Amenorrhea, Secondary


Article Author:
Megan Lord


Article Editor:
Manjusha Sahni


Editors In Chief:
Amie Kim
Todd May
Matthew Varacallo


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
11/22/2018 1:13:22 PM

Introduction

Secondary amenorrhea occurs when a patient who has passed menarche goes six months or longer without menses. While some sources only require three months without menses to diagnose amenorrhea, the American College of Obstetricians and Gynecologists uses the former definition.[1][2]

Etiology

There are three general causes of secondary amenorrhea: hormonal disturbance leading to a lack of a normal menstrual cycle, physical damage to the endometrium which prevents its growth, or obstruction of the outflow path of the menstrual blood.

Epidemiology

Pregnancy, lactation, and menopause are common, physiologic causes of secondary amenorrhea. Prevalence of secondary amenorrhea due to all other causes is approximately 2% - 5%.[3][4]

Pathophysiology

There are many potential causes of secondary amenorrhea. Hormonal causes include pregnancy, lactation, thyroid dysfunction, hyperprolactinemia, hyperandrogenism (including polycystic ovarian syndrome), hypogonadotropic hypogonadism (hypothalamic-pituitary dysfunction), and suppression of the endometrium by hormonal birth control. Structural causes include damage to the endometrium (Asherman’s syndrome) and obstruction of the outflow tract (cervical stenosis).

History and Physical

History in a patient with secondary amenorrhea should include a full menstrual history. It is important to ascertain what birth control method the patient is using, as the progestin-containing birth control methods (including combined oral contraceptive pills) suppress growth of the endometrium and may lead to secondary amenorrhea. The pattern of menses is also important - does the patient have a long history of infrequent and irregular periods (suggesting anovulation), or was the amenorrhea abrupt? Were there any inciting events before the onset of secondary amenorrhea, such as childbirth, surgery, trauma, pelvic infection, or D and C? Patients should be asked about headaches, vision changes, and galactorrhea to assess for hyperprolactinemia from pituitary prolactinoma. Thyroid symptoms should also be evaluated (fatigue, weight changes, skin/hair/nail changes, palpitations, tachycardia). Hirsutism and acne suggest PCOS, so patients should be asked about unwanted hair growth and acne. Patients should be asked about stressors and exercise routines, as excessive stress or exercise may lead to hypogonadotropic hypogonadism.

Physical examination should include calculation of body mass index (BMI), as well as assessment of acanthosis nigricans, hirsutism, acne, and virilization.

Evaluation

The first step in the evaluation of any patient with secondary amenorrhea is a urine pregnancy test. Every contraceptive method has a failure rate, and anyone who is menstruating is potentially fertile, regardless of age. [5][6]

If the pregnancy test is negative, consider the clinical picture: hirsutism, acne, and a long history of infrequent and irregular menses suggest polycystic ovarian syndrome. By the Rotterdam criteria, a patient may be diagnosed with PCOS if she has two of the following: clinical or chemical hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries on ultrasound. So if a patient has evidence of hirsutism and oligo- or amenorrhea, she can be diagnosed with PCOS without further laboratory testing or imaging.

If history and physical exam are not consistent with PCOS, a TSH should be ordered. Both hyper- and hypothyroidism can lead to menstrual dysfunction.

If TSH is normal, check a serum prolactin. Elevated serum prolactin suggests prolactinoma.

If prolactin is normal, the next step is to perform a progestin challenge. The patient is given oral progesterone (typically medroxyprogesterone, Provera, 10mg PO qDay x10 days). After stopping the progesterone, the patient would be expected to have a withdrawal bleed. If there is no withdrawal bleed, this means that a) there is insufficient endogenous estrogen to stimulate the growth of the endometrium, b) the endometrium has been damaged and is unable to grow, or c) the outflow of menstrual blood has been obstructed.

If a patient who has a withdrawal bleed also has hirsutism, suspect PCOS, ovarian or adrenal tumors, or Cushing syndrome.

If the patient does not experience a withdrawal bleed after progestin challenge, the next step is an estrogen-progestin challenge, in which the patient is given combined estrogen and progesterone (such as combined oral contraceptives). If the endometrium is intact and the outflow is not obstructed, the estrogen from the oral contraceptives would be expected to trigger the growth of the endometrium, and stopping the oral contraceptives should lead to a withdrawal bleed. If a patient has a negative progestin challenge (no withdrawal bleed after progesterone treatment) but a positive estrogen-progestin challenge (bleeding after one month of combined oral contraceptives), suspect hypogonadism and check FSH and estradiol.

If FSH is elevated and estradiol is low, suspect ovarian failure. (The pituitary is yelling at the ovaries to make estrogen, but they are not responding.)

If FSH is low and estradiol is low, suspect hypothalamic-pituitary dysfunction, such as due to stress, exercise, or pituitary infarct (Sheehan’s syndrome).

If the estrogen-progesterone challenge is negative (no bleeding after a month of combined oral contraceptives), suspect damage to the endometrium (Asherman’s syndrome) or outflow obstruction, such as from cervical stenosis. Transvaginal ultrasound may be performed to evaluate for hematometra (trapped menstrual blood in the uterus). Hysteroscopy would be an appropriate next step to evaluate for Asherman’s syndrome. If trapped blood is evacuated during cervical dilation, this suggests cervical stenosis as the cause and is also potentially curative.

