Pathophysiology Quick Find

The menstrual cycle is an orderly progression of

hormonal events in the female body that results in the
release of an egg. Menstruation occurs when an egg
released by the ovary remains unfertilized;
subsequently, the soggy decidua of the endometrium
(which was primed to receive a fertilized egg) is
sloughed in a flow of menses in preparation for
another cycle.

The menstrual cycle can be divided into 3 physiologic

phases: follicular, ovulatory, and luteal. Each phase
has a distinct hormonal secretory milieu. When one
diagnoses the disease processes responsible for
amenorrhea, consideration of the target organs of
Author Information
these reproductive hormones (hypothalamus,
Introduction
pituitary, ovary, uterus) is helpful. Menstrual Cycle
Clinical Details
Section 3 of 10 Primary And
MENSTRUAL CYCLE Secondary
Amenorrhea
Author Information Introduction Menstrual Cycle Clinical Details Primary And
Secondary Amenorrhea Amenorrhea With Delayed Puberty Amenorrhea With Amenorrhea With
Normal Puberty Algorithms For Evaluation Of Amenorrhea Management Of Delayed Puberty
Amenorrhea Bibliography
Amenorrhea With
Normal Puberty
Follicular phase Algorithms For
Evaluation Of
Amenorrhea
In physiologic terms, the first day of menses is Management Of
considered the first day of the menstrual cycle. The Amenorrhea
following 13 days of the cycle are designated the Bibliography
follicular phase. The hypothalamus is the initiator of
the follicular phase. The gonadotropin-releasing Click for related
hormone (GnRH) pump located in the hypothalamus images.
releases GnRH in a pulsatile fashion into the portal
vessel system surrounding the anterior pituitary
 Continuing
gland. GnRH interacts with the anterior pituitary gland Education
to release follicle-stimulating hormone (FSH) in the
CME available for
follicular phase. FSH is secreted into the circulation
this topic. Click
and interacts with the granulosa cells surrounding the here to take this
developing oocytes. CME.

As levels of progesterone, estradiol, and inhibin

decline 2-3 days before menses, the hypothalamus Patient Education
begins to release higher levels of FSH, which recruits Women's Health
oocytes for the next menstrual cycle. As FSH Center
increases during the early portion of the follicular
phase, it interacts with granulosa cells to stimulate Eating Disorders
the aromatization of androgens into estradiol. Center

Pregnancy and
Early in the follicular phase, both estradiol and FSH Reproduction
increase the FSH-receptor content of the developing Center
follicles. Over the next several days, the steady
increase of estradiol (E2) levels exerts a progressively Amenorrhea
greater suppressive influence on pituitary FSH Overview
release. Only one selected lead follicle, with the
Amenorrhea
largest reservoir of estrogen, can withstand the Causes
declining FSH environment. The remaining oocytes
that initially were recruited with the lead follicle Amenorrhea
undergo atresia. Immediately prior to ovulation, the Symptoms
combination of E2 and FSH leads to the production of
luteinizing-hormone (LH) receptors on the granulosa Amenorrhea
cells surrounding the lead follicle. Treatment

Anorexia Nervosa
During the late follicular phase, estrogen positively Overview
influences LH secretion, instead of suppressing
pituitary LH secretion as it does early in the follicular Birth Control
phase. To have this positive effect, the E2 level must Overview
achieve a sustained elevation for several days. The
LH surge promotes maturation of the dominant Birth Control FAQs
oocyte, the release of the oocyte and then the
luteinization of the granulosa cells and the
surrounding theca cells of the dominant follicle
resulting in progesterone production. The appropriate
level of progesterone arising from the maturing
dominant follicle contributes to the precise timing of
the mid-cycle surge of LH. E2 promotes uterine
endometrial gland growth, which allows for future
implantation.
Ovulatory phase

Ovulation occurs approximately 34-36 hours after the

onset of the LH surge or 10-12 hours after the LH
peak and 24-36 hours after peak E2 levels. The rise in
progesterone increases the distensibility of the
follicular wall and enhances proteolytic enzymatic
activity, which eventually breaks down the
collagenous follicular wall.

After the ovum is released, the granulosa cells

increase in size and take on a yellowish pigmentation
characteristic of lutein. The corpus luteum then
produces estrogen, progesterone, and androgens
and becomes increasingly vascularized.

Luteal phase

The lifespan and steroidogenic capacity of the corpus

luteum depend on continued tonic LH secretion from
the pituitary gland. The corpus luteum secretes
progesterone that interacts with the endometrium of
the uterus to prepare it for implantation. This process
is termed endometrial decidualization. In the normal
ovulatory menstrual cycle, the corpus luteum declines
in function 9-11 days after ovulation. If the corpus
luteum is not rescued by human chorionic
gonadotropin (hCG) hormone from the developing
placenta, menstruation reliably occurs 14 days after
ovulation. If conception occurs, placental hCG
maintains luteal function until placental production of
progesterone is well established.

The menstrual cycle is a complex but coordinated

system of hormonal changes and organ responses.
The main directive of the menstrual cycle is to
stimulate growth of a follicle to release an egg and
prepare a site for implantation if fertilization should
occur. Absence of fertilization results in the timely
release of the prepared endometrium, which is
termed menses.

At birth, female infants have a predetermined number

of primordial follicles that are arrested in the diplotene
stage of meiotic prophase until stimulation at puberty.
Until puberty, the hypothalamus is in a quiescent
state. At age approximately 8 years, GnRH is
synthesized in the hypothalamus and released. The
adrenal cortex begins to produce
dehydroepiandrostenedione to initiate the start of
adrenarche (ie, the development of sexual hair). The
orderly progression of puberty begins with breast
budding (thelarche) then continues with the growth of
pubic hair (pubarche), accelerated growth, and
menses (menarche). In the United States, the
average age of girls at menarche is 12.8 years, with a
range of 9-16 years.

Section 4 of 10
CLINICAL DETAILS
Author Information Introduction Menstrual Cycle Clinical Details Primary And
Secondary Amenorrhea Amenorrhea With Delayed Puberty Amenorrhea With
Normal Puberty Algorithms For Evaluation Of Amenorrhea Management Of
Amenorrhea Bibliography

The differential diagnosis of amenorrhea is broad and

can range from genetic abnormalities to endocrine
disorders and psychological, environmental, and
structural anomalies. To facilitate prompt and
accurate diagnostic workup, obtaining a thorough
history and preforming detailed physical examination
is essential. In the differential diagnosis of primary or
secondary amenorrhea, the most important step in
diagnosis is to exclude pregnancy. Always consider
pregnancy first. After pregnancy is excluded, an
algorithmic approach is followed to narrow the
diagnostic possibilities. Causes of primary and
secondary amenorrhea overlap considerably;
therefore, ascertaining the patient's sexual
development is the key to differentiating these
conditions.

See the Algorithms for Evaluation of Amenorrhea

below to determine the most logical course leading to
a specific diagnosis.

History

An adequate history comprises childhood growth and

development, among other areas, including height
and weight charts and age at thelarche and
menarche. Ascertaining the age at menarche of the
patient's mother and sisters is advisable because the
age at menarche in family members can occur within
a year of the age in others. The duration and flow of
menses, cycle days, day and date of last menstrual
period, presence or absence of molimina (breast
soreness and mood change immediately before
menses) are necessary pieces of information. Any
history of chronic illness, trauma, surgery, and
medications is also important. A sexual history should
be obtained in a confidential manner. Information
regarding substance use, exercise, diet, home and
school situations, and psychosocial issues should be
elicited. A comprehensive review of symptoms should
include vasomotor symptoms, hot flashes, virilizing
changes, galactorrhea, headache, fatigue,
palpitations, nervousness, hearing loss, and visual
changes.

Physical examination

Physical examination begins with vital signs, including

height and weight, and with sexual maturity ratings.
Physical examination findings are as follows:

 Generalized findings
o Anorexia - Cachexia, bradycardia,
hypotension, and hypothermia
o Pituitary tumor - Funduscopic changes,
visual field impairment, and cranial
nerve signs
o Polycystic ovary (PCO) syndrome -
Acne, acanthosis nigricans, and obesity
o Inflammatory bowel disease - Fissure,
skin tags, and occult blood found on
rectal examination
o Gonadal dysgenesis (eg, Turner
syndrome) - Webbed neck, increased
carrying angle, and lack of breast
development
 Breast findings
o Galactorrhea - Breast palpation
o Delayed puberty - Underdeveloped with
sparse pubic hair
o Gonadal dysgenesis (eg, Turner
 syndrome) - Undeveloped breasts with
normal growth of pubic hair
 Pubic hair and external genitalia findings
o Hyperandrogenism - Pubic hair
distribution and excess facial hair
o Androgen insensitivity syndrome -
Absent or sparse axillary and pubic hair
with breast development
o Delayed puberty - Without breast
development
o Adrenal or ovarian tumors -
Clitoromegaly and virilization
o Pelvic fullness - Pregnancy, ovarian
mass, and genital anomalies
 Vaginal findings
o Imperforate hymen - Distension or
bulging of the external vagina
o Agenesis (Rokitansky-Hauser
syndrome) - Foreshortened vagina
without uterus and normal pubic hair
o Androgen insensitivity syndrome -
Foreshortened vagina without uterus
and absent pubic hair
 Uterine findings: If the uterus is enlarged,
pregnancy must be excluded.
 Cervical findings
o Assess the vaginal canal, the effect of
estrogen on the vaginal mucosa, and
mucus secretion.
o The presence of mucus suggests that
the ovaries are producing estradiol (E2)
(unopposed by progesterone).
o Clear, abundant mucus after cycle day
20 suggests anovulation.
o Lack of mucus and a dry, pale vagina
suggest that no current production of E2.

Laboratory evaluation

The history and physical findings help in selecting

tests in a female patient with amenorrhea. Possible
tests include endocrinologic and chemical tests to
detect chronic disease processes.

