Monitoring sexual hormones in women going to high altitude – a pilot study

Monitoring sexual hormones in women going to high altitude – a pilot study | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Monitoring sexual hormones in women going to high altitude – a pilot study Aijan Taalaibekova , Michelle Meyer , Stefanie Ulrich , Gulzada Mirzalieva , Maamed Mademilov , Mona Lichtblau , Cornelia Betschart , Talant M. Sooronbaev , Silvia Ulrich , Konrad E. Bloch , Michael Furian doi: https://doi.org/10.1101/2024.12.04.24318483 Aijan Taalaibekova 1 National Center of Cardiology and Internal Medicine , Bishkek, Kyrgyzstan Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: Aijan_taalaibekova{at}bk.ru Michelle Meyer 2 Pulmonology Department, University Hospital Zurich , Zurich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stefanie Ulrich 2 Pulmonology Department, University Hospital Zurich , Zurich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gulzada Mirzalieva 1 National Center of Cardiology and Internal Medicine , Bishkek, Kyrgyzstan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maamed Mademilov 1 National Center of Cardiology and Internal Medicine , Bishkek, Kyrgyzstan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mona Lichtblau 2 Pulmonology Department, University Hospital Zurich , Zurich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Cornelia Betschart 3 Gynecology Department, University Hospital Zurich , Zurich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Talant M. Sooronbaev 1 National Center of Cardiology and Internal Medicine , Bishkek, Kyrgyzstan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Silvia Ulrich 2 Pulmonology Department, University Hospital Zurich , Zurich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Konrad E. Bloch 2 Pulmonology Department, University Hospital Zurich , Zurich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Furian 2 Pulmonology Department, University Hospital Zurich , Zurich, Switzerland 4 Research Department, Swiss University of Traditional Chinese Medicine , Bad Zurzach, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background The susceptibility to acute mountain sickness (AMS) in relation to sexual hormones in women remains elusive, partly because hormones could not be conveniently measured. We evaluated a novel kit for self-monitoring sexual hormones in women and recorded AMS incidence during high-altitude sojourns. Methods Two groups of healthy, premenopausal women, mean±SD age 23.1±2.3 y, residing <1,000m underwent baseline evaluations at 760 m before travelling to and staying for 2 days and nights (48 hours) at 3,100 m or 3,600 m, respectively. Participants self-monitored morning urine sexual hormone concentrations (estrone-1-glucuronide, E1G, pregnanediol-3-alpha-glucuronide, PdG, and luteinizing hormone, LH) daily for 30d including altitude sojourns using the simple “Proov” kit (MFB Fertility Inc). Follicular and luteal menstrual cycle phases detected by LH peak, altitude-related adverse health effects (ARAHE), AMS (Lake Louise score 2018 [LLS] ≥ 3 points including headache) and pulse oximetry (SpO 2 ) were assessed. Results 1,172 of 1,250 (93.8%) hormone measurements were successful, 78 of 1,250 (6.2%) failed due to nonadherence or technical failure. At 3,600 m, mean differences in urinary PdG concentration were 3.8 mcg/ml (95%CI, 0.6 to 7.1) between luteal and follicular cycle phases. At 3,100 m, corresponding difference was 8.5 mcg/ml (95%CI, 5.0 to 12.0). At 3,100 m, 9 of 21 (43%) women were diagnosed with AMS with SpO 2 of 93.0±1.6% and LLS of 0.3±1.4 in the morning after the first night. At 3,600 m, 12 of 21 (57%) women had AMS (p=0.355 versus 3,100 m) with SpO 2 of 86.8±1.8% (p<0.05 vs. 3,100 m) and LLS of 1.9±1.4 (p<0.05 vs. 3,100 m). Conclusion Self-monitoring female sexual hormones during high-altitude field studies with the employed kit is feasible and provides physiologically plausible trends of hormone levels over the menstrual cycle. Our data provide a valuable basis for designing further studies to evaluate AMS susceptibility in women. Introduction To date, there is no reliable, validated, and simple tool for monitoring hormonal concentrations or reliably identifying menstrual cycle phases in women during altitude sojourns. The validation of a reliable tool is particularly important since the pathophysiology of altitude-related adverse health effects (ARAHE), particularly acute mountain sickness (AMS) and factors for individual susceptibility remain elusive ( Imray et al., 2010 ). Importantly, it has not yet been quantitatively assessed whether