Understanding Menstrual Cycle Effects on Physical Performance, Substrate Metabolism, and psychiatric symptoms in women.

Lately, women’s health and "living according to your cycle" have gained much attention on social media platforms, and a lot of people are looking for evidence while claiming that nutrition and physical health knowledge and guidelines produced by research don’t account adequately for the cyclical variations a woman’s body goes through psychologically and physiologically throughout the menstrual cycle, pre and post menarche, and pre and post menopause. This article is an attempt to break down the facts behind the potential and limitations of studying the menstrual cycle and the factors that go into the interpretation of the physiological and physiological effects accompanying the hormonal fluctuations and their effect on several pathways and health outcomes.

First: how is the menstrual cycle studied and what are the limitations?

Multiple scientific endeavors had recently focused on addressing the epidemiological research concerning the characterization of the menstrual cycle, its limitations, and the caution needed when interpreting the results before arriving at recommendations for future research. (Jukic, 2020)?(Allshouse et al., 2018) (Wang et al., 2020).

For instance, research on the effects of menstrual cycle fluctuations on sleep patterns can be challenging due to several factors. There is often variability in how menstrual phases are defined across different studies, and menstrual phase status is not always confirmed using hormonal assays. To ensure accurate measurement of sleep and circadian rhythms, it is recommended to stabilize sleep-wake patterns before lab entry. Additionally, there may be specific sleep alterations associated with the luteal phase of the menstrual cycle. (Shechter & Boivin, 2010a)

One of the limitations in studying the circadian rhythm and sleep architecture changes in the context of menstrual cycle phases’ associated variability and circadian variation in the secretion of different hormones across the menstrual cycle are the environmental factors acting as confounders and affecting the interpretation of the observed outcome, for example, ambient light exposure, posture changes, and the sleep-wake cycle, which likely contribute to discrepancies. (Baker & Driver, 2007) (Shechter & Boivin, 2010b)

Methods of dividing the menstrual cycle, as well as sampling frequency, can also be causes of inconsistencies in the scientific literature (Shechter & Boivin, 2010b).

Another example, for instance, is the evidence for the effectiveness of systemic oestrogen to prevent UTI recurrent infections, a topic that will be discussed briefly in the following section and that is based on a few studies with substantial methodological limitations. These studies have not met all the criteria for the ideal study to assess the efficacy of systemic estrogen for recurrent UTI prevention.

Another consideration is an observational study and the potential biases associated with it as opposed to a randomized controlled trial (Mainini et al., 2020).

Small sample size and cross-sectional design, which limit the ability to draw definitive conclusions Additionally, women are excluded from taking prevention supplements, which restricts the number of potential candidates. lack of standardization of the agents used for prophylaxis, which could impact the results. Finally, sampling context—for example, sampling for the urobiome in the absence of acute infection—may cause bias in the results towards non-uro-pathogenic microorganisms. (Vaughan et al., 2021)

Furthermore, prolonged menstrual cycles may not be an accurate reflection of changes in ovulation, as there is substantial variability in follicular and luteal phase length within women. These limitations have both research and clinical implications, as clinicians and investigators should be aware that menstrual cycle length alone may not be sufficient for evaluating ovulatory function in patients. They should consider additional methods, such as ovulation predictor kits or hormonal testing, to confirm ovulation. (Jukic, 2020)

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Challenges in conducting research on menstrual health, including identifying selection bias and generalizability across app-based and traditional epidemiologic studies, Clinicians should be aware of these limitations when interpreting research findings and should encourage further research to improve our understanding of menstrual health. (Jukic, 2020)

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Differences in the definitions of menstrual and intermenstrual bleeding intensity can also limit comparisons across studies. Clinicians should be aware of these differences when interpreting research findings and should use standardized definitions for menstrual bleeding intensity in clinical practice. (Jukic, 2020)

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Understanding the limitations of menstrual health research is crucial for clinicians to provide comprehensive care for patients. Clinicians should consider additional methods to confirm ovulation, be aware of the limitations in research, and use standardized definitions for menstrual bleeding intensity to optimize menstrual health and promote long-term health and well-being. (Jukic, 2020)

In a meta-analysis (McNulty et al., 2020), the limitations were the low quality of most of the included studies and the variability in research design, participant characteristics, and type of performance measured. Moreover, the methods used to identify and verify the menstrual cycle phase in the included studies were inconsistent, which may limit the generalizability of the findings. Therefore, the results should be interpreted with caution, and individualized approaches should be taken based on each individual's response to exercise performance across the menstrual cycle.

Regarding substrate metabolism assessment, not all studies carefully consider the nuances of female physiology in their menstrual cycle and hormonal research, and some studies may have used methods that are open to question (Hackney, 2021).

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The use of self-reported menstrual cycle characteristics, which may be subject to measurement error, and the relatively homogeneous racial/ethnic and educational backgrounds of the study participants, which may limit the generalizability of the findings, (Wang et al., 2020)

The heterogeneity of the study methodologies and the lack of consensus on the diagnosis and assessment of premenstrual psychiatric symptoms are also considered limitations of research in this area. (Handy et al., 2022)

A study by Schmalenberger et al. (2021) suggested some practical recommendations for studying the menstrual cycle, suggesting tools like self-report tools, ovulation prediction kits, hormone assays, ultrasound imaging, and wearable devices. They also recommended considering the study design and sample size when studying the menstrual cycle, as well as controlling for confounding factors such as age, body mass index (BMI), and medication use.

