Menopause is defined as the end of a woman's reproductive period, associated with the decreased production of estradiol and progesterone by the ovaries (1). With increased life expectancies worldwide, it is estimated that by 2025, the number of post-menopausal women will reach 1.1 billion (2). The gradual or sudden cessation of ovarian follicular function can manifest in a number of psychological, somatic and urogenital menopause symptoms that have a significant impact on the quality of life of women (3). These severity of climacteric complaints is routinely determined by using the Kupperman Menopause Index (KMI) and the menopause rating scale (MRS) (4,5) that evaluate menopause-related somato-vegetative, psychological and urogenital symptoms (6).

Insomnia is considered one of the most common symptoms of menopause, occurring in over half of climacteric women (7–11). Chronic poor sleep has the most profound negative effect on the quality of life of menopausal women (12–14), and can also lead to the development and exacerbation of cardiovascular and metabolic diseases (15). Therefore, addressing emerging sleep symptoms during menopause may significantly improve the overall health and wellbeing of women.

Systemic estrogen/progestin menopausal hormone therapy (MHT) is one of the most common treatments used to counteract menopausal symptoms, such as hot flashes, night sweats and urogenital atrophy (16). However, in women with a previous history of breast cancer, conventional estrogen/progestin MHT may increase the risk of recurrence. This risk may be reduced by the use of progestogens, and among these, is the synthetic steroid tibolone, whose metabolites have estrogenic, progestogenic and androgenic properties (17). The effect of MHT on sleep quality remains poorly understood. Several randomized clinical trials have demonstrated that estrogen/progestin MHT results in slightly improved sleep quality in menopausal women with vasomotor symptoms (18,19). However, significant heterogeneity in the selection criteria of the trial participants and formulations of MHT make it is difficult to determine whether the same effect could be achieved in general population of menopausal women (19).

Sleep disturbances can be either evaluated by objective methods such as polysomnography, or by using patient-filled questionnaires, such as the self-rated Pittsburgh Sleep Quality Index (PSQI) that assesses sleep quality and disturbances over a time interval (20,21). A systematic review by Devine et al demonstrated that questionnaires filled by the patient are an accurate tool for predicting the quality of sleep, and evaluating the efficacy of different treatments (22).

In this study we use PSQI to assess the effects of estrogen/progestin and progestogen MHT on sleep quality, and further examined the effects of MHT on the overall quality of life of women experiencing menopausal symptoms.

This study comprised of 342 women with an average age (SD) of 50.3 (5.6) years. The baseline demographic and medical characteristics for all the subjects are summarized in Table I. The mean weight of the participants was 56.5 (7.3) kg and the average age at the onset of menses was 14.3 (1.6) years. The majority of women enrolled in this study (95.9%) had no family history of breast disease. In addition, the majority of women did not suffer from or were treated for cervical, endometrial or ovarian cancer prior to exhibiting menopausal symptoms (100, 99.7 and 100%, respectively). The majority of women did not have a confirmed diagnosis of endometriosis and uterine fibroids (99.4 and 95.9% respectively), and had not undergone any type of urogenital surgical interventions (98.8%). The majority of participants also had no previous history of hypertension (93.9%), diabetes (98.8%), lipid metabolism disorders (94.2%), gallbladder disease (94.4%) or thyroid dysfunction (90.6%).

At the start of the study (baseline), the mean PSQI score of the participants was 9.16 (4.84) points, indicative of a poor sleep quality (Table II). At 1 month after the commencement of beginning MHT, the participants reported significantly improved sleep quality as indicated by the reduction in the PSQI global sleep quality score (decrease of 1.53 points; P<0.0001), as compared to the baseline score. The PSQI score further decreased at 2 months after the commencement of MHT (2.21 points, P<0.0001), and continued to remain significantly below baseline scores throughout the 3 years of continuous treatment (P<0.0001). After 3 years of MHT, the participants continued to maintain a mean decrease (SD) of 2.19 (0.21) points (1.3-fold) as compared to the baseline score (Fig. 1).

The mean (SD) KMI score of the participants at the baseline was 18.63 (9.86) (Table III). We observed a 6.37 (1.59) point decrease in the score during the 1st month of MHT (P<0.0001). The KMI scores continued to gradually decline throughout the course of hormone therapy, reaching an average of 9.9 (7.33), with a decrease of 8.73 (1.92) points compared to the baseline score (P<0.0001; Fig. 2).

