Ultradian Rhythms in Heart Rate Variability and Distal Body Temperature Anticipate the Luteinizing Hormone Surge Onset (original) (raw)
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Scientific Reports, 2020
The menstrual cycle is characterized by predictable patterns of physiological change across timescales. Although patterns of reproductive hormones across the menstrual cycle, particularly ultradian rhythms, are well described, monitoring these measures repeatedly to predict the preovulatory luteinizing hormone (LH) surge is not practical. In the present study, we explored whether non-invasive measures coupled to the reproductive system: high frequency distal body temperature (DBT), sleeping heart rate (HR), sleeping heart rate variability (HRV), and sleep timing, could be used to anticipate the preovulatory LH surge in women. To test this possibility, we used signal processing to examine these measures in 45 premenopausal and 10 perimenopausal cycles alongside dates of supra-surge threshold LH and menstruation. Additionally, urinary estradiol and progesterone metabolites were measured daily surrounding the LH surge in 20 cycles. Wavelet analysis revealed a consistent pattern of DBT and HRV ultradian rhythm (2-5 h) power that uniquely enabled anticipation of the LH surge at least 2 days prior to its onset in 100% of individuals. Together, the present findings reveal fluctuations in distal body temperature and heart rate variability that consistently anticipate the LH surge, suggesting that automated ultradian rhythm monitoring may provide a novel and convenient method for non-invasive fertility assessment. The fertility-awareness-method (FAM), a set of practices used to estimate the fertile and infertile days of the menstrual cycle, is challenging to implement and to study, and existing studies of its effectiveness are inconclusive 1. However, an observation-based method of family planning or contraception has several potential benefits, including a lack of hormonal disruption, personalization, and relatively low cost. One challenge inherent to current FAM practices is the reliance on historical basal body temperature and symptom trends (e.g., breast tenderness, libido, cervical fluid) that can vary substantially by individual, within-individual from cycle-to-cycle 2 , and that provide predominantly retrospective information. The challenges of FAM have led the majority of those seeking to avoid pregnancy to adopt another form of contraception. Unfortunately, the most widely used method, female hormonal contraception, has short and long term risks for many users, including increased breast cancer rate 3,4 , luteal phase deficiency 5 , dysmenorrhea 5,6 , altered cognition 7,8 , and depressed mood 9,10. These risks, combined with increasing recognition that many physiological systems vary in a structured manner across the menstrual cycle 11-14 , provide the impetus to develop FAM approaches that employ high-temporal-resolution, non-invasive measures of physiology. The menstrual cycle is a continuous, rhythmic succession of endocrine, ovarian, and uterine events. Briefly, the cycle begins with onset of menstruation, followed by rising levels of estradiol, follicular maturation, and proliferation of the uterine lining 15,16. Ovulation, which is triggered by numerous factors including estradiol, a surge of luteinizing hormone (LH), the presence of a mature Graafian follicle, and likely time of day 17 , frequently occurs between 1/2 and 3/4 of the way through the cycle in humans 18. Other physiological systems, including metabolism 19, 20 and autonomic balance 21 , fluctuate with the menstrual cycle. An individual is mostly likely to become pregnant during the time leading up to, and shortly past, the ovulation event, making identification of this peri-ovulatory period central for the successful use of the FAM.
The Journal of Clinical Endocrinology & Metabolism, 2006
Context: The incidence of menstrual disorders declines during adolescence. The mechanism responsible is unknown. Objective: The objective of the study was to test the hypothesis, formulated a priori, that the dependence of LH pulsatility and ovarian function on energy availability declines with gynecological age (years since menarche). Design: The study was a controlled experiment repeated in two menstrual cycles, performed 2001-2004. Setting: The study was conducted at a university laboratory and general clinical research center. Participants: The study population consisted of healthy, habitually sedentary, young women of normal body composition with 5-8 yr (adolescents, n ϭ 9) and 14-18 yr (adults, n ϭ 10) of gynecological age recruited by advertisement from approximately 9000 women aged 18-34 yr in a college community. Samples were similar in age of menarche, length of menstrual cycle and luteal phase, body size and composition, aerobic capacity, and dietary intake. None were withdrawn due to adverse effects. Interventions: Interventions included energy availabilities of 45 and 10 kcal/kg of fat-free mass per day for 5 d in the early follicular phases of separate menstrual cycles in random order. Main Outcome Measures: LH pulsatility, estradiol, and luteal phase length were measured. Results: Low energy availability reduced LH pulse frequency in adolescents (P Ͻ 0.01) but not adults (P ϭ 0.39), did not increase LH pulse amplitude in either group (both P ϭ 0.13), and suppressed 24-h mean LH in adolescents (P ϭ 0.01) but not adults (P ϭ 0.72). Estradiol was unaffected (both P ϭ 0.48), but the subsequent luteal phase was shorter in adolescents (P Ͻ 0.01). Conclusions: In women of normal body composition, the response of LH pulsatility and ovarian function to 5 d of low energy availability disappears by 14 yr of gynecological age.
