02-03/2022, Review , 074-083

Position paper, 070-073 | DOI: 10.53260/grem.22302031

ISGE Statement on Purified and Specific Cytoplasmic Pollen Extract, PureCyTonin® as a non-hormonal alternative for the treatment of menopausal symptoms

Andrea Riccardo Genazzani, Leila Adamyan, Sarah Berga, Martin Birkhaeuser, Mark Brincat, Antonio Cano, Cuauhtemoc Celis, Peter Chedraui, Nilson Roberto De Melo, Blazej Meczekalski, Alfred O. Mueck, Frederick Naftolin, Rossella E. Nappi, Nicola Pluchino, Xiangyan Ruan, Tommaso Simoncini, Nestor Siseles, John Stevenson, Charles Sultan, Basil C. Tarlatzis, Svetlana Vujović, Andrzej Milewicz

Therapeutic approaches for vasomotor symptoms and sleep disorders in menopausal women

DOI: doi.org/10.53260/grem.22302032 | Citation

Santiago Palacios, Skouby Sven, Luis Beltrán, Tommaso Simoncini, Cuauhtémoc Celis-Gonzales, Martin Birkhaeuser, Nestor Siseles, Andrea Riccardo Genazzani

  • Santiago Palacios CONTACT Instituto Palacios de Salud y Medicina de la Mujer, Madrid, Spain
  • Skouby Sven Department of Gynecology and Obstetrics, Herlev University Hospital, Copenhagen, Denmark
  • Luis Beltrán Applied Biology Program, Nueva Granada Military University, Cajica (Cundinamarca), Colombia
  • Tommaso Simoncini Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • Cuauhtémoc Celis-Gonzales Federación Mexicana de Colegios de Ginecología y Obstetricia (FEMECOG), México, México
  • Martin Birkhaeuser Department Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine, University of Bern, Bern, Switzerland
  • Nestor Siseles Consultant Professor, Department of Gynecology, University of Buenos Aires, Buenos Aires, Argentina
  • Andrea Riccardo Genazzani Department of Obstetrics and Gynecology, University of Pisa, Pisa, Italy

Abstract

Introduction:

Vasomotor symptoms and their concomitant sleep disorders affect quality of life and well-being of menopausal women. Menopausal hormone therapy is the first prescribed option for treating vasomotor symptoms such as hot flushes and insomnia. However, menopausal hormone therapy is contraindicated for women with current or prior history
of breast cancer. Therefore, in women with contradictions or those that refuse hormonal/pharmacological options it is necessary to consider non-pharmacological/non-hormonal treatments.

Aim:

The aim of this review is to provide an update on the non-pharmacological/non-hormonal interventions for treating vasomotor symptoms and sleep disorders during menopause.

Methods:

We reviewed the literature regarding vasomotor symptoms and several sleep disorder interventions reported in PubMed, Google Scholar, and Web of Science. Particularly, this scientific update was focused on non-hormonal -pharmacological and non-pharmacological treatments. We considered studies showing possible and potential side effects from these interventions for peri- and postmenopausal women regarding their prior health conditions, current lifestyles and their ethnicities.

Results:

There are non-pharmacological treatments without side effects that alleviate simultaneously hot flushes and insomnia. These represent reasonable and efficacious interventions especially in the presence of contraindications to menopausal hormone therapy or when women are particularly motivated towards natural approaches.

Conclusions:

It is necessary to continue evaluating non-pharmacological alternatives in order to avoid potential side effects and toxicity of pharmacological treatments. These alternatives could present long-term patients’ compliance in simultaneous treatments for hot flushes and chronic sleep disorders such as insomnia.

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Full Article

Introduction

Aging, socio and economic factors, health status (e.g. -- cardiovascular diseases), vasomotor symptoms (VMS), hormonal variation, and psychiatric illness (depression and anxiety), have been identified as potential causes of sleep disorders during the menopausal transition (perimenopause), menopause and postmenopause [1-8]. VMS such as hot flushes (HF)/sweating affect 80% of women during the peri- and postmenopause [9]. HF are characterized as a loss of heat as consequence of estrogen driven changes in neurotransmitters, causing thermoregulatory instabilities at the hypothalamus [10-12]. There is also peripheral vasodilatation, that leads to increases in sweating and chills, that could be accompanied by anxiety [13]. There is evidence showing how HF are concerning up to 80% of women attending health care providers, indicating that 30% of women exhibited moderate and severe HF lasting from 1 to 2 years up to 10 years [14]. These studies also report that the severity and frequency of HF are higher in women with prior poor psychological (e.g., stress), and health status (e.g., obesity and cardiovascular diseases). Furthermore, the severity of HF is also dependent on dietary and other habits (e.g., smoking), that could concomitantly cause sleep disorders during the menopause transition and postmenopause [15,16].

Sleep disorders like insomnia, obstructive sleep apnea (OSA), and restless legs syndrome (RLS, also known as Willis-Ekbom Disease), could increase among perimenopausal and postmenopausal women [17-20]. All of these disorders lead to occupational, cognitive, psychological, behavioral, and physical distress in women, affecting both their wellbeing and quality of life [21-25]. Furthermore, these sleep disorders can cause work accidents, absenteeism, and low performance [26,27]. Additional symptoms affecting women’s quality of life associated with sleep disorders include muscle pain, headaches, sexual and genitourinary malfunction [14,28-30]. Several lines of evidence point out a need of having reliable treatments that simultaneously ameliorate VMS and sleep disorders in women transitioning to menopause and experiencing the postmenopause [31]. Menopausal Hormone Therapy (MHT) is a general treatment for all symptoms related to the menopause. However, for women with estrogen dependent diseases and thromboembolic events, MHT is contraindicated, suggesting the need of both developing and implementing alternative treatments. These additional options are also needed for those women who do not want to take hormones during their different menopausal stages. Therefore, this review reports scientific evidence regarding the use of alternative options to MHT that ameliorate sleep disorders caused by hormonal variation. Particularly this review is focused on the possible association between VMS and sleep disorders to identify and propose non-hormonal/non-pharmacological alternatives for simultaneously treating these symptoms in peri- and postmenopausal women who have contraindication for MHT use or those who don’t wish to take hormones.

