Women in space: A review of known physiological adaptations and health perspectives.

Exposure to the spaceflight environment causes adaptations in most human physiological systems, many of which are thought to affect women differently from men. Since only 11.5% of astronauts worldwide have been female, these issues are largely understudied. The physiological nuances affecting the female body in the spaceflight environment remain inadequately defined since the last thorough published review on the subject. A PubMed literature search yielded over 2200 publications. Using NASA's 2014 review series 'The effects of sex and gender on adaptation to space' as a benchmark, we identified substantive advancements and persistent knowledge gaps in need of further study from the nearly 600 related articles that have been published since the initial review. This review highlights the most critical issues to mitigate medical risk and promote the success of missions to the Moon and Mars. Salient sex-linked differences observed terrestrially should be studied during upcoming missions, including increased levels of inflammatory markers, coagulation factors and leptin levels following sleep deprivation; correlation between body mass and the severity of spaceflight-associated neuro-ocular syndrome; increased incidence of orthostatic intolerance; increased severity of muscle atrophy and bone loss; differences in the incidence of urinary tract infections; and susceptibility to specific cancers after exposure to ionizing radiation. To optimize health and well-being among all astronauts, it is imperative to prioritize research that considers the physiological nuances of the female body. A more robust understanding of female physiology in the spaceflight environment will support crew readiness for Artemis missions and beyond.

A rodent model of human dose-equivalent progestin-only implantable contraception.

BACKGROUND: Long-acting, reversible contraceptives (LARC; progestin only) are an increasingly common hormonal contraceptive choice in reproductive aged women looking to suppress ovarian function and menstrual cyclicity. The overall objective was to develop and validate a rodent model of implanted etonogestrel (ENG) LARC, at body size equivalent doses to the average dose received by women during each of the first 3 years of ENG subdermal rod LARC use. METHODS: Intact, virgin, female Sprague-Dawley rats (16-wk-old) were randomized to 1 of 4 groups (n = 8/group) of ENG LARC (high-0.30µg/d, medium-0.17µg/d, low-0.09µg/d, placebo-0.00µg/d) via a slow-release pellet implanted subcutaneously. Animals were monitored for 21 days before and 29 days following pellet implantation using vaginal smears, ultrasound biomicroscopy (UBM), saphenous blood draws, food consumption, and body weights. Data were analyzed by chi-square, non-parametric, univariate, and repeated measures 2-way ANOVA. RESULTS: Prior to pellet implantation there was no difference in time spent in estrus cycle phases among the treatment groups (p > 0.30). Following pellet implantation there was a dose-dependent impact on the time spent in diestrus and estrus (p < 0.05), with the high dose group spending more days in diestrus and fewer days in estrus. Prior to pellet insertion there was not an association between treatment group and estrus cycle classification (p = 0.57) but following pellet implantation there was a dose-dependent association with cycle classification (p < 0.02). Measurements from the UBM (ovarian volume, follicle count, corpora lutea count) indicate an alteration of ovarian function following pellet implantation. CONCLUSION: Assessment of estrus cyclicity indicated a dose-response relationship in the shift to a larger number of acyclic rats and longer in duration spent in the diestrus phase. Therefore, each dose in this model mimics some of the changes observed in the ovaries of women using ENG LARC and provides an opportunity for investigating the impacts on non-reproductive tissues in the future.

Low resting metabolic rate in exercise-associated amenorrhea is not due to a reduced proportion of highly active metabolic tissue compartments.

Exercising women with menstrual disturbances frequently display a low resting metabolic rate (RMR) when RMR is expressed relative to body size or lean mass. However, normalizing RMR for body size or lean mass does not account for potential differences in the size of tissue compartments with varying metabolic activities. To explore whether the apparent RMR suppression in women with exercise-associated amenorrhea is a consequence of a lower proportion of highly active metabolic tissue compartments or the result of metabolic adaptations related to energy conservation at the tissue level, RMR and metabolic tissue compartments were compared among exercising women with amenorrhea (AMEN; n = 42) and exercising women with eumenorrheic, ovulatory menstrual cycles (OV; n = 37). RMR was measured using indirect calorimetry and predicted from the size of metabolic tissue compartments as measured by dual-energy X-ray absorptiometry (DEXA). Measured RMR was lower than DEXA-predicted RMR in AMEN (1,215 ± 31 vs. 1,327 ± 18 kcal/day, P < 0.001) but not in OV (1,284 ± 24 vs. 1,252 ± 17, P = 0.16), resulting in a lower ratio of measured to DEXA-predicted RMR in AMEN (91 ± 2%) vs. OV (103 ± 2%, P < 0.001). AMEN displayed proportionally more residual mass (P < 0.001) and less adipose tissue (P = 0.003) compared with OV. A lower ratio of measured to DXA-predicted RMR was associated with lower serum total triiodothyronine (ρ = 0.38, P < 0.001) and leptin (ρ = 0.32, P = 0.004). Our findings suggest that RMR suppression in this population is not the result of a reduced size of highly active metabolic tissue compartments but is due to metabolic and endocrine adaptations at the tissue level that are indicative of energy conservation.

