Amenorrhea SGD

Amenorrhea
• OBJECTIVES:

• The student should be able to:

– obtain a good history and perform a thorough
physical examination
– know the types of amenorrhea and its causes
– know the diagnostic procedures to request to
confirm the diagnosis and its rationale
– know what treatment to offer
 Case
 
• A 25 year-old G1 P0 (0-0-1-0) consulted
because she had no menses for 8 months.
She underwent curettage for the first
pregnancy which ended up in an abortion.
She also has facial acne and hirsutism. BMI is
35. Pelvic exam was normal.
 Guide Questions:

1. What additional information, if any, would you want to

learn from the history and physical examination?
2. What are the salient features?
3. What is your provisional diagnosis?
4. What are your considerations and differential diagnosis?
5. What diagnostic examinations would you request for? And
how will this help you in reaching the diagnosis?
6. What is Polycystic Ovarian Syndrome? Its Pathophysiology?
Signs and Symptoms? Its consequences?
7. How will you manage this case?
 1. What are the salient features?

• 24 years old
• G1P0 (0-0-1-0)
• Facial acne and hirsutism
• Curettage for abortion
• BMI = 35
• Normal pelvic exam
 2. What is your provisional diagnosis?

• Secondary Amenorrhea probably

secondary to Polycystic Ovarian Syndrome
(PCOS)
Differentiate Primary from Secondary Amenorrhea:

• Primary amenorrhea
• Defined as the absence of menses in a woman who has
never menstruated by the age of 16.5 years.
• Another definition includes girls who have not
menstruated within 5 years of breast development .
Breast development (thelarche ) should occur by age 13
or otherwise requires evaluation.
• The incidence is less than 0.1%
Secondary amenorrhea
• Defined as the absence of menses for an arbitrary
period, usually longer than 6 to 12 months.
• The incidence of secondary amenorrhea of more than
6 months’ duration in a survey of a general population
of Swedish women of reproductive age was found to
be 0.7%.
• The incidence was significantly higher in women
younger than 25 years and those with a prior history
of menstrual irregularity.
 3. What are your considerations and
differential diagnosis?
PRIMARY AMENORRHEA
• Although numerous classifications have
been used for the various causes of primary
amenorrhea, it has been found most clinically
useful to group them on the basis of whether
secondary sexual characteristics (breasts) and
female internal genitalia (uterus) are present
or absent.
 Uterus
+ + (IV) + - (I)
Hypothalamic Gonadal Failure
Pituitary Turner syndrome
Ovarian Pure gonadal dysgenesis
Uterine Kallman syndrome

Breast - + (II) - - (III)

Androgen Resistance Agonadism
Congenital absence of the 17,20 desmolase
Uterus
BREASTS ABSENT AND UTERUS PRESENT
All individuals with no breast development and a uterus present have no
ovarian estrogen production as a result of a gonadal disorder or a CNS
hypothalamic-pituitary abnormality
 
• GONADAL FAILURE (HYPERGONADOTROPIC HYPOGONADISM)
 
• Most common cause of primary amenorrhea, occurring in almost 50% of
those with this symptom.

• Most frequently caused by a chromosomal disorder or deletion of all or part

of an X chromosome, but it is sometimes caused by a genetic defect and,
rarely, 17 a-hydroxylase deficiencies.

• If gonadal development is absent in the presence of a 46,XX or 46,XY

karyotype (called pure gonadal dysgenesis ), a gene disorder may be present,
because it has been reported to occur in siblings
 
• Deletion of the entire X chromosome (as occurs in Turner’s
syndrome) or of the short arm (p) of the X chromosome
results in short stature. In place of the ovary a band of
fibrous tissue called a gonad al streak is present. When
ovarian follicles are absent, synthesis of ovarian steroids
and inhibin does not occur. Breast development does not
occur because of the very low circulating E2 levels .
Because the negative hypothalamic-pituitary action of
estrogen and inhibin is not present, gonadotropin levels
are markedly elevated, with FSH levels being higher than
LH. Estrogen is not necessary for mullerian duct
development or wolffian duct regression, so the internal
and external genitalia are phenotypically normal female.
HYPOTHALAMIC FAILURE (HYPOGONADOTROPHIC HYPOGONADISM)
 
