Menstrual Cycle Irregularity Case File

Menstrual Cycle Irregularity Case File

Eugene C. Toy MD, Donald Briscoe, MD, FA  AFP, Bruce Britton, MD, Joel J. Heidelbaugh, MD, FA  AFP, FACG

Case 50

A 28-year-old nulliparous woman presents for evaluation of irregular menstrual cycles for the past year. They occur on average only once every 2 or 3 months and she has gone as long as 4 months without a cycle. Currently, she states her last cycle occurred 11 weeks ago. Her cycles have been "mostly" regular, usually occurring every 30 days. Her menarche occurred at age 13, and she has never been on hormonal contraception. She does not smoke, does not drink alcohol, and does not exercise. She is sexually active in a monogamous relationship with a male partner who uses condoms for contraception. On review of systems, she reports a 30-lb weight gain in the past 18 months, but denies other constitutional symptoms. On examination, she is noted to be obese, with a body mass index (BMI) of 36, and her other vital signs are within normal limits. She has fine hair growth on her face and a velvety thickening of the skin on her neck. Her general physical examination is unremarkable. A pelvic examination reveals normal external genitalia, no vaginal or cervical discharge, no cervical motion tenderness, and no uterine or adnexal masses.

⯈ What is the most likely diagnosis?

⯈ What is the initial step in evaluation of this condition?

⯈ What therapy can best regulate her menstrual cycle?

ANSWER TO CASE 50

Menstrual Cycle Irregularity

Summary: A 28-year-old woman presents for evaluation of irregular menstrual cycles over the past year. She is obese, has gained 30 lb, and is found to be hirsute. She has acanthosis nigricans, a skin condition characterized by dark, velvety discoloration in body creases whereby the skin becomes thickened. Her pelvic examination is unremarkable.

• Most likely diagnosis: Anovulatory menstrual cycles secondary to polycystic ovary syndrome (PCOS)
• Initial laboratory test: Pregnancy test
• Treatment to regulate cycle: Oral contraceptive pills

ANALYSIS

Objectives

1. Learn the common causes of irregular menstrual cycles.
2. Develop an understanding of a rational workup of menstrual cycle abnormalities.
3. Learn the management of common menstrual cycle disorders.

Considerations

Menstrual cycles are considered normal if they occur at regular intervals of 21 to 35 days in length. During their reproductive years, most women will at some point experience early, late, or missed menstrual cycles, and it will be considered to be normal. When this occurs on a rare occasion and pregnancy is ruled out, watchful waiting is usually indicated, with resumption of normal menstrual cycles almost always occurring.

The differential diagnosis of persistent menstrual cycle irregularities is broad. Pregnancy must be ruled out in a woman with a significant menstrual pattern change. After pregnancy is excluded, numerous neuroendocrine and genitourinary conditions must be considered.

In a normal (highly simplified) menstrual cycle, the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). As the FSH level rises, it causes an ovarian follicle to mature and release estrogen which induces endometrial proliferation. A mid-cycle LH surge causes ovulation, and the follicle is transformed into the corpus luteum that secretes progesterone, which compacts and matures the endometrium. If pregnancy does not occur, the production of progesterone abruptly decreases, resulting in sloughing of the endometrium and a menstrual bleed.

In our case of an obese, hirsute woman with ongoing weight gain and irregular menses, PCOS should be the initial consideration after pregnancy has been excluded. PCOS is defined as a syndrome of insulin resistance and androgen excess and has substantial metabolic impact. It is associated with infertility, hirsutism, acne, obesity, and the metabolic syndrome. PCOS is diagnosed via the Rotterdam criteria, requiring two of the following three manifestations:

• Hyperandrogenism, evidenced by hirsutism or elevated serum androgen levels (eg, testosterone, androstenedione, or dehydroepiandrostenedione [DHEA])
• Oligomenorrhea with cycle length greater than or equal to 35 days
• Multifollicular ovaries on pelvic ultrasound, defined as 12 or more small follicles in an ovary

Anovulation is the menstrual cycle irregularity associated with PCOS. Without ovulation, there is a failure of luteal production of progesterone, resulting in an absence of normal menstruation. Women with PCOS can have induced menstrual bleeding by providing periodic supplemental progesterone or by using combination oral contraceptive pills (estrogen and progesterone). Weight loss is very important in women with PCOS to increase fertility, as a loss of even 2% to 5% of body weight can greatly increase rates of pregnancy. Insulin resistance in PCOS is treated with metformin and thiazolidinediones. Infertility secondary to PCOS is treated with clomiphene citrate, aromatase inhibitors, and gonadotropins.