Reductions in urinary collection frequency for assessment of reproductive hormones provide physiologically representative exposure and mean concentrations when compared with daily collection.

OBJECTIVE: To determine if reducing the frequency of urinary sample collection from daily to 5, 3, or 2 days per week during a menstrual cycle or 28-day amenorrheic monitoring period provide accurate representations of the reproductive hormone metabolites estrone-1-glucuronide (E1G) and pregnanediol glucuronide (PdG) exposure and mean concentrations. METHODS: Exercising women presenting with eumenorrhea or exercise-associated menstrual disturbances collected daily urine samples for the assessment of E1G and PdG concentrations. After enzyme immunoassay analysis of the daily samples, E1G and PdG data were systematically removed from each menstrual cycle or amenorrheic monitoring period to mimic three reduced collection frequencies, representing 5, 3, and 2 days per week. Exposure and mean concentration were calculated for both hormones and all four urinary collection frequencies. RESULTS: E1G and PdG exposure and mean cycle concentrations derived from reduced collection frequencies were not different from daily collection (P > 0.05), independent of whether menstrual cycles and monitoring periods were analyzed together or separately. Bland-Altman analysis indicated acceptable agreement between each reduced collection frequency and daily collection. CONCLUSIONS: Compared with daily urinary collection, a reduced collection frequency of 5, 3, or 2 days each week provides accurate E1G and PdG profiles of collection periods of various lengths and types of menstrual function. Reduction of urinary sample collection frequency may enable researchers to reduce participant burden and costs, increase compliance, and study a wider range of study populations.

Inflammaging and Bone Loss in a Rat Model of Spinal Cord Injury.

Spinal cord injury (SCI) results in significant loss of sublesional bone, adding to the comorbidity of SCI with an increased risk of fracture and post-fracture complications. Unfortunately, the effect of SCI on skeletal health is also likely to rise, as the average age of SCI has increased and there are well-known negative effects of age on bone. To date, however, the impact of age and age-associated inflammation (inflammaging) on skeletal health after SCI remains largely unknown. To address this, we compared bone parameters in young (3 month) and middle-aged (9 month) male and female rats with a moderate thoracic contusion injury, to age- and sex-matched sham-operated controls. Skeletal parameters, locomotor function, and serum cytokine levels were assessed at both subchronic (30 days) and chronic (180 days) time points post-injury. We hypothesized that SCI would lead to a dramatic loss of bone immediately after injury in all SCI groups, with inflammaging leading to greater loss in middle-aged SCI rats. We also predicted that whereas younger rats might re-establish bone properties in more chronic phases of SCI, middle-aged rats would not. Supporting these hypothesis, trabecular bone volume was significantly lower in male and young female SCI rats early after injury. Contrary to our hypothesis, however, there was greater loss of trabecular bone volume, relative to age-matched shams, in young compared with middle-aged SCI rats, with no effects of SCI on trabecular bone volume in middle-aged female rats. Moreover, despite recovery of weight-supported locomotor activity, bone loss persisted into the chronic phase of injury for the young rats. Bone formation rates were lower in young male SCI rats, regardless of the time since injury, whereas both young and middle-aged female SCI rats had lower bone formation in the subchronic but not the chronic phase of SCI. In middle-aged rats, SCI-induced higher osteoclast surfaces, which also persisted into the chronic phase of SCI in middle-aged females. Neither age nor SCI-induced increases in inflammation seemed to be associated with bone loss. In fact, SCI had more dramatic and persistent effects on bone in male rats, whereas aging and SCI elevated serum cytokines only in female rats. Overall, this study demonstrates SCI-induced loss of bone and altered bone turnover in male and female rats that persists into the chronic phase post-injury. The sex- and age-dependent variations in bone turnover and serum cytokines, however, underscore the need to further explore both mechanisms and potential therapeutics in multiple demographics.

12-months of increased dietary intake does not exacerbate disordered eating-related attitudes, stress, or depressive symptoms in women with exercise-associated menstrual disturbances: The REFUEL randomized controlled trial.