There was a significant [3.56 (1.05) points (P<0.0001)] decrease in the mean MRS scores of the participants during the 1st month of MHT as compared to baseline (Fig. 3). Subsequent hormone treatment did not result in further significant changes in the MRS scores (Fig. 3), and the average score at 3 years after the commencement of MHT was 4.7 (4.6), as compared to 8.66 (6.17) at baseline, an equivalent of 3.96 (2.01)-point decrease (P<0.0001; Table IV and Fig. 3).

We then evaluated whether different MHT regimens (femoston or tibolone) had a different impact on the changes in the PSQI scores. In the subgroup of participants receiving femoston, the baseline mean PSQI score was 9.14 (4.84) points (Table V). During the 1st and 2nd months of MHT, the PSQI score improved significantly, exhibiting a decrease of 1.62 (1.01) (P=0.04), and 2.26 (0.72) points (P=0.0002) respectively, comparing to baseline (Fig. 4). There was no further significant decrease in the PSQI score, maintaining a stable 2.28 (0.67)-points difference compared to the initial score prior to the commencement of MHT (P<0.005).

In the small subgroup of 14 participants with a previous history of breast cancer, who were receiving tibolone MHT, no significant effect of the hormonal therapy was observed on the PSQI scores (P=0.956; Table VI).

In the present study, we examined the effects of hormone replacement therapy on self-reported menopausal symptoms in general, and the quality of sleep of post-menopausal women in particular. The mechanisms through which estrogen/progestin therapies may improve sleep quality are not yet well known. A previous study using rodents suggested that estrogen consolidates circadian sleep-wake rhythms in female rats (24). Alternatively, the effects of estradiol on sleep/wake cycles may be explained by a reduction in prostaglandin synthesis in the ventrolateral preoptic nucleus of the hypothalamus (25). It is also possible that estrogen therapy may improve sleep quality indirectly, by relieving nocturnal hot flashes (26). In this study, it was found that MHT induced a rapid decrease in the PSQI scores as early as 1 month after the commencement of therapy. Sleep improvement further continued through the 2nd month of MHT, resulting in a >1.3-fold decrease in the PSQI score compared to the baseline assessment. Notably, after the initial improvement of the PSQI scores achieved after 2 months of MHT, there was no further significant improvement in sleep quality, with the PSQI scores maintaining the same decrease of 2.19 points compared to baseline.

In this study, the dynamics of sleep quality improvement observed in participants receiving MHT, coincided with a similar pattern of overall improvement in menopausal symptoms, as indicated by the KMI and MRS scores. It was demonstrated, that similar to the PSQI scores, patients reported the most significant decrease in the severity of menopausal symptoms during the first months of MHT. A major improvement was reported by the 2nd month of therapy. Prolonged treatment did not result in any further alleviation of symptoms, although it rather helped to maintain the KMI and MRS scores that were decreased during the initial months of hormone replacement therapy. While the precise mechanisms through which menopausal transition affect sleep quality remain unclear, previous studies have demonstrated that symptoms, such as nocturnal hot flashes, mood disorders and sleep-disordered breathing are the main contributors to a poor sleep quality (9,27–29). It is possible, therefore, that the immediate partial relief of these symptoms by hormone replacement therapy may have led to a similarly rapid improvement in the sleep quality of the participants.

There is still limited evidence as regards the effects of a conventional estrogen/progestin MHT, such as femoston, on sleep quality. It has been demonstrated that progesterone may have a sedative effect (30), and estrogen is able to increase overall sleep time, and decrease sleep onset latency (31), and awakening after sleep onset (32). In this study, femoston was found to have a marked and rapid effect on self-reported sleep quality, with the PSQI score decreasing 1.32-fold during the first 2 months of the treatment. This decrease was maintained throughout the 3 years of the study period, suggesting that estrogen/progestin MHT results in a stable improvement of sleep quality. Of note, MHT with tibolone did not improve sleep quality in a small group of participants with a previous history of breast disease. Tibolone is a synthetic steroid that has progestogenic, androgenic, and estrogenic effects, shown to improve insomnia via stimulation of the production and release of β-endorphin (33,34). It is possible that the lack of an effect of tibolone on sleep quality in this study is related to an insufficient number of participants receiving this MHT. Better designed, larger clinical studies are thus required to examine the efficiency of tibolone in improving the sleep quality of menopausal women.

In conclusion, this study found that hormone replacement therapy had an immediate and long-lasting positive effect on sleep quality and on the general well-being of women experiencing menopausal symptoms. While a conventional estrogen/progestin MHT with femoston resulted in a marked improvement of sleep quality, tibolone treatment had no effect on the PSQI score. Further clinical studies with larger patient groups are required to compare the effects of both MHT regiments on sleep quality.