women are more, equally or less prone than men to develop AMS men ( Derstine et al., 2023a ). The unresolved issue might originate from underrepresentation of women in high altitude studies, lack of powered sex-specific analyses or the poor characterization of premenopausal women in regard of the menstrual cycle phase, sex hormone concentrations and cycle day while staying at high altitude. Hormonal changes related to the menstrual cycle phases can alter breathing control, which may result in different altitude-related adaptations. Progesterone, which is up-regulated during the luteal phase, is a well-known respiratory stimulant associated with elevated minute ventilation and decreased PaCO 2 during the luteal phase compared to the follicular phase ( Behan and Wenninger, 2008 ; Richalet et al., 2020 ). Despite these observations at low altitude, previous studies found no relationship between menstrual cycle phase or sex hormones and AMS susceptibility, however, both studies did not quantify and assess sex hormones and cycle phase at high altitude. In contrast, a small study conducted in 1997 and 1998 assessed sex hormone levels at high altitude and found a significant difference in AMS incidence of 15% between menstrual cycle phases, though it concluded that the difference was not clinically relevant. Based on these previous reports and technological advancements, the primary purpose of this prospective pilot study was to evaluate the tolerability of using a commercially available fertility self-monitoring kit to measure urinary sex hormone concentrations and to determine the menstrual cycle phases and cycle days when travelling to high altitude. Additionally, to enable sample size estimations and provide preliminary insights into potential differences in clinical and physiological outcomes between the luteal and follicular menstrual cycle phases, additional outcomes such as AMS, nocturnal pulse oximetry, subjective sleep quality and vital signs were assessed. Methods Study design and setting This prospective, non-randomized pilot study was conducted at the National Center of Cardiology and Internal Medicine, Respiratory Medicine Department, Bishkek (760 m), Kyrgyzstan; at the Swiss-Kyrgyz High-Altitude Clinic in Tuja Ashu (3,100 m), Kyrgyzstan, which is a 4 hour bus ride away from the first location and where participants spent 2 days and nights (48 hours); and at the High Altitude Kumtor Gold Mine operation facility (3,600 m), Kumtor, Kyrgyzstan, 8 hours by bus, where participants also spent 2 days and nights (48 hours). The ascent to 3,100 m (Expedition 1, n=21) was performed in July 2022; the ascent to 3,600 m (Expedition 2, n=21) in September 2022 and both altitude ascents were scheduled independently of the menstrual cycle phases or cycle days of the participants. Sixteen participants from Expedition 1 participated also in Expedition 2 and 5 new participants had to be recruited ( Figure 1 ). Download figure Open in new tab Figure 1. Study design of the pilot study. A pilot study validating the commercially available fertility monitor Proov to monitor hormones and menstrual cycle phases before, during and after an altitude sojourn. Women monitored their hormone for 30 consecutive days. During the hormone monitoring they ascended and stayed for 2-day and nights (48 hours) at either 3,100 (Expedition 1) or 3,600 m (Expedition 2), respectively. Participants in this study were recruited through advertisements at different universities around Bishkek. Included were premenopausal, eumenorrheic, non-smoking, healthy women with a BMI>18 kg/m 2 and <30 kg/m 2 , aged 18 to 44 years, living at altitudes under 1,000 m. Exclusion criteria were any pre-existing disease, regular intake of medication (including oral contraception), other types of hormonal contraceptives (hormonal intrauterine device, vaginal ring, subcutaneous injections or implants), pregnancy or nursing, and any altitude trip <4 weeks prior to the study. The study was approved by the Ethic Committee of the National Center of Cardiology and Internal Medicine named after academician M. Mirrakhimov (Protocol No. 07 in the year of 2022) and participants provided written informed consent. Hormone monitoring All participants monitored urine metabolite concentrations of estrogen, luteinizing hormone, and progesterone for 30 consecutive days using two different sex hormone monitoring devices, described in detail below. Proov Full Cycle Hormone Insights Kit (Proov, MFB Fertility Inc., CO, US) This device was used during both Expedition 1 & 2. The procedure requires a hormone test strip into a fresh morning