Chapter-IV. Blood pressure and heart rate variability as function of ovarian cycle in young women

Transcription

1 Blood pressure and heart rate variability as function of ovarian cycle in young women

2 INTRODUCTION In human females, the menstrual cycle begins with the onset of menstrual flow on day 1. The menstrual phase (generally lasting between 4 and 6 days) is defined by the shedding of the thickened endometrium, a process known as menstrual bleeding. The second follicular or proliferative phase continues until ovulation, typically days from 7 to 14. The luteal or secretory phase begins at ovulation and continues until the onset of the menstrual flow, typically days 15 through 28 (Muizzuddin et al., 2005). Cyclic changes have been documented in sex hormones during course of menstrual cycle. The level of estrogen hormone is higher during follicular phase and lower during luteal phase; however, vice versa occurs for the progesterone (Carr and Blackwell, 1993; Hawkins and Matzuk, 2008). It has been proposed that examination of variability in blood pressure and heart rate during different phases of the menstrual cycle in premenopausal apparently healthy women may be helpful in understanding the effect of hormones on BP regulation (Tsai et al., 2003). A few reports are available on the monthly patterns of blood pressure and effects of different phases of menstrual cycle on BP in premenopausal women using ambulatory blood pressure monitoring (Manhem et al., 1991, 1992; Karpanou et al., 1993; Heintz et al., 1996; Litschauer et al., 1998; Goldstein et al., 1999; Williamson et al., 1999). Mostly, these studies are conducted during follicular and luteal phases of the menstrual cycle. It has been documented that SBP (Manhem et al., 1991, 1992) and HR (Goldstein et al., 1999) were significantly higher during the luteal phase as compared to the follicular phase. Higher level of HR during luteal phase was explained in terms of higher daytime and nighttime norepinephrine. On the contrary, in some studies, significant differences could not be validated for blood pressure values during different phases of menstrual cycle in females (Heintz et al., 1996; Litschauer et al., 1998; Williamson et al., 1999). Heintz et al. (1996) also reported that variability in 24-h, daytime and nighttime SBP, DBP, and HR are independent of phases of the menstrual cycle in two groups of women, who were with and without oral contraceptives. However, they further highlighted that during both the phases, SBP and DBP were significantly higher in women taking oral contraceptives. Ph.D. Thesis submitted by Nishtha Vaidya 150

3 An association between sleep-wake cycle and hormone secretion has been established. This relationship was found to be influenced by the menstrual cycle (Shechter and Boivin, 2010). These authors emphasized that sleep of healthy women and in women with premenstrual dysphoric disorder (PMDD) alters during the menstrual cycle on account of this interaction. Women with PMDD also experience alterations of circadian rhythms during their symptomatic luteal phase (Shechter and Boivin, 2010). Further, most of the hormones, including melatonin, cortisol, thyroid stimulating hormone (TSH), and prolactin (PRL) are regulated by the circadian rhythm and sleep-wake cycle in humans (Shechter and Boivin, 2010). Menstrual cycle is further modulated by the fluctuations in gonadotropic and sex steroid hormones. In women, heart rate variability (HRV) is known to be influenced by various factors, such as endogenous sex hormones, hormone replacement therapy, menopause, menstrual cycle, body mass index (BMI), and physical conditioning. Relationship of circadian variation of heart rate with BMI, age and menstrual cycle has been studied in healthy young female subjects and results indicate that these factors have the prognostic value for heart rate variability (Vallejo et al., 2005). Further, the HR reactivity - a predictor of future hypertension remains high during the luteal phase than the follicular phase in normotensive women (Manhem et al. 1991). However, such difference in HR reactivity between the two menstrual phases was not apparent in hypertensive subjects (Manhem et al., 1992). Studies on relationship between different phases of menstrual cycle and circadian variability in BP and HR are inadequate. Therefore, objectives of the present study were: to evaluate the effects of different phases of menstrual cycle on circadian rhythm characteristics of blood pressure (BP) and heart rate (HR) in young healthy women. to examine the day-night variability and nocturnal dipping pattern in BP as function of menstrual phases in the said population. Ph.D. Thesis submitted by Nishtha Vaidya 151

4 MATERIALS AND METHODS Part A: Circadian rhythm in blood pressure and heart rate during different phases of the menstrual cycle in young normotensive women Subjects: Thirteen normotensive females (age range: y; mean ± SE: ± 0.79 y; median: 25 y) with regular menstrual cycle were randomly selected for the present study. We determined the normal menstrual cycle status from self-reports of a predictable cycle ranging from 28 to 30 days. Subjects were excluded if they were on birth control pills, other hormones, or vasoactive medications. The subjects were day active and did not report any obvious clinical complications. Demographic and anthropometric characteristics: Various demographic [age] and anthropometric variables [height (cm); weight (kg); body surface area, BSA (m 2 ); and body mass index, BMI (kg/m 2 )] of each subject were recorded. Range of sleep (23:00 02:00) and awake timings (06:30 09:00) of the subjects were recorded on the basis of their sleep log. All subjects reported regular 28/30 day-menstrual cycle for at least one month prior to the study. All participants signed a written informed consent. The study obtained approval of the Institutional Ethics Committee on Human Research of the Pt. Ravishankar Shukla University, Raipur, India. Procedure: All subjects were agreed to participate in the study during working days. Blood pressure (BP) and heart rate (HR) were recorded with the help of ABPM during a 48- h period on days 1, 8, 15, and 22 of the menstrual cycle, approximately representing the beginning of menstruation, follicular, ovulation, and luteal phase, respectively. The BP and HR monitoring was conducted randomly, but with reference to Ph.D. Thesis submitted by Nishtha Vaidya 152