Approach To:

Menstrual Cycle Irregularity

DEFINITIONS

AMENORRHEA: Absence of menstrual bleeding for 6 or more months when a woman is not pregnant

MENOMETRORRHAGIA: Heavy menstrual flow or prolonged duration of flow occurring at irregular intervals

MENORRHAGIA: Excessive menstrual flow, or prolonged duration of flow (>7 days), occurring at regular intervals

METRORRHAGIA: Bleeding occurring at irregular intervals

CLINICAL APPROACH

A thorough history is the initial component of the evaluation of menstrual irregularities. The history of presenting complaint should examine both the specific abnormality that is occurring and when it was first noted. Encouraging the woman with menstrual irregularities to use a menstrual calendar can be very valuable in this setting. Associated symptoms including weight gain or loss, galactorrhea, and heat or cold intolerance, should be documented. A complete past medical history should be obtained, including a complete reproductive health history detailing age at menarche, history of any previous menstrual cycle abnormalities, medications (especially anticoagulants, phenytoin, antipsychotics, tricyclic antidepressants [TCAs] , and corticosteroids), contraception, infections, surgeries, and sexual practices along with pregnancies and their outcomes is required. A social history focusing on psychosocial stressors, substance use, exercise, eating habits, and sexual activity should be documented.

The general physical examination should attempt to identify medical conditions that can cause menstrual abnormalities. Extremes of body mass index-both obese and underweight conditions-can directly affect menstruation. Hirsutism and/ or acne should prompt the clinician to consider a workup for androgen excess. The thyroid gland should be examined for size, consistency, and the presence of nodules. Skin and hair changes may also occur with thyroid and other endocrine conditions. Breasts should be examined for galactorrhea. Unexplained bruising or easy bleeding may occur with concomitant coagulopathies.

The pelvic examination is a critical component in the evaluation of the woman with menstrual irregularities. Initial efforts should be made to determine whether the blood is coming from the uterus or another anatomic site, as urethral, rectal, vaginal wall, or cervical bleeding can easily be mistaken for menstrual abnormality. Signs of pelvic infection should be noted and cultures collected, as cervicitis may predispose to cervical bleeding. A Papanicolaou (Pap) smear should be performed according to current cervical cancer screening guidelines. A bimanual examination should note the size and consistency of the uterus and the presence of any uterine or adnexal masses or tenderness. In women who have never been sexually active, the pelvic examination should be conducted carefully. Unless the bleeding is severe, in which case examination under anesthesia may be warranted, the examination may be deferred until after a trial of medical therapy. A pelvic ultrasound may also be considered to evaluate for potential anatomic abnormalities including uterine fibroids or masses, adnexal masses, or tumors.

Abnormal Bleeding Associated With Regular Menstrual Cycles

Menorrhagia with regular intervals between bleeding is suggestive that regular ovulation is occurring. This implies that the endocrine pathways are functioning normally and that the problem may be anatomic within the genital or hematologic system. Leiomyomata (uterine fibroids), especially those that are submucosal in the uterus, are a common cause of heavy uterine bleeding. They create an increased endometrial surface area with a resultant increase in menstrual bleeding. Endometrial polyps may cause menorrhagia by a similar mechanism. Coagulopathy that is inherited (most commonly von Willebrand disease) or due to medications ( eg, warfarin) is also a common cause of abnormal menstrual bleeding. Liver disease, thrombocytopenia, and hematologic disorders predisposing to bleeding may also contribute.

