Breast

Prolactin normally stimulates breast tissue growth, differentiation, and lactation. Gynecomastia (breast enlargement) and galactorrhea (lactation) are expected consequences of antipsychotic-induced hyperprolactinemia in both men and women, although the actual risk of breast-related side effects is not well delineated (Schreiber and Segman 1997). Estimates of the frequency of galactorrhea in women treated with typical antipsychotics vary, with reports of up to half of premenopausal women experiencing galactorrhea, but this side effect is rarely reported in men (Ghadirian et al. 1982; Gitlin 1994; Inoue et al. 1980; Windgassen et al. 1966). One of the few studies to date that has systematically inquired about breast changes naturalistically followed 150 women with schizophrenia treated for 75 days with a variety of typical antipsychotics (Windgassen et al. 1996). Nineteen percent (28/150) of the women admitted to galactorrhea. The mean prolactin value for these patients was 55 ng/mL, but 4 patients with galactorrhea had prolactin levels within the normal range. Previous pregnancy, premenopausal status, and neuroleptic dose were significantly associated with likelihood of galactorrhea. A meta-analysis of pivotal clinical trials comparing risperidone with placebo and/or haloperidol found that only 1.5% (7/451) of risperidone-treated and 3.3% (1/30) of haloperidol-treated women spontaneously reported galactorrhea (Kleinberg et al. 1999). No men in this study (n=1,330) spontaneously reported galactorrhea, and 0.5% (4/1032) of risperidone-treated men spontaneously reported gynecomastia. Because this study relied on spontaneous report, it is likely that these numbers greatly underestimate the true incidence of breast changes associated with risperidone and haloperidol.

Prolactin is thought by some to be a "promoter" of breast cancer, stimulating the growth of mammary tumor cells and potentially affecting the rate of progression of breast cancer (Goffin et al. 1999; Llovera et al. 2000). Theoretically, the risk of breast cancer would increase only with long-term high prolactin levels (Hankinson et al. 1999). The relationship of prolactin to breast cancer risk in postmenopausal women has been investigated in several studies, with some finding positive associations (Ingram et al. 1990; Rose and Pruitt 1981) and others finding no relationship (Bernstein et al. 1990; Secreto et al. 1983). The best study conducted to date is a large, well-designed, retrospective-prospective study examining premorbid prolactin levels with later risk of breast cancer conducted as part of the prospective Nurses' Health Study (Hankinson et al. 1999). In this study there was a doubling of breast cancer risk in women with prolactin levels greater than 14 ng/mL compared with those with prolactin levels less than 6.5 ng/mL. It is important to note that the investigators controlled for estrogen use (which could elevate prolactin and thus confound the study results) as well as other factors known to affect breast cancer risk. This magnitude of risk increase is similar to that found for estrogen replacement therapy (Writing Group for the Women's Health Initiative Investigators 2002).

Studies of breast cancer risk associated with drug-related prolactin elevations are at this point inadequate to permit any conclusions to be drawn. Methodological problems include the small number of women in most studies, and the duration of exposure to the prolactin-elevating drug may not be documented or may be of insufficient duration to influence risk. One study found the 5-year incidence of breast cancer in older (>50 years) chronically hospitalized women to be about 3/100, which is about 10-fold higher than the 5-year general population risk (Halbreich et al. 1996); however, most studies of chronic exposure to phenothiazines or haloperi-dol in chronically hospitalized patients do not find elevated risk of breast cancer (Costa et al. 1981; Goode et al. 1981; Mortensen 1987, 1994). The results of studies examining breast cancer risk with use of reserpine (an an-tihypertensive agent with prolactin elevation as a side effect) are mixed as well, with some studies finding elevated risk of breast cancer (Armstrong et al. 1976; Heinonen et al. 1974; Stanford et al. 1986) but others finding no relationship (Aromaa et al. 1976; Curb et al. 1982; Labarthe and O'Fal-lon 1980; Laska et al. 1975; Mack et al. 1975; Shapiro et al. 1984). These studies varied in the duration of exposure to reserpine, further complicating the interpretation of these results, because only long-term exposure to higher prolactin levels is theorized to influence breast cancer risk (Hankin-son et al. 1999).

Thus the impact of antipsychotic-induced increases in prolactin on breast cancer risk is at this point theoretical at best, with no consistent data suggesting increased risk of breast cancer associated with long-term exposure to prolactin-elevating antipsychotics. However, the results from the prospective Nurses' Health Study (Hankinson et al. 1999) indicate that further study is needed.

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