SEMINAR ON WORK UP FOR

AMENORRHEA
PRESENTED BY
1. ENDEGENA TADESSE C2
2. ENDESHAW SIMENEH C2
3. EYOEL KASSAHUN C2
MODERATEOR DR. GEBRESENBET
(RESIDENT)
 OUTLINES
• INTRODUCTION
• CLASSIFICATION
• PRIMARY AMENORRHEA
• DEFINITION & ETIOLOGY
• DIAGNOSIS
• TREATMENT
• SECONDARY AMENORRHEA
• DEFINITION & ETIOLOGY
• DIAGNOSIS
• TREATMENT
 INTRODUCTION
• Evaluation and management of a patient with amenorrhea is
common in gynecology.
• Amenorrhea has classically been defined as primary or
secondary.
• Although this distinction does suggest a relative likelihood of
finding a particular diagnosis, the approach to diagnosis and
treatment is similar or either presentation
 CONT.
• Off course, amenorrhea is a normal state prior to puberty,
during pregnancy and lactation, with certain drugs such COCs,
and following menopause.
• Evaluation is considered or an adolescent:
(1) who by age 13 has not menstruated or shown other evidence
o pubertal development, or
(2) who has reached other pubertal milestones but has not
menstruated by age 15 or within 3 years o thelarche
 CONT.
• Secondary amenorrhea of 3 months or oligomenorrhea involving
ewer
than nine cycles a year is also investigated
• in some circumstances, testing reasonably may be initiated
despite the absence of these strict criteria. Examples include a
patient with the stigmata o turner syndrome, obvious
virilization, or a history of uterine curettage.
• An evaluation or delayed puberty is also considered be ore the
ages listed above i the patient or her parents are concerned
 NORMAL MENSTRUAL CYCLE
• Ovarian unction in a normal menstrual cycle is divided into the
follicular phase (preovulatory), ovulation, and luteal phase
(postovulatory).
• Regular and spontaneous menstruation requires:-
(A) an intact hypothalamic–pituitary–ovarian endocrine axis
(B) an endometrium competent to respond to steroid hormone
stimulation; and
(c) an intact outflow tract from internal to external genitalia.
 CLASSIFICATION
• The prevalence o pathologic amenorrhea ranges from 3 to 4
percent in reproductive-aged populations
• Numerous classification systems of the diagnosis of
amenorrhea have been developed, and all have their strengths
and weaknesses.
• This system divides causes o amenorrhea into anatomic versus
hormonal etiologies, with further division into congenital versus
acquired disorders
 PRIMARY AMENORRHEA
• Etiology of primary amenorrhea
A. Hormonal
1. Hypergonadotropic hypogonadism
Premature ovarian insufficiency
• Inherited- (gonadal dysgenesis, single gene D/O)
• Acquired- infectious, autoimmune, iatrogenic, env’tal etc
 CONT.
2. EU gonadotropic
• Inherited
• Polycystic ovarian syndrome
• Late-onset congenital adrenal hyperplasia
• Ovarian tumors (steroid-producing)
• Acquired- hyperprolactinemia, thyroid disease etc
 CONT.
3. Hypo gonadotropic hypogonadism
• Disorders of the hypothalamus
• Inherited :- kallmann syndrome, HHS
• Acquired :- eating disorder
• Disorders of the anterior pituitary gland
• Inherited :- Septo-optic dysplasia
• Acquired :- Pituitary adenoma, Sheehan syndrome,
surgery ,inflammation
 CONT.
B. Anatomic cause
• Congenital
Müllerian agenesis
 Imperforate hymen
Transverse vaginal septum
Cervical atresia
Labial agglutination or fusion
• Acquired
Cervical stenosis
Asherman syndrome
 HYPERGONADOTROPIC HYPOGONADISM
• It refers to any process in which ovarian function is decreased or
absent (hypogonadism).
• The gonadotropins, LH and FSH, have increased levels
(hypergonadotropic).
• Due to a lack of negative feedback
• The primary dysfunction at the level of the ovary, rather than
centrally at the hypothalamus or pituitary.
• Premature ovarian insufficiency is defined as loss of oocytes and
the surrounding support cells prior to age 40 years.
 CONT.
 Gonadal dysgenesis

Based on the karyotype:-

A) normal karyotype
• 1/3 of patients with gonadal dysgenesis will have a normal
karyotype (46,XX or 46,XY) and are said to have "pure"
gonadal dysgenesis.