Disordered eating-related attitudes are a leading cause of energy deficiency and menstrual disturbances in exercising women. Although treatment recommendations include psychological counseling with increases in dietary intake, a key concern is whether increased dietary intake may exacerbate negative eating behaviors. OBJECTIVE: To determine the effects of a 12-month nutritional intervention on eating-related attitudes and psychological characteristics in exercising women with oligomenorrhea/amenorrhea (Oligo/Amen). METHODS: Intent-to-treat analysis of the REFUEL randomized controlled trial (#NCT00392873) in 113 exercising women (age [mean±SEM]:] 21.9 ± 0.4 yrs; BMI: 20.9 ± 0.2 kg/m2). Women were randomized to increase energy intake 20-40% above baseline energy needs (Oligo/Amen+Cal, n = 40) or maintain energy intake (Oligo/Amen Control, n = 36) while maintaining their exercise behaviors. A reference group of ovulatory women (OVref, n = 37) maintained diet and exercise behaviors. Body composition, eating attitudes, stress, and depressive symptoms were assessed at baseline and every 3 months. RESULTS: At baseline, the Oligo/Amen groups had higher drive for thinness, cognitive restraint, and eating disorder risk than OVref group (p < 0.001). Increased energy intake led to increases in percent body fat and fat mass (p < 0.010), but not psychobehavioral outcomes, in the Oligo/Amen+Cal compared to Oligo/Amen Control group. Independent of group, cognitive restraint decreased (p < 0.001) and resilient coping increased (p < 0.007) over 12-months, while perceived stress (p = 0.143) and depressive symptoms (p = 0.344) were unchanged. DISCUSSION: Long-term nutritional intervention consisting of modest increases in dietary intake with guidance from a registered dietician and a psychologist increases body and fat mass without increasing disordered eating-related attitudes, stress, or depressive symptoms in exercising women with Oligo/Amen.

Bone mineral density in response to increased energy intake in exercising women with oligomenorrhea/amenorrhea: the REFUEL randomized controlled trial.

BACKGROUND: Energy deficiency can result in menstrual disturbances and compromised bone health in women, a condition known as the Female Athlete Triad. OBJECTIVES: The REFUEL randomized controlled trial assessed the impact of increased energy intake on bone health and menstrual function in exercising women with menstrual disturbances. METHODS: Exercising women with oligomenorrhea/amenorrhea (Oligo/Amen) were randomly assigned to an intervention group (Oligo/Amen + Cal, n = 40, mean ± SEM age: 21.3 ± 0.5 y; weight: 55.0 ± 1.0 kg; BMI: 20.4 ± 0.3 kg/m2) who increased energy intake 20%-40% above baseline energy needs for 12 mo or a control group (Oligo/Amen Control, n = 36; mean ± SEM age: 20.7 ± 0.5 y; weight: 59.1 ± 1.3 kg; BMI: 21.3 ± 0.4 kg/m2). Energy intake and expenditure, metabolic and reproductive hormones, body composition, and areal bone mineral density (aBMD) were assessed. RESULTS: Oligo/Amen + Cal improved energy status [increased body mass (2.6 ± 0.4 kg), BMI (0.9 ± 0.2 kg/m2), fat mass (2.0 ± 0.3 kg), body fat percentage (2.7% ± 0.4%), and insulin-like growth factor 1 (37.4 ± 14.6 ng/mL)] compared with Oligo/Amen Control and experienced a greater likelihood of menses (P < 0.05). Total body and spine aBMD remained unchanged (P > 0.05). Both groups demonstrated decreased femoral neck aBMD at month 6 (-0.006 g/cm2; 95% CI: -0.011, -0.0002 g/cm2 ; time main effect P = 0.043) and month 12 (-0.011 g/cm2; 95% CI: -0.021, -0.001 g/cm2; time main effect P = 0.023). Both groups demonstrated a decrease in total hip aBMD at month 6 (-0.006 g/cm2; 95% CI: -0.011, -0.002 g/cm2; time main effect P = 0.004). CONCLUSIONS: Although higher dietary energy intake increased weight, body fat, and menstrual frequency, bone mineral density was not improved, compared with the control group. The 12-mo intervention may have been too short and the increase in energy intake (∼352 kcal/d), although sufficient to increase menstrual frequency, was insufficient to increase estrogen or improve aBMD. Future research should refine the optimal nutritional and/or pharmacological interventions for the recovery of bone health in athletes and exercising women with Oligo/Amen.This trial was registered at clinicaltrials.gov as NCT00392873.

