**Menstrual Cycle and Physical Effort**

## Magdalena Wiecek

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79675

#### **Abstract**

In addition to affecting the sexual organs in women, ovarian hormones have a wide- impact on processes related to metabolism, water and electrolyte balance, thermoregulation, and redox balance. Differences in the estradiol and progesterone concentrations- during the follicular and luteal phases, as well as the increase in the concentration of- these hormones under the influence of physical exercise, may cause a different course of- exercise response in women depending on the phase of menstrual cycle. Estrogens affect- the metabolism of women by reducing the rate of gluconeogenesis and glycogenolysis- and, at the same time, by increasing the share of lipids in covering energy requirements.- Progesterone affects respiratory system parameters causing, among others, an increase- in pulmonary ventilation. The resultant antagonistic action of progesterone and estradiol is the effect on thermoregulatory mechanisms. Increased estradiol concentration at- the low progesterone concentration level causes water and electrolyte retention. In turn,- an increased level of progesterone leads to loss of water and sodium, causing a decrease- in the volume of plasma during the postovulatory phase of the menstrual cycle. The processes described above are related to metabolic changes affecting the ability to perform- physical efforts.-

**Keywords:** menstrual cycle, aerobic efforts, anaerobic efforts, acid-base balance, redox balance-

#### **1. Introduction**

Knowledge about the physiology of physical efforts is mostly based on research results in- which only men participated. However, the increasing participation of women in many- sports disciplines encourages observation of the physiological reactions and effects regarding intense physical efforts on the body of women associated with the process of sports- training [1, 2].-

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A decrease in the level of sex hormones during rest, as a result of heavy and long-term training, can lead to disorders in the menstrual cycle of a woman [2, 3]. These disorders most have the characteristics of rare menstrual periods (oligomenorrhea) or secondary amenorrhea (amenorrhoea secundaria). In women with regular menstruation, burdened by sports training, anovulatory cycles or shortened luteal phases often occur. It is also possible to exclude the impact of physical exercise related to training on the later menarche age [2, 4]. The factors conducive to hormonal abnormalities are large decreases in body mass and the amount of adipose tissue, resulting not only from significant training loadsbut also frequent disorders in the way of eating [5]. Long-lasting estrogen deficiency leads to a decrease in bone density, causing deterioration of its structure, which may contribute to osteoporosis in the future [6]. Abnormalities in the way of eating, menstrual disorders, and disturbances in bone metabolism observed in women practicing various sports were called the "triad syndrome" [2, 7, 8]. Therefore, one should look for an answer to the question on how to program women's training in order to achieve high sports results without negative consequences for their health [1].-

Assessing physiological responses induced by physical exercise in women, cyclic changes in the level of sex hormones that occur during the reproductive period in every normal menstrual cycle cannot be overlooked. The menstrual cycle is the result of complex interaction of the hypothalamus, pituitary gland, and ovarian hormones, which, apart from acting on the sexual organs, exhibit a broad, nonspecific effect on various processes related to metabolism, water, and electrolyte balance or thermoregulation in women [2, 9–13]. As shown in studies on animals, differences related to estradiol levels are a factor influencing the diversified use of energy substrates [14, 15]. Distinct differences in estradiol and progesterone levels between the follicular and luteal phases, as well as an increase in the concentration of these hormones under the influence of physical exercise, may cause a different course of exercise response in women depending on the phase of the menstrual cycle [2, 10, 16].-

Research suggests that estrogens affect the metabolism of women by reducing the rate of gluconeogenesis and glycogenolysis and, at the same time, increase the share of lipids in covering energy demand [17–22]. The increased use of lipids as a source of energy occurs due to the increase in the amount of free fatty acids, which results from the increased synthesis of triglycerides and in the rate of lipolysis [23]. The effect of estradiol on metabolic processes in the liver, muscles, and adipose tissue can be achieved by changing the activity of key enzymes, changing membrane permeability or indirectly through changes in hormone levels: insulin, glucagon, cortisol, hGH, or catecholamines [24, 25].-

Progesterone affects the parameters of the respiratory system, causing, inter alia, an increase in pulmonary ventilation per minute (VE) [26]. In the postovulatory phase, a higher resting level of oxygen uptake (VO2 ) is also observed [27].-

The resultant antagonistic effect of progesterone and estradiol is the effect on thermoregulatory mechanisms, which leads to an increase in the body's core temperature during the luteal phase of the menstrual cycle [12, 28–30].-