Reduced volume of menstrual bleeding associated with regular ovulation is a less common occurrence. Asherman syndrome occurs with scarring within the uterine cavity caused by trauma from uterine curettage. It can result in the reduction in the size of the uterus as the walls become scarred and adherent to each other. This may result in minimal or even absent menstruation in the setting of normal hormonal function. A scarred and obstructed cervical os can cause a similar clinical picture.

Abnormal Bleeding Associated With Irregular Menstrual Cycles

Bleeding that is unpredictable in terms of timing and flow is known as dysfunctional uterine bleeding (DUB) and generally implies an abnormality within the hypothalamic-pituitary-ovarian axis. This pattern commonly occurs shortly after menarche and as a woman approaches menopause. At other times, it signals anovulation. In this setting, the endometrium is continuously stimulated by estrogen and sloughs off irregularly. Chronic anovulation should be evaluated with serum prolactin and LH levels.

Continuous estrogen stimulation can also lead to endometrial hyperplasia and endometrial carcinoma. Risk factors for endometrial carcinoma include a history of anovulatory menstrual cycles, obesity, nulliparity, age older than 35, the use of tamoxifen, or of unopposed exogenous estrogen.

The evaluation of a woman with DUB is dependent on age and risk factors. In the period after menarche, watchful waiting is usually indicated, with correction of the problem usually occurring within 1 to 2 years. In women younger than 35 years who are not at increased risk of endometrial cancer, treatment including hormonal cycling may be offered without workup beyond the history and physical examination.

Further evaluation is indicated for women with risk factors for endometrial cancer, women younger than age 35 with continued symptoms despite treatment, and postmenopausal women with uterine bleeding. The standard workup includes a pelvic ultrasound and an endometrial biopsy. Transvaginal pelvic ultrasound provides information on uterine size and the presence of masses, and can assess the thickness of the endometrium, which correlates with the risk of hyperplasia. An endometrial biopsy can be performed quickly and easily in the office setting, using a thin, disposable, sampling device. The combination of sonographic measurement of endometrial thickness and endometrial biopsy is highly sensitive and specific for the diagnosis of endometrial cancer. Hysteroscopy (endoscopic evaluation of the uterine cavity) can directly visualize endometrial masses, polyps, or other abnormalities, and allows for directed biopsy. It is often performed with dilation and curettage (D&C), which sharply removes almost the entire endometrial lining for diagnostic and therapeutic purposes.

When the workup does not reveal malignancy, anovulatory bleeding is usually responsive to treatment with either combined estrogen and progestin oral contraceptives (OCPs) or progestin alone. A progestin can be given for 7 to 10 days with a subsequent withdrawal bleed expected to occur within a week following the completion of the course. Both of these regimens have been shown to reduce the risk of developing endometrial hyperplasia and carcinoma. When medical treatments fail, or when symptoms are severe, surgical options may be required. Hysterectomy provides definitive treatment and is necessary in the case of a malignancy. Endometrial ablative procedures are also available and widely used.

CASE CORRELATION

• See also Case 11 (Health Maintenance in Adult Female) and Case 29 (Health Maintenance, Adolescent).

COMPREHENSION QUESTIONS

50.1 A 42-year-old obese G2P2 woman presents for evaluation of irregular menstrual bleeding for a year. She has had painless vaginal bleeding in various amounts at various times of the month. She has a history of smoking a half a pack of cigarettes per day for 10 years. She has two children, is on no medications, and has no significant medical history. She took an oral contraceptive agent for 5 years during her teen years. Her examination reveals her uterus to be slightly enlarged, but without masses or tenderness. The remainder of her examination is unremarkable. A pregnancy test is negative. Which of the following is the most significant risk factor for her having endometrial cancer?

A. Smoking

B. Parity

C. Body habitus

D. History of oral contraceptive use

50.2 A 35-year-old woman has had irregular menstrual cycles since high school. She frequently misses cycles and has never been pregnant. When she has cycles, they are very light and last for only a few days. She has had mild-tomoderate comedonal and pustular acne since late adolescence and in recent years has developed some hair growing under her chin. She denies taking any medications or history of other gynecologic or medical problems. Which of the following is the most appropriate evaluation for the initial workup of her problem?

