INTRODUCTION
Women, social context and health
Currently, women perform an important socioeconomic role, which has been progressively
conquered. Due to the changes that took place since the 1970s, women now have the
freedom to look for education, finding a job and be financially independent. However,
the equality among genders is not yet totally established[1], as their increased importance and participation in society was not accompanied
by decrease on long-standing classical women-related activities, such as household
responsibilities and maternal tasks. This partial alteration in women’s lifestyle
may bring an overload and markedly increases the vulnerability to stressing factors
and, consequently, to health risks and compromised well-being[2]
,
[3].
In conjunction to this social scenario, the female organism seems to be more vulnerable
to stressing factors by nature. This predisposition is well explained by the hormonal
changes that occur during the menstrual cycle. The premenstrual or luteal phase is
frequently associated with mood alterations, being negativity and irritability very
commonly observed[4]. When these symptoms affect social life, relationships and work, it may be a case
of premenstrual syndrome. During this phase, women seem more prone to anxiety and
depression disorders, as well as increased sleepiness and insomnia[5].
In this sense, it might be noticed that two concurrent factors, among others, contribute
to women’s high predisposition to stress[2]
,
[3]: 1. The lifestyle modern women are subjected to, which leads to overlap of several
social, work and domestic activities, and 2. Women’s hormonal background, which explains
related factors, such as mood oscillations and higher likelihood to anxiety and depression
disorders. Despite parallel and independent, these two factors share an important
feature: both are closely related to women’s sleep pattern.
Women’s sleep
Sleep is an important aspect of the female physiology, as it appears to be directly
influenced by hormonal variation. This influence can be observed both in short term,
concomitantly with menstrual cycle, as well as in long term, ontogenetically from
early life until the postmenopausal period. Regarding the sleep across the menstrual
cycle, evidences suggest that sleep is mostly disturbed during the mid-luteal phase,
when steroidal hormones levels start to decline[6]. During this phase, women tend to experience an increased number of awakenings and
arousals during sleep, if compared with the follicular phase[7]
-
[9]. These findings attest the impact of hormonal oscillations on the onset of sleep
complaints. The same impact might be seem across the lifespan, as shifts on hormonal
patters observed during puberty and menopausal transition are associated with increased
prevalence of insomnia[6].
Considering premenopausal women (i.e. women on their fertile age range, from the menarche
until the menopausal transition - not to be confused with peri or postmenopause -
[Figure 1]), they present a unique pattern of sleep disorder, reasonably different from what
is observed in men and closely related to a hormonal background[6]
,
[10]
-
[14]. Subjective complaints of disrupted and insufficient sleep, poorer sleep quality,
difficulties falling sleep, frequent night awakenings, longer awake periods after
sleep onset and recurrent nightmares are all more frequently reported by women in
comparison to men[13]
,
[15]
-
[18]. These complaints might be associated with sleep disorders, such as insomnia and
obstructive sleep apnea. Gender specificities play an important role in these sleep
complaints, as it seems to be increased in women with irregular menstrual cycles[12], during the menstruation[19] and in those with severe premenstrual syndrome[9].
Figure 1 Women’s life-span and menopause-related events. Premenopause representes the entire
period before the menopause. Adapted from Hachul et al (78).
Among all the sleep-related complaints reported by premenopausal women, the increased
prevalence of insomnia is probably the most remarkable and clinically relevant sleep
characteristic[20]. The prevalence of insomnia is somewhat difficult to achieve due to methodological
caveats, such as the definition of insomnia, the diagnostic criteria, sampling biases
among studies and source population[20]. Even so, it is estimated that about 12-40% percent of all women reports insomnia-compatible
symptoms[21]
-
[29]. In all cases, women are twice as likely to experience insomnia throughout their
lifespan compared to men[30], and the female to male prevalence ratio of insomnia is approximately 1.5/1[31]. Taking together, these studies indicate a strong relationship between hormonal
variation observed in women and the higher prevalence of insomnia.
Sleep and female steroidal hormones
As aforementioned, hormonal oscillation seem to underlie all major sleep complaints
in women, as observed across the menstrual cycle and in association with puberty,
pregnancy and menopausal transition[6]. As an example, it has been suggested that the increase on the prevalence of sleep
complaints and disorders in women during post menopause occurs due to the decrease
of the plasmatic levels of steroidal hormones[32]. Despite several studies have suggested a direct relationship between steroidal
hormones and sleep, the mechanisms behind these sleep changes are still poorly understood.
