Amenorrhea is the absence of menstruation and can be primary or secondary. Primary amenorrhea refers to the absence of menstruation by age 15 in the presence of secondary sexual characteristics or by age 13 without characteristics. Secondary amenorrhea is the absence of menses for longer than 6 months in a previously menstruating woman. Common causes include pregnancy, polycystic ovarian syndrome, thyroid issues, and prolactinomas. An evaluation involves assessing sexual development, examining the reproductive tract, and obtaining levels of FSH, TSH, and prolactin to help determine the cause. Further tests like an MRI or karyotype may then be needed.

1. 96
1. What is amenorrhea?
Amenorrhea is the absence of menstruation in a woman of childbearing age. It is divided into two
types: primary and secondary.
2. What is the difference between primary and secondary amenorrhea?
• Primary amenorrhea is defined as the initial absence of menstruation by age 15 years in the
­presence of secondary sexual characteristics (breast development, pubic hair, growth acceleration),
or within 5 years of initial breast development (see Chapter 21). The incidence of primary amenor-
rhea is 0.1%.
• Secondary amenorrhea is defined as the absence of menses for longer than 6 months or the
absence of menses for at least three previous cycle intervals in a woman who was previously
menstruating. The incidence of secondary amenorrhea is 0.7%.
3. What are the most common causes of primary amenorrhea?
The most common cause of primary amenorrhea is gonadal dysgenesis, such as in Turner syndrome.
This accounts for more than 40% of cases. Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser Syn-
drome) is the second most common cause, accounting for 15% of patients with primary amenorrhea.
4. What is the most common cause of secondary amenorrhea?
Pregnancy.
5. How can the causes of amenorrhea be categorized?
The causes of amenorrhea can be categorized as disorders of the following:
• Uterus or outflow tract
• Ovary
• Pituitary
• Hypothalamus or central nervous system
• Endocrine system
Table 22-1 is an overview of the causes of primary and secondary amenorrhea.
6. What are the first steps in determining the cause of amenorrhea?
A careful history and physical examination are the first steps to narrow the differential diagnosis.
Pregnancy should always be excluded. The following should be considered:
• Does the patient have evidence of normal pubertal development? Breast development signals
exposure to estrogen, and normal pubic or axillary hair signifies androgen production or exposure.
• Is the reproductive tract normal on examination?
• Is any evidence of hirsutism, excess androgens, or excess cortisol present?
• Does the patient have a history of emotional, physical, or nutritional stress?
• Are any signs of a hypothalamic or pituitary problem noted? Ask whether the patient has had any
headaches, seizures, visual field defects, vomiting, changes in sleep or appetite, or galactorrhea.
• Is the patient taking any medications, or has she received chemotherapy or radiation therapy?
7. What initial blood tests should be performed in a patient with amenorrhea?
• A pregnancy test is performed.
• Thyroid function tests are used to rule out hypothyroidism.
• Prolactin level: Evaluate for hyperprolactinemia, which can occur even in the absence of galactor-
rhea. If hyperprolactinemia is identified, a magnetic resonance imaging (MRI) scan of the brain with
intravenous (IV) contrast should be performed to rule out a prolactinoma.
• Follicle-stimulating hormone (FSH) level: Determine whether failure of the hypothalamic-pituitary
axis or ovary exists. High FSH levels indicate that the hypothalamus is functioning properly but with
no feedback inhibition response from the ovaries. This condition indicates primary ovarian failure.
Low or low-normal levels of FSH indicate hypothalamic dysfunction.
CHAPTER22
AMENORRHEA
Michelle S. Özcan, MD, and Travis W. McCoy, MD
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2. Amenorrhea 97
8. In what two syndromes does the patient have breast development but no uterus
is present?
1. In müllerian agenesis, the ovaries develop appropriately but the uterus does not; sometimes the
vagina is absent as well. Because of the presence of estrogen, breast development is normal.Associ-
ated renal anomalies are common (horseshoe kidney, pelvic kidney, unilateral renal agenesis, ureteral
duplication) and should be ruled out with a renal ultrasound scan or intravenous pyelography.
2. In androgen insensitivity syndrome (AIS), an X-linked recessive defect exists in androgen
receptors. This disorder causes genotypic males (46 XY) to be phenotypically female because
Table 22-1. Common causes of Primary and Secondary Amenorrhea
Common Causes of Primary Amenorrhea
CATEGORY APPROXIMATE FREQUENCY (%)
Absent Breasts and Increased FSH 40
45 X and variants 20
46 XX 15
46 XY 5
Absent Breasts and Low or Normal FSH 30
Constitutional delay 10
Prolactinoma 5
PCOS 3
Stress or anorexia 3
CAH 3
Kallmann syndrome 2
Breast Development Present 30
Müllerian agenesis 10
Androgen insensitivity 9
Constitutional delay 8
Transverse vaginal septum 2
Imperforate hymen 1
Common Causes of Secondary Amenorrhea
CATEGORY APPROXIMATE FREQUENCY (%)
Low or Normal FSH 66
Chronic anovulation (PCOS)
Hypothyroidism
Hyperprolactinemia
Other pituitary tumor/disorder
Cushing syndrome
Weight loss/anorexia
Nonspecific hypothalamic
Ovarian Failure (High FSH) 12
46 XX
Abnormal karyotype
Anatomic 7
Asherman syndrome
Hyperandrogenic States 2
Ovarian tumor
Nonclassic CAH
Undiagnosed Conditions
Data from Current evaluation of amenorrhea. ASRM educational bulletin. Fertil Steril. 2008;90:S219-S225.