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Second, lifestyle affects the reproductive health of females and vice versa.

An internet-based survey of 42,879 women aged 15–45 found that dysmenorrhea, psychological complaints, and tiredness were the most common menstrual symptoms, with 38% of women reporting being unable to perform all their regular daily activities during their menstrual period. The study suggests a need for improved education and support for women experiencing menstrual symptoms and increased awareness and understanding among both patients and healthcare providers. (Schoep et al., 2019)

"A retrospective cohort study" aimed to investigate menstrual cycle length and patterns in a global cohort of women using a mobile phone app. They analyzed data from a mobile phone app called Clue, which is designed to help women track their menstrual cycles and associated symptoms. The study included data from over 600,000 women from 180 countries and found that the majority of women had a regular menstrual cycle with a cycle length that varied by less than 7 days. However, a significant proportion of women had irregular cycles, which may be indicative of underlying health conditions such as polycystic ovary syndrome (PCOS) or thyroid dysfunction.

They also found that the average menstrual cycle length was 29.3 days, with a standard deviation of 8.8 days, and they also identified the following patterns: Regular cycles were when women had a cycle length that varied by less than 7 days. Women with irregular cycles had a cycle length that varied by more than 7 days. Women with short cycles had a cycle length of less than 21 days, and women with long cycles had a cycle length of more than 38 days. The majority of women (76%) had a cycle length that varied by less than 7 days, indicating a regular menstrual cycle. Women with irregular cycles (cycle lengths that varied by more than 7 days) accounted for 24% of the sample. Women with short cycles (cycle length of less than 21 days) accounted for 0.3% of the sample, while women with long cycles (cycle length of more than 38 days) accounted for 1.9% of the sample. Age, BMI, and geographical location were found to be significant predictors of menstrual cycle length and patterns. (Grieger & Norman, 2020) (Bull et al., 2019)

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The characteristics of the menstrual cycle are important indicators of a woman's health, and environmental factors can affect these characteristics. Menstrual disturbance is linked to various medical conditions such as migraine, asthma, and endocrine-pathies, and clinicians should prioritize the assessment and management of menstrual irregularities to help optimize menstrual health in women and promote long-term health and well-being. The heritability value for menstrual cycle interval and duration is low, with a significant non-shared environmental effect on cycle interval and a shared environmental effect on cycle duration. Therefore, clinicians should encourage patients to maintain a healthy lifestyle and avoid environmental factors that may negatively impact their menstrual cycle. Further research is necessary to better understand the mechanisms underlying these influences and to develop effective interventions for optimizing menstrual health in women. (Jahanfar, 2012)?(Pp et al., 1994) (Windham et al., 1999) (Fenster et al., 1999) (R.J. et al., 2006) (Krassas et al., 1999) (Treloar et al., 2002) (Critchley et al., 2001) (B et al., 2002) (Ho et al., 2001)

A comprehensive review by Campbell et al. (2021) found that some studies suggest that a diet high in fat and low in fiber may be associated with longer menstrual cycle length and irregularity. Both too little and too much exercise can disrupt menstrual cycle length and regularity, with the optimal level of exercise varying depending on individual factors such as age, weight, and menstrual history. High levels of stress can disrupt the menstrual cycle, leading to longer cycle length and irregularity. Exposure to environmental toxins such as pesticides, phthalates, and bisphenol A may disrupt the menstrual cycle and lead to longer cycle length and irregularity. Factors such as shift work, night-time light exposure, and the use of hormonal contraceptives may also impact menstrual cycle length and regularity. They also highlighted the need for further research to better understand the relationship between modern living and menstrual cycle characteristics, as well as the importance of an individualized approach when assessing the impact of modern living on menstrual cycle length and regularity. that the impact of modern living on menstrual cycle characteristics may have implications for women's health and fertility, as longer cycle length and irregularity may be associated with reduced fertility and an increased risk of reproductive disorders such as PCOS. Further research is still needed to optimize the application of these findings.

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One narrative review focused on summarizing the factors behind the irregularities and delay of the regular ovulatory cycle post menarche and the effect of the regularities and delay on the reproductive health and overall quality of life. (Saei Ghare Naz et al., 2022a). Their research was based on the fact that several factors, including genetics, race/ethnicity, intrauterine situation, social factors, geographical factors, lifestyle, and chronic diseases, can cause the variation between the onset of menarche and the onset of the regular cycle in adolescent girls. Observational studies had attributed the irregularities to the high serum level of androgens and the immaturity of the neuro-endocrine system, particularly the hypothalamic-pituitary-ovarian axis (HPO) (West et al., 2014). (Shaw et al., 2012). The hypothalamic-pituitary-ovarian (HPO) axis is responsible for regulating the menstrual cycle and ovulation. The hypothalamus secretes GnRH, which stimulates the pituitary gland to release FSH and LH. FSH and LH act on the ovaries to stimulate the growth and maturation of follicles, which contain the eggs. The release of LH triggers ovulation, and the remaining follicle cells from the corpus luteum produce progesterone. (Reed & Carr, 2018)