5 individual s menstrual cycle in order to have the data on comparable physiological state The normal menstrual cycle was verified with each subject that day 22 was followed by menstruation within 6 9 days. Assessment of characteristics of circadian rhythms in blood pressure and heart rate during different phases of menstrual cycle in women The variables were monitored in each subject following the protocol mentioned in Chapter-II. Part B: Daytime and nighttime blood pressure and heart rate during different phases of the menstrual cycle in young normotensive women Twenty-four hour, daytime, and nighttime averages of SBP, DBP, MAP, and HR were obtained separately during different phases of the menstrual cycle for each subject, participated in Part A. Statistical analysis: Data on blood pressure and heart rate during different menstrual phases, such as menstruation, follicular, ovulation, and luteal were retrieved and analyzed using specific A&D software. Cosinor rhythmometry was used for documenting a circadian rhythm in SBP, DBP, MAP, DP, and HR during different phases of the cycle (Nelson et al., 1979). Day/night ratio was computed for the studied variables during each phase. Other statistical techniques, such as One-way and two-way ANOVA followed by Duncan s multiple-range test were used whenever required. Correlation analysis was used to investigate the relationship between paired variables. Data were analyzed with the help of software, namely SPSS (version 10) and Analysis ToolPak (Microsoft Excel). Ph.D. Thesis submitted by Nishtha Vaidya 153

6 RESULTS Part A: Circadian rhythm in blood pressure and heart rate during different phases of the menstrual cycle in young normotensive women Table 4.1 illustrates demographic, anthropometric & sleep characteristics, and day/night BP ratio in young women. Decrement Prevalence of extreme dippers, dippers and non-dippers: Among 13 young women 1 (7.69%), 9 (69.23%) and 3 (23.08%) subjects were extreme dippers (ED), dippers (D) and non-dippers (ND), respectively. Rhythm characteristics of blood pressure variables and heart rate Rhythm detection: Results of Cosinor rhythmometry of the time series on SBP, DBP, MAP, DP, and HR rhythm in young women during different phases of the menstrual cycle are summarized in Tables A statistically significant circadian rhythm (τ = 24 h) in SBP was validated in 12, 9, 13 and 11 subjects during menstruation, follicular, ovulation and luteal phases, respectively (Table 4.2). Similarly, a significant rhythm was documented for other variables, namely DBP, MAP, DP, and HR in most of the subjects, irrespective of the menstrual phases (Tables ). The rhythm detection ratio of all studied variables was high in all phases, except follicular phases. During follicular phase the ratio was high for HR only (Table 4.7). Figure 4.1 (A-E) illustrates the best-fitting cosine curves for SBP, DBP, MAP, DP, and HR in different phases of menstrual cycle, such as menstruation, follicular, ovulation and luteal at group level. The curves shown in this figure were constructed using the mathematical model, Yt (i) = M + A cos (ωt i + Ø). Curves show a statistically significant circadian rhythm in SBP, DBP, MAP, DP, and HR, irrespective of phase Ph.D. Thesis submitted by Nishtha Vaidya 154

7 of menstrual cycle (Figure 4.1 A-E). Figures indicate that the average values of SBP, DBP, MAP, and DP were higher during ovulation phase. Tables present 24-h average, amplitude and acrophase of SBP, DBP, MAP, DP, and HR in each subject during different phases of the menstrual cycle. The Mesor, amplitude and acrophase of each variable were obtained at the fixed window of 24 h. Circadian 24-h average (Mesor): Systolic blood pressure (SBP): The results of Cosinor rhythmometry indicated interindividual differences in 24-h average of SBP, irrespective of phases of the menstrual cycle (Table 4.2). During menstruation phase the highest circadian Mesor of SBP ( ± 1.92 mmhg) was observed in F # 9 and the lowest (94.83 ± 1.06 mmhg) in F # 5 with a range of mmhg. Subject F # 5 exhibited the highest circadian Mesor of SBP ± 7.38 mmhg and ± 2.20 mmhg during follicular and ovulation phases, respectively. The lowest Mesor ± 1.18 mmhg and ± 1.04 was observed in F # 4 during follicular and ovulation phases, respectively. In these two phases the range of Mesor was mmhg and mmhg. During luteal phase the Mesor varied from ± 0.83 mmhg (F # 10) to ± 2.59 mmhg (F # 5) with a range of mmhg (Table 4.2). Diastolic blood pressure (DBP): An inter-individual difference in 24-h average of DBP was noticed, irrespective of phases of the menstrual cycle (Table 4.3). During menstruation phase the highest circadian Mesor of DBP (75.76 ± 1.80 mmhg) was observed in F # 9 and the lowest (63.59 ± 0.92 mmhg) in F # 5 with a range of mmhg. During follicular phase the highest circadian Mesor (76.48 ± 4.76 mmhg) was noticed in F # 5 and the lowest (59.74 ± 1.43) in F # 3. The Mesor had a range of mmhg. The highest circadian Mesor (80.76 ± 1.93 mmhg) was observed in F # 5 and the lowest (62.67 ± 0.78 mmhg) in F # 4 with a range of mmhg during ovulation phase. Further, during luteal phase the Mesor varied between ± 0.79 mmhg (F # 7) and ± 1.83 mmhg (F # 8) with a range of mmhg (Table 4.3). Ph.D. Thesis submitted by Nishtha Vaidya 155

