CLINICAL GUIDELINESCLINICAL GUIDELINES
FOR FOR
EVALUATION AND EVALUATION AND MANAGEMENT OF MANAGEMENT OF
AMENORRHEAAMENORRHEA
CLINICAL GUIDELINESCLINICAL GUIDELINES
FOR FOR
EVALUATION AND EVALUATION AND MANAGEMENT OF MANAGEMENT OF
AMENORRHEAAMENORRHEA
Primary Amenorrhea: State in which menarche does not occur
Secondary Amenorrhea: State in which cessation of menstrual periods occurs after menarche
ENDOCRINOLOGY 2
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
–± ?
ENDOCRINOLOGY 5
0
50
100
150
200
250
Day1 Day 12 Day 13 Day 14 Day 22 Day 26
LHFSHEstrogenProgestrone
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)
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)
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
FSH Serum level
Low / normal
High
Hypogonadotropichypogonadim
Gonadal dysgenesis
- 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
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
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%
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)
Classic
Turner’s
Turner
Variant
True gonadal
Dysgenesis
Mixed
Dysgenesis
phenotype Female Female Female Ambiguous
Gonad Streak Streak Streak - Streak
- Testes
Height Short - Short
- Normal
Tall Short
Somatic stigmata
Classical ± Nil ±
karyotype XO XX/XO or abnormal X
46-XX(Pure)
46-XY (Swyer)
XO/XY
• 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
Steroidogenic enzyme defects (17-hydroxylase)
Ovarian resistance syndrome Autoimmune oophoritis Postinfection (eg. Mumps) Postoopherectomy Postradiation Postchemotherapy
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)
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
• Normal height• 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.
• 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 (? Hormone replacement therapy [HRT] )
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
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)
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
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 (estrogen deficiency)
A minority of women taking the progestogen-only pill may have reversible long term amenorrhoea due to complete suppression of ovulation
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
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)
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)
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 )
. 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
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
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.
Androgen Insensitivity Syndrome Hypogonadism Klinefelter’s Syndrome (XXY) Swyer syndrome (XY but no gonads,
treated as a girl e.g. with estrogen etc.) 5 alpha-reductase deficiency (5-ARD) –
(XY) vagina and labia, as well as penis that can ejaculate
– androgenic insensitivity 1. XY: X chromosome is responsible for the testosterone receptors
i. These receptors become insensitive to testosterone
ii. Child is born with appearance of female genitalia
**Mullerian inhibiting system is okay; so internal organs are not female**
Klinefelter’s syndrome Gonadotropin receptor
mutations Cryptorchidism Androgen biosynthesis
disorders Varicocele Congenital anorchia
Mumps orchitis Radiation Antineoplastic drugs Ketoconazole Glucocorticoid excess Trauma Testicular torsion Autoimmune orchitis Cirrhosis Chronic renal failure HIV infection Idiopathic
Congenital Acquired
Isolated hypogonadotropic hypogonadism
Kallman’s syndrome DAX1 mutation GPR 54 mutation Leptin or leptin receptor
mutations Gonadotrope receptor mutations Hypopituitarism
Hyperprolactinemia Androgen therapy GnRH analog therapy Glucocorticoid therapy Critical illness Chronic illness Diabetes mellitus Opiates Pituitary mass lesions Infiltrative diseases Sellar surgery Sellar radiation
Congenital Acquired
How would you evaluate this patient?
Total testosterone: 134 ng/dL (176-781)
Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0)
What is the initial diagnosis?
Primary hypogonadismWhat is the next step in work up?
Klinefelter’s syndrome Gonadotropin receptor
mutations Cryptorchidism Androgen biosynthesis
disorders Varicocele Congenital anorchia
Mumps orchitis Radiation Antineoplastic drugs Ketoconazole Glucocorticoid excess Trauma Testicular torsion Autoimmune orchitis Cirrhosis Chronic renal failure HIV infection Idiopathic
Congenital Acquired
Confirmed low testosterone
Check LH+FSH (SA if infertility)
High gonadotropins – 1o Low/low nl gonadotropins – 2o
Karyotype Prolactin, other pituitary hormones, iron studies, sella MRI
How would you evaluate this patient?
Total testosterone: 134 ng/dL (176-781)
Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0)What is the initial diagnosis?
Primary hypogonadism
What is the next step in work up?
Karyotype: 47 XXY
Incidence ~ 1/1,000 live male births Extra X chromosome, usually 47 XXY Phenotype strongly influenced by CAGn repeat
in the androgen receptor gene Manifestations
› Hypogonadism› Gynecomastia› Behavioral disorders› Bronchiectasis/emphysema/bronchitis› Mediastinal germ cell tumors› Non-Hodgkin’s lymphoma› Diabetes mellitus› Lower extremity varicosities
Abnormality Frequency (%)
Abnormal testicular histology 100
Decreased testicular length 99
Azoospermia 93
Low testosterone 79
Decreased facial hair 77
Increased gonadotropins 75
Decreased sexual function 68
Gynecomastia 55
Decreased axillary hair 49
Decreased penis length 41
Gordon DL et al. Arch Intern Med (1972) 130:720
Primary goal is to restore testosterone levels to the laboratory reference range
Prescribe only for patients with confirmed hypogonadism
Role in “treating” decline in testosterone levels with aging uncertain
Multiple preparations› Oral› Intramuscular› Transdermal› Buccal
Signs and symptoms of hypogonadism depend on when the condition occurs in development
Initial evaluation focuses on distinguishing between primary and secondary hypogonadism› Primary: LH elevated, testosterone low› Secondary: LH low, testosterone low
Goal of testosterone replacement is physiological testosterone levels and preservation of testosterone-dependent physiological functions
Idiopathic
Kallmann’s syndrome (X-linked): impaired migration of GnRH neuronesanosmia, disturbance colour vision, dyskinesis
Prader-Willi syndrome (aut. dom., chromosome 15): obesity, muscle hypotonia, mental retardation, short stature, small hands/feet, cryptorchidism, HH
Mutations in pathway for GnRH secretion and action (KAL, DAX1, GnRH receptor, etc….)