• The etiology of the gonadal failure is poorly understood, but
is likely due to single gene defects or destruction of
gonadal tissue in utero, perhaps by infection or toxins.
• Vanishing testes syndrome
 CONT.
B) abnormal karyotype
• Turner syndrome (45,X) karyotype is found in about half of
these patients,
• Mosaicism 45,X/46,XX , 45,X/46,XY
• Both accounts for about two thirds of gonadal dysgenesis .
• Associated somatic defects including short stature, webbed
neck, low hairline, shield-shaped chest, and cardiovascular
defects
• 90% never have menstrual bleeding
2. Acquired abnormalities
 CONT.
 Clinical features
• The external female genitalia, uterus, and fallopian tubes
develop normally until puberty when estrogen-induced
maturation fails to occur.
• Menstrual pattern is the most common presenting symptom,
but there is no characteristic menstrual history that heralds the
onset of spontaneous primary ovarian insufficiency
• Manifestation of turner syndrome, sexual infantilism
HYPOGONADOTROPIC HYPOGONADISM
• The primary abnormality lies in the hypothalamic-pituitary axis.
• A decrease in gonadotropin stimulation of the ovaries leads to
loss of ovarian hormone production.
• In these patients, LH and FSH levels, are at detectable range
(<5 miu/ml).
• However, levels may be undetectable in patients with IHH,
kallmann syndrome and absent pituitary function
• Hypogonadotropic hypogonadism disorders leading to luteal
dysfunction, oligomenorrhea, and amenorrhea.
 CONT.
Disorders of the hypothalamus
• Congenital
• Idiopathic hypogonadotropic hypogonadism(IHH)
• Kallmann's syndrome
• X-linked, autosomal dominant or autosomal recessive
disorder
• Associated with cleft palate, unilateral renal
agenesis, cerebellar ataxia, epilepsy,
neurosensory hearing loss,
• Kallmann syndrome can be distinguished from IHH by
olfactory testing.
 CONT.
Acquired
• Hypothalamic amenorrhea," this diagnosis encompasses
three main categories:
Eating disorders,
 Excessive exercise,
Stress.
• Tumor , radiation ,trauma, infection
• Infiltrative disease
• Pseudocyesis
DISORDERS OF THE ANTERIOR PITUITARY
GLAND
• Inherited
• Septoptic dysplasia--mutation in the PROP1 gene
• Mutations in genes that encode the LH or FSH -beta
subunits or the gnrh-receptor (rare causes)
• Acquired
• Pituitary adenomas
• Hyperprolactinemia
 EUGONADOTROPIC HYPOGONADISM
• Due to relatively normal gonadotropin levels, these patients will
secrete estrogen and therefore can be said to have chronic
anovulation with estrogen present.
• This is in contrast to the patients with ovarian failure or
hypothalamic-pituitary failure in which estrogen is low or absent.
 Polycystic ovarian syndrome
Non classic CAH
Ovarian tumor
Hyperprolactinemia and
 Hypothyroidism
 ANATOMIC CAUSES
• Lower outflow tract obstruction
• Congenital anatomic lesions of the uterus and
vagina — congenital abnormalities account for 20 percent of
cases of primary amenorrhea.
• Menses cannot occur without an intact uterus, endometrium,
cervix, cervical os, and vaginal conduit.
• Pelvic or lower abdominal pain is a common presenting
symptom
• Amenorrhea is associated with imperforate hymen, a complete
transverse vaginal septum , isolated vaginal atresia
 CONT.
 Müllerian agenesis
• Partial or complete
• Amenorrhea may result from outflow obstruction or from a lack
of endometrium in cases involving uterine agenesis.
• In complete müllerian agenesis, often called mayer-rokitansky-
küster-hauser syndrome, patients fail to develop any Mullerian
structures and on examination are found to have only a vaginal
dimple.
 CONT.
Complete androgen insensitivity syndrome(cais)
• X-linked recessive disorder (46,XY subjects appear as normal
women.
• These patients are resistant to testosterone due to a defect in
the androgen receptor
• Phenotypically normal females at birth.
• External genitalia appear normal;
• Scant or absent pubic and axillary hair
• Vagina is shortened or blind ending
 CONT.
