Amenorrhea

Continuing Education Activity

Amenorrhea is defined as the absence of menstruation during the reproductive years of a woman's life. Physiological states of amenorrhea are seen, most commonly during pregnancy and lactation (breastfeeding). It can be classified as primary and secondary amenorrhea. The causes of amenorrhea are diverse. This activity outlines the evaluation and management of amenorrhea and highlights the role of the interprofessional team in managing and improving care for patients with this condition. This activity examines when this condition should be considered on a differential diagnosis and how to evaluate it properly.

Objectives:

• Identify various etiologies of both primary and secondary amenorrhea.
• Review treatment options available for both primary and secondary amenorrhea.
• Describe the differential diagnoses of both primary and secondary amenorrhea.
• Explain interprofessional team strategies for improving care coordination and communication to diagnose and care for patients with amenorrhea to improve outcomes.

Introduction

Female menstrual cycle normally comprises a 28 to 30-day cycle, which contains 2 phases, the proliferative phase and the secretory phase. At the end of the cycle, the uterine lining starts shedding off, which is a normal phenomenon of female menstruation.[1][2][3]

The absence of menstruation during the female during the reproductive ages of approximately 12 to 49 years is known as amenorrhea.

There are primary and secondary causes of amenorrhea.

The most common cause of amenorrhea is pregnancy, and it is the first thing that needs to be ruled out when investigating such a patient. In general, if a female does not have menses for 6 months, she has amenorrhea.

Etiology

Primarily amenorrhea is classified into 2 types determined by pathogenesis.[4]Primary amenorrhea is the absence of initiation of menses, and secondary amenorrhea is an absence of menses in a previously normal menstruating female. There are many other types of classification of amenorrhea based on the anatomy of female reproductive organs, but this is the most accepted form of classifying the causes of amenorrhea.

Causes of Primary Amenorrhea

• Pregnancy
• Hypogonadtrophichypogonadism
• Endocrine lesions
• Congenital abnormalities
• Tumors

Causes of Secondary Amenorrhea

• Weight loss
• Chronic ovulation
• Pituitary tumor
• Cushing syndrome
• Ovarian tumors

Epidemiology

Amenorrhea is not life-threatening, but the loss of the menstrual cycle has been associated with a high risk of hip and wrist fractures. In the US, amenorrhea affects about 1% of women. Recent studies indicate that childhood obesity may contribute to the early onset of menarche.

Pathophysiology

The absence of menses in a female of reproductive age is related to the disturbance of normal hormonal, physiological mechanism, or female anatomic abnormalities. The normal physiological mechanism works by balancing hormones and providing feedback between the hypothalamus, pituitary, ovaries, and uterus.

During normal female menstruation cycle, gonadotropin-releasing hormone (GnRH) is released from the hypothalamus, and it works on the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and these 2 hormones from the pituitary act on ovaries and ovaries finally make estrogen and progesterone to work on the uterus to carry out the follicular and secretory phase of the menstrual cycle. Any defect at any level of this normal physiology of females can cause amenorrhea.

On the other hand, deviation from the normal anatomy of the reproductive organs of a female can also cause amenorrhea.

History and Physical

During the history and physical examination, clinicians first need to ask about the age of a patient and at what age the patient started menses at puberty (menarche). This information is important to determine and differentiate between primary and secondary amenorrhea. If the patient was not menstruating at all, then it must be primary amenorrhea. All other cases will be secondary amenorrhea.[5][6]

After chronological age, the most important thing to determine is the psychosocial age of the patient, as well as their intelligence quotient (IQ) to rule out any chromosomal cause of primary amenorrhea. After that, clinicians should inquire about the other aspects of growth like breast bud development because an absence of breast bud by the age of 13 to 14 years indicates estradiol deficiency, and there is a need for further investigation.

To rule out secondary amenorrhea, physicians need to determine the time frame of the absence of menses in the previously normal menstruating female. The most important cause of secondary amenorrhea is pregnancy, so it should be ruled out first. They should then ask about previous surgeries for Asherman syndrome.

History of night sweats, sleep disturbance, and hot flushes for premature ovarian failure, history of chemotherapy, and radiation therapy for neoplasm should be obtained because these can also cause ovarian failure in young females. Polycystic ovary syndrome (PCOS) should be ruled out in accordance with the Rotterdam criteria.

Vision test and sense of smell should be performed for pituitary adenoma and Kallman syndrome. A history of medication is very important because antipsychotics are one of the most common causes of high prolactin levels, which lead to amenorrhea. The use of contraception, cocaine, opioids, antiepileptics can cause the failure of menstruation to occur, dieting, strenuous exercise, history of weight loss, and anorexia nervosa can be determined by proper history taking to ascertain the cause of amenorrhea.

History of neurosarcoidosis, hemochromatosis, and presence of any chronic illness should be detected to determine the exact reason as these diseases greatly affect the hypothalamic-pituitary axis, which plays a vital role in controlling the female menstrual cycle.

Physical examination includes the general physical examination, which can be used to determine causes like malnutrition or hepatomegaly. The examination also should include:

• Measuring height, weight, and fat index of the patient to look for the presence of any chronic illness
• Checking body mass index (BMI) to rule out anorexia nervosa and malnutrition
• Checking for dental erosions 
• Looking for metacarpophalangeal calluses or bruises
• Checking the skin for hirsutism, hair loss, or acne to investigate possible hyperandrogenemia

Acanthosis nigricans (a skin condition) can also provide a clue for PCOS. Examing the breasts, pubic hair, and the clitoral index is also an important part of the physical examination in the female with amenorrhea. Turner syndrome can be ruled out through a normal chest examination. Clinicians should also perform a fundal examination to rule out pregnancy and a vaginal examination to check for hematocolpos in an imperforate hymen.