In the woman's body, we also observe changes in the total water content associated with the menstrual cycle phase. Observations of some authors indicate that elevated estradiol concentration at low concentration of progesterone causes the retention of water and electrolytes in the body [31]. In turn, the increased level of progesterone, by blocking the action of aldosterone in the kidneys, leads to loss of water and sodium-[32], causing a decrease in plasma volume during the postovulatory phase of the menstrual cycle [33].-

All processes described above are directly related to metabolic changes affecting the ability to perform physical efforts. Differences in the use of substrates and in the intensity of individual energy changes during muscle work of different intensities, resulting from hormonal changes in the course of the menstrual cycle, may affect, e.g., the activity of the adrenergic system, the amount of lactic acid formed in muscle tissue and its level in the blood, and changes in the level of acid-base balance parameters or indicators of oxidative stress [2, 10, 16, 34]. Therefore, it can be expected that cyclical fluctuations in the level of endogenous ovarian hormones in women will affect the extent and size of exercise responses. However, the test results are not unequivocal.-

## **2. Methods**

Original and review scientific publications regarding the level of cardiopulmonary reactions, thermoregulation processes, and oxidative stress as a result of aerobic and anaerobic efforts during various phases of the menstrual cycle were reviewed. Conclusions were formulated on the basis of tests in which hormonal evaluation of the menstrual cycle was conducted.-

## **3. Exercise responses during the menstrual cycle**

#### **3.1. Aerobic exercise**

It is generally accepted that the maximal oxygen uptake index (VO2max) is the indicator of aerobic efficiency, the level of which is directly determined during gradual physical exercise, performed up to the individual maximum intensity ("until exhaustion"). Such effort leads to the maximum involvement of the oxidative phosphorylation process while activating the processes of anaerobic adenosine triphosphate (ATP) resynthesis (phosphocreatine, anaerobic glycolysis). VE, cardiac output, and blood oxygen capacity are important factors determining the level of VO2max [35].-

#### *3.1.1. Cardiorespiratory effect-*

One of the first studies comparing the physiological and biochemical stress response of women at the time of the menstrual cycle, during which laboratory testing days were determined based on sex hormone levels, was carried out by Jurkowski etal. [36]. In these studies, immediately after two 20-minute physical efforts at an intensity of 40 and 70% VO2max, respectively, the woman performed a physical effort at an intensity of 90% VO2max-"until exhaustion." The time of extreme exercise was almost twice as long in the luteal phase. In the luteal phase, higher values of the maximum minute pulmonary ventilation (VEmax) were also noted. The maximum heart rate (HRmax) and VO2maxdid not differ between the menstrual cycle phases [36].-

However, these data are not fully confirmed in the results of research conducted by other authors. The time of continuing the effort of gradually increasing work intensity did not differ significantly between the follicular and luteal phases of the menstrual cycle [37]. Similar in both phases of the menstrual cycle, Nicklas etal. [17] found that the time of continuing work "until exhaustion " was for the intensity of 70% VO2max, and McCracken etal. [38] noted it for the intensity of 90% VO2max.-

The results of some studies indicate a significantly higher level of resting oxygen uptake during the postovulatory phase [27, 39]. However, most authors agree that the menstrual cycle phases do not significantly affect VO2 , neither at rest nor during submaximal and maximal intensity efforts [37, 40–45].-

The conclusions from laboratory tests differ regarding the assessment of the influence of the menstrual cycle phases on the level of pulmonary ventilation. Schoene etal. [46] and Das [47] reported higher resting VEvalues in the luteal phase of the menstrual cycle. During stress tests, Jurkowski etal. [36], as well as Hessemer and Bruck [39], obtained higher values in the postovulatory phase. However, differences between phases in the exercise level of this parameter are not statistically significant in many studies [37, 43, 45, 48].-

Significant inter-phase differences concerning the maximal heart rate were noted by Pivarnik etal. [41]. In this research, HRmaxwas higher in the luteal phase by 10 beats per minute.- Higher resting and exercise heart rate in the luteal phase were also noted by other researchers [39, 46, 49]. Some authors, however, did not find significant differences in the values of HRmax- [37, 40, 43, 45, 48].-

De Souza etal. [48], comparing the physiological responses of women with normal menstrual cycles and women with secondary menstrual irregularities, obtained similar results for both groups. In eumenorrheic women, both during the 40-minute effort at 80% intensity VO2max- and during the graded test "until exhaustion," in the luteal phase, slightly higher levels of oxygen uptake, pulmonary ventilation, and heart rate were found. However, the postexercise concentration of lactate in the blood was lower in this phase. Nevertheless, the differences between phases were not statistically significant [48].-