8 Mean arterial pressure (MAP): An inter-individual difference in 24-h average of MAP was observed, irrespective of phases of the menstrual cycle (Table 4.4). The highest circadian Mesor of MAP (89.08 ± 1.66 mmhg) was observed in F # 9 and the lowest (74.00 ± 0.90 mmhg) in F # 5 with a range of mmhg during menstruation phase. The Mesor varied between ± 1.31 mmhg (F # 3) and ± 4.86 mmhg (F # 5) during follicular phase. The range of the Mesor was mmhg. Further, during ovulation phase the highest circadian Mesor (94.04 ± 1.79 mmhg) was observed in F # 5 and the lowest (73.32 ± 0.77 mmhg) in F # 4 with a range of mmhg. The highest (86.35 ± 1.93 mmhg) and the lowest (74.92 ± 0.85 mmhg) circadian Mesor was observed in F # 5 and F # 2, respectively during luteal phase. The range of Mesor was mmhg (Table 4.4). Double Product (DP): An inter-individual difference in 24-h average of DP was observed, irrespective of phases of the menstrual cycle (Table 4.5). During menstruation phase the highest circadian Mesor of DP ( ± 2.83) was observed in F # 9 and the lowest (78.43 ± 1.75) in F # 4 with a range of mmhg. The highest circadian Mesor ( ± 1.92 mmhg) was noticed in F # 9 and the lowest (65.62 ± 1.50 mmhg) in F # 3 with a range of mmhg during follicular phase. Moreover, Mesor varied between ± 3.99 mmhg (F # 5) and ± 1.62 mmhg (F # 3) during ovulation phase with a range of 27.8 mmhg. Subject F # 5 exhibited the highest (98.67 ± 3.02 mmhg) and F # 4 exhibited the lowest (72.66 ± 3.09 mmhg) circadian Mesor during luteal phase. Mesor had a range of mmhg (Table 4.5). Heart rate (HR): An inter-individual difference in 24-h average of HR was observed, irrespective of phases of the menstrual cycle (Table 4.6). During menstruation phase the highest circadian Mesor of HR (96.69 ± 0.98 beats/ min) was observed in F # 3 and the lowest (74.43 ± 1.08 beats/ min) in F # 4 with a range of beats/ min. During follicular phase the highest circadian Mesor of HR (89.26 ± 0.99 beats/ min) was noticed in F # 9 and the lowest (67.60 ± 0.99 beats/min) in F # 3 with a range of beats/ min. During ovulation phase the highest circadian Mesor of HR (91.80 ± 1.16 beats/ min) was observed in F # 10 and the lowest (71.05 ± 1.10 beats/ min) in F # 3. The Mesor had a range of beats/ min. The highest circadian Mesor (93.72 ± Ph.D. Thesis submitted by Nishtha Vaidya 156

9 2.62 beats/ min) was observed in F # 9 and the lowest (67.19 ± 1.65 beats/ min) in F # 4 with a range of beats/ min (Table 4.6). Further, one-way ANOVA followed by Duncan s multiple-range test was employed to find out the effect of different phases of menstrual cycle on the Mesors of SBP, DBP, MAP, DP, and HR. Results are summarized in Table 4.8. The factor phase did not produce any significant effect on Mesors of SBP, DBP, MAP, DP, and HR (Table 4.8). Circadian Amplitude: Tables summarize the results of Cosinor rhythmometry of the time series on SBP, DBP, MAP, DP, and HR on individual basis. At group level the circadian amplitudes of these rhythms are presented in Table 4.9. Systolic blood pressure (SBP): An inter-individual variation in circadian amplitude of SBP rhythm was observed, irrespective of phases of menstrual cycle (Table 4.2). The highest circadian amplitude (15.75) was observed in F # 12 and the lowest (2.53) in F # 11 with a range of mmhg during menstruation phase. F # 1 exhibited the highest circadian amplitude of SBP (16.09) and the lowest (1.16) was noticed in F # 11 with a range of mmhg during follicular phase. Further, during ovulation phase, the circadian amplitude was observed between 6.83 (F # 11) and (F # 5) with a range of mmhg. Range of the amplitude was mmhg during luteal phase. The highest circadian amplitude (21.19) was observed in F # 5 and the lowest (3.51) in F # 6. The 95% confidence limits for the circadian amplitudes in most of the subjects overlapped with each other in the respective phases (Table 4.2). Diastolic blood pressure (DBP): An inter-individual variation in circadian amplitude was observed for DBP, irrespective of phases of the cycle (Table 4.3). Circadian amplitude of DBP was the highest (11.05) in F # 13 and the lowest (2.50) in F # 10 with a range of 8.55 mmhg during menstruation phase. During follicular phase the highest circadian amplitude of DBP (10.02) was noticed in F # 9 and the lowest (1.22) in F # 5. The amplitude had a range of 8.8 mmhg. Further, F # 9 exhibited the lowest circadian amplitude (4.52) and F # 5 the highest (21.16) during ovulation phase. The range of amplitude was mmhg. During the luteal phase the highest circadian Ph.D. Thesis submitted by Nishtha Vaidya 157

10 amplitude (15.49) was observed in F # 12 and the lowest (2.82) in F # 11 with a range of mmhg. The 95% confidence limits for the circadian amplitudes in most of the subjects overlapped with each other in the respective phases (Table 4.3). Mean arterial pressure (MAP): An inter-individual variation in circadian amplitude was observed for MAP, irrespective of phases of the cycle (Table 4.4). The highest circadian amplitude of MAP (12.45) was observed in F # 12 and the lowest (2.48) in F # 11 with a range of 9.97 mmhg during menstruation phase. During follicular phase the highest circadian amplitude (10.97) was noticed in F # 1 and the lowest (2.20) in F # 11. Amplitude had a range of 8.77 mmhg. Further, subject F # 5 showed the highest amplitude (21.86) and F # 9 exhibited the lowest (6.24) during ovulation phase with a range of mmhg. During luteal phase, the circadian amplitudes were observed between 3.64 (F # 11) and (F # 12) with a range of mmhg. The 95% confidence limits for the circadian amplitudes in most of the subjects overlapped with each other in the respective phases (Table 4.3). Double product (DP): An inter-individual variation in circadian amplitude was also observed for DP, irrespective of phases of the cycle (Table 4.5). The highest circadian amplitude of DP (30.71) was observed in F # 13 and the lowest (13.67) in F # 10. Amplitude had a range of mmhg during menstruation phase. During follicular phase the highest circadian amplitude (23.08) was noticed in F # 1 and the lowest (11.69) in F # 7 with a range of mmhg. During ovulation phase the highest circadian amplitude (25.67) was observed in F # 7 and the lowest (15.41) in F # 9 with a range of mmhg. During luteal phase, the circadian amplitudes were observed between 6.60 (F # 6) and (F # 2) with a range of mmhg. The 95% confidence limits for the circadian amplitudes in most of the subjects overlapped with each other in the respective phases (Table 4.5). Heart rate (HR): An inter-individual variation in circadian amplitude was observed for HR, irrespective of phases of the cycle (Table 4.6). F # 13 exhibited the highest circadian amplitude (19.18) and the lowest (7.74) was observed in F # 6 with a range of mmhg during menstruation phase. During follicular phase the highest circadian amplitude (12.64) was noticed in F # 8 and the lowest (3.33) in F # 5. The range of amplitude was 9.31 mmhg. During ovulation phase the highest (18.72) and Ph.D. Thesis submitted by Nishtha Vaidya 158