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The onset of regular ovulatory menstrual cycles in adolescence is influenced by a variety of factors, including genetic diversity, lifestyle factors such as diet and physical activity, body fat, stressors, hormonal diseases and medications, social and geographical factors, and exposure to air toxins or pollutants during prenatal and childhood periods. Understanding these factors and their impact on the onset of regular menstrual cycles is crucial for clinicians to provide comprehensive care for adolescent patients. Clinicians should educate patients and their families on the importance of maintaining a healthy lifestyle, including a balanced diet and regular physical activity, for optimizing menstrual health. They should also encourage patients to manage stress through relaxation techniques and to seek medical attention for hormonal diseases or medications that may affect menstrual health. Additionally, clinicians should advise patients to avoid exposure to air toxins or pollutants, especially during prenatal and childhood periods, and to discuss any concerns about menstrual irregularities with their healthcare provider. Further research is necessary to better understand the mechanisms underlying these influences and to develop effective interventions for optimizing menstrual health in adolescents. By addressing these factors and educating patients, clinicians can help optimize menstrual health in adolescent patients and promote long-term health and well-being. (Yermachenko & Dvornyk, 2014) (Forman et al., 2013) (Dossus et al., 2012a) (Viner et al., 2012) (J?rvelaid, 2005; Behie & O’Donnell, 2015). (D’Aloisio et al., 2013) (Parent et al., 2003) (Canelón & Boland, 2020; Saei Ghare Naz et al., 2022b)

A multidisciplinary approach is needed to address the complex interplay between these factors and their impact on the hypothalamic-pituitary-ovarian (HPO) axis. Further research is necessary to better understand the mechanisms underlying these influences and to develop effective interventions for optimizing menstrual health in adolescents. (Saei Ghare Naz et al., 2022b) (Ramezani Tehrani et al., 2014) Clavel-Chapelon & E3N-EPIC Group, European Prospective Investigation into Cancer, 2002) (Riestra et al., 2011) (Farahmand et al., 2020) (Sun et al., 2018) (Zhang et al., 2008) (Zhang et al., 2008) (Feigelson et al., 1997) (Berkey et al., 2000) (Günther et al., 2010) (Frisch & McArthur, 1974) (Farahmand et al., 2012) (Dossus et al., 2012b)

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A study by Kwak et al. (2019) found significant differences in the prevalence of irregular menstruation among adult South Korean women based on several factors, including spousal status, waist circumference (WC), body mass index (BMI), smoking status, stress, age at menarche, and childbirth status. Obese women with high WC and BMI values are at risk of hormonal changes that cause menstrual irregularity, and mental stress can also lead to menstrual problems by facilitating corticotrophin release and hormonal imbalances. High levels of job strain, exhaustion, and stress related to working conditions are known risk factors for gynecologic pain. Irregular life patterns, stress, and dietary changes can also contribute to menstrual irregularity. (Zhou et al., 2010) (Wei et al., 2009) (Nohara et al., 2011) (Attarchi et al., 2013) (Figà-Talamanca, 2006) (Yamamoto et al., 2009). Physical and mental fatigue, irregular mealtimes and working hours, stress, and dietary changes can contribute to overwhelming feelings in women's daily lives, impacting reproductive health and menstrual irregularity, underscoring the importance of self-care and counseling interventions. (Kim & Ko, 2015a). Clinicians should consider these factors when evaluating and treating menstrual irregularities in adult women. They should encourage patients to maintain a healthy lifestyle, including a balanced diet and regular exercise, to manage stress through relaxation techniques or counseling, and to avoid smoking. Clinicians should also consider additional hormonal testing or imaging to confirm menstrual irregularity and identify any underlying conditions that may be contributing to the irregularity.

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This study's strengths include its large sample size and specific analysis of the association between irregular menstruation and socioeconomic status. However, the study's limitations include a lack of causal relationships, uncontrolled confounders, and a need for a clear definition of irregular menstruation in future studies. Clinicians should be aware of these limitations when interpreting research findings and should encourage further research to improve our understanding of menstrual health. (Kwak et al., 2019)

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Understanding the factors that contribute to menstrual irregularity is crucial for clinicians to provide comprehensive care for adult women. By addressing these factors, clinicians can help optimize menstrual health in this population and promote long-term health and well-being. Further research is necessary to better understand the mechanisms underlying these influences and to develop effective interventions for optimizing menstrual health in adult women.

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The significance of the sleep-wake cycle in regulating the cycle during puberty was highlighted, with sleep affecting the Gn-RH (gonadotropin-releasing hormone) hormone release, of which the sleep-wake cycle of this hormone varies during puberty; this important hormone is affected during waking hours by steroid hormones, including estradiol and progesterone, as they mediate the neuronal signals input. (McCartney, 2010).?Moreover, immature LH (luteinizing hormone) release in post-menarche during sleep has a role in the irregularity of the menstrual cycle. (Sun et al., 2019). In a population-based cross-sectional study among South Korean female adolescents, sleep duration of less than 5 hours per day was associated with menstrual irregularities, showing that enough sleep is important for the reproductive health of female adolescents. (Nam et al., 2017). Ovarian and pituitary gland hormones are directly affected by sleep; a biorhythmic disruption that can affect menstruation was found to be caused by a lack of sleep (Kim & Ko, 2015b). (Mahoney, 2010)

