Female reproductive tract microbiota and recurrent pregnancy loss: a nested case-control study.

RESEARCH QUESTION: Is the composition of the endometrial or vaginal microbiota associated with recurrent pregnancy loss (RPL)? DESIGN: Endometrial and vaginal samples were collected from 47 women with two or more consecutive pregnancy losses and 39 healthy control women without a history of pregnancy loss, between March 2018 and December 2020 at Helsinki University Hospital, Helsinki, Finland. The compositions of the endometrial and vaginal microbiota, analysed using 16S rRNA gene amplicon sequencing, were compared between the RPL and control women, and between individual vaginal and endometrial samples. The mycobiota composition was analysed using internal transcribed spacer 1 amplicon sequencing for a descriptive summary. The models were adjusted for body mass index, age and parity. False discovery rate-corrected P-values (q-values) were used to define nominal statistical significance at q < 0.05. RESULTS: Lactobacillus crispatus was less abundant in the endometrial samples of women with RPL compared with controls (mean relative abundance 17.2% versus 45.6%, q = 0.04). Gardnerella vaginalis was more abundant in the RPL group than in controls in both endometrial (12.4% versus 5.8%, q < 0.001) and vaginal (8.7% versus 5.7%, q = 0.002) samples. The individual vaginal and endometrial microbial compositions correlated strongly (R = 0.85, P < 0.001). Fungi were detected in 22% of the endometrial and 36% of the vaginal samples. CONCLUSIONS: Dysbiosis of the reproductive tract microbiota is associated with RPL and may represent a novel risk factor for pregnancy losses.

The effect of paternal and maternal factors on the prognosis of live birth in couples with recurrent pregnancy loss.

INTRODUCTION: Currently, recurrent pregnancy loss (RPL) examinations focus on the woman, although paternal factors are also involved. Men in couples with RPL have higher sperm DNA fragmentation levels than fertile men, but the effect of sperm DNA damage on couple's later prognosis is unknown. Advanced maternal age and obesity are associated with RPL, but paternal lifestyle factors are less studied. Therefore, we aimed to study the associations of couples' lifestyle factors, causes of RPL, and sperm DNA fragmentation with their prognosis of future live birth. MATERIAL AND METHODS: This descriptive cohort study comprised 506 couples investigated for RPL at Helsinki University Hospital, Finland, between 2007 and 2016, linked with national health and population registers. The primary outcome was couple's live birth after RPL investigations. Data on couple's background factors, including age, body mass index, smoking, and alcohol use, were collected from medical records. Sperm DNA fragmentation index was analyzed from 211 men using the sperm chromatin dispersion test. The associations between background factors, sperm DNA fragmentation, and cumulative probability of live birth over time were analyzed using cross-tabulations and age-adjusted Cox regression. RESULTS: In all, 352 of 506 couples (69.6%) achieved live birth. Maternal age, unexplained RPL, prolonged pregnancy attempts before investigations, paternal obesity, and maternal smoking were associated with prognosis: unadjusted hazard ratio for couple's live birth for women aged 35-39 vs younger than 30 years was 0.63 (95% confidence interval [CI] 0.47-0.84), and for 40 years or older was 0.36 (95% CI 0.22-0.58). Age-adjusted hazard ratio for unexplained vs explained RPL was 1.39 (95% CI 1.12-1.72), for couple's pregnancy attempt at least 4 years vs less than 2 years was 0.50 (95% CI 0.33-0.76), for paternal body mass index at least 30 kg/m2 vs less than 25 kg/m2 was 0.67 (95% CI 0.46-0.98), and for maternal smoking was 0.71 (95% CI 0.51-0.99). Altogether, 96/135 (71.1%) couples with normal (<15%), 38/60 (63.3%) with intermediate (15-30%), and 11/16 (68.8%) with high sperm DNA fragmentation index achieved live birth (p = 0.56). CONCLUSIONS: In couples with RPL, prolonged pregnancy attempts, a cause found in RPL examinations, lifestyle factors, and maternal age are negatively associated with their prognosis of future live birth. Sperm DNA fragmentation was not associated, but the number of men with damaged spermatozoa was small. We suggest that clinicians include women and men in RPL counseling because couple's joint lifestyle seems to determine their later prognosis.

Menopausal hot flushes do not associate with changes in heart rate variability in controlled testing: a randomized trial on hormone therapy.