#### *3.1.2. Metabolic effect-*

It is undisputed that a gradual increase in the intensity of effort leads to an increase in anaerobic energy recovery processes. This causes an increase in the concentration of lactic acid in- the blood, causing changes in the level of acid-base balance parameters [50–52]. Therefore,- it is of great importance in the assessment of endurance capacities to determine the location of metabolic thresholds, using blood lactate measurement or based on the dynamics of- changes in ventilation indicators. The first metabolic threshold is defined by the first ventilatory threshold, the aerobic or anaerobic threshold (AT), and means the addition of anaerobic- metabolism. The second metabolic threshold is referred to as the second ventilatory threshold,- respiratory compensation point (RCP), or the threshold of uncompensated metabolic acidosis- [50, 52–55]. The severity of anaerobic transformation after exceeding this threshold causes- hyperventilation and leads to the development of fatigue induced by incomplete metabolic- acidosis [52, 56].-

The results of many studies indicate the lack of clear influence of the menstrual cycle phases on resting and postexercise levels of lactate and acid-base balance parameters in the blood [17, 37, 43, 48, 57, 58].-

One of the studies [45], during which women performed a graded test, indicated lower blood lactate and lower respiratory exchange ratio (RER) values for submaximal loads in the luteal phase. Resting levels and maximum values of blood lactate concentration did not significantly differ in both phases of the menstrual cycle [45]. Significantly, higher levels of lactate in the follicular phase were found by Lavoie etal. [59] during a 90-minute effort at intensity of approximately 63% VO2max. Similar results were obtained by Jurkowski etal. [36] during an effort of 90% intensity VO2maxand McCracken etal. [38] during a graded test. The authors found a statistically significant, higher level of resting blood lactate concentration in the follicular phase of the menstrual cycle. Also, increases in lactate concentration and decreases in buffering bases, after efforts with higher loads, were significantly greater in the follicular phase than the luteal phase [36]. Differences between phases in the postexercise lactate level were maintained for 30minutes of restitution [38].-

The purpose of the Devries etal.'s study [60] was, among others, to determine the effect of menstrual cycle phase upon glucose turnover and muscle glycogen utilization during moderate-intensity endurance exercise. In these studies, healthy, recreationally active young women underwent a primed constant infusion of glucose with muscle biopsies taken before and after a 90-minute cycling exercise at intensity of 65% VO2max. In the studies, it was demonstrated that women in the luteal phase have lesser reliance on carbohydrate sources to fuel endurance exercise compared with follicular phase. It was evidenced by a lower glucose rate of appearance and disappearance as well as metabolic clearance rate and lower glycogen utilization during and at the end of exercise [60].-

 Higher oxidation of lipids and lower oxidation of carbohydrates in the luteal phase during- submaximal efforts at an intensity higher than 50% VO2maxhave also been demonstrated in- other studies [61–63]. It was also noticed that interphase differences in the use of energy- substrates are related to the effort intensity. During a 30-minute treadmill run, healthy, wellmenstruating women performed three 10-minute efforts at the following intensities: 30, 60,- and 75% VO2max, successively. Higher lipid oxidation in the luteal phase was found during- low- and moderate-intensity exercise, while there were no interphase differences during exercise at an intensity of 75% VO2max [20]. Similar results were obtained that in cycling efforts,- higher lipid oxidation in the luteal phase was found at the 30% intensity VO2maxand 50%- VO2max, but not at 70% VO2max [64]. On the other hand, they are not confirmed by this study,- in which, on the basis of RER, there were no differences between phases in the proportions- of energy substrate consumption (lipids/carbohydrates) during efforts of a wide intensity- range, i.e., 45% VO2max [65], 50% VO2max [66], 65% VO2max [65], 70% VO2max [67], as well as 80% VO2max-[48].-

 Later research [68], in which young female rowers (female athletes and women practicing recreationally and taking/not taking oral contraceptive pills) performed a graded test on a rowing ergometer during the follicular and luteal phases of the menstrual cycle, showed that there are no interphase differences in the level of power output, ventilator equivalents of O2 (VE/VO2 ), HR, and blood lactate concentration at maximal and aerobic-anaerobic transition intensities in all three groups. However, higher values were observed for ventilatory equivalents of CO2 (VE/VCO2 ) at both intensities in the luteal phase compared with the follicular phase in the group of women taking contraceptive pills [68]. There were no significant interphase differences in the oxidation of carbohydrates and fats during resting (before the exercise) or during the 1-hour rowing exercise at 70% VO2max. Energy expenditure, oxygen uptake, HR, and lactate concentration were similar in the follicular and luteal phases during this exercise [69]. In both phases of the menstrual cycle, the female rowers obtained similar values of VO2maxand VO2 at the threshold of anaerobic transitions [69]. These results are consistent with those previously presented by Smekal etal. [70], who showed that there are no significant intergroup differences in the level of power output, VO2 , RER, HR, and blood lactate concentration at rest, at maximal load, and at different thresholds of aerobic and anaerobic metabolism (lactate thresholds, respiratory thresholds: AT and RCP), which were measured during a cycle test in eumenorrheic women. In this study, minute ventilation and VE/VO2 and VE/VCO2 indices were higher in the luteal phase at rest, exhaustion, and AT [70].-

