5.+clinical+guidelines+for+evaluation+and+management+of+amenorrhea
TRANSCRIPT
CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF
AMENORRHEA
CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF
AMENORRHEA
www.Medixl.com
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.
CNS-Hypothalamus-PituitaryOvary-uterus Interaction
Neural control Chemical control
Dopamine (-)
Norepiniphrine (+)
Endorphines (-)
Hypothalamus
Gn-RH
Ant. pituitary
FSH, LH
Ovaries
Uterus
ProgesteroneEstrogen
Menses
–± ?
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)
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)
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)
AMENORRHOEA AN APPROACH FOR DIAGNOSIS
• HISTORY• PHYSICAL EXAMINATION• ULTRASOUND EXAMINATION
Exclude PregnancyExclude Cryptomenorrhea
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)
Imperforate hymen
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
AMENORRHEAAbsent or poor secondary sex Characteristics
FSH Serum level
Low / normal
High
Hypogonadotropichypogonadim
Gonadal dysgenesis
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)
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
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
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
Asherman’s syndrome
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)
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%
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)
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
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
Mosaic (46-XX / 45-XO) (Classic 45-XO)
Turner’s syndrome
Ovarian dysgenesis
None-dysgenesis ovarian failure
Steroidogenic enzyme defects (17-hydroxylase)
Ovarian resistance syndrome Autoimmune oophoritis Postinfection (eg. Mumps) Postoopherectomy Postradiation Postchemotherapy
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)
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
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.
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)
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
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)
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
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
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
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)
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)
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 )
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
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
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.
THANK YOUFOR YOUR ATTENTION
AMENORRHEADarren Farley, M.D.
Department of Obstetrics and Gynecology
UKSM-Wichita
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
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
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
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)
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
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)
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
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
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
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
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
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