Interestingly, the sleep-wake cycle affects hormonal secretion like melatonin and cortisol, which are also affected by environmental factors like stress and light exposure; similarly, thyroid stimulating hormone and prolactin are affected by the menstrual cycle in women (Shechter & Boivin, 2010a). Generally, hormones like cortisol, thyroid stimulating hormone (TSH), prolactin (PRL), and melatonin are known to be affected by sleep in addition to playing a role in its organization (Duffy & Dijk, 2002). (Van Cauter et al., 2007) (Zisapel, 2005)?(Suchecki & Tufik, 2005); the menstrual cycle plays a role in modulating hormones as well as a similar role in regulating body temperature due to fluctuations in gonadotropic and sex steroid hormones. (Shechter & Boivin, 2010a). Where changes in hormones across the menstrual cycle cause a 0.3–0.4 oC?increase in core body temperature while concurrently reducing the circadian variation.?Sweating, vasodilatation, thermal conductance, and skin blood flow thresholds change as a result, which is attributed to the thermogenic properties of progesterone. Kuwahara et al., 2005) (Baker et al., 2001a) (Cagnacci et al., 2002) (Y et al., 2005) (Cagnacci et al., 1996) (Kolka & Stephenson, 1997) Progesterone is known to have neuro-active metallopeptides, which act as agonistic modulators of central nervous system GABAA-receptors in a benzodiazepine-like manner. (Lancel et al., 1996a) (Driver et al., 1996a), can affect sleep architecture; also, its synthetic analogues (agonists) have similar effects; for example, megestrol acetate reduces REM sleep in male participants. (Lancel et al., 1996b) Wiedemann et al. (1998) (Friess et al., 1997). Additionally, progesterone is claimed to increase body temperature in the luteal phase, causing variations in the sleep system. (Shechter & Boivin, 2010c) Furthermore, decreased levels of the anxiolytic progesterone metabolite allopregnanolone during the LP are found in PMDD patients (Rapkin et al., 1997) (Monteleone et al., 2000). It should be noted that reduced plasma and whole-blood serotonin levels found in PMDD patients compared to controls implicate the serotonergic system, which is also a precursor for melatonin synthesis, and SSRIs are the most commonly used clinical treatment for the disorder. Serotonin is a precursor of melatonin synthesis. (Rapkin et al., 1987) Taylor et al., 1984; Pearlstein, 2002) (Rapkin et al., 1997)

It was found that sleep disturbance complaints are common among women in their luteal phase of the cycle, showing a correlation between the severity of pre-menstrual symptoms and the increased incidence of day sleeping. These results were found through a sleep-wake diary filled out by 32 healthy women twice daily for only two cycles. Even though the disturbances were reported in all subjects, given the limitations mentioned above that still challenge research in this area, there could be some limitations to generalizing this conclusion. (Manber & Bootzin, 1997), another study found that these symptoms are more common in women suffering from Late Luteal Phase Dysphoric Disorder (LLPDD), where the evaluated data of 1000 women seeking treatment or evaluation was done using the American Psychiatric Association's DSM-IV, "Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition," which is a manual published by the American Psychiatric Association (APA) that provides criteria and descriptions for the diagnosis of mental disorders. The DSM-IV was first published in 1994 and was later revised and replaced by the DSM-IV-TR (Text Revision) in 2000. American Psychiatric Association, 2000. Diagnostic and statistical manual of mental disorders, text revision (4th ed.). Washington, DC: Author, " with women who had had mental disorders in the past but not present having a significantly greater, but very small, relative risk of LLPDD. (Hurt et al., 1992)

Sleep architecture was reported to be an aspect affected by menstrual phases, meaning the organization and patterns of sleep cycles, the stages of sleep, and the frequency and duration of each stage (Baker et al., 2002a). (Baker et al., 1999; Driver et al., 1996b). Usually, the complaints are reported by women in late premenstrual and premenstrual days; however, polysomnography (PSG), which is a diagnostic test that records a variety of physiological parameters during sleep to help diagnose sleep disorders, has indicated disrupted sleep during this time less frequently (Kryger et al., 2010). Variation in the stages affected in sleep architecture during different menstrual cycle phases exists in scientific literature with inconsistency among studies, particularly REM (rapid eye movement) sleep, a stage of sleep characterized by rapid, random eye movements, muscle paralysis, and increased brain activity, and is associated with dreaming and Slow wave sleep (SWS) is a stage of deep sleep characterized by slow, synchronized brain waves, reduced muscle activity, and a decreased heart and respiratory rate. Baker et al., 2007) (Baker et al., 2001b) (Driver et al., 2005) (Parry et al., 1999) (Baker et al., 2002b) (Ito et al., 1993) (Parry et al., 1989)

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The findings of Shechter & Boivin (2010)c suggest that most studies found no significant changes in melatonin, cortisol, TSH, and PRL levels, yet some studies reported phase delays for melatonin, cortisol, and TSH during the luteal phase compared to the follicular phase. Interestingly, changes in TSH and PRL (decreased TSH amplitude and increased PRL amplitude) levels during the luteal phase were opposite to those seen after partial nocturnal sleep deprivation, although PSG-based estimates of sleep showed no differences at different menstrual phases. (Baumgartner et al., 1993)

