Hormonal Changes in the Menstrual Cycle and Reproductive Aging

Menstrual cycle hormone changes associated with reproductive aging and how they may relate to symptoms Amanda Allshouse MS1 Jelena Pavlovic MD PhD2 and Nanette Santoro MD3 1Department of Biostatistics Colorado School of Public Health Aurora Colorado 2Department of Neurology Albert Einstein College of Medicine Bronx New York 3Department of Obstetrics and Gynecology University of Colorado School of Medicine Keywords Reproductive aging perimenopause gonadotropins folliculogenesis Introduction For most women the unpredictable menstrual and hormonal events of the perimenopause follow decades of predictable cycles and hormone patterns By a median age of 47 years both the outward evidence of normal reproductive functiona menstrual period every 25 35 daysand the internal hormonal milieu begin to demonstrate marked variability1 These changes cause disruption which can be emotionalpsychological or can involve more somatic symptoms that are related to specific hormonal events or patterns This article will review the hormonal changes within menstrual cycles and discuss within and betweencycle individual hormonal patterns that relate to changes in sleep mood and headache Studying Sex Hormones During the Menopausal Transition Types of Studies Challenges in studying sex hormones in perimenopausal women include study design measurement participant burden incomplete knowledge around theoretical models time money and complexities of statistical analysis As such largescale efforts to characterize hormones in the research setting are infrequent Studies that are interviewsurvey only without biological sampling can describe what women are experiencing thinking or feeling but preclude linking that information to mechanistic evidence about hormonal levels or changes that are part of the experience Designs that include one instance of biologic Corresponding Author Nanette Santoro MD Department of Obstetrics and Gynecology University of Colorado School of Medicine 12631 E 17th Avenue Mail Stop B198 Aurora Colorado 80045 NanetteSantoroucdenveredu Phone 3037242041 FAX 3037242061 Disclosure statement Dr Santoro is a consultant for OgedaAstellas Pharmaceuticals and has stock options with Menogenix Inc Publishers Disclaimer This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting typesetting and review of the resulting proof before it is published in its final citable form Please note that during the production process errors may be discovered which could affect the content and all legal disclaimers that apply to the journal pertain HHS Public Access Author manuscript Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Published in final edited form as Obstet Gynecol Clin North Am 2018 December 454 613628 doi101016jogc201807004 Author Manuscript Author Manuscript Author Manuscript Author Manuscript sampling allow for a snapshot of hormones and symptoms and their correlation Sampling of women annually or at other intervals allows for a withinperson picture of a trend over time Both crosssectional and longitudinal biospecimen sampling must indicate the phase of a menstrual cycle during which the sampling occurred and this must be consistent for all women in the study protocol Daily biologic sampling for an entire menstrual cycle allows for the fullest description of sex hormones Herein we will discuss major contributing design features of studies that have informed the current knowledge of sex hormones during the years preceding menopause Longitudinal Biologic Sampling A longitudinal study design includes the same person at multiple points over time The Rotterdam study described below enrolled multiple cohorts over time so while all participants are followed longitudinally some participants have been followed longer than others In contrast in a crosssectional study information from each participant is obtained only once While cross sectional studies are easier to operationalize and analyze the data from such a study would not be useful in the study of sex hormones among women approaching menopause for a number of reasons Sex hormones change within a person more consistently than across women if averaging across women the change over time could be obscured by betweenwomen differences In order to characterize a biologic sample measured on for instance the 46th day of a menstrual cycle by how far it precedes the final menstrual period FMP longitudinal followup is required as it is not yet possible to know the time to FMP until a year after it has happened Chronological age cannot substitute for reproductive age as women reach menopause at different ages A commonly used way to characterize sex hormone change over time can be achieved with annual sampling of the same woman Annual serum sampling per study protocol occurs early in the follicular phase for each study described This timing will miss the large midcycle spikes in estradiol luteinizing