Primary Care Update
Secondary amenorrhea: Don’t dismiss it as ‘normal’
Laboratory tests rule out pregnancy, medical causes
A young or middle-aged patient who stops menstruating may be pregnant or have an underlying medical problem that, left undiagnosed, could cause obesity, sexual dysfunction, infertility, osteoporosis, endometrial hyperplasia, or endometrial cancer.
Yet clinicians too often dismiss secondary amenorrhea as a “normal” result of a mental disorder or psychotropic. Psychiatrists need to:
- identify when a psychiatric disorder or drug disrupts menses
- diagnose medical causes, including thyroid dysfunction, pituitary adenomas, and polycystic ovary syndrome (PCOS).
This article outlines the most common and serious causes of secondary amenorrhea among psychiatric patients, and offers an algorithm for ruling out medical problems in nonpregnant women of child-bearing age who have stopped menstruating for 3 months. The diagnostic approach described here does not apply to women with primary amenorrhea (have never menstruated).
Psychotropics that may cause amenorrhea
Antipsychotics (chlorpromazine, haloperidol, risperidone)
Sex hormone-binding globulin elevation
Association with PCOS unknown mechanism
SSRIs: Selective serotonin reuptake inhibitors
PCOS: Polycystic ovary syndrome
CASE REPORT: NO PREGNANCY, NO PERIOD
Two years ago Ms. J, age 28, was diagnosed with depression. Her psychiatrist prescribed fluoxetine, 20 mg/d titrated across 4 weeks to 40 mg/d. About 4 months later, she experienced her first manic episode. The psychiatrist changed the diagnosis to bipolar I disorder and added risperidone, 2 mg/d, to manage her mania.
Ms. J’s bipolar disorder has been under control for 1 year, but she reports that her menstruation stopped 6 months ago. She is sexually active; she and her partner use spermicide-coated condoms. She does not want to be pregnant now but might want to bear a child within the next year. Several home pregnancy tests across 6 months were negative.
The patient is obese (5 feet, 5 inches, 186 lbs, body mass index 31) and has gained about 30 pounds during the past year. Vital signs are normal; psychiatric examination indicates normal mood and affect. Skin exam reveals mild papular acne on her face and back and increased hair growth on her chin. Other physical findings—including cardiac, lung, and neurologic examinations—are normal.
Laboratory evaluation reveals a prolactin level of 105 ng/mL, a negative serum ß-Hcg reading, and normal TSH, FSH, DHEA-S and testosterone levels.
Discussion. Ms. J’s history, physical examination, and laboratory tests suggest several possible causes of secondary amenorrhea:
- Are psychotropics or a prolactin-secreting tumor elevating her prolactin level?
- Does she have PCOS, as her weight gain, hirsutism, and acne might indicate?
- Is her bipolar disorder a factor? Consider psychiatric illness, medication side effects, and medical causes when evaluating secondary amenorrhea.
Patients with high emotional stress may have amenorrhea or menstrual irregularities related to hypothalamic dysfunction. 1 Also:
Anorexia nervosa has been shown to cause hypothalamic dysfunction, leading to amenorrhea. 2 A correlation exists between weight loss and menses cessation, and between regain of weight and menses resumption. 2
Depression. Estradiol levels are lower in depressed women than in euthymic women, probably because of altered hypothalamic-pituitary axis (HPA) function. Also, physical distress is correlated with menses disruption. 3
In a 3-year study of women ages 36 to 45, 4 those with a history of depression exhibited 1.2 times the rate of perimenopause as nondepressed women. Subjects with Hamilton Rating Scale for Depression scores >8 at enrollment had twice the rate of perimenopause after 3 years compared with nondepressed women. The findings suggest that depression might increase a woman’s risk of ceasing ovarian function in her 30s or 40s. Natural menopause on average begins at age 51. 5
In another study, 6 16 of 32 women with PCOS had Center for Epidemiological Studies-Depression Rating Scale scores indicating depression (≥16). The study suggests a high prevalence of depression among women with PCOS, but was limited by possible selection bias, no further diagnostic evaluation for depression, small sample size, and lack of an age-matched control group.
Bipolar disorder. High rates of menstrual disturbances have been reported among women with bipolar disorder. 7 Although the mechanism has not been ascertained, disruption of HPA function similar to that seen in depression is likely. 7
MEDICATIONS AND AMENORRHEA
Medications can cause amenorrhea, primarily through hyperprolactinemia—although other mechanisms may be involved (Table 1). Prolactin suppresses hypothalamic luteinizing hormone-releasing hormone (LHRH) production, leading to decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thus reducing circulating estrogen. Prolactin-secreting pituitary tumors and drug side effects mostly commonly cause hyperprolactinemia.
Antipsychotics. Phenothiazines such as chlorpromazine, butyrophenones such as haloperidol, and the atypical antipsychotic risperidone raise prolactin levels via dopamine-receptor antagonism.
Other atypical antipsychotics—including aripiprazole, clozapine, olanzapine, quetiapine, and ziprasidone—are associated with lower serum prolactin levels than risperidone. 8,9 Preliminary studies suggest, for example, that switching patients from risperidone to quetiapine may help resume menstruation without worsening psychotic symptoms, 10 and that amenorrhea often resolves after the patient is switched to another atypical antipsychotic. 11
SSRIs. All selective serotonin reuptake inhibitors except sertraline are associated with hyperprolactinemia and can lead to amenorrhea in some patients. 12
Differential diagnosis of secondary amenorrhea
* Turner’s syndrome: A rare chromosomal disorder characterized by short stature, lack of sexual development at puberty.
† Asherman’s syndrome: Endometrial adhesions, scar tissue that develop after uterine curettage or infections.
