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).
Table 1
Psychotropics that may cause amenorrhea
| Effect | Drug/class |
|---|---|
| Prolactin elevation | Antipsychotics (chlorpromazine, haloperidol, risperidone) SSRIs (citalopram, escitalopram, fluoxetine) |
| Sex hormone-binding globulin elevation | Carbamazepine |
| Association with PCOS unknown mechanism | Valproic acid |
| 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.
PSYCHIATRIC ILLNESS
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