 Diagnosis
• Primary amenorrhea is evaluated most efficiently by focusing on
the presence or absence of breast development, the presence or
absence of the uterus and the FSH level :-
 if there is no breast development and the FSH level is elevated,
diagnosis is gonadal dysgenesis
 If the uterus is absent and FSH is normal, diagnosis is Mullerian
agenesis or androgen insensitivity syndrome
If the FSH is normal, and both breast development and the
uterus are present, then the work-up on causes of secondary
amenorrhea
 CONT.
 Step 1: history
• has she completed other stages of puberty
• Is there a family history of delayed or absent puberty
• What is the woman's height relative to family members?
• Are there any symptoms of virilization?
• Has there been stress, change in weight, diet, or exercise habits,
or illness that might result in hypothalamic amenorrhea?
• Is she taking any drugs that might cause or be associated with
amenorrhea?
• Is there galactorrhea
 CONT.
 Step 2: physical examination
• An evaluation of pubertal development, including current height,
weight, and arm span and an evaluation of the woman's growth
chart.
• An assessment of breast development
• A careful genital examination should be performed for clitoral
size, pubertal hair development, intactness of the hymen, depth
of the vagina, and presence of a cervix, uterus, and ovaries
• Examination of the skin for hirsutism, acne, striae, increased
pigmentation, and vitiligo.
• Evaluation for the classic physical features of turner syndrome
 CONT.
 Step 3: basic laboratory testing
• The single most important step in the evaluation is to determine
whether there are any anatomic abnormalities of the vagina,
cervix, or uterus.
• If a normal vagina or uterus is not obviously present, pelvic U/S
should be performed to confirm the presence or absence of
ovaries, uterus, and cervix
• Uterus absent — absent uterus, evaluation should include a
karyotype and measurement of serum testosterone. For
distinguish between abnormal Mullerian development and
androgen insensitivity syndrome
 CONT.
• Uterus present — for patients with normal Mullerian structures, an
endocrine evaluation should be performed includes measurement of
serum B-HCG to exclude pregnancy and of serum FSH
 A high serum FSH concentration is indicative of primary ovarian
failure. A karyotype done to identify complete or partial deletion
of the X chromosome or the presence of Y chromatin
 A low or normal serum FSH concentration suggests disorders of
the hypothalamic-pituitary axis.
 Serum prolactin and thyrotropin should be measured if FSH is
low or normal serum testosterone and DHEA should be measured
 TREATMENT
 Goal of treatment should be directed at…
 Correcting the underlying pathology
 Helping woman to achieve fertility (if desired)
 Preventing the complications of disease process
 Consequences of untreated amenorrhea/oligomenorrhea:
 Hypoestrogenism – osteoporosis, infertility
 Hyperestrogenism – heart disease, stroke, diabetes mellitus,
breast cancer (controversial), endometrial hyperplasia and
endometrial cancer
 CONT.
 Treatment of the underlying pathology
Surgery may be required in patients with either congenital
anatomic lesions
Hypothyroidism should be treated with thyroid replacement,
levothyroxine 1.6 mcg/kg per day.
Patients with hyperprolactinemia should receive a dopamine
agonist, such as bromocriptine or cabergoline
In patients with complete androgen insensitivity, the testes
should be removed after pubertal development is complete to
prevent malignant degeneration
 CONT.
• Estrogen replacement
• This therapy is instituted in essentially every patient with
hypogonadism to avoid osteoporosis
• Thus, treatment is instituted quickly. Women with a uterus also
require continuous or intermittent progesterone administration to
protect against endometrial hyperplasia or cancer
• Therapy is usually initiated with 0.625 mg/day of conjugated
estrogens or 1 mg/day of estradiol.
• Estrogen given daily in combination with progestin or
progesterone
 CONT.
• Medroxyprogesterone acetate may be administered at a dose of
2.5 mg daily or 5 to 10 mg for 12 to 14 days every 1 to 2
months.
• Oral micronized progesterone may be administered at a dose of
100 mg daily or 200 mg for 12 to 14 days every 1 to 2 months.
• Likewise, progesterone suppositories may be administered at a
dose of 50 mg daily or 100 mg for 12 to 14 days every 1 to 2
months.
 CONT.
 Infertility treatment
• Alternative approaches may be required in a patient who
desires conception.
• Stem cells also have been proposed for poi, but loss of
ovarian reserve is best
Considered irreversible at present. In vitro fertilization using
a donor oocyte to conceive.