Epidemiology, prevalence, and incidence of sleep disorders during menopause

The Study of Women's Health Across the Nation (SWAN) reports sleep disorders in 37% of premenopausal women, 47% of perimenopausal, and from 35% to 60% of postmenopausal women [13].  Similar results have been reported in another longitudinal study performed in Canada, which shows how pre and perimenopausal women have better self-reporting sleep quality than postmenopausal ones. Specifically, postmenopausal women exhibit a higher risk of presenting either insomnia or OSA, than pre- or perimenopausal ones.  This study also shows that there is not an apparent association between menopausal status and the RLS [8] ). Additional supportive evidence comes from multiethnic cross-sectional studies, showing that women during the menopausal transition and postmenopause exhibit higher risks of having sleep disturbances than non-menopausal women [33]. For instance, Li et al. [34] and Zhang et al. [35] show that Chinese women exhibit an incidence of sleep disorders between 50% to 55% during the perimenopause. Additionally, a study in Korea shows that both peri- and postmenopausal women have between 1.5 to 1.73 times higher chance of having poor sleep quality than premenopausal ones [36]. Japanese perimenopausal women exhibit sleep disorders within a range of incidence between 33% to 51% [37,38]. Likewise, and according to the Pittsburg Sleep Quality Index (PSQI), 39.5% of premenopausal women and 46.3% of postmenopausal Latin American surveyed women, exhibit poor sleep quality, which intensify the severity of menopausal symptoms [39]. Similar results were obtained from Argentinian women showing that 46.7% of postmenopausal women presented poor sleep quality [40]. Kravitz et al. [41] report that the incidence of poor sleeping in Caucasian women is 40%. Likewise, Madaeva et al. [42] report that European – Russian women exhibit a sleep disorder prevalence of 61.2% and 65.5% for peri- and postmenopausal women respectively. Furthermore, the latter authors also report that women belonging to the ethnic group Buryats, show a prevalence of sleep disorders in 63.5% and 72.9% of pre- and postmenopausal women, respectively [42]. Overall, these studies also report that women exhibiting sleep disorders are prone to presenting severe cardiovascular diseases and depression, which reduce women’s quality of life and quotidian performance. Therefore, both longitudinal and cross-sectional studies report multifactorial evidence showing that sleep disorders during the menopause transition and post menopause are related to hormone levels, affecting women independently of their ethnicities (Table I). These lines of evidence also emphasize that menopause related hormonal changes are possibly affecting both women’s thermoregulatory physiology and sleep quality simultaneously. These evidences here presented indicate the need to develop integral interventions/treatments that act concomitantly on VMS and sleep disorders among affected women at any menopausal stage.

Sleep disorders are influenced by hormonal variation in menopausal women

Hormonal changes influence sleep cycles. There is a significant correlation between hormonal status and sleep quality indicating that ovarian / sexual hormones regulate women’s sleep [43]. For example, during menstrual cycles, there are recurrent changes in production of estradiol (E2), progesterone, luteinizing hormone, follicle stimulating hormone (FSH), prolactin, and growth hormone, altering sleep quality and circadian rhythms [25,44]. Similarly, during the perimenopause, research based on polysomnographic studies, demonstrates how high levels of FSH are linked to sleep architecture. Scientific evidence shows how increases in FSH is positively associated with wakefulness after sleep onset and negatively associated with slow wave sleep [14,45]. Furthermore, data from the SWAN longitudinal study with 8 years of following up of a cohort of more than 3,000 multiethnic women, show that women during their early menopausal transition, and postmenopausal stage exhibit significant difficulties in falling sleep, waking up several times during night, and waking up early [46]. Supporting odd ratio values, from a polysomnogram based study, were significantly associated with decreases in E2 and increases in FSH. In addition, it has been reported that low levels of estrogen, alterations in E2 to total testosterone ratio, can lead to insomnia in perimenopausal women, causing anxiety, depression, or hypertension [47-49]. Moreover, in both peri- and postmenopausal women, there are decreases in both E2 and melatonin levels that exacerbate the difficulties of falling asleep and waking up several times [32]. Concerning to the role of progesterone in sleep quality, there is evidence showing that micronized progesterone treatment, can improve sleep disorders in postmenopausal women [50], suggesting the possible role of this hormone in women’s sleep patterns. Other sleep problems such as OSA in postmenopausal women might be caused by the loss of the protective effects of either estrogen and/or progesterone. Likewise, it has been demonstrated that reductions in progesterone levels can promote both fat redistribution and increases in neck circumference, fostering aerial obstructions among postmenopausal women affected with OSA [8]. On the other hand, RLS and its association with hormone levels is still a matter of research. Polo-Kantola et al. [51] reported among asymptomatic postmenopausal women, the independence between RLS and both E2 and FSH levels. This study suggests that pathophysiology of the RLS is more related to aging than hormone levels. RLS pathophysiology is linked with both iron deficiency and decreases in dopamine, with levels that tend to drop with aging. The later indicates that not only postmenopausal women are prone to exhibit higher prevalence of RLS, but also the role of neurotransmitters regulating sleep-wake dynamics [52-54]. Overall, these facts allude that variation in the secretion of sexual hormones induces sleep disorders during the perimenopause, and the postmenopause. This apparent relationship has been a key factor for developing research to propose treatments such as MHT for enhancing women’s quality of life.

Vasomotor symptoms might be associated with sleep disorders

Insomnia is the commonest reported sleep disorder during the menopause and its transition [8,30,32,55-58]. Moreover, insomnia is considered as a secondary consequence of VMS, including HF, night sweats, and palpitations, which are in relation to estrogen levels [59-61]. For instance, Campbell and Murphy [62] have shown how HF cause insomnia in 29% of women [62]. Similarly, the SWAN study indicates that women with moderate to severe HF exhibit up to 3 times more probabilities of presenting sleep disorders (e.g., night awakenings and insomnia), than women without HF [32]. Furthermore, HF and sweating are statistically related to depression, and anxiety, which also lead to insomnia and vice versa [5,27,31,63-66]. On the other hand, symptoms associated to sleep apnea, in postmenopausal women, include night sweats, daytime sleepiness, and headaches [67], indicating a possible association between VMS and OSA. For example, intermediate, and severe OSA, could be related to severe VMS in perimenopausal women with hypertension and a body mass index of less than 25 kg/m2 [68]. This report advocates how thermoregulatory neuronal control, associated with HF, are possibly working together with both respiration and sleep hormonal regulators such as progesterone, estrogen, and FSH [12,69]. Moreover, low levels of progesterone increase fat accumulation and distribution reducing breathing capabilities in menopausal women [8]. In addition, women treated with MHT for the alleviation of HF, reduced their sleep disorder complaints associated with OSA and RLS. However, there is not sufficient data to establish a strong and direct cause - effect relationship between OSA or RLS and VMS. A study reporting the causes of sleep disorders in peri- and postmenopausal women shows independence between RLS and VMS [1]. This array of evidence suggests that both sleep disorders and VMS could co-exist, and are each other secondarily linked to sexual hormone withdrawal such as estrogen and progesterone and variations in FSH and melatonin.

Treatments for VMS and their concomitant sleep disorders

Pharmacological hormonal interventions

MHT is the first prescribed therapy for VMS, and it is prescribed for managing sleep disorders during the different stages of the menopause. Particularly this intervention, has shown efficacy by increasing sleep quality among women experiencing VMS exclusively [70,71]. However, there are reports of women presenting adverse effects and consequently non compliances leading to refusing MHT and turning to non-hormonal treatments as a “natural” alternative [72,73]. Several guidelines recommend MHT for both short periods of time and low doses. Nevertheless, since the first publication in 2002 of the US clinical trial of the Women’s Health Initiative (WHI) Study, the number of MHT prescriptions has dropped 60% in European populations, by 46% in the USA and by 28% in Canada [74-76]. In Asian populations such as Korea, over 70% of women were prescribed MHT for less than 1 year [77].

One alternative to pharmacological interventions are phytoestrogen supplements, which are found in soybeans (isoflavones), in Humulus lupulus, flaxseed (lignans), fruits, vegetables and whole grains [78,79]. Isoflavone based therapy has shown efficacy in reducing the severity of HF [78-85]. There is evidence showing no correlation between isoflavones’ dosage and the severity and frequency of HF [86]. Regarding sleep disorders, isoflavone interventions in Asian populations have shown positive results increasing both sleep quality and duration during the peri- and postmenopause [84,85]. However, there are reports showing no correlation or negatively affecting sleep quality with some ethnic nuances [86-89]. Overall evidence shows that the efficacy of phytoestrogen intervention for treating HF and insomnia is not conclusive or generalizable.

