Amenorrhea - Define, Cause, Sign and Symptoms, Type- Pathological and Physiological Amenorrhea and It's Treatment and management, Cushing Syndrome - Define, Causes, Sign And Symptoms in PPT

 Definitions:
Amenorrhea means complete absence of
menstruation in patients during the
reproductive years. It is not a disease, but
a symptom.
 Pathophysiology:
Amenorrhea occurs if the hypothalamus
and pituitary fail to provide appropriate
gonadotropin stimulation to the ovary,
resulting in inadequate production of
estradiol or in failure of ovulation and
progesterone production. Amenorrhea
can also occur if the ovaries fail to
produce adequate amounts of
estradiol despite normal and
appropriate gonadotropin stimulation
by the hypothalamus and pituitary

Classification of amenorrhea:
A) Physiological amenorrhea:
1- Before puberty: due to suppression of the
hypothalamo-pit.-ovarian axis which is
sensitive to the low level of estrogen
2- Pregnancy: due to pregnancy hormones;
estrogen & progesterone which suppress
gonadotropins.
3- Postpartum: Lactation amenorrhea is due to
prolactin which alters LH & FSH secretion or
inhibits GTH release
4- Postmenopausal: due to intrinsic ovarian
failure (depletion of ovarian follicles)

B) Pathological amenorrhea :
I- False amenorrhea (Cryptomenorrhea):
Actually, menstruation takes place but there is an
obstruction to menstrual outflow produced by
congenital or acquired conditions:
a. Congenital causes:
1. Imperforate hymen: the represents the most common form of
vaginal outflow obstruction.
Symptoms: normal young girls complaining of :-
○ Cyclic lower abdominal (menstrual) pain
○ Lower abdominal swelling:
○ Retention of urine or difficulty with micturition.

Examination:
 General examination: normal 2ry sex characters
 Abdominal examination: pelvi-abdominal swelling
may be felt.
 Local examination: bulging membrane at the
introitus which appear as a dark blue or purple
color due to retained blood. Gentle pressure on
the swelling will transmit a thrill to the vaginal
membrane.
2- Vaginal septum & atresia with a functioning
uterus: a transverse vaginal septum or
failure of canalization of the entire vagina.
The uterus develops normally 
hematometra & hematosalpinx when
menstruation is established.

Treatment:
 Excision of vaginal septum.
 For vaginal atresia: Laparotomy (open
the uterine cavity)  drainage
 Artificial vagina is constructed with a
therich skin graft.
3 - Atresia of the cervix with a
functioning uterus: is rare.
b- Acquired causes of
crytomenorrhoea:
1- Adhesive vaginitis: due to senile
vaginitis or due to radiotherapy or
chemical burns
2- Cervical stenosis: due to excessive
cauterization, amputation of the cervix,
trachelorrhaphy and Fothergil
operation
II - True amenorrhea: may be primary or
secondary
Drainage of hematocolpos

Primary amenorrhea
I- Constitutional  Delayed puberty
II- Hypothalamic  Frolich's syndrome
 Laurance Moon Bidle syndrome.
III- Pituitary causes  Pituitary infantilism.
- Selective gonadotrophin deficiency
- Panhypopituitrism
IV- Ovarian causes  Congenital defects
- Gonadal dysgenesis
- True hermaphroditism
 I ry ovarian failure
 Prepubertal PCOD
 Insensitive ovarian syndrome.
V- Uterine causes  Congenital absence
 Hypoplasia
 Refractory endometrium
VI- Adrenocortical disorders  Congenital adrenal hyperplasia
 Congenital adrenogenital syndrome
& related disturbances
•Causes:

* Definition of primary amenorrhea: failure of
menarche to occur when expected in relation
to the onset of pubertal development.
It is defined either as absence of menses by age 14
years with the absence of growth or development of
secondary sexual characteristics or as absence of
menses by age 16 years regardless of growth and
devlopment of secondary sexual characteristics.
*Prevalence: about 0.3%
I) Constitutional: no pathology in the endocrine axis.
Constitutional pubertal delay: is caused by
immature pulsatile release of gonadotrophin-
releasing hormone; maturation eventually occurs
spontaneously.
 Common cause (20%)
 Under stature and delayed bone age (X-ray Wrist
joint)
 Positive family history
 Diagnosis by exclusion and follow up
 No anatomical abnormality and endocrine
investigations show normal results.
 Prognosis is good
 No drug therapy is required – Reassurance
Constitutional delay