hormone LH and FSH that prompt ovulation Sampling during the luteal phase of the cycle would be challenging to coordinate as timing would require knowledge of when ovulation occurred a far less obvious event than the start of a menstrual cycle Luteal phase biologic sampling is necessary however to reliably characterize events like progesterone production and the secondary estrogen surge Longitudinal biologic sampling is essential for fullcycle characterization of hormones measured in urine such as in the Study of Womens Health Across the Nation SWAN Daily Hormone Study DHS described below The steepness with which hormones rise and fall can only be characterized when biologic sampling is obtained every day from the same woman during one cycle How to best characterize hormones within a cycle is an evolving area of research eg whole cycle average absolute peak difference between peak and trough percent change in days following peak Characterizing or parameterizing sex hormones in a clinically meaningful manner requires pairing with other health information from the same individual as the DHS which included a daily diary during the month urine was collected allowed researchers to do Statistical analysis of data collected in a longitudinal study can be carried out using only one observation per person To fully utilize the longitudinal nature of the data sophisticated Allshouse et al Page 2 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript statistical methods are required consideration of the impact of missing data due to dropout or other reasons is critical Longitudinal Epidemiological Studies of Reproductive Hormones Across the Menopause Transition In the 1960s and 1970s clinicians were informed by their experience in practice rather than populationbased data which was not yet available By the 1980s available studies of midlife women largely focused on alleviating symptoms rather than cultivating an understanding of the in vivo patterns and mechanisms of reproductive aging2 Methodological problems common to many but not all of these studies included an absence of baseline data retrospective reporting absent or inaccurate measurement of endogenous hormones absence of appropriate control groups for studies of hormone therapy and lack of diversity of study participants2 The Rotterdam Study The Rotterdam Study began in 1990 as a prospective study of men and women to determine causes of latelife diseases3 Recruitment occurred in four phases 1990 2000 both of age 55 and older and 2006 age 4554 by 2008 14926 persons were included In 2016 a new cohort was added of persons age 4055 with plans to enroll an additional 4000 by 2019 Additional inclusion criteria included residence in particular districts within the Netherlands As part of the genomics biomarker and microbiome studies biological samples have been banked As part of a Reproductive Traits study age at menopause and sex hormones measured in serum will be investigated for their impact on health later in life The Rotterdam Study remains open and revisits participants in all cohorts around every 45 years The Melbourne Womens Midlife Health Project Melbourne was a communitybased study of Australianborn women started in 1991 with 9 years of annual interviews of participants aged 4555 at enrollment all of whom had menstruated in the previous 3 months and were not using hormone therapy4 This was the first study to follow women annually establish patterns of change in cardinal reproductive hormones follicle stimulating hormone FSH estradiol inhibins A and B sex hormone binding globulin SHBG testosterone free testosterone index FTI and dehydroepiandrosterone DHEAS and to link them to symptoms Of the 438 women initially enrolled 88 were retained in the 9th year only 8 were not yet menopausal at the end of followup Blood was sampled between days 4 and 8 of the menstrual cycle to standardize them to the follicular phase of the menstrual cycle and other measures included interviews menstrual calendars quality of life and measures of bone density The Seattle Midlife Womens Health Study The Seattle Midlife Womens Health Study began enrollment in 1990 and was designed to illuminate womens symptom experience during the menopausal transition5 In its second and third phases a urinary hormone assay component was included The Seattle study was community based screening 1428 women and following 390 longitudinally in all phases Age upon enrollment was 3555 years and followup continued for 23 years For a subset Allshouse et al Page 3 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript first morning voided urine was collected on the 6th day of the cycle follicular phase at monthly intervals between July 1996 and 2001 quarterly between 2001 and 2005 and annually through 2006 Urine was assayed for estrone glucuronide the chief urinary metabolite of estradiol FSH total testosterone cortisol epinephrine and norepinephrine Other measures