Regarding the role of hormones on sleep, it is suggested that the two major female
sexual hormones classes are involved: estrogens and progestagens.
It is argued that progestogens have an important hypnotic effect. According to the
results of a double-blind placebo controlled crossover trial, progestagen administration
in men leads to a significant increase on slow-wave sleep and decrease on the slow
wave frequency spectral power during non-REM sleep, which resembles the EEG profile
induced by gabaergic drugs[33]. It leads to reduction on sleep latency, as well as some positive effects on sleep
disorders such as periodic limb movements disorder, bruxism and obstructive sleep
apnea syndrome (for a review, see Andersen et al.[34]). Progesterone is also a potent respiratory stimulant, being related to an increased
dilation of the superior airway as well[34]. Therefore, the decrease on progestagen levels explains the development of sleep
obstructive apnea syndrome on postmenopausal women[35].
Studies conducted in animal models have provided information regarding the potential
mechanism of the hypnotic effects of progestagens. It has been verified that progesterone
is capable of altering the sleep pattern as an agonist of the GABA-A receptors[36]. This effect was reversed when the animals received an antagonist of the GABA-A
receptor, confirming the relationship between the progesterone and gabaergic receptors[37]. It is very likely that progesterone does not act directly on GABA-A receptors though,
but rather involves the activity of a metabolite named allopregnanolone (5α-pregnane-3α-ol-20-one).
This neurosteroid is the final responsible for the GABAergic agonism[38], being also related to other GABA-related effects, such as anxiolysis[34]
,
[38].
Estrogens also have an important effect on the sleep pattern, despite slightly less
well understood than the effects of progestagens. Evidences coming from estrogen replacement
therapy suggests a hypnotic effect, since it ameliorates most of the sleep-related
complaints of perimenopausal women[6]. Additionally, data on rodents suggest that estrogen seems to have an important
effect on the consolidation of the sleep-wake cycle, as ovariectomized female rats
treated with estrogen display a better balance of sleep when compared with control-ovariectomized
females. In this case, estrogen promoted both REM and non-REM sleep during the light
phase (the typical sleep period in rodents) and reduced it during the dark phase (typical
wakefulness period in rodents)[39]
,
[40]. The mechanisms underlying hypnotic effects of estrogen probably involves signaling
via E2 receptors on areas such as the ventrolateral preoptic area, involved on sleep
onset and maintenance, and the lateral hypothalamus, where hypocretinergic neurons
are located[6].
Regardless of the isolated effects of each of these hormones, the actual effects of
sexual hormones on sleep, including its hypnogenic potential, its effects on sleep
architecture and its benefits over sleep complaints seem to be a combination of both
estrogen and progestagens. It not clear how much each of these hormones contributes
to these sleep modulations.
Insomnia and pharmacological treatment
According to the DSM-V, persistent insomnia is defined as a difficulty to initiate
or maintain sleep, with frequent awakenings or difficulty in reinitiating sleep. It
must be present for at least three months, occurring at least three nights a week,
with diurnal effects[41]. Its importance has been highlighted due to its diurnal repercussions which comprises
10% of the population[42], with loss of concentration, mood alterations and tiredness[43]. Concurrently to persistent insomnia, DSM-V also defines episodic insomnia, similar
to the previous but with duration of one to three months, and recurrent insomnia,
when two or more episodes are diagnosed in one year[41].
Considering the increased prevalence, insomnia is an important matter from a public
health perspective, due to its high social and economic impact[31]
,
[43]. This condition represents a significant burden to public health, as it leads to
increased demand for medical and psychiatric care[43]
,
[44]. It also represents a problem for employment relationships, since insomnia has been
related to reduced productivity, decreased work efficiency and absenteeism[43]
,
[44]. It is estimated that the overall costs related to insomnia, both related to direct
and indirect expenses, are between U$92.5 and U$107.5 billion per year in the United
States[31].
Additionally, to its public health aspects, insomnia is also a significant problem
at individual level, since it is associated with several psychiatric and medical consequences.