Pharmacological non-hormonal interventions

It is widely accepted that serotonin and norepinephrine are implicated in the generation of HF. Therefore, antidepressants are an alternative for those women searching non-hormonal treatments. Evidence shows that women treated with selective serotonin re-uptake inhibitors (SSRI) (e.g., fluoxetine and paroxetine), and selective norepinephrine re-uptake inhibitors (SNRI) (e.g., venlafaxine) decrease the frequency and severity of their HF [90]. However, these treatments are not recommended for patients with breast cancer. It has been reported that SSRI and SNRI reduce tamoxifen efficacy by inhibiting the CYP2D6, preventing the bioactivation of tamoxifen to its active metabolite [91,92]. The effect of SSRI and SNRI on sleep come from their inhibitory effect on both serotonin and norepinephrine reuptake [93]. Specifically, and during the first week of treatment, some classes of SSRI may deteriorate sleep quality leading to insomnia or somnolence complaints, and then daytime dysfunction whereas others can promote sleep [94,95]. In addition, SSRI and SNRI present other side effects such as nausea, dizziness, headache, and dry mouth. Moreover, SSRI and SNRI based treatments are contraindicated in neuroleptic patients, those with the serotonergic syndrome or those using monoamine oxidase (MAO) inhibitors. The moderate response and side effects associated with SSRI and SNRI based treatments frequently cause patient’s non-compliance [96].

In addition, antihypertensive drugs such as clonidine (alpha-adrenergic agonist) could be considered a non-hormonal alternative for VMS and sleep disorders. However, the efficacy of clonidine treatment for HF frequency is modest [97,98]. The possible mechanism of action could involve the reduction of norepinephrine levels, which are elevated as consequence of estrogen withdrawal and HF [99]. Despite this, clonidine treatment leads to the appearance of side effects including dizziness, light-headedness, hypotension, and dry mouth, which make it a less desirable alternative [99] and is not currently recommended [100]. Concerning sleep disorders most of the studies have been performed in children and adolescents with attention-deficit hyperactivity disorder (ADHD). Miyazaki et al. [101] showed that low doses of clonidine increased rapid eye movement (REM) sleep. However, now it is known that clonidine alters NREM/REM sleep cycle by reducing REM sleep in a dose dependent manner as it reduces the release of norepinephrine thus maintaining the activity of REM on neurons [101]. Further investigation is needed regarding the efficacy of clonidine for the treatment of sleep disorders during menopausal stages [102,103].

Other proven pharmacological non-hormonal treatments for HF and sleep disorders are anti-epileptic drugs such as gabapentin. This molecule is an analogue of the gamma-aminobutyric acid (GABA) used as an anticonvulsant. This option reduces the frequency of HF by 47-71% in four clinical trials [104-106]. Moreover, GABA based treatment has shown effectivity in either menopausal or in tamoxifen-induced menopausal women [107] and could be considered as a treatment option for HF in women with breast cancer [108-110]. Nevertheless, GABA’s associated side effects include somnolence, ataxia, and dizziness. Evidence from a meta-analysis, which compared single-agent gabapentin with placebo for treating HF, shows that adverse events were significantly more frequent among those taking gabapentin than among those taking the placebo [111]. Concerning sleep disorders, it has been demonstrated that gabapentin enhances slow-wave sleep in patients with primary insomnia, improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal [112]. Similarly, patients on single doses of gabapentin between 250 and 500 mg showed significantly longer sleep duration and greater depth than patients on placebo [113].

Finally, the effects of benzodiazepines on HF frequency and severity have not been studied. However, treatments based on short half-life benzodiazepines are the main option for sleep disorders including chronic insomnia and sleep-onset insomnia. Secondary side effects after benzodiazepine discontinuation include rebound insomnia and withdrawal symptoms [114]. Other molecules such as selective dual orexin receptor antagonist (suvorexant) or melatonin agonists (Ramelteon) are only efficient for insomnia.

Even though there are several options for either sleep disorders or VMS not too many represent an integral option for treating VMS and sleep disorders simultaneously. In conclusion, pharmacological options present side effects outweighing their benefits. Therefore, it is necessary to evaluate non-pharmacological alternatives in order to avoid the side effects and potential toxicity of pharmacological treatments. These alternatives could improve patients’ long-term compliance when treating simultaneously HF and sleep disturbances.

Non-pharmacological treatments for VMS and sleep disorders

Lifestyle changes, behavioral therapies, holistic techniques, food supplements, and herbal therapies are considered as non-pharmacological interventions. In general, lifestyle interventions include habits that promote reductions in core body temperature. For example, these treatments advocate reductions and avoidance of habits that involve alcohol, and hot and spicy food. However, there are no clinical studies evidencing any significant effect of adopting these habits on HF severity and frequency [115].

Concerning sleep disorders, European guidelines propose good hygiene rules: physical exercise, controlling substance use and avoiding environmental factors that disrupt sleep, such as light, temperature, and noise [116]. Moreover, practicing moderate exercise can contribute to decrease VMS during the menopause improving quality of life, cognitive and physical function, and reducing all mortality causes [117]. Evidence from longitudinal and cross-sectional studies shows that peri- and postmenopausal women who work out on a daily basis exhibit lower HF frequency than sedentary ones, independently of their ethnicity [13,118-122]. Similarly, evidence shows that sedentary habits tend to increase levels of cholesterol, triglycerides, and apolipoprotein A, which lead to an increase of HF frequency and severity [123]. Likewise, in obese women, weight loss might be associated with a decrease or the total elimination of HF [124]. Consistently, results from 4 randomized controlled trials have shown that weight loss may be effective in the management or resolution of sleep disorders including OSA (measured by changes in Apnea Hypoapnea Index) [125]. Likewise, physical activity also increases sleep efficiency and duration in mid-aged and elderly women, irrespective of the type of working-out practice and intensity [126]. For instance, yoga reduces vasomotor, psychological, somatic, and urogenital symptoms during both peri- and postmenopausal stages [127,128]. However, results on the effects of yoga on sleep disorders are still controversial [129,130]. Moreover, Wang et al. [131] reported that four randomized controlled trials revealed no evidence for the effects of yoga compared with the control group in improving the sleep quality (assessed with the PSQI) for peri/postmenopausal women using. Analogously, holistic breathing techniques including paced respiration, hypnosis and acupuncture show different results regarding the frequency and severity of HF and their associated sleep disorders [132]. Accordingly, various studies show how slow-paced respiration or hypnosis significantly reduces frequency and intensity of HF in menopausal women [133-135]. Finally, acupuncture could reduce the frequency and severity of HF and improve menopausal women’s quality of life [136].  Likewise, this treatment also improves sleep quality in peri- and postmenopausal women [137].

Complementary medicine as Cognitive Behavioral Therapy (CBT) has a positive effect on both HF and sleep disorders and consequently on depression in postmenopausal and breast cancer survivors [138,139]. This intervention implies behavioral activation and changing negative thoughts. Mindfulness-Based Cognitive Therapy (MBCT) not only reduces symptoms of depression, stress, and anxiety, but also HF during the menopausal transition, in both healthy menopausal and those with breast cancer [139-142]. Then CBT shows efficacy in general population reducing both hot flushes and insomnia. Likewise, CBT is currently recommended as a first line treatment in healthy midlife women with insomnia and moderate VMS [141].

