Amenorrhea Differential Diagnoses

  • Author: Vaishali Popat, MD, MPH; Chief Editor: Bryan D Cowan, MD,†   more...
 
Updated: Jun 8, 2011
 
 

Diagnostic Considerations

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. Because 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, Turner syndrome (45,X), and mosaicism. The remaining diagnoses should be considered in patients with both primary and secondary amenorrhea.

Since regular menstruation reflects a properly functioning hypothalamic-pituitary-gonadal axis, a logical approach is to consider disorders based upon the levels of control of the menstrual cycle: uterus, ovary, pituitary, and hypothalamus.

Amenorrhea with delayed puberty

Puberty is considered delayed when no breast development is evident at 13 years, pubic hair is absent at 14 years, and menarche is absent at 15 years (which is 2 standard deviations above the mean age for menarche). 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, with loss of part of an X chromosome or translocation, or with a normal karyotype (46,XX) and streak ovaries.

Individuals with Perrault syndrome have gonadal dysgenesis, a normal karyotype, and neurosensory deafness. Swyer syndrome is illustrated by a phenotypically immature female with a 46,XY karyotype without testis-determining factor on the Y chromosome.

These patients have normal female external genitalia, a patent vagina, and a normal uterus. The gonads are testes. They have no breast development, in contrast to individuals with androgen insensitivity. 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. An elevated erythrocyte sedimentation rate (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 occurs when FSH and LH levels are low. Hypogonadotropic hypogonadism may present prior to or after the completion of puberty. The most common causes of hypogonadotropic hypogonadism include chronic illness, starvation, excessive exercise, anorexia nervosa, depression, stress, and marijuana use. Hypogonadotropic hypogonadism involves slowed gonadotropin-releasing hormone (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. Kallmann syndrome occurs during embryonic development when GnRH-secreting neurons fail to migrate from the olfactory area to the hypothalamus. The gene KAL1 codes for the protein associated with normal migration. Other syndromes associated with hypothalamic dysfunction include Prader-Willi syndrome and Laurence-Moon-Biedl syndrome.

Amenorrhea with normal puberty

Frequently, pubertal development occurs at a normal rate, but primary amenorrhea may occur and may be associated with hirsutism. These individuals are eugonadal. The most common cause in this setting is polycystic ovarian syndrome (PCOS), which is characterized by anovulation, oligo-ovulation, androgen excess (clinical or biochemical), ultrasonographic demonstration of increased ovarian stroma and accumulation of antral follicles (polycystic appearance), and obesity.[33]

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, which manifests as 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 that result in excessive 17-hydroxyprogesterone levels. This deficiency is also termed nonclassic congenital adrenal hyperplasia and can occur in 1-10% of women with hirsutism.

Rarely, patients with hypothalamic amenorrhea may have hyperandrogenic/polycystic ovaries. Wang et al explored the coexistence of these 2 disorders in women with hypothalamic amenorrhea/PCOS, and found that over time, these patients may fluctuate between symptoms of hypothalamic amenorrhea and polycystic ovarian syndrome, depending on the status of their hypothalamic activity.[34]

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 dysfunction 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. It is often associated with a hypothalamic hypogonadotropic etiology.

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.

Premature ovarian failure is more accurately termed primary ovarian insufficiency (POI) because women with spontaneous POI may have intermittent ovarian function, and, as a group, demonstrate a pregnancy rate of 5-10%.[35] (For an in-depth discussion, see Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure].)

Prodromal POI is a state of ovarian insufficiency in which FSH levels are elevated and menses are irregular but not to the degree required to make a diagnosis of overt POI. This is likely on a continuum with diminished ovarian reserve (a state in which women respond poorly to exogenous gonadotropin stimulation) and overt POI (a state of drastically reduced fertility).

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) and metoclopramide (Reglan).

Amenorrhea may be caused by thyroid disorders, including hyperthyroidism and hypothyroidism. Hypogonadotropic hypogonadism can occur from the same causes as delayed puberty. In addition, Sheehan syndrome, which results from panhypopituitarism after pituitary infarction from postpartum hemorrhage or shock, can manifest as pubertal amenorrhea.

Amenorrhea that results 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 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) is present in 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 estradiol. The diagnosis is suggested by absence of endometrial stripe on uterine ultrasonography and confirmed by hysteroscopy evaluation or by absence of bleeding after cyclic therapy with estrogen and later progestin for several weeks.

A case report has been published of a woman in whom persistent secondary amenorrhea developed due to intrauterine adhesions after selective embolization of the uterine arteries for control of refractory primary postpartum hemorrhage. Adverse effects of these new lifesaving technologies remain to be evaluated long term.[36]

Clinically significant infections that destroy the endometrial lining can also result in primary or secondary amenorrhea.

Diagnostic strategy

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 performing a detailed physical examination is essential.[37]

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[38] ; 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.