• Those without a demonstrable lesion and a low gonadotropin level were
previously thought to have primary pituitary failure (hypogonadotropic
hypogonadism). However, when stimulated with GnRH, there is an
increase in FSH and LH levels, indicating that the basic defect is either
hypothalamic with insufficient GnRH synthesis or a CNS neurotransmitter
defect, resulting in inadequate GnRH synthesis or release, or both.
•  
• GnRH secretion occurs after migration of these specific cells from the
olfactory lobe to the hypophysis during embryogenesis, anosmia may
also occur in some patients with gonadotropin deficiency. This is caused
by a specific defect of the KAL gene (Xp 22-3), which is responsible for
neuronal migration and is known as Kallman’s Syndrome.
•  
• PITUITARY FAILURE

• Any anatomic lesion of the hypothalamus or pituitary can be a

cause of low gonadotropin production. These lesions can be
congenital (e.g ., stenosis of aqueduct, absence of sellar floor ) or
acquired (tumors).

• Many of these lesions, particularly pituitary adenomas, result in

elevated prolactin levels

• Non–prolactin-secreting pituitary tumors (chromophobe

adenomas), as well as craniopharyngiomas, may not be associated
with hyperprolactinemia and can rarely be the cause of primary
amenorrhea with low gonadotropin levels.
 BREASTS DEVELOPMENT PRESENT
AND UTERUS ABSENT
A. ANDROGEN RESISTANCE

• Androgen resistance syndrome , originally termed

testicular feminization , is a genetically transmitted
disorder in which androgen receptor synthesis or action
does not occur.

• Incidence of 1/60,000 .The syndrome is cause d by the

absence of an X-chromosome gene responsible for the
cytoplasmic or nuclear testosterone receptor function. It
is an X-linked recessive or sex-linked autosomal dominant
disorder, with transmission through the mother.
• These individuals have an XY karyotype and normally functioning
male gonads that produce normal male levels of testosterone and
dihydrotestosterone. But due to a lack of receptors in target
organs, there is lack of male differentiation of the external and
internal genitalia. The external genitalia remain feminine, as
occurs in the absence of sex steroids. Wolffian duct development,
which normally occurs as a result of testosterone stimulation, fails
to take place. Because mullerian duct regression is induced by
antimullerian hormone (AMH ), also called mullerian-inhibiting
substance (MIS, a glycoprotein synthesized by the Sertoli cells of
the fetal testes), this process occurs normally in these individuals
because steroid receptors are unnecessary for the action of
glycoproteins. Thus, people with this condition have no female or
male internal genitalia, normal female external genitalia, and a
short or absent vagina.
• Testes that are intra-abdominal or that occur in
the inguinal canal have an increased risk of
developing a malignancy (gonadoblastoma or
dysgerminoma), with an incidence reported to be
approximately 20%. However, these malignancies
rarely occur before age 20. Therefore, it is usually
recommended that the gonads be left in place
until after puberty is completed to allow full
breast development and epiphyseal closure to
occur. After these events occur, which is typically
around age 18, the gonads should be removed.
CONGENITAL ABSENCE OF THE UTERUS (UTERINE
AGENESIS, UTEROVAGINAL AGENESIS, ROKITANSKY-
KUSTER-HAUSER SYNDROME)

• This disorder is the second most frequent cause of primary

amenorrhea. It occurs in 1 in 4000 to 5000 female births
and accounts for approximately 15% of individuals with
primary amenorrhea.

