Antipsychotics, Hyperprolactinemia, and Risk of Endometrial Cancer


Do prolactin-elevating antipsychotics put women at risk for endometrial cancer?

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Elevated blood prolactin levels are a potential adverse effect of antipsychotic medications. Hyperprolactinemia in women may be associated with an increased risk of endometrial cancer, a hormone-sensitive malignancy.1

The only previous study in this area found that antipsychotics (mostly first-generation agents) were associated with a 5-fold increased risk of endometrial cancer.2 In a recent study, Klil-Drori and colleagues3 explored the association between antipsychotic-induced hyperprolactinemia and endometrial cancer, including comparisons between prolactin-elevating and prolactin-sparing agents.

Study design

The authors extracted data from the United Kingdom Clinical Practice Research Datalink (CPRD), which includes information on more than 13 million general practice patients. Data from the CPRD were linked with the Hospital Episode Statistics (HES) repository, which contains hospital information for over half of the subjects in the CPRD.

The authors studied a cohort of women with a first-ever antipsychotic prescription between 1900 and 2013. Inclusion criteria were age older than 18 and at least 1 year of medical information prior to cohort entry. Women with a history of a prolactinoma, endometrial cancer, or hysterectomy were excluded. Subjects were followed until a diagnosis of endometrial cancer, hysterectomy, death, exit from the CPRD, or the end of the study period (December 31, 2014).

Cases of newly diagnosed endometrial cancer were identified in the CPRD or HES. Up to 20 controls were matched to each case on age, year of cohort entry, HES linkability, and duration of follow-up. Antipsychotics were classified into prolactin-elevating and prolactin-sparing (aripiprazole, asenapine, clozapine, olanzapine, quetiapine, sertindole) agents. Exposure to prolactin-elevating antipsychotics was defined as at least 3 prescriptions with a 12-month period between cohort entry and index date.

The reference group consisted of subjects with a least 1 antipsychotic prescription who did not meet the definition of exposure to prolactin-elevating agents. Data were analyzed using conditional logistic regression models, controlling for potential confounding effects of body mass index, alcohol use, smoking, medical comorbidities and history of cancer, and medications associated with endometrial cancer or prolactin modulation.


The 65,930 women who met study inclusion criteria contributed 366,112 person-years of follow-up. One hundred thirty-nine incident cases of endometrial cancer were matched with 1603 controls. The use of prolactin-elevating antipsychotics was not associated with endometrial cancer risk after adjustment for potential confounders (odds ratio = 1.00; 95% confidence interval, 0.68-1.48). Neither the cumulative duration of antipsychotic use, nor the age at antipsychotic initiation, moderated the associations. These findings were robust to multiple sensitivity analyses.

The authors noted that this was the first population-based study of prolactin-elevating antipsychotics and endometrial cancer risk. Although data on blood prolactin levels were not available, they concluded that their findings suggested that antipsychotic-induced hyperprolactinemia is not an important uterine carcinogen.

The bottom line

The use of prolactin-elevating versus prolactin-sparing antipsychotics was not associated with endometrial cancer risk in this cohort.


Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor and Editorial Board Member for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.


1. Levina VV, Nolen B, Su Y, et al. Biological significance of prolactin in gynecologic cancers. Cancer Res. 2009;69:5226-5233.
2. Yamazawa K, Matsui H, Seki K, Sekiya S. A case-control study of endometrial cancer after antipsychotic exposure in premenopausal women. Oncology. 2003;64:116-123.
3. Klil-Drori AJ, Yin H, Abenhaim HA, et al. Prolactin-elevating antipsychotics and the risk of endometrial cancer. J Clin Psychiatry. 2017;78:714-719.

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