INTRODUCTION:
The menstrual cycle is exclusive to females in humans and some of the primates, caused because of complex interplay amongst the hypothalamus, anterior pituitary gland, ovaries, and uterus, also undergo sequential structural, functional, and hormonal changes in the organs system and its parts which function in reproduction. This is connected and controlled by cyclical fluctuations in the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) of the pituitary, and sex hormones such as estrogen and progesterone. Bayer & Decherney, 19931 has expressed that the hormonal changes during this cyclic process result in ovulation. The length of the cycle is typically variable in women, but an average figure is 28 days from the start of one menstrual period to the start of the next. The menstrual cycle involves two main cycles; the uterine cycle and the ovarian cycle. The former is divided into the proliferative phase, the secretory phase, and the menstrual phase. The latter is divided into the follicular phase and the luteal phase (Ganong 2010).2 In the study of Olayaki et al., 2008, 3 deliberated that serum magnesium and cardiovascular parameters during the early follicular, the peri-ovulatory and the mid-luteal phases of the menstrual cycle. Estrogen is known to enhance magnesium utilization and uptake by soft tissues and bones. This may be one of the mechanisms by which estrogen gives the preventive effect of heart diseases and osteoporosis. Moreover, Seelig 19934 has stated in his study that it may be a possible mechanism of fluctuation in magnesium level with changes in estrogen level during the menstrual cycle. The agreement studies were done by Artraga et al.5 and Dincer et al., 6 report estradiol may be a physiological modulator that regulates magnesium concentration directly or indirectly. The evidence in the previous literature observes that 17-β estradiol concentration is the lowest during the early follicular phase and in the peri-ovulatory phase appreciated as highest. Then, it declines about 50 % during the mid-luteal phase.7
Magnesium is a divalent cation with the ability to form a chelate. Therefore, magnesium has a central role in biological and physiological processes. Magnesium influences blood pressure regulation by modulating vascular tone and reactivity8 the increased intracellular sodium and calcium and a loss of potassium may be caused by an intracellular magnesium deficiency. One of the previous studies expressed that intracellular magnesium deficiency results from an increase in intracellular sodium and calcium and a loss of potassium9 the evidenced fact made in the advances of the signifying magnesium in the cardiac cell metabolism that leads to numerous cardiovascular disorders is accompanied by hypomagnesaemia or magnesium deficiency.10
Magnesium has a stronger effect on the cyclic nature of cardiovascular parameters during the menstrual cycle, seen as the lowest concentration of serum magnesium associated with the highest levels of systolic and diastolic blood pressure during this period serum estrogen concentration is expected to be the highest. Literature evidence that cardiovascular changes accompany systemic changes in various phases of the menstrual cycle. Additionally, various studies evidence changes in systemic arterial blood pressure during the menstrual cycle. The study by Dunne et al., 1991 reveals that both systolic and diastolic blood pressures were the highest in the menstrual phase11.
Also, studies have evidenced that systolic and diastolic blood pressures were found to be increased in the peri-ovulatory phase3 Studies have deliberated that blood pressure changes occur during the menstrual cycle. Though, there is uncertainty regarding the phase in which the changes occur. The menstrual cycle is a significant part of a women's life. It is an agreed-upon fact that the hormonal changes that occur during the menstrual cycle. Further exploring is needed to conceptualize that these changes might be related to the other cyclical changes during the menstrual cycle.
MATERIALS AND METHODS:
This study is a cross-sectional analytical study. Forty apparently healthy reproductive-aged female students (18- 25 years) were selected as a sample population. The subjects with BMI above 23kg/m2, those with a known history of diseases and those taking oral contraception pills or Depo-Provera injection, regular vitamins, and magnesium supplementation, and those with a history of lactation for one year prior to the study were excluded.
Determination of intracellular magnesium level
A venous blood sample on heparin was collected in a metal-free container and centrifuged. After elimination of plasma, erythrocytes were washed with normal saline solution and further centrifuged at 4000 rotations per minute, for 5 minutes duration.