CAH, Congenital adrenal hyperplasia; FSH, follicle-stimulating hormone; PCOS, polycystic ovarian syndrome.
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3. 98 REPRODUCTIVE ENDOCRINOLOGY
target tissues cannot respond to circulating androgens (female external genital development is
the default). These patients have gonads, and male levels of testosterone and dihydrotestosterone
are present. Wolffian duct development, however, fails to occur because of the receptor defect.
Müllerian structures (uterus and upper vagina) also do not develop because antimüllerian hor-
mone (AMH) is still produced by the gonads. Patients have a 20% chance of gonadal malignancy
(dysgerminoma or gonadoblastoma), and the gonads should be removed after the patient reaches
sexual maturity. Breast development occurs normally because of estrogen produced by the
­peripheral conversion of androgens. The absence of androgen action results in absent or scant
pubic and axillary hair.
9. What tests should be performed on an otherwise normal 15-year-old girl with
primary amenorrhea with no evidence of breast growth or pubic hair? (The vagina
and uterus are present.)
An absence of breast development indicates a lack of estrogen, so an FSH level is needed.
• Elevated FSH (hypergonadotropic hypogonadism) indicates gonadal failure. A karyotype should
be performed and often shows an X chromosome abnormality, the most common being Turner
syndrome. These patients should have an electrocardiogram, chest radiography, intravenous
­pyelography, and thyroid function tests to rule out other medical problems that coincide with
gonadal dysgenesis 30% of the time. If any part of a Y chromosome is present in the karyotype, the
gonads should be removed because of the risk of gonadal malignancy.
• Low or low-normal FSH (hypogonadotropic hypogonadism) can be seen in cases of constitutional
delay, severe stress, or hypothalamic or pituitary dysfunction. Thyroid function tests, IGF-1 (a
reflection of growth hormone production), and prolactin should be assessed. In cases of low FSH,
MRI with IV contrast should be performed to evaluate for hypothalamic or pituitary masses (Fig. 22-1).
10. What are the hypothalamic causes of amenorrhea?
• Dysfunctional gonadotropin-releasing hormone (GnRH) secretion: can occur with polycystic
ovarian syndrome, excessive exercise, eating disorders, and malnutrition
• Isolated gonadotropin deficiency: can be caused by Kallmann syndrome (lack of GnRH neurons,
associated with anosmia) or be idiopathic
• Infection: tuberculosis, encephalitis or meningitis, syphilis, or sarcoidosis
• Neoplasms: craniopharyngioma, Langerhans cell histiocytosis, other tumors
11. What are pituitary causes of amenorrhea?
• Cell damage leading to deficient luteinizing hormone and FSH secretion: can occur with
autoimmune disease, thrombosis, or hemorrhage (Sheehan syndrome, see Chapter 68)
• Neoplasms: most commonly prolactinoma, but also inactive adenomas or other hormone-secreting
pituitary tumors including growth hormone leading to acromegaly and adrenocorticotropic hor-
mone, with resulting Cushing syndrome
KEY POINTS: PRIMARY AMENORRHEA
1. Primary amenorrhea is classically defined as the absence of menses by age 13 years with
no secondary sexual characteristics or by age 15 years with evidence of secondary sexual
­development.
2. Gonadal dysgenesis (e.g., Turner syndrome) and müllerian agenesis are the most common causes of
primary amenorrhea.
3. Patients with müllerian agenesis and androgen insensitivity present with breast development but no
uterus. These conditions can be differentiated with a karyotype or testosterone level.
4. Initial laboratory workup of amenorrhea should include FSH, TSH, and prolactin determinations.
5. Patients with primary amenorrhea and hypergonadotropic hypogonadism (elevated FSH) should
have a karyotype performed.
6. Patients with primary amenorrhea and hypogonadotropic hypogonadism should have an MRI scan of
the brain with IV contrast performed.
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4. Amenorrhea 99
Figure 22-1. Workup of primary amenorrhea. CNS, Central nervous system; FSH, follicle-stimulating hormone.
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5. 100 REPRODUCTIVE ENDOCRINOLOGY
12. What are the causes of primary ovarian insufficiency (POI)?
POI is defined as ovarian failure before the age of 40 years. It is also referred to as premature ovarian
failure. It has several causes:
• Genetic defects, including Turner syndrome and fragile X syndrome. If any XY cells are pres-
ent on karyotype, the gonads should be removed immediately to decrease the risk of germ cell
malignancy.