urine sample for 10 –20 seconds, collected before any food or fluid intake. The Proov multi-hormone test strip lateral flow assay uses gold nanoparticles and buffered sample pads to adjust for pH and hydration levels, filter unwanted particulates and bind contaminants in urine that may interfere with test accuracy. The strip contains three test lines and one control line, corresponding to estrone-1-glucuronide (E1G), pregnanediol-3-alpha-glucuronide (PdG), and luteinizing hormone (LH) (beta subunit). After 10 minutes, the participant takes a photo of the urine test strip with the smartphone and uploads it onto the company server using the Proov app. The application server employs machine learning algorithms specifically tailored to analyze photographed images of the test strip, accounting for variations in camera, lighting, and operating system, while also verifying input and output regularities and mathematically deriving the associated hormone levels ( Wegrzynowicz et al., 2022 ). In the case of internet connection loss, the company can conduct offline analysis if the time, day and picture of the test strip of the participant are provided. In this study, daily concentrations of sex hormones E1G, PdG and LH were extracted from the Proov app. Mira Fertility Tracking Kit ( Mira – Crow Canyon PL, San Ramon, CA, USA) This device was used during Expedition 2. Identical to the Proov testing procedure, Mira analysis requires to dip a hormone test strip for 10 –20 seconds into a fresh urine sample collected in the morning before any fluid or food intake. Thereafter, the strip will be inserted into the Mira device to initiate the quantitative analysis of estrogen-3-glucuronide (E3G), LH and PdG. After approximately 21 minutes the results will be synchronized with the Mira smartphone app through Bluetooth. In case of an analysis error, the strip cannot be re-analyzed. Together with the information regarding the first day of the participant’s last menstrual bleeding, the measured sex hormones were visually plotted. Based on the visually confirmed LH peak and increment of PdG, the follicular (first day of menstrual bleeding to LH peak) and luteal menstrual cycle phases (LH peak to end of cycle) were identified. Medical history, symptoms, and clinical examination A medical history has been obtained, including information on menstrual cycle length, and the starting and ending days of the participants’ last menstruation. Physical examination included measurements of weight, height, blood pressure, heart rate, and cardiac and pulmonary auscultation. At altitudes, adverse events and AMS incidences were assessed, using both the revised and original Lake Louise questionnaires (LLQ), as well as the Environmental Symptom Questionnaire cerebral score (AMSc) ( Roach et al., 2018 ; Sampson et al., 1983 ). Primary definition of AMS incidence was a 2018 LLQ score of ≥3 points including headache, over the two-day period at high altitude; secondary AMS definitions included a 1993 LLQ score of ≥3 points and an AMSc of ≥0.7. Since previous studies in both sick and healthy persons traveling to high altitudes reported the occurrence of non-AMS related ARAHE ( Furian et al., 2022 ), this pilot study additionally assessed the incidence of ARAHE at high altitudes. ARAHE was defined as any medical health condition (including AMS) that occurred at high altitude and required medical intervention or premature descent. Nocturnal pulse oximetry was performed at 760 m and at 3,600 m to assess nocturnal oxygenation. Sleepiness was assessed with the Karolinska Sleepiness Scale and subjective sleep quality with a 100-mm visual analogue scale ranging from 0 (extremely poor) to 100 (excellent) ( Kaida et al., 2006 ). Outcomes The main outcomes included the proportion and comparison of successful applications of the Proov and Mira hormone test kits, their failure rates, and reasons for failure. Additional outcomes included daily hormone concentrations throughout the menstrual cycle, differences in estrogen and progesterone concentrations between the follicular and luteal menstrual cycle phases, and the timing of the LH peak, defined as the day with the highest median value of 3 consecutive daily concentrations. The incidence of AMS and other ARAHE, nocturnal pulse oximetry, and subjective sleep quality as well as physiological variables in the different menstrual cycle phases were determined. Statistics No sample size estimation was performed for this pilot study. A convenience sample of 20 participants per expedition to 3,100 m and 3,600 m were recruited. The feasibility of hormone monitoring at low and high