Determination of serum magnesium level:
The blood sample is collected in a metal-free container without preservatives like citrate, ethylenediamine tetraacetic acid, and oxalate. Red cells were separated immediately. Unhaemolysed serum was used to determine serum magnesium level. Then serum magnesium level was determined by using the Calmagite method.
Measurement of systemic arterial blood pressures:
Systemic brachial arterial blood pressures were measured in lying position by the indirect method, using a mercury sphygmomanometer. The level of pressure at which the Korotkoff sound was first heard (phase I) was taken as systolic blood pressure (SBP) and the level of pressure at which the Korotkoff sound disappeared (phase V) as diastolic blood pressure (DBP). The average of three measurements taken at a one-minute interval was used. Then the mean arterial pressure (MAP) was calculated by the following formula:
MAP = DBP + 1/3
(SBP - DBP)
Determination of urinary LH surge
Urinary LH surge was determined by LH kit according to the menstrual calendar, the dates of menstruation were recorded from the first day of menstruation for two successive menstrual cycles. Also in accordance with menstrual calendars, different phases of the menstrual cycle were determined individually to confirm ovulation, LH surge was detected by LH test strip during the peri-ovulatory period i.e 14 ± 2 days before the start of the next cycle. Determination of different phases of the menstrual cycle individually for the subjects. By using a menstrual calendar, the dates of recorded menstruation were from the first day of menstruation for two consecutive menstrual cycles. Conferring to their menstrual calendars, diverse phases of the menstrual cycle were determined individually to confirm ovulation, LH surge spotted by LH test strip during the peri-ovulatory period that is 14 plus or minus two days prior to the next cycle begins.
Procedure:
For the current study forty (40) healthy reproductive-aged female medical students were chosen as a subject from the University of Medicine Magway. The students who volunteered for the study as subjects, written informed consent were taken from all. As preliminary assessments, the history was collected from all subjects that included menstrual history, gynecological history, and further physical examination is done. The subject's body weight was measured wearing light clothes without shoes by a weighing machine. The weight measured was in kilogram to the proximal decimal place. Standing height was measured using a measuring tape.
The subject was instructed to stand erect, putting their heels and knees close together with foot spread straight, and forward position, hands, and arms were hanging loose and relaxed with palms facing at the middle.
The indices calculated were the head position of the sample subjects they look forward, straight at her outer angle of the eye and the external meatus acoustics maintaining a horizontal plane, and the body mass index was calculated. The inclusion and exclusion criteria were used for the selection of the sample. Every subject was provided a menstrual calendar and explained how to record it. The subjects were instructed to record it for two successive menstrual cycles and to take the first visit during days 1-4 of the third cycle.
The subjects were instructed to visit three times the Department of Physiology, the University of Medicine, Magway on days 1-4, days 12-17, and days 21-24 of the menstrual cycle, according to their menstrual calendars. They were instructed to take their diet more or less the same during sample collection. On the first visit, subjects were posed individually to determine different phases of their menstrual cycle according to their menstrual calendars. Every subject was provided five LH test strips to determine urinary LH surge for confirmation of ovulation during the peri-ovulatory phase. They were explained on their knowledge on performing the test. They were instructed to perform the test daily for 5 days until the LH surge has been detected during the peri-ovulatory period (14 ± 2) days before the start of their next cycle.
On each visit, the subjects were instructed to fast overnight (both liquid and solid food) from 10:00 pm to 8:00 am. The next morning, six milliliters of fasting venous blood samples were collected from the antecubital vein under aseptic condition. Three milliliters of blood were kept in the metal-free container containing heparin for erythrocyte magnesium level. The remaining three milliliters of blood without anticoagulants were promptly centrifuged for serum separation. Erythrocyte and serum magnesium levels were measured on the day of sample collection. After 15-minute supine rest, systemic arterial blood pressures were taken by indirect method. The average of three measurements taken one-minute interval was used. After getting systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP) was calculated.