Herbal therapies have been studied as a natural alternative to treat HF and sleep disorders. However, in some cases the effectiveness and their mode of action is not fully demonstrated. Particularly, the active ingredients of black cohosh (Actaea racemosae) could act as selective estrogen receptor agonists, dopaminergic and serotonergic pathway modulators, as well as acting as antioxidant and anti-inflammatory agents [143]. Accordingly, a Cochrane review based on 16 randomized clinical trials in 2,027 perimenopausal or postmenopausal women, report that there was no significant difference in HF frequency between women treated with black cohosh and those with placebo [144]. It seems that the effectiveness of black cohosh depends on the type of used extract. The hydroalcoholic extract BNO 1055 has been proposed as a therapy for HF and sweating. Jarry et al. [145] reported lack of binding activity to ER-α or ER-β receptors with this extract.  Moreover, BNO 1055 extract is also well suited to improve sleeping quality via the activation of the GABAergic system. However, potential side effects could occur such as gastrointestinal disorders (e.g., upper abdominal symptoms, diarrhea), allergic skin reactions (e.g., hives, itching, skin rash), facial or peripheral swelling (facial or peripheral edema), and weight gain. Regarding side effects, suspected hepatotoxicity was previously reported, but a meta-analysis of five randomized, double-blind, controlled clinical trials addressing 1,020 women showed no evidence that black cohosh has any adverse effect on the liver function [146].

Another available natural product is the Purified and Specific Cytoplasmic Pollen Extract (known as PureCyTonin®) which has demonstrated in several trials its efficacy at reducing HF, night sweats, and sleep disorders in perimenopausal and menopausal women [147-152]. Moreover, evidence from several in vitro and in vivo tests show that these extracts do not have either estrogenic action or uterotrophic effects and does not interfere with tamoxifen efficacy [153] which has led to propose it as a safe non-hormonal alternative treatment to MHT for menopausal symptoms [154].

The reduction in symptom scores reported from postmenopausal women treated with Purified and Specific Cytoplasmic Pollen Extract is not mediated by estrogen or estrogen-like pathways as shown in the study of Seeger et al. [155] in which no proliferation of MCF-7 cells could be demonstrated. Therefore, the Purified and Specific Cytoplasmic Pollen Extract could be a non-hormonal alternative for managing menopausal symptoms in cancer survivors and for women with contraindications to MHT [156,157]. Concerning sleep disturbances, patients treated with Purified and Specific Cytoplasmic Pollen Extract showed significant decrease of 48.5% in the frequency of HF and 50.1% in sleep disturbances and mood disorders [158].  Similar results have been reported by Lello et al. [159] who evaluated the effect of pollen extracts in 108 menopausal women. Their results show that HF, night sweats, difficulties in falling asleep, and fatigue were significantly reduced without presenting side effects [159].

Recently, a comparison between the effect of pollen extracts and isoflavones in sleep disorders in menopausal women showed significant greater improvement in sleep quality for the pollen treated group compared to the isoflavone group at both three (-24.7% versus -9.3%, p<0.001) and six months (-52.9% vs -4.0%; p<0.001), mainly for the scores related to subjective sleep quality, sleep latency and habitual sleep efficiency. Pollen extracts achieve a greater improvement of HF, sleep disturbances, and menopause-related symptoms than soy isoflavones and it is mainly effective when the quality of sleep is the most disturbing complaint [160].  Concerning the mode of action of Purified and Specific Cytoplasmic Pollen Extract, it seems to act on the hypothalamic thermoregulation center where HF are generated, acting similar to SSRI yet without their side effects [161]. Additionally, tryptophan, a precursor of serotonin, is present in the extract amount. The average measured level of tryptophan in pollen extracts is about 0.09 mg/tablet [162].  Thus, pollen extract appears to maintain the availability of serotonin in hypothalamic serotonergic neurons, partially explaining its efficacy in HF and sleep disturbances.

There are other non-pharmacological /non-hormonal alternative options such as nutraceuticals. Reported evidence comes from the effects of L-tryptophan, melatonin, and magnesium on HF and sleep disorders. However, in patients with breast, or cervical cancer who develop VSM, asthenia and insomnia, nutritional tryptophan supplementation at a dosage of 3 g per day is well tolerated, improving these symptoms and thus quality of life [163]. The effects of 5-Hydroxytriptophan (5-HTP), immediate precursor of serotonin, have been studied in trials with a dosage of 150 mg/day showing no significant amelioration of the frequency of HF [164]. Concerning sleep, scientific evidence concludes that tryptophan reduces sleep latency and increases subjective rating of sleepiness during the day. Tryptophan mechanism of action can be through melatonin enhancement of serotonin effects [165].

Melatonin based nutraceutical treatments for sleep disorders have been tested in adults and children. Melatonin interventions show little dependence and habituation without aftereffects and general minor side effects. Different meta-analyses show that doses of melatonin between 3 to 6 mg significantly improve sleep compared to placebo, reducing sleep onset latency, increasing total sleep time, and improving overall sleep quality in patients with primary sleep disorders [166]. Furthermore, melatonin formulations in doses from 1 mg to 1.9 mg have proven efficacy and they are accepted in some European countries [167].

Moreover, a randomized placebo-controlled study among breast cancer survivors demonstrated that melatonin was associated with an improvement in subjective reported sleep quality, without any significant adverse effects [168].

In a general trend, woman with sleep problems improve their sleep quality with small doses of melatonin [169]. However, evidence shows a non-role of melatonin in reducing VMS [170].

Finally, magnesium is likely to be a reasonable causal link between VMS and the menopause. However, magnesium supplementation has been tested in menopausal women who have had breast cancer failing to reduce HF [171]. On the other hand, Abbasi et al. [172] have shown how low magnesium levels are associated with nervous excitability and poor sleep quality. Particularly these authors examined the independent role of magnesium in the treatment of insomnia. Supplementation of magnesium appears to improve subjective measures of insomnia such as Insomnia Severity Index Score, sleep efficiency, sleep time and sleep onset latency, early morning awakening.

 

Conclusions

This review reports how the transition to menopause and post menopause involve a wide spectrum of endocrine, health and age associated changes interacting simultaneously, which affect women’s sleep quality. Several lines of evidence show reductions in HF frequency and severity in women treated with MHT, improving their sleep quality. Even though there are several MHT alternatives options for either sleep disorders or VMS not many represent an option for treating both symptoms simultaneously. Nevertheless, pharmacological options present side effects outweighing their benefits. Non-pharmacological treatments, such as hygienic dietary measures, behavioral therapies, holistic technics, food supplements, and herbal therapies are considered as natural options. Particularly, CBT and purified and specific cytoplasmic pollen extracts could cover both HF and sleep disorders without side effects. However, it is necessary to continue evaluating non-pharmacological alternatives in terms of their efficacy and safety for the treatment of menopausal HF and sleep disorders.

Media

Table 1
Table 1 Menopausal transition and postmenopause sleep disorders are related to hormone levels, affecting women independently of their ethnicities.