11 the lowest (5.52) circadian amplitude was observed in F # 7 and F # 5, respectively with a range of 13.2 mmhg. The circadian amplitudes were observed between 4.38 (F # 6) and (F # 9) with a range of mmhg during luteal phase. The 95% confidence limits for the circadian amplitudes in most of the subjects overlapped with each other in the respective phases (Table 4.6). Further, one-way ANOVA followed by Duncan s multiple-range test was employed to find out the effect of different phases of menstrual cycle on the amplitudes of SBP, DBP, MAP, DP, and HR. Results are summarized in Table 4.9. The factor phase did not produce any significant effect on amplitudes of SBP, DBP, MAP, DP, and HR. Further, results of Duncan s multiple-range test indicate that the amplitudes of all rhythms were decreased during follicular phase as compared to other phases, though the decrement in amplitude was significant for DP rhythm only. The amplitude of DP was significantly lower during follicular phase as compared to the ovulation phase (Table 4.9). Circadian peak (Acrophase): Tables summarize the results of Cosinor rhythmometry indicated the acrophase of SBP, DBP, MAP, DP, and HR on individual basis. At group level the circadian amplitudes of these rhythms are presented in Table Systolic blood pressure (SBP): An inter-individual variation in the circadian peak of SBP was noticed, irrespective of phases of the cycle (Table 4.2). The acrophase spread for SBP was 7.6 h. The acrophase occurred at the earliest (12.4 h) in F # 2 and the latest (20.0 h) in F # 8 during menstruation phase. During follicular phase the acrophase occurred at the latest (19.1 h) in F # 10 and the earliest (12.9) in F # 2 with an acrophase spread of 6.2 h. Further, acrophase occurred at the earliest (8.13 h) in F # 2 and the latest (20.2 h) in F # 1. The acrophase spread for SBP was 8.6 h during ovulation phase. During luteal phase the acrophase occurred at the latest (21.3 h) in F # 7 and the earliest (11.9 h) in F # 11. The acrophase spread was relatively wide, i.e., 9.4 h (Table 4.2). Diastolic blood pressure (DBP): An inter-individual variation in the circadian peak of DBP was noticed, irrespective of phases of the cycle (Table 4.3). During Ph.D. Thesis submitted by Nishtha Vaidya 159

12 menstruation phase the acrophase occurred at the earliest (12.9 h) in F # 2 and the latest (19.8 h) was observed in F # 8. Acrophase spread was 6.9 h. Acrophase occurred at the earliest (12.2 h) and the latest (19.8 h) in F # 10 and F # 11, respectively with an acrophase spread of 7.6 h during follicular phase. The acrophase occurred between 12.4 h (F # 2) and 21.9 h (F # 1) during ovulation phase. The acrophase spread for DBP was 9.5 h. Further, during luteal phase the acrophase occurred at the earliest (13.8 h) in F # 10 and the latest (20.6 h) was observed in F # 7 with a spread of 6.8 h (Table 4.3). Mean arterial pressure (MAP): An inter-individual variation in the circadian peak of DBP was noticed, irrespective of phases of the cycle (Table 4.4). The earliest acrophase (12.7 h) occurred in F # 2 and the latest (19.2 h) was observed in F # 8 during menstruation phase. The acrophase spread for MAP was 7.2 h. During follicular phase the acrophase occurred at the latest (19.7 h) in F # 7 and the earliest (12.7) in F # 11 with an acrophase spread of 7.0 h. The acrophase occurred at the latest (21.1 h) in F # 1 and the earliest (12.1 h) in F # 2 during ovulation phase. Acrophase spread for MAP was 9.0 h. During luteal phase the acrophase occurred between 13.2 h (F # 11) and 20.9 h (F # 7) with a spread of 7.7 h (Table 4.4). Double product (DP): An inter-individual variation in the circadian peak of DP was also noticed, irrespective of phases of the cycle (Table 4.5). The acrophase timings of DP appeared to be much more stable with a spread of only 4.3 h during menstruation phase. It always occurred between 14.3 h (F # 7) and 18.6 h (F # 8). During follicular phase the acrophase occurred at the latest (18.7 h) in F # 7 and the earliest (13.4) in F # 6 with an acrophase spread of 5.3 h. Further, the earliest (13 h) and the latest (18.1 h) acrophase occurred in F # 1 and F # 2, respectively with a spread of 5.1 h during ovulation phase. During luteal phase the acrophase occurred at the latest (19.2 h) in F # 7 and the earliest (13.6-h) in F # 10 with a spread of 5.6 h (Table 4.5). Heart rate (HR): An inter-individual variation in the circadian peak of HR was also noticed, irrespective of phases of the cycle (Table 4.6). The acrophase spread for HR was very stable, i.e., 3.8 h only during menstruation phase. It always occurred between 14.3 h (F # 7) and 18.1 h (F # 8). During follicular phase the acrophase occurred at the latest (18.3 h) in F # 7 and the earliest (14.0 h) in F # 4 barring the Ph.D. Thesis submitted by Nishtha Vaidya 160

13 subject F # 5. Acrophase spread was 4.3 h only. The acrophase occurred at the latest (18.4 h) in F # 9 and the earliest (11.5 h) was observed in F # 5 and spread for HR rhythm was 6.9 h during ovulation phase. The acrophase occurred between 14.3 h (F # 10) and 18.6 h (F # 4) with a spread of only 4.3 h during luteal phase (Table 3.7). Furthermore, one-way ANOVA followed by Duncan s multiple-range test was employed to find out the effect of different phases of menstrual cycle on the acrophase of SBP, DBP, MAP, DP, and HR. Results are summarized in Table Acrophase of SBP, DBP, MAP, DP, and HR rhythm was not found to be influenced by the factor phase. Effect of different phases of the menstrual cycle on day/night ration of SBP, DBP, MAP, and HR: 24-h, daytime, and nighttime averages of SBP, DBP, HR, and MAP were obtained separately for each subject during different phases of the menstrual cycle. Day/night ratio was computed for individual variable using the daytime and nighttime values. Results indicate that the factor phase did not produce any significant effect on day/night ratio of SBP, DBP, MAP, and HR. However, ratio of the SBP declined significantly during follicular phase than luteal phase. Further, day/night ratio of the DBP and MAP were also low during follicular phase than that of the other phases, however difference was not significant (Table 4.11, Figure 4.2). Part B: Daytime and nighttime blood pressure and heart rate during different phases of the menstrual cycle in young normotensive women Effect of factor phase of menstrual cycle on 24-h, daytime and nighttime BP variables and HR Tables show the 24-h, daytime and nighttime averages of SBP, DBP, MAP, and HR at group level. Tables also represent the results of one-way ANOVA followed Ph.D. Thesis submitted by Nishtha Vaidya 161