• Individuals with complete uterine agenesis have normal

ovaries, with regular cyclic ovulation and normal
endocrine function. Women with this disorder have
normal breast and pubic and axillary hair development but
have a shortened or absent vagina, in addition to absence
of the uterus. Congenital renal abnormalities, skeletal
abnormalities, cardiac and other congenital abnormalities
may occur in some of these individuals. Majority of these
disorders are caused by an isolated developmental defect,
but on occasion the condition is genetically inherited.
 ABSENT BREAST AND UTERINE
DEVELOPMENT
 
• Individuals with no breast or uterine
development are rare. They usually have a
male karyotype, elevated gonadotropin levels,
and testosterone levels in the normal or below
-normal fem ale range. The differential
diagnosis for this phenotype includes 17 £
-hydroxylase deficiency, 17,20-desmolase
deficiency, and agonadism.
 BREAST DEVELOPMET AND UTERUS
PRESENT
•  This is the second largest category of
individuals with primary amenorrhea,
accounting for approximately one third of
them. In the series reported by Maschchak
and colleagues, approximately 25% of these
individuals had hyperprolactinemia and
prolactinomas. The remaining women had
profiles similar to those with secondary
amenorrhea and thus should be
subcategorized and treated similarly as women
with secondary amenorrhea.
 SECONDARY AMENORRHEA

• Secondary amenorrhea can result from

disorders in the CNS_hypothalamic-pituitary
axis, ovary or uterus.

– 12% of cases resulted from a primary ovarian

problem
– 62 % from a hypothalamic disorder
– 16% from a pituitary problem (including
prolactinomas), and
– 7% from a uterine disorder.
 UTERINE CAUSE
• Intrauterine adhesions (IUAs) or synechiae (Asherman’s syndrome)
can obliterate the endometrial cavity and produce secondary
amenorrhea.

• The most frequent antecedent factor for IUAs is endometrial

curettage associated with pregnancy—either evacuation of a live or
dead fetus by mechanical means or postpartum or postabortal
curettage. Curettage after a missed abortion may result in a high
percentage of adhesion formation (30%).

• IUAs may also occur after diagnostic dilatation and curettage in a

non-pregnant woman, so this procedure is performed only when
indicated. A less common cause of IUA us severe endometritis or
fibrosis following myomectomy, metroplasty or cesarean delivery.
This cause is more probable if a temporal relationship exists between
the onset of symptoms and uterine curettage.
 
• Diagnosis of IUAs is confirmed by use of
hysterography or hysteroscopy.
• Sequential administration of estrogen-
progestogen can be used as the initial
diagnostic procedure when IUA is suspected,
however, withdrawal bleeding usually occurs
following its administration, hence making it
non-specific. Therefore, steroid administration
is usually not be performed prior to indirect or
direct visualization of the uterine cavity.
 OVARIAN CAUSES
• The ovaries may fail to secrete sufficient estrogen to
produce endometrial growth if the follicles are
damaged as a result of infection, interference with
blood supply, or depletion of follicles caused by
bilateral cystectomies.

• These women may become amenorrheic after a

variable period of time has elapsed following medical
treatment of a bilateral tubo-ovarian abscess, after
bilateral cystectomy for benign ovarian neoplasms,
or sometimes after a hysterectomy during which the
vascular supply to the ovaries is compromised (also
called cystic degeneration of the ovaries).
• Premature ovarian failure (POF) or Premature ovarian
insufficiency (POI) occurs when the the ovaries cease to
produce sufficient estrogen to stimulate endometrial growth
several years before the age of physiologic menopause. This
usually occurs before the age of 40. Condition may be
transient following permanent ovarian failure, such that some
women may ovulate and conceive during this transition
period. POI usually occurs after gonadall irradiation or
systemic chemotherapy and in women with steroid hormonal
enzyme deficiencies.

• Individuals with POI may also have an autoimmune disease

such as hypoparathyroidism, Hashimoto’s thyroiditis or
Addison’s disease. Women with POI who do not have clinical
evidence of autoimmune disease have antibodies to
gonadotropins as well as to several other endocrine organs
such as the thyroid and adrenal glands, suggesting an
autoimmune origin.
 PITUITARY CAUSES
I. Neoplasms

• Hyperprolactinemia can produce disorders of gonadotropin sex steroid

function,resulting in menstrual cycle derangement such as oligomenorrhea
and amenorrhea and anovulation as well as inappropriate lactation or
galactorrhea. Symptoms occur because the elevated prolactin levels interfere
with gonadotropin release which appears to be related to the abnormal
gonadotropin-releasing hormone (GnRH) release.