References

  1. Freedman RR, Roehrs TA. Sleep disturbance in menopause. Menopause. 2007;14:826-9.
  2. Kravitz HM, Zhao X, Bromberger JT, et al. Sleep disturbance during the menopausal transition in a multi-ethnic community sample of women. Sleep. 2008;31:979-90.
  3. LeBlanc AJ, Reyes R, Kang LS, et al. Estrogen replacement restores flow-induced vasodilation in coronary arterioles of aged and ovariectomized rats Am J Physiol Regul Integr Comp Physiol. 2009;297:R1713-23.
  4. Bruyneel M. Sleep disturbances in menopausal women: aetiology and practical aspects. Maturitas. 2015;81:406-9.
  5. Freeman EW, Sammel MD, Gross SA, Pien GW. Poor sleep in relation to natural menopause: a population-based 14-year follow-up of midlife women. Menopause. 2015;22:719-26.
  6. Chojnacki C, Kaczka A, Gasiorowska A, Fichna J, Chojnacki J, Brzozowski T. The effect of long-term melatonin supplementation on psychosomatic disorders in postmenopausal women. J Physiol Pharmacol. 2018;69.
  7. Han Y, Lee J, Cho HH, Kim MR. Sleep disorders and menopause. J Menopausal Med. 2019;25:83-7.
  8. Zolfaghari S, Yao C, Thompson C, et al. Effects of menopause on sleep quality and sleep disorders: Canadian Longitudinal Study on Aging. Menopause. 2020;27:295-304.
  9. Geiger PJ, Eisenlohr-Moul T, Gordon JL, Rubinow DR, Girdler SS. Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms. Menopause. 2019;26:1318-23.
  10. Archer DF, Sturdee DW, Baber R, et al. Menopausal hot flushes and night sweats: where are we now? Climacteric. 2011;14:515-28.
  11. Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014;142:115-20.
  12. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;34:211-27.
  13. Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol. 2000;152:463-73.
  14. Santoro N. Perimenopause: from research to practice. J Womens Health (Larchmt). 2016;25:332-9.
  15. Kronenberg F. Menopausal hot flashes: a review of physiology and biosociocultural perspective on methods of assessment. J Nutr. 2010;140:1380S-5S.
  16. Thurston RC, Santoro N, Matthews KA. Are vasomotor symptoms associated with sleep characteristics among symptomatic midlife women? Comparisons of self-report and objective measures. Menopause. 2012;19:742-8.
  17. Cirignotta F, Mondini S, Zucconi M, Lenzi PL, Lugaresi E. Insomnia: an epidemiological survey. Clin Neuropharmacol. 1985;8 Suppl 1: S49-S54.
  18. Shaver JL, Woods NF. Sleep and menopause: a narrative review. Menopause. 2015;22:899-915.
  19. Huang T, Lin BM, Redline S, Curhan GC, Hu FB, Tworoger SS. Type of menopause, age at menopause, and risk of developing obstructive sleep apnea in postmenopausal women. Am J Epidemiol. 2018;187:1370-9.
  20. Perger E, Mattaliano P, Lombardi C. Menopause and sleep apnea. Maturitas. 2019;124:35-8.
  21. Morin CM, LeBlanc M, Daley M, Gregoire JP, Mérette C. Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med. 2006;7:123-30.
  22. Bolge SC, Joish VN, Balkrishnan R, Kannan H, Drake CL. Burden of chronic sleep maintenance insomnia characterized by nighttime awakenings. Popul Health Manag. 2010;13:15-20.
  23. Panay N, Palacios S, Davison S, Baber R. Women’s perception of the menopause transition: a multinational, prospective, community-based survey. Gynecological and Reproductive Endocrinology and Metabolism. 2021;2:178-83.
  24. Bounous V, Rosso R, Cipullo I, Accomasso F, Biglia N. Cognition and early menopause in breast cancer patients: an update. Gynecological and Reproductive Endocrinology and Metabolism. 2020; 1:23-8.
  25. Baker FC, Lee KA. Menstrual cycle effects on sleep. Sleep Med Clin. 2022;17:283-94.
  26. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3:S7-S10.
  27. Zhou Q, Wang B, Hua Q, et al. Investigation of the relationship between hot flashes, sweating and sleep quality in perimenopausal and postmenopausal women: the mediating effect of anxiety and depression. BMC Womens Health. 2021;21:293.
  28. Brincat M, Studd JW. Menopause–a multi system disease. Baillieres Clin Obstet Gynaecol. 1988;2:289-316.
  29. Nelson LM, Covington SN, Rebar RW. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril. 2005;83:1327-32.
  30. Joffe H, Massler A, Sharkey KM. Evaluation and management of sleep disturbance during the menopause transition. Semin Reprod Med. 2010;28:404-21.
  31. Bianchi MT, Kim S, Galvan T, White DP, Joffe H. Nocturnal hot flashes: relationship to objective awakenings and sleep stage transitions. J Clin Sleep Med. 2016;12:1003-9.
  32. Kravitz HM, Joffe H. Sleep during the perimenopause: a SWAN story. Obstet Gynecol Clin North Am. 2011;38:567-86.
  33. Xu Q, Lang CP. Examining the relationship between subjective sleep disturbance and menopause: a systematic review and meta-analysis.  2014;21:1301-18.
  34. Li L, Wu J, Pu D, et al. Factors associated with the age of natural menopause and menopausal symptoms in Chinese women. Maturitas. 2012;73:354-60.
  35. Zhang JP, Wang YQ, Yan MQ, Li ZA, Du XP, Wu XQ. Menopausal symptoms and sleep quality during menopausal transition and postmenopause. Chin Med J (Engl). 2016;129:771-7.
  36. Hwang JH, Lee K, Choi E, et al. Sleep quality and associated factors in premenopausal, perimenopausal, and postmenopausal women in Korea: findings from the K-Stori 2016. Nat Sci Sleep. 2021;13:1137-45.
  37. Terauchi M, Hirose A, Akiyoshi M, Owa Y, Kato K, Kubota T. Subgrouping of Japanese middle-aged women attending a menopause clinic using physical and psychological symptom profiles: a cross-sectional study. BMC Womens Health. 2014;14:148.
  38. Xu Q, Lang CP. Examining the relationship between subjective sleep disturbance and menopause: a systematic review and meta-analysis. Menopause. 2014;21:1301-18.
  39. Blümel JE, Cano A, Mezones-Holguín E, et al. A multinational study of sleep disorders during female mid-life. Maturitas. 2012;72:359-66.
  40. Valiensi SM, Belardo MA, Pilnik S, Izbizky G, Starvaggi AP, Castelo Branco C. Sleep quality and related factors in postmenopausal women. Maturitas. 2019;123:73-7.
  41. Kravitz HM, Ganz PA, Bromberger J, Powell LH, Sutton-Tyrrell K, Meyer PM. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause. 2003;10:19-28.
  42. Madaeva IM, Semenova NV, Kolesnikova LI. [Ethnic features of sleep disorders in climacteric women]. Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119:44-9.
  43. Brown AMC, Gervais NJ. Role of ovarian hormones in the modulation of sleep in females across the adult lifespan. Endocrinology. 2020;161:bqaa128.
  44. Zheng H, Harlow SD, Kravitz HM, et al. Actigraphy-defined measures of sleep and movement across the menstrual cycle in midlife menstruating women: Study of Women’s Health Across the Nation Sleep Study. Menopause. 2015;22:66-74.
  45. Antonijevic IA, Murck H, Frieboes RM, Uhr M, Steiger A. On the role of menopause for sleep-endocrine alterations associated with major depression. Psychoneuroendocrinology. 2003;28:401-18.