If the cycle length is 27 days, testing began on day 11. If the length is 30 days, testing begins on day 14 respectively. The subjects were instructed to take a second visit on the next day if the test result was positive.
RESULTS:
The serum magnesium levels were significantly (p <0.001) lower in the PO than the EF and the ML. The systolic blood pressures were significantly (p <0.05) higher in the PO than the EF and the ML. In the EF, there was a significant negative correlation between serum magnesium level and diastolic blood pressure (r = -0.374, n = 40, p <0.05) as well as serum magnesium level and mean arterial pressure (r = -0.354, n = 40, p < 0.05). Here no significant correlation is depicted between serum magnesium level and systolic blood pressure (Figure 2). Also, in the PO, no significant correlation was observed between serum magnesium level and systemic arterial blood pressures (Figure 3). In the ML, there was significant negative correlation between serum magnesium level and systolic blood pressure (r = -0.651, n = 40, p <0.001), diastolic blood pressure (r = -0.607, n = 40, p <0.001), and mean arterial pressure (r = -0.661, n = 40, p <0.001). (Figure 4)
(A)
(B)
Figure 1. Serum magnesium level (Panel A) and systemic arterial blood pressures (Panel B) during different phases of the menstrual cycle
Serum magnesium level Lines represent mean values.
Systolic blood pressure EF
= Early follicular phase
Mean arterial pressure PO
= Periovulatory phase
Diastolic blood pressure ML = Midluteal phase
Figure 2. Correlation between serum magnesium level and systemic arterial pressures in the early follicular phase
Systolic blood pressure – Serum magnesium
level
Mean arterial pressure – Serum magnesium level
Diastolic blood pressure – Serum magnesium level
Figure 3. Correlation between serum magnesium level and systemic arterial pressures in the peri-ovulatory phase
Systolic blood pressure – Serum magnesium level
Mean arterial pressure – Serum magnesium level
Diastolic blood pressure – Serum magnesium level
Figure 4. Correlation between serum magnesium level and systemic arterial pressures in the midluteal phase
Systolic blood pressure – Serum magnesium level
Mean arterial pressure – Serum magnesium level
Diastolic blood pressure – Serum magnesium level
DISCUSSION:
The current study indicates that the serum magnesium levels of all subjects in the three phases of the menstrual cycle were within the normal range from 1.6 to 2.6 mg/dL. Conversely, the study revealed that serum magnesium levels varied significantly during the menstrual cycle in healthy young women. The serum magnesium level progression significantly decreased from the early follicular phase to the peri-ovulatory phase, then increasing noticeably towards the mid-luteal phase. Thus, the serum magnesium level is lowest and significantly decreased in the peri-ovulatory phase. Yet, a significant difference between serum magnesium levels of the early follicular phase and the mid-luteal phase was not found. The shreds of studies from the previous literature also showed that found to be supportive with regard to serum magnesium levels varied significantly during the menstrual cycle.12-15
Rosenstein et al. (1993) revealed in their studies that serum magnesium levels varied during the menstrual cycle showed no statistical significance16.The mechanism for the observed cyclic changes in magnesium levels during the menstrual cycle still remains debatable with controversies.
The decrease in serum magnesium level during the peri-ovulatory phase might be due to the pre-ovulatory estrogen peak. Estrogen is known to enhance magnesium utilization and uptake by soft tissues and bones4. The normal estrogen production rate is 36 μg/day in the early follicular phase, 380μg/day in the pre-ovulatory phase, and 250μg/day in the mid-luteal phase2. In the present study, the level of serum magnesium varied inversely with the normal estrogen production rate during the menstrual cycle. In the early follicular phase, the estradiol production rate is the lowest and the serum magnesium level was found to be the highest. When estradiol production rate peaks in the pre-ovulatory phase, the serum magnesium level was found to be the lowest. In the mid-luteal phase, serum magnesium level increased according to the decline of estradiol production rate. These findings were consistent with the study of Olayaki et al. (2008) 3 in which serum magnesium level in the mid-luteal phase was lower than the early follicular phase value.