It has been associated, either in short or long term, with depression, anxiety, substance
abuse, cognitive impairment, metabolic disorders (diabetes, dyslipidemia and obesity)
and cardiovascular disease (for review, check[45]). As insomnia is markedly more prevalent among women than in men (as mentioned on
the women’s sleep section), all these co-morbidities impact women on a bigger proportion.
There is an intense search for therapies to reduce the complaints of insomnia and
all its related consequences, especially among women. Presently, non-benzodiazepine
hypnotics, known as Z-drugs, has been largely employed for the treatment of insomnia,
among which one can highlight zolpidem[46]. This drug acts as a selective agonist of the alpha-1 subunit of the GABA-A receptor,
the main receptor responsible for the inhibition of neurotransmission in the central
nervous system. It is highly prescribed in the whole world due its short term effectiveness,
as well as for its safety, very high when compared with the entire class of the benzodiazepines[47].
Some studies have demonstrated the efficacy of zolpidem in improving the quality of
sleep in patients with chronic insomnia[48]
-
[50]. However, despite its general good efficacy and safety, some reports of side effects
and reduced therapeutic potential has been published, encompassing tolerance, rebound
insomnia, residual effects, impairments on motor performance and memory deficits[51]
,
[52]. Reports have demonstrated an abuse potential for zolpidem[53], although lower then with benzodiazepines, as well as some associations with psychosis,
amnesia, parasomnias, hallucinations, suicidal ideation and other side-effects[54]
-
[56].
Considering the significant prevalence and consequences of insomnia and the limitation
reported on the continuous use of zolpidem, new pharmacological therapeutic strategies
should be sought. This is especially relevant when insomnia is secondary co-morbid
to other conditions. In such conditions, drugs acting on the primary condition might
be more adequate to treat insomnia. As examples, one may cite the use of antidepressants
(e.g.: amitriptyline, trazodone, doxepin and mirtazapine) when insomnia is co-morbid
with major depression; atypical antipsychotics (e.g.: olanzapine and quetiapine) when
it is secondary to bipolar disorder or psychotic episodes; or anticonvulsants (e.g.:
gabapentin, pregabalin and gaboxadol) when it arouses from epilepsy or chronic pain.
In these cases, those specific drugs might be more specific to the mechanisms of the
underlying cause of insomnia.
This condition is similar to the observed in women, case in which the pathophysiology
of insomnia seem to be linked to a hormonal background[57]
,
[58]. Consequently, steroid hormones levels might be seen as a potential mechanism for
therapeutic approaches[6]
,
[34].
HYPOTHESIS
Based on the aforementioned discussion, we hypothesize that sexual hormones (mainly
progestagens) used as contraceptives could have positive effects on the sleep pattern
in premenopausal women. Our hypothesis is driven by four main facts: 1. the high incidence
of insomnia and sleep complaints among women; 2. the sleep-promoting effects of sexual
hormones, 3. the promising results acquired in preclinical research and 4. the benefits
of treating insomnia and its comorbidities with a single therapeutic approach.
A few trials about the effects of contraceptives on sleep supports this hypothesis,
despite of some inconsistencies on the results. Previous epidemiological studies from
our research group have shown that oral contraceptive users display a reduced incidence
of snoring and awakenings[12]
,
[59]. Polysomnographic data proves that women who were using hormonal contraceptives
demonstrated better sleep efficiency and a smaller sleep apnea and hypopnea indexes
when compared with women that did not use hormonal contraceptives in different menstrual
cycle phases[59].
Further studies also show increase in N2 sleep, despite presenting a decrease in non-REM
sleep time[60]
,
[61]. Data from hormonal replacement therapy in postmenopausal women also support this
hypothesis, being effective in reducing sleep complaints during this period[30]
,
[62]. Combined hormonal therapy is also effective in decreasing the severity of apnea
in women from 50 to 59 years of age[63]. Conversely, a recent trial have failed to detect any relevant sleep-promoting effect
on the use of estrogen-progestin therapy[64].