altitudes, as well as during experimental field expeditions, was quantified using descriptive statistics on successful instances of hormone monitoring, hormone concentrations, and failure rates associated with the use of the Proov or Mira devices , respectively. Based on the findings of the two devices, menstrual cycle phases, ovulation day, and failure rates were compared using Chi-square test statistics and Pearson correlation. AMS incidences and physiological variables were then compared between menstrual cycle phases and between altitudes using mixed linear regressions to compute mean differences and 95% confidence intervals. Continuous outcomes are presented as means ± SE and binary outcomes as numbers and proportions. Two exploratory regression models were used to evaluate 1) the associations between sex hormone concentrations and SpO 2 (mixed linear regression model); 2) the associations between menstrual cycle phases and the incidence of AMS (logistic regression model). Due to the small sample size, the parameters for the mixed models were predefined. Therefore, in the model for SpO 2 , sex hormones (E1G, LH and PdG) and assessment altitudes (760 m, 3,100 m and 3,600 m) were used as predictors. A two-sided p-value of 0.05 was considered statistically significant. Statistical analyses were performed in STATA version 15 (StataCorp LLC, College Station, Texas, USA). Results The study flow chart is presented in Figure 1 . Out of 26 participants with a mean ± SD age of 23.5±2.5 years, a total of 21 (80.7%) went to 3,100 m; 21 (80.7%) went to 3,600 m and 16 (61.5%) participants completed both expeditions ( Table 1 ). The menstrual cycle length assessed with the Proov app was 29±2 days and almost identical with what participants reported during the screening visit (30±2 days). The maximum deviation between the assessed and reported menstrual cycle length was 9 days. View this table: View inline View popup Download powerpoint Table 1: Participant demographics Hormone monitoring and comparisons between menstrual cycle phases When using the Proov hormone test kit, the daily urinary hormone measurement error rates were 4.5% (95%CI of 3.0 to 6.5%) in the group travelling to 3,100 m, 7.9% (95%CI of 5.9 to 10.3%) in those travelling to 3,600 m, and 6.2% overall (95%CI of 5.0 to 7.7%) ( Table 1 ). At 3,600 m, the corresponding error rate when using the Mira hormone test kit was 12.2% (95%CI of 9.8 to 15.0%, P<0.001 between error rates of Proov vs. Mira at 3,600 m). The urinary hormone monitoring and the assignment of the participants to a specific menstrual cycle phases and cycle day while staying at altitude were successful and are illustrated in Figure 2 , Upper Panel . Figure 2 , Lower Panel shows the proportions of participants suffering from AMS during the follicular compared to the luteal phase, however, exploratory mixed logistic regression analysis showed no association between menstrual cycle phases and the incidence of AMS defined by the 2018 LLQ criteria (Odds ratio of 0.50, 95%CI 0.09 to 2.8, p=0.430). Table 2 shows the comparison of the menstrual cycle phases and the mean differences (95%CI) in other physiological and clinical outcomes between the luteal and follicular phases. Both progesterone and estrogen were higher during the luteal compared to the follicular phase. During the nights at 3,600 m, participants in the luteal phase showed a trend toward faster SpO 2 acclimatization between nights 1 and 2, with a mean difference (95%CI) of 2.1% (−0.3 to 4.6), p = 0.085, compared to participants in the follicular phase ( Table 3 ). These findings align with the results from mixed linear regression analysis on daytime SpO 2 , showing a positive correlation with PdG concentration and a negative correlation with E1G and absolute altitude of measurement ( Supplement Table S2 ). Download figure Open in new tab Figure 2. Hormone profile and acute mountain sickness incidence. Upper panel shows the mean hormone concentrations assessed by Proov for each menstrual cycle in coloured dots. The connecting line represents a smoother of the corresponding hormone. This figure indicates a commonly seen hormone profile of oestrogen (E1G), progesterone (PdG) and luteinizing hormone (LH) and confirms the feasibility of assessing hormones by urine stripes. The follicular phase was defined as the time from the first day of menstrual bleeding to the LH peak (Cycle Day 16 in the figure), while the luteal phase was defined as the time from the LH peak to the day before the next menstrual bleeding. Lower panel shows the absolute number of participants staying at altitude, stratified