The menstrual cycle interacts with circadian processes to alter hormonal rhythms and sleep organization, potentially leading to sleep disturbances during the LP in healthy women or LP-associated pathology, such as PMDD. While circadian hormone rhythms are generally not significantly altered across the menstrual cycle, studies have reported variable results, including changes in the timing of hormones and melatonin secretion. Nonpharmacological therapies for PMDD symptoms that target the sleep-wake cycle and circadian rhythms, like phototherapy and sleep deprivation, may be effective in improving mood and sleep quality. Researchers studying sleep and circadian rhythms in women should control for and document menstrual cycle phase and consider the role of age-related neuroendocrine changes in sleep regulation. Clinicians should be aware of the potential impact of menstrual cycle-related sleep disturbances in evaluating and treating menstrual-related disorders. Women with PMDD may benefit from nonpharmacological therapies that target the sleep-wake cycle and circadian rhythms. Researchers studying sleep and circadian rhythms in women should consider menstrual cycle phases and age-related neuroendocrine changes. By addressing these factors, clinicians can help optimize menstrual health in women and promote long-term health and well-being. Further research is necessary to better understand the mechanisms underlying these influences and to develop effective interventions for optimizing menstrual health in women. (Shechter & Boivin, 2010a)

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There is evidence that melatonin can decrease pro-inflammatory cytokines and reduce mast cells’ proliferation and activation in cystitis, attenuating the severity of it and the accompanied inflammation. (Fathollahi et al., 2015). As mentioned earlier, melatonin is one of the hormones affected by menstrual phase variation and regulating circadian rhythms and the sleep-wake cycle, and as a study found that menopausal women have increased sleep abnormalities than pre-menopausal women and loss of circadian robustness (Gómez-Santos et al., 2016), the circadian system controls urinary bladder function and how disruptions to this system can lead to bladder disorders such as nocturia. Melatonin, a hormone that regulates circadian rhythms, has the potential to treat these bladder disorders by acting on both central and peripheral mechanisms. Further research is necessary to fully understand the relationship between the circadian system and bladder function and the specific mechanisms by which melatonin influences the bladder (Ramsay & Zagorodnyuk, 2023). There is also evidence that exogenous melatonin can improve the quality of sleep (subjectively) in postmenopausal women with sleep disturbances (Treister-Goltzman & Peleg, 2021). Moreover, disruption of the pineal gland's circadian rhythms, indicated by a decrease in melatonin production, may play a role in the onset and progression of menopause. A randomized, double-blind, controlled trial by Bellipanni et al. (2001) on peri-menopausal and menopausal women to investigate the effect of exogenous melatonin on pituitary (LH, FSH), ovarian, and thyroid hormones (T3 and T4) concluded that reduced melatonin levels during ageing may indicate an impairment in ovarian function regulation by the pineal and pituitary glands, leading to fertility decline, but melatonin treatment may help restore a more youthful pattern of regulation.

As women age, the follicle cohort shrinks, leading to a decline in the total oocyte pool. Anti-mullerian hormone (AMH) and inhibin B, which help maintain ovulatory capacity, decline throughout reproductive life. Follicle-stimulating hormone (FSH) rises, especially in the early follicular phase. Ultrasound assessment of small, antral follicles provides a measure of ovarian reserve.

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The Penn Ovarian Ageing Study (POAS) identified a stage that divides STRAW Stage 2 (early transition phase of menopause), the early transition, into a late premenopausal and the early transition based on the number of irregular menstrual cycle events. The process of follicle loss is initially compensated for by lower AMH and inhibin B and intermittently rising FSH. (Burger et al., 2002) Ahmed Ebbiary et al., 1994; Burger et al., 2002; Hansen et al., 2012; Gracia et al., 2005; Hansen et al., 2008).

The first stage of the menopause transition is characterized by a critical drop in follicle numbers that leads to changes in a woman's menstrual cycle. This drop in follicle numbers is preceded by at least a decade of rising follicle-stimulating hormone (FSH) and reduced inhibin A and B, as well as anti-mullerian hormone (AMH), but these hormonal adjustments are clinically silent. The process of follicle maturation and oocyte growth is altered due to high FSH stimulation and increased follicular aromatase. Follicles grow earlier in the cycle, and ovulation occurs earlier in the menstrual cycle. Oocytes of reproductively ageing women are more prone to meiotic spindle abnormalities and a loss of mitochondrial DNA, which can lead to more frequent and variable menstrual periods, more variable hormone production, a lesser likelihood of consistent ovulation, and brief bouts of amenorrhea. These changes can destabilize women in several ways, such as causing mood changes and affecting overall well-being. Clinical symptoms like mood disorders, sleep disturbances, and pain symptoms are attributed to the fluctuation of oestrogen, particularly during the menopausal transition, which would require a personalized approach to manage symptoms. During the transition, women experience longer periods of amenorrhea, which can be hypoestrogenic and hypergonadotropic. However, when cycles do occur, they remain likely to be ovulatory and potentially fertile. Evidence of luteal activity (ELA) is typically present in these cycles, but non-ELA cycles may have a robust oestrogen rise or no oestrogen production at all. Moreover, poor sleep quality and sleep disruption are common during the transition and have been associated with fluctuations in hormones, particularly lower estradiol and higher levels of testosterone and FSH. Longitudinal studies are needed to better understand the biological mechanisms underlying these symptoms and changes in hormone levels to optimize management strategies. Overall, understanding the physiological and clinical implications of the menopausal transition is crucial to promoting women's health and well-being. Understanding these physiological changes in the context of women's reproductive health It is essential to monitor ovarian reserve and menstrual irregularities to identify any potential issues early on. (Allshouse et al., 2018) (Welt et al., 1999) Klein et al., 2002) (Klein et al., 1996) (Santoro et al., 2003) (Shaw et al., 2015) (Santoro et al., 1996) (Keefe et al., 1995) (Battaglia et al., 1996) (Battaglia et al., 1996) (Welt et al., 1999) (Klein et al., 2002) (Klein et al., 1996) (Santoro et al., 2003) (Shaw et al., 2015)

