Amenorrhea and dysmenorrhea

Amenorrhea and dysmenorrhea

I. Problem/Condition.

Primary amenorrhea is the absence of menses by age 15 in the presence of normal sexual development or when, secondary sexual characteristics are not present, the absence of menses by age 13. Secondary amenorrhea is the cessation of menses for 3 months. Because primary amenorrhea is usually a pediatric problem, this chapter will focus on secondary amenorrhea.

Note, many of the conditions that can cause secondary amenorrhea may also cause oligomenorrhea, which is defined as less than nine menstrual cycles over the course of a year, as well as menorrhagia and metrorrhagia, collectively referred to as dysfunctional uterine bleeding.

Dysmenorrhea is pain with menstruation. It is a crampy uterine pain felt in the abdomen and pelvis, which may be associated with headache, nausea, vomiting, and back or leg pain, and lasts for 24–72 hours after the start of menstrual flow. Primary dysmenorrhea occurs in the absence of any pelvic pathology. This usually starts once ovulatory cycles are established after menarche and may improve over time and after childbirth. Its prevalence is difficult to estimate but ranges from 25–50% in adult women, and up to 95% in adolescents. Secondary dysmenorrhea is the result of pelvic pathology and often starts after age 20, though it may occur earlier. It usually represents a change from usual patterns of menstrual pain and may be accompanied by menorrhagia, dyspareunia, or chronic pelvic pain.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The differential diagnosis for secondary amenorrhea can be classified by the anatomic location of the problem. However, most cases are caused by four broad conditions: polycystic ovarian syndrome (PCOS), hypothalamic amenorrhea, hyperprolactinemia, and ovarian failure.

Classification by anatomic location

Uterus

• Intrauterine adhesions (Asherman’s syndrome)—from damage to the endometrium

• Cervical stenosis

Ovary

• Premature ovarian failure—many causes in women under the age of 40 including autoimmune, genetics, chemotherapy, pelvic radiation, mumps, and idiopathic

• Menopause

• Tumors: granulosa-theca cell, Brenner, cystic teratoma, mucinous/serous cystadenoma, Krukenberg tumor, craniopharyngioma, metastatic disease

• Polycystic ovarian syndrome

Hypothalamus (from disruption of gonadotropin-releasing hormone)

• Stress

• Excessive exercise

• Eating disorder or malnutrition

• Pseudocyesis (false pregnancy)

• Lactation

• Infection: tuberculosis, syphilis, encephalitis, and meningitis

• Infiltrative disease: sarcoidosis, hemochromatosis

• Chronic illness: renal or hepatic disease, diabetes, inflammatory bowel disease

• Celiac disease

• Tumors: craniopharyngioma, germinoma, hamartoma, Langerhans cell histiocytosis, teratoma, endodermal sinus tumor, lymphoma, metastatic disease

• Cranial radiation

Pituitary

• Pituitary tumors: prolactinomas, other hormone secreting tumors (adrenocorticotropic hormone [ACTH], thyroid stimulating hormone [TSH], growth hormone [GH], gonadotropin)

• Systemic prolactin-secreting tumors: renal cell carcinoma, ovarian dermoid cyst, teratoma, gonadoblastoma, bronchogenic carcinoma

• Metastatic disease or Langerhans cell histiocytosis

• Sheehan syndrome: pituitary necrosis after postpartum hemorrhage

• Lymphocytic hypophysitis

• Infiltrative disease: sarcoidosis, hemochromatosis

• Empty sella

• Traumatic brain injury or subarachnoid hemorrhage

• Drugs which increase prolactin secretion: oral or injectable contraceptives, classical antipsychotics, some atypical antipsychotics especially risperidone, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, H2 receptor antagonists, verapamil, opiate pain medications, cocaine

Adrenal

• Cushing’s syndrome

• Adult onset adrenal hyperplasia

Thyroid

• Hypothyroid

• Hyperthyroid

Classification by gynecologic and non-gynecologic factors

• Secondary dysmenorrhea can be caused by gynecologic and non-gynecologic factors.

Gynecologic

• Endometriosis

• Adenomyosis

• Leiomyomas

• Ovarian cysts

• Pelvic adhesions

• Pelvic inflammatory disease and other pelvic infections

• Uterine polyps

• Cervical stenosis

• Congenital obstructive Müllerian malformations

Non-gynecologic

• Inflammatory bowel disease

• Irritable bowel syndrome

• Celiac disease

• Abdominal masses

• Appendicitis—areas of inflammation or adhesions from prior infection may be aggravated by pelvic congestion during menses

• Interstitial cystitis

• Urinary tract infection

• Nephrolithiasis

• Ureteropelvic junction obstruction

• Psychogenic

B. Describe a diagnostic approach/method to the patient with this problem

Diagnosis is through history, physical examination, and tests as described in the sections below.

