EVALUATION OF

AMENORRHEA
RLBKHLL- PGY4
 DEFINITION
 Primary amenorrhea  can be diagnosed if a patient
has normal secondary sexual characteristics but no
menarche by 16 years of age. If a patient has no
secondary sexual characteristics and no menarche,
primary amenorrhea can be diagnosed as early as 14
years of age (<0.1%)
 Secondary amenorrhea  cessation of menses once
they have begun (1%)
 Some authors suggest the absence of menses for 6
months
 Normal feature in prepubertal, pregnant, and
postmenopausal females
 In females of reproductive age, first determine whether
pregnancy is the etiology
 Puberty
1. Breast 10.8 y +/- 1.1
2. Pubic hair 11.0y +/- 1.2
3. Menarche 12.9y +/- 1.2
DIFFERENTIAL DIAGNOSIS
 genetic abnormalities
 endocrine disorders
 Psychological
 Environmental
 Structural anomalies

 Diagnosis unique to primary amenorrhea include vaginal

agenesis, androgen insensitivity syndrome, and gonadal
dysgenesis.The remaining diagnoses should be
considered in patients with both primary and secondary
amenorrhea
 ETIOLOGIES
Generalized pubertal delay
 Constitutional delay
 Hypergonadotropic hypogonadism
 Turner syndrome
 Gonadal dysgenesis with mosaic karyotype
 Pure gonadal dysgenesis (Perrault syndrome, Swyer syndrome)
 Gonadotropin-resistant ovary syndrome: savage syndrome
 FSH-receptor mutation
 Acquired causes (eg, high-dose alkylating chemotherapy, pelvic radiation,
autoimmune oophoritis)
 Congenital thymus aplasia
 Hypogonadotropic hypogonadism
 Chronic conditions (eg, starvation, excessive exercise, depression, psychological
stress, marijuana use, Crohn disease, cystic fibrosis, sickle cell disease,
thalassemia major, HIV infection, renal disease, thyroid disease, diabetes
mellitus, anorexia nervosa)
 Slow-growing CNS tumors (eg, adenomas, craniopharyngiomas, meningiomas,
pituitary microadenomas)
 Isolated gonadotropin deficiency (kallman sd, midline defects)  primary amen
 Acquired miscellaneous disorders (eg, infiltration disorders [sarcoidosis,
Langerhans cell histiocytosis, hemochromatosis, syphilis, tuberculomas],
ischemia disorders [caused by trauma, aneurysm, obstruction of the aqueduct of
Sylvius] and destruction [concentrated, high-dose exposure to radiation])
 Puberty delayed when no breast development is
evident at 13.5 years, pubic hair is absent at 14
years, and menarche is absent at 16 years
 Most common cause of delayed puberty is
constitutional delay
 Another common reason is ovarian failure, also
termed hypergonadotropic hypogonadism
 Elevated levels of (FSH) and (LH) with low
estrogen
 HYPERGONADOTROPIC
HYPOGONADISM
 most common example of hypergonadotropic
hypogonadism is Turner syndrome (45,XO) karyotype
 webbed neck, short stature, broad shieldlike chest,
anomalous auricles, and hypoestrogenemia resulting in
sexual immaturity
 Gonadal dysgenesis is caused by a mosaic karyotype
and streak ovaries
 Perrault syndrome = gonadal dysgenesis, a normal
karyotype, and neurosensory deafness
 Sawyer syndrome = phenotypically immature female with
a 46,XY karyotype without testis-determining factor on
the Y chromosome.
 Gonadotropin-resistant ovary syndrome, characterized
by FSH-resistant ovaries, rare cause
 HYPOGONADOTROPIC
HYPOGONADISM
 FSH and LH levels are low
 Chronic illness  malabsorption and
malnutrition
 CNS Tumors compress the portal vessels
 affect flow of GnRH from the
hypothalamus to the pituitary gland
 Prolactinomas are most common pituitary
tumors
 ETIOLOGIES
NORMAL PUBERTY