by menstrual cycle days. The green coloured proportion of the bars represent the number of participants without acute mountain sickness (acute mountain sickness was defined as a 2018 Lake Louise questionnaire score of ≥3 points including headache.); the red proportion of the bars represent the number of participants with, or the days after the diagnosis of acute mountain sickness. For example, when a participant experienced acute mountain sickness on day 2 at 3,600 m, this person was medically treated and, if feasible, descended to low altitude on day 3, however, day 2 and 3 were marked as AMS-positive in this figure. View this table: View inline View popup Download powerpoint Table 2: Insights into menstrual cycle phase-related differences at high altitude View this table: View inline View popup Download powerpoint Table 3: Nocturnal pulse oximetry stratified by menstrual cycle phases AMS and other ARAHE During the altitude sojourns, 9 of 21 (43%) participants at 3,100 m and 12 of 21 (57%) at 3,600 m developed AMS ( Table 4 , p=0.355 between altitudes). At 3,600 m, 24% of participants experienced other ARAHEs not related to AMS, including fainting (N=1) and fever (N=1) on the day of arrival; panic attack (N=1) during the first night and abdominal pain (N=1) and diarrhea (N=1) over the time course of the 2 days and nights ( Table 4 ). As shown in Figure 3 , a high proportion of participants who experienced an ARAHE or AMS at 3,100 m also experienced one at 3,600 m. View this table: View inline View popup Download powerpoint Table 4: AMS and other ARAHE incidence rates Download figure Open in new tab Figure 3. Incidences of altitude-related adverse health effects (ARAHE) and acute mountain sickness (AMS) in participants travelling to 3,100 and 3,600 m (N = 16). The data from 16 participants who completed both expeditions were analyzed. Green bars indicate participants free of ARAHE (A) or AMS (B) while red bars indicate participants suffering from ARAHE or AMS at the respective altitude. Acute mountain sickness was defined as a 2018 Lake Louise questionnaire score of ≥3 points including headache. Secondary outcomes On the morning of day 2 at 3,100 m, no significant differences were observed in vital parameters nor subjective sleep quality compared to 760 m, except for an expected decrease in SpO 2 ( Table 5 ) . In contrast, at 3,600 m, a significant decrease in SpO 2 and subjective sleep quality as well as a significant increase in diastolic blood pressure, heart rate and AMS severity were observed ( Table 5 ). At 3,600 m, nocturnal SpO 2 dropped and oxygen desaturation index increased during the first night compared to 760 m, but significantly improved during the second night ( Supplement Table S1 ). View this table: View inline View popup Download powerpoint Table 5: Secondary findings assessed in the morning on day 2 Discussion This pilot study confirms that daily urinary sex hormone concentration monitoring using the commercially available fertility apps Proov and Mira is feasible for several consecutive days at high altitudes of up to 3,600 m, with the Proov device associated with lower error rates compared to Mira . Nevertheless, both hormone testing kits provide physiologically plausible urinary sex hormone concentrations to determine menstrual cycle phases and cycle days before, during, and after a high-altitude sojourn and can be considered as tools for future studies in premenopausal women evaluating susceptibility to AMS and its dependence on menstrual cycle phases. An important finding was that during the 2-day sojourns at high altitudes, the incidence of AMS was 43% at 3,100 m and 57% at 3,600 m. Moreover, other ARAHEs in the absence of AMS were observed at 3,600 m, encompassing fainting, fever, panic attacks, abdominal pain and diarrhoea. This underscores the diverse array of hypoxia-related, clinically relevant conditions in women that have rarely been reported. AMS and ARAHE The comparably high incidence of AMS observed in our study is confirmed by generally accepted data. In a study by Li et al., during a two-day stay at an altitude of 3,270 m, women had a higher incidence of AMS than men (50% vs. 10%, p<0.05). Furthermore, multivariable regression analysis showed that not only the incidence, but also the severity of AMS, was significantly higher in women than in men ( Li et al., 2022 ). In contrast, the 2023 UIAA statement on AMS in women suggests that there is no sex difference in AMS susceptibility; however, this statement has not been quantitatively confirmed by any meta-analysis examining the influence of sex on AMS. This situation, together