Urinary tract infections (UTIs) are a common issue in menopausal women, affecting 35–40% of them and being caused by Escherichia coli in 85% of cases. (Mody & Juthani-Mehta, 2014a) (Gupta et al., 2017) The fall in oestrogen levels during menopause can lead to urogenital mucosal changes, predisposing women to bladder infections. (Szadowska-Szlachetka et al., 2019) Faubion et al. (2017)

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Urinary tract infections (UTIs) are common in menopausal women due to the fall in oestrogen levels, which can lead to urogenital mucosa changes that predispose women to bladder infections, which can have a significant impact on their quality of life. Antibiotic resistance is an emerging issue for E. coli, Klebsiella, and Enterobacteria strains, which are already resistant to third generation cephalosporins and carbapenems. Therefore, researchers are finding suitable adjuvant therapies for UTIs that do not rely solely on antibiotics. It is recommended to follow the standard rules of treatment and prevention, such as reducing constipation, using antibiotic therapy only if necessary, and acidifying the urine to reduce bacteria on the bladder mucosa. (Mody & Juthani-Mehta, 2014b) (Tamadonfar et al., 2019) (Selekman et al., 2018)

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To prevent and treat UTIs, various natural approaches can be used, such as prebiotics, including inulin and Lactobacillus acidophilus, which help control constipation, and D-mannose, which reduces bacteria's adhesion to the urothelium. Cranberry acidifies urine, inhibiting the adhesion of microorganisms, while bearberry has an antiseptic action on the bladder and urethra. Olive leaves have depurative, anti-inflammatory, and laxative properties, while Orthosiphon is useful in UTIs of a bacterial and inflammatory character. Hygienic-behavioral rules such as intimate hygiene and avoiding bladder irritants are recommended. Drinking at least 1.5 liters of water per day is also recommended. (Mainini et al., 2020) (Aragón et al., 2018) (Bustamante et al., 2020) (Homayouni et al., 2014) Shim et al. (2016) (Kranjec et al., 2014) (Sihra et al., 2018; Rauf et al., 2019; Fu et al., 2017) (Moore et al., 2019) (Gorzynik-Debicka et al., 2018) (Yuan et al., 2015) (Bokhari et al., 2018) (Ashraf et al., 2018). Oral immunostimulants, vaginal vaccines, and bladder instillations with hyaluronic acid and chondroitin sulfate are also promising options for preventing UTIs. (Caretto et al., 2017)

In postmenopausal women, systemic oestrogen has been studied as a potential preventive measure against recurrent UTIs. However, the evidence for its effectiveness is based on a few studies with substantial methodological limitations. Therefore, the use of systemic oestrogen for recurrent UTI prevention should be evaluated on a case-by-case basis. A literature review found limited evidence for the use of systemic oestrogen for the prevention of recurrent UTIs in postmenopausal women, and the existing studies have substantial methodological limitations, highlighting the need for careful consideration of the use of systemic oestrogen in clinical practice. (Fox et al., 2021). (Mainini et al., 2020)

A review of randomized controlled trials found that oral oestrogen therapy had no significant effect on preventing rUTIs compared to a placebo. However, vaginal oestrogen treatment was associated with a lower pH and a reduced number of rUTIs, although adverse events such as vaginal discomfort were reported. These findings suggest that clinicians should consider vaginal oestrogen treatment as a potential option for preventing rUTIs in menopausal women while monitoring for adverse events. Furthermore, it is important to note that menopausal oestrogen levels are implicated in the pathogenesis of pelvic floor disorders and rUTIs, highlighting the need for further research to optimize the therapeutic potential of oestrogen therapy for rUTI prevention in menopausal women. A multidisciplinary approach is required to effectively prevent and treat rUTIs in menopausal women, taking into account the potential limitations of systemic oestrogen for recurrent UTI prevention and considering alternative approaches. Clinicians should also monitor for adverse events and evaluate the benefits and risks of each therapy on a case-by-case basis. (Raz & Stamm, 1993) (Alperin et al., 2019; Chen et al., 2021) (Keating et al., 2005) (Lüthje et al., 2013)

UTIs are also associated with mood changes and anxiety, and the use of a nutraceutical approach may be useful in non-complicated cases. However, in other cases, an antibiotic approach should be considered. Clinicians should be aware of the potential limitations of systemic oestrogen for recurrent UTI prevention and consider alternative approaches. Overall, a multidisciplinary approach is needed to effectively prevent and treat UTIs in menopausal women. (Renard et al., 2014) (Riemma et al., 2019; Mainini et al., 2020).