Systemic arterial blood pressures increased significantly from the early follicular phase to the peri-ovulatory phase during which the levels of serum magnesium were the lowest. Thereafter, systemic arterial blood pressures decreased to a lower level during the mid-luteal phase while magnesium levels increased back to their higher levels. However, there was no significant difference between systemic arterial blood pressures of the early follicular phase and the mid-luteal phase. The results of this study are in line with the previous study by Olayaki et al. 20083.
Nevertheless, the study of Nishtha (2012) demonstrated that there were blood pressure variances for the period of the menstrual cycle but not statistically significant17. Magnesium might even have a stronger effect on the cyclic nature of blood pressure during the menstrual cycle. It is likely that increase in magnesium levels might be accompanied by a decrease in systemic arterial blood pressures and vice versa. In the early follicular phase, there was a significant negative correlation between serum magnesium level and diastolic blood pressure (r = -0.374, n = 40, p <0.05), mean arterial pressure (r = -0.354, n = 40, p <0.05).
It is depicted in the study, negative correlation between the serum magnesium level and systolic blood pressure was r = -0.281, n = 40, p >0.05, which was not significant. Since the fact is, magnesium has more effect on vascular tone cause vasodilation also in reducing total peripheral resistance. One of the previous studies reveals that magnesium modulates the vascular tone regulating endothelium and smooth muscle cell functions along with the important role in nitric oxide (NO) release. Animal studies show that magnesium increased the production of prostacyclin without causing vasodilation.18
In the peri-ovulatory phase, there was no significant negative correlation between serum magnesium level and systolic blood pressure (r = -0.128, n = 40, p >0.05), diastolic blood pressure (r = -0.208, n = 40, p >0.05) and mean arterial pressure (r = -0.179, n = 40, p >0.05).
In this study, serum magnesium level was the lowest (1.95±0.16mg/dL) and systemic arterial blood pressures were the highest in the peri-ovulatory phase. It coincided with the highest production rate of estradiol in the body (380μg/day)2. Therefore, the blood pressure raising effect of low serum magnesium level might be counterbalanced by the blood pressure-lowering effect of estrogen. It could be a possible explanation for being not a significant negative correlation between serum magnesium level and systemic arterial blood pressures in this phase.
In the mid-luteal phase, there was a significant negative correlation between serum magnesium level and systolic blood pressure (r = -0.651, n = 40, p <0.001), diastolic blood pressure (r = -0.607, n = 40, p <0.001) and mean arterial pressure (r = -0.661, n = 40, p <0.001). In this phase, serum magnesium level rose back to 2.16 ± 0.17 mg/dL. Estradiol secretion rate is 250μg/day and progesterone secretion rate is the highest (25mg/day)2.
Effects of these ovarian hormones increase blood pressure by lowering the effect of magnesium, and a negative correlation was found to be highly significant (p < 0.001). Thus, magnesium is considered as one of the factors that persuade the cyclical changes in blood pressure during the phases of the menstrual cycle in young reproductive women.
CONCLUSION:
The study concludes there are cyclical changes in serum magnesium level as well as systemic arterial blood pressures during the menstrual cycle in young reproductive women and the patterns of these changes were opposite. The blood pressure-lowering effect of magnesium seemed to be related to the fluctuation of estrogen levels during the menstrual cycle.
CONFLICT OF INTEREST:
There is no conflict of interest between authors.
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Received on 24.11.2021 Modified on 30.12.2021
Accepted on 08.02.2022 © RJPT All right reserved
Research J. Pharm.and Tech 2022; 15(2):751-756.
DOI: 10.52711/0974-360X.2022.00125