If the history and physical findings suggest an

ovarian-axis problem with normal puberty, TSH,
prolactin, follicle-stimulating hormone (FSH), and LH
measurements are the first line of testing. If hirsutism
is predominant on examination, include androgen
testing of testosterone, dehydroepiandrosterone
sulfate (DHEAS), androstenedione, and 17-OH
progesterone to determine the organ of cause (eg,
adrenal gland vs ovary).

If the history or physical findings suggest a chronic

disease process, the following may be indicated
including measurement of the erythrocyte
sedimentation rate (ESR), liver function tests, BUN
determination, creatinine determination, and
urinalysis.

Bone age is important in differentiating pubertal

delays as a cause.

To evaluate the CNS, a coned view of the sella

turcica or MRI of the pituitary is indicated. Many
specialists prefer MRI.

PRIMARY AND SECONDARY Section 5 of 10

AMENORRHEA
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With Delayed Puberty Amenorrhea With Normal Puberty Algorithms For Evaluation Of Amenorrhea Management
Of Amenorrhea Bibliography

Primary amenorrhea is defined either as absence of menses by age 14

years with the absence of growth or development of secondary sexual
characteristics (eg, breast development) or as absence of menses by age 16
years with normal development of secondary sexual characteristics.

Secondary amenorrhea is defined as the cessation of menstruation for at

least 6 months or for at least 3 of the previous 3 cycle intervals. Since only 3
diagnoses are unique to primary amenorrhea and never cause secondary
amenorrhea, differentiating primary from secondary amenorrhea does little to
enhance the clinician's understanding of the etiology.

Diagnoses unique to primary amenorrhea include vaginal agenesis,

androgen insensitivity syndrome, and Turner syndrome (45,XO). The
remaining diagnoses should be considered in patients with both primary and
secondary amenorrhea.

The causes of amenorrhea are listed below. Organize clinical evaluation on

the basis of sexual development and basic developmental physiology. With
such a vast differential diagnosis, one way to organize and memorize the
causes of amenorrhea can be in its relationships with generalized pubertal
delay, normal pubertal development, or abnormalities of the genital tract.

Causes of amenorrhea

 Generalized pubertal delay

o Constitutional delay
o Hypergonadotropic hypogonadism
 Turner syndrome
 Gonadal dysgenesis with mosaic karyotype
 Pure gonadal dysgenesis (Perrault syndrome, Swyer
syndrome)
 Gonadotropin-resistant ovary syndrome
 Acquired causes (eg, high-dose alkylating
chemotherapy, pelvic radiation, autoimmune oophoritis)
o 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)
 Abnormal hypothalamic development (eg, Kallmann
syndrome, Prader-Willi syndrome, and Laurence-Moon-
Biedl syndrome)
 Acquired miscellaneous disorders (eg, infiltration
disorders [sarcoidosis, Langerhans cell histiocytosis,
syphilis, tuberculomas], ischemia disorders [caused by
trauma, aneurysm, obstruction of the aqueduct of
Sylvius] and destruction [concentrated, high-dose
exposure to radiation])
 Normal puberty
o 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)
o Associated with absence of hirsutism or virilization (eg,
immaturity of the hypothalamic-pituitary-ovarian axis,
pregnancy)
o Hypergonadotropic hypogonadism (eg, ovarian failure, high-
 dose alkylating chemotherapy, pelvic radiation, autoimmune
oophoritis)
 Anomalies of the genital tract
o Müllerian agenesis (eg, Mayer-Rokitansky-Kuster-Hauser
syndrome) breast present
o Congenital or acquired anatomic obstruction (eg, imperforate
hymen, transverse vaginal septum, Asherman syndrome,
endometrial destruction due to severe infection or surgery)
o Androgen insensitive syndrome-absent uterus with normal
breast development

AMENORRHEA WITH DELAYED Section 6 of 10

PUBERTY
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With Delayed Puberty Amenorrhea With Normal Puberty Algorithms For Evaluation Of Amenorrhea Management
Of Amenorrhea Bibliography

Hypergonadotropic hypogonadism

Puberty is considered 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. The most common cause of delayed puberty is constitutional delay.
Another common reason for delayed puberty is ovarian failure, which is also
termed hypergonadotropic hypogonadism. Elevated levels of follicle-
stimulating hormone (FSH) and luteinizing-hormone (LH) characterize
hypergonadotropic hypogonadism with low estrogen production.

The most common example of hypergonadotropic hypogonadism is found in

Turner syndrome, which is caused by a 45,X karyotype. Clinical
manifestations of Turner syndrome include a webbed neck, short stature,
broad shieldlike chest, anomalous auricles, and hypoestrogenemia resulting
in sexual immaturity. Gonadal dysgenesis fits the same pattern of high FSH
and LH and low estradiol (E2) levels. Gonadal dysgenesis is caused by a
mosaic karyotype with an abnormal X chromosome or with a normal
karyotype (46,XX) and streak ovaries. Individuals with Perrault syndrome
have gonadal dysgenesis, a normal karyotype, and neurosensory deafness.
Sawyer syndrome is illustrated by a phenotypically immature female with a
46,XY karyotype without testis-determining factor on the Y chromosome.
Another rare cause of hypergonadotropic hypogonadism is gonadotropin-
resistant ovary syndrome, which is characterized by FSH-resistant ovaries.

Acquired causes of hypergonadotropic hypogonadism can result from high-

dose alkylating chemotherapy and radiation treatments to the pelvis.
Elevated ESR and anti-ovarian antibody levels may suggest autoimmune
oophoritis, but such tests are rarely needed. Autoimmune oophoritis is an
exclusionary diagnosis. Like all forms of hyperandrogenic hypogonadotropic
amenorrhea, these conditions are not reversible.

Hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism occurs when FSH and LH levels are low.

The most common causes of hypogonadotropic hypogonadism include
chronic illness, starvation, excessive exercise, anorexia nervosa,
depression, stress, and marijuana use. Hypogonadotropic hypogonadism
involves slowed GnRH release caused by multifactorial components of
decreased body fat and increased beta endorphins.

Chronic illness can affect pubertal development adversely by interfering with

metabolism through malabsorption and poor nutrition (eg, Crohn disease,
diabetes mellitus, hypothyroidism and hyperthyroidism, cystic fibrosis,
anorexia nervosa, excessive exercise).

Tumors in the CNS can compress the portal vessels and impede the flow of
GnRH from the hypothalamus to the pituitary gland. Pituitary adenomas,
craniopharyngiomas, and meningiomas are examples of slow-growing
nonmetastatic tumors that are uncommon causes of hypogonadotropic
hypogonadism. Anterior pituitary prolactinomas releasing prolactin hormone
are the most common pituitary tumors to cause hypogonadotropic
hypogonadism.

Other acquired disorders can disrupt pituitary function by destructive means,

such as ischemia, infiltration, and obstruction. Head trauma, cranial
aneurysms, and infiltrative processes (eg, sarcoidosis, syphilis,
tuberculomas) are examples of conditions that can disrupt pituitary function.

Abnormal development of the hypothalamus can result in hypogonadotropic

hypogonadism. Kallmann syndrome manifests with anosmia, pubertal delay,
and a normal response to exogenous gonadotropins from an embryonic lack
of protein coded for by the gene KAL1, which prevents GnRH-producing
cells from migrating from the olfactory area to the hypothalamus. Other
syndromes associated with hypothalamic dysfunction include Prader-Willi
syndrome and Laurence-Moon-Biedl syndrome.

AMENORRHEA WITH NORMAL Section 7 of 10

PUBERTY
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With Delayed Puberty Amenorrhea With Normal Puberty Algorithms For Evaluation Of Amenorrhea Management
Of Amenorrhea Bibliography

Frequently, amenorrhea with normal puberty is associated with hirsutism.

The most common cause in this setting is PCO syndrome. PCO syndrome is
characterized by anovulation, hirsutism, and obesity. Other than anovulation,
the other characteristics may not always be present. Ovarian hyperthecosis
results in hyperandrogenicity, which is evident by signs of hirsutism, acne,
and obesity and can be associated with type 2 diabetes mellitus and
acanthosis nigricans. Hyperthecosis can also cause virilization, as seen in
clitoromegaly, temporal balding, and deepened voice change. See Polycystic
Ovarian Syndrome for an in-depth discussion of this entity.

Another cause of hirsutism is the rare late-onset 21-hydroxylase deficiency,

which is caused by mutations in the 21-hydroxylase gene resulting in
excessive 17-hydroxyprogesterone levels. This deficiency is 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.

Anovulation remains the most common cause of amenorrhea in the setting

of nonvirilization. Anovulation is caused by immaturity of the hypothalamic-
pituitary-ovarian axis, which can be apparent after discontinuation of various
hormonal contraception medications and can result in loss of menses for
several months. Idiopathic premature menopause occurs in 1% of women
younger than 40 years. Premature ovarian failure can be idiopathic,
secondary to chemotherapy or radiation therapy, or autoimmune in origin.

Hyperprolactinemia is a pituitary cause of amenorrhea in the presence of

normal puberty. Hyperprolactinemia can occur as a consequence of
breastfeeding, microadenomas of the pituitary, and use of psychoactive
medications (eg, haloperidol, phenothiazines, amitriptyline, benzodiazepines,
cocaine, marijuana).

Amenorrhea may be caused by thyroid disorders, including hyperthyroidism

and hypothyroidism. Hypogonadotropic hypogonadism can occur from the
same causes as delayed puberty (see Amenorrhea with Delayed Puberty).
In addition, Sheehan syndrome, which results from panhypopituitarism after
pituitary infarction from postpartum hemorrhage or shock, can manifest as
pubertal amenorrhea.

Amenorrhea resulting from genital tract anomalies can arise from the
absence of reproductive organs. Mayer-Rokitansky-Hauser syndrome is an
anomaly of the genital tract characterized by vaginal agenesis. The uterus is
usually absent, and the vagina is foreshortened. Because the ovaries
function normally and produce estradiol (E2), breasts are normal in shape
and contour. Pubarche is also normal in this patient population; therefore,
pubic hair remains normal. Mayer-Rokitansky-Hauser syndrome accounts for
15% of primary amenorrhea cases and is second to Turner syndrome as the
most common cause of primary amenorrhea.