Evaluation

The evaluation should include:

• Beta hCG to rule out pregnancy because pregnancy is the most common cause of amenorrhea
• Prolactin level to rule out prolactinoma
• Testosterone and DHEAS to rule out hyperandrogenism
• FSH and LH for hypothalamic amenorrhea, BMI (to look for malnutrition, anorexia nervosa, and excessive strenuous exercise)
• Pelvic ultrasound and adrenal CT for androgen-secreting tumors and other anatomical defects like Mayor-Rokitansky-Kauser-Hauser syndrome
• Progesterone challenge test: This test is performed to differentiate between the anovulation, anatomic, and estradiol deficiency as causes of amenorrhea. Progesterone is administrated to the patient in the form of intramuscular injection and after progesterone is withdrawn. If bleeding takes place within 2 to 7 days, the cause must be the anovulation, but if no bleeding takes place after progesterone withdrawal, the causes are other than anovulation or premature ovarian failure. These other causes can include estradiol deficiency or anatomic defects like cervical stenosis and Asherman syndrome.
• Karyotyping is sometimes an important test for Turner and androgen insensitivity syndromes.

Treatment / Management

Treatment mainly depends on the cause of amenorrhea. If the cause of amenorrhea is estrogen deficiency, estrogen can be administered. If amenorrhea is due to malnutrition, a proper diet plan can cure the patient successfully. For anorexia nervosa and stress-induced amenorrhea, cognitive-behavioral therapy and SSRIs can help. Dopamine agonist drugs like cabergoline can treat prolactinoma, and if large, surgery can provide a full cure. The appropriate surgical procedure can treat anatomical causes of amenorrhea. PCOS can be handled by combined oral contraceptives and metformin. SSRI can treat stress-induced hypothalamic amenorrhea.[7][8][9]

There is good evidence that patients with menstrual irregularities are at high risk for bone fractures, and hence osteoporosis prevention should be the next step. Patients should be offered vitamin D and calcium supplements.

Because amenorrhea can also affect self-esteem, a mental health consult is necessary.

Women with stress, eating disorders should undergo behavior modification.

Differential Diagnosis

• Anorexia nervosa
• Depression
• Anxiety disorders
• Ovarian insufficiency
• Pregnancy
• Prolactinoma

Prognosis

Loss of the menstrual cycle is associated with wrist and hip fractures, bone thinning, declining fertility, and premature ovarian failure.

Deterrence and Patient Education

Patients diagnosed with amenorrhea need long-term follow-up because resumptions of menstrual cycles may take months or years.

Pearls and Other Issues

The causes of amenorrhea are diverse, and an interprofessional approach is required. Patients must be followed up for several years to ensure that the menstrual cycle has returned.

Enhancing Healthcare Team Outcomes

Amenorrhea is a common problem at some point in the life of most females. After ruling out pregnancy, however, determining the cause can be a challenge. Asides from the gynecologist, the disorder is best managed by an interprofessional team of healthcare workers that includes an endocrinologist, dietitian, internist, mental health worker, and fertility expert. Besides trying to determine the cause of amenorrhea, other professionals need to managed other secondary features of the problem.

Since osteoporosis is a major risk factor in women with amenorrhea, these patients need to follow up with an endocrinologist, dietitian, and pharmacist. The patients need to be prescribed vitamin D and calcium supplements for months or even years. Since amenorrhea results in infertility, this also leads to depression and anxiety in many females. In these cases, a mental health professional may be needed to provide emotional support. Women who undergo surgery to excise the prolactinoma need neurosurgery follow-up to ensure that no other hormone deficit has occurred due to surgery. Finally, women who have amenorrhea due to exercise need extensive cognitive behavior therapy from a psychologist. In addition, these women need to be seen by a dietitian to ensure that they eat healthily.

The follow-up of women with amenorrhea is often long-term as no treatment works right away; the resumption of menstrual cycles may take months or years, and this can be an agonizing time for most women. The clinician, nurse, and pharmacist must coordinate care, treatment, and education of the family and patient to assure close follow-up. Only with an interprofessional team approach can the quality of life of these women be improved.

Outcomes

The outcomes in women with amenorrhea depend on the cause. Some women with PCOS need lifelong treatment as they are at high risk for adverse cardiac events and metabolic syndrome. Patient education is vital, and the patient should be encouraged to pay attention to factors that affect bone density. In addition, these women need to eat a healthy diet fortified with calcium and participate in regular exercise. [2][10] [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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7.

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8.

Christ JP, Gunning MN, Fauser BCJM. Implications of the 2014 Androgen Excess and Polycystic Ovary Syndrome Society guidelines on polycystic ovarian morphology for polycystic ovary syndrome diagnosis. Reprod Biomed Online. 2017 Oct;35(4):480-483. [PubMed: 28733169]

9.

Chanson P, Raverot G, Castinetti F, Cortet-Rudelli C, Galland F, Salenave S., French Endocrinology Society non-functioning pituitary adenoma work-group. Management of clinically non-functioning pituitary adenoma. Ann Endocrinol (Paris). 2015 Jul;76(3):239-47. [PubMed: 26072284]

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Disclosure: Gul Nawaz declares no relevant financial relationships with ineligible companies.

Disclosure: Alan Rogol declares no relevant financial relationships with ineligible companies.