#### *3.1.3. Oxygen capacity of the blood-*

Another important factor determining the level of VO2maxis the oxygen capacity of the blood depending on the content of hemoglobin in the blood and its affinity for oxygen and on the total volume of blood [35]. The high correlation coefficient between hemoglobin concentration and the VO2maxvalue indicates a significant role of this protein in aerobic capacity [71]. A higher level of hemoglobin in the blood in the luteal phase was confirmed by Jurkowski etal. [36]. Increased oxygen availability in tissues during the luteal phase may also result in a higher core temperature during this phase, as well as an elevated level of 2,3-DPG, causing a decrease in the affinity of hemoglobin to oxygen [12, 72]. However, studies carried out by Dombovy etal. [40] showed a slight decrease in the hemoglobin level during the luteal phase. In this research, the differences between phases in the resting level of hemoglobin did not affect the value of VO2max, which did not differ between phases.-

Stephenson and Kolka [33] found that the resting values of hemoglobin and hematocrit (HCT) are slightly elevated in the luteal phase. Interphase differences in the level of these parameters increased during passive heating and remained unchanged during the exercise with an intensity of approximately 80% VO2max. Elevated levels of HCT in the luteal phase were also noted by Stachenfeld etal. [11, 12].-

#### *3.1.4. Plasma volume*

Based on the results of earlier studies [33], it may be assumed that higher resting HCT in the luteal phase results from the smaller plasma volume during it. Gaebelein and Senay [32] suggest that the reason for this phenomenon may be an increase in the luteal phase of vascular wall permeability to plasma proteins. Other studies do not support these views [13]. The authors performed an experiment involving seven women, in whom administering a gonadoliberin inhibitor (GnRH) reduced the level of endogenous estradiol and progesterone. Then, successively at intervals of a few days, they added extrinsic preparations containing synthetic derivatives of estradiol and progesterone. In this way, they obtained a ratio of sex hormone concentrations corresponding to, according to the concept of Janse de Jonge [16], the earlyfollicular, late-follicular, and middle-luteal phases. They found that at elevated levels of both hormones, which correspond to the middle of the luteal phase, the volume of plasma is the largest and constitutes about 17% of the total volume of extracellular fluids. At the same time, in this situation we observe the lowest permeability of blood vessel walls for plasma proteins. Slightly smaller plasma volume and greater permeability of blood vessel walls were observed in a situation corresponding to the late-follicular phase. However, the differences were not statistically significant. Due to the much smaller volume of extracellular fluids, plasma was then 21%. In the situation when only the GnRH inhibitor was administered, the plasma volume was the lowest, and the permeability of blood vessel walls was the largest for albumin. At the same time, the total volume of extracellular fluids was the highest, with a plasma volume of approximately 16%. Differences in the volume of extracellular fluids may be reflected in small changes in the body mass of women during the menstrual cycle [37].-

Stephenson and Kolka [33] found that a 9-minute effort at an intensity of about 80% VO2max- caused a significantly larger loss of plasma volume during the follicular phase. The percentage changes in plasma volume reached −15.8 and-−13.3% in the follicular and luteal phases, respectively [33]. Other authors did not find significant interphase differences in plasma volume changes immediately after exercise and during the restitution period [12, 37, 38, 48].-

#### **3.2. Anaerobic exercise**

In the majority of studies assessing the influence of sex hormones on women's exercise responses, efforts were made of constant submaximal intensity or gradually increasing until reaching maximal oxygen uptake, i.e., "until exhaustion." However, there is little information on the interphase variation in response to typical anaerobic efforts [73–78].-

The concept of anaerobic capacity of an organism encompasses a set of factors determining the performance of short-term work, during which large force and maximal generated power are developed. These include skeletal muscle mass, the supply of muscle energy substrates [ATP, phosphocreatine (PCr), glycogen], and enzyme activity of anaerobic processes. The large buffer capacity that allows tolerance of homeostatic disorders and rapid restitution in the pH range is also extremely important [79].