  46. Harlow SD, Gass M, Hall JE, et al; STRAW + 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab. 2012;97:1159-68.
  47. Sowers MR, Eyvazzadeh AD, McConnell D, et al. Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition. J Clin Endocrinol Metab. 2008;93:3478-83.
  48. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146:1387-94.
  49. Javaheri S, Redline S. Insomnia and risk of cardiovascular disease. Chest. 2017;152:435-44.
  50. Nolan BJ, Liang B, Cheung AS. Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data. J Clin Endocrinol Metab. 2021;106:942-51.
  51. Polo-Kantola P, Rauhala E, Erkkola R, Irjala K, Polo O. Estrogen replacement therapy and nocturnal periodic limb movements: a randomized controlled trial. Obstet Gynecol. 2001;97:548-54.
  52. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 2004;5:385-91.
  53. Khan FH, Ahlberg CD, Chow CA, Shah DR, Koo BB. Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome. J Neurol. 2017;264:1634-41.
  54. Oh J, Petersen C, Walsh CM, Bittencourt JC, Neylan TC, Grinberg LT. The role of co-neurotransmitters in sleep and wake regulation. Mol Psychiatry. 2019;24:1284-95.
  55. Wesstrom J, Nilsson S, Sundstrom-Poromaa I, Ulfberg J. Restless legs syndrome among women: prevalence, co-morbidity and possible relationship to menopause. Climacteric. 2008;11:422-8.
  56. Guidozzi F. Sleep and sleep disorders in menopausal women. Climacteric. 2013;16:214-9.
  57. Galvan T, Camuso J, Sullivan K, et al. Association of estradiol with sleep apnea in depressed perimenopausal and postmenopausal women: a preliminary study. Menopause. 2017;24:112-7.
  58. El Khoudary SR, Greendale G, Crawford SL, et al. The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause. 2019;26:1213-27.
  59. Al-Safi ZA, Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertil Steril. 2014;101:905-15.
  60. Lampio L, Polo-Kantola P, Polo O, Kauko T, Aittokallio J, Saaresranta T. Sleep in midlife women: effects of menopause, vasomotor symptoms, and depressive symptoms. Menopause. 2014;21:1217-24.
  61. Abdi F, Mobedi H, Roozbeh N. Hops for Menopausal Vasomotor Symptoms: Mechanisms of Action. J Menopausal Med. 2016;22:62-4.
  62. Campbell SS, Murphy PJ. The nature of spontaneous sleep across adulthood. J Sleep Res. 2007;16:24-32.
  63. Ban HJ, Kim SC, Seo J, Kang HB, Choi JK. Genetic and metabolic characterization of insomnia. PLoS One. 2011;6:e18455.
  64. de Zambotti M, Colrain IM, Baker FC. Interaction between reproductive hormones and physiological sleep in women. J Clin Endocrinol Metab. 2015;100:1426-33.
  65. Vousoura E, Spyropoulou AC, Koundi KL, et al. Vasomotor and depression symptoms may be associated with different sleep disturbance patterns in postmenopausal women. Menopause. 2015;22:1053-57.
  66. Pinkerton JV, Abraham L, Bushmakin AG, Cappelleri JC, Komm BS. Relationship between changes in vasomotor symptoms and changes in menopause-specific quality of life and sleep parameters. Menopause. 2016;23:1060-6.
  67. Proserpio P, Marra S, Campana C, et al. Insomnia and menopause: a narrative review on mechanisms and treatments. Climacteric. 2020;23:539-49.
  68. Gao CC, Kapoor E, Lipford MC, et al. Association of vasomotor symptoms and sleep apnea risk in midlife women. Menopause. 2018;25:391-8.
  69. Rajagopal KR, Abbrecht PH, Tellis CJ. Control of breathing in obstructive sleep apnea.  1984;85:174-80.
  70. Cintron D, Lipford M, Larrea-Mantilla L, et al. Efficacy of menopausal hormone therapy on sleep quality: systematic review and meta-analysis. Endocrine. 2017;55:702-11.
  71. Schaedel Z, Holloway D, Bruce D, Rymer J. Management of sleep disorders in the menopausal transition. Post Reprod Health. 2021;27:209-14.
  72. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society.  2017;24:728-53.
  73. De Franciscis P, Colacurci N, Riemma G, et al. A Nutraceutical Approach to Menopausal Complaints. Medicina (Kaunas). 2019;55:544.
  74. Heinig M, Braitmaier M, Haug U. Prescribing of menopausal hormone therapy in Germany: current status and changes between 2004 and 2016. Pharmacoepidemiol Drug Saf. 2021;30:462-71.
  75. Buist DS, Newton KM, Miglioretti DL, et al. Hormone therapy prescribing patterns in the United States. Obstet Gynecol. 2004;104:1042-50.
  76. Guay MP, Dragomir A, Pilon D, Moride Y, Perreault S. Changes in pattern of use, clinical characteristics and persistence rate of hormone replacement therapy among postmenopausal women after the WHI publication. Pharmacoepidemiol Drug Saf. 2007;16:17-27.
  77. Park CY, Lim JY, Kim WH, Kim SY, Park HY. Evaluation of menopausal hormone therapy use in Korea (2002-2013): A nationwide cohort study. Maturitas. 2021;146:57-62.
  78. Poluzzi E, Piccinni C, Raschi E, Rampa A, Recanatini M, De Ponti F. Phytoestrogens in postmenopause: the state of the art from a chemical, pharmacological and regulatory perspective. Curr Med Chem. 2014;21:417-36.
  79. Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 2006;54:164-75.
  80. Chen M, Rao Y, Zheng Y, et al. Association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women: a meta-analysis of epidemiological studies. PLoS One. 2014;9:e89288.
  81. Hooper L, Ryder JJ, Kurzer MS, et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update. 2009;15:423-40.
  82. Li L, Lv Y, Xu L, Zheng Q. Quantitative efficacy of soy isoflavones on menopausal hot flashes. Br J Clin Pharmacol. 2015;79:593-604.
  83. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials.  2012;19:776-90.
  84. Cui Y, Niu K, Huang C, et al. Relationship between daily isoflavone intake and sleep in Japanese adults: a cross-sectional study. Nutr J. 2015;14:127.
  85. Cao Y, Taylor AW, Zhen S, Adams R, Appleton S, Shi Z. Soy isoflavone intake and sleep parameters over 5 years among Chinese adults: longitudinal analysis from the Jiangsu Nutrition Study. J Acad Nutr Diet. 2017;117:536-44.e2.
  86. Albert A, Altabre C, Baró F, et al. Efficacy and safety of a phytoestrogen preparation derived from Glycine max (L.) Merr in climacteric symptomatology: a multicentric, open, prospective and non-randomized trial. Phytomedicine. 2002;9:85-92.
  87. Hachul H, Brandão LC, D’Almeida V, Bittencourt LR, Baracat EC, Tufik S. Isoflavones decrease insomnia in postmenopause. Menopause. 2011;18:178-84.
  88. Davinelli S, Scapagnini G, Marzatico F, Nobile V, Ferrara N, Corbi G. Influence of equol and resveratrol supplementation on health-related quality of life in menopausal women: A randomized, placebo-controlled study. Maturitas. 2017;96:77-83.
  89. Sun J, Jiang H, Wang W, Dong X, Zhang D. Associations of urinary phytoestrogen concentrations with sleep disorders and sleep duration among adults. Nutrients. 2020;12:2103.
  90. Loprinzi CL, Sloan J, Stearns V, et al. Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol. 2009;27:2831-7.