Treatment / Management

Treatment depends on the underlying cause of the amenorrhea.[7][8]

  • Polycystic ovarian syndrome is treated with weight loss, metformin for insulin resistance, and cycle control with combined oral contraceptives or endometrial protection with progestin-containing birth control methods (medroxyprogesterone acetate depot injection, etonogestrel subcutaneous implant, or levonorgestrel intrauterine system).
  • Hypothyroidism is treated with thyroxine replacement.
  • Hyperthyroidism is treated with thioamides, ablation, or surgery.
  • Hyperprolactinemia is treated with bromocriptine, cabergoline, or excision of prolactinoma.
  • Ovarian failure may be treated with hormone replacement, depending on the patient’s age, symptoms, and other risk factors.
  • Hypothalamic-pituitary dysfunction may be treated with lifestyle changes or with hormone replacement.
  • Asherman’s syndrome is treated with hysteroscopic lysis of adhesions.
  • Cervical stenosis is treated with cervical dilation.

Pearls and Other Issues

Always remember to order a urine pregnancy test!

Bear in mind that hormonal contraceptives inhibit the hypothalamic-pituitary axis, so patients must be off hormonal contraceptives for at least three months before testing FSH and estradiol. Standard estradiol assays do not detect ethinyl estradiol, the estrogen in birth control.

Remember that it is common and not pathologic for patients on hormonal contraception to be amenorrheic. Amenorrhea on birth control does not require further evaluation unless there are other concerning symptoms.

Enhancing Healthcare Team Outcomes

There are many causes of secondary amenorrhea and thus it is important to have a multidisciplinary team involved in the investigation and management of this disorder. The biggest concern today apart from infertility is the ongoing bone loss that occurs as a result of lack of sex hormones. Healthcare workers including nurse practitioners should educate the patient on the importance of bone health while they are being worked up for the cause of the secondary amenorrhea. Besides increasing calcium in the diet, the patient should participate in regular exercise. The loss of fertility in many women is also associated with significant emotional distress and hence a referral to a mental health counselor is recommended. The outcomes of women with secondary amenorrhea depend on the cause. [5]

 


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Amenorrhea, Secondary - Questions

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What should be the first test for a 30-year-old female presenting with amenorrhea and galactorrhea?



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A mother brings in her 17-year-old daughter for a three-month history of amenorrhea. The patient had normal menses from age 12 until recently. The patient denies sexual activity and refuses a pelvic exam. Which of the following is the least important question?



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Which of the following medications is most likely to cause amenorrhea as a result of hyperprolactinemia?



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A patient of childbearing age presents with amenorrhea. She has had a normal puberty and has normal anatomy. Her thyroid stimulating hormone, prolactin, and follicle stimulating hormone levels are normal, and a pregnancy test is negative. What is the next step in management?



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What is the most common cause of secondary amenorrhea in a 25-year-old female?



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What test will tell if a woman has secondary amenorrhea and is still ovulating?



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What should be done for a woman at 6 weeks from her last menstrual period with spotting and a positive qualitative urine test for beta hCG and a transvaginal ultrasound revealing no pregnancy or gestational sac in the uterus or adnexa?



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Exercise-induced amenorrhea is caused by a problem in which of the following?



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A female dancer with regular menses for several years presents with a 8 week history of amenorrhea without pain. Pelvic exam is normal. Urine hCG is positive. What is the most probable diagnosis?



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During a 15-year-old well visit, a patient that had regular menstrual cycles prior to this encounter tells you that she has not had her period in 3 months. She denies sexual activity. What is the best next step?



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Amenorrhea, Secondary - References

References

Sehemby MAS,Bansal PAK,Sarathi V,Kolhe A,Kothari K,Jadhav S,Lila AR,Bandgar TR,Shah N, Virilising ovarian tumors: a single center experience. Endocrine connections. 2018 Nov 1     [PubMed]
Maciejewska-Jeske M,Szeliga A,Męczekalski B, Consequences of premature ovarian insufficiency on women's sexual health. Przeglad menopauzalny = Menopause review. 2018 Sep     [PubMed]
Martini MG,Solmi F,Krug I,Karwautz A,Wagner G,Fernandez-Aranda F,Treasure J,Micali N, Associations between eating disorder diagnoses, behaviors, and menstrual dysfunction in a clinical sample. Archives of women's mental health. 2016 Jun     [PubMed]
Chandeying P,Pantasri T, Prevalence of conditions causing chronic anovulation and the proposed algorithm for anovulation evaluation. The journal of obstetrics and gynaecology research. 2015 Jul     [PubMed]
Pereira K,Brown AJ, Secondary amenorrhea: Diagnostic approach and treatment considerations. The Nurse practitioner. 2017 Sep 21     [PubMed]
Chaloutsou K,Aggelidis P,Pampanos A,Theochari E,Michala L, Premature Ovarian Insufficiency: An Adolescent Series. Journal of pediatric and adolescent gynecology. 2017 Dec     [PubMed]
Current evaluation of amenorrhea. Fertility and sterility. 2006 Nov     [PubMed]
Rosenfield RL, Puberty and its disorders in girls. Endocrinology and metabolism clinics of North America. 1991 Mar     [PubMed]

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