The cause of premenstrual dysphoric disorder (PMDD) is largely unknown. It has been hypothesized that normal ovarian function triggers PMDD-related biochemical events within the brain and that serotonin plays an important role. In the present study, positron emission tomography (PET) and [carbonyl-11C]WAY-100635 were used to examine serotonin 5-HT1A receptors in a control group of women and in a group of women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). Each subject's menstrual cycle was confirmed by ultrasonography of the ovaries as well as with hormone levels in blood and urine. The 5-HT1A binding potential was measured in six regions of interest and calculated according to the simplified reference tissue model. In the raphe nuclei, the 5-HT1A binding potential changed from the follicular to the luteal phase of the menstrual cycle in asymptomatic controls. In women with PMDD, the observed change between phases was significantly smaller. The results are in concordance with previously reported challenge studies of 5-HT1A receptor-mediated effects indicating different serotonergic responses between women with PMDD and controls. The study principally provides new support, in vivo, for a serotonergic dysregulation in women with PMDD.
Premenstrual dysphoric disorder (PMDD) is a cyclic mood disorder characterized by affective, behavioural and somatic symptoms that appear during the late luteal phase of the menstrual cycle. PMDD is diagnosed in approximately 3% to 8% of women of reproductive age with irritability, tension, dysphoria and mood lability as the most prominent symptoms (American Psychiatric Association, 1994).
The cause of PMDD is largely unknown. Although many hypotheses have been put forward, the current consensus is that normal ovarian function, rather than hormone imbalance, represents a cyclic trigger for PMDD-related biochemical events within the central nervous system (Schmidt et al., 1998). Serotonin has been suggested as an important neurotransmitter in the pathophysiological mechanisms underlying PMDD. Abnormal serotonergic activity is associated with depression and anxiety disorders, with which PMDD seems to share significant features (Halbreich, 1995 and Landen and Eriksson, 2003). In addition, selective serotonin reuptake inhibitors (SSRIs) have been found highly effective in the treatment of PMDD, as compared with other non-SSRI drugs, which have been reported to be less effective (Eriksson et al., 1995, Yonkers et al., 1997 and Dimmock et al., 2000).
Among the subtypes of serotonin receptors characterized today, the 5-HT1A receptors are of specific interest for premenstrual dysphoria. Bancroft et al. (1991) used l-tryptophan in a challenge test of growth hormone (GH), a response that is supposed to be mediated by 5-HT1A receptors. They reported a blunted response in both menstrual phases in women with premenstrual symptoms as compared with controls. Additionally, Yatham (1993) reported a blunted prolactin response to buspirone challenge in the follicular phase of women with premenstrual dysphoria, suggesting 5-HT1A receptor subsensitivity as a possible trait marker for this disorder.
Regional density of 5-HT1A receptors in the living human brain is possible to investigate by using positron emission tomography (PET) and the highly specific radioligand [carbonyl-11C]WAY-100635 ( Farde et al., 1998). Previous PET studies using [carbonyl-11C]WAY-100635 in patients with mood disorders have reported moderate to pronounced reductions of 5-HT1A receptor binding in different brain areas including medial temporal cortex and dorsal raphe nucleus ( Drevets et al., 1999 and Sargent et al., 2000). PET studies of gender-specific effects on 5-HT1A receptors binding have found higher 5-HT1A receptor binding potentials in females than in males, and no age effect on 5-HT1A receptors in women ( Cidis Meltzer et al., 2001 and Parsey et al., 2002). However, there are very few PET studies of the interaction between gonadal hormones and the serotonergic system in the human brain. Moses et al. (2000) used PET and [18F]altanserin to study the effects of estrogen and progesterone treatment in five postmenopausal women. Increased 5-HT2A receptor-binding potentials were found in widespread areas of the cerebral cortex following hormonal administration relative to baseline values. To date, no PET study has been published on the effects of phases of the menstrual cycle on 5-HT1A receptor binding.
Based on the previous literature, we hypothesized that there might be differences in serotonin receptor densities between women with PMDD and asymptomatic controls. The aim of the present study was thus to examine the 5-HT1A receptor-binding density in women with PMDD compared with asymptomatic controls, at two different phases of the menstrual cycle, by using PET and the selective radioligand [carbonyl-11C]WAY-100635.