 SECONDARY AMENORRHEA
• Secondary amenorrhea is clinically defined as the absence of
menses for more than 3 cycle intervals, or 6 consecutive
months, in a previously menstruating woman
• Incidence: from 3% in the general population to 100% under
conditions of extreme physical or emotional stress
 CAUSES
• Pregnancy — pregnancy is the most common cause of
secondary amenorrhea. It may occur even in women who claim
that they have not been sexually active or are positive that
intercourse occurred at a "safe" time.
• A pregnancy test (measurements of serum or urinary human
chorionic gonadotropin [HCG]) is recommended as a first step in
evaluating any woman with amenorrhea.
 CONT.
• Once pregnancy has been ruled out, the most common causes
of secondary amenorrhea are disorders of :-
• ovary — 40 percent
• Hypothalamus — 35 percent
• Pituitary — 19 percent
• Uterus — 5 percent
• Other — 1 percent
 HORMONAL CAUSES
• Eugonadotropic hypogonadism
• Chronic anovulation (PCOS)
• Hypothyroidism, Cushing syndrome
• High prolactin level
• Late-onset CAH
• Ovarian tumor
 CONT.
• Hypogonadotropic hypogonadism
• Eating disorders, stress, excessive exercise
• Pituitary tumor/empty Sella
• Sheehan syndrome
• Hypergonadotropic hypogonadism
• Gonadal failure: mumps oophoritis , chemotherapy or
radiation-induced ovarian failure
 ANATOMIC CAUSE
• Anatomic disorders
• Asherman syndrome (intrauterine synechiae)
• Cervical stenosis
 HYPERGONADOTROPIC HYPOGONADISM
• Autoimmune disorders  40 % of POI cases
• Complete surgical removal or excision of the ovaries
• Pelvic radiation
• Chemotherapy
• Cigarette smoking, heavy metals, solvents, pesticides, and
industrial chemicals have detrimental effect on follicular health
 HYPOGONADOTROPIC HYPOGONADISM
Hypothalamic amenorrhea (functional disorders)
A. Eating disorders
• Anorexia nervosa
• Severe caloric restriction, weight loss,
• Self-induced vomiting, and Compulsive exercise
• Bulimic women
• Eat in binges then purge to vomit and Weight loss is
less severe
 CONT.
• Acquired pituitary dysfunction
• Pituitary adenomas are the most common cause of acquired
pituitary dysfunction
• Sheehan syndrome
• Refers to panhypopituitarism that develops after massive
postpartum hemorrhage complicated by hypotension
• In its most severe form, patients develop shock and
pituitary apoplexy
 EUGONADOTROPIC AMENORRHEA
• Chronic anovulation with estrogen present
• Polycystic ovarian syndrome
• Diagnosis is based on the presence of at least two of the
following characteristics:
a) Oligomenorrhea or amenorrhea;
b) Clinical and/or biochemical signs of hyperandrogenism;
c) Polycystic ovaries on U/S;
• Exclusion of other etiologies (CAH, androgen-secreting
tumors, cushing's syndrome)
 DIAGNOSIS
• Once pregnancy and Asherman's syndrome have been excluded,
all of the remaining causes of amenorrhea are associated with
anovulation due to hypothalamic, pituitary, or ovarian disorders.
• Step 1: rule out pregnancy — a pregnancy test is
recommended as a first step in evaluating any woman with
secondary amenorrhea. Measurement of serum beta subunit of
HCG is the most sensitive test.
 CONT.
• Step 2: history — the woman should be questioned about any
past medical history, risk factors, or symptoms that might
suggest any of the major causes of secondary amenorrhea or
oligomenorrhea
• Has there been stress, change in weight, diet or exercise habits,
or illness
• Is the woman taking any drugs that might cause or be
associated with amenorrhea?
• Does the woman have acne, hirsutism, or deepening of the
voice?
• Are there symptoms of headaches, visual field defects, fatigue,
 CONT.
• Are there any symptoms of estrogen deficiency, including hot
flashes, vaginal dryness, poor sleep, or decreased libido? These
symptoms may be prominent in the early stages of ovarian
insufficiency
• Is there galactorrhea (suggestive of hyperprolactinemia), or
hirsutism, acne, and a history of irregular menses
• Is there a history of obstetrical catastrophe, severe bleeding,
dilatation and curettage, or endometritis or other infection that
might have caused scarring of the endometrial lining
 CONT.
