystic ovary syndrome

The most common cause of chronic anovulation Hyperandrogenism ; LH/FSH ratio Insulin resitance is a major biochemical feature (

blood insulin level hyperandrogenism ) Long term risks: Obesity, hirsutism, infertility,

type 2 diabetes, dyslipidemia, cardiovasular risks, endometrial hyperplassia and cancer

• Treatment depends on the needs of the patient and preventing long term health problems

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Page 28: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Hypogonadotrophic Hypogonadism

• Normal hight• Normal external and internal

genital organs (infantile)• Low FSH and LH• MRI to R/O intra-cranial pathology.• 30-40% anosmia (kallmann’s

syndrome)• Sometimes constitutional delay• Treat according to the cause

(HRT), potentially fertile.

Page 29: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Constitutional pubertal delay

• Common cause (20%)• Under stature and

delayed bone age ( X-ray Wrist joint)• Positive family history• Diagnosis by exclusion and

follow up • Prognosis is good (late developer)• No drug therapy is

required – Reassurance (? HRT)

Page 30: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Sheehan’s syndrome

Pituitary inability to secrete gonadotropins

Pituitary necrosis following massive obstetric hemorrhage is most common cause in women

Diagnosis : History and E2,FSH,LH + other pituitary deficiencies (MPS

test) Treatment : Replacement of deficient hormones

Page 31: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Weight-related amenorrhoea

Anorexia Nervosa 1o or 2o Amenorrhea is often first sign A body mass index (BMI) <17 kg/m²

menstrual irregularity and amenorrhea Hypothalamic suppression Abnormal body image, intense fear of weight

gain, often strenuous exercise Mean age onset 13-14 yrs (range 10-21 yrs) Low estradiol risk of osteoporosis Bulemics less commonly have amenorrhea

due to fluctuations in body wt, but any disordered eating pattern (crash diets) can cause menstrual irregularity.

Treatment : body wt. (Psychiatrist referral)

Page 32: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Exercise-associated amenorrhoea

Common in women who participate in sports (e.g. competitive athletes, ballet dancers)

Eating disorders have a higher prevalence in female athletes than non-athletes

Hypothalamic disorder caused by abnormal gonadotrophin-releasing hormone pulsatility, resulting in impaired gonadotrophin levels, particularly LH, and subsequently low oestrogen levels

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Contraception related amenorrhea Post-pill amenorrhea is not an entity Depot medroxyprogesterone acetate Up to 80 % of women will have amenorrhea

after 1 year of use. It is reversible (oestrogen deficiency)

A minority of women taking the progestogen-only pill may have reversible long term amenorrhoea due to complete suppression of ovulation

Page 34: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Late onset congenital adrenal hyperplasia Autosomal recessive trait Most common form is due to

21-hydroxylase deficiency Mild forms Closely resemble

PCO Severe forms show Signs of

severe androgen excess High 17-OH-progesterone

blood level Treatment : cortisol

replacement and ? Corrective surgery

Page 35: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Cushing’s syndrome

Clinical suspicion : Hirsutism, truncal obesity, purple striae, BP

If Suspicion is high : dexamethasone suppression test

(1 mg PO 11 pm ) and obtaine serum cortisol level at 8 am :

< 5 µg/ dl excludes cushing’s 24 hours total urine free cortisol

level to confirm diagnosis 2 forms ; adrenal tumour or ACTH

hypersecretion (pituitary or ectopic site)

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Utero-vaginal Agenisis Mayer-Rokitansky-Kuster-Hauser syndrome

15% of 1ry amenorrhea Normal breasts and Sexual Hair

development & Normal looking external female genitalia

Normal female range testosterone level Absent uterus and upper vagina & Normal

ovaries Karyotype 46-XX 15-30% renal, skeletal and middle ear

anomalies Treatment : STERILE ? Vaginal creation

( Dilatation VS Vaginoplasty)

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Androgen insensitivity

Testicular feminization syndrome X-linked trait Absent cytosol receptors Normal breasts but no sexual

hair Normal looking female

external genitalia Absent uterus and upper

vagina Karyotype 46, XY Male range testosterone level Treatment : gonadectomy

after puberty + HRT ? Vaginal creation (dilatation

VS Vaginoplasty )

Page 38: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

General Principles of management of Amenorrhea

. Attempts to restore ovulatory function

. If this is not possible HRT (oestrogen and progesterone) is given to hypo-estrogenic amenorrheic women (to prevent

osteoporosis; atherogenesis). Periodic progestogen should be taken by euestrogenic

amenorrheic women (to avoid endometrial cancer). If Y chromosome is present gonadectomy is indicated. Many cases require frequent re-evaluation

Page 39: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Hormonal treatmentPrimary Amenorrhea with absent secondary sexual characteristics

To achieve pubertal development Premarin 5mg D1-D25 + provera 10mg D15-D25 X

3 months; 2.5mg premarin X 3 months and 1.25mg premarin X 3 monthsMaintenance therapy 0.625mg premarin + provera OR ready HRT

preparation OR 30µg oral contraceptive pill

Page 40: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Summary Although the work-up of amenorrhea may seem to be

complex, a carefully conducted physical examination with the history, and Looking to the patient as a bioassay for endocrine abnormalities, should permit the clinician to narrow the diagnostic possibilities and an accurate diagnosis can be obtained quickly.

Management aims at restoring ovulatory cycles if possible, replacing estrogen when deficient and Progestogegen to protect endometrium from unopposed estrogen.

• Frequent re-evaluation and reassurance of the patient.

Page 41: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

THANK YOUFOR YOUR ATTENTION

Page 42: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

AMENORRHEADarren Farley, M.D.

