Positive effects of hormone therapy on sleep: compelling evidence or not?

A ppearing in this issue and based on data from the Radiologic Evaluation and Breast Density Study where women were asked to suspend hormone therapy (HT) before screening mammography, Tom et al showed that after a short-term suspension (2 mo) of ovarian HT, midlife to older women (45-80 y; mean, 60 y) reported a worsening of sleep quality. These data can be construed as further positive evidence that ovarian hormones are favorable at least to perceived sleep quality; however, this is not without question. In women, evidence of how ovarian hormones affect sleep quality mainly comes from studies assessing sleep after HT withdrawal or, more often, with HT administration or is perhaps inferred from studying women for whom varying natural hormone levels are measured or are categorized by menopausal status. As emphasized by Tom et al, studies of HT withdrawal effects on sleep quality are few. In their study, compared with women who continued HT, those who suspended HT reported more nights of sleep disturbances during the past week, as evidenced in a lower overall mean sleep quality index score and in item scores for the number of nights with difficulty falling asleep, waking too early, and sleeping poorly. Tom et al declared that their finding was similar to a Kaiser Permanente (KP) study within which they interpreted that withdrawal resulted in a Bmoderate[ increase in sleep problems. In the cited KP study, Grady et al reported that of 377 women who attempted to stop HT, 280 (74%) were successful. After stopping, a large majority (70%) reported Bno[ or Bmild[ symptoms, and about 30% reported troublesome symptoms. Of those reporting troublesome symptoms, vasomotor symptoms (VMS) such as flushes (88%) and excessive sweating (76%) predominated, and difficulty sleeping (54%), fatigue (39%), depression (38%), and vaginal dryness (38%) were reported to a lesser degree. These observations highlight that upon suspending HT, a subset of women is vulnerable to bothersome symptoms and many are bothered by VMS, which remains a controversial contributor to sleep disruptions. In both the Tom et al and KP studies, women were not blind to condition (HT continuation or not) and indeed motivated themselves to suspend HT, raising a question about expectations and symptom reporting. In a recent article by Joffe et al, midlife women reporting insomnia and VMS, albeit with mild to moderate depressed mood, were subjected to one of three conditions: estradiol, zolpidem, or placebo. All three conditions (including placebo) produced improved symptoms (sleep and VMS) with no detectable differences between the treatments. This implies that a strong Bexpectation of positive gain[ is in play from taking a pill. For withdrawal studies such as the Tom et al study, perhaps in a subset of women, a Breversed placebo effect[ might be contributing to symptom reporting. Tom et al also compared their results to a report by Ockene et al of women suspending HT within the Women’s Health Initiative (WHI). They interpreted from this WHI data analysis that women who suspended taking HT (estrogen plus progesterone; n = 4,085) reported no poorer sleep quality than women who suspended taking placebo (n = 4,320), which failed to corroborate their findings and would have supported the reverse placebo effect mentioned previously. However, my scrutiny of the WHI article revealed that about twice as many women reported sleep difficulties (17.7%) after discontinuing HT than placebo (8.4%; P G 0.01; Table 2). Rather than the opposite, this observation is more in support of the Tom et al findings, even in the face of a lower prevalence of symptom reporting, and provides no support for the reverse placebo idea. In the WHI study, the most prevalent symptoms reported upon discontinuing HT were pain/stiffness (36.8%), feeling tired (21.3%), VMS (21.2%), difficulty sleeping (17.7%), bloating or gas (11.5%), and depressed mood in previous week (10.5%). For women discontinuing placebo, the most prevalent symptoms were pain/stiffness (22.2%) and feeling tired (11.6%); some also reported difficulty sleeping (8.4%). Tom et al speculated that the difference of their findings (a worsening of perceived sleep, also seen in the KP study) from those in the WHI study (no worsening according to their interpretation) could be caused by the proportion of women taking HT for symptom management versus for disease prevention/health promotion. Varying these proportions in a sample would influence the number of women bothered by symptoms at the start of taking HT. Women seeking help for menopause symptoms are assumedly those most affected by symptoms (experience most severely, coherent with being most bothered) and are most likely to have been prescribed HT. Logically, such women would be more likely to have a return of symptoms upon suspension of HT than would the women less affected. Indeed in the KP study, more women who took HT for the relief of symptoms (57% of 377 women), reported troublesome symptoms after HT cessation (37%) compared to those who took it for other reasons (26%) (P G 0.01). How prevalent symptoms are before initiation of HT is often not revealed in studies and is certainly not for sleep per se; this is true for the Tom et al and KP studies. VMS are often specified, and