Primary amenorrhea (cont.)
II) Hypothalamic:
1- Frolich's syndrome (Dystrophia adiposo-genitalis):
- Characterized by:
• Adiposity
• Absence of 2ry sex characters
• Atrophy of genital organs (small uterus, acute AVF, pin hole
external os and short vagina)
- Laboratory diagnosis:
•  Pituitary gonadotrophins •  Estrogen
- Treatment: no specific treatment. Treatment to relieve amenorrhea &
obesity by:
a- Reduction of weight
b- Thyroid hormone
c- Estrogen & progesterone
d- Pituitary gonadotophins FSH & LH
2- Laurance Moon Biedl's syndrome: in addition to findings
in Frolich's syndrome there is: retinitis pigmentosa,
polydactly & mental deficiency
Frolich's syndrome

III) Pituitary causes:
Pituitary infantilism: the failure in the pituitary may be:
a- Selective pituitary failure:
- Specific failure to produce GTH
- Characters:
I. No secondary sex characters.
II. Amenorrhea
III. Genital atrophy
IV. Dwarfism
b- Panhypopituitrism:
- Thyroid failure (Hypotension - hypoglycemia)
- Adrenal failure
-  17 ketosteroids

IV) Ovarian causes:
1- Congenital developmental defects:
a. Gondal dysgenesis: is spectrum of disorders with
associated hypergonadotropic Hypogonadism.
Chromosomally abnormal Chromosomally normal
- Classic Turner ’s syndrome (45XO) - 46XX (Pure gonadal dysgeneis)
- Turner variants (45XO/46XX) - 46XY (Swyer’s syndrome)
- Mixed gonadal dygenesis (45XO/46XY)
Characters of ovarian dysgenesis:
amenorrhea, stunted growth, genital atrophy and
absence of secondary sex characters
Expel:- - Turner’s syndrome
- True Hermaphroditism
- male hermaphroditism

Turner’s syndrome:
 Turner's syndrome is caused by either a
complete absence or a partial abnormality
of one of the two X chromosomes.
 Sexual infantilism and short stature.
 Associated abnormalities, webbed neck,
coarctation of the aorta, high-arched
pallate, cubitus valgus, broad shield-like
chest with widely spaced nipples, low
hairline on the neck, short metacarpal
bones and renal anomalies.
 High FSH and LH levels.
 Bilateral streaked gonads (formed of
stroma only & no follicles).
 Karyotype: 80 % 45, X0 and 20% mosaic
forms (46XX/45X0)
 Treatment: HRT
Turner’s syndrome

b. True hermaphroditism:
any mixture of ovary, testis,
and ovotestis – either
unilateral or bilateral is
possible, with ovarian tissue
more functional. The most
common is 46,XX

c. Male hermaphroditism (androgen insensitivity):
formerly known as testicular feminization
syndrome
 Genetically mediated ( X-linked trait )
 Affected individuals have Karyotype 46, XY and have
normal testes (undescended) with normal production
of testosterone and normal conversion to
dihydrotestosterone
 Absent cytoplasmic testosterone receptors
 Due to absence of receptors in target organs, there is
a lack of male differentiation of the external and
internal genitalia. Therefore, external genitalia remain
female and Wolffian duct development fails to take
place. Also, Müllerian duct regression is induced by
anti-müllerian hormone which is produced by the
Sertoli cells of the fetal testes. Therefore, these
individuals have:

Male hermaphroditism
(cont.) Normal female appearance
 No female or male internal genitalia
 Normal female external genitalia
 Short or absent vaginal pouch
 Scanty or absent pubic/axillary hair
 Normal or enhanced breasts
Treatment:
 Operative removal of the testicles after
puberty due to ↑ risk of malignancy
(gonadoblastoma) found in 25% of
patients
 Surgical correction of the vagina
(artificial vagina)
T. F. syndrome

2- 1ry Ovarian failure: due to:
 Genetic ovarian dysgenesis
 Non-dysgenesis ovarian failure
 Steroidogenic enzyme defects (17-hydroxylase)
 Autoimmune oophoritis
 Postinfection (eg. Mumps)
 Postoopherectomy
 Postradiation
 Postchemotherapy
Gonadotropins (FSH/LSH) will be high,
similar to menopause. The ovary is not
responding to pituitary GTH at puberty

