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