OBJECTIVE: To compare in controlled cardiovascular autonomic function tests the effects of hormone therapy (HT) on heart rate variability (HRV) responses in postmenopausal women with and without pretreatment hot flushes. DESIGN: A randomized placebo-controlled trial. SETTING: Finland, Helsinki University Central Hospital. POPULATION: A total of 150 recently postmenopausal and healthy women with prospectively evaluated hot flushes. METHODS: Women (72 with and 78 without hot flushes) were randomized to receive estradiol alone or in combination with medroxyprogesterone acetate or placebo for 6 months. Time and frequency domain measures of HRV were assessed at baseline and after HT with short-term recordings during paced quiet and deep breathing and with active orthostatic tests, both under carefully controlled laboratory conditions to avoid confounding factors present in long-term ambulatory HRV measurements. MAIN OUTCOME MEASURES: Responses of time and frequency domain measures of HRV to HT. RESULTS: At baseline HRV was similar in women with and without hot flushes. Pretreatment hot flushes did not associate with changes in time domain parameters of HRV during controlled quiet or deep breathing or active orthostatic tests after different types of HT. However, HT reduced HRV in very low frequency power in women with pretreatment hot flushes (from 371 ± 40 to 258 ± 28 ms(2) , p = 0.018). HT did not have an effect on other frequency domain measures during quiet breathing or active orthostatic tests. CONCLUSIONS: Hormone therapy did not significantly modify the HRV responses in women with or without hot flushes under controlled short-term measurements of the cardiovascular autonomic nervous system.

Evidence for a role of hot flushes in vascular function in recently postmenopausal women.

OBJECTIVE: Observational studies indicate that postmenopausal hormone therapy (HT) prevents cardiovascular disease, but randomized clinical trials have not confirmed this effect. Hot flushes were more likely to be present in women starting HT in observational studies, whereas these symptoms were mild or absent among women attending randomized clinical trials. We hypothesized that vascular function may differ in women with and without vasomotor hot flushes. METHODS: One hundred forty-three recently postmenopausal women showing a broad range of variation in hot flushes were studied with radial artery tonometry. Pulse wave analyses were assessed at baseline and after nitroglycerin and salbutamol challenges. Wilcoxon signed rank test was used for paired comparisons after challenges with nitroglycerin and salbutamol. RESULTS: Neither baseline arterial stiffness nor endothelial function differed between women without or with mild, moderate, or severe hot flushes. However, after nitroglycerin challenge, the time to the onset of the reflected wave (dependent on pulse wave velocity) was 9.5% longer (P=.014), and the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) was 13.9% longer (P=.025) in women with severe hot flushes as compared with asymptomatic women. CONCLUSION: Women with severe vasomotor hot flushes show greater vascular responsiveness to nitroglycerin than women without hot flushes. This may partially explain the conflicting data between observational and randomized HT studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00668603 LEVEL OF EVIDENCE: II.

Effect of hot flushes on vascular function: a randomized controlled trial.

OBJECTIVE: To compare the vascular responses to hormone therapy in women with and without hot flushes. METHODS: We randomly assigned 143 healthy, recently postmenopausal women (mean age 52.4+/-0.2 years, time since menopause 19.5+/-0.9 months) with intolerable hot flushes (more than seven moderate/severe episodes per day) or tolerable hot flushes (fewer than three mild episodes per day) to receive 1 mg of transdermal estradiol gel, oral estradiol (2 mg) with and without daily medroxyprogesterone acetate, or placebo for 6 months. Vascular function was assessed by pulse-wave analysis and endothelial function testing with nitroglycerin and salbutamol challenges. RESULTS: Hot flushes did not affect the changes in arterial or aortic stiffness or endothelial function in response to various forms of hormone therapy. However, in women with tolerable hot flushes, oral estradiol caused a decrease of 13.2% (P=.028) in the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) after nitroglycerin. In addition, the time to the reflected wave (dependent on pulse-wave velocity) after nitroglycerin was decreased by 8.4% (P=.018). These effects were not seen in women with intolerable hot flushes or with the other treatment regimens. CONCLUSION: Women without troublesome hot flushes are susceptible to unfavorable vascular effects after oral estrogen treatment, resulting in less compliant vasculature. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00668603. LEVEL OF EVIDENCE: I.

Health-related quality of life in women with or without hot flashes: a randomized placebo-controlled trial with hormone therapy.