with the revised LLS definition of AMS in 2018 and the lack of any recent prospective studies on AMS in women and men, does not allow evidence-based conclusions on sex-differences in AMS susceptibility. Underlying sex-differences potentially contributing to the higher AMS susceptibility in women could be related to the lower hypoxic ventilatory response compared to men. In a study by Camacho-Cardenosa et al. ( Camacho-Cardenosa et al., 2022 ), it was shown that, during the first hours of hypoxia, SpO 2 decreased more markedly in women than in men, probably due to an initially lower and/or less efficient respiratory response to moderate hypoxia. In addition, there is evidence that women experience headaches more frequently at low altitudes ( Li et al., 2023 ), indicating a potential susceptibility to AMS-like symptoms even before climbing to high altitude. This pre-existing condition may contribute to the development of AMS ( MacGregor et al., 2006 ). Adding even further variability, studies have reported differences in ventilation rates throughout the menstrual cycle ( Loeppky et al., 2001 ; Rael et al., 2021 ; da Silva et al., 2006). In particular, PdG, acting on both peripheral and central chemoreceptors, is thought to be a potent respiratory stimulant ( Bairam et al., 2015 ) enhancing minute ventilation during the mid-luteal phase compared to the follicular menstrual cycle phases ( Bayliss and Millhorn, 1992 ; Beidleman et al., 1999 ). Our exploratory analysis showed the same correlation, indicating that higher PdG concentrations are associated with higher daytime SpO 2 values ( Supplement Table S2 ), independent of location. Nevertheless, several previous studies and recommendations concluded that there are no sex-related differences in AMS susceptibility ( Derstine et al., 2023b ). The controversies will remain until we obtain robust findings from prospective studies specifically designed and powered to investigate and detect sex-related differences in AMS (defined by the revised LLS). With the emergence of wearables and modern technologies, this challenge become solvable, as demonstrated in our study that monitored hormones and determining menstrual cycle phases and cycle days of women staying at high altitudes. Our findings in premenopausal women are promising and important since they highlight the high adherence of participants monitoring urine hormones. Proov Limitations This study was designed as a pilot study; therefore, due to the small sample size, the differences in the risk of AMS between menstrual cycle phases and altitudes that we found require corroboration in further studies. We applied a 30-day hormone-monitoring regimen; however fewer consecutive days of urine hormone monitoring might be sufficient to determine the menstrual cycle phases in participants staying at altitude. Despite the long duration of hormone monitoring, the observed error rate remained minimal and adherence of the participants high, suggesting that this approach is feasible in future studies. Absence of internet access may hamper immediate analysis of urinary hormone levels with the Proov kit. However, by being aware of such conditions, taking a photograph of the test strip noting the date and time allows for offline analysis at a convenient later time, which significantly reduces the risk of data loss. Conclusion This pilot study in healthy, premenopausal women demonstrated good adherence and feasibility in monitoring female sexual hormones using the commercially available fertility monitoring kits and apps Proov and Mira during a sojourn at high altitudes. Premenopausal women showed a high AMS incidence at both 3,100 m and 3,600 m. The findings of this pilot study allow for evidence-based sample size estimations for future studies in women investigating AMS incidence and the efficacy of preventive AMS measures while monitoring and controlling for potential confounders such as sex hormones and menstrual cycle phases. For example, in a randomized, placebo-controlled parallel trial at 3,600 m investigating whether acetazolamide can reduce the incidence of AMS from 57% by 50% to 28.5%, a total of 94 women (48 per group), taking either acetazolamide or placebo, would be required for the final analysis, with 80% power and a two-sided alpha level of 5%. Data Availability All data produced in the present study are available upon reasonable request to the authors. Funding This study was partly funded by the Swiss National Sciences Foundation (210361). Authorship confirmation statement AT, MM, MF: Made substantial contributions to the conception and design of the