• Step 3: physical examination — the examination in women
with secondary amenorrhea should include measurements of
height and weight. A body mass index greater than 30 kg/m2 is
observed in women with PCOS.
• Women with a BMI less than 18.5 kg/m2 may have eating
disorder
• The patient should be examined for hirsutism, acne, striae,
acanthosis nigricans, vitiligo, and easy bruisability.
• Breasts should be examined for evidence of galactorrhea, and
vulvovaginal exam should look for signs of estrogen deficiency
 CONT.
• Step 4: basic laboratory testing — in addition to
measurement of serum HCG to rule out pregnancy, minimal
laboratory testing should include measurements of serum
prolactin, FSH, and TSH to test for hyperprolactinemia, ovarian
failure, and thyroid disease.
• If there is clinical evidence of hyperandrogenism, serum total
testosterone should be measured
 CONT.
 Assessment of estrogen status
• Estrogen status can be assessed with a progestin withdrawal
test, measurement of endometrial thickness on ultrasound, or a
serum estradiol
• Patients are given progesterone and followed for withdrawal
bleed
• If bleeding  estrogen and intact endometrium and patent
outflow tract are present
• If no bleeding  then a patient is given estrogen followed by
progesterone treatment
• If a woman again fails to bleed, then an anatomic
 TREATMENT
• The treatment of amenorrhea depends on the etiology as well as
the aims of the patient
• Goals of the treatment:
• Correcting the underlying pathology
• Helping the woman to achieve fertility, if desired
• Prevention of complications of the disease process (eg,
estrogen replacement to prevent osteoporosis; treating
hirsutism
 Asherman’s syndrome
• Hysteroscopic lysis of adhesions followed by long-term estrogen
administration to stimulate regrowth of endometrial tissue
• 5 mg of conjugated estrogen in a divided dose daily for 30 days
• 10 mg daily of medroxyprogesterone acetate, given
concurrently with the last 10 days of estrogen therapy
 CONT.
• Hypothyroidism
• Should be treated with thyroid replacement
• Hyperprolactinemia
• Dopamine agonist, such as bromocriptine or cabergoline
• Surgery for macroadenomas if secondary deficits, such as
visual changes, are observed
 Polycystic ovarian syndrome
• Cyclic progesterone treatment or oral contraceptives or other
forms of estrogen-progesterone treatment
• Insulin-sensitizing agents such as metformin in those with
insulin resistance
• Hyperandrogenism  oral contraceptives and/or spironolactone
 Hypothalamic amenorrhea
• Moderation or reduction of activity, weight gain and resolution of
illness or emotional stress, when appropriate
• For athletic women adequate caloric intake or reduced
exercise
• Nonathletic women who are underweight or have nutritional
deficiencies  nutritional counseling
• All women athletes with amenorrhea 1200 to 1500 mg of
calcium daily and supplemental vitamin D (400 IU daily)
• In a patient with an eating disorder  psychiatric intervention
 Estrogen replacement
• In essentially every patient with hypogonadism to avoid osteoporosis
• Treatment should be instituted quickly
• Women with a uterus also require continuous or intermittent
progesterone administration to protect against endometrial
hyperplasia or cancer
• No consensus on an optimal regimen in these patients
• Combination oral contraceptive pills can be used
• Duration of treatment, for most patients, continuation until
approximately age 50
 INFERTILITY TREATMENT
• Adequate treatment of hyperprolactinemia and thyroid disease
• Surgical correction for anatomic abnormalities or use of a
surrogate to carry a gestation
• POI  IVF using a donor oocyte to conceive
• Hypogonadotropic hypogonadism  pulsatile GnRH or
gonadotropins
• PCOS  clomiphene citrate
 PATIENT EDUCATION
• Adequately counsel patients about their diagnosis, the long-term
implications of this diagnosis, and the treatment options
• Potential for future childbearing
• Risks of unopposed estrogen action
• Counsel about the importance of estrogen replacement to
protect against bone loss
 REFERENCES
• WILLIAMS GYNECOLOGY, 4TH EDITION.
• UpTo-Date 2018REFERREFFERUUIRRRRRIS
• CURRENT DIAGNOSIS & TREATMENT OBSTETRICS &
GYNECOLOGY, 11TH EDITION.