CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF AMENORRHEA
Primary Amenorrhea: State in which menarche does not occur
Secondary Amenorrhea: State in which cessation of menstrual periods occurs after menarche
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.
Absence of menstruation for 3 or more months in a
previously menstruating women of reproductive
CNS-Hypothalamus-Pituitary Ovary-uterus Interaction Neural control Chemical control Dopamine (-) Norepiniphrine (+) Endorphines (-) Hypothalamus Gn-RH Ant. pituitary FSH, LH Ovaries Uterus Progesterone Estrogen Menses – ± ?
Inadequate hormonal stimulation of the endomerium “ Anovulatory amenorrhea ”
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)
Hypothalamic-pituitary dysfunction (stress, weight loss or gain, exercise, pseudocyesis)
Feminizing ovarian tumour
Non-gonadal endocrine disease (thyroid, adrenal)
Musculinizing ovarian tumour
Cushing ’ s syndrome
Congenital adrenal hyperplasia (late onset)
- Hypothalamic-pituitary failure
- Severe dysfunction
infiltrative, infectious &
involving hypothalamus or pituitary
- Ovarian failure
- Gonadal dysgenesis
- Premature ovarian failure
- Enzyme defect
- Resistant ovaries
- Radiotherapy, chemotherapy
- Musculinizing ovarian tumour
- Cushing’s syndrome
- Congenital adrenal hyperplasia (late onset)
AMENORRHOEA AN APPROACH FOR DIAGNOSIS
Exclude Pregnancy Exclude 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)
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 characters 3. Amenorrhea with signs of androgen excess 4. Amenorrhea with absent uterus and vagina
FSH Serum level Low / normal High Hypogonadotropic hypogonadim Gonadal dysgenesis
- FSH, LH, Prolactin, TSH
Provera 10 mg PO daily
x 5 days
+ Bleeding No bleeing Prolactin TSH Further Work-up (Endocrinologist) - Mild hypothalamic dysfunction - PCO ( LH/FSH) Review FSH result And history (next slide)
FSH Low / normal High Hypothalamic-pituitary Failure Ovarian failure If < 25 yrs or primary amenorrhea karyoptype If < 35 yrs R/O autoimmune disease ?? Ovarian biopsy head CT- scan or MRI - Severe hypothalamic dysfunction - 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 hair Absent breasts & sexual hair
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
Amenorrhea Signs of androgen excess Testosterone, DHEAS, FSH, and LH DHEAS 500-700 mug/dL DHEAS >700 mug/dL TEST. >200 ng/dL Serum 17-OH Progesterone level Late CAH Adrenal hyperfunction U/S ? MRI or CT Ovarian Or adrenal tumor Lower elevations PCOS (High LH / FSH)
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.
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
• 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)
Replacement of deficient hormones
1 o or 2 o Amenorrhea is often first sign
A body mass index (BMI) <17 kg/m ² menstrual irregularity and amenorrhea
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
15-30% renal, skeletal and middle ear anomalies
Treatment : STERILE ? Vaginal creation ( Dilatation VS Vaginoplasty)
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 months
0.625mg premarin + provera OR ready HRT preparation OR 30 µ g 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
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**
Gonadotropin receptor mutations
Androgen biosynthesis disorders
Chronic renal failure
Isolated hypogonadotropic hypogonadism
GPR 54 mutation
Leptin or leptin receptor mutations
Gonadotrope receptor mutations
GnRH analog therapy
Pituitary mass lesions
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?
Gonadotropin receptor mutations
Androgen biosynthesis disorders
Chronic renal failure
Confirmed low testosterone Check LH+FSH (SA if infertility) High gonadotropins – 1 o Low/low nl gonadotropins – 2 o 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 CAG n repeat in the androgen receptor gene
Mediastinal germ cell tumors
Lower extremity varicosities
Gordon DL et al. Arch Intern Med (1972) 130:720 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
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
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
Kallmann’s syndrome (X-linked):
impaired migration of GnRH neurones
anosmia, 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
Case 1 Answer: Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function pregnancy 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 1 Endometrial 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/m 2 . 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/L LH 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/L LH 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/L LH 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?
repeat FSH & LH
bone mineral densitometry
Treatment should be with hormone replacement therapy combined with egg donation is fertility is required.