work, investigation, acquisition, analysis, and interpretation of data for the work, writing – original draft, giving final approval of the version to be published, and agreeing to be accountable for all aspects of the work, ensuring that questions related to its accuracy or integrity are appropriately investigated and resolved. SU, AB, GM, MM, ML, CB, TMS, SU, KEB: Contributed significantly to the acquisition, analysis, and interpretation of data for the work, critically reviewed it for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work, ensuring that questions related to its accuracy or integrity are appropriately investigated and resolved. Conflict of interest disclosure The evaluation of the Proov Full Cycle Hormone Insights Kit and the Mira Fertility Tracking Kit was conducted solely for research purposes to assess a potential method for monitoring sex hormones at altitude. The authors declare no commercial, financial, or other conflicts of interest with Proov , Mira or any other industry partners relevant to the content of this manuscript. Acknowledgement We gratefully acknowledge all participants for taking part in this study. Footnotes ↵ * Shared first authorship Abbreviations AMS Acute Mountain sickness E1G Etrone-1-glucuronide PdG Pregnanediol-3-alpha-glucuronide LH Luteinizing hormone ARAHE Altitude-related adverse health effects LLS Lake Louise score SpO 2 Oxygen saturation PaCO 2 Partial pressure of carbon dioxide BMI Body mass index LLQ Lake Louise questionnaires UIAA International Climbing and Mountaineering Federation References 1. ↵ Bairam A , Uppari N , Mubayed S , et al. An Overview on the Respiratory Stimulant Effects of Caffeine and Progesterone on Response to Hypoxia and Apnea Frequency in Developing Rats . Adv Exp Med Biol 2015 ; 860 : 211 – 220 ; doi: 10.1007/978-3-319-18440-1_23 . OpenUrl CrossRef PubMed 2. ↵ Bayliss DA and Millhorn DE . Central Neural Mechanisms of Progesterone Action: Application to the Respiratory System . Journal of Applied Physiology 1992 ; 73 ( 2 ): 393 – 404 ; doi: 10.1152/jappl.1992.73.2.393 . OpenUrl CrossRef PubMed Web of Science 3. ↵ Behan M and Wenninger JM . Sex Steroidal Hormones and Respiratory Control . Respir Physiol Neurobiol 2008 ; 164 ( 1–2 ): 213 – 221 ; doi: 10.1016/j.resp.2008.06.006 . OpenUrl CrossRef PubMed Web of Science 4. ↵ Beidleman BA , Rock PB , Muza SR , et al. Exercise V̇e and Physical Performance at Altitude Are Not Affected by Menstrual Cycle Phase . Journal of Applied Physiology 1999 ; 86 ( 5 ): 1519 – 1526 ; doi: 10.1152/jappl.1999.86.5.1519 . OpenUrl CrossRef PubMed Web of Science 5. ↵ Camacho-Cardenosa A , Camacho-Cardenosa M , Tomas-Carus P , et al. Acute Physiological Response to a Normobaric Hypoxic Exposure: Sex Differences . Int J Biometeorol 2022 ; 66 ( 7 ): 1495 – 1504 ; doi: 10.1007/s00484-022-02298-y . OpenUrl CrossRef PubMed 6. ↵ Derstine M , Jean D , Beidleman BA , et al. Acute Mountain Sickness and High Altitude Cerebral Edema in Women: A Scoping Review—UIAA Medical Commission Recommendations . High Altitude Medicine & Biology 2023a ; doi: 10.1089/ham.2023.0043 . OpenUrl CrossRef 7. ↵ Derstine M , Jean D , Beidleman BA , et al. Acute Mountain Sickness and High Altitude Cerebral Edema in Women: A Scoping Review—UIAA Medical Commission Recommendations . High Altitude Medicine & Biology 2023b ; doi: 10.1089/ham.2023.0043 . OpenUrl CrossRef 8. ↵ Furian M , Mademilov M , Buergin A , et al. Acetazolamide to Prevent Adverse Altitude Effects in COPD and Healthy Adults . NEJM Evidence 2022 ; 1 ( 1 ): EVIDoa2100006 ; doi: 10.1056/EVI-Doa2100006 . OpenUrl CrossRef 9. ↵ Imray C , Wright A , Subudhi A , et al. Acute Mountain Sickness: Pathophysiology, Prevention, and Treatment . Progress in Cardiovascular Diseases 2010 ; 52 ( 6 ): 467 – 484 ; doi: 10.1016/j.pcad.2010.02.003 . OpenUrl CrossRef PubMed Web of Science 10. ↵ Kaida K , Takahashi M , Åkerstedt T , et al. Validation of the Karolinska Sleepiness Scale against Performance and EEG Variables . Clinical Neurophysiology 2006 ; 117 ( 7 ): 1574 – 1581 ; doi: 10.1016/j.clinph.2006.03.011 . OpenUrl CrossRef PubMed Web of Science 11. ↵ Li T , Tan L , Furian M , et al. Sex-Specific Difference in the Effect of Altitude on Sleep and Nocturnal Breathing in Young Healthy Volunteers . J Clin Med 2022 ; 11 ( 10 ): 2869 ; doi: 10.3390/jcm11102869 . OpenUrl CrossRef PubMed 12. ↵ Li X , Yang C , Lv J , et al. Global, Regional, and National Epidemiology of Migraine and Tension-Type Headache in Youths and Young Adults Aged 15–39 Years from 1990 to 2019: Findings from the Global Burden of Disease Study 2019 . The Journal of Headache and Pain 2023 ; 24 ( 1 ): 