Oral Estradiol Impact on Mitigating Unloading-Induced Bone Loss in Ovary-Intact Rats.

BACKGROUND: The impact of the spaceflight environment on endogenous estrogen production in female crewmembers and the resulting impact on other adaptations, like bone loss, is an under-investigated topic. Hence, we investigated the interaction of exogenous 17- estradiol (E2) treatment and disuse to test the hypothesis that E2 treatment would mitigate disuse-induced bone loss.METHODS: There were 40 virgin female Sprague-Dawley rats (5 mo old) randomized to placebo (PL; 0 ppm E2) or estrogen (E2; 10 ppm E2) treatments, delivered via custom-made rodent diets; half of each group was randomized to either weightbearing (WB) or hindlimb unloading (HU) for 39 d.RESULTS: We observed expected lower values after HU (615%) in volumetric BMD and cross-sectional areas at the proximal tibia metaphysis (PTM, by pQCT), 20% lower %BV/TV (nonsignificant) at the PTM, and 11% lower femoral neck maximal load; none of these HU-induced impacts were modified by E2. Impaired PTM periosteal expansion was observed in all E2-treated rats, with smaller (13 to 18%) cross-sectional areas. Midshaft tibial geometry was unaffected by E2 treatment, but large reductions (73 to 81%) in periosteal bone formation indices were observed in E2-treated rats.DISCUSSION: In summary, modest supplementation of exogenous E2 did not mitigate decrements in volumetric BMD, PTM cross-sectional geometry, or femoral neck strength observed with HU. However, numerous independent impacts of E2 treatment were observed, with significant suppression of periosteal bone formation indices. If maintained over time, this might impact negatively on cortical bone integrity during prolonged nonweightbearing.Mantri AV, Allaway HCM, Brezicha JE, Hogan HA, Bloomfield SA. Oral estradiol impact on mitigating unloading-induced bone loss in ovary-intact rats. Aerosp Med Hum Perform. 2021; 92(2):6574.

Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use. Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833). Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980). Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception. Clinical Trial Registration: www.ClinicalTrials.gov registration NCT02367833.

A pilot study on the utility of reduced urine collection frequency protocols for the assessment of reproductive hormones in adolescent girls.

BACKGROUND: The objectives of this study were to assess the feasibility of and compliance to collecting urine samples in pre- and postmenarcheal girls and to determine if a less than daily collection frequency was sufficient for assessing ovarian function. METHODS: Twenty-five postmenarcheal girls (11-17 years) collected samples using either a two or a three samples/week protocol during one menstrual cycle. Exposure and mean estrone-1-glucuronide (E1G) and pregnanediol glucuronide concentrations were calculated, and evidence of luteal activity (ELA) was evaluated. Sixteen premenarcheal girls (8-11 years) collected one sample/month for six consecutive months. Samples were analyzed for E1G concentration. Participant compliance was calculated using dates on the urine samples and paper calendars. RESULTS: Participants collecting three samples/week were more compliant to the protocol than those collecting two samples/week (83.6%±2.6% vs. 66.8%±6.6%; p=0.034). There were no differences (p>0.10) regarding paper calendar return (81.8%±12.2% vs. 92.9%±7.1%), recording menses (55.6%±17.6% vs. 92.3%±7.7%) or sample collection (88.9%±11.1% vs. 84.6%±10.4%) between the two protocols. The average cycle length was 30.5±1.3 days and 32% of cycles had ELA. The premenarcheal girls were 100% compliant to the protocol. Only 68.8% of participants returned the paper calendar and 81.8% of those participants recorded sample collection. The average E1G concentration was 15.9±3.8 ng/mL. CONCLUSIONS: Use of a less than daily collection frequency during one menstrual cycle in postmenarcheal, adolescent girls is feasible and provides informative data about ovarian function. Collection of one sample/month in premenarcheal girls is feasible and detects the expected low E1G concentrations. Alternate strategies to the use of a paper calendar should be considered.

The physiology of functional hypothalamic amenorrhea associated with energy deficiency in exercising women and in women with anorexia nervosa.