The Journal of Clinical Endocrinology & Metabolism, 2003
To investigate the dependence of LH pulsatility on energy availability (dietary energy intake minus exercise energy expenditure), we measured LH pulsatility after manipulating the energy availability of 29 regularly menstruating, habitually sedentary, young women of normal body composition for 5 d in the early follicular phase. Subjects expended 15 kcal/kg of lean body mass (LBM) per day in supervised exercise at 70% of aerobic capacity while consuming a clinical dietary product to set energy availability at 45 and either 10, 20, or 30 kcal/kg LBM⅐d in two randomized trials separated by at least 2 months. Blood was sampled daily during treatments and at 10-min intervals for the next 24 h. Samples were assayed for LH, FSH, estradiol (E 2), glucose, -hydroxybutyrate, insulin, cortisol, GH, IGF-I, IGF-I binding protein (IGFBP)-1, IGFBP-3, leptin, and T 3. LH pulsatility was unaffected by an energy availability of 30 kcal/kg LBM⅐d (P > 0.3), but below this threshold LH pulse frequency decreased, whereas LH pulse amplitude increased (all P < 0.04). This disruption was more extreme in women with short luteal phases (P < 0.01). These incremental effects most closely resembled the effects of energy availability on plasma glucose, -hydroxybutyrate, GH, and cortisol and contrasted with the dependencies displayed by the other metabolic hormones (simultaneously P < 0.05). These results demonstrate that LH pulsatility is disrupted only below a threshold of energy availability deep into negative energy balance and suggest priorities for future investigations into the mechanism that mediates the nonlinear dependence of LH pulsatility on energy availability. (J Clin Endocrinol Metab 88: 297-311, 2003) Abbreviations: BBT, Basal body temperature; CEE, controlled exercise energy expenditure; E 2 , estradiol; 24EB, 24-h energy balance; 24EE, 24-h energy expenditure; -HOB; -hydroxybutyrate; IRMA, immunoradiometric; LBM, lean body mass; PO 2 , pressure of O 2 ; RER, respiratory exchange ratio; VO 2max , maximum oxygen uptake.
The Journal of Clinical Endocrinology & Metabolism, 2019
Objective Determine the interrelations between reductions in energy availability (EA), luteinizing hormone (LH) pulse frequency, and the induction of menstrual disturbances in previously sedentary, ovulatory women. Methods Secondary analysis of a randomized controlled trial consisting of a 3-month controlled diet and supervised exercise program. EA was calculated daily by measured energy intake (kcal) and exercise energy expenditure (kcal) normalized to fat-free mass (kg) and averaged during baseline and each of 3 intervention menstrual cycles. Blood samples were obtained every 10 minutes for 24 hours in the early follicular phase before the intervention and after 3 months of diet and exercise (n = 14). LH pulse dynamics were assessed by Cluster. Linear mixed models determined whether EA predicts LH pulse frequency and LH pulse frequency predicts luteal phase defects (LPDs). Results Subjects were 20 ± 1 years old, 165.1 ± 1.4 cm tall, and weighed 58.9 ± 1.5 kg. LH pulse frequency de...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2009
Objective: To assess computerised least-squares analysis of quantitative basal temperature (LS-BT) against urinary pregnanediol glucuronide (PdG) as an indirect measure of ovulation, and to evaluate the stability of LS-QBT to wake-time variation. Study design: Cross-sectional study of 40 healthy, normal-weight, regularly menstruating women aged 19-34. Participants recorded basal temperature and collected first void urine daily for one complete menstrual cycle. Evidence of luteal activity (ELA), an indirect ovulation indicator, was assessed using Kassam's PdG algorithm, which identifies a sustained 3-day PdG rise, and the LS-QBT algorithm, by determining whether the temperature curve is significantly biphasic. Cycles were classified as ELA+ or ELAÀ. We explored the need to pre-screen for wake-time variations by repeating the analysis using: (A) all recorded temperatures, (B) wake-time adjusted temperatures, (C) temperatures within 2 h of average wake-time, and (D) expert reviewed temperatures. Results: Relative to PdG, classification of cycles as ELA+ was 35 of 36 for LS-QBT methods A and B, 33 of 34 (method C) and 30 of 31 (method D). Classification of cycles as ELAÀ was 1 of 4 (methods A and B) and 0 of 3 (methods C and D). Positive predictive value was 92% for methods A-C and 91% for method D. Negative predictive value was 50% for methods A and B and 0% for methods C and D. Overall accuracy was 90% for methods A and B, 89% for method C and 88% for method D. The day of a significant temperature increase by LS-QBT and the first day of a sustained PdG rise were correlated (r = 0.803, 0.741, 0.651, 0.747 for methods A-D, respectively, all p < 0.001). Conclusion: LS-QBT showed excellent detection of ELA+ cycles (sensitivity, positive predictive value) but poor detection of ELAÀ cycles (specificity, negative predictive value) relative to urinary PdG. Correlations between the methods and overall accuracy were good and similar for all analyses. Findings suggest that LS-QBT is robust to wake-time variability and that expert interpretation is unnecessary. This method shows promise for use as an epidemiological tool to document cyclic progesterone increase. Further validation relative to daily transvaginal ultrasound is required. ß
Asia-Oceania Journal of Obstetrics and Gynaecology, 1991
The biologically active luteinizing hormone concentrations (as measured by testosterone production by mouse Leydig cells in response to LH) were measured in integrated hourly blood samples collected over 24-hour study periods during different stages of the menstrual cycle from a group of regularly cyclic women. Time series analyses were used to analyse the ultradian rhythms in each individual 24-hour LH profile. Fast Fourier transform (FFT) showed the presence of several ultradian rhythms with different periodicities (varying from 4.4 to 22 hours) in most of the L H profiles. In some of the LH profiles several ultradian rhythms appeared to co-exist. The commonest significant rhythm as detected by the FFT had a periodicity of 7-9 hours during both the follicular phase (40% of the subjects) and the mid cycle (50% of the subjects) and a periodicity of 5-7 hours during the luteal phase (44% of the subjects).