Androgen insensitivity syndrome (previously termed testicular feminization)

accounts for 10% of patients with amenorrhea. Androgen insensitivity
syndrome is caused by an abnormality of the androgen receptor. The
gonads are testicles producing testosterone; however, testosterone has no
effect because the androgen receptor is nonfunctional. The phenotypic
appearance in patients with this condition is female, but the circulating
hormonal pattern is male. Androgen insensitivity syndrome is a maternal X-
linked recessive disease in which the testes remain intra-abdominal or
partially descended, and pubic hair is sparse.

Spontaneous testicular regression is a rare disorder of genetic males that

results in a female phenotype with an absent uterus. In addition, certain
enzyme 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.

Primary amenorrhea can result from an imperforate hymen, which presents

as a boggy uterus and cyclic abdominal pain. Asherman syndrome occurs
after an overzealous curettage of the endometrial lining, which results in
adhesions or synechiae that prevent the endometrium from responding to E 2.
Clinically significant infections that destroy the endometrial lining can also
result in primary or secondary amenorrhea.

ALGORITHMS FOR EVALUATION OF Section 8 of 10

AMENORRHEA
Author Information Introduction Menstrual Cycle Clinical Details Primary And Secondary Amenorrhea Amenorrhea
With Delayed Puberty Amenorrhea With Normal Puberty Algorithms For Evaluation Of Amenorrhea Management
Of Amenorrhea Bibliography

Algorithm for evaluation of amenorrhea with delayed puberty

Obtain the following laboratory results: thyroid function; bone age; and
luteinizing-hormone (LH), follicle-stimulating hormone (FSH), and prolactin
levels.

 If TSH levels are elevated and thyroxine (T4) levels are low, the cause
is hypothyroidism.
 If the bone age is delayed, the cause is constitutional delay.
 If the bone age is normal, obtain LH, FSH, and prolactin levels.
 If LH and FSH levels are elevated, obtain a karyotype.
o If the karyotype is 45,XO, the cause is gonadal dysgenesis (ie,
 Turner syndrome). Amenorrhea can also occur when 1 of the 2
X chromosomes is abnormal, such as a ring chromosome, or if
a partial loss of the p or q arm of the X chromosome is occurs.
o If the 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.
 If LH and FSH levels are low or within the reference range, obtain a
head MRI.
o If head MRI findings are abnormal, the cause is pituitary tumor,
pituitary destruction, or hypothalamic disease.
o If prolactin levels are elevated, obtain a head MRI.
 If head MRI findings are abnormal, the cause is pituitary
tumor or a brain lesion disrupting the pituitary stalk. If
the MRI finding is normal, the cause may be marijuana
use or psychiatric medicine, specifically dopamine
antagonist medications, which lead to a decrease in
prolactin inhibiting factor and a subsequent increase in
serum prolactin levels.
 If head MRI findings are normal with normal history and
physical examination findings, the etiology may be drug
use, an eating disorder, athleticism, or psychosocial
stress.
 If head MRI findings are normal but clinical evaluation
and screening study findings are abnormal, chronic
disease can be excluded.

Algorithm for evaluation of amenorrhea with normal puberty with

uterus present

Obtain a pregnancy test.

 If the pregnancy test result is positive, refer the patient to the

appropriate specialist.
 If the pregnancy test result is negative, obtain TSH, prolactin, FSH
and LH levels.
 If the TSH level is elevated, the diagnosis is hypothyroidism.
 If the prolactin level is elevated, hyperprolactinemia is the diagnosis.
Causes include prolactinoma, CNS tumors and medications.
 If the FSH level is low, obtain MRI of the head. If the MRI is abnormal,
consider hypothalamic disease, pituitary disease or pituitary tumor. If
MRI is normal, proceed with clinical evaluation to exclude chronic
disease, anorexia nervosa, marijuana or cocaine use, and social or
psychological stresses.
 If FSH is elevated, ovarian failure is the diagnosis. Obtain a
 karyotype.
o If the karyotype is abnormal, consider pure gonadal
dysgenesis, such as Turner syndrome or mosaic or mixed
gonadal dysgenesis.
o If the karyotype is normal (46 XX), the cause is ovarian failure.
o Consider premature ovarian failure, autoimmune oophoritis,
exposure to radiation or chemotherapy, resistant ovary
syndrome or multiple endocrine neoplasm (MEN) syndrome.
 If TSH, prolactin, and FSH levels are within reference range, perform
a progestin challenge test.
o If withdrawal bleeding occurs, consider anovulation secondary
to PCO syndrome.
o If no withdrawal bleed occurs, proceed with estradiol priming
followed by a progestin challenge.
o 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.

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NAMA

amenore

DEFINISI

amenore adalah tidak terjadinya menstruasi.

jika menstruasi tidak pernah terjadi maka disebut amenore primer, jika menstruasi pernah terjadi
tetapi kemudian berhenti selama 6 bulan atau lebih maka disebut amenore sekunder.

amenore yang normal hanya terjadi sebelum masa pubertas, selama kehamilan, selama menyusui dan
setelah menopause.
PENYEBAB

Amenore bisa terjadi akibat kelainan di otak, kelenjar hipofisa, kelenjar tiroid, kelenjar
adrenal, ovarium (indung telur) maupun bagian dari sistem reproduksi lainnya.

Dalam keadaan normal, hipotalamus (bagian dari otak yang terletak diatas kelenjar
hipofisa) mengirimkan sinyal kepada kelenjar hipofisa untuk melepaskan hormon-hormon
yang merangsang dilepaskannya sel telur oleh ovarium.
Pada penyekit tertentu, pembentukan hormon hipofisa yang abnormal bisa menyebabkan
terhambatnya pelepasan sel telur dan terganggunya serangkaian proses hormonal yang
terlibat dalam terjadinya menstruasi.

Penyebab amenore primer:

1. Tertundanya menarke (menstruasi pertama)

2. Kelainan bawaan pada sistem kelamin (misalnya tidak memiliki rahim atau vagina,
adanya sekat pada vagina, serviks yang sempit, lubang pada selaput yang
menutupi vagina terlalu sempit/himen imperforata)
3. Penurunan berat badan yang drastis (akibat kemiskinan, diet berlebihan, anoreksia
nervosa, bulimia, dan lain lain)
4. Kelainan bawaan pada sistem kelamin
5. Kelainan kromosom (misalnya sindroma Turner atau sindroma Swyer) dimana sel
hanya mengandung 1 kromosom X)
6. Obesitas yang ekstrim
7. Hipoglikemia
8. Disgenesis gonad
9. Hipogonadisme hipogonadotropik
10. Sindroma feminisasi testis
11. Hermafrodit sejati
12. Penyakit menahun
13. Kekurangan gizi
14. Penyakit Cushing
15. Fibrosis kistik
16. Penyakit jantung bawaan (sianotik)
17. Kraniofaringioma, tumor ovarium, tumor adrenal
18. Hipotiroidisme
19. Sindroma adrenogenital
 20. Sindroma Prader-Willi
21. Penyakit ovarium polikista
22. Hiperplasia adrenal kongenital

Penyebab amenore sekunder:

1. Kehamilan
2. Kecemasan akan kehamilan
3. Penurunan berat badan yang drastis
4. Olah raga yang berlebihan
5. Lemak tubuh kurang dari 15-17%extreme
6. Mengkonsumsi hormon tambahan
7. Obesitas
8. Stres emosional
9. Menopause
10. Kelainan endokrin (misalnya sindroma Cushing yang menghasilkan sejumlah besar
hormon kortisol oleh kelenjar adrenal)
11. Obat-obatan (misalnya busulfan, klorambusil, siklofosfamid, pil KB, fenotiazid)
12. Prosedur dilatasi dan kuretase
13. Kelainan pada rahim, seperti mola hidatidosa (tumor plasenta) dan sindrom
Asherman (pembentukan jaringan parut pada lapisan rahim akibat infeksi atau
pembedahan).
GEJALA

Gejalanya bervariasi, tergantung kepada penyebabnya.

Jika penyebabnya adalah kegagalan mengalami pubertas, maka tidak akan ditemukan
tanda-tanda pubertas seperti pembesaran payudara, pertumbuhan rambut kemaluan dan
rambut ketiak sert perubahan bentuk tubuh.

Jika penyebabnya adalah kehamilan, akan ditemukan morning sickness dan pembesaran
perut.
Jika penyebabnya adalah kadar hormon tiroid yang tinggi maka gejalanya adalah denyut
jantung yang cepat, kecemasan, kulit yang hangat dan lembab.

Sindroma Cushing menyebabkan wajah bulat (moon face), perut buncit dan lengan serta
tungkai yang kurus.

Gejala lainnya yang mungkin ditemukan pada amenore:

 Sakit kepala
 Galaktore (pembentukan air susu pada wanita yang tidak hamil dan tidak sedang
menyusui)
 Gangguan penglihatan (pada tumor hipofisa)
 Penurunan atau penambahan berat badan yang berarti
 Vagina yang kering
 Hirsutisme (pertumbuhan rambut yang berlebihan, yang mengikuti pola pria),
perubahan suara dan perubahan ukuran payudara

DIAGNOSA

Diagnosis ditegakkan berdasarkan gejala, hasil pemeriksaan fisik dan usia penderita.

Pemeriksaan yang biasa dilakukan adalah:

 Biopsi endometrium
 Progestin withdrawal
 Kadar prolaktin
 Kadar hormon (misalnya testosteron)
 Tes fungsi tiroid
 Tes kehamilan
 Kadar FSH (follicle stimulating hormone)< LH (luteinizing hormone), TSH (thyroid
stimulating hormone)
 Kariotipe untuk mengetahui adanya kelainan kromosom
 CT scan kepala (jika diduga ada tumor hipofisa).