The urobiome may be a therapeutic target for prevention and treatment options, emphasizing the importance of prevention in improving care for postmenopausal women affected by rUTI. (Jung & Brubaker, 2019)

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A study, which is a cross-sectional analysis of baseline data from 64 women enrolled in a longitudinal cohort study, found that menopausal women using vaginal oestrogen therapy with recurrent UTIs and matched controls did not have significant differences in the abundance of Lactobacilli, but there were trends towards different Lactobacillus species between groups. Additionally, women with recurrent UTIs who took daily antibiotics had different microbial compositions compared to controls without recurrent UTIs. The findings suggest that it may not be one particular microbe within the urobiome that is associated with recurrent UTIs but rather a shift in the balance of Lactobacilli or particular species of Lactobacilli compared to anaerobic bacteria. These results highlight the importance of considering the potential associations between microbial composition and several covariates, such as sexual activity, age, BMI, and history of diabetes (which can emphasize the endocrinological interplay between associative variations with changes of the menstrual cycle in the female body and the essential hormones regulating key physiological processes), which also could serve as significant confounders of microbial results if not incorporated into analyses. Clinicians should also be aware of the limitations of this cross-sectional study, including its small sample size, and that further, larger studies are needed to confirm these findings and explore potential therapeutic interventions for recurrent UTIs in menopausal women. Overall, the study underscores the importance of a multidisciplinary approach to the prevention and treatment of recurrent UTIs in menopausal women, considering both systemic and topical therapies and taking into account individual patient characteristics and microbial compositions. (Vaughan et al., 2021)

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The menstrual cycle is a valuable model for studying the influence of ovarian steroids on emotion, behavior, and cognition. Studies suggest improved prefrontal cortex function during high estradiol levels and emotional processing changes during the luteal phase, with progesterone being a key factor in increased amygdala reactivity and emotional memory. Inconsistencies in menstrual cycle effects could be due to the modulatory effects of estradiol and/or progesterone on classical neurotransmitters, serotonin, GABA, and neuropeptides. However, there is insufficient evidence to support hypotheses regarding cognitive skills and menstrual cycle phases. (Sundstrom Poromaa et al., 2003; Protopopescu et al.,?2005; Amin et al.,?2006). (Gingnell et al.,?2012; Bayer et al., 2014).?(Andreano and Cahill,?2010; (Ferree et al., 2011). (Ertman et al.,?2011) (Bryant et al.,?2011) (Ferree et al.,?2011; Soni et al.,?2013); (Conway et al., 2007; van Wingen et al.,?2007; Derntl et al.,?2008b,?2013; Gasbarri et al.,?2008; Guapo et al., 2009);?(Comasco et al.,?2014); (Sommer, 1973); (Sherwin, 2012). Jacobs and D'Esposito (2011) (Smith et al., 2014) Bethea et al.,?2002; van Wingen et al.,?2008).?

?A comprehensive review of the literature on psychiatric symptoms that occur across the menstrual cycle in adult women According to a systematic review of 60 articles (Handy et al., 2022), the hormonal changes that occur during the menstrual cycle, specifically the fluctuations in oestrogen and progesterone levels, may contribute to the development of psychiatric symptoms such as depression, anxiety, irritability, and mood swings in women, particularly during the premenstrual phase. Non-pharmacological interventions, such as cognitive-behavioral therapy and lifestyle modifications, are suggested to have a potential benefit in managing premenstrual psychiatric symptoms in women during the hormonal fluctuations associated with the menstrual cycle. Healthcare providers should strive to improve awareness and understanding of the menstrual cycle’s effects on psychiatric symptoms among patients and their peers alike. However, it’s worth noting that the studies in this systematic review had limitations, and further research is still in demand in this area.

These findings have clinical implications for individuals with menstrual-related mood disorders, as they may experience emotional processing changes during the luteal phase. Clinicians should be aware of the potential impact of ovarian steroid fluctuations on emotional processing and consider incorporating this into treatment plans. Further research is needed to better understand the mechanisms underlying these influences and develop more effective treatment options for individuals with menstrual-related mood disorders. Additionally, understanding the modulatory effects of estradiol and progesterone on neurotransmitters and neuropeptides may inform the development of targeted interventions for emotional disorders more broadly. (Sundstr?m, Poromaa, & Gingnell, 2014)

?

?

?

Regarding physical exercise, the impact of menstrual cycle (MC) phases on physical performance varies depending on the performance variable being measured due to changes in muscle activation, substrate metabolism, thermoregulation, and body composition. While some research suggests that MC phases affect strength, aerobic, and anaerobic performance differently, other studies have found no significant difference in performance between MC phases in eumenorrheic athletes. Therefore, clinicians should consider the individual athlete's performance goals and the predominant performance variable being utilized when developing training plans based on the MC phase. (Carmichael et al., 2021) (Szmuilowicz et al., 2006) (Akturk et al., 2013) (McKee & Cameron, 1997) (Julian et al., 2017) (Marshall, 1963)

?

Based on current research, endurance performance may be best early in the MC, while anaerobic and strength performance may be best in the ovulatory phase. Strength and aerobic performance may be worst in the late luteal phase, and anaerobic performance could be worst in the late follicular phase. Clinicians should consider these potential impacts when evaluating and treating female athletes and developing training plans and performance goals. Fluctuations in bioavailable testosterone during the ovulatory phase may impact strength, while changes in tissue stiffness throughout the MC may affect muscle properties. The shift in thermoregulatory set point during the luteal phase may impact performance depending on activity duration. The effect of the MC phase on body composition is not well understood but may be affected by changes in oestrogen and progesterone. Substrate availability and metabolism may also vary in different phases of the MC and impact endurance performance. (Carmichael et al., 2021) (Abdelsattar et al., 2018) (Yim et al., 2018) (Maciejczyk et al., 2015) (Maciejczyk et al., 2014; Frandsen et al., 2020) (Hackney et al., 1994a) (Oosthuyse & Bosch, 2010a) (Janse de Jonge, 2003) (Julian et al., 2017) (Girard et al., 2015) (Bryant et al., 2008; Cook et al., 2018) (Smith et al., 2002)

?