Hormonal contraceptives are available either as a combination of two hormones (progestagen
and estrogen) or as a single hormonal component (usually progestogen). They are available
in different formats and administrations protocols, including oral contraceptives,
intravaginal rings, and transdermal patches, among others. It shall be pointed out
that most of the studies on the field either used only one type of hormonal contraceptive
(progestagen-only or combined presentations) or did not controlled which hormonal
contraceptive the participants were using. This in an important limitation, once there
is an enormous variety of synthetic estrogens and progestagen in the market. The lack
of a proper control and reporting of the type of contraceptives being used in clinical
trials introduces experimental biases and impairs to address adequately its potential
therapeutic effects.
Few studies have focused on more specific and unbiased hormonal administration, and
those focusing on progestogens have provided promising results. On a recent trial
Leeaunkulsathean et al.[65] showed that both micronized progesterone and dydrogesterone significantly improved
sleep quality in peri-postmenopausal women with insomnia. These results are corroborated
by several previous studies, all of them reporting positive effects of progestagen
therapy on sleep in postmenopausal women[11]
,
[66]
-
[68]. All these studies have focused on polysomnographic outcomes such as sleep efficiency,
time spent awake after sleep onset and other objective polysomnographic measures.
This shows that the applicability of progestagens over sleep goes further than its
effects on sleep apnea and breathing, affecting directly sleep continuity measures.
It is worthy to mention that the contraceptives have a specter of action much bigger
than its primary function, being regularly used for indications other than contraception
itself. Contraceptives are the current choice therapy for the treatment of polycystic
ovaries syndrome[69] and dysmenorrhea[70]. Other studies indicate that the use of a combined oral contraceptive is also effective
for the treatment of facial acne[71] and other androgynisms, such as seborrhea, alopecia and hirsutism[72]. In the same way, there is a reduction of the risk of ovarian, endometrial and colorectal
cancer development, among the users of hormonal contraceptives (for revision, see
Schindler[73]). Specifically to progestogens, these drugs present effects not only on contraception,
but also on other hormone-related condition and even in cognitive and behavioral functions[74]. Therefore, the current proposal expands the therapeutic potential of contraceptives
to insomnia in women; a condition deeply related to sexual hormones just as all the
above.
Every secondary use of contraceptives requires a thoughtful investigation about the
better hormonal composition, doses, treatment schedule and route of administration.
This detailed analysis has never been performed for the potential hypnogenic effects
of contraceptives. Most of the trials relating contraceptives and sleep have been
composed by convenience samples, or have had sleep measures as secondary outcomes.
Such lack of specificity is the possible reason for the inconsistencies on the results
disclosed above. It is also the reason why estrogen-based therapies or combined contraceptives
cannot be disregarded from its potential sleep promoting effects, even considering
that present data points out to progestagen as a more reliable therapeutic option.
In summary, we hypothesize that the use of contraceptives could be taken as a therapeutic
alternative to treat insomnia in premenopausal women. A definitive conclusion on the
therapeutic use of contraceptives for insomnia depends upon a proper and unbiased
analysis of their hypnogenic potential (as disclosed on the next section).
RESEARCH AGENDA
Considering the complexity of the current hypothesis, one single study would hardly
be able to address it on its whole. A double-blind clinical trial on the use of contraceptives
among premenopausal women with insomnia would be obviously the best choice to address
the present hypothesis. However, a single clinical trial cannot address all the possible
variations on the use of contraceptives and its potential effects on sleep and insomnia.
In this sense, prior experimental and theoretical approaches are needed as preparatory
steps for a proper clinical trial. These previous steps would provide information
about which are the best hormonal composition, doses, treatment schedule and route
of administration to be tested on a clinical trial. Below a research agenda is proposed,
designed in order to address the present hypothesis:
-
Population-based cross-sectional studies: Epidemiological transversal data might be useful to dissect the contraceptives being
used by a given population and the profile of the women using each different type
of contraceptive. A few transversal epidemiological studies have collected data about
contraceptive use and sleep (such as the São Paulo Epidemiological Sleep Study - EPISONO[59]), but more detailed population-base data are warranted, especially on what regards
the prevalence of use of different types of hormonal contraceptives.
-
Clinical meta-analysis: A meta-analysis on the effects of contraceptives on women’s sleep would be a clever
way to gather all the data available on the field and to synthesize the current evidence.