PENGOBATAN

Pengobatan tergantung kepada penyebabnya.

Jika penyebabnya adalah penurunan berat badan yang drastis atau obesitas, penderita
dianjurkan untuk menjalani diet yang tepat.
Jika penyebabnya adalah olah raga yang berlebihan, penderita dianjurkan untuk
menguranginya.

Jika seorang anak perempuan belum pernah mengalami menstruasi dan semua hasil
pemeriksaan normal, maka dilakukan pemeriksaan setiap 3-6 bulan untuk memantau
perkembangan pubertasnya.
Untuk merangsang menstruasi bisa diberikan progesteron.
Untuk merangsang perubahan pubertas pada anak perempuan yang payudaranya belum
membesar atau rambut kemaluan dan ketiaknya belum tumbuh, bisa diberikan estrogen.

Jika penyebabnya adalah tumor, maka dilakukan pembedahan untuk mengangkat tumor
tesebut.

Tumor hipofisa yang terletak di dalam otak biasanya diobati dengan bromokriptin untuk
mencegah pelepasan prolaktin yang berlebihan oleh tumor ini.
Bila perlu bisa dilakukan pengangkatan tumor. Terapi penyinaran biasanya baru dilakukan
jika pemberian obat ataupun pembedahan tidak berhasil.

www.medicastore.com/cybernet/detail_pyk.php?idktg=17&iddtl=563

What Is It?
Amenorrhea means that a woman of childbearing age fails to menstruate.

A woman normally menstruates every 23 to 35 days. The cycle is regulated by the

portion of the brain called the hypothalamus, which also controls body
temperature, appetite and blood pressure. The hypothalamus stimulates the
pituitary gland (located near the base of the brain) to release two hormones that
regulate the female reproductive cycle: luteinizing hormone and follicle-stimulating
hormone. These hormones influence the production of the hormones estrogen and
progesterone, which are responsible for cyclic changes in the lining of the uterus,
including menstruation. In order for a woman to have regular menstrual cycles, her
hypothalamus, pituitary gland, ovaries and uterus must be functioning properly.
Her cervix and vagina must also have a normal anatomy for menstrual blood to
pass through.

There are two types of amenorrhea:

Primary amenorrhea occurs when a woman has not had her first menstrual
period (menarche) by age 16. This condition, also called "delayed menarche," is
most often due to late puberty, which is fairly common in teenage girls who are
very thin or very athletic. These young women are typically underweight, and their
bodies have not experienced the normal puberty-related rise in body fat that
triggers the beginning of menstruation. In other girls, the delay of menstruation
may be due to Turner's syndrome, a genetic disorder involving the sex
chromosomes, or to abnormal female reproductive organs.

Secondary amenorrhea happens when a woman who has menstruated previously

fails to menstruate for three months. Secondary amenorrhea can be caused by:

 Pregnancy (the most common cause)

 Breastfeeding (lactation)
 Menopause, the normal age-related end of menstruation
 Premature ovarian failure (menopause before age 40)
 Hysterectomy (surgical removal of the uterus)
 Stopping birth control pills
 Use of a long-acting progesterone, such as Depo-Provera, for birth control
 Tumors of the pituitary gland, especially prolactinomas
 Polycystic ovary disease, a condition that causes abnormal levels of estrogen,
luteinizing hormone and other hormones
 Endocrine disorders such as Cushing's syndrome, in which there are very high
levels of cortisol, an adrenal hormone, or hyperthyroidism, abnormally high
levels of thyroid hormone
 Emotional or physical stress
 Rapid weight loss
 Obesity
 Frequent strenuous exercise
 Chronic (long-term) illness, such as colitis, kidney failure or cystic fibrosis
 Chemotherapy for cancer
 Cysts or tumors in the ovaries

Amenorrhea affects 2% to 5% of all women of childbearing age in the United

States. Female athletes, especially young women, may be more likely to have
amenorrhea. While exercise or physical activity itself does not cause amenorrhea, it
is more likely to occur in women who exercise very intensely or who increase the
intensity of exercise rapidly. Women who engage in sports associated with lower
body weight, such as ballet dancing or gymnastics, are more likely to develop
amenorrhea than women in other sports.

Symptoms
Amenorrhea is a symptom in itself. Any associated symptoms will depend on the
problem that is causing the missed menstrual periods. For example, various forms
of hormone imbalance may cause amenorrhea together with excess body and facial
hair, acne, a lowering of the voice, an altered sex drive, breast milk secretions,
weight gain, or several or all these symptoms.

Diagnosis
Your doctor will ask you about:

 The date of your last menstrual period

 Whether you are sexually active
  Your birth control methods
 Your pregnancy history
 Your eating habits, rapid weight changes, obesity or extreme underweight
 Your typical monthly menstrual patterns (regular cycles or irregular cycles)
 The age when your mother entered menopause (many mothers and
daughters enter menopause at about the same age)
 The amount of stress in your life, and how you deal with it
 Your exercise regimen
 The types of medications you are taking

If your doctor is concerned about a specific cause of amenorrhea, such as a

hormonal abnormality, he or she will ask additional questions about specific
hormone-related symptoms, such as acne, increased body hair, extreme sensitivity
to cold temperatures, dry skin, constipation, hair loss or unusual breast secretions.
If you are an athlete, especially a runner, your doctor will ask you to describe your
training program, particularly if your body fat is below 22% or if your weight is less
than 80% of ideal.

Next, your doctor will review your medical history and do a general physical
examination, followed by a thorough pelvic exam. Once your doctor has
determined that you are not pregnant, he or she will try to identify the underlying
cause of your absent periods. In many cases, this can be done with the following
simple tests:

 Blood and urine tests — These can detect imbalances of female hormones
caused by problems with the pituitary gland or ovaries. If problems are
found, additional tests can be done to check whether your levels of thyroid
and adrenal hormones are normal.

 Pelvic ultrasound — This painless test uses sound waves to look for
problems in the structure of your uterus and ovaries.
 Progesterone challenge test — Your doctor may treat you with the
hormone progesterone for a few days to see whether this causes you to have
a menstrual period. If menstrual bleeding occurs, your amenorrhea is
probably related to a condition called anovulation, which means you are not
releasing a mature egg in the middle of your menstrual cycle. If bleeding
does not occur, your doctor will order blood tests to check your levels of
follicle-stimulating hormone. These levels can help to determine whether
your problem is in the ovaries or hypothalamus.

If these tests do not pinpoint the cause of your missed periods, additional
specialized testing may be necessary. Diagnosing amenorrhea sometimes can be
fairly complicated, since there are so many potential causes.

Expected Duration
In many teenagers with primary amenorrhea, puberty is late, but there is no
permanent problem. For women with secondary amenorrhea, how long amenorrhea
lasts depends on the cause. For example, pregnancy will stop a woman's menstrual
periods until after childbirth, while a woman who stops taking birth control pills
may not have a period for three months to a full year. Emotional or physical stress
may block the release of luteinizing hormone, causing amenorrhea that lasts for as
long as the source of stress remains. Rapid weight loss or gain, medications and
chronic illness also can cause a woman to miss one or more periods. Amenorrhea is
permanent after menopause begins or after hysterectomy.
Prevention
In many cases, teenage girls can help to prevent primary amenorrhea by following
a sensible exercise program and by maintaining a normal weight for their height
and age. Primary amenorrhea caused by anatomic abnormalities of the
reproductive tract cannot be prevented. To prevent secondary amenorrhea that is
related to diet, over-exercise or stress, you can take the following steps:

 Eat a low-fat diet that meets your recommended daily nutritional needs.
 Exercise moderately, but not excessively, to maintain an ideal body weight
and muscle tone.
 Find healthy outlets for emotional stress and daily conflicts.
 Balance work, recreation and rest.
 Avoid excessive alcohol consumption and cigarette smoking.

Treatment
Primary amenorrhea caused by late puberty usually does not need to be treated
because the condition will go away on its own. For primary amenorrhea caused by
certain genetic (inherited) abnormalities, treatment depends on the problem. For
example, if a genetic defect prevents the ovaries from functioning properly, a
young girl may be given supplemental ovarian hormones to allow her to develop
normal secondary sex characteristics (breast development, pubic hair) and to
prevent osteoporosis (bone-thinning disease), which can be caused by low estrogen
levels. If amenorrhea is caused by a structural problem, such as a vagina that is an
unusual shape or doesn't have an opening, surgery is usually necessary.

If you have secondary amenorrhea due to menopause or a hysterectomy, your

doctor will prescribe medications to prevent osteoporosis and other complications
of low estrogen levels. For other forms of secondary amenorrhea, the type of
treatment depends on the cause:

 Stress — If emotional stress is the problem, your doctor may advise you to
enroll in a stress-management course.

 Obesity — If obesity is triggering the condition, your doctor will outline a diet
and exercise program aimed at helping you lose weight and improve overall
fitness.
 Excessive athletic training — If strenuous training is interrupting your
menstrual cycle, your doctor will recommend a more moderate program. This
will help normal menstruation to start again. It also will also decrease your
risk of conditions related to low levels of estrogen, such as osteoporosis,
heart disease, infertility and thinning of the tissues lining the vagina.
 Hormone imbalance — If altered hormone levels are preventing ovulation
(release of an egg from the ovary), your doctor may prescribe supplemental
hormones.
 Tumors or cysts in the ovaries, uterus or pituitary gland — If cysts or
tumors are causing amenorrhea, treatment depends on their type and
location. Surgery is sometimes necessary.

When To Call A Professional

 You should contact your doctor if you have reached your 14th birthday and have
not started to develop breasts or pubic hair, or if you have reached your 16th
birthday and have not had your first menstrual period.

If you are sexually active, call your doctor if you miss a period, since you will need
to have a pregnancy test. If you are not sexually active, see your doctor if you
have missed three consecutive menstrual periods, or if your periods are irregular.