14 by the Duncan s multiple-rest test that was employed to find out the effect of factor phase on 24-h, daytime and nighttime averages of the studied variables separately. Results indicate that factor phase did not produce any significant effect on 24- h or daytime or nighttime SBP and HR (Tables 4.12 and 4.15). In case of DBP, a significant effect of factor phase was noticed on nighttime averages only. Nighttime DBP was significantly low during luteal phase as compared to other three phases, namely menstruation, follicular and ovulation (Table 4.13). Likewise results (based on Duncan s multiple-rest test) were also obtained for MAP, though the effect of factor phase was not significant. Nighttime MAP was significantly low during luteal phase than that of menstruation, follicular and ovulation phases (Table 4.14). Effects of factors phase and time on BP variables and HR Table 4.16 represents the summary of two-way ANOVA that was applied to examine the effects of factors, phases of menstrual cycle (menstruation vs. follicular vs. ovulation vs. luteal) and time (day vs. night) on SBP, DBP, MAP, and HR. Only the factor time produced a statistically significant effect on SBP (p<0.01), DBP (p<0.001), MAP (p<0.001), and HR (p<0.001). However, none of the interaction effects are significant. Relationship of daytime & nighttime BP and heart rate with demographic & anthropometric variables, and sleep parameters Pearson s correlation coefficients of daytime and nighttime SBP, DBP, MAP, and HR with demographic & anthropometric variables (age, height, weight, BSA, and BMI) and sleep parameters (wake time, sleep time and sleep length) at group level as function of phases of menstrual cycle are shown in Tables During menstruation phase, daytime HR was statistically significantly negatively (p<0.01) correlated with height and positively (p<0.05) with wake time. The nighttime DBP exhibited statistically significant negative (p<0.01) relationship with age (Table 4.17). Ph.D. Thesis submitted by Nishtha Vaidya 162

15 During follicular phase, significant positive association was noticed between daytime MAP and BSA (p<0.05). Nighttime SBP, DBP and MAP exhibited significant positive correlation with sleep time (p<0.05) and wake time (p<0.01, p<0.01) (Table 4.18). Furthermore, during ovulation phase none of the pairs of variables exhibited significant relationship, irrespective of time (Table 4.19). Moreover, during luteal phase only nighttime SBP and MAP exhibited significant negative correlation with age (p<0.05) (Table 4.20). Ph.D. Thesis submitted by Nishtha Vaidya 163

16 Table 4.1 Demographic, anthropometric and sleep characteristics in young women Attribute Description Number of female subjects 13 Age (y): Median/ range 25/22-32 Height (cm) ± 1.03 Weight (kg) ± 2.37 BMI (kg/m 2 ) ± 0.89 BSA (m 2 ) ± 0.03 Sleep time: range (h) 22:30 02:00 Awake time: range (h) 06:30 09:00 Sleep length: range (h) 06:30-10:00 ED/D/ND 1/9/3 Average span of menstrual cycle (days) BSA Body surface area; BMI Body mass index; ED Extreme dipper; D Dipper; ND Non-dipper Ph.D. Thesis submitted by Nishtha Vaidya 164

17 Table 4.2 Cosinor Summary: Characteristics of SBP rhythm during different phases of menstrual cycle in young women. Rhythm parameters were computed at fixed windows with τ = 24 h Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Menstruation Phase F # < ± (17.42, 07.05) 14.9 (16.59, 13.24) F # < ± (13.75, 04.30) 12.4 (14.71, 10.02) F # < ± (13.72, 06.12) 18.0 (19.58, 16.39) F # < ± (09.91, 01.45) 14.0 (17.20, 10.84) F # < ± (11.44, 04.39) 14.3 (16.19, 12.44) F # < ± (18.93, 03.50) 16.3 (18.85, 13.80) F # < ± (10.83, 04.15) 14.0 (15.75, 12.29) F # < ± (08.16, 03.41) 20.0 (21.77, 18.24) F # < ± (16.51, 04.00) 16.2 (18.64, 13.69) F # < ± (13.08, 00.38) 16.2 (21.02, 11.38) F # < ± F # < ± (19.05, 12.45) 17.9 (18.78, 17.01) F # < ± (19.53, 06.12) 17.0 (19.04, 14.97) Follicular Phase F # < ± (23.32, 08.87) 15.8 (17.47, 14.13) F # < ± (11.75, 04.16) 12.9 (15.11, 10.70) F # ± F # < ± (10.65, 02.12) 13.7 (16.23, 11.13) F # ± F # < ± (19.67, 07.12) 13.3 (15.27, 11.40) F # ± F # < ± (13.45, 00.34) 12.9 (17.54, 08.22) F # < ± (16.85, 07.61) 15.4 (16.91, 13.86) F # < ± (10.09, 04.94) 19.1 (20.44, 17.71) F # ± F # < ± (12.39, 02.78) 15.8 (17.47, 14.13) F # < ± (13.30, 02.64) 12.9 (15.11, 10.70) Continued Ph.D. Thesis submitted by Nishtha Vaidya 165