3- Prepubertal polycystic ovarian syndrome
4- Resistant (insensitive ovary syndrome):
 1ry amenorrhea with well developed pubic &
axillary hair
 Atrophic vaginal & endometrial mucosa
 Elevation of FSH & LH with low estrogen
 N/E of the ovary  resemble prepubertal organ
 M/E  show numerous primordial follicles not
passed to mature size
 Treatment: Ovulation induction by GTH ( high
doses)

V) Uterine causes:
1- Mayer-Rokitansky-Kuster-Hauser
Syndrome(MRKH) (utero-vaginal agenesis):
15% of primary amenorrhea. It is due to
congenital absence of mullerian ducts and is
characterized by:
 Normal secondary sexual development &
external female genitalia
 Normal female range testosterone level
 Absent uterus , fallopian tube, upper vagina
and normal ovaries
 Karyotype 46-XX
 15-30% renal, skeletal and middle ear
anomalies
DD: Testicular Feminization Syndrome
Treatment: dilatation or vaginoplastyin order to
lead to a normal sexual life
2- Severe degrees of hypoplasia
3- Refractory endometrium

VI) Disorders of adrenal gland:
Adrenogenital syndrome: Late
onset congenital adrenal
hyperplasia (CAH)
 Autosomal recessive trait
 Most common form is due to 21-
hydroxylase deficiency in adrenal glands,
androgens can not be converted to
corticosteroids  Female
pseudohermaphroditism.
 Severe forms show signs of severe
androgen excess  Defeminization &
masculinization
 High 17 α -OH-progesterone blood level
 Treatment: cortisol replacement and may
be corrective surgery for external genitalia
Late onset CAH

Diagnosis of primary amenorrhea:
 History: obtaining a thorough history is
essential and comprises:
 Childhood growth and development including
height and weight charts and age at thelarche.
 Age at menarche of the patient's mother and
sisters
 History of chronic illness, trauma, surgery, and
medications
 Information regarding exercise, diet and
psychosocial issues.
 History of symptoms as cyclic lower abdominal
pain , virilizing changes

Diagnosis of primary amenorrhea (cont.)
Physical examination: special attention should be directed toward
evaluating
General:
Body dimensions ( Height & span) and habitus.
Distribution and extent of body hair
Muscle mass or other signs of virilization.
Extent of breast development by Tanner staging
Look for signs of Turner syndrome
Abdominal: look for pregnancy or pelviabdominal mass e.g ovarian mass
or hematocolpos
Local examination: of external and internal genitalia, with emphasis to
look for
Presence or absence of the uterus
Presence or absence of patent vagina or vaginal pouch
Evidence of exposure to androgens (pubic hair distribution and
clitoromegaly).
Imperforate hymen
Pelvic fullness (pregnancy, ovarian mass, and genital anomalies)
P/R: for virgins, hematocolpos

U/S examination: If a genital examination is
not feasible, an abdominal ultrasound may be
useful to confirm the presence or absence of
the uterus.
Investigations of primary amenorrhea:
 Pregnancy test
 Physical examination to determine presence of
uterus
 FSH
N.B. Some patients will not demonstrate any obvious etiology for their
amenorrhea on history and physical examination. These patients can
be subjected to work up in a logical manner using a stepwise
approach after pregnancy is excluded.

Evaluation of primary amenorrhea

* Treatment of primary amenorrhea:
 If possible, the aim of therapy is correction of the cause e.g.
 Bromocripitine therapy for prolactinoma
 Specific therapy for malnutrition, malabsorption, weight loss,
anorexia nervosa, etc
 Imperforate hymen: cruciate incision
 Transverse vaginal septum: surgical removal
 Hypoplasia or absence of cervix in presence of functioning
uterus  hysterectomy is required as repair of the cervix has not
been successful
 Absent or short vagina: progressive dilatation or Mcindo’s
split thickness graft
 Patients with karyotype XY or mosaic gonads should be
removed
 Clomiphene citrate is ineffective in patients with hypogonadism
due to hypoestrogenism but HMG or pulsatile Gn RH can be
effective
 Patients with physiologic delay  reassurance
 Patients with all forms of gonadal failure and hypogonadotropic
hypogonadism  cyclic estrogen and progestin therapy