OBJECTIVE: We assessed the impact of hot flashes and various forms of hormone therapy on health-related quality of life and sexual well-being in recently postmenopausal women. METHODS: We prospectively interviewed 150 healthy women about hot flashes and health-related quality of life (using the Women's Health Questionnaire and the McCoy Female Sexuality Questionnaire), menopause-related symptoms, and general health. The women were classified into those with (n = 72) and without (n = 78) hot flashes and treated for 6 months with transdermal estradiol (1 mg/d), oral estradiol (2 mg/d) with or without medroxyprogesterone acetate (5 mg/d), or placebo. RESULTS: At baseline, hot flashes contributed most strongly to poor sleep (correlation coefficient r = -0.525, P < 0.0001), somatic symptoms such as muscle pains (r = -0.348, P < 0.0001), menstrual cycle-resembling complaints (r = -0.304, P < 0.0001), anxiety and fears (r = -0.283, P < 0.0001), decreased memory and concentration (r = -0.279, P = 0.001), and sexual behavior (r = -0.174, P = 0.035). The different hormone therapy regimens alleviated hot flashes equally effectively and were therefore combined into a single group for further analysis. In women with baseline flashes, hormone therapy use significantly improved the scores for sleep (0.787 [0.243] vs 0.557 [0.249], hormone therapy vs placebo, P = 0.001, at 6 mo), memory and concentration capacity (0.849 [0.228] vs 0.454 [0.301], P < 0.0001, at 6 mo), and anxiety and fears (0.942 [0.133] vs 0.826 [0.193], P = 0.005, at 6 mo). Hormone therapy use showed no significant impact on these variables in women without baseline flashes. CONCLUSIONS: Hot flashes contribute differently to various variables affecting health-related quality of life shortly after menopause. Estradiol or an estradiol-medroxyprogesterone acetate combination similarly alleviates hot flashes and improves health-related quality of life in relation to elimination of hot flashes. Hormone therapy use does not confer any detectable quality-of-life benefit over placebo in women without disturbing baseline flashes.

Premenstrual symptoms in fertile age are associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

OBJECTIVE: Because premenstrual symptoms in fertile age resemble menopausal symptoms, many women with premenstrual symptoms fear that they have an increased risk for developing vasomotor symptoms in menopause. We investigated the impact of premenstrual symptoms on the occurrence and severity of menopausal vasomotor symptoms and quality of life. METHODS: One hundred fifty recently postmenopausal healthy women recorded hot flashes prospectively (23, none; 34, mild; 30, moderate; 63, severe), and their quality of life was assessed using the Women's Health Questionnaire. We measured the occurrence of premenstrual symptoms in fertile age using the Premenstrual Symptoms Screening Tool and calculated a premenstrual score reflecting symptom severity. RESULTS: One hundred seven women (89.2%) reported premenstrual symptoms (median score, 7.0; range, 0-38), which had impaired work efficiency or social relations in 64 women (53.3%). The occurrence of premenstrual symptoms was similar in women with and without hot flashes of different magnitudes, as the mean (SEM) premenstrual score was 7.8 (1.4) for no hot flashes, 5.0 (1.0) for mild hot flashes, 7.7 (1.3) for moderate hot flashes, and 9.4 (1.2) for severe hot flashes (P = 0.10). The severity of premenstrual symptoms failed to correlate with the severity of postmenopausal hot flashes (r = 0.087, P = 0.346). A history of premenstrual symptoms was associated with impaired memory and concentration capacity (r = -0.448, P < 0.001), depressive mood (r = -0.263, P = 0.02), sleep problems (r = -0.282, P = 0.01), and feeling less attractive (r = -0.260, P = 0.02) during the first menopausal years. CONCLUSIONS: The occurrence of premenstrual symptoms in fertile age is associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

Effect of hot flushes on cardiovascular autonomic responsiveness: a randomized controlled trial on hormone therapy.

OBJECTIVES: To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol+medroxyprogesterone acetate (MPA) use. STUDY DESIGN AND MAIN OUTCOME MEASURES: Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. RESULTS: Hot flushes were accompanied with a significant reduction (-2.2±0.7 vs. 1.3±1.1 beats/min, p=0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (-2.2±1.3 vs. 2.8±1.5 beats/min, p=0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. CONCLUSIONS: Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA.

Cardiovascular autonomic responsiveness in postmenopausal women with and without hot flushes.

OBJECTIVES: During menopausal transition autonomic balance is known to shift towards sympathetic dominance, but the role of vasomotor hot flushes in this phenomenon is not understood. We compared cardiovascular autonomic responsiveness between women with and without hot flushes. STUDY DESIGN AND MAIN OUTCOME MEASURES: One hundred fifty recently postmenopausal healthy women with varying degree of hot flushes (none, mild, moderate, severe) underwent comprehensive cardiovascular autonomic nervous testing (controlled and deep breathing, active orthostatic test, Valsalva manoeuvre and handgrip test) assessing both sympathetic and parasympathetic activity. The responses of heart rate, heart rate variability and blood pressure in these tests were evaluated. RESULTS: Responses in heart rate showed differences between the study groups only in the Valsalva manoeuvre where the tachycardia ratio in all symptomatic women was lower (p=0.041) than in women without hot flushes. Neither change in the heart rate variability analyses nor the blood pressure responses were affected by hot flush status. However, there was a non-significantly higher maximum systolic (140 (112-182)mmHg vs. 135 (102-208)mmHg) and diastolic blood pressure (94 (72-112)mmHg vs. 90 (66-122)mmHg) following the handgrip test in women without hot flushes vs. all the symptomatic women. CONCLUSIONS: Menopausal hot flushes seem to be associated with a possibly increased sympathetic preponderance without an effect on parasympathetic activity in cardiovascular autonomic responses. This may imply a potentially negative impact on cardiovascular health in women experiencing hot flushes.