included yearly health questionnaires health diaries menstrual calendars and buccal smears Followup for each participant ended up to five years after menopause with 2013 the final year of followup for the study The Penn Ovarian Aging Study The Penn Ovarian Aging Study POAS6 is a longitudinal cohort study of women recruited in Philadelphia County PA Eligible women had at least 1 ovary a uterus at least one menstrual period within the previous 3 months a cycle duration of 2235 days and age between 3547 years Exclusions included some medications medical conditions that might affect hormones pregnancy or nonEnglish fluency Of 1426 women aged 3547 screened 436 of 578 eligible were enrolled over 18 months in 1996 and 1997 Enrolled women were of either black or white race Blood samples were collected in the early follicular phase of the menstrual cycle days 26 during all 28 study visits over 14 years spaced as 2 visits 1 menstrual cycle apart occurring every 9 months for the first five years of the study then annually for years 615 After 14 years of followup 67 of participants remained active Phoneonly interviews were done in years 1517 with a full followup in year 18 final year A unique feature of the POAS design is backtoback monthly samples and 9month spacing of the paired visits in the first 5 years The Study of Womens Health Across the Nation SWAN and the Daily Hormone Study DHS SWAN7 used a prospective multicenter design initiated to characterize the natural history of the menopausal transition A screening interview of 16065 US women during 19951996 constituted the sampling frame for the longitudinal study Sites in Pittsburgh PA Boston MA Detroit MI area Chicago IL Los Angeles CA Oakland CA area and Newark New Jersey recruited women of black and white races and Japanese Chinese and Hispanic ethnicities8 Upon enrollment women were aged 4055 years followup is ongoing SWANs design allows for investigation of raceethnicity culture or geographic region based differences or adjustment for these characteristics in other analyses Sex hormones are available from serum drawn during annual visits Timing of the fasting blood draw was targeted to the early follicular phase days 25 after menses among menstruating women and within 90 days of baseline examination date anniversary The DHS included a subset of SWAN participants with the first DHS visit coinciding with approximately the first annual SWAN followup Eighthundred fortyeight women completed the first DHS visit Women collected a daily first morningvoid urine beginning with the start of one menstrual cycle and stopping with onset of the subsequent cycle or after 50 days in the absence of a second cycle During collection a daily diary was used to record mood and menopausal symptoms and a follicular phase blood draw after the menstrual period that ended the urine collection was done DHS visits were offset from SWAN visits by half a year there would be two instances of a blood draw from these Allshouse et al Page 4 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript women in each year of dualparticipation in addition to the urine samples from the DHS The DHS was designed to continue for up to 10 years or for a fixed number of days one year after the FMP whichever came first Whole cycle hormones allow for characterization of a cycle in terms of the timing of presumed ovulation9 and parameters within a cycle indicating longerterm patterns of hormonal change10 Limitations of studies performed to date ExclusionsWith the exception of the Rotterdam Study which does not seek to characterize cycle patterns all of the studies described above excluded women who did not have at least somewhat regular menstrual cycles While this design feature is essential to allow investigators to define the FMP it eliminates women with irregular or absent menses Polycystic ovary syndrome PCOS is prevalent in up to 20 of women11 and is diagnosed in part by irregular menses Treatment for PCOS can involve birth control pills which is an exclusion criterion for the studies presented herein Among women age 3545 years an estimated 11 have undergone a hysterectomy12 Functional hypothalamic amenorrhea FHA13 is another cause of secondary amenorrhea present in about 5 of adult women Premature ovarian failure or insufficiency the loss of ovarian function before age 40 is found in 1 of adult women14 Pregnancy and lactation were also exclusions for most studies but this likely had a minor impact as only 02 of women between ages 40 and 44 gave birth in 201215 Approximately 11 of women in the US between ages 40 and 44 use hormonal contraception16 Taken together potentially more than a third of adult women have not contributed data to studies of the menopausal transition to date It is important to keep this in mind when interpreting the data and applying it to patient care Geographic considerationsThe Rotterdam Melbourne Seattle and Penn studies included women living in or