Amenorrhea, Absence of Bleeding

Rachel J. Miller MD
Basics
Description
Amenorrhea is the absence of menses. It may be divided into primary and
secondary amenorrhea:
o Primary amenorrhea refers to the absence of menses by age 13 with no
breast development, or by age 15 with normal secondary sexual
development. Or absence of menses 5 years after thelarche.
o

Secondary amenorrhea is the absence of menses for 90 days or 3

months in females who previously menstruated.

Amenorrhea is a sign of an underlying disease mechanism, and therapy should

be directed at treating the specific condition.

Most causes of secondary amenorrhea can also cause primary amenorrhea if

the onset is prior to menarche.

Epidemiology
Amenorrhea affects females during their reproductive years.
The incidence of secondary amenorrhea is 3.3%:
o

7.6% of females ages 1524,

3% ages 2534, and

3.7% ages 3544 years have amenorrhea

Risk Factors
Obesity
Weight loss

Excessive exercise

Chronic disease

Genetics
Amenorrhea can be associated with multiple genetic disorders but, no single
mutation causes it.
See Gonadal dysgenesis; Ovarian Insufficiency/Premature Ovarian Failure
(POF)
Pathophysiology
Normal menstrual function requires an intact hypothalamic-pituitary-ovarianuterine/vaginal axis.
Normally, the hypothalamus releases pulsatile GnRH, which stimulates the
pituitary to release FSH and LH.

These gonadotropins act on the ovaries to stimulate follicular development,

ovulation, and the resulting corpus luteum.

The ovaries secrete estrogen and progesterone, which stimulate proliferation

and maturation of the uterine endometrium.

In the absence of fertilization, menstrual blood exits through a normal outflow

tract.

Any disruption or abnormality in this axis can cause amenorrhea.

Associated Conditions
Multiple, see Differential Diagnosis
Diagnosis
Signs and Symptoms
Absence of menses
History
The patient should be questioned regarding:
Age at thelarche, pubarche, and menarche
Menstrual history

Sexual activity

Pregnancy history

History of uterine instrumentation

Eating and exercise habits, weight loss

Galactorrhea, headaches, anosmia, visual field defects, polyuria, polydipsia

Symptoms of estrogen deficiency such as hot flushes or vaginal dryness

Signs of androgen excess

Medication use

Illicit drug use

Risk factors for tuberculosis or HIV

Family history:
o

Menarche

Height

Infertility

Autoimmune and genetic disorders

Physical Exam
Growth pattern
Height and weight (BMI)

Tanner staging

Evidence of androgen excess, such as acne, hirsutism, clitoromegaly

Cushing disease stigmata

Thyroid exam

Breast exam, especially looking for galactorrhea

External genitalia

Internal genitalia if developmentally appropriate

Tests
Pregnancy must be evaluated in both primary and secondary amenorrhea.
Labs
Urine or serum -hCG
TSH

Prolactin

If signs of hyperandrogenism:

Serum DHEAS and testosterone

17-hydroxyprogesterone

If symptoms or signs of hypoestrogenism:

o

FSH

Estradiol

If symptoms/physical findings suggestive of genetic disorder or POF <30

years:
o

Karyotype

Imaging
Bone age if concern for constitutional delay
Transabdominal pelvic ultrasound to confirm presence of uterus and normal
gonads or evaluate for polycystic ovaries

If elevated prolactin levels:

o

MRI of brain to rule out pituitary tumor (i.e., prolactinoma)

If history of uterine instrumentation:

o

Hysterosalpingogram

Differential Diagnosis
Infection
Chronic disease or infection
Uterine infectious sequelae
Metabolic/Endocrine

POF:
o

Turner syndrome

Gonadal dysgenesis

Complete androgen insensitivity

Hyperprolactinemia:

Hypothyroidism

Prolactinoma

Medications

Pituitary disease:
o

Empty sella syndrome

Hypothalamic dysfunction:
o

Anorexia nervosa

Excessive exercise

Kallmann syndrome

Cushing's disease:
o

Congenital adrenal hyperplasia

Immunologic
Autoimmune premature ovarian failure
Tumor/Malignancy
Prolactinoma
Androgen producing tumors
Trauma
See Sheehan Syndrome.
Drugs
Iatrogenic:
Chemotherapy (i.e., cyclophosphamide)
Radiation therapy

Hormonal contraceptives

Medications that induce hyperprolactinemia

Levonorgestrel intrauterine system

Leuprolide

Other/Miscellaneous
Physiologic:

Prepubertal

Pregnancy and lactation

Menopause

Congenital outflow tract anomalies:

o

Mllerian agenesis

Androgen insensitivity syndrome

Imperforate hymen

Transverse vaginal septum

Acquired outflow tract abnormalities:

o

Uterine synechiae/Asherman syndrome

Cervical stenosis

PCOS

P.3
Management
General Measures
Always treat the underlying etiology.
Weight loss for overweight or obese patients

Normalization of BMI and appropriate exercise behaviors for patients with

excessive exercise and disordered eating

Special Therapy
Complementary and Alternative Therapies
Healthy, well-balanced diet to achieve normal BMI
Appropriate, moderate exercise to achieve or maintain normal BMI
Medication (Drugs)
Always treat the underlying etiology:
Thyroid replacement if hypothyroid
Dopamine-agonist if hyperprolactinemia

Metformin if PCOS and insulin resistant

Cyclical estrogen-progesterone

Combined estrogen-progesterone oral contraceptive pills, patches, or vaginal

ring

Patients seeking pregnancy may require ovulation induction with clomiphene

citrate, exogenous gonadotropins, or pulsatile GnRH.

Surgery
Hymenotomy if imperforate hymen
Resection of vaginal septum

Tumor resection

Lysis of intrauterine synechiae

If gonadal dysgenesis or androgen insensitivity syndrome, consideration for

gonadectomy to prevent malignant transformation

Followup
Disposition
The evaluation of and treatment for amenorrhea is performed in the outpatient setting.
Issues for Referral
Many etiologies for amenorrhea can be managed by the primary care provider.
Conditions that require the help of a specialist may include:
o

Congenital outflow tract anomaly: Pediatric gynecologist or

reproductive endocrinologist

Uterine synechiae: Gynecologist or reproductive endocrinologist

POF: Endocrinologist, gynecologist, reproductive endocrinologist

Pituitary tumors: Neurosurgeon and endocrinologist

Anorexia nervosa: Psychiatrist or eating disorder specialist

PCOS: Endocrinologist, reproductive endocrinologist, or gynecologist

Other types of tumors: Oncologist, gynecologist, gynecologic or

surgical oncologist

Infertility: Obstetrician/Gynecologist or reproductive endocrinologist

Patient Monitoring
Prognosis is based on the underlying etiology.
Many patients will begin or resume menses following therapy for the
underlying condition, especially in cases of endocrine diseases, functional
hypothalamic dysfunction, and PCOS.

Prolonged hypoestrogenic states may lead to bone mineral density loss.

Many causes of amenorrhea result in anovulation and infertility if patients

remain undiagnosed and untreated.

Women with PCOS may also have insulin resistance and should be screened
for diabetes.

Prolonged amenorrhea, particularly in obese females, is a risk factor for

endometrial cancer.

Bibliography

American College of Obstetrics and Gynecology Committee on Practice BulletinsGynecology. Management of infertility caused by ovulatory dysfunction. Obstet
Gynecol. 2002;99(2):347358.
Mitan LAP. Menstrual dysfunction in anorexia nervosa. J Pediatr Adolesc Gynecol.
2004;17:8185.
Munster K, et al. Secondary amenorrhoea: Prevalence and medical contact: A cross
sectional study from a Danish county. Br J Obstetr Gynecol. 1992;99:430433.
Pettersson F, et al. Epidemiology of secondary amenorrhea: Incidence and prevalence
rates. Am J Obstet Gynecol. 1973;117:8086.
The Practice Committee of the American Society for Reproductive Medicine. Current
evaluation of amenorrhea. Fertil Steril. 2006:86(Suppl 4):S148S155.
Speroff L, et al. Clinical Gynecologic Endocrinology and Infertility, 7th ed. 2004.
Welt CK, et al. Etiology, diagnosis, and treatment of primary amenorrhea. UpToDate
Online 14.3, 2005.
Welt CK, et al. Etiology, diagnosis, and treatment of secondary amenorrhea.
UpToDate Online 14.3, 2005.
Miscellaneous
Clinical Pearls
The most common cause of amenorrhea is pregnancy.
Abbreviations
DHEASDehydroepiandrosterone
FSHFollicle stimulating hormone
GnRHGonadotropin releasing hormone
hCGHuman chorionic gonadotropins
LHLuteinizing hormone
PCOSPolycystic ovarian syndrome
POFPremature ovarian failure
Codes
ICD9-CM
256.8 Amenorrhea (due to ovarian dysfunction)
256.8 Amenorrhea (hyperhormonal)
626.0 Amenorrhea (primary or secondary)
Patient Teaching
Prevention
Amenorrhea may be prevented by:
Treating underlying conditions
Maintaining an appropriate body weight