• Pathologic causes of hyperprolactinemia are prolactin-secreting pituitary

adenomas (prolactinomas) and other pituitary tumors that cause acromegaly
and Cushing’s disease. Other causes for hyperprolactinemia include
hypothalamic diseases, various pharmacologic agents, hypothyroidism,
chronic renal disease or any chronic type of breast nerve stimulation such as
may occur with thoracic operation, herpes zoster or chest trauma.

• Although most pituitary tumors secrete prolactin, some do not and may be
associated with secondary amenorrhea. Chromophobe adenomas are the
most common non-prolacti0secreting pituitary tumors. Patients may also
present with acromegaly and/or Cushing’s disease.
II. Non-neoplastic lesions

• Pituitary cells can also become damaged or necrotic as

a result of anoxia, thrombosis, or hemorrhage. When
pituitary cell destruction occurs as a result of a
hypotensive episode during pregnancy, the disorder is
called Sheehan’s syndrome. When the disorder is
unrelated to pregna ncy, it is called Simmonds’
disease.

• It is important to diagnose this cause of secondary

amenorrhea because, pituitary damage can be
associated with decreased secretion of other pituitary
hormones , particularly ACTH and TSH, in addition to
LH and FSH. Thus, these women may have secondary
hypothyroidism or adrenal insufficiency that may
seriously impair their health, in addition to their
decreased estrogen levels.
CENTRAL NERVOUS AND HYPOTHALAMIC CAUSES

1. Lesions

• Same anatomic lesions in the brainstem or

hypothalamus that cause primary
an=menorrhea can also produce secondary
amenorrhea.

• These lesions include craniopharyngiomas,

granulomatous disease (eg tuberculosis,
sarcoidosis) and sequelae of encephalitis
2. Drugs

• Phenothiazne derivatives, certain antihypertensive

agents, anesthetics, psychoactive drugs, antiemetics,
dopamine receptor antagonist , dopamine,
bromocriptine,cabergoline and SSRIs can also
produce amenorrhea without hyerprolactinemia,
although prolactin levels may be elevated.

• Oral contraceptives can inhibit ovulation by acting

on the hypothalamus to suppress GnRH and directly
on the pituitary to suppress FSH and LH. This
condition may persist for several months even after
the OCPs are discontinued producing the syndrome
Postpill amenorrhea.
3. Stress and Exercise 
• Stressful situations including a sudden change
in environment (eg. Going away to school),
death in the family, or divorce can produce
amenorrhea.
•  
• Amenorrhea associated with strenuous
exercise is also related to stress. Feicht and
coworkers have reported that the incidence of
secondary amenorrhea in runners has a
positive correlation with the number of miles
run per week.
4. Weight loss

• Both male and fem ale animals who are malnourished have
decreased reproductive capacity. Weight loss is also associated
with amenorrhea in women and has been classified into two
groups, the moderately underweight group includes individuals
whose weight is 15% to 25% below ideal body weight and
severely underweight women, whose weight loss is more than
25% of ideal body weight. Weight loss can occur from excessive
dietary restrictions as well as malnutrition.

• Amenorrhea associated with weight loss appears to be caused

mainly by failure of normal GnRH release with the lack of
pituitary response under extreme conditions. Hypoleptinemia
as well as GH and thyroid dysfunction contribute to these
findings .