near the eponymous region SWAN intentionally expanded and overrecruited multiple underrepresented races and ethnicities in multiple locations However the southeast and southwest US have been missing from all studies namely Alabama Arizona Arkansas Georgia Florida Kentucky Louisiana Mississippi New Mexico North Carolina Oklahoma South Carolina Tennessee Texas Virginia and West Virginia As these regions of the country have different weather patterns cultures and structures unmeasured regional differences in hormonal patterns could exist among women who live and are traversing menopause there Respondent burdenCollection of urine completion of lengthy questionnaires allowing research staff to swab for samples disclosing personal information and repeating this process year after year is burdensome for participants While the most frequent sampling possible would be ideal for precision of estimation the less frequently a participant is contacted the less burdensome their participation and the more likely they will continue Ethnic and racial minorities are frequently overrecruited for studies thereby burdening this population for research more so than their counterparts of white race Very detailed protocols such as the DHS in tandem with its parent study SWAN could theoretically be used to determine the optimal frequency of sampling to ensure precision while minimizing respondent burden Allshouse et al Page 5 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript In summary features of what would characterize a goldstandard study of hormones include prospective longitudinal design diversity of the cohort multiple visits in a year herculean efforts to maximize retention fullcycle characterization of hormones within a woman and extensive biological sampling The DHS is a high quality source of complete hormone characterization during the final years of reproductive function however like most studies designed to characterize midlife women its strict exclusion criteria precluded a substantial portion of women from participating As such and as should be the case with any study care should be taken in extrapolating results to the appropriate population Changes in menstrual cycle patterns and hormones with progression to menopause As women age the follicle cohort shrinks along with the decline in the total oocyte pool17See Quinn MM Cedars MI Declining Fertility with Reproductive Aging How to Protect Your Patients Fertility by Knowing the Milestones Gracia CR Freeman EW Onset of the Menopause Transition The Earliest Signs and Symptoms and Harlow SD Menstrual Cycle Changes as Women Approach the Final Menses What Matters in this issue for more detail Briefly antimullerian hormone AMH a stable product of very small but growing follicles that reflects the available remaining follicle complement most accurately declines throughout reproductive life18 The decline in AMH may directly release ovarian follicles from inhibition allowing the less responsive follicles in the ovary to activate and to maintain the ovulatory capacity of the human menstrual cycle in the face of everdwindling gametes Inhibin B which is produced by later stage growing follicles also declines with reproductive aging reflecting the reduced follicle cohort size over time Secondary to these ovarian changes folliclestimulating hormone FSH rises19 especially in the early follicular phase20 This rise in FSH appears necessary to maintain normal folliculogenesis because the remaining follicles have a higher threshold for activation and stimulation Finally ultrasound assessment of small antral follicles 29mm in size antral follicle count also provides a measure of ovarian reserve21 The process of follicle loss is initially compensated by lower AMH and inhibin B and intermittently rising FSH STRAW 2 the early transition and then becomes intermittently uncompensated STRAW 1 the late transition until follicle exhaustion is complete at menopause STRAW stage 01 Investigators from the Penn Ovarian Aging Study POAS identified a stage that divides the STRAW Stage 2 the early transition into a late premenopause with only 1 irregular menstrual cycle event and the early transition 2 or more cycle length changes22 Menstrual cycle changes will be briefly reviewed for each of these stages The Early Transition including POAS late premenopause Compensated Follicle Failure This first stage of the menopause transition can be conceptualized as a critical drop in follicle numbers that causes the first noticeable changes in a womans menstrual cycle She then experiences one of two events a her cycles become noticeably less regular or b she skips a menstrual cycle and then resumes her previous pattern At least a decade of rising FSH and reduced inhibin A and B23 and AMH precede this event but these hormonal adjustments are clinically silent reflecting the compensatory mechanisms invoked to Allshouse et al Page 6 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript maintain regular cyclicity and potential fertility in the face of follicle loss These changes are described in Figure 1 In addition to these changes in circulating hormones the process of follicle maturation is altered and there are changes within oocytes Follicles grow earlier in the cycle than ever before24 due to high FSH stimulation and they grow more rapidly2526 Increased follicular aromatase27 leads to maintenance of midreproductive or even higher than midreproductive estrogen production28 Follicle growth becomes dysregulated in that ovulation occurs earlier in the menstrual cycle25 and follicle diameter at the time of ovulation is smaller26 than in midreproductive womens cycles Oocytes of reproductively aging women are more prone to meiotic spindle abnormalities29 and to have a loss of mitochondrial DNA30 These deficits likely underlie the propensity for older reproductive aged women to undergo nondisjunction during gametogenesis and to have a greater risk of chromosomal abnormalities in conceived offspring Whether these defects are correctable is not known but certainly a topic of active investigation31 The underlying physiologic changes described herein predict a hormonal environment that has more frequent and more variable menstrual periods more variable hormone production a lesser likelihood of consistent ovulation and brief bouts of amenorrhea Collectively these changes can destabilize women in several ways The Late Transition Longer Periods of Uncompensated Follicle Failure As women enter the late transition they are subject to longer periods of amenorrhea 60 days These bouts can contain a variety of patterns of hormone production but eventually they become more uniformly hypoestrogenic and hypergonadotropic When cycles do occur they remain relatively likely to be ovulatory with robust rises in progesterone production and therefore potentially fertile Menstrual Cycle Patterns Throughout the Transition The most common type of menstrual cycle observed in women as they transition appears to be an ovulatory cycle These cycles have evidence of luteal activity ELA typically defined as a robust and sustained rise in progesterone or in its metabolite pregnanediol glucuronide Pdg when urinary studies are performed Cycles that do not have a robust rise in progesterone or Pdg may reflect a failed ovulation or an inadequate luteal phase Examples of these cycle types have been described in reproductively aging women26 It is important to keep in mind however that luteal phase progesterone production occurs across a spectrum and lesser degrees of progesterone production even though they might result in a cycle being classified as anovulatory may not necessarily reflect a failure of follicle growth and estradiol production Most studies have not combined hormonal assessments with follicle assessments and thus it is impossible to know the sequence of ovarian events An example of a completely anovulatory cycle accompanied by initially normal follicle growth and a normal menstrual cycle length is provided in Figure 2 SWAN performed the most comprehensive assessment of menstrual cycles in perimenopausal women to date In the early phases of the SWAN DHS the FMP was not Allshouse et al Page 7 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript known for all participants and thus cycles could not be organized by proximity to the FMP However the vast majority of cycles most of which in retrospect were from the early transition had an ovulatory pattern with a robust rise in Pdg 80932 As women progressed towards menopause the amount of Pdg produced in the luteal phase declined33 but overall preservation of a robust ovulatory pattern remained for the majority of participants until about 5 years before the FMP34 By the year before the FMP only 23 of cycles retained this ovulatory pattern Figure 3 indicates the dropoff in cycles with an ovulatory pattern as women approached the FMP The LutealOutofPhase LOOP CycleHale et al defined a type of menstrual cycle pattern unique to women in the menopausal transition35 The accelerated follicle growth that occurs in older reproductive aged women appears related to abnormally early growth of follicles from the previous luteal phase The wave of follicles recruited during the luteal phase of the cycle are close to maturation at the time of menses leading to a very rapid very early second ovulatory event hence the name lutealoutofphase to characterize this cycle type Figure 4 LOOP events are associated with higher luteal estradiol exposure as well as rapidly successive progesterone excursions Cycles Without Evidence of Luteal ActivityThe nonELA cycles described in the SWAN DHS36 do not simply represent cycles without robust estrogen production NonELA cycles may have a robust estrogen rise that mimics nearly exactly the estrogen rise seen in a clearly ovulatory cycle or there may be an atypically large estrogen rise or they may be no