A. Serum TSH

B. Serum karyotype

C. Serum estradiol

D. Urine cortisol

E. Serum FSH

50.3 A 28-year-old woman complains of irregular spotting between cycles for the past 2 months. She has been previously healthy and has never been pregnant. She has been sexually active for the past 6 months with the same male partner. On examination, her only positive findings are a mildly enlarged and moderately tender uterus. Her pregnancy test is negative. Which of the following is the most probable diagnosis?

A. Uterine leiomyoma

B. Cervical carcinoma

C. Endometritis

D. Endometrial cancer

E. Urinary tract infection

ANSWERS

50.1 C. This patient's obesity is the most significant risk factor for endometrial cancer, due to chronically elevated unopposed estrogen levels stored in adipose tissue. Parity is protective for endometrial cancer. Risk factors for endometrial cancer include anovulatory menstrual cycles, obesity, nulliparity, age greater than 35, and use of tamoxifen or unopposed exogenous estrogen. Interestingly, smoking is a negative risk factor for endometrial cancer.

50.2 A. Estrogen does not have a role in the initial workup for anovulation; serum karyotype is useful for premature ovarian failure but not for anovulation. Urine cortisol may help in the diagnosis of Cushing disease, but not generally indicated unless the patient has other stigmata of corticosteroid excess such as abdominal striae, easy brusability, and buffalo hump. TSH is indicated in DUB workup. Both total serum testosterone levels and prolactin are useful. Thus, in general, a pregnancy test, TSH, and prolactin level are the initial tests for the evaluation of menstrual irregularities.

50.3 C. Endometritis is a common cause of vaginal spotting. It is generally a polymicrobial infection caused by an ascending infection of normal vaginal flora. Commonly isolated organisms include gonorrhea, Chlamydia trachomatis, Ureaplasma urealyticum, Peptostreptococcus, Gardnerella vaginalis, and the group B Streptococcus species. The patient's history makes cervical cancer less likely. Leiomyoma or polyps are possible, but less likely with her history of recent spotting and sexual activity. Endometrial cancer would also be unlikely in a patient with previously regular menses. While a urinary tract infection may cause hematuria in cases of severe cystitis, it would not cause uterine enlargement or tenderness. The diagnosis of endometritis can be confirmed with an endometrial biopsy showing inflammatory cells, in particular plasma cells.

CLINICAL PEARLS

⯈ The first test performed on a woman with menstrual cycle irregularities should be a pregnancy test.

⯈ A history of anovulatory cycles does not confer absolute protection against pregnancy. Ovulation may occur intermittently and irregularly. If the woman does not want to become pregnant, she should be counseled on contraceptive options.

⯈ Women with PCOS should be treated and monitored appropriately, due to an elevated risk of concomitant factors with cardiometabolic syndrome.

REFERENCES

Ely JW, Kennedy CM, Clark EC, Bowdler NC. Abnormal uterine bleeding: a management algorithm. ] Am Board Fam Med. 2006;19:590-602. 

Hall JE. Disorders of the female reproductive system. In: Kasper D, Fauci A, Hauser S, et al., eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY : McGraw-Hill Education; 2015. Available at: http://accessmedicine.mhmedical.com. Accessed May 25, 2015. 

Hickey M, Higham JM, Fraser I. Progestogens with or without estrogen for irregular uterine bleeding associated with anovulation. Cochrane Database Sys Rev. Sept 12, 2012;9:CD001895. 

Norman RJ, Dewailly, D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007; 370:685-697. 

Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014:89(5):341-346. 

Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician. 2009; 79(8):671-676. 

Sweet MG, Schmidt-Dalton TA, Weiss PM. Evaluation and management of abnormal uterine bleeding in premenopausal women. Am Fam Physician. 2012; 85(1):35-43. 

Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive, and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010; 8:41. 

Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill as treatment for primary dysmenorrhea. Cochrane Database Syst Rev. Apr 15 2009;CD002120.

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