Prognosis
Amenorrhea rarely is caused by a life-threatening condition. In most instances,
symptoms and conditions related to amenorrhea are reversible and treatable.

www.intelihealth.com

Amenorrhea: Evaluation and Treatment

TARANNUM MASTER-HUNTER, M.D., UNIVERSITY OF MICHIGAN MEDICAL SCHOOL,
ANN ARBOR, MICHIGAN
DIANA L. HEIMAN, M.D., UNIVERSITY OF CONNECTICUT SCHOOL OF MEDICINE,
HARTFORD, CONNECTICUT

Patient information: A handout on amenorrhea, written by the authors of this article, is provided on page
1387.
A PDF version of this document is available. Download PDF now (9 pages /190 KB).

A thorough history and physical examination as well as laboratory testing can help
narrow the differential diagnosis of amenorrhea. In patients with primary amenorrhea,
the presence or absence of sexual development should direct the evaluation.
Constitutional delay of growth and puberty commonly causes primary amenorrhea in
patients with no sexual development. If the patient has normal pubertal development
and a uterus, the most common etiology is congenital outflow tract obstruction with a
transverse vaginal septum or imperforate hymen. If the patient has abnormal uterine
development, müllerian agenesis is the likely cause and a karyotype analysis should
confirm that the patient is 46,XX. If a patient has secondary amenorrhea, pregnancy
should be ruled out. The treatment of primary and secondary amenorrhea is based on
the causative factor. Treatment goals include prevention of complications such as
osteoporosis, endometrial hyperplasia, and heart disease; preservation of fertility; and,
in primary amenorrhea, progression of normal pubertal development. (Am Fam
Physician 2006;73:1374-82, 1387. Copyright © 2006 American Academy of Family
Physicians.)

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. Secondary amenorrhea is the absence of menses for three months in
 women with previously normal menstruation and for nine months in women with
previous oligomenorrhea. Secondary amenorrhea is more common than primary
amenorrhea. 1-3

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References
A female patient with primary amenorrhea and sexual development, C 1, 18
including pubic hair, should be evaluated for the presence of a uterus and
vagina.
Women with secondary amenorrhea should receive pregnancy tests. C 1-3, 6
Women with polycystic ovary syndrome should be tested for glucose C 21
intolerance.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C =

consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT
evidence rating system, see page 1313 or http://www.aafp.org/afpsort.xml.

Pubertal changes typically occur over a three-year period and can be measured using
Tanner staging. The normal progression of female puberty is illustrated in Table 1. The
4 4,5

normal menstrual cycle involves a complex interaction between the hypothalamic-

pituitary-ovarian axis and the outflow tract. Any disruption in this interaction can cause
amenorrhea.

Evaluation
Physicians should conduct a comprehensive patient history and a thorough physical
examination of patients with amenorrhea (Table 2 ). Many algorithms exist for the
2,6-8

evaluation of primary amenorrhea; Figure 1 is one example. Laboratory tests and

1,7,9,10

radiography, if indicated, should be performed to evaluate for suspected systemic

disease. If secondary sexual characteristics are present, pregnancy should be ruled out.
Routine radiography is not recommended, however. 7

TABLE 1
Normal Female Pubertal Development
Tanner stage
Developmental stage Breast Pubic hair
(age in years) Anatomic drawing development development
Initial growth acceleration Elevation of papilla only; no pubic 1 1
(8 to 10) hair
Thelarche (9 to 11) See adrenarche for stage 2 2 1
development
Adrenarche (9 to 11) 2 2

Peak growth (11 to 13) 3 3

Menarche (12 to 14) 4 4

Adult characteristics (13

5 5
to 16)

Illustrations by Renee Cannon.

Information from references 4 and 5.

Figure 2 is an algorithm for the evaluation of secondary amenorrhea. The most

1-3,6

common cause of secondary amenorrhea is pregnancy. After pregnancy is ruled out, the
initial work-up should be based on patient history and physical examination findings.
Prolactin levels should be checked in most patients. The risk of amenorrhea is lower
with subclinical hypothyroidism than with overt disease. However, the effects of
subclinical hypothyroidism on menstruation and fertility are unclear, and abnormal
thyroid hormone levels can affect prolactin levels; therefore, physicians should
consider measuring thyroid-stimulating hormone (TSH) levels. A study of 127
3,11,12 13

women with adult-onset amenorrhea showed that 7.5 percent of participants had
abnormal prolactin levels and 4.2 percent had abnormal TSH levels.

Evaluation of Primary Amenorrhea

 Figure 1. Algorithm for the evaluation of primary amenorrhea. (FSH = follicle-stimulating
hormone; LH = luteinizing hormone.)
Information from references 1, 7, 9, and 10.

TABLE 2
History and Physical Examination Findings Associated with Amenorrhea
Findings Associations
Patient history
Exercise, weight loss, current or previous chronic illness, illicit drug use Hypothalamic amenorrhea
Menarche and menstrual history Primary versus secondary
amenorrhea
Prescription drug use Multiple, depending on
medication
Previous central nervous system chemotherapy or radiation Hypothalamic amenorrhea
Previous pelvic radiation Premature ovarian failure
Psychosocial stressors; nutritional and exercise history Anorexia or bulimia nervosa
Sexual activity Pregnancy
Family history
Genetic defects Multiple causes of primary
amenorrhea
Pubic hair pattern Androgen insensitivity syndrome
Infertility Multiple
Menarche and menstrual history (mother and sisters) Constitutional delay of growth
and puberty
Pubertal history (e.g., growth delay) Constitutional delay of growth
and puberty
Physical examination
Anthropomorphic measurements; growth chart Constitutional delay of growth
and puberty
Body mass index Polycystic ovary syndrome
Dysmorphic features (e.g., webbed neck, short stature, widely spaced Turner's syndrome
nipples)
Rudimentary or absent uterus; pubic hair Müllerian agenesis
Striae, buffalo hump, significant central obesity, easy bruising, Cushing's disease
hypertension, or proximal muscle weakness
Tanner staging (Table 1) Primary versus secondary
amenorrhea
Thyroid examination Thyroid disease
Transverse vaginal septum; imperforate hymen Outflow tract obstruction
Undescended testes; external genital appearance; pubic hair Androgen insensitivity syndrome
Virilization; clitoral hypertrophy Androgen-secreting tumor
Review of systems
Anosmia Kallmann syndrome
Cyclic abdominal pain; breast changes Outflow tract obstruction or
müllerian agenesis
Galactorrhea; headache and visual disturbances Pituitary tumor
Hirsutism or acne Polycystic ovary syndrome
Signs and symptoms of hypothyroidism or hyperthyroidism Thyroid disease
Vasomotor symptoms Premature ovarian failure

Information from references 2 and 6 through 8.

If TSH and prolactin levels are normal, a progestogen challenge test (Table 3 ) can help
3,14

evaluate for a patent outflow tract and detect endogenous estrogen that is affecting the
endometrium. A withdrawal bleed usually occurs two to seven days after the challenge
test. A negative progestogen challenge test signifies an outflow tract abnormality or
3

inadequate estrogenization. An estrogen/progestogen challenge test (Table 3 ) can

3,14

differentiate the two diagnoses. A negative estrogen/progestogen challenge test

typically indicates an outflow tract obstruction. A positive test indicates an abnormality
within the hypothalamic-pituitary axis or the ovaries.

Evaluation of Secondary Amenorrhea

 Figure 2. Algorithm for the evaluation of secondary amenorrhea. (TSH = thyroid-stimulating
hormone; MRI = magnetic resonance imaging; FSH = follicle-stimulating hormone; LH =
luteinizing hormone.)
Information from references 1 through 3 and 6.

Gonadotropin levels can further help determine the source of the abnormality. Elevated
follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels suggest an
ovarian abnormality (hypergonadotropic hypogonadism). Normal or low FSH or LH
levels suggest a pituitary or hypothalamic abnormality (hypogonadotropic
hypogonadism). Magnetic resonance imaging (MRI) of the sella turcica can rule out a
pituitary tumor. Normal MRI indicates a hypothalamic cause of amenorrhea. 3

TABLE 3
Guidelines for Progestogen and Estrogen/Progestogen Challenge Tests
Drug Dosing Duration
Progestogen challenge test
Medroxyprogesterone acetate (Provera) 10 mg orally once per day Seven to 10 days
Norethindrone (Aygestin) 5 mg orally once per day Seven to 10 days
Progesterone 200 mg parenterally once per day Single dose
Progesterone micronized 400 mg orally once per day Seven to 10 days
Progesterone micronized gel (4 or 8%) Intravaginally every other day Six applications
Estrogen/progestogen challenge test
Conjugated equine estrogen (Premarin) 1.25 mg orally once per day 21 days
or
Estradiol (Estrace) 2 mg orally once per day 21 days
followed by
Progestational agent As noted above As noted above

Information from references 3 and 14.

Differential Diagnosis of Primary Amenorrhea

Causes of primary amenorrhea should be evaluated in the context of the presence or
absence of secondary sexual characteristics. Table 4 includes the differential diagnosis
3,6,15

of primary amenorrhea.