1. Historical information important in the diagnosis of this problem

Amenorrhea

Important basic historical information includes how long the symptoms have been present and if there are associated systemic symptoms including:

• Hot flashes, and vaginal dryness which indicate hypoestrogenism with ovarian failure

• Increase in breast size and/or galactorrhea, which suggest hyperprolactinemia

• Hirsutism, acne, or deepening of the voice to suggest hyperandrogenism as in PCOS

A complete past medical history including surgical, obstetric, and gynecologic procedures, medication list, and review of systems may provide clues to causes of amenorrhea. Social history should focus on sources of stress and, if applicable, eating and exercise habits.

Dysmenorrhea

The hospitalist should clarify:

• When symptoms started (i.e. near menarche or later, once cycles were more established)

• Age at menarche—dysmenorrhea is more likely with early menarche

• Duration of usual menstrual cycle, how much bleeding, and how often

• When during the cycle the pain occurs; typical is within 1–3 days of onset of menses

• If pain only occurs with menses, or if it is present at other times during the cycle (as may be the case with endometriosis)

• If pain impacts usual activities

• Response to non-steroidal anti-inflammatory medications (NSAIDs) or oral contraceptives—no response may suggest secondary cause

• Smoking history—smokers are more likely to have dysmenorrhea

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Amenorrhea

Measure weight and body mass index (BMI): if elevated this may point to PCOS, and if decreased, may point to an eating disorder, malnutrition, or excessive exercise. A gynecologic examination should be done with attention to signs of atrophy from decreased estrogen, lower outflow tract obstruction, and palpable masses. Undertake a focused neurologic examination for visual fields. Other systemic exams may be useful: for example, signs of cortisol excess for Cushing’s syndrome or androgen excess in PCOS.

Primary dysmenorrhea

Examination, including gynecologic exam should be normal.

Secondary dysmenorrhea

Gynecologic exam may show:

• Cervical stenosis—under normal circumstances examiner should be able to pass a probe such as a pap smear brush through the cervix

• Palpable pelvic and abdominal masses

• Signs of endometriosis—uterosacral ligament nodules with lateral displacement of cervix, visible endometriosis lesions in the vagina or cervix

If dysmenorrhea is from other systemic illness, exam should be led by historical cues.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Amenorrhea

To start, check a urine or serum human chorionic gonadotropin (hCG). If this does not indicate pregnancy, the next step is to check prolactin and follicle stimulating hormone (FSH), as well as thyroid stimulating hormone (TSH). If indicated by history and examination, ultrasound can be done to look for masses or other abnormal pelvic anatomy. If adhesions are suspected, ultrasound should be followed by hysterogram or hysteroscopy. If prolactin is elevated and a pituitary tumor is on the differential diagnosis, or if FSH is in the low-to-normal range with no obvious cause (such as an eating disorder), the patient should have magnetic resonance imaging (MRI) focusing on the sella turcica to look for pituitary mass.

Primary dysmenorrhea

There are no specific tests for diagnosis other than a characteristic history and a normal examination.

Secondary dysmenorrhea

The patient should have an ultrasound looking for masses or other abnormal anatomy, and a urinalysis if urologic causes are part of the differential diagnosis. Endometriosis is diagnosed by laparoscopy, though imaging may show suggestive lesions.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Amenorrhea

Elevated prolactin:

• Prolactin greater than 100ng/ml: pituitary adenoma or empty sella syndrome

• Prolactin 20–100ng/ml: pregnancy, lactation, hypothyroidism, medications, renal or hepatic disease, ectopic production

Elevated FSH:

• Premature ovarian failure

• Menopause

Normal or low FSH:

• Weight loss or excessive exercise

• Anorexia

• PCOS

• Hypothyroid

• Cushing’s syndrome

• Pituitary tumor, empty sella syndrome, Sheehan syndrome

• Chronic illness

• Radiation

Primary dysmenorrhea

Because it is a clinical diagnosis based on key historical features and a normal examination, there is no particular lab testing or imaging that should be done routinely.

Secondary dysmenorrhea

For diagnosis it requires history, examination or imaging—ultrasound or MRI—suggesting pathology associated with the pain.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Amenorrhea

Normal estradiol is expected with PCOS. However, levels may fluctuate and are therefore not helpful in distinguishing PCOS from other causes of amenorrhea.

The progesterone challenge test does not effectively distinguish if estrogen is present. Up to 20% of women with normal levels of estrogen and oligomenorrhea or amenorrhea have no withdrawal bleeding with progesterone. This test also has a high false negative rate.

Dysmenorrhea

Primary dysmenorrhea is a clinical diagnosis and there are no specific tests to confirm the diagnosis. Further testing should only be done if secondary dysmenorrhea is suspected.