Secondary amenorrhea
 Definition: the cessation of menstruation for at least 6 months
or for at least 3 of the previous 3 cycle intervals.
 Prevalence: about 3%
I- Constitutional  Acute infections
 Chronic debilitating diseases
 Nutritional disorders
 Psychological disturbances
 Endocrinal (thyroid & pancreas)
II- Hypothalamic  Frolich's syndrome
 Diseases mid brain
 Idiopathic hypothalamic insufficiency
 Chiari frommel syndrome
 Iatrogenic (drugs & steroids)
III- Pituitary causes  Adenomas: . Acidophil .Basophil
. Chromophobe Simmond’s D.
 Hypofunction panhypopit. Sheehan’s
( Insufficiency) Levi-lorian syndrome.
IV- Ovarian causes (A) Partial failure: as
 Chronic anovulation
 Stein leventhal syndrome ( PCOD)
 Estrogenic ovarian tumours
 Hyperthecosis ovarii
 Masculinizing ovarian tumours.
Premature menop.
(B) Complete ovarian failure Casteration
T B
V- Uterine causes  Hysterectomy.
 Over curettage.
TB
 Endometrial. destruction. Radiation
Infection
 Asherman's syndrome.
 Uterine atrophy.
VI- Adrenocortical disorders  Addison's disease.
 Tumours of adrenal cortex.
 Cushing's syndrome.
 Virilism due to excess androgen.

1. Constitutional amenorrhea:
1. Acute infections: influenza & fevers
2. Chronic debilitating diseases: as anemia, liver cirrhosis, T.B.
3. Nutritional disturbances: malnutrition & extreme obesity.
4. Psychological:
a. Major & minor psychosis
b. Emotional shock following trauma
c. Pseudocyesis characterized by:
1. An obsession of pregnancy
2. Weight gain.
3. Normal secondary sex characters & pelvic organs
4. lactation
5. Disturbed FSH/LH ratio.
6. HCG -ve
d. Anorexia nervosa

d- Anorexia nervosa: disease
of adolescence & is
characterized by
 1ry or 2ry amenorrhea is often first
sign
 A body mass index (BMI) <17 kg/m²
 Hypothalamic suppression
 Abnormal body image, emaciation,
intense fear of weight gain, often
strenuous exercise
 Sense of wellbeing despite weight
loss
 Mean age of onset 13-14 yrs (range
10-21 yrs)
 Bulemics less commonly have
amenorrhea due to fluctuations in
body weight.
Anorexia nervosa

5) Endocrinal:
a- Pancreas (D.M): causes menstrual
disturbances
b- Thyroid:
Anorexia nervosa
1- Cretinism & Childhood myxedema 
amenorrhea..
2- Adult myxedema
3- Hyperthyroidism
Treatment of thyroid disorders:
- For myxedema  L- thyroxin
- For hyperthyroidism  anti-thyroid drugs

II) Hypothalamic amenorrhea:
1- Frolich’s syndrome
2- Diseases of mid brain
3- Idiopathic hypothalamic insufficiency
4- Chiari-Frommel syndrome: represents a prolonged physiological lactational
amenorrhea due to inhibition of PRL inhibiting factor of hypothalamus and is characterized
by: . Atrophy of vaginal & uterine mucosa
. Sustained breast developments
. Low pituitary gonadotropins
N.B if unassociated with pregnancy, the presence of pituitary tumour should be
considered e.g. Ahumada Del Castello syndrome.
DD of postpartum amenorrhea:
 Physiological condition (lactation or pregnancy)
 Sheehan's syndrome & anterior pituitary necrosis
 History of postpartum D&C causing infection and endometrial scarring
(Asherman's syndrome)
 Chiari-Fromel syndrome - Cesarian Hysterctomy
 Amenorrhea-galactorrhea

- Phenothiazine derivatives
- Oral contraceptive pills
They  hypothalamic releasing
hormone (prolonged effect in some
cases can occur)
5- latrogenic (Drugs & steroids):