• Toxins can include chemotherapy, radiation, and certain viruses.
• Autoimmune disease: This can also cause thyroiditis, diabetes, and primary adrenal insufficiency
(Addison disease).
• Metabolic disorders: These disorders include galactosemia.
• Up to 80% of the time, POI is idiopathic.
13. When should a karyotype be ordered in a patient with amenorrhea?
• Patients with primary amenorrhea who have breasts but no uterus (differentiates between andro-
gen insensitivity and müllerian agenesis)
• Patients with primary amenorrhea and gonadal failure, to diagnose Turner syndrome or Swyer
syndrome (XY gonadal dysgenesis)
• Patients with secondary amenorrhea who have POI or signs of Turner syndrome (e.g., short stature,
webbed neck, high arched palate, shield chest)
14. What medications can cause amenorrhea?
• Medications that stimulate prolactin secretion: Prolactin has an inhibitory effect on GnRH secretion.
• Dopamine antagonists: Dopamine is a negative feedback inhibitor of prolactin release, so these
medications lead to increased prolactin secretion. Antidepressants, (e.g., tricyclics), antipsychot-
ics (e.g., risperidone and haloperidol), and some antiemetics (e.g., metoclopramide) are in this
category.
• Selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) can
induce amenorrhea through hyperprolactinemia. Other medications with this property include
histamine receptor antagonists (H2-blockers), reserpine, methyldopa, opiates, benzodiazepines,
barbiturates, estrogens, and antiandrogens.
15. What causes athletic amenorrhea, and should it be treated?
In athletes, amenorrhea can result from high physiologic stress levels, energy deficit, or abnormal
eating habits. Physiologic stress can increase catechol estrogens and β-endorphins and cause the
hypothalamus to decrease the pulse frequency of GnRH release. Over time, the hypogonadotropic
hypogonadism that ensues can lead to osteoporosis and stress fractures. The combination of
disordered eating, amenorrhea, and osteoporosis is referred to as the female athlete triad. Athletic
amenorrhea should be treated; patients should be encouraged to improve their diet, decrease stress
levels, and decrease the amount of strenuous exercise if possible. Estrogen and progesterone should
be replaced (oral contraceptives are a good option) if lifestyle changes are not effective.
16. What rare enzyme defects can cause amenorrhea?
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that can be caused by a vari-
ety of enzyme defects involved in steroidogenesis. Symptoms result from excessive or deficient pro-
duction of mineralocorticoids, androgens, and estrogens. The most common enzyme deficiency in CAH
is that of 21-hydroxylase. Girls with classic CAH caused by 21-hydroxylase deficiency have ambigu-
ous genitalia at birth as a result of exposure to androgens in utero, as well as salt wasting (hypona-
tremia and hypovolemia) from decreased mineralocorticoids. The nonclassic form of 21-hydroxylase
deficiency, however, may manifest in adolescents or young adults with oligomenorrhea or amenorrhea
and hirsutism. 17-Hydroxyprogesterone is elevated in patients with 21-hydroxylase deficiency.
Another enzyme deficiency in CAH is that of 17α-hydroxylase, which causes a lack of sex
steroid and cortisol production and elevated mineralocorticoids. Girls with this defect have normally
developed external genitalia but experience delayed puberty and primary amenorrhea because of a
lack of estrogen production. Excess mineralocorticoids can also lead to hypertension, hypernatremia,
and hypokalemia. These patients require exogenous estrogen and progesterone to attain sexual
maturity and prevent osteoporosis.
Other enzyme defects include defects of 11β-hydroxylase and 3β-hydroxysteroid
dehydrogenase.
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6. Amenorrhea 101
Bibliography
1. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen
in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 1997;99:505–512.
2. Current evaluation of amenorrhea. ASRM educational bulletin. Fertil Steril. 2008;90:S219–S225.
3. Lentz GM, Lobo RA, Gershenson DM, Katz VL, eds. Comprehensive Gynecology. 6th ed. Philadelphia: Mosby; 2012.
4. Fritz MA, Speroff L, eds. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia: Lippincott Williams
Wilkins; 2011.
KEY POINTS: SECONDARY AMENORRHEA
1. The most common cause of secondary amenorrhea is pregnancy.
2. Hypothalamic and pituitary causes of secondary amenorrhea include idiopathic conditions, eating
disorders or excessive exercise, infection, and neoplasms (most commonly prolactinoma).
3. POI is usually idiopathic but can also result from Turner syndrome, fragile X syndrome, metabolic
and autoimmune disorders, or chemotherapy or radiation therapy.
4. Medications that stimulate prolactin secretion include antipsychotics, antidepressants, gastrointestinal
medications, antihypertensives, and hormones.
5. Nonclassic CAH caused by 21-hydroxylase deficiency can cause secondary amenorrhea and hirsutism.
17-Hydroxyprogesterone is elevated in these patients.
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