18 Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Ovulation Phase F # < ± (16.41, 04.11) 20.2 (22.71, 17.60) F # < ± (14.57, 06.95) 11.6 (13.02, 10.23) F # < ± (13.70, 03.42) 17.0 (19.12, 14.86) F # < ± (15.71, 08.63) 15.4 (16.44, 14.27) F # < ± (31.20, 15.79) 18.2 (19.42, 16.91) F # < ± (17.98, 09.04) 13.4 (14.72, 12.08) F # < ± (13.35, 06.55) 17.5 (18.82, 16.23) F # < ± (16.96, 03.52) 15.1 (18.25, 11.97) F # < ± (17.60, 01.95) 13.8 (17.29, 10.30) F # < ± (16.22, 06.82) 17.3 (19.16, 15.52) F # < ± (09.62, 04.04) 15.3 (16.86, 13.83) F # < ± (18.85, 03.87) 15.9 (18.57, 13.29) F # < ± (22.99, 06.65) 14.2 (16.45, 11.96) Luteal Phase F # < ± (12.45, 03.55) 14.8 (16.88, 12.65) F # < ± (16.44, 09.79) 15.2 (16.32, 14.11) F # ± F # < ± (26.06, 05.32) 17.4 (20.27, 14.45) F # < ± (30.57, 11.81) 15.3 (16.85, 13.67) F # < ± F # < ± (08.65, 02.42) 21.3 (23.66, 18.94) F # < ± (19.96, 01.10) 14.5 (18.69, 10.40) F # < ± (19.56, 07.50) 17.2 (17.95, 16.51) F # < ± (13.59, 08.23) 13.3 (14.32, 12.31) F # < ± (11.97, 00.17) 11.9 (16.63, 07.17) F # < ± (28.81, 11.54) 16.0 (17.83, 14.19) F # < ± (13.67, 07.22) 15.8 (16.86, 14.72) SBP Systolic blood pressure; a From an F-test of null amplitude rejection hypothesis Ph.D. Thesis submitted by Nishtha Vaidya 166

19 Table 4.3 Cosinor Summary: Characteristics of DBP rhythm during different phases of menstrual cycle in young women. Rhythm parameters were computed at fixed windows with τ = 24 h Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Menstruation Phase F # < ± (13.38, 03.01) 14.4 (17.05, 11.81) F # < ± (11.32, 04.85) 12.9 (14.69, 11.18) F # < ± (10.48, 05.54) 18.7 (19.93, 17.41) F # < ± (07.47, 00.04) 15.4 (20.60, 10.27) F # < ± (10.03, 03.87) 13.2 (15.08, 11.33) F # < ± (17.77, 03.89) 16.4 (18.67, 14.06) F # < ± (09.05, 02.94) 14.3 (16.25, 12.25) F # < ± (07.66, 02.78) 19.8 (21.81, 17.76) F # < ± (14.84, 03.26) 15.6 (18.28, 12.90) F # ± F # < ± (05.04, 00.02) 14.2 (19.70, 08.72) F # < ± (14.07, 07.53) 17.9 (19.15, 16.58) F # < ± (16.86, 05.24) 16.4 (18.39, 14.31) Follicular Phase F # < ± (13.33, 03.62) 16.4 (18.79, 14.10) F # < ± (11.34, 03.31) 13.8 (16.21, 11.47) F # ± F # < ± (10.85, 03.34) 13.2 (15.17, 11.30) F # ± F # < ± (13.21, 04.14) 13.8 (15.93, 11.69) F # < ± (08.23, 00.38) 19.6 (24.30, 15.00) F # < ± (15.68, 02.23) 14.1 (17.28, 10.94) F # < ± (14.31, 05.72) 14.4 (16.19, 12.66) F # < ± (07.63, 02.30) 19.8 (21.92,17.58) F # ± F # < ± (11.21, 02.19) 16.5 (19.31,13.60) F # < ± (12.97, 03.71) 15.1 (16.99, 13.20) Continued Ph.D. Thesis submitted by Nishtha Vaidya 167

20 Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Ovulation Phase F # < ± (12.59, 00.78) 21.9 (25.81, 17.94) F # < ± (11.61, 05.85) 12.4 (13.69, 11.17) F # < ± (10.94, 01.64) 16.1 (18.91, 13.33) F # < ± (13.72, 08.40) 15.4 (16.27, 14.46) F # < ± (28.07, 14.25) 18.8 (20.02, 17.61) F # < ± (12.73, 05.35) 13.2 (14.83, 11.54) F # < ± (14.99, 07.86) 16.9 (18.10, 15.79) F # < ± F # ± F # < ± (12.60, 03.97) 17.9 (20.24, 15.49) F # < ± (09.16, 04.23) 15.7 (17.03, 14.29) F # < ± (13.49, 02.13) 13.7 (16.38, 10.95) F # < ± (18.07, 03.58) 14.0 (16.83, 11.18) Luteal Phase F # < ± (09.39, 01.34) 14.9 (17.88, 11.93) F # < ± (13.67, 08.09) 15.0 (16.10, 13.86) F # < ± (11.20, 00.98) 16.3 (19.89, 12.77) F # < ± (22.42, 04.70) 16.1 (18.96, 13.26) F # < ± (21.89, 06.72) 15.7 (17.73, 13.70) F # < ± (08.23, 02.82) 14.1 (15.84, 12.29) F # < ± (07.66, 02.47) 20.6 (22.87, 18.39) F # < ± (13.02, 00.97) 15.3 (19.18, 11.44) F # < ± (13.51, 04.43) 17.1 (19.04, 15.09) F # < ± (11.34, 06.92) 13.8 (14.75, 12.81) F # ± F # < ± (22.04, 08.94) 14.7 (16.41, 12.94) F # < ± ( 11.20, 05.86) 16.1 (17.18, 15.01) DBP Diastolic blood pressure See also legends to Table 4.2 Ph.D. Thesis submitted by Nishtha Vaidya 168