A) Pituitary tumors: produce
- Pressure affects  Bitemporal hemianopia
- Endocrine disturbances
C/P: History of headache & visual disturbances
Diagnosis: X - ray sella turcica, C.T scan & MRI,
visual field defects.
1) Acidophil adenoma: source of growth hormone
. Characters:
a- Excessive growth of hands & feet
b- ↑ in coarseness of all features
c- ↑ size of nose & lower Jaw  prognathism
d- Polyuria, polydepsia & muscle weakness.
. Laboratory:
- Serum growth hormone
- Absence of urinary gonadotrophins
- Impaired glucose tolerance.
Acromegaly
Secondary amenorrhea
III) Pituitary causes of amenorrhea:

Pituitary T. (cont.)
2) Basophil adenoma( Cushing's syndrome):
Characters: see diagram
3) Chromophobe adenoma:
- Amenorrhea due to destruction of pituitary
tissue
- Prolactin producing adenoma are associated
with Forbes Albright syndrome
characterized by persistent lactation in
absence of a previous pregnancy
- Atrophy of uterine & vaginal mucosa
- Small sized ovaries
- Galactorrhea
Diagnosis: PRL assay
Any level > 120 ng % indicates investigation
for pituitary tumor
Cushing's syndrome

B) Pituitary insufficiency (Scarring):
- Simmond's disease: panhypopituitrism
- Sheehan syndrome:
Etiology:
1-Postpartum hemorrhage
2-Shock
3-Puerperal sepsis
4-Fracture base, meningitis
5-Use of ergot (pituitary thrombosis)
Criteria of Sheehan 's syndrome:
After immediate recovery of pituitary thrombosis
or postpartum collapse, amenorrhea and failure
of lactation occur

Sheehan syndrome (cont.) :
Signs:
A) Early:
1- Atrophy of uterus & vagina 2- Slight weight gain
B) Late:
1- Loss of axillary & pubic hair 2-  B. Pressure
3- Loss of weight & wasting 4- Susceptibility to infection
5- Apathy 6- Premature senility
7- Adrenal failure 8- Insulin intolerance
N.B Amelioration of disease is mostly due to compensatory
hypertrophy of lower remaining pituitary cells. Pregnancy can
occur.
Laboratory diagnosis: panhypopituitrism
-  or absent GTH -  17 Ketosteroids
-  T3 & T4 - Flat glucose tolerance test.
- Anemia

IV) Ovarian causes:
1- Premature menopause:
- Caused by disappearance of
oocytes from the ovary
- Etiology: germ cells damage due
to radiation, methotrexate, T.B,
surgical removal and
auto-immune diseases
2- PCOD (Stein Leventhal
Syndrome): see ovulation
disorders Asherman's syndrome

Secondary amenorrhea (cont.)
V) Uterine causes: destruction of the endometrium due to T.B or
Asherman's syndrome
Diagnosis:
- Endometrial curettage for T.B
- HSG & Hysteroscopy for Asherman's syndrome
VI- Disorders of adrenal gland:
1- Adrenogenital syndrome: see before
2- Cushing's syndrome: due to excess secretion of corticosteroids by
adrenals
3- Adrenal tumours:
Characters:
1- Marked hypertension due to  corticosteroids
2- Early amenorrhea
3- 17 ketosteroids  Not suppressed by dexamethasone
4- DHEA-S is specific to adrenal androgens
5- Defeminization and masculinization

N.B. Causes of amenorrhea & galactorrhea:
- Lactation
- Chiari Frommel syndrome - Ahumada
- Del Castello
- Pituitary tumours - Drugs
Causes of hirsutism & amenorrhea:
- PCOD - Ovarian tumours
- Adrenal tumours - Drugs

Diagnosis of a case of amenorrhea:
1- History taking:
– Personal history: age to exclude menopause
– Risk of pregnancy : Pregnancy symptoms
– Associated symptoms, e.g. galactorrhoea, hirsutism, hot flushes, dry vagina,
symptoms of thyroid disease
– Recent change in body weight
– Recent emotional upsets
– Level of exercise
– Previous menstrual and obstetric history
– Previous surgery, e.g. endometrial curettage, oophorectomy
– Previous abdominal, pelvic, or history cranial radiotherapy
– Past history: of drugs, operations as D &C
– Family, e.g. of early menopause
– Drug history, e.g. progestogens, combined oral contraceptive, chemotherapy
– Symptoms of  Intracranial tension