estrogen production at all NonELA cycles with an estrogen rise may or may not have an accompanying LH surge and the amount of Pdg produced is variable but insufficient to meet the criteria for an ovulatory cycle These cycle patterns appear to be associated with differing symptomatology Table 1 indicates the classification of nonELA cycles and their associated bleeding patterns This work is ongoing and further classifications may emerge Linking Hormones to Symptoms The menopausal transition has long been associated with a number of symptoms with vasomotor symptoms recognized as the cardinal menopausal symptom See Gracia CR Freeman EW Onset of the Menopause Transition The Earliest Signs and Symptoms in this issue While other symptoms such as mood disorders sleep disturbances and headaches have been long recognized to significantly affect quality of life in menopause their recognition as being specifically related to reproductive hormones during the transition remains controversial This controversy is due in part to a lack of studies targeting midlife women with nonvasomotor symptoms and conflicting methodologies for characterizing reproductive staging There is also a scarcity of longitudinal studies including both hormone and symptoms data Many studies relating hormones to changes in symptoms across the menopausal transition use only a single point of hormone and symptom assessment performed no more than annually The prevailing hypothesis is that the erratic fluctuations in hormones estrogen in particular results in susceptibility to symptoms mood changes sleep disturbance headache and ultimately syndrome depression insomnia migraine presentation but the knowledge of precise hormonal change and resulting biological mechanisms remains limited The hormone and daily symptom diary data used by the Allshouse et al Page 8 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript SWAN DHS can provide information on trajectories of both hormonal and symptom changes hot flashes mood headache and others across and within women Mood A majority of women of perimenopausal age endorse symptoms of depression in cross sectional studies See Bromberger JT Epperson CN Depression During and After the Perimenopause Impact of Hormones Genetics and Environmental Determinants of Disease in this issue for more details on mood and the perimenopause An 153 fold increased risk of depressive symptoms has been seen in longitudinal studies of menopausal transition37 The effects of changing estrogen on perimenopausal mood reflect the prevailing opinion that as the levels of estrogen vary widely and decline susceptibility to mood symptoms and major depression increases38 Estrogen has long been implicated in the activity of neurotransmitters involved in depressive symptoms namely serotonin 5HT and norepinephrine NE Estrogen exerts antidepressant properties by regulating the synthesis metabolism and receptor activity of 5HT and NE Wider fluctuations in estradiol E2 levels and FSH are associated with worse mood symptoms37 Longterm trajectories of mood symptoms have also been examined in SWAN but day to day changes in mood in association with menstrual cycles have not yet been reported Four distinct trajectories of depressive symptoms were identified in the Australian Longitudinal Study of Womens Health over a 15year follow up with 80 of women having low scores 9 with increasing scores 85 with decreasing depression scores and 25 of women with stable high depression scores A recent study used a mathematical model latent class analyses to group women going through the different stages of menopause into one of six symptom classes39 Women in the highest symptom class LC1 reported a high intensity of most symptoms including physical and psychological symptoms such as depression and anxiety followed by women with moderate intensity of most symptoms LC2 Lower symptom classes included women with moderate intensity of a subset of symptoms vasomotor symptoms pain fatigue sleep disturbances and physical health symptoms women with numerous milder symptoms LC3 LC5 and women who were relatively asymptomatic LC6 In premenopause 10 of women were classified in LC1 16 in LC2 14 in LC3 26 in LC4 14 in LC5 and 20 in LC6 and the majority of women remained in the same latent class while transitioning through menopause further supporting the need to study individual hormonal and symptom fingerprints of women by examining multiple years of follow up40 Sleep Poor sleep quality and sleep distruption are frequently observed in the menopause transition41 and have most typically been attributed to vasomotor symptoms which have been seen as the primary risk factor for sleep disruption in midlife women4243See Kravitz HM Kazlauskaite R Joffe H Sleep Health and Metabolism in Midlife Women and Menopause Food for Thought in this issue for more information on sleep and perimenopause However fluctuations in hormones have been associated with sleep