Fertility and Sterility, 2008
Objective: To determine whether leptin and LH secretion in normal women is related to changes in metabolic rate. Setting: Academic medical center. Patient(s) and Design: Ten young women with normal weight and menses were studied during the early follicular phase. Leptin and LH levels were sampled every 15 minutes over a 24-hour period. Metabolic rate was frequently sampled using indirect calorimetry. Luteinizing hormone pulsatility was analyzed using a Cluster Program analysis. Intervention(s): None. Main Outcome Measure(s): Leptin, LH, and metabolic rate levels. Result(s): All subjects demonstrated a diurnal leptin curve. Luteinizing hormone pulses were increased in amplitude and slower after the leptin peak. The average (AESE) number of LH pulses per 6 hours slowed from 4.30 AE 0.42 to 3.00 AE 0.42 pulses after the leptin peak, whereas pulse amplitude increased from 1.64 AE 0.26 to 2.51 AE 0.42 mIU/mL after the leptin peak. The LH interpulse interval increased from 85.1 AE 3.64 minutes to 108.8 AE 10.26 minutes after the leptin peak. Metabolic rate began to drop approximately 4-6 hours before leptin levels peaked, going from 1.66 AE 0.24 to 1.15 AE 0.04 kcal/min after the leptin peak. Conclusion(s): There is a significant association between the timing of the leptin peak, the nightly slowing of LH pulses, and the fall in metabolic rate, suggesting a metabolic cycle in normal individuals. (Fertil Steril Ò 2008; 90:1161-8.
The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception, 2015
Objective The aim of the study was to examine relationships and interindividual variations in urinary and serum reproductive hormone levels relative to ultrasound-observed ovulation in menstrual cycles of apparently normally menstruating women. Methods This was a prospective study of normally menstruating women (no known subfertility), aged 18-40 years (n = 40), who collected daily urine samples and attended the study centre for blood samples and transvaginal ultrasound during one complete menstrual cycle. Serum luteinising hormone (LH), progesterone, estradiol, urinary LH, pregnanediol-3- glucuronide (P3G) and estrone-3-glucuronide were measured. Ultrasound was conducted by two physicians and interpreted by central expert review. Results Menstrual cycle length varied from 22 to 37 days (median 27 days). Ovulation by ultrasound ranged from day 8 to day 26 (median day 15). Serum and urinary hormone profiles showed excellent agreement. Estrogen and LH hormone peaks in urine and serum ...
Rapid pulses of luteinizing hormone during the ovarian cycle
BJOG: An International Journal of Obstetrics and Gynaecology, 1990
Luteinizing hormone has been shown to be secreted in a complex pattern of low-amplitude, high-frequency pulses superimposed on high-amplitude, low-frequency pulses. To test the hypothesis that the rapid, small pulses vary during the ovarian cycle, 16 normal women were studied on two occasions each, in the early and late follicular phases of one cycle or the luteal and following early follicular phase. Blood samples were taken every 1 min for 1 h. Statistical methods of time series analysis were applied to the data. There were significant amplitude differences between subjects at all stages of the cycle. We found no evidence to support the hypothesis that the frequency of the small rapid pulses varied during folliculogenesis. The results for the luteal phase, while less uniform, showed no consistent change. It is suggested that the rapid pulses may be related to function of the hypothalamic-pituitary axis rather than direct ovarian control. We have recently shown that luteinizing hormone (LH) is secreted in a complicated pattern of superimposed pulses. In addition to the previously recognized major pulses which occur every 1-2 h (
Proceedings of the …, 1998
Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.