Anticonvulsants used as mood stabilizers to treat bipolar disorder may cause menstrual irregularities, although most data relate to women with seizure disorders.
Valproic acid has been associated with PCOS in patients with epilepsy, 13 although it is unknown whether the agent’s androgenizing effects vary with age. Carbamazepine, which increases sex hormone-binding globulin, may also lead to menstrual disorders by decreasing bioavailability of circulating estrogen. 14 Consider switching a patient with disrupted menses to lithium, lamotrigine, or oxcarbazepine, which have not been associated with menstrual dysfunction.
Pregnancy is the most common cause of menses cessation, followed by ovarian, hypothalamic, pituitary, or uterine dysfunction (Table 2). Hypothalamic and pituitary dysfunction often cause amenorrhea in psychiatric patients, whereas ovarian causes are common among all patients with secondary amenorrhea. 15
Ovarian. In PCOS, the ovaries and sometimes the adrenal glands produce excess androgens, leading to infrequent or light periods (oligomenorrhea) or amenorrhea.
Patients with depression are prone to ovarian failure in their 30s or 40s, possibly because of chronic HPA disruption. 4 Premature ovarian failure also is common among patients with Turner’s syndrome, a rare chromosomal disorder characterized by short stature and lack of sexual development at puberty. Ovarian failure also can occur spontaneously.
Hypothalamic. Functional hypothalamic amenorrhea occurs in mood and eating disorders. Emotional stress, excessive physical exercise, and nutritional deficiencies reduce LHRH secretion by the hypothalamus, which interrupts the reproductive cycle. Cardiovascular disease, respiratory disease, cancer, and other acute and chronic medical illnesses can cause significant physiologic stress, thus leading to HPA dysfunction. Hypothalamic amenorrhea is treated by targeting the underlying psychiatric or medical condition.
Pituitary. Prolactin-secreting pituitary tumors, such as a pituitary adenoma, must be ruled out in patients whose prolactin levels remain high after a medication change. 15 Hypothyroidism also can trigger hyperprolactinemia by causing pituitary gland hyperplasia.
Uterine. Women who have had uterine curettage or infections can develop adhesions and scar tissue that ablate the endometrial lining. This condition, called Asherman’s syndrome, is the most common uterine cause of menstrual disruption.
EVALUATING SECONDARY AMENORRHEA
When a patient presents with secondary amenorrhea, immediately rule out pregnancy because psychiatric disorders often are managed differently in pregnant than in nonpregnant women. 16
Next, take a thorough patient history to determine whether referral is necessary. Ask about weight loss (intentional or unintentional), increased stressors, or a medical illness that may point to functional hypothalamic amenorrhea. Galactorrhea or vision changes—particularly loss of peripheral vision—could suggest a pituitary tumor. Skin changes, cold intolerance, fatigue, or constipation could indicate hypothyroidism.
Menopausal symptoms such as hot flashes and vaginal dryness could point to premature ovarian failure. Galactorrhea may indicate high prolactin levels. Obesity, hirsutism, or acne could point to PCOS. Consider Asherman’s syndrome in patients with endometritis or who have had a uterine dilation and curettage.
Laboratory testing. Once pregnancy is ruled out, measure prolactin. If it exceeds 25 ng/mL by 15 ng/mL or more, do a confirmative second prolactin test. If a patient is taking a prolactin-raising medication and her prolactin was not gauged before treatment, change to a prolactin-sparing agent, then measure her prolactin 2 weeks later. 17
When to refer. If prolactin persistently exceeds 50 ng/mL even after changing medications, refer the patient for brain MRI to rule out a pituitary tumor.
Tests for other underlying medical causes of secondary amenorrhea—and when to perform them—are shown in the algorithm. Psychiatrists can give these tests or refer the patient to her primary care physician.
Algorithm Laboratory evaluation of secondary amenorrhea
Communication between care team members is key to determining treatment. If a medical problem arises during psychiatric treatment, call the patient’s primary care physician or send a letter describing the problem. Also send the referring physician available lab reports.
CASE CONTINUED: TREATMENT CHANGE
Ms. J’s psychiatrist tapered risperidone to 1 mg/d for 2 weeks, then switched to olanzapine, 5 mg/d. Three weeks later, her prolactin decreased to 25 ng/mL. She continued fluoxetine, 40 mg/d, and tolerated the change in antipsychotics.
Ms. J’s bipolar disorder remains well-controlled, but menses had not resumed for another 2 months, so the psychiatrist referred Ms. J back to her primary care physician. Androgenizing and pituitary tumors were ruled out based on normal TSH, prolactin, and testosterone levels. Ms. J was diagnosed as having PCOS based on her constellation of signs and symptoms. She was started on metformin, an insulin sensitizer used to treat PCOS, and was referred to a dietitian to help her lose weight.
One year later, Ms. J still struggles with weight control, but menstruation is back to normal.
- Lean M, De Smedt G. Schizophrenia and osteoporosis. Int Clin Psychopharmacol 2004;19:31-5.
- Berga SL, Marcus MD, Loucks TL, et al. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril 2003;80:976-81.
- Carr BR, Bradshaw KD. Disturbances of menstruation and other common gynecologic complaints in women. In: Braunwald E, Hauser SL, Fauci AS, et al (eds). Harrison’s principles of internal medicine(15th ed). New York: McGraw-Hill, 2001:Chapter 52.
Drug brand names
- Aripiprazole • Abilify
- Carbamazepine • Tegretol
- Chlorpromazine • Thorazine
- Clozapine • Clozaril
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Haloperidol • Haldol
- Lamotrigine • Lamictal
- Lithium • Eskalith, others
- Metformin • Glucovance, others
- Olanzapine • Zyprexa
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Sertraline • Zoloft
- Valproic acid • Depakene
- Ziprasidone • Geodon
The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
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