disturbance during the menopausal transition independent of VMS suggesting that not all perimenopausal sleep disturbances are explained by night sweats and that menopausal Allshouse et al Page 9 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript transition related hormonal changes can independently lead to sleep disturbance4446 When daytoday menstrual cycle hormones were assessed along with daily selfreported trouble sleeping the periovulatory phase of the cycle was associated with the least trouble sleeping42 This implies that daily hormonal exposures influence sleep Independent of VMS nighttime awakenings and difficulty falling and staying asleep during the menopausal transition and postmenopause have been associated with lower estradiol4147 Difficulty falling asleep and remaining asleep has been associated with higher levels of FSH48 and more rapidly increasing levels of FSH41 In contrast to SWAN there was no consistent change in estradiol testosterone T and FSH in relation to sleep disruption in the Penn Ovarian Aging cohort49 Headaches and pain Pain symptoms are generally perceived as a common symptom of aging and not specifically transitionrelated though women are at greater risk for developing pain disorders and exhibit greater sensitivity to noxious stimuli compared to men Past studies suggest that perimenopause is associated with increased prevalence of some pain disorders such as headache5051 and musculoskeletal pain52 however the effect of the stage of the menopausal transition on the frequency of subjective pain complaints has not been completely explored Postmenopausal women report greater musculoskletal pain than premenopausal women52 but this was a study limited to a single annual followup and based on a onetime retrospective assesment of musculoskeletal pain complaints over the prior 4 weeks rather than a daily prospective assessment Bodily pain aches joint pain and stiffness have been associated with estradiol variability in the Penn Ovarian Aging Study53 In contrast joint pain and back pain were not associated with urinary levels of estrone or FSH in the Seattle Midlife Womens Health Study54 Though migraine headache has long been recognized to be hormonally regulated in women no study to date has focused on specific sex hormone changes over the menopausal transition Overall stable and rising estrogen levels such as seen in pregnancy have been associated with fewer attacks of migraine while rapidly changing estrogen levels such as seen in perimenopause have been associated with more frequent migraine attacks Migraine affects close to a quarter of perimenopausal aged women and is a priority for further study using adequate methodology The SWAN DHS substudy has been the only study to date to compare withinwoman change in hormones in migraineurs compared to controls Women with history of migraine had a faster urinary E1c decline over the 2 days following the luteal peak than controls this finding was independent of headache occurrence in the cycle of study suggesting an endogenous difference in estrogen processing in women with migraine as compared to women without history of migraine10 DHS data are currently being used to further examine the daytoday occurrence of headache in relation to daily hormone changes in women with migraine Conclusions Current data from a number of longitudinal studies of perimenopausal women are being used to describe how reproductive hormone change over time affects womens symptom Allshouse et al Page 10 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript experience In addition to characterization of cycles and their eventual breakdown longitudinal daytoday sampling indicates that both sleep and headache vary in relation to specific hormone patterns Overall hormonal instability appears to be associated with worse symptoms but more research is needed A better understanding of how hormone patterns may cause symptoms in midlife women will inform appropriate approaches to treatment Acknowledgements The Study of Womens Health Across the Nation SWAN has grant support from the National Institutes of Health NIH DHHS through the National Institute on Aging NIA the National Institute of Nursing Research NINR and the NIH Office of Research on Womens Health ORWH Grants U01NR004061 U01AG012505 U01AG012535 U01AG012531 U01AG012539 U01AG012546 U01AG012553 U01AG012554 U01AG012495 The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA NINR ORWH or the NIH REFERENCES 1 Harlow SD Gass M Hall JE et al Executive summary of the Stages of Reproductive Aging Workshop 10 addressing the unfinished agenda of staging reproductive aging J Clin Endocrinol Metab 201297115968 PubMed 22344196 2 Rostosky SS Travis CB MENOPAUSE RESEARCH AND THE DOMINANCE OF THE BIOMEDICAL MODEL 19841994 Psychology of Women Quarterly 199620285312 3 Ikram MA Brusselle GGO Murad SD et al The Rotterdam Study 2018 update on objectives design and main results Eur J Epidemiol 