• A severe psychiatric disorder called anorexia nervosa is also

associated with severe weight loss and amenorrhea.
5. Functional Hypothalamic Amenorrhea

• There is a group of individuals with secondary

amenorrhea who do not ingest drugs, do not
engage in strenuous exercise, are not
undergoing environmental stress, and have
not lost weight. No pituitary, ovarian, or
uterine abnormalities are present in these
individuals. The general term functional
hypothalamic amenorrhea (FHA) has been
used to characterize this disorder.
• During normal ovulatory cycles, LH is secreted in a
pulsatile manner that varies in frequency and amplitude
at different times of the cycle, being more rapid in the
follicular phase than in the luteal phase. Women with
amenorrhea caused by hypothalamic dysfunction do not
exhibit these characteristic cyclic alterations in LH
pulsatility. They have no pulses or have a persistent
pattern of pulsatility that is normally found in only one
portion of the ovulatory cycle, usually the slow frequency
normally found in the luteal phase, despite having a
steroid milieu similar to that in the follicular phase.
Because each LH pulse represents a response to a pulse of
GnRH, it appears that those with FHA have an
abnormality in the normal cyclic variations of GnRH
pulsatility , probably because of an abnormality in the
CNS neurotransmitter s an d possibly produced by
increased opioid activity.
6. Polycystic Ovary Syndrome

• Polycystic ovary syndrome (PCOS ) is a heterogenous

disorder that may present with prolonged periods of
amenorr hea, although the more typical menstrual
pattern is one of irregularity or oligomenorrh ea.
Women need not be overweight or obese , or have
symptom s and signs of hyperandrogenism, whi ch
typically occurs.

• Most women will have an elevated serum LH level but

this level may also be normal in some and its is not
required as a diagnostic criterion. Nevertheless, the
diagnosis of PCO S may be confirmed by visualizing
polycystic ovaries on ultrasound, particularly in the
absence of classic findings such as hyperandrogenism.
4. What additional information, if any, would you want
to learn from the history and physical examination?
5. What diagnostic examinations would you request for?
And how will this help you in reaching the diagnosis?

• All women who consult a clinician for the

symptom of secondary amenorrhea should
have a diagnostic evaluation initiated at that
visit, even though 6 months may not have
elapsed since her last menstrual period. The
clinician should first take a detailed history
and perform a physical examination to rule
out pregnancy as a cause of the amenorrhea.
• The clinician should also determine whether there is the
possibility of IUAs. Any instrumentation of the endometrial cavity,
particularly temporally related to pregnancy, should alert the
clinician to the possibility of IUAs. The initial diagnostic evaluation
to determine whether IUAs are present is placement of a uterine
sound into the uterine cavity, followed by a hysterography or
hysteroscopy. The diagnosis The diagnosis can also be confirmed
by detecting presumptive evidence of ovulation by means of a
biphasic basal temperature or an elevated serum progesterone
level.
 
• If uterine abnormality has been ruled out, the history should
disclose whether medications are currently being used or if oral
contraceptives have been recently discontinued. In addition,
questions regarding diet, weight loss, stress, and strenuous
exercise are pertinent.
• A history of hot flushes, decreasing breast size,
and/or vaginal dryness, and physical examination are
helpful in estimating the degree of estrogen
deficiency.

• If the history and physical examination fail to reveal

the cause of the amenorrhea, a CBC, urinalysis, and
serum chemistries should be carried out to rule out
systemic disease. A sensitive TSH assay should also be
performed to rule out the uncommon asymptomatic
thyroid disorders that produce secondary
amenorrhea and serum E2, FSH, and prolactin levels
should be measured.
6. What is Polycystic Ovarian Syndrome? Signs and
Symptoms? Its Pathophysiology?Consequences?
• Polycystic Ovarian Syndrome (PCOS) 

• Polycystic ovary syndrome was originally described in 1935 by

Stein and Leventhal as a syndrome consisting of amenorrhea,
hirsutism, and obesity in association with enlarged polycystic
ovaries.
 
• The classic definition of PCOS includes women who are
anovulatory and have irregular periods as well as
hyperandrogenism, as determined by signs such as hirsutism or
elevated blood levels of androgens, testosterone, or DHE AS.
This should be in the absence of enz ymatic disorders (e.g ., 21-
hydroxylase deficiency), Cushing ’s syndrome, or tumors.