21 Table 4.4 Cosinor Summary: Characteristics of MAP rhythm during different phases of menstrual cycle in young women. Rhythm parameters were computed at fixed windows with τ = 24 h Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Menstruation Phase F # < ± (14.47, 04.57) 14.6 (16.73, 12.55) F # < ± (11.92, 04.84) 12.7 (14.59, 10.87) F # < ± (11.27, 05.95) 18.4 (19.68, 17.14) F # < ± (07.87, 00.77) 14.8 (18.38, 11.27) F # < ± (10.22, 04.18) 13.6 (15.38, 11.84) F # < ± (17.34, 04.58) 16.4 (18.39, 14.32) F # < ± (09.41, 03.57) 14.2 (15.91, 12.42) F # < ± (07.67, 03.14) 19.9 (21.67, 18.06) F # < ± (14.80, 04.05) 15.8 (18.15, 13.45) F # ± F # ± F # < ± (15.39, 09.51) 17.9 (18.87, 16.88) F # < ± (17.26, 05.95) 16.6 (18.47, 14.71) Follicular Phase F # < ± (16.24, 05.71) 16.1 (17.98, 14.28) F # < ± (11.30, 03.67) 13.5 (15.77, 11.25) F # ± F # < ± (10.50, 03.20) 13.4 (15.32, 11.43) F # ± F # < ± (14.93, 05.53) 13.6 (15.47, 11.73) F # < ± (07.67, 00.33) 19.7 (24.37, 15.00) F # < ± (14.39, 01.97) 13.8 (16.97, 10.57) F # < ± (14.63, 06.72) 14.8 (16.30, 13.28) F # < ± (08.28, 03.31) 19.5 (21.17, 17.75) F # ± F # < ± (11.36, 02.54) 16.1 (18.73, 13.51) F # < ± (12.45, 03.77) 15.5 (17.35, 13.69) Continued Ph.D. Thesis submitted by Nishtha Vaidya 169

22 Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Ovulation Phase F # < ± (13.21, 02.15) 21.1 (24.18, 18.08) F # < ± (12.20, 06.52) 12.1 (13.29, 10.95) F # < ± (11.23, 02.78) 16.5 (18.65, 14.30) F # < ± (14.05, 08.81) 15.4 (16.22, 14.50) F # < ± (28.24, 15.49) 18.6 (19.68, 17.49) F # < ± (14.19, 06.87) 13.3 (14.67, 11.89) F # < ± (14.28, 07.53) 17.1 (18.27, 15.97) F # < ± (12.29, 01.42) 15.2 (19.08, 11.30) F # < ± (12.25, 00.23) 13.4 (18.39, 08.47) F # < ± (13.59, 05.10) 17.6 (19.70, 15.60) F # < ± (09.21, 04.26) 15.6 (16.91, 14.19) F # < ± (14.34, 02.88) 14.6 (17.09, 12.13) F # < ± (18.94, 05.36) 14.1 (16.36, 11.81) Luteal Phase F # < ± (10.01, 02.47) 14.8 (17.15, 12.54) F # < ± (14.40, 08.85) 15.1 (16.11, 14.03) F # < ± (11.16, 23.98) 16.3 (21.56, 11.01) F # < ± (23.13, 05.05) 16.6 (19.37, 13.76) F # < ± (23.54, 09.60) 15.5 (17.05, 14.00) F # < ± (07.57, 02.10) 14.3 (16.37, 12.13) F # < ± (07.85, 02.55) 20.9 (23.06, 18.67) F # < ± (14.61, 01.65) 15.0 (18.43, 11.54) F # < ± (15.09, 05.89) 17.1 (18.83, 15.45) F # < ± (11.83, 07.58) 13.6 (14.49, 12.72) F # ± F # < ± (23.60, 10.01) 15.2 (16.88, 13.52) F # < ± (11.71, 06.61) 16.0 (16.94, 15.02) MAP Mean arterial pressure See also legends to Table 4.2 Ph.D. Thesis submitted by Nishtha Vaidya 170

23 Table 4.5 Cosinor Summary: Characteristics of DP rhythm during different phases of menstrual cycle in young women. Rhythm parameters were computed at fixed windows with τ = 24 h Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Menstruation Phase F # < ± (31.87, 15.69) 16.4 (17.68, 15.10) F # < ± (23.17, 09.51) 14.9 (16.62, 13.19) F # < ± (29.08, 15.53) 17.7 (19.00, 16.49) F # < ± (23.35, 11.06) 15.5 (16.90, 14.18) F # < ± (20.65, 11.83) 15.1 (16.21, 13.99) F # < ± (29.37, 06.34) 15.9 (18.13, 13.60) F # < ± (24.58, 08.36) 14.3 (16.20, 12.35) F # < ± (22.80, 14.02) 18.6 (19.60, 17.60) F # < ± (33.06, 14.39) 16.6 (18.09, 15.03) F # < ± (20.94, 06.39) 17.2 (19.41, 14.98) F # < ± (24.49, 11.25) 16.2 (17.61, 14.78) F # < ± (30.92, 21.86) 17.3 (18.03, 16.60) F # < ± (39.27, 22.15) 16.6 (17.68, 15.60) Follicular Phase F # < ± (34.01, 12.15) 16.5 (18.36, 14.61) F # < ± (24.47, 09.59) 14.7 (16.42, 12.93) F # < ± (18.2, 07.73) 17.0 (18.50, 15.43) F # < ± (22.31, 10.93) 13.8 (14.98, 12.56) F # ± F # < ± (30.96, 10.04) 13.4 (15.46, 11.24) F # < ± (17.05, 06.32) 18.7 (20.65, 16.79) F # < ± (26.87, 07.27) 13.6 (15.85, 11.36) F # < ± (27.37, 13.98) 17.5 (18.73, 16.25) F # < ± (23.07, 12.15) 18.4 (19.64, 17.15) F # < ± (18.29, 05.25) 16.0 (18.14, 13.95) F # < ± (26.06, 11.25) 15.1 (16.57, 13.65) F # < ± (20.32, 04.55) 15.4 (17.67, 13.19) Continued Ph.D. Thesis submitted by Nishtha Vaidya 171

