Secondary Amennorhea
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Transcript Secondary Amennorhea
Secondary amenorrhoea in
adolescence
Dr. KL Ng
United Christian Hospital
Case history
13 year-old girl
Admitted with secondary amenorrhoea in
Jan/2004
History of Present Illness
Features of anorexia nervosa since Feb 03
– Distorted body image
– Dietary manipulation
Intentional restriction of dietary
Pre-occupied by food
– Excessive exercise
– Purging
– Physical symptoms
Fatigue easily
Poor exercise tolerance
Cold extremities
Constipation
Secondary Amenorrhea
Menarche at the age of 12
– Regular cycle of 28 – 30 days
– Last 6-7 days
– Normal flow, no clot / flooding
No menses since July 2003
Puberty started at 8yrs
Consonant
growth spurt
Insignificant past medical history / drug
use
Normal development
Excessive weight loss
– Pre-morbid weight : 53 kg (March 03)
– Weight on admission : 30.3 kg
Excessive exercise
– Basketball, badminton, rope-jumping, hula loops
– 3-4 hr daily
No sexual history
No symptoms of androgen excess
– hirsuitism
– Acne
Stressful
– Self-demanding in academic result and
appearance
– Felt depressed if goal not met
Family History
Paternal height : 158 cm
Maternal height : 150 cm
Mother’s age of menarche : 13 yrs
No family history of
– Thyroid disease
– AN
Father got DM
Physical Examination
Stable vital signs
Wt 30.3 kg (~ 1 kg below 3rd percentile)
Ht 149 cm ( 25th percentile)
BMI : 13.64
% of body fat: 7.09%
Thinning of subcutaneous fat
Loss of muscle bulk
Loose skin folds
Lanugos hair over the back
Normal systemic review
Pubertal stage
– B4, P3, A3
No signs of androgen excess
Thryoid status : euthyroid
No signs of gonadal dysgenesis
No anosmia
No visual defect
Laboratory / Imaging Res
Investigations
CBC
}
L/RFT
} all normal
Bone profile }
Thyroid function test
TSH (0.35 – 5.50)
2.73 mU/L
Free T4 (11.5 – 23.2)
12.5 pmol/L
Prolactin 5.9
(1.4 – 24.2)
LHRH stimulation test
LH (U/L)
-15 min
<0.5
0 min
<0.5
30 min
1.2
60 min
0.9
FSH (U/L)
5.4
4.6
8.2
8.8
Estradiol (pmol/L) <74
Ultrasound abdomen
<74
– Uterus normal configuration
– Normal ovaries with no adnexal masses
Provera withdrawal test
– No menses on withdrawal of drug
Diagnosis: Anorexia nervosa (DSM-IV diagnostic
criteria)
Normal menstrual physiology
1.
2.
3.