126 ; doi: 10.1186/s10194-023-01659-1 . OpenUrl CrossRef 13. ↵ Loeppky JA , Scotto P , Charlton GC , et al. Ventilation Is Greater in Women than Men, but the Increase during Acute Altitude Hypoxia Is the Same . Respiration Physiology 2001 ; 125 ( 3 ): 225 – 237 ; doi: 10.1016/S0034-5687(00)00221-8 . OpenUrl CrossRef PubMed Web of Science 14. ↵ MacGregor EA , Frith A , Ellis J , et al. Incidence of Migraine Relative to Menstrual Cycle Phases of Rising and Falling Estrogen . Neurology 2006 ; 67 ( 12 ): 2154 – 2158 ; doi: 10.1212/01.wnl.0000233888.18228.19 . OpenUrl CrossRef PubMed 15. ↵ Rael B , Alfaro-Magallanes VM , Romero-Parra N , et al. Menstrual Cycle Phases Influence on Cardiorespiratory Response to Exercise in Endurance-Trained Females . Int J Environ Res Public Health 2021 ; 18 ( 3 ): 860 ; doi: 10.3390/ijerph18030860 . OpenUrl CrossRef PubMed 16. ↵ Richalet J-P , Lhuissier F and Jean D . Ventilatory Response to Hypoxia and Tolerance to High Altitude in Women: Influence of Menstrual Cycle, Oral Contraception, and Menopause . High Alt Med Biol 2020 ; 21 ( 1 ): 12 – 19 ; doi: 10.1089/ham.2019.0063 . OpenUrl CrossRef PubMed 17. ↵ Roach RC , Hackett PH , Oelz O , et al. The 2018 Lake Louise Acute Mountain Sickness Score . High Alt Med Biol 2018 ; 19 ( 1 ): 4 – 6 ; doi: 10.1089/ham.2017.0164 . OpenUrl CrossRef PubMed 18. ↵ Sampson JB , Cymerman A , Burse RL , et al. Procedures for the Measurement of Acute Mountain Sickness . Aviat Space Environ Med 1983 ; 54 ( 12 Pt 1 ): 1063 – 1073 . OpenUrl PubMed Web of Science 19. da Silva SB , de Sousa Ramalho Viana E and de Sousa MBC . Changes in Peak Expiratory Flow and Respiratory Strength during the Menstrual Cycle . Respiratory Physiology & Neurobiology 2006 ; 150 ( 2 ): 211 – 219 ; doi: 10.1016/j.resp.2005.03.001 . OpenUrl CrossRef PubMed 20. ↵ Wegrzynowicz AK , Beckley A , Eyvazzadeh A , et al. Complete Cycle Mapping Using a Quantitative At-Home Hormone Monitoring System in Prediction of Fertile Days , Confirmation of Ovulation, and Screening for Ovulation Issues Preventing Conception. Medicina (Kaunas ) 2022 ; 58 ( 12 ): 1853 ; doi: 10.3390/medicina58121853 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted December 06, 2024. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Monitoring sexual hormones in women going to high altitude – a pilot study Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Monitoring sexual hormones in women going to high altitude – a pilot study Aijan Taalaibekova , Michelle Meyer , Stefanie Ulrich , Gulzada Mirzalieva , Maamed Mademilov , Mona Lichtblau , Cornelia Betschart , Talant M. Sooronbaev , Silvia Ulrich , Konrad E. Bloch , Michael Furian medRxiv 2024.12.04.24318483; doi: https://doi.org/10.1101/2024.12.04.24318483 Share This Article: Copy Citation Tools Monitoring sexual hormones in women going to high altitude – a pilot study Aijan Taalaibekova , Michelle Meyer , Stefanie Ulrich , Gulzada Mirzalieva , Maamed Mademilov , Mona Lichtblau , Cornelia Betschart , Talant M. Sooronbaev , Silvia Ulrich , Konrad E. Bloch , Michael Furian medRxiv 2024.12.04.24318483; doi: https://doi.org/10.1101/2024.12.04.24318483 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Cardiovascular Medicine Subject Areas All Articles Addiction Medicine (573) Allergy and Immunology (865) Anesthesia (302) Cardiovascular Medicine (4454) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (610) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1515) Epidemiology (15244) Forensic Medicine (30) Gastroenterology (1131) Genetic and Genomic Medicine (6617) Geriatric Medicine (669) Health Economics (1002) Health Informatics (4554) Health Policy (1372) Health Systems and Quality Improvement (1614) Hematology (543) HIV/AIDS (1270) Infectious Diseases (except HIV/AIDS) (15931) Intensive Care and Critical Care Medicine (1106) Medical Education (624) Medical Ethics (147) Nephrology (670) Neurology (6626) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1148) Occupational and Environmental Health (957) Oncology (3345) Ophthalmology (980) Orthopedics (369) Otolaryngology (421) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1696) Pharmacology and Therapeutics (693) Primary Care Research (714) Psychiatry and Clinical Psychology (5462) Public and Global Health (9253) Radiology and Imaging (2207) Rehabilitation Medicine and Physical Therapy (1371) Respiratory Medicine (1197) Rheumatology (597) Sexual and Reproductive Health (715) Sports Medicine (530) Surgery (714) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a0300098cdfe09d6',t:'MTc4MDAwMDA3MA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();