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.

Differential Diagnoses

Proceed to Workup
 
 
Contributor Information and Disclosures
Author

Vaishali Popat, MD, MPH  Clinical Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health

Vaishali Popat, MD, MPH is a member of the following medical societies: American College of Physicians and Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Shannon D Sullivan, MD, PhD  Staff Physician, Department of Endocrinology, Washington Hospital Center

Shannon D Sullivan, MD, PhD is a member of the following medical societies: American Medical Association, American Thyroid Association, Endocrine Society, and Society for the Study of Reproduction

Disclosure: Nothing to disclose.

Suzanne R Trupin, MD, FACOG  Clinical Professor, Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women's Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical Center

Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, Association of Reproductive Health Professionals, International Society for Clinical Densitometry, and North American Menopause Society

Disclosure: Nothing to disclose.

Lawrence M Nelson, MD, MBA  Head of Integrative Reproductive Medicine Group, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health

Lawrence M Nelson, MD, MBA is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Endocrine Society, and Society for Experimental Biology and Medicine

Disclosure: Nothing to disclose.

Elizabeth Alderman, MD  Director of Fellowship Training Program, Director, Adolescent Ambulatory Service, Professor, Clinical Pediatrics, Department of Pediatrics, Division of Adolescent Medicine, Albert Einstein College of Medicine and Children's Hospital at Montefiore

Elizabeth Alderman, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, North American Society for Pediatric and Adolescent Gynecology, and Society for Adolescent Medicine

Disclosure: Merck Honoraria Speaking and teaching

Wayne Wolfram, MD, MPH  Associate Professor, Department of Emergency Medicine, Mercy St Vincent Medical Center

Wayne Wolfram, MD, MPH is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Pediatrics, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Kenneth M Bielak, MD  Clinic Director of Family Practice Center, Associate Professor, Department of Family Medicine, University of Tennessee Health Science Center College of Medicine

Kenneth M Bielak, MD is a member of the following medical societies: American Academy of Family Physicians, American College of Sports Medicine, American Medical Association, and American Medical Society for Sports Medicine

Disclosure: Nothing to disclose.

Tamara Prodanov, MD  Research Assistant, National Institutes of Child Health and Human Development, National Institutes of Health

Disclosure: Nothing to disclose.

Sharon N Covington, LCSW-C, BCD  Clinical Assistant Professor, Department of Obstetrics and Gynecology, Georgetown University School of Medicine; Associate Investigator, Integrative Reproductive Medicine Unit, Reproductive Biology and Medicine Branch, National Institutes of Child Health and Human Development, National Institutes of Health; Private Practice, Covington and Hafkin and Associates; Director of Psychological Support Services, Shady Grove Fertility Reproductive Science Center

Sharon N Covington, LCSW-C, BCD is a member of the following medical societies: Academy of Certified Social Workers, American Orthopsychiatric Association, American Society for Reproductive Medicine, National Association of Social Workers, and Society for Assisted Reproductive Technologies

Disclosure: Nothing to disclose.

Karim Anton Calis, PharmD, MPH, FASHP, FCCP  Adjunct Clinical Investigator, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Clinical Professor, Medical College of Virginia, Virginia Commonwealth University School of Pharmacy; Clinical Professor, University of Maryland School of Pharmacy

Karim Anton Calis, PharmD, MPH, FASHP, FCCP is a member of the following medical societies: American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and Endocrine Society

Disclosure: Nothing to disclose.

Gayla S Harris, MD  Associate Professor, Department of Obstetrics and Gynecology, University of Tennessee Medical Center

Gayla S Harris, MD is a member of the following medical societies: American Society for Reproductive Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Thomas Michael Price, MD  Associate Professor of Reproductive Endocrinology, Director of Reproductive Fellowship Training Program, Duke University Medical Center

Thomas Michael Price, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Phi Beta Kappa, and Society for Gynecologic Investigation

Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee Consulting; Gerson Lehrman Group Advisor Consulting fee Consulting; Roche/GSK Spokesperson Consulting fee Consulting; Adiana Grant/research funds PI

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

A David Barnes, MD, PhD, MPH, FACOG  Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)

A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association

Disclosure: Nothing to disclose.

Andrea L Zuckerman, MD  Assistant Professor of Obstetrics/Gynecology and Pediatrics, Tufts University School of Medicine; Division Director, Pediatric and Adolescent Gynecology, Tufts Medical Center

Andrea L Zuckerman, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, North American Society for Pediatric and Adolescent Gynecology, and Society for Adolescent Medicine

Disclosure: Nothing to disclose.

Chief Editor

Bryan D Cowan, MD,†  Former Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Former Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Former Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center

Bryan D Cowan, MD,† is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Somya Verma, MD, to the development and writing of a source article.

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Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.
Primary amenorrhea flowchart.
 
 
 
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