 Associated with hyperandrogenicity (eg, PCO

syndrome, late-onset 21-hydroxylase deficiency
[nonclassic congenital adrenal hyperplasia],
immaturity of the hypothalamic-pituitary-ovarian
axis, Cushing disease, androgen-producing
ovarian or adrenal tumors, ovarian stromal
hypertrophy)
 Anovulation with absence of hirsutism or
virilization (eg, immaturity of the hypothalamic-
pituitary-ovarian axis, pregnancy)
 Hypergonadotropic hypogonadism (eg, ovarian
failure, high-dose alkylating chemotherapy,
pelvic radiation, autoimmune oophoritis)
 ASSOCIATED
HYPERANDROGENISM
 Frequently associated with hirsutism
 most common cause is PCO syndrome
 late-onset 21-hydroxylase deficiency, caused by
mutations in the 21-hydroxylase gene resulting in
excessive 17-hydroxyprogesterone levels, also termed
nonclassic congenital adrenal hyperplasia and can occur
in 1-10% of women with hirsutism
 Other causes of hyperandrogenism include Cushing
disease, ovarian stromal hypertrophy, and androgen-
producing tumors of the ovary and adrenal glands
 Exogenous anabolic steroid use should be considered in
the differential for hyperandrogenic amenorrhea
 PCO
 at least two of the following :
1. oligoovulation or anovulation (usually
manifested as oligomenorrhea or amenorrhea),
2. elevated levels of circulating androgens
(hyperandrogenemia) or clinical manifestations
of androgen excess (hyperandrogenism)
3. polycystic ovaries as defined by
ultrasonography
 LH – dependent ovarian overproduction of
androgens
 Anovulatory cycles may lead to dysfunctional
uterine bleeding and decreased fertility
 CHRONIC ANOVULATION
 Anovulation remains most common
cause of amenorrhea in the setting of
nonvirilization
 Chronic anovulation of central origin
(hypogonadotropic hypogonadism):
1. hypothalamic chronic anovulation
2. Hyperprolactinemic chronic anovulation
3. hypopituitarism
 Hypothalamic chronic anovulation: (HCA)
• slowed GnRH release (multifactorial, decreased
body fat and increased beta endorphins)
• Also called functional amenorrhea
• Abrupt cessation of menses without anatomic or
endocrine abnormality
• Anorexia nervosa is most severe form of HCA,
simple weight loss, malnutrition, exercice
(athletics), emotional stress
• All have low or normal gonadotropins, elevated
cortisol
 Hyperprolactinemia :
• 15% of amenorrhea cases
• >75% of women with amenorrhea +
galactorrhea
• 50% have pituitary tumor
• Consider primary hypothyroidism
 Hypopituitarism :
• Clinical presentation depends on age of onset
• Suspicion if L/O pubic and axillary hair, atrophy
of external genitalia in a women previously
menstruating
• r/o postpartum pituitary necrosis (Sheehan’s
syndrome), Failure of lactation is an earlier sign
• Sx : weakness, fatigability, lack of libido, cold
intolerance, short stature (during childhood)
• galactorrhea, headaches, or reduced peripheral
vision could be a sign of intracranial tumor
• Skin smooth, thin, cool, pale, slow pulse low BP
• Low Gntropin, low gonadal steroids
 PREMATURE OVARRIAN
FAILURE
 amenorrhea, hypoestrogenism, and increased
gonadotropin levels occurring before 40 years of age and
is not always irreversible
 0.1 percent of women are affected by 30 years of age
and one percent by age 40
 increased risk of osteoporosis and heart disease
 can be associated with autoimmune endocrine disorders
such as hypothyroidism, Addison’s disease, and
diabetes
 Patients younger than 30 years  karyotype to rule out
presence of a Y chromosome and the need for removal
of gonadal tissue
 Ovarian biopsy and antiovarian antibody testing have not
been shown to have clinical benefit
 ETIOLOGIES
Anomalies of the genital tract
 Müllerian agenesis (eg, Mayer-Rokitansky-
Kuster-Hauser syndrome) breast present,
uterus-
 Androgen insensitive syndrome-absent uterus
with normal breast development
 Most common : Congenital or acquired outflow
obstruction (eg, imperforate hymen, transverse
vaginal septum, Asherman syndrome,
endometrial destruction due to severe infection
or surgery)
 Labial fusion seen in female
pseudohermaphrodism (CAH or exposure to
maternal androgens in utero)
 Mayer-Rokitansky-Hauser
syndrome
 anomaly of the genital tract characterized by
vaginal agenesis
 Uterus is usually absent, vagina is foreshortened
 Ovaries function normally and produce estradiol
(E2)  breasts normal
 Pubarche also normal
 Karyotype 46,XX and is sterile
 Accounts for 15% of primary amenorrhea cases
and is second to Turner syndrome as the most
common cause of primary amenorrhea
 May require reconstructive surgery
 Spontaneous testicular regression: rare disorder
of genetic males that results in a female
phenotype with an absent uterus and sec sex
characteristics (sexual infantism)
 Enzymatic deficiencies affecting androgen
production can result in male
pseudohermaphrodites
 All disorders that are phenotypically female but
chromosomally male (XY) require that the
gonads be removed to avert cancerous changes
 Asherman syndrome occurs after an
overzealous curettage of the endometrial
lining  adhesions or synechiae