20173280750 PubMed 29064009 4 Guthrie JR Dennerstein L Taffe JR Lehert P Burger HG The menopausal 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16691084 53 Freeman EW Sammel MD Lin H et al Symptoms associated with menopausal transition and reproductive hormones in midlife women Obstet Gynecol 200711023040 PubMed 17666595 54 Mitchell ES Woods NF Pain symptoms during the menopausal transition and early postmenopause Climacteric 20101346778 PubMed 20497030 Allshouse et al Page 13 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Key Points As opposed to midreproductive life perimenopausal cycles have less predictable physiologic features such as ovulation and more variability in reproductive hormones over time Intensive longitudinal study designs provide the clearest picture of the transition but not all women seen by clinicians are represented in these samples Symptoms such as headache and trouble sleeping vary across the menstrual cycle but others such as hot flashes are related to increased longerterm hormone variability Allshouse et al Page 14 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Synopsis Key cycle changes occur as women transition from reproductive life to the menopause and they can be roughly linked to menopausal staging It is important to understand the types of studies that inform our current knowledge Patterns of symptoms within menstrual cycles sleep headache generally favor worsening in association with the perimenstrual phase of the cycle and patterns of chronic symptoms such as hot flashes and adverse mood appear to be worse when hormones are more variable Allshouse et al Page 15 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Figure 1 Summary of the events involved in the compensated failure of follicle growth during the menstrual cycle in the early transition Reduced inhibin B and AMH reflective of the smaller follicle cohort remove restraint on follicle activation and growth and allow FSH to rise in the early follicular phase Elevated FSH and accelerated follicle development lead to earlier ovulation of a smaller follicle Since the follicle has greater aromatase activity normal estradiol levels are preserved and may even be higher than midreproductive aged womens cycles The earlier ovulation leads to a greater proportion of the cycle being spent in the luteal phase and the reduced steroid and protein hormones from the corpus luteum fail to restrain FSH in the luteal phase leading to recruitment of the next cycles dominant follicle prior to menses Allshouse et al Page 16 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Figure 2 Follicle growth and estradiol production without ovulation in a perimenopausal woman The participant had a 28 day intermenstrual interval Note the early rise in estradiol to 300 pgml 1101 nmolliter without evidence of large follicle growth and no sign of subsequent progesterone production Peak estradiol production is seen on cycle day 6 Day 12 on the graph and peak follicle growth to over 20 mm is apparent by cycle day 18 Day 0 on the graph From Santoro N Isaac B NealPerry G et al Impaired folliculogenesis and ovulation in older reproductive aged women J Clin Endocrinol Metab 200388115506 with permission Allshouse et al Page 17 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Figure 3 The proportion of cycles with robust progesterone production called ELA evidence of luteal activity in the figure declines as women approach the final menstrual period FMP but the change is most striking in the latter few years before FMP From Santoro N Crawford SL El Khoudary SR et al Menstrual Cycle Hormone Changes in Women Traversing Menopause Study Of Womens Health Across the Nation J Clin Endocrinol Metab 2017 1027 2222 with permission Allshouse et al Page 18 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Figure 4 Lutealoutofphase LOOP cycle and its underlying mechanisms A wave of follicle growth that is initiated in the prior luteal phase causes very early ovulation immediately after or concurrent with menses from the prior cycle Higher estradiol levels and rapid re exposure to progesterone result From Hale GE Hughes CL Burger HG et al Atypical estradiol secretion and ovulation patterns caused by luteal outofphase LOOP events underlying irregular ovulatory menstrual cycles in the menopausal transition Menopause 2009161509 with permission Allshouse et al Page 19 Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Author Manuscript Author Manuscript Author Manuscript Author Manuscript Allshouse et al Page 20 Table 1 Cycles without luteal activity identified in the SWAN DHS and their hormonal and expected menstrual correlates Hormonal Pattern LH surge Pdg pattern Bleeding pattern Estrogen rise Variable but low Menses when estrogen falls Estrogen rise Variable but low Menses when estrogen falls No estrogen rise NA None No menses Obstet Gynecol Clin North Am Author manuscript available in PMC 2019 December 01