III. Management while the Diagnostic Process is Proceeding

A. Management of amenorrhea and dysmenorrhea

Amenorrhea

The management of amenorrhea depends on the underlying cause. In most cases treating the underlying illness is the treatment for amenorrhea. In the case of drug-induced amenorrhea, the offending agent should be discontinued if possible. Amenorrhea from excessive exercise or weight loss can be treated by decreasing exercise or gaining weight until menses return. This is important due to the bone loss that may occur if left untreated.

Sheehan syndrome, ischemic pituitary necrosis in the setting of postpartum hemorrhage, usually presents distant in time from the inciting event. But, recognizing this existence of this diagnosis and providing prompt, appropriate supportive care in the postpartum period can prevent the condition.

Primary Dysmenorrhea

NSAIDs other than aspirin are the mainstay of treatment and have been shown to reduce the pain of primary dysmenorrhea. Aspirin and acetaminophen are less effective. Topical heat has also been shown to be effective. Combined oral contraceptives may have some benefit as well, and are often used, though the evidence in support of this is less rigorous. The levonorgestrel-releasing IUD has also been shown to improve dysmenorrhea and may be equal to or better than combined oral contraceptives. There is no specific evidence for or against the use of opiate pain medications.

Secondary dysmenorrhea

Treatment should be directed at the underlying cause in addition to the supportive management of pain as for primary dysmenorrhea.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Amenorrhea is not a common primary presenting symptom in hospital medicine, but is an important historical feature of systemic illness. Diagnosing it may depend primarily on obtaining a good history.

Prolactin and FSH levels can help to narrow the differential diagnosis of secondary amenorrhea. If the prolactin level is mildly elevated, it should be repeated as certain factors including stress, breast stimulation, and exercise may cause slight increases in prolactin.

Significant or changing dysmenorrhea in an adult woman should prompt evaluation for secondary causes.

IV. What's the evidence?

Fourman, LT, Fazeli, PK. “Neuroendocrine causes of amenorrhea- an update”. The Journal of Clinical Endocrinology and Metabolism. vol. 100. 2015. pp. 812-824.

Harel, Z. “Dysmenorrhea in adolescents and young adults: etiology and management”. Journal of Pediatric and Adolescent Gynecology. vol. 19. 2006. pp. 363-371.

Imai, A, Matsunami, K, Takagi, H, Ichigo, S. “Levonorgestrel-releasing intrauterine device used for dysmenorrhea: five-year literature review”. Clinical and Experimental Obstetrics and Gynecology. vol. 41. 2014. pp. 495-8.

Klein, DA, Poth, MA. “Amenorrhea: an approach to diagnosis and management”. American Family Physician. vol. 87. 2013. pp. 781-8.

Torre, DL, Falorni, A. “Pharmacological causes of hyperprolactinemia”. Therapeutics and Clinical Risk Management. vol. 3. 2007. pp. 929-951.

Latthe, PM, Champaneria, R, Khan, KS. “Dysmenorrhoea”. Clinical Evidence. vol. 02. 2011. pp. 813

Lentz, GM, Katz, VL, Lentz, GM, Lobo, RA, Gershenson, DM. “Primary and secondary dysmenorrhea, premenstrual syndrome and premenstrual dysphoric disorder”. Comprehensive Gynecology. 2007. pp. 901-914.

Lobo, RA, Katz, VL, Lentz, GM, Lobo, RA, Gershenson, DM. “Hyperprolactinemia, galactorrhea and pituitary adenomas”. Comprehensive Gynecology. 2007. pp. 963-978.

Lobo, RA, Katz, VL, Lentz, GM, Lobo, RA, Gershenson, DM. “Primary and secondary amenorrhea and precocious puberty”. Comprehensive Gynecology. 2007. pp. 933-961.

Marjoribanks, J, Ayeleke, RO, Farquhar, C, Proctor, M. “Nonsteroidal anti-inflammatory drugs for dysmenorrhea”. Cochrane Database of Systematic Reviews 2015.

Master-Hunter, TM, Heiman, D. “Amenorrhea: evaluation and treatment”. American Family Physician. vol. 73. 2006. pp. 1374-82.

Osayande, AS, Mehulic, S. “Diagnosis and initial management of dysmenorrhea”. American Family Physician. vol. 89. 2014. pp. 341-346.

“Practice Committee of the American Society of Reproductive Medicine: Current evaluation of amenorrhea”. Fertility and Sterility. vol. 90. 2008. pp. S219-225.

Roberts-Wilson, TK, Spencer, JB, Fantz, CR. “Using an algorithmic approach to secondary amenorrhea: avoiding diagnostic error”. Clin Chim Acta. vol. 423. 2013. pp. 56-61.

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