24 Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Ovulation Phase F # < ± (27.94, 13.35) 18.1 (19.54, 16.58) F # < ± (24.04, 13.03) 13.0 (14.12, 11.90) F # < ± (22.06, 10.17) 16.9 (18.17, 15.62) F # < ± (26.74, 15.25) 15.9 (16.92, 14.95) F # < ± (32.92, 06.14) 16.4 (19.45, 13.44) F # < ± (35.66, 14.89) 14.1 (15.75, 12.53) F # < ± (30.98, 20.35) 16.9 (17.64, 16.13) F # < ± (30.46, 09.19) 14.6 (17.18, 12.10) F # < ± (24.34, 06.48) 16.3 (18.86, 13.76) F # < ± (30.32, 14.20) 17.9 (19.50, 16.26) F # < ± (21.80, 11.28) 16.6 (17.84, 15.40) F # < ± (33.30, 14.32) 15.6 (16.98, 14.14) F # < ± (33.03, 13.76) 13.7 (15.34, 12.12) Luteal Phase F # < ± (16.27, 05.00) 15.9 (17.87, 14.01) F # < ± (30.72, 21.41) 15.7 (16.42, 14.88) F # < ± (16.90, 02.66) 15.1 (18.24, 12.04) F # < ± (29.53, 09.03) 18.2 (20.50, 15.98) F # < ± (35.36, 13.71) 16.0 (17.69, 14.37) F # < ± (11.83, 01.37) 16.4 (20.07, 12.77) F # < ± (22.63, 12.94) 19.2 (20.38, 17.94) F # < ± (36.33, 13.54) 14.7 (16.54, 12.96) F # < ± (11.65, 03.42) 17.1 (19.29, 14.98) F # < ± (23.33, 14.98) 13.6 (14.50, 12.75) F # < ± (24.50, 12.52) 14.4 (15.52, 13.20) F # < ± (30.46, 14.44) 16.7 (18.21, 15.18) F # < ± (27.81, 18.04) 15.9 (16.59, 15.12) DP Double product; See also legends to Table 4.2 Ph.D. Thesis submitted by Nishtha Vaidya 172

25 Table 4.6 Cosinor Summary: Characteristics of HR rhythm during different phases of menstrual cycle in young women. Rhythm parameters were computed at fixed windows with τ = 24 h Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Menstruation Phase F # < ± (19.31, 11.03) 17.5 (18.51, 16.48) F # < ± (14.52, 06.37) 16.3 (17.76, 14.81) F # < ± (17.16, 10.55) 17.8 (18.74, 16.77) F # < ± (16.53, 08.87) 16.2 (17.34, 15.09) F # < ± (12.32, 07.10) 15.7 (16.80, 14.64) F # < ± (14.18, 01.30) 15.4 (18.56, 12.20) F # < ± (13.75, 04.88) 14.3 (16.16,12.45) F # < ± (16.91, 10.31) 18.1 (19.07, 17.07) F # < ± (19.02, 09.89) 16.9 (18.10, 15.69) F # < ± (12.29, 04.20) 17.3 (19.28, 15.23) F # < ± (18.76, 09.84) 16.2 (17.40, 15.04) F # < ± (15.84, 10.23) 16.8 (17.73, 15.95) F # < ± (24.05, 14.31) 16.5 (17.44, 15.55) Follicular Phase F # < ± (14.56, 05.14) 17.6 (19.62, 15.53) F # < ± (15.88, 07.43) 15.4 (16.79, 14.08) F # < ± (14.51, 07.73) 16.3 (17.51, 15.13) F # < ± (15.87, 08.26) 14.0 (15.14, 12.92) F # ± F # < ± (14.55, 04.35) 14.3 (16.43, 12.13) F # < ± (12.43, 06.23) 18.3 (19.68, 17.00) F # < ± (20.06, 05.23) 14.3 (16.59, 11.94) F # < ± (14.54, 07.51) 19.2 (20.35, 17.99) F # < ± (15.22, 07.70) 17.7 (19.01, 16.37) F # < ± (13.82, 06.60) 16.1 (17.41, 14.86) F # < ± (15.61, 07.77) 15.2 (16.47, 14.02) F # < ± (09.80, 01.27) 14.9 (17.74, 12.04) Continued Ph.D. Thesis submitted by Nishtha Vaidya 173

26 Subject code Age Data point Rhythm detection a Rhythmadjusted mean, M SE Amplitude, A (95% CL) Acrophase, Ø in h (95% CL) Ovulation Phase F # < ± (17.50, 09.63) 16.7 (17.86, 15.55) F # < ± (13.60, 07.85) 14.4 (15.38, 13.44) F # < ± (13.47, 05.38) 17.0 (18.50, 15.54) F # < ± (14.93, 08.75) 16.5 (17.40, 15.58) F # ± F # < ± (18.17, 08.47) 15.2 (16.54, 13.77) F # < ± (22.05, 15.39) 16.7 (17.39, 16.10) F # < ± (15.52, 04.04) 15.0 (17.75, 12.17) F # < ± (13.57, 04.24) 18.4 (20.68, 16.03) F # < ± (15.61, 08.02) 18.3 (19.70, 16.83) F # < ± (13.56, 07.09) 17.2 (18.41, 15.95) F # < ± (17.82, 08.04) 15.4 (16.73, 14.08) F # < ± (16.25, 05.19) 13.9 (16.01, 11.87) Luteal Phase F # < ± (08.47, 01.46) 17.8 (20.58, 14.99) F # < ± (18.63, 12.31) 15.9 (16.77, 15.03) F # < ± (09.36, 02.78) 14.6 (16.89, 12.33) F # < ± (14.28, 03.36) 18.6 (21.26, 15.95) F # < ± (12.46, 02.00) 17.4 (20.74, 14.15) F # < ± (07.83, 00.93) 17.1 (20.75, 13.36) F # < ± (17.43, 11.50) 18.4 (19.30, 17.52) F # < ± (20.15, 09.53) 15.2 (16.53, 13.78) F # < ± (28.62, 10.65) 17.2 (18.96, 15.42) F # < ± (12.91, 06.26) 14.3 (15.66, 12.95) F # < ± (16.48, 09.78) 15.1 (16.02, 14.21) F # < ± (10.69, 01.91) 18.0 (21.10, 14.99) F # < ± (16.83, 11.08) 15.9 (16.57, 15.15) HR Heart rate See also legends to Table 4.2 Ph.D. Thesis submitted by Nishtha Vaidya 174