An energy deficiency is the result of inadequate energy intake relative to high energy expenditure. Often observed with the development of an energy deficiency is a high drive for thinness, dietary restraint, and weight and shape concerns in association with eating behaviors. At a basic physiologic level, a chronic energy deficiency promotes compensatory mechanisms to conserve fuel for vital physiologic function. Alterations have been documented in resting energy expenditure (REE) and metabolic hormones. Observed metabolic alterations include nutritionally acquired growth hormone resistance and reduced insulin-like growth factor-1 (IGF-1) concentrations; hypercortisolemia; increased ghrelin, peptide YY, and adiponectin; and decreased leptin, triiodothyronine, and kisspeptin. The cumulative effect of the energetic and metabolic alterations is a suppression of the hypothalamic-pituitary-ovarian axis. Gonadotropin releasing hormone secretion is decreased with consequent suppression of luteinizing hormone and follicle stimulating hormone release. Alterations in hypothalamic-pituitary secretion alters the production of estrogen and progesterone resulting in subclinical or clinical menstrual dysfunction.

Current and past menstrual status is an important determinant of femoral neck geometry in exercising women.

UNLABELLED: Menstrual status, both past and current, has been established as an important determinant of bone mineral density (BMD) in young exercising women. However, little is known regarding the association between the cumulative effect of menstrual status and indices of bone health beyond BMD, such as bone geometry and estimated bone strength. PURPOSE: This study explores the association between cumulative menstrual status and indices of bone health assessed using dual-energy x-ray absorptiometry (DXA), including femoral neck geometry and strength and areal BMD (aBMD), in exercising women. METHODS: 101 exercising women (22.0±0.4years, BMI 21.0±0.2kg/m(2), 520±40min/week of self-reported exercise) participated in this cross-sectional study. Women were divided into three groups as follows based on their self-reported current and past menstrual status: 1) current and past regular menstrual cycles (C+P-R) (n=23), 2) current and past irregular menstrual cycles (C+P-IR) (n=56), 3) and current or past irregular cycles (C/P-RIR) (n=22). Current menstrual status was confirmed using daily urinary metabolites of reproductive hormones. DXA was used to assess estimates of femoral neck geometry and strength from hip strength analysis (HSA), aBMD, and body composition. Cross-sectional moment of inertia (CSMI), cross-sectional area (CSA), strength index (SI), diameter, and section modulus (Z) were calculated at the femoral neck. Low CSMI, CSA, SI, diameter, and Z were operationally defined as values below the median. Areal BMD (g/cm(2)) and Z-scores were determined at the lumbar spine, femoral neck, and total hip. Low BMD was defined as a Z-score<-1.0. Chi-square tests and multivariable logistic regression were performed to compare the prevalence and determine the odds, respectively, of low bone geometry, strength, and aBMD among groups. RESULTS: Cumulative menstrual status was identified as a significant predictor of low femoral neck CSMI (p=0.005), CSA (p≤0.024), and diameter (p=0.042) after controlling for confounding variables. C+P-IR or C/P-RIR were four to eight times more likely to exhibit low femoral neck CSMI or CSA when compared with C+P-R. Lumbar spine aBMD and Z-score were lower in C+P-IR when compared with C+P-R (p≤0.003). A significant association between menstrual group and low aBMD was observed at the lumbar spine (p=0.006) but not at the femoral neck or total hip (p>0.05). However, after controlling for confounding variables, cumulative menstrual status was not a significant predictor of low aBMD. CONCLUSION: In exercising women, the cumulative effect of current and past menstrual irregularity appears to be an important predictor of lower estimates of femoral neck geometry, as observed by smaller CSMI and CSA, which may serve as an another means, beyond BMD, by which menstrual irregularity compromises bone strength. As such, evaluation of both current and past menstrual status is recommended to determine potential risk for relatively small bone geometry at the femoral neck.

Long-Duration Spaceflight Increases Depth Ambiguity of Reversible Perspective Figures.

The objective of this study was to investigate depth perception in astronauts during and after spaceflight by studying their sensitivity to reversible perspective figures in which two-dimensional images could elicit two possible depth representations. Other ambiguous figures that did not give rise to a perception of illusory depth were used as controls. Six astronauts and 14 subjects were tested in the laboratory during three sessions for evaluating the variability of their responses in normal gravity. The six astronauts were then tested during four sessions while on board the International Space Station for 5-6 months. They were finally tested immediately after return to Earth and up to one week later. The reaction time decreased throughout the sessions, thus indicating a learning effect. However, the time to first percept reversal and the number of reversals were not different in orbit and after the flight compared to before the flight. On Earth, when watching depth-ambiguous perspective figures, all subjects reported seeing one three-dimensional interpretation more often than the other, i.e. a ratio of about 70-30%. In weightlessness this asymmetry gradually disappeared and after 3 months in orbit both interpretations were seen for the same duration. These results indicate that the perception of "illusory" depth is altered in astronauts during spaceflight. This increased depth ambiguity is attributed to the lack of the gravitational reference and the eye-ground elevation for interpreting perspective depth cues.