Diagnosis of a case of amenorrhea: (cont.)
2- Examination:
General: for
 Height and weight: calculate body mass index if
appropriate.
 Signs of excess androgens, e.g. hirsutism, acne
 Signs of virilization, e.g. deep voice, clitoromegaly in
addition to hirsutism, and acne
 Signs of thyroid disease .
 Acanthosis nigricans: this hyperpigmented thickening of
the skin folds of the axilla and neck is a sign of
profound insulin resistance. It is associated with
polycystic ovary syndrome (PCOS) and obesity.
 Breast examination for galactorrhoea.
 Fundoscopy and assessment of visual fields if there is
suspicion of pituitary tumour.

Diagnosis of a case of amenorrhea
Abdominal examination:
 Pelvi-abdominal masses: exclude pregnancy in every
case of 2 ry amenorrhea.
 Pubic hair
 Striae as in Cushing's syndrome.
Local pelvic examination:
 Vulva: development is an index of ovarian function
 Vagina: thin & poorly developed in hypogonadism
 Cervix: stenosis
 Uterus: masses - size

3- Investigations:
A- Clinical investigations:
i - Examination under anesthesia ii - Uterine sounding
iii - Vaginal smear iv -Cervical mucus
v - Endometrial biopsy vi- Hormonal withdrawal test
(progesterone)
See work up of 2ry amenorrhea
B- Laboratory investigations:
- Pergnancy test: in every case of secondary amenorrhea
- T3&T4 - Glucose.T.T - Hormonal assays:
1) Gonadotrophins (FSH & LH):
* High in: primary ovarian failure and premature menopause
• Low in: pituitary failure
2) Estrogen:
* High in: pregnancy and functioning ovarian cyst
* Low in: primary ovarian failure, menopause, virilizing ovarian tumours and
Cushing' s syndrome
3) 17 ketosteroids, 17 OH progesterone & DHEA S: high in adrenogenital
syndrome adrenal hyperplasia and adrenal tumours
C- Radiological: - X- ray chest (T.B) - X-ray skull - HSG
- C. T & MRI - Ultrasonography (TA & TVS)
D- Endoscopic: hysteroscopy, laparoscopy & ovarian biopsy

Work up of secondary amenorrhea

Treatment of secondary amenorrhea :treat the cause
1- Asherman’s syndrome:
 Hysteroscopic resection with scissors or electrocautery
 Pediatric Foley catheter placed in uterine cavity for 7-10
days
 Systemic B. spectrum antibiotic and 2 month course of
high dose estrogen with monthly progesterone
withdrawal to prevent reformation of adhesions.
2- Ovarian failure:
- Estrogen replacement
- Gonadectomy when y cell line is present

Treatment of secondary amenorrhea :
3- Hypothalamo-pituitary lesions and dysfunctions:
CNS tumours: surgical removal, radiation therapy or combination of both
for CNS tumours other than prolactinomas
Thyroid disorders: thyroid hormone, radioactive iodine or antithyroid drugs
Hyperprolactinemia:
- Discontinue medications leading to hyperprolactinemia.
- Bromocriptine - Rarely, surgery for large pit. tumours
Panhypopititirism: various replacement regimens
- Estrogen replacement therapy for lack of gonadotropins
- Corticosteroid replacement for lack of ACTH
- Thyroid hormone for lack of TSH
- Synthetic vasopressin

3- Hypothalamo-pituitary lesions and
dysfunctions (cont.):
Hormonally active ovarian tumors  surgical removal
Obesity, malnutrition, chronic disease, Cushing's syndrome,
acromegaly: should be treated
Pseudocyesis and stress induced amenorrhea 
psychotherapy
Exercise - induced amenorrhea  moderation of activity
and weight gain where appropriate
Anorexia nervosa  multiple approach, severe cases
require hospitalization
Chronic anovulation or PCO syndrome: differ according to
whether pregnancy is desired or not
Congenital adrenal hyperplasia: Dexamethazone 0.5mg at
bed time.

Amenorrhea - Define, Cause, Sign and Symptoms, Type- Pathological and Physiological Amenorrhea and It's Treatment and management, Cushing Syndrome - Define, Causes, Sign And Symptoms in PPT

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