TABLE 4
Causes of Amenorrhea
Hyperprolactinemia Hypergonadotropic Hypogonadotropic
Prolactin ≤ 100 ng per mL (100 hypogonadism hypogonadism (continued)
mcg per L) Gonadal dysgenesis Excessive exercise
Altered metabolism Turner's syndrome* Excessive weight loss or
Liver failure Other* malnutrition
Renal failure Postmenopausal ovarian failure Hypothalamic or pituitary
Ectopic production Premature ovarian failure destruction
Bronchogenic (e.g., Autoimmune Kallmann syndrome*
carcinoma) Chemotherapy Sheehan's syndrome
Gonadoblastoma Galactosemia Normogonadotropic
Hypopharynx Genetic Congenital
Ovarian dermoid cyst 17-hydroxylase deficiency Androgen insensitivity
Renal cell carcinoma syndrome syndrome*
Teratoma Idiopathic Müllerian agenesis*
Breastfeeding Mumps Hyperandrogenic anovulation
Breast stimulation Pelvic radiation Acromegaly
Hypothyroidism Hypogonadotropic Androgen-secreting tumor
Medications hypogonadism (ovarian or adrenal)
Oral contraceptive pills Anorexia or bulimia nervosa Cushing's disease
Antipsychotics Central nervous system tumor Exogenous androgens
Antidepressants Constitutional delay of growth and Nonclassic congenital
Antihypertensives puberty* adrenal hyperplasia
Histamine H2 receptor Chronic illness Polycystic ovary syndrome
blockers Chronic liver disease Thyroid disease
Opiates, cocaine Chronic renal insufficiency Outflow tract obstruction
Prolactin > 100 ng per mL Diabetes Asherman's syndrome
Empty sella syndrome Immunodeficiency Cervical stenosis
Pituitary adenoma Inflammatory bowel disease Imperforate hymen*
Thyroid disease Transverse vaginal septum*
Severe depression or Other
psychosocial stressors Pregnancy
Cranial radiation Thyroid disease

*-Causes of primary amenorrhea only.

Information from references 3, 6, and 15.
PRESENCE OF SECONDARY SEXUAL CHARACTERISTICS
If a patient with amenorrhea has breast development and minimal or no pubic hair, the
usual diagnosis is androgen insensitivity syndrome (i.e., patient is phenotypically
female but genetically male with undescended testes). A karyotype analysis is needed to
determine proper treatment. If testes are present, they should be removed because of the
high risk of malignant transformation after puberty. 1

If a patient has normal secondary sexual characteristics, including pubic hair, the
physician should perform MRI or ultrasonography to determine if a uterus is present.
Müllerian agenesis (the congenital absence of a vagina and abnormal uterine
development [usually rudimentary]) causes approximately 15 percent of primary
amenorrhea. The etiology is thought to involve embryonic activation of the
16

antimüllerian hormone, causing malformation of the female genital tract. Patients may
7,17

have cyclic abdominal pain if there is endometrial tissue in the rudimentary uterus,
mittelschmerz, or breast tenderness. An absent or truncated vagina and an abnormal
adult uterus confirm müllerian agenesis. Karyotype analysis should be performed to
determine if the patient is genetically female. 8

If the patient has a normal uterus, outflow tract obstruction should be considered. An
imperforate hymen or a transverse vaginal septum can cause congenital outflow tract
obstruction, which typically is associated with cyclic abdominal pain from blood
accumulation in the uterus and vagina. If the outflow tract is patent, the physician
1

should continue an evaluation similar to that for secondary amenorrhea (Figure 2 ). 1-3,6 1

ABSENCE OF SECONDARY SEXUAL CHARACTERISTICS

Diagnosis of patients with amenorrhea and no secondary sexual characteristics is based
on laboratory test results and karyotype analysis. The most common cause of
hypogonadotropic hypogonadism (low FSH and LH levels) in primary amenorrhea is
constitutional delay of growth and puberty. A detailed family history also may help
16,17

detect this etiology, because it often is familial. Hypogonadotropic hypogonadism

associated with constitutional delay of growth and puberty is indistinguishable from
that associated with hypothalamic or pituitary failure. Watchful waiting is appropriate
10

for constitutional delay of growth and puberty. Kallmann syndrome, which is

associated with anosmia, also can cause hypogonadotropic hypogonadism. 18

Hypergonadotropic hypogonadism (elevated FSH and LH levels) in patients with

primary amenorrhea is caused by gonadal dysgenesis or premature ovarian failure.
Turner's syndrome (45,XO karyotype) is the most common form of female gonadal
dysgenesis. Characteristic physical findings include webbing of the neck, widely
spaced nipples, and short stature. Mosaicism occurs in approximately 25 percent of
patients with Turner's syndrome. These patients often have a more normal phenotype
19

with spontaneous onset of puberty and menarche. Other rare causes of pure gonadal
dysgenesis can occur with a 46,XY or XX karyotype. 7
Differential Diagnosis of Secondary Amenorrhea
After pregnancy, thyroid disease, and hyperprolactinemia are eliminated as potential
diagnoses, the remaining causes of secondary amenorrhea are classified as
normogonadotropic amenorrhea, hypogonadotropic hypogonadism, and
hypergonadotropic hypogonadism; each is associated with specific etiologies (Table
4 ).
3,6,15

HYPOTHYROIDISM
Other clinical signs of thyroid disease are usually noted before amenorrhea presents.
Mild hypothyroidism is more often associated with hypermenorrhea or oligomenorrhea
than with amenorrhea. Treatment of hypothyroidism should restore menses, but this
may take several months. 12

HYPERPROLACTINEMIA
A patient with markedly elevated prolactin levels, galactorrhea, headaches, or visual
disturbances should receive imaging tests to rule out a pituitary tumor. Adenomas are
the most common cause of anterior pituitary dysfunction. A prolactin level more than
15

100 ng per mL
(100 mcg per L) suggests a prolactinoma, and MRI should be performed. If tumor is
excluded as the cause, medications (e.g., oral contraceptive pills, antipsychotics,
antidepressants, antihypertensives, histamine H blockers, opiates) are the next most
2

common cause of hyperprolactinemia. Medications usually raise prolactin levels to less

than 100 ng per mL. When hyperprolactinemia is not related to tumor, physicians
15

should identify and treat or eliminate the underlying cause. Table 4 lists common
3,6,15

etiologies of hyperprolactinemia.

If asymptomatic microadenomas (smaller than 10 mm) are found on MRI, repeat

prolactin measurements and imaging should be performed to monitor for progression.
Microadenomas are slow growing and rarely malignant. Treatment of microadenomas
should focus on management of infertility, galactorrhea, and breast discomfort. A
dopamine agonist can help improve symptoms and fertility. Bromocriptine (Parlodel) is
effective, but cabergoline (Dostinex) has been shown to be superior in effectiveness and
tolerability. Macroadenomas may be treated with dopamine agonists or removed with
20

transsphenoidal resection or craniotomy, if necessary.

NORMOGONADOTROPIC AMENORRHEA
Two common causes of normogonadotropic amenorrhea are outflow tract obstruction
and hyperandrogenic chronic anovulation. The most common cause of outflow
obstruction in secondary amenorrhea is Asherman's syndrome (intrauterine synechiae
and scarring, usually from curettage or infection). Hysterosalpingography,
3

hysteroscopy, or sonohysterography can help diagnose Asherman's syndrome. Other

causes of outflow tract obstruction include cervical stenosis and obstructive fibroids or
polyps.
 Polycystic ovary syndrome (PCOS) is the most common cause of hyperandrogenic
chronic anovulation. The National Institutes of Health diagnostic criterion for PCOS is 21

chronic anovulation and hyperandrogenism

with no other identified secondary cause. The primary etiology of PCOS is unknown,
but resistance to insulin is thought to be a fundamental component. 21

The diagnosis of PCOS is primarily clinical, although laboratory studies may be needed
to rule out other causes of hyperandrogenism (Table 5 ). Significantly elevated
6,21

testosterone or dehydroepiandrosterone sulfate levels indicate a possible androgen-

secreting tumor (ovarian or adrenal). Levels of 17-hydroxyprogesterone can help
diagnose adult-onset congenital adrenal hyperplasia. Cushing's disease is rare;
therefore, patients should only be screened when characteristic signs and symptoms
(e.g., striae, buffalo hump, significant central obesity, easy bruising, hypertension,
proximal muscle weakness) are present. 21,22

TABLE 5
Laboratory Evaluation of Hyperandrogenism
Findings Indications
Serum testosterone (normal: 20 to 80 ng per dL [0.7 to 2.8 nmol per L])
≤ 200 ng per dL (6.9 nmol per L) Consider hyperandrogenic chronic anovulation*
> 200 ng per dL Evaluate for androgen-secreting tumor
Serum dehydroepiandrosterone sulfate (normal: 250 to 300 ng per dL [0.7 to 0.8 µmol per L])
≤ 700 ng per dL (1.9 µmol per L) Consider hyperandrogenic chronic anovulation*
> 700 ng per dL Evaluate for adrenal or ovarian tumor
Serum 17-hydroxyprogesterone (normal: < 2 ng per mL (6.1 nmol per L])†
> 4 ng per mL (12.1 nmol per L) Consider adrenocorticotropic stimulation test to diagnose
congenital adrenal hyperplasia
Dexamethasone suppression test (if clinically indicated)††
Morning cortisol level > 5 µg per dL Evaluate for Cushing's disease
(138 nmol per L)§

*- These values are not specific for diagnosis of hyperandrogenic chronic anovulation.
†-Morning level during follicular phase of menstrual cycle.
††-For an overnight dexamethasone suppression test, the physician should administer a 1-mg dose of dexamethasone
orally between 11 p.m. and midnight and draw a single blood sample for serum cortisol testing at 8 a.m. the following
day.
§-Morning cortisol level in a healthy patient with an intact hypothalamic-pituitary axis. There is some variability in the
cutoff values that can affect sensitivity and specificity of the test. Patients should receive further testing to confirm
Cushing's disease.
Information from references 6 and 21.

Patients with PCOS have excess unopposed circulating estrogen, increasing their risk of
endometrial cancer threefold. The insulin resistance associated with PCOS increases a
21

patient's risk of diabetes mellitus two- to fivefold; therefore, testing for glucose
intolerance should be considered. 21-24

The primary treatment for PCOS is weight loss through diet and exercise. Modest
weight loss can lower androgen levels, improve hirsutism, normalize menses, and
decrease insulin resistance. It may take months to see these results, however. Use of
21

oral contraceptive pills or cyclic progestational agents can help maintain a normal
endometrium. The optimal cyclic progestin regimen to prevent endometrial cancer is
unknown, but a monthly 10- to 14-day regimen is recommended. Insulin sensitizing
21

agents such as metformin (Glucophage) can reduce insulin resistance and improve
ovulatory function. 21,25,26

HYPERGONADOTROPIC HYPOGONADISM
Ovarian failure can cause menopause or can occur prematurely. On average,
menopause occurs at 50 years of age and is caused by ovarian follicle depletion.
Premature ovarian failure is characterized by 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
27

40 years of age). Approximately 50 percent of women with premature ovarian failure

28

have intermittent ovarian functioning with a 5 to 10 percent chance of achieving

29

natural conception.

