Allopregnanolone concentrations and premenstrual syndrome

Abstract

Objective: To evaluate basal allopregnanolone and progesterone in both phases of the menstrual cycle in women suffering from premenstrual syndrome (PMS) and their response to a GnRH test. Design: We selected 56 women (28 patients with PMS and 28 controls) aged between 18 and 32 years. Blood samples were drawn in both follicular and phases. Twenty-eight women (14 patients with PMS and 14 controls) underwent a GnRH test in the luteal phase. Methods: We evaluated allopregnanolone by RIA, using a specific antibody. Serum progesterone and oestradiol were determined using a commercially available RIA kit. Results: Luteal phase allopregnanolone concentrations were significantly lower in patients with PMS than in controls. Progesterone concentrations were significantly lower in patients with PMS in both the follicular and the luteal phase. Serum oestradiol concentrations were in the normal range in both groups of women, although slightly greater in those with PMS. Allopregnanolone and progesterone responses to a GnRH test were significantly blunted in women with PMS. Conclusions: Diminished concentrations of allopregnanolone and progesterone, its precursor, and a blunted response to the GnRH test lead us to hypothesise that patients with PMS may suffer from an inadequate production of ovarian neuroactive steroids, especially in the luteal phase. This would lead to an impaired anxiolytic GABA A -mediated response in stressful physiological and psychological conditions, and may in part explain various psychoneuroendocrine symptoms that arise during PMS.

Neurosteroids in the context of stress: Implications for depressive disorders

“…It is also consistent with the endocrine challenge work of Monteleone et al (2000) and Lombardi et al (2004) in PMDD women. Despite the fact that those investigators reported lower, and not higher, baseline allopregnanolone in PMDD (Table 1), in response to an ACTH stimulation test following dexamethasone suppression, PMDD women had a significantly blunted adrenal allopregnanolone response compared with controls during the luteal phase (see Fig.…”

“…Thus, these data suggest that histories of depression may be associated with persistent, long-term effects on allopregnanolone responsivity to stress and that the greater likelihood of prior depression in PMDD women may have contributed to previous findings for lower allopregnanolone concentrations or blunted allopregnanolone responsivity to challenge in PMDD women (Rapkin et al, 1997;Monteleone et al, 2000;Girdler et al, 2001;Lombardi et al, 2004). Moreover, to the extent that allopregnanolone negatively modulates the HPA axis following stress, then our results are also consistent with HPA axis abnormalities seen in depression, since it is well established that a large proportion of patients with melancholy depression are hypercortisolimic (Nemeroff, 1998) and show exaggerated HPA axis responses to mental stress (Heim et al, 2000;Young and Breslau, 2004).…”

“…Lower allopregnanolone concentrations in PMDD women were also found in 2 subsequent studies. Monteleone et al (2000) found lower plasma allopregnanolone in 28 women seeking help from a PMS clinic compared with non-help seeking controls during the luteal but not in the follicular phase, and Lombardi et al (2004) found that PMS women had lower baseline allopregnanolone levels in the luteal phase only, though higher testosterone, DHEA and a DHEA/allopregnanolone ratio in both cycle phases. In contrast to the studies reviewed above, the first study from our laboratory to assess plasma allopregnanolone concentrations in 25 PMDD women compared with 13 non-PMDD controls found that PMDD women had higher luteal phase plasma allopregnanolone concentrations and a greater allopregnanolone/progesterone ratio than controls.…”

“…Some methodological differences across studies that may, either independently or in combination, influence findings are also summarized in Table 1. One methodological factor involves differences in the diagnostic criteria employed for PMDD since only some of the existing studies relied on DSM criteria (Wang et al, 1996;Rapkin et al, 1997;Girdler et al, 2001), while others did not (Schmidt et al, 1994;Monteleone et al, 2000;Lombardi et al, 2004). Differences across studies in the assessment and inclusion or exclusion of women with current or past psychiatric illness might also impact on findings since histories of depression are more prevalent in PMDD populations (Pearlstein et al, 1990;Cohen et al, 2002), since reduced allopregnanolone concentrations are consistently found in patients with current depression as summarized above, and since our own work suggests that histories of depressive disorders impact on allopregnanolone concentrations, at least during stress (see below).…”

Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder

“…Although estrogen and progesterone have been shown in some studies to enhance and diminish HPA axis activation (Fonseca et al, 2001;Patchev et al, 1994), respectively, ALLO concentrations in plasma and brain increase as a result of stress (Barbaccia et al, 1997(Barbaccia et al, , 2001), perhaps as a compensatory mechanism. Women with PMDD fail to demonstrate the normal increase in ALLO seen in healthy subjects under conditions of stress (Monteleone et al, 2000;Girdler et al, 2001;Droogleever Fortuyn et al, 2004;Lombardi et al, 2004), or during HPA axis activation with ACTH administration (Genazzani et al, 1998;Lombardi et al, 2004). In the context of this study, the acoustic startle procedure can be viewed as mildly stress inducing.…”