Department of Obstetrics and Gynecology

UKSM-Wichita

Page 43: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Definitions and Epidemiology Primary amenorrhea

absence of normal menstruation in a patient without previously established cycles

no periods by age 14 with no secondary sex changes

absence of menarche by age 16 regardless of secondary sex changes

no periods by 2 years after the start of secondary sex changes

< 0.1-2.5% of reproductive age women

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Definitions and Epidemiology Secondary amenorrhea

absence of menses for 3 cycle lengths in oligomenorrhea, or for 6 months after having regular menses

1-5% of the population

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Clinical Presentation

Historymilestones, development, diet, exercise, wt

changedrug use (antipsychotics, hormones, narcs, anti-

HTN’ssystemic disease (hypothyroidism, adrenal insuff.,

GH excess)past surgery, glactorrhea, hirsutismgyn/ob hx (hemorrhage, D&C, infection)genetic history

Page 46: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Clinical Presentation Physical

ht, wt, vitalssigns of thyroid dz (protuberant eyes, enlarged gland, puffy

face, heat/cold intolerance)secondary sex changes

○ thelarche (breast devel): avg. age 10.8 yrs; indication of estrogen exposure

○ adrenarche (pubic/axillary hair development): avg. age 11 and indicates ovarian and adrenal androgen production and end organ response

decreased breast size or vaginal dryness indication decreasing estrogen exposure (or increasing androgens)

presence of a cervix (confirms presence of a uterus)

Page 47: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Etiology Primary amenorrhea

gonadal failure is most common causeuterovaginal agenesis is second most common cause

Anorexia nervosa is the most common cause of amenorrhea overall in teens

Secondary amenorrheapregnancy is most common cause49-62% have hypothalamic disorders, including PCO7-16% have pituitary disorders10% have ovarian disorders7% have Ashermans syndrome

Page 48: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

DDx and Tx in Primary Amenorrhea:2nd sex changes absent, cervix present

50% of patientsprimary ovarian disorders

○ Turner’s sd; pure gonadal dysgenesis; chromosomal mosaics; structural abnormalities of the sex chromosomes

CNS, hypothalamic, or pituitary failure○ anatomic lesions; Kallman’s sd; anorexia nervosa or

bulimia; exercise induced; constitutional delay; hyperprolactinemia

Endocrinopathies (17 alpha hydroxylase deficiency)

Page 49: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

DDx and Tx in Primary Amenorrhea:2nd sex changes absent, cervix present Work up includes measuring FSH

if >40 and less than 30y/o○ do karyotype

if Y chromosome exists, excise gonadsif 46XX, r/o 17a-hydroxylase deficiency

○ replace estrogen/progesterone, and if 17a-hydroxylase deficient, replace steroids also

if low, then a problem with the CNS, hypothalamic, or pituitary exists○ measure serum prolactin○ consider CT○ no karyotype needed (all are 46XX)○ replace estrogen/progesterone○ consider GH○ fertility requires assistance

Page 50: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

DDx and Tx in Primary Amenorrhea:2nd sex changes present, cervix present May present w/ primary or secondary amenorrhea 1/3 of pts with primary amenorrhea have breasts and a uterus, 1/4 of these

have hyperprolactinemia CNS or hypothalamic causes

○ anatomic lesions (can appear with or without secondary sex changes○ drugs affecting prolactin levels (stimulators and inhibitors)○ stress, exercise, and eating disorders○ PCOS○ functional hypothalamic amenorrhea

Pituitary causes Ovarian causes (elevated gonadotropin and low estrogen)

radiation and chemo; premature ovarian failure; ovarian resistance sd; PCOS; infection; vascular injury; cystetomy

Uterine causes (only group in this category who will show normal endocrine findings

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DDx and Tx in Primary Amenorrhea:2nd sex changes present, cervix present Work up

r/o pregnancyr/o hyperprolactinemiaif prolactin level elevated, evaluate thyroid functionmeasure FSH and LHmeasure 17a-hydroxylase progesterone and

progesteronedo a progesterone challenge test

Treatmentdopamine agonist therapycombination OCP therapyestrogen replacement

Page 52: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

DDx and Tx in Primary Amenorrhea:2nd sex changes present, cervix absent

androgen insensitivity (testicular feminization sd) mullerian anomalies or agenesis work up

karyotype and testosterone level if nl body hair and female testosterone levels, uterine

agenesis is present and pt is sterile○ karyotype is to r/o male pseudohermaphrodism○ IVP should be done to r/o renal anomalies○ may need reconstructive surgery

pts with AI are usually raised as girls (XY)○ remove gonads after breast development and epiphyseal

closure○ replace estrogen

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DDx and Tx in Primary Amenorrhea:2nd sex changes absent, cervix absent <1% of primary amenorrhea

pts are 46XY, but have abnormality in testosterone synthesis

mullerian inhibiting factor causes internal female organs to regress

DDx17a-hydroxylase deficiency17,20 desmolase deficiencyagonadism

Lab: elevated gonadotropins and low-normal female testosterone levels

Tx: remove testicles and replace estrogen; no need for progesterone

Page 54: 5.+Clinical+Guidelines+for+Evaluation+and+Management+of+Amenorrhea

Secondary Amenorrhea Differential

similar to that of primary amenorrhea with cervix and secondary sex changes present

Work up r/o pregnancy r/o hyperprolactinemia if prolactin level elevated, evaluate thyroid function measure FSH and LH measure 17a-hydroxylase progesterone and progesterone do a progesterone challenge test

Treatment dopamine agonist therapy combination OCP therapy estrogen replacement