Women with premature ovarian failure have an increased risk of osteoporosis and heart
disease. The condition also can be associated with autoimmune endocrine disorders
29-31

such as hypothyroidism, Addison's disease, and diabetes mellitus. Therefore, fasting

27,29

glucose, thyroid-stimulating hormone (TSH), and, if clinically appropriate, morning

cortisol levels should be measured. Other laboratory testing should be determined based
on the individual patient. Approximately 20 to 40 percent of women with premature
32

ovarian failure will develop another autoimmune disorder; therefore, if initial

laboratory tests are normal, periodic screening should be considered. Patients younger
than 30 years should receive a karyotype analysis to rule out the presence of a Y
chromosome and the need for removal of gonadal tissue. Ovarian biopsy and
29

antiovarian antibody testing have not been shown to have clinical benefit. 27,29

HYPOGONADOTROPIC HYPOGONADISM
Hypothalamic amenorrhea is associated with abnormalities in gonadotropin-releasing
hormone (GnRH) secretion and disruption of the hypothalamic-pituitary-ovarian axis.
The condition often is caused by excessive weight loss, exercise, or stress. Other causes
are listed in Table 4. The mechanism of how stress or weight loss affects GnRH
3,6,15

secretion is unknown. Treatment of hypothalamic amenorrhea depends on the

33-35

etiology. Women with excessive weight loss should be screened for eating disorders
and treated if anorexia nervosa or bulimia nervosa is diagnosed. Menses usually will
return after a healthy body weight is acheived. 35

Young athletes may develop a combination of health conditions called the female
athlete triad that includes an eating disorder, amenorrhea, and osteoporosis. Menses
may return after a modest increase in caloric intake or a decrease in athletic training.
Similar to patients with eating disorders, athletes with continued amenorrhea are at risk
of bone loss. In adolescent athletes, the bone loss occurs during peak bone mass
development and may not be reversible. Weight-bearing exercise may partially protect
36,37

against bone loss.

38

In patients with amenorrhea caused by eating disorders or excessive exercise, the use of
oral contraceptive pills or menopausal hormone therapy may decrease bone turnover
and partially reverse bone loss; however, neither therapy has been shown to
significantly increase bone mass. Bisphosphonates, traditionally used to treat
38

postmenopausal osteoporosis, are possible teratogens and have not been studied as a
therapy in women of reproductive age. Adequate calcium and vitamin D intake are
recommended for these patients.

www.aafp.org/afp/20060415/1374.html

Secondary Amenorrhea

Lack of menstrual periods in a woman that has had periods

previously

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Background

Secondary amenorrhea is the absence of menstrual periods for 6

months in a woman who had previously been regular, or for 12
months in a woman who had irregular periods.

This problem is seen in about 1% of women of reproductive age.

Primary amenorrhea is when the woman has never had a period in

her life. This page will not discuss primary amenorrhea which is rare.
The causes of primary amenorrhea are also quite different from
secondary amenorrhea.

The most common cause of secondary amenorrhea in reproductive

age women is pregnancy and this should always be excluded by
physical exam and laboratory testing for the pregnancy hormone -
HCG.
History

A good history can reveal the etiologic diagnosis in up to 85% of

cases of amenorrhea.

A detailed menstrual history should be taken.

Any history of galactorrhea (milky discharge from the breasts) is

important and indicates the need for a prolactin hormone level to rule
out hyperprolactinemia.

A woman who has had hot flashes, breast atrophy and decreased
libido along with her amenorrhea may have premature ovarian
failure.

Certain medications such as phenothiazines (used for psychiatric

disorders) and some narcotics can cause amenorrhea, usually in
association with an elevated prolactin and galactorrhea.

A large amount of weight loss or gain can also lead to anovulation -

as can stress or extensive exercise.

Anorexia nervosa is often accompanied by secondary amenorrhea.

Both Cushing's disease (over activity of adrenal glands) and

hypothyroidism (under-functioning thyroid gland) can cause
amenorrhea.

If the patient has a history of severe postpartum hemorrhage (very

heavy bleeding after a delivery), she may have pituitary insufficiency
from infarction (Sheehan's syndrome).

When amenorrhea follows a D&C (dilation and curettage) one should

suspect intrauterine adhesions (Asherman's syndrome), particularly
if the procedure was pregnancy related.

Asherman's can also occasionally be seen following other types of

uterine surgery such as metroplasty, myomectomy or cesarean
section.

Amenorrhea following cervical conization can be due to procedure

related cervical stenosis.
Following discontinuation of oral contraception some women will not
have periods for up to several months. However, the reported
incidence for amenorrhea lasting more than 6 months after the pill is
stopped is 0.8% which is essentially the same as the incidence of
amenorrhea in the general population. Therefore, amenorrhea of
greater than 6 months duration after oral contraceptive use is not
related to the pill use.

Physical examination (what the OB/GYN doctor will look for on the
exam)

Signs of androgen excess such as hirsutism (excess hair growth)

and clitoromegaly (enlargement of the clitoris).

The breast exam may reveal galactorrhea.

Estrogen deficiency may be suggested on pelvic exam by a smooth

vagina that lacks the normal rugae (wrinkles) and a dry endocervix
with no mucous.

Workup after history and physical (what the doctor will do next)

If the history and physical exam are suggestive of a certain etiology

then the initial laboratory or radiographic workup can be tailored
appropriately.

For example, a 32 year old woman who has previously had regular
menses presents with 10 months of amenorrhea following a
curettage for heavy bleeding associated with an incomplete abortion.
She has no signs or symptoms that suggest ovarian failure or
thyroid disease. There is no galactorrhea and she uses no
medications or street drugs. She most likely has intrauterine
adhesions causing her amenorrhea. A reasonable approach to this
patient would be an hCG level to rule out pregnancy, an FSH level to
demonstrate the presence or absence of ovarian function, and then a
hysterosalpingogram or hysteroscopy if these first 2 tests are
normal. One could also do the entire diagnostic workup as
recommended for patients without any etiology apparent. However,
for the sake of efficiency and cost-effectiveness, the workup can
sometimes be more directed.
Some patients will not demonstrate any obvious etiology for their
amenorrhea on history and physical exam. These patients can be
worked up in a logical manner using a stepwise approach.
Diagnostic approaches may vary, however, differences between them
pertain mainly to the order in which tests are performed.

There are several ways that a workup for secondary amenorrhea can
be approached. One reasonable diagnostic approach is described
here. If your doctor did things differently, that doesn't mean that he
or she was wrong or that this approach is wrong. Every case should
be treated individually.

In the approach described here, the first tests to perform after

pregnancy is ruled out are a progesterone withdrawal test as well as
a TSH (thyroid stimulating hormone) and prolactin level.

Thyroid function

Both hypothyroidism and hyperprolactinemia can cause primary or

secondary amenorrhea. If these entities are discovered, appropriate
therapy should result in resumption of regular menstrual periods.

Progestational challenge (progesterone withdrawal test)

The progestational challenge test is performed by giving oral

medroxyprogesterone acetate 10 mg daily for 7-10 days or
progesterone in oil 100-200 mg intramuscularly. A positive response
is any bleeding more than light spotting that occurs within 2 weeks
after the progestin is given. This bleeding will usually occur 2-7 days
after the progestin is finished. Withdrawal bleeding will usually be
seen if the patient's estradiol level is 40 pg/ml or more.

If the patient experiences bleeding after the progestin she has

estrogen present but is not ovulating. If no withdrawal bleeding
occurs, either the patient has very low estrogen levels or there is a
problem with the outflow tract such as uterine synechiae (adhesions)
or cervical stenosis (scarring).

Women with withdrawal bleeding

We will first consider the diagnostic evaluation of the woman with
withdrawal bleeding and normal prolactin and TSH levels. The basic
diagnosis at this point is anovulation for which there are many
causes. If there is a history of recent stress, weight loss, medications
or street drugs, these factors could be causing the amenorrhea.

Some experts believe that an LH and FSH level may be helpful at this
point. If the LH is high (above about 10 MIU/ml) and the LH/FSH ratio
is above 2:1, this supports the clinical diagnosis of polycystic
ovarian disease (PCO).

However, many patients with PCO do not demonstrate this high

LH/FSH ratio. Testosterone and DHEAS levels may be useful in
women with PCO, especially in the presence of hirsutism or other
signs of hyperandrogenism (excess male hormones).

Chronic anovulation should be managed by periodic progestin

withdrawal, or oral contraceptive pills if the patient does not desire
pregnancy at this time.

If she desires pregnancy, induction of ovulation with clomiphene

citrate or injectable gonadotropins can be discussed.

If the anovulatory state has been longstanding, one should consider

endometrial biopsy to rule out significant hyperplasia or carcinoma
of the endometrium.

Women without withdrawal bleeding

We will now consider the evaluation of patients who do not have

withdrawal bleeding after the progestin challenge. These patients
have either a hypoestrogenic state or a compromised outflow tract.

There are 2 ways to approach the next step.

1. One way is to give estrogen to ensure endometrial proliferation,

followed by a progestin to induce withdrawal. A course of 2.5 mg of
Premarin for 21 days including 10 mg of Provera on days 17-21 will
be adequate.

If bleeding occurs, her amenorrhea is due to hypoestrogenism.

If bleeding does not occur, then the patient most likely has outflow
tract obstruction - either Asherman's syndrome or cervical stenosis.
2. The other approach is to perform an FSH level. If the level is high
(above 30-40 MIU/ml), the woman has premature ovarian failure (see
below) and does not need the estrogen and progestin challenge. If
the FSH is normal, it is still a good idea to proceed with the course of
estrogen and progestin as described above.