 Clinically significant infections that destroy

the endometrial lining can also result in
primary or secondary amenorrhea.
 Androgen insensitivity syndrome
 Previously termed testicular feminization
 Accounts for 10% of patients with amenorrhea
 Caused by an abnormality of the androgen receptor
 Gonads are testicles producing testosterone; however,
testosterone has no effect because the androgen
receptor is nonfunctional
 Phenotypic appearance is female and raised as girls but
the circulating hormonal pattern is male
 Karyotype 46,XY
 testes remain intra-abdominal or partially descended,
and pubic hair is sparse, no uterus
 Surgical removal of gonads, estrogen replacement
 HISTORY
 childhood growth and development,
including height and weight charts and age
at thelarche and menarche
 age at menarche of mother and sisters
 duration and flow of menses, cycle days,
day and date of last menstrual period
 history of chronic illness, trauma, surgery,
and medications, sexual history,
substance use, exercise, diet, home and
school situations, and psychosocial issues
 PHYSICAL EXAM
 vital signs, including height and weight, and sexual
maturity rating
 Anorexia - Cachexia, bradycardia, hypotension, and
hypothermia
 Pituitary tumor - Funduscopic changes, visual field
impairment, and cranial nerve signs
 Polycystic ovary (PCO) syndrome - Acne, acanthosis
nigricans, and obesity
 Inflammatory bowel disease - Fissure, skin tags, and
occult blood
 Gonadal dysgenesis (eg, Turner syndrome) - Webbed
neck, increased carrying angle, and lack of breast
development
 Galactorrhea - Breast palpation
 Delayed puberty – Underdeveloped breast with sparse
pubic hair
 Hyperandrogenism - Pubic hair distribution and excess
facial hair
 Androgen insensitivity syndrome - Absent or sparse
axillary and pubic hair with breast development
 Adrenal or ovarian tumors - Clitoromegaly and virilization
 Pelvic fullness - Pregnancy, ovarian mass, and genital
anomalies
 Imperforate hymen - Distension or bulging of the external
vagina
 Vaginal agenesis (Rokitansky-Hauser syndrome)
LABORATORY EVALUATION
 PRL> 20  primary vs secondary
PRL is elevated in > 1/3 of amenorrhea
 FSH> 30 mIU/ml  ovarian failure, if pt younger
than 30 y do karyotype
 LH is elevated in PCO, LH/FSH elevated
 LH is normal or slightly decreased in females
with HP dysfunction
 LH & FSH < 10 mIU/ml  assess sella turcica
 Testosterone > 200 ng/ml r/o androgen
secreting ovarian cancer
 DHEAS > 7 mcg/ml r/o adrenal neo
 DHEAS 5-7 mcg/ml consider CAH
 evaluation of amenorrhea with
delayed puberty
 thyroid function
 bone age
 luteinizing-hormone (LH)
 follicle-stimulating hormone (FSH)
 Prolactin
 TSH elevated and fT4 low  hypothyroidism
 Bone age delayed  constitutional delay
 Bone age normal  LH, FSH, and prolactin levels
 LH and FSH levels elevated  obtain a karyotype
 If karyotype is 45,XO, the cause is gonadal dysgenesis
(ie, Turner syndrome)
 If karyotype is 46,XX, the primary cause is ovarian failure
 Perform an autoimmune workup (Consider an etiology
of autoimmune oophoritis, effects of radiation therapy or
chemotherapy, 17-alpha-hydroxylase deficiency, or
resistant ovary syndrome)
 LH and FSH low or within the reference
range  obtain a head MRI.
 Check for pituitary tumor, pituitary
destruction, or hypothalamic disease
 If prolactin levels are elevated, obtain a
head MRI ( r/o secondary causes)
 evaluation of amenorrhea with
normal puberty