If there were enough data to draw conclusions, raised from well-designed clinical
studies, a meta-analysis would be able to detect them, providing relevant clinical
data. As per the literature review done to draw the current hypothesis, it is likely
that there is no data for such purpose, mainly due to the heterogeneity among study
designs, populations, outcomes and contraceptives tested. In any case, only a properly
designed systematic review and meta-analysis on the field would be able to gather
the literature, summarize the evidences on a reliable fashion and provide the state-of-the-art
about the relationship between contraceptive use and sleep.
-
Preclinical meta-analysis: Pre-clinical meta-analysis (or meta-analysis of animal data) is an innovative experimental
research tool, usually employed under a translational research context. Despite not
as usual as the regular clinical meta-analyses, preclinical meta-analysis have gained
attention over the last few years, serving for the purposes of both experimental and
clinical researchers. This research method arose due to the need to comprehensively
overview the literature on animal studies before any new clinical trial[75]
-
[77], providing solid background information regarding mechanisms, pharmacology and other
related issues. In this sense, a meta-analysis about sexual hormones administration
and sleep would not be performed only with the intention to summarize effects, but
rather to explore data. It might aim on topics such as the possible effect of different
hormonal sources, doses, administrations routes, administrations schedules, etc. Additionally,
these pre-clinical meta-analyses could provide insight about the specific mechanisms
of action for the hypnogenic effects of sexual hormones. In any case, this meta-analysis
should be able to provide information to drive a better clinical trial design.
-
Clinical trials: Only after these previous steps, which could be done in parallel, a clinical trial
would be feasible. The data arisen from the aforementioned studies would be critical
for a proper study design, as it would define which are the best hormonal contraception
formulations to be tested, the most feasible doses and the best treatment schedules.
In other words, the preliminary steps would define the details on a potential clinical
trial. An additional point regards a proper evaluation of the costs and expenses encompassed
on designing and running a clinical trial. Due to the limited amount of data, a trial
on this field would only be feasible and economically justifiable if preliminary data
demonstrates potential positive results. In the case of sustained negative data on
these previous steps, mainly on the meta-analyses, it would probably be reflected
on negative results on further clinical trials. If the performance of clinical trials
are justifiable based on previous results, we recommend not to set a general trial,
but rather to first analyze the effects of micronized progesterone, as it has already
demonstrated relevant positive effects on the sleep of postmenopausal women. A second
clinical trial could then evaluate commercial contraceptives in different formulations,
doses and treatment regimens. Another important approach on these trials would be
to understand the different possible effects of each of the four generations of progestagens
available.
Each of the proposed steps on research agenda presented above has its limitations.
For instance, cross-sectional studies cannot stablish causal relationships, meta-analysis
are subjected to the limitations, heterogeneity and biases on the original studies,
and clinical trial encompasses different challenges on the definition of an appropriate
experimental design and sample selection. In any case, as long as the limitations
are specific to each proposed step, the outcomes are common point among them all.
Thus, we believe that four steps altogether will be able to generate a good estimate
on the actual effect of contraceptives on premenopausal women’s sleep, by diluting
the effect of possible research biases and aggregating evidences on the field.
CONCLUSIONS
An important aspect of the modern woman´s life was the introduction of the use of
contraceptive methods. These instruments allowed the permanence of woman at the workplace
and consequently, a later maternity. From the several existing methods, we highlight
the use of hormonal contraceptives, which can be used in different configurations:
pills, epidermic adhesives and intravaginal rings.
There are several studies about the use of hormonal therapy and sleep in women during
the peri and post-menopausal phases, besides the results obtained by experimental
models, suggesting that there are steroidal hormone effects upon sleep induction.
However, there are few studies evaluating the effects of the hormonal contraceptives
on sleep parameters in women during reproductive stages. Non-benzodiazepine hypnogenics
are the newest generation for the improvement of sleep disturbances, especially in
women. On the other hand, hormonal contraceptives are commonly used premenopausal
women and its effects might be equivalent to those of zolpidem and drugs alike.
The investigation based on this hypothesis could provide one more therapeutic element
at the physician´s disposal when prescribing a determined contraceptive to the patients,
allowing for the adjustment of indication to their individual complaints and for the
treatment of possible sleep alterations. The use of a hormonal contraceptive with
only one isolated progestagen, a sleep inducing hormone, might modify the quality
of sleep of women with insomnia.