?

?

Further research is necessary to better understand the mechanisms underlying these influences and to develop effective athlete management strategies to optimize performance and maintain health in female athletes. Clinicians should also encourage female athletes to track their MC and adjust their training accordingly. By considering the impact of the MC phase on physical performance, clinicians can help female athletes optimize their athletic performance and promote long-term health and well-being. (Carmichael et al., 2021)

?

However, it is important to note that there are inconsistent findings on mechanistic outcomes, such as muscle and tendon stiffness or substrate metabolism, throughout the MC. Therefore, clinicians should be aware of these inconsistencies and encourage further research to better understand the effects of MC on athlete performance. (Carmichael et al., 2021) (Crewther et al., 2011) Pallavi et al., 2017) (Tenan et al., 2013) (Del Vecchio et al., 2019) (Phillips et al., 1996) (Kim & Ko, 2015a)

?

Overall, understanding the potential impacts of MC on physical performance is crucial for clinicians to provide comprehensive care for female athletes. By considering these factors in training and performance planning, clinicians can help female athletes optimize their athletic performance while promoting long-term health and well-being. (Carmichael et al., 2021)

?

?

A meta-analysis of studies investigating exercise performance across different phases of the menstrual cycle found that exercise performance may be trivially reduced during the early follicular phase but was consistent across all other phases. However, the quality of the studies was generally low, and there was considerable variability between studies, which may have influenced the results. Therefore, a personalized approach is recommended based on individual responses to exercise performance across the menstrual cycle, and further research is needed to better understand the potential effects of endogenous ovarian hormones on exercise performance. The study highlighted the potential role of ovarian hormones, particularly oestrogen and progesterone, in mediating exercise performance across the menstrual cycle. Oestrogen is known for its anabolic effects, regulation of substrate metabolism, and neuroexcitatory effects, while progesterone has antiestrogenic effects. The study suggests that exercise performance may be mediated by the concentration of endogenous ovarian hormones in some exercising women. The findings have clinical implications, as the impact of menstrual symptoms on exercise performance may affect athletic performance or exercise goals. (McNulty et al., 2020)

?

Moreover, age, body composition, and physical activity status may influence the effect of female steroid sex hormones (FSHH) on substrate metabolism, where physically active women may have a more weakened response to FSSH fluctuations. For instance, during certain phases of the menstrual cycle when oestrogen levels are higher, women may be better able to utilize carbohydrates as a fuel source during exercise, while during other phases when progesterone levels are higher, they may be more efficient at burning fat. (Mujika & Taipale, 2019) (Sims & Heather, 2018) (Stachenfeld, 2018)?(Bunt, 1990)?(Shaw et al., 2015) While other studies had found that higher oestrogen levels may result in higher fat oxidation and lower carbohydrate oxidation during endurance running, and that carbohydrate oxidation rates may be lower and fat oxidation rates may be higher in the luteal phase than in the follicular phase during cycling exercise, some studies argue that these effects (of FSHH fluctuations) can be amplified by factors such as low carbohydrate dietary intake and changes in the ratio of oestrogens to progesterone (Lariviere et al., 1994) (Zderic et al., 2001a) (Hackney et al., 2000) (Berend et al., 1994) (Wenz et al., 1997) (McCracken et al., 1994) (Hackney et al., 1991) (Hackney et al., 1994b) (Hackney, 2021)

This influence, for instance, has value when evaluating the exercise performances and weight management of females. Understanding how FSSH fluctuations affect substrate metabolism can help optimize exercise and nutrition strategies for women. (Newell-Fugate, 2017)?(Elliott-Sale et al., 2021) (Welt et al., 1999; Klein et al., 2002; Klein et al., 1996) (Santoro et al., 2003) (Hackney, 2021)

However, it’s important to note that the evidence is not entirely clear, and more research is still in demand, as there are still studies that found no significant effect of the fluctuations on the utilization of carbohydrates and fats during exercise (Horton et al., 2002). (Oosthuyse & Bosch, 2010b) (Zderic et al., 2001b) (Devries et al., 2006) (Hackney, 1999)?(Nicklas et al., 1989) (Beckett et al., 2002) (Chappell & Hackney, 1997) (Hackney, 1990) (Hackney, 2021)

Conclusion:

In conclusion, menstrual cycle phases can potentially impact physical performance, substrate metabolism, and psychiatric symptoms in women. While research has provided valuable insights into these effects, the evidence is inconsistent, and further understanding is necessary. A personalized approach based on individual responses to menstrual cycle phases is recommended for athlete management and healthcare interventions. Healthcare providers should improve awareness and understanding of the menstrual cycle's effects on psychiatric symptoms among patients and peers, and non-pharmacological interventions can help manage these symptoms. Understanding the potential impacts of the menstrual cycle on physical performance is crucial for optimizing athletic performance and promoting long-term health in female athletes. By considering these factors in training and performance planning, clinicians can help female athletes optimize their athletic performance while promoting long-term health and well-being. Overall, more research is needed to better understand the effects of menstrual cycle phases on women's health and well-being and to develop effective interventions to manage these effects.

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