  91. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:30-9.
  92. Jordan VC. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids. 2007;72:829-42.
  93. Wichniak A, Wierzbicka A, Walęcka M, Jernajczyk W. Effects of Antidepressants on Sleep. Curr Psychiatry Rep. 2017;19:63.
  94. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry. 2004;65 Suppl 16:27-32.
  95. Aarts N, Zuurbier LA, Noordam R, et al. Use of selective serotonin reuptake inhibitors and sleep quality: a population-based study. J Clin Sleep Med. 2016;12:989-95.
  96. Greden JF. Unmet need: what justifies the search for a new antidepressant? J Clin Psychiatry. 2002;63 Suppl 2:3-7.
  97. Goldberg RM, Loprinzi CL, O’Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994;12:155-8.
  98. Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000;132:788-93.
  99. Brück K, Zeisberger E. Adaptive changes in thermoregulation and their neuropharmacological basis. Pharmacol Ther. 1987;35:163-215.
  100. Sideras K, Loprinzi CL. Nonhormonal management of hot flashes for women on risk reduction therapy. J Natl Compr Canc Netw. 2010;8:1171-9.
  101. Miyazaki S, Uchida S, Mukai J, Nishihara K. Clonidine effects on all-night human sleep: opposite action of low- and medium-dose clonidine on human NREM-REM sleep proportion. Psychiatry Clin Neurosci. 2004;58:138-44.
  102. Gentili A, Godschalk MF, Gheorghiu D, Nelson K, Julius DA, Mulligan T. Effect of clonidine and yohimbine on sleep in healthy men: a double-blind, randomized, controlled trial. Eur J Clin Pharmacol. 1996;50:463-5.
  103. Spiegel R, DeVos JE. Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. Br J Clin Pharmacol. 1980;10 Suppl 1:165S-168S.
  104. Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause. 2008;15:310-8.
  105. Aguirre W, Chedraui P, Mendoza J, Ruilova I. Gabapentin vs. low-dose transdermal estradiol for treating post-menopausal women with moderate to very severe hot flushes. Gynecol Endocrinol. 2010;26:333-7.
  106. Pinkerton JV, Kagan R, Portman D, Sathyanarayana R, Sweeney M; Breeze 3 Investigators. Phase 3 randomized controlled study of gastroretentive gabapentin for the treatment of moderate-to-severe hot flashes in menopause. Menopause. 2014;21:567-73.
  107. Toulis KA, Tzellos T, Kouvelas D, Goulis DG. Gabapentin for the treatment of hot flashes in women with natural or tamoxifen-induced menopause: a systematic review and meta-analysis. Clin Ther. 2009;31:221-35.
  108. Guttuso T Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101:337-45.
  109. Loprinzi CL, Qin R, Balcueva EP, et al. Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1. J Clin Oncol. 2010;28:641-7.
  110. Pandya KJ, Morrow GR, Roscoe JA, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet. 2005;366:818-24.
  111. Yoon SH, Lee JY, Lee C, Lee H, Kim SN. Gabapentin for the treatment of hot flushes in menopause: a meta-analysis. Menopause. 2020;27:485-93.
  112. Lo HS, Yang CM, Lo HG, Lee CY, Ting H, Tzang BS. Treatment effects of gabapentin for primary insomnia. Clin Neuropharmacol. 2010;33:84-90.
  113. Rosenberg RP, Hull SG, Lankford DA, et al. A randomized, double-blind, single-dose, placebo-controlled, multicenter, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance. J Clin Sleep Med. 2014;10:1093-100.
  114. Gillin JC, Spinweber CL, Johnson LC. Rebound insomnia: a critical review. J Clin Psychopharmacol. 1989;9:161-72.
  115. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society.  2015;22:1155-72; quiz 1173-4.
  116. Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26:675-700.
  117. Alsubaie SF, Alkathiry AA, Abdelbasset WK, Nambi G. The physical activity type most related to cognitive function and quality of life. Biomed Res Int. 2020;2020:8856284.
  118. Col NF, Guthrie JR, Politi M, Dennerstein L. Duration of vasomotor symptoms in middle-aged women: a longitudinal study. Menopause. 2009;16:453-7.
  119. Ivarsson T, Spetz AC, Hammar M. Physical exercise and vasomotor symptoms in postmenopausal women. Maturitas. 1998;29:139-46.
  120. Bailey TG, Cable NT, Aziz N, et al. Exercise training reduces the acute physiological severity of post-menopausal hot flushes. J Physiol. 2016;594:657-67.
  121. Daley A, Stokes-Lampard H, Macarthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2011;(5):CD006108.
  122. Daley A, Stokes-Lampard H, Thomas A, MacArthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2014;(11):CD006108.
  123. Whiteman MK, Staropoli CA, Langenberg PW, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol. 2003;101:264-72.
  124. Freeman EW, Sammel MD, Grisso JA, Battistini M, Garcia-Espagna B, Hollander L. Hot flashes in the late reproductive years: risk factors for Africa American and Caucasian women. J Womens Health Gend Based Med. 2001;10:67-76.
  125. Johansson K, Neovius M, Lagerros YT, et al. Effect of a very low energy diet on moderate and severe obstructive sleep apnoea in obese men: a randomised controlled trial. BMJ. 2009;339:b4609.
  126. Dolezal BA, Neufeld EV, Boland DM, Martin JL, Cooper CB. Corrigendum to “Interrelationship between sleep and exercise: a systematic review”. Adv Prev Med. 2017;2017:5979510.
  127. Cramer H, Peng W, Lauche R. Yoga for menopausal symptoms-A systematic review and meta-analysis. Maturitas. 2018;109:13-25.
  128. Shepherd-Banigan M, Goldstein KM, Coeytaux RR, et al. Improving vasomotor symptoms; psychological symptoms; and health-related quality of life in peri- or post-menopausal women through yoga: An umbrella systematic review and meta-analysis. Complement Ther Med. 2017;34:156-64.
  129. Panjwani U, Dudani S, Wadhwa M. Sleep, cognition, and yoga. Int J Yoga. 2021;14:100-8.
  130. Nguyen TM, Do TTT, Tran TN, Kim JH. Exercise and quality of life in women with menopausal symptoms: a systematic review and meta-analysis of randomized controlled trials. Int J Environ Res Public Health. 2020;17:7049.
  131. Wang WL, Chen KH, Pan YC, Yang SN, Chan YY. The effect of yoga on sleep quality and insomnia in women with sleep problems: a systematic review and meta-analysis. BMC Psychiatry. 2020;20:195.
  132. Huang AJ, Phillips S, Schembri M, Vittinghoff E, Grady D. Device-guided slow-paced respiration for menopausal hot flushes: a randomized controlled trial. Obstet Gynecol. 2015;125:1130-8.
  133. Barton DL, Schroeder KCF, Banerjee T, Wolf S, Keith TZ, Elkins G. Efficacy of a biobehavioral intervention for hot flashes: a randomized controlled pilot study. Menopause. 2017;24:774-82.
  134. Otte JL, Carpenter JS, Roberts L, Elkins GR. Self-hypnosis for sleep disturbances in menopausal women. J Womens Health (Larchmt). 2020;29:461-3.
  135. Chamine I, Atchley R, Oken BS. Hypnosis intervention effects on sleep outcomes: a systematic review. J Clin Sleep Med. 2018;14:271-83.
  136. Chiu HY, Pan CH, Shyu YK, Han BC, Tsai PS. Effects of acupuncture on menopause-related symptoms and quality of life in women in natural menopause: a meta-analysis of randomized controlled trials.  2015;22:234-44.