 pregnancy test
 If pregnancy test negative, obtain TSH, prolactin, FSH and LH levels
 Women < 30 years need to be evaluated by karyotype
 hyperprolactinemia  prolactinoma, CNS tumors and medications
 FSH low  MRI head (hypothalamic disease, pituitary disease or
pituitary tumor vs chronic disease, anorexia nervosa, marijuana or
cocaine use, and social or psychological stresses)
 FSH elevated, ovarian failure is the diagnosis karyotype
 karyotype abnormal  consider pure gonadal dysgenesis, such as
Turner syndrome or mosaic or mixed gonadal dysgenesis
 karyotype normal (46 XX)  ovarian failure ( premature ovarian
failure, autoimmune oophoritis, exposure to radiation or
chemotherapy, resistant ovary syndrome)
 If TSH, prolactin, and FSH levels are within
reference range, perform a progestin challenge
test
 If withdrawal bleeding occurs, consider
anovulation secondary to PCO syndrome
 If no withdrawal bleed occurs, proceed with
estradiol priming followed by a progestin
challenge
 If the challenge does not induce menses,
consider Asherman syndrome or outlet
obstruction
 If hirsutism is present, check testosterone,
DHEAS, and 17-OH progesterone level
 If the testosterone and DHEAS levels are within
the reference range or moderately elevated,
perform a progesterone challenge (If withdrawal
bleeding occurs, the diagnosis is PCOS)
 If the 17-OH progesterone level is elevated, the
diagnosis is adult onset adrenal hyperplasia
 Testosterone or DHEAS elevated r/o neoplasm
 evaluation of genital tract
abnormalities
 Obtain a pelvic sonography
 If the uterus is absent, obtain a karyotype
 If the karyotype is 46,XY, obtain testosterone levels.
 If testosterone levels are within reference range or are high
(male range), the cause is androgen insensitivity
 If testosterone levels are within reference range or are low
(female range), the cause is testicular regression or gonadal
enzyme deficiency
 If the karyotype is 46,XX, the cause is müllerian
agenesis (ie, Rokitansky-Kuster-Hauser syndrome)
 TREATMENT
 directed at correcting the underlying pathology
 outflow tract abnormalities  surgery
 Dopamine agonists for hyperprolactinemia
 OCP for decreased estrogen production (ovarian
or central)
 Estrogen required to maintain female secondary
sexual characteristics & bone density (Loss of
menstrual regularity has been associated with
an increased risk of wrist and hip fractures)
 Functional  ameliorate stressful
situation, decrease exercise, correct
weight loss + estroge

 Gonadotropin therapy or the use of

pulsatile GnRH therapy is required to
induce ovulation
THANK YOU