The next step in the women that do not bleed after the combined
hormonal regimen is either hysterosalpingography or hysteroscopy.
If adhesions are found, they should be hysteroscopically lysed if the
patient is desirous of pregnancy or menses.

Intrauterine adhesions are rare in the absence of a history of pelvic

infection or curettage. Therefore, if the pelvic exam is normal and the
history is not consistent with development of adhesions,
consideration can be given to skipping the estrogen-progestin step.

FSH testing

If the patient did bleed after the combined hormonal regimen (or if
that step was skipped) the next test to obtain is an FSH level. This
should not be drawn for at least 2 weeks after the estrogen-progestin
regimen is completed so that the level is not affected by the
exogenous estrogen.

If the FSH is greater than 30-40 MIU/ml, the patient almost certainly
has ovarian failure. Midcycle FSH peak levels in ovulatory cycles
should not be this high. FSH levels that are in the menopausal range
should be checked at least once again in about 4 weeks. An estradiol
level can be checked as well for further confirmation. With ovarian
failure, the estrogen level will be low (usually less than 20-30 pg/ml).

Ovarian failure (premature menopause)

Once ovarian failure is confirmed consideration should be given to 2

special etiologic situations.

If the woman is under 30, a karyotype should be performed to rule

out any mosaicism involving a Y chromosome. This is important
because of the high risk (about 25%) for a gonadal malignancy
developing if there is any testicular tissue present. If a Y
chromosome is found the gonads should be surgically excised.
These tumors apparently do not appear after age 30 so that
karyotypic analysis is then no longer necessary. Other chromosomal
anomalies will occasionally be found. These are usually either 45X
(Turner's syndrome) or some variation of Turner's mosaic.

The other special category of premature ovarian failure is that

associated with autoimmune disease. These patients have
autoimmune related dysfunction of other endocrine organs. The
most common association is with thyroid disease, but the
parathyroids and adrenals can also be affected. Therefore, it is
prudent to screen for these conditions. Thyroid function tests and
thyroid antibody levels should be obtained. A morning cortisol level
or a corticotropin (ACTH) stimulation test assesses adrenal reserve.
Serum calcium, phosphate and protein levels are ordered to evaluate
possible hypoparathyroidism. A CBC with differential, sedimentation
rate, anti-nuclear antibody and rheumatoid factor may be useful in
further assessing any possible autoimmune dysfunction.

Laboratory evidence of autoimmune phenomenon is much more

prevalent than clinically significant disease. Several studies have
shown laboratory evidence of immune problems in about 15-40% of
women with premature ovarian failure. Thyroid and Lupus-related
antibodies are most commonly found.

It is presently unknown as to what the incidence of clinically

apparent autoimmune disease will be in these patients when
followed over time. Women with well documented premature ovarian
failure should be placed on estrogen/progestin replacement therapy
if there are no contraindications. This will provide some protection
against osteoporosis and cardiovascular disease by eliminating the
severely hypoestrogenic state associated with menopause.

Regardless of the etiology, there currently is no effective treatment

that will be likely to result in a pregnancy (with her own eggs) for
premature ovarian failure. However, some women will spontaneously
ovulate on occasion and pregnancy can occur although it is unusual.
Those pregnancies that do occur are almost always in women on
estrogen replacement therapy. These women should be educated
about this possibility.

Egg donation with in vitro fertilization (IVF) can be a very effective

therapy for women with premature ovarian failure that desire
pregnancy.

In general, ovarian biopsy is not indicated in patients with premature

ovarian failure since no clinically useful information will be obtained.
Hypothalamic-pituitary failure

Patients who do not bleed after the progestin challenge but do after
estrogen/progestin and have normal or low FSH and LH levels make
up the final group of patients to be discussed. These patients have
hypothalamic-pituitary failure. Some medications (e.g.
phenothiazines) as well as extremes of weight loss, stress or
exercise can cause this type of secondary amenorrhea. A pituitary or
hypothalamic tumor would be a rare finding in these patients who
were all screened with prolactin levels at the beginning of the
diagnostic evaluation. However, if there is no cause apparent from
the history, it would be prudent to obtain a baseline CT (or MRI)
evaluation of the sellar region to rule out a space occupying lesion.

Patients with normal prolactin levels and normal imaging studies

have hypothalamic amenorrhea of uncertain etiology. If the
amenorrhea and lack of withdrawal bleeding persists, prolactin levels
should be measured annually since a small microadenoma could be
present that is escaping laboratory and radiographic detection.

Weight loss as a result of anorexia nervosa is an important diagnosis

to make because of the mortality rate of 5-15%. Psychiatric
counseling is indicated in most, if not all cases.

In this condition, as well as in the other hypothalamic amenorrhea

situations, the patients can be significantly hypoestrogenic (a low
estrogen situation similar to menopause). If the state is persistent,
hormone replacement therapy should be considered for protection
against osteoporosis. One approach is to get an estradiol level and if
it is less than 30 pg/ml, counsel the patient that hormonal
replacement therapy is indicated.

Secondary amenorrhea is a symptom that can be caused by many

pathological states. The diagnostic evaluation should lead to the
correct diagnosis without undue delay if the problem is attacked
logically in a stepwise manner.

www.advancedfertility.com
Primary amenorrhea

Primary amenorrhea is the absence of the menstrual period by the age of 16. Treatment
of amenorrhea may range from hormonal supplementation for developmental
abnormalities of the reproductive system to surgery for tumors of the pituitary.

www.nlm.nih.gov/medlineplus/ency/article/001218.htm

Amenorrhea - primary
Definition:
This condition is the absence of any menstrual flow in a woman who has never
menstruated by the age of 16.

Alternative Names:
Primary amenorrhea; No periods; Absent periods; Absent menses

Causes, incidence, and risk factors:

Most girls begin menstruating between ages 9 and 18, with an average around 12 years
old. Primary amenorrhea is not considered to have occurred until a girl is beyond age 16,
if she has undergone other normal changes that occur during puberty. Primary
amenorrhea may occur with or without other signs of puberty.

There are many possible causes of primary amenorrhea:

 Drastic weight reduction (resulting from poverty, fad dieting, anorexia nervosa,
bulimia, very strenuous exercise, or other cause)
 Malnutrition
  Genital abnormalities present since birth (absence of the uterus or vagina, vaginal
septum, cervical stenosis, imperforate hymen)
 Hypoglycemia
 Extreme obesity
 Gonadal dysgenesis
 Hypothyroidism and hyperthyroidism
 Chronic (long term) illnesses
 Cystic fibrosis
 Cushing's disease
 Polycystic ovarian disease
 Galactorrhea
 Chromosomal abnormalities such as Turner's syndrome (XO), or Swyer's
syndrome (XY)
 Hypogonadotropic hypogonadism
 Testicular feminization syndrome
 True hermaphroditism
 Adrenogenital syndrome
 Congenital heart disease (cyanotic)
 Congenital adrenal hyperplasia
 Craniopharyngioma, ovarian tumors, adrenal tumors
 Prader-Willi syndrome
 Pregnancy

Primary amenorrhea in the United States occurs in less than 0.1% of girls.

Signs and tests:

 Physical examination and medical history
 Urine pregnancy test
 Progesterone withdrawal
 Chromosome analysis
 Serum chemistry (serum gonadotropin)
o LH
o FSH
o Prolactin
o TSH
o T3 and T4
 Urine chemistry, 17-ketosteroids
 Head CT
 Head MRI scan
 Ultrasound, pelvic region
 Laparoscopy

Treatment:
Treatment depends on the cause of the amenorrhea. Primary amenorrhea caused by
developmental abnormalities (which may result when the parts of the female reproductive
system did not form properly before birth) may require hormonal supplementation,
surgery, or both.

Pituitary tumors, located in the brain, are usually treated with bromocriptine, a drug that
inhibits the abnormally high prolactin secretion caused by these tumors. Surgical removal
may also be necessary. Radiation therapy is usually reserved for situations in which other
medical or surgical treatment regimens are not successful.

In any case, support and counseling for the patient and family is necessary. This will
address specific concerns and provide guidance regarding anticipated sexual
development.

If the problem causing the amenorrhea is not correctable, then the patient and health care
provider should consider the possibility of creating pseudomenstruation. This is a
menstrual period that is caused by hormonal treatment rather than natural causes.

For women who do not have other reproductive abnormalities, work up for amenorrhea is
delayed until after age 16.

If the condition is caused by systemic disease, treatment of the disease should allow
menstruation to begin.

Expectations (prognosis):
Overall the outlook is good, depending on the cause of the amenorrhea. If the
amenorrhea is caused by one of the following conditions, there is a good possibility of
correcting the amenorrhea through medication, lifestyle change, or surgery:

 Normal delay of onset (up to age 14 or 15)

 Drastic weight reduction (resulting from poverty or fad dieting)
 Hypoglycemia
 Extreme obesity
 Hypogonadotropic hypogonadism
 Chronic illness
 Malnutrition
 Congenital heart disease (cyanotic)
 Hyperthyroidism
 Imperforate hymen
 Adrenogenital syndrome

If the amenorrhea is caused by one of the following conditions, it is unlikely that the
amenorrhea can be corrected by any intervention:

 Congenital abnormalities of the genital system

 Gonadal dysgenesis
 Turner's syndrome (XO)
 Testicular feminization syndrome
 True hermaphroditism
 Cystic fibrosis
 Craniopharyngioma
 Prader-Willi syndrome

If the amenorrhea cannot be corrected, as long as there is a uterus, it may be possible to

create a pseudomenstruation with medications to help the young woman feel more like
her friends or family.

Complications:
Emotional distress or crisis about being different from friends or family can occur.

Calling your health care provider:

Call your health provider if your daughter is older than age 16 and has not yet begun
menstruating.

www.umc-cares.org