  137. Wang Z, Zhai F, Zhao X, et al. The efficacy and safety of acupuncture for perimenopausal insomnia: a protocol for a network meta-analysis. Medicine (Baltimore). 2020;99:e23741.
  138. Norton S, Chilcot J, Hunter MS. Cognitive-behavior therapy for menopausal symptoms (hot flushes and night sweats): moderators and mediators of treatment effects. Menopause. 2014;21:574-8.
  139. Green SM, Key BL, McCabe RE. Cognitive-behavioral, behavioral, and mindfulness-based therapies for menopausal depression: a review. Maturitas. 2015;80:37-47.
  140. Ayers B, Smith M, Hellier J, Mann E, Hunter MS. Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial.  2012;19:749-59.
  141. Guthrie KA, Larson JC, Ensrud KE, et al. Effects of pharmacologic and nonpharmacologic interventions on insomnia symptoms and self-reported sleep quality in women with hot flashes: a pooled analysis of individual participant data from four MsFLASH trials. Sleep. 2018;41:zsx190.
  142. Woods NF, Mitchell ES, Schnall JG, et al. Effects of mind-body therapies on symptom clusters during the menopausal transition. Climacteric. 2014;17:10-22.
  143. Ruhlen RL, Sun GY, Sauter ER. Black cohosh: insights into its mechanism(s) of action. Integr Med Insights. 2008;3:21-32.
  144. Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev. 2012;2012:CD007244.
  145. Jarry H, Metten M, Spengler B, Christoffel V, Wuttke W. In vitro effects of the Cimicifuga racemosa extract BNO 1055. Maturitas. 2003;44 Suppl 1:S31-8.
  146. Naser B, Schnitker J, Minkin MJ, de Arriba SG, Nolte KU, Osmers R. Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract. Menopause. 2011;18:366-75.
  147. Winther K, Rein E, Hedman C. Femal, a herbal remedy made from pollen extracts, reduces hot flushes and improves quality of life in menopausal women: a randomized, placebo-controlled, parallel study. 2005;8:162-70.
  148. Elia D, Mares P. Evaluation de la tolérance et de l’efficacité d’un complément alimentaire Sérélys® (Femal®) chez les femmes en période de ménopause. Génésis. 2008;135:12-5.
  149. Druckmann R, Lachowsky M, Elia D. Evaluation de la qualité de vie, de l’efficacité et de la tolérance de Sérélys chez les femmes en période de péri-ménopause et ménopause. Génésis. 2015;183:10-3.
  150. Kimura H, Gruber P. Perimenopausal symptoms such as hot flushes and mood swings are reduced by a standardised pollen pistil extract. Climacteric. 2002;5(Suppl. 1):85.
  151. D’Alterio M, Giancane E, Cornacchia S, et al. GCFem, PI82, vitamin E in menopause treatment: benefits for peri and postmenopausal neurovegetative symptoms. Multidisc J Women’s Health 2015;4(1).
  152. Paszkowski T, Skrzypulec-Plinta V. Assessment of quality of life in women using Femelis Meno. Menopause Rev. 2018;2:77-85.
  153. Goldstein SR, Espié M, Druckmann R. Does purified Swedish pollen extract, a nonhormonal treatment for vasomotor symptoms, inhibit the CYP2D6 enzyme system? Menopause. 2015;22:1212-4.
  154. Hellström AC, Muntzing J. The pollen extract Femal–a nonestrogenic alternative to hormone therapy in women with menopausal symptoms. Menopause. 2012;19:825-9.
  155. Seeger H, Ruan X, Neubauer H, Brucker S, Mueck AO. Membrane-initiated effects of Serelys® on proliferation and apoptosis of human breast cancer cells. Gynecol Endocrinol. 2018;34:353-6.
  156. Biglia N, Bounous V, De Seta F, Lello S, Nappi RE, Paoletti AM. Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update. 2019;13:909.
  157. Espié M. Bouffées de chaleur et cancer du sein: quelle prise en charge efficace et sans risque ? Cancer au féminin. 2013;1-16.
  158. Fait T, Sailer M, Regidor PA. Prospective observational study to evaluate the efficacy and safety of the pollen extract Sérélys® in the management of women with menopausal symptoms. Gynecol Endocrinol. 2019;4:360-3.
  159. Lello S, Capozzi A, Xholli A, Cagnacci A. Italian Society of Menopause (SIM) and Italian Society of Gynecology of the Third Age of Women (SIGiTE), and of Writing Group of the Pollen Extract in Menopause Italian Study Group. The benefits of purified cytoplasm of pollen in reducing menopausal symptoms in peri- and post-menopause: an Italian multicentre prospective observational study. Minerva Obstet Gynecol. 2022;74:516-21.
  160. De Franciscis P, Conte A, Schiattarella A, Riemma G, Cobellis L, Colacurci N. Non-hormonal treatments for menopausal symptoms and sleep disturbances: a comparison between purified pollen extracts and soy isoflavones. Curr Pharm Des. 2020;26:4509-14.
  161. Appel K, Veit J, Diaz P, Palacios S. Purified and specific cytoplasmic pollen extract, PureCyTonin®, a non-hormonal treatment for hot flushes, inhibits serotonin reuptake. Gynecological and Reproductive Endocrinology and Metabolism 2020;1:64-8.
  162. Svensson U. Report EUDAKG Eurofins Steins Laboratorium. Method EU 152/2009. AR-16-LW-035803-012016;2009.
  163. Peña Vivas J, Alonso Garcia A, Fernández Rivero G, et al. [L-tryptophan as dietetic supplement and treatment for hot flashes, astenia, and insomnia in cancer patients]. Nutr Hosp. 2021;38:568-74.
  164. Freedman RR. Treatment of menopausal hot flashes with 5-hydroxytryptophan.  2010;65:383-5.
  165. Sutanto CN, Loh WW, Kim JE. The impact of tryptophan supplementation on sleep quality: a systematic review, meta-analysis, and meta-regression. Nutr Rev. 2022;80:306-16.
  166. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8:e63773.
  167. Sharkey KM, Fogg LF, Eastman CI. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res. 2001;10:181-92.
  168. Chen WY, Giobbie-Hurder A, Gantman K, et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Res Treat. 2014;145:381-8.
  169. Amstrup AK, Sikjaer T, Mosekilde L, Rejnmark L. The effect of melatonin treatment on postural stability, muscle strength, and quality of life and sleep in postmenopausal women: a randomized controlled trial. Nutr J. 2015;14:102.
  170. Cole KM, Clemons M, Alzahrani M, et al. Vasomotor symptoms in early breast cancer-a “real world” exploration of the patient experience. Support Care Cancer. 2022;30:4437-46.
  171. Park H, Qin R, Smith TJ, et al. North Central Cancer Treatment Group N10C2 (Alliance): a double-blind placebo-controlled study of magnesium supplements to reduce menopausal hot flashes. Menopause. 2015;22:627-32.
  172. Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B. The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial. J Res Med Sci. 2012;17:1161-9.

Keywords: , , , , ,

Citation: Palacios S.,Sven S.,Beltrán L.,Simoncini T.,Celis-Gonzales C.,Birkhaeuser M.,et al. Therapeutic approaches for vasomotor symptoms and sleep disorders in menopausal women, GREM Gynecological and Reproductive Endocrinology & Metabolism (2023); 02-03/2022:074-083 doi: 10.53260/grem.22302032

Published: January 31, 2023