Menstrual cycle is defined at 3 levels:
Endometrial response (proliferative &
secretory phases)
Ovarian response (follicular & luteal
phases)
Pituitary responses (FSH & LH levels)
Follicular phase
Corpus luteum involution occurs with resulting
low levels of estradiol and progesterone, in turn,
increases FSH & LH
FSH stimulates maturation of ovarian follicles,
one follicle predominating
Under the influence of estrogen, “proliferative
phase” of endometrium occurs
In mid- and late-follicular phase, FSH begins to
fall
Ovulation
Preovulatory estradiol surge leads to a
midcycle LH surge
A mature follicle releases an oocyte and
becomes corpus luteum
Luteal phase
Corpus luteum produces large amount of
progesterone and increased levels of estrogen, lead
to falling levels of LH & FSH
Progesterone stimulates endometrial
differentiation into “secretory” endometrium
Corpus luteum involutes with decreased levels of
estrogen & progesterone. Sloughing of
endometrium
Feedback systems
Negative feedback: estradiol and
progesterone suppress LH and FSH
Positive feedback: rising estradiol
>200pg/ml during preovulation leads to
positive feedback surge of LH, causing
ovulation
Amenorrhoea
Absence of menstrual bleeding
First menarchal year, 95th percentile for cycle
length is 90 days
Primary amenorrhoea, Secondary amenorrhoea
Primary Amenorrhoa
Absence of menses by age 14 yrs + absence of
secondary sexual characteristics
Absence of menses by age 16 yrs + normal
secondary sexual characteristics
Developmental abnormalities of ovaries, genital
tracts or ext. genitalia
Gonadal dysgenesis (50%)
Associated with delayed puberty
Secondary Amenorrhoea
Cessation of mens. for at least 6 mons
At least 3 of the previous 3 cycle intervals
Distinction between primary and secondary
amenorrhoea not absolute
Primary ovarian failure
Gonadal dysgenesis
Irradiation/chemotherapy/postoperative
Autoimmune oophoritis
‘Resistant ovary syndrome’
“Functional ovarian failure”
Secondary ovarian failure
Hypothalamo-pituitary
dysfunction
Functional disorders
Polycystic ovary syndrome
Genital tract disorders
Ovarian tumours
Gonadotrophin deficiency
Hyperprolactinaemia
Hypothalamo-pituitary tumors
Irradiation/chemotherapy/Postoperative
Empty sella syndrome
Weight loss/anorexia nervosa
Exercise
Psychogenic
Chronic illness
LH
+
Theca Cell
CHOLESTEROL
StAR
side-chain
cleavage
3β
PREGNENOLONE
PROGESTERONE
17 α -hydroxylase
17-HYDROXYPREGNENOLONE
3β
17 α -hydroxylase
17-HYDROXYPROGESTERONE
17,20-lyase
DEHYDROEPIANDROSTERONE
17,20-lyase
3β
ANDRONSTENEDIONE
17β-HSD5
TESTOSTERONE
FSH
5α-R
+
DIHYDROTESTOSTERONE
aromatase
Granulosa
Cell
ESTRONE
17 β -HSD1
ESTRADIOL
Clinical Assessment (history)
Systemic diseases (Thyroid)
Family history
Past medical history
Pubertal growth and development
Emotional status
Medications (heroin, methadone)
Clinical Assessment (history)
Nutritional status, recent wt. changes
Exercise history
Sexual history
Past menstrual history
History of androgen excess (PCOS, ovarian
or adrenal tumours)
C. Assessment (examination)
Signs of systemic dis. or malnutrition
Sexual maturity rating
Genitalia
Bw / Bh / BMI
Signs of androgen excess
C. Assessment (examination)
Signs of thyroid dysfunction
Signs of gonadal dysgenesis
Breast examination
Visual field / Fundi
Lab. Studies
Pregnancy test*
CBP / LRFT / urinalysis
TSH / FT4
Prolactin
BA
FSH / Estradiol /LH
Hyperprolactinaemia
Pituitary tumour or lesion disrupting the pit. stalk
>200ng/mL suggests macroprolactinoma
High blood and CSF prolactin levels
Serum level correlates with tumour’s size
Psychiatric drugs, hypothyroidism, stress, eating
disorder can also raise prolactin level
Functional gonadotrophin defic.
FSH
Elevated FSH level (40mIU/L) ovarian
failure
2 exceptions
1.
Bone age </= 11ys
2.
Partial ovarian failure
Elevated FSH
Chromosomal studies (Turner syndrome variants)
Autoimmune endocrinopathies
Functional ovarian failure (17 hydrolylase defic.)
Ovarian resistance syndromes (Gn receptor’s
mutation)
Ovarian biopsy (no diagnostic value)
LH
Non specific for ovarian failure
Elevated in 60-70% of patients with PCOS
Elevated in cases of 17-20 lyase deficiency,
17-hydroxylase deficiency
FSH not elevated, BA >11yrs
1.
2.
Assess degree of estrogenization
Plasma estradiol level
Progestin withdrawal test
Estradiol
Simplest test
Diurnal and cyclical variations
Normal serum levels despite well
documented ovarian failure (Partial ovarian
failure)
Progestin withdrawal test
Estrogen effect at the level of endometrium
Vaginal bleeding after a course of
medroxyprogesterone acetate, 5mg daily PO
for 5 days,
Endometrial thickness > 5mm by scanning
Progestin withdrawal test
+ ve response indicates serum estradiol levels
greater than 40pg/mL
+ ve response hyperprolactinemia, thyroid
dysfunction, androgen excess(PCOS)
- ve response hypothalamic-pituitary failure,
ovarian failure
Anorexia nervosa, drug abuse, heavy exercise may
or may not withdraw to progesterone
- Withdrawal bleeding
(hypoestrogenic)
GnRH test
- FSH hyperresponseive partial ovarian failure
- brisk LH response (>/= 7 IU/L) delayed
puberty
- FSH & LH not hyperresponsive delayed
puberty or Gonadotrophin def.
Gonadotrophin defic.may not be established until
16yrs of age
+ Withdrawal bleeding
(normoestrogenic)
Hypothalamic anovulation
(athletic, psychogenic, post-pill)
Nonhypothalamic extraovarian disorders
(pregnancy, Cushing syndrome,
hypothyroidism, endometritis, drug abuse)
Hyperprolactinemia
Hyperandrogenism (PCOS)
Imaging studies
Pelvis US: hypoplastic ovaries, endometrial
disorders, polycystic ovaries
MRI hypothalamus-pituitary area:
gonadotrophin deficiency, hyperprolactinemia
FSH ELEVATED
Chromosome studies
Electrolytes
abnormal
normal
Hereditary ovarian failure
Acquired ovarian failure
Turner syndrome variants
FSH NOT ELEVATED
Pubertal stage & Bone age
Estradiol, Progestin withdrawal
hypoestrogenic
normoestrogenic
GnRH or
GnRH agonist test
FSH
hyperresponsive
Partial primary
Ovarian failure
FSH & LH not
hyperresponsive
Delayed
puberty
Androgens
Ultrasound
Thyroid / Cortisol
Prolactin
Gonadotropin
deficiency
Prolactin
excess
Hypothalamic
anovulation
normal
Androgen
excess
abnormal
Endometrial
disorder
Extra-HPG
disorder
Anorexia nervosa
Childhood psychiatric disorder
0.5-1% amongst adolescents
DSM-IV and ICD-10 criterion
Syndrome of amenorrhoea, undernutrition
from voluntary starvation and psychosocial
dysfunction
Endocrine disturbances in AN
Amenorrhoea-oligomenorrhoea (wt. change
10-15%)
Delayed puberty
Hypothyroidism
Hypercortisolism
Hypoglycaemia
Osteopenia & osteoporosis
Amenorrhoea in AN
Weight changes of 10-15% of body weight
Fat stores <17%
Return of menses within 6 mons of reaching
90% of ideal body weight or 23% of fat
store
Hypoth.-Pit.-Ovar. axis in AN
Isolated hypogonadotrophic hypogonadism
Hypothalamic origin
Low basal Gns, low estradiol levels
Blunted Gns response to GnRH
24h LH profile: Decrease in both frequency
& amplitude
Normalized with weight recuperation
Aetiology of hypo-hypog. In AN
Malnutrition (Leptin)
Hypothalamic dysfunction
Neurotransmitter alternation
Melatonin
Leptin and amenorrhoea
Synthesized by adipose tissue
Regulate food intake & energy expenditure
Receptors expressed in anterior pituitary and
gonads
Regulate GnRH secretion
Initiation and maintenance of gonadal function
Loss of adipose tissue in AN Decreases leptin
level GnRH def.
Management of amenorrhoea
in AN
Rehydration and metabolic stabilization
Psychotherapy
Behavior modification
Family counseling