May be difficult to distinguish from constitutional delay
GnRH tests can sometimes help but results may be unreliable
CASES
Case 1 Answer: Full physical examination
Serum endocrinology:FSH, LH, prolactin, thyroid
functionpregnancy test
Ultrasound scan of the pelvis (uterus and ovaries)
Case 1 Results
FSH of 2.2 iu/L
LH 15.0 iu/L
normal prolactin and thyroid function
The ultrasound scan demonstrated the presence of polycystic ovaries and an endometrial thickness of 15 mm.
Case 1 What should the management be?
Case 1Endometrial hyperplasia is a risk factor for oligo / amenorrhoeic women with PCOS because of unopposed oestrogen stimulating progressive hyperplasia and potentially malignancy / adenocarcinoma. Regular withdrawal bleeds should be induced either with cyclical progestogens or the COC pill.
If fertility is required then ovulation induction should be instituted with clomifene citrate followed by gonadotrophin therapy if this is unsuccessful.
If the patient is overweight she should be encouraged to lose weight. Women with polycystic ovary syndrome have insulin resistance and at an increased of cardiovascular disease and type II diabetes.
Case 2 An 18 year old woman presents with primary amenorrhoea (she has never had a period).
She has developed small breasts and has some pubic hair. She is very overweight with a body mass index of 39 kg/m2.
What investigations should be performed in order to make the diagnosis?
Case 2 Answer: Full physical examination
Serum endocrinology:FSH, LH, prolactin, thyroid
function(pregnancy test)
Ultrasound scan of the pelvis (uterus and ovaries)
Case 2 Results FSH of 0.5 iu/LLH of 0.5 iu/L
normal prolactin and thyroid function
The ovaries appear small on ultrasound scan, as does the uterus. What is the diagnosis?
Case 2
Hypogonadotrophic hypogonadism
Usually of hypothalamic origin and may be congenital, such as Kallmann's Syndrome (association with lack of smell)
The low gonadotrophin concentrations have failed to stimulate ovarian development and adequate puberty.
The small amount of breast development and pubic hair can be explained by oestrogen being produced in the peripheral fat and adrenal androgen secretion.
Overall this patient will be oestrogen deficient and bone mineral densitometry should be performed to exclude osteoporosis.
Case 2 What is the treatment?
Case 2
If the patient wishes to be pregnant, first line treatment would be pulsatile GnRH or gonadotrophin stimulation of the ovaries with a preparation that contains both FSH and LH bio-activity (ie, one of the traditional hMG preparations rather than recombinant FSH).
Otherwise HRT should be given.
Case 2
Do you need to image the pituitary / hypothalamus?
Case 2
Do you need to image the pituitary / hypothalamus?
Yes in adults with secondary amenorrhoea and hypog/hypog or hyperPRL, but tumours less common in adolescents if no other symptoms and normal PRL
Case 2
The patient was administered HMG at increasing high doses, but failed to produce any demonstrable follicular growth as assessed both by ultrasound scan and persistently low serum oestradiol concentrations.
Can you explain?
Case 2
This patient appears to have a second pathology and may well have primary ovarian failure combined with hypothalamic hypogonadotrophic hypogonadism, thus explaining the combination of ovarian failure with low gonadotrophin concentrations.
Case 3 An 18 year old woman presents with primary amenorrhoea (she has never had a period).
She has a normal body mass index and no other obvious problems.
What investigations should be performed in order to make the diagnosis?
Case 3 Answer: Full physical examination
Serum endocrinology:FSH, LH, prolactin, thyroid
function(pregnancy test)
Ultrasound scan of the pelvis (uterus and ovaries)
Case 3 Results FSH of 0.5 iu/LLH of 0.5 iu/L
serum prolactin concentration: 5,000 mu/L What is the diagnosis?What further investigations should be done?
Case 3
Hyperprolactinaemia
A repeat prolactin should be measured.
The diagnosis is likely to be that of a macro-adenoma of the pituitary gland and therefore either MRI or CT imaging of pituitary should be performed.
What treatment should be provided?
Case 3
Dopamine agonists: Bromocriptine or Cabergoline
Check visual fields
Case 4 An 18 year old woman presents with primary amenorrhoea (she has never had a period).
She has a normal body mass index and no other obvious problems.
What investigations should be performed in order to make the diagnosis?
Case 4 Answer: Full physical examination
Serum endocrinology:FSH, LH, prolactin, thyroid
function(pregnancy test)
Ultrasound scan of the pelvis (uterus and ovaries)
Case 4 Results FSH of 40 iu/LLH of 30 iu/L
What is the diagnosis?What further investigations should be done?
Case 4
Primary ovarian failure / premature ovarian failure
What further investigations should be performed?
Case 4
• repeat FSH & LH• karyotype • bone mineral densitometry• auto-antibody screen
Treatment should be with hormone replacement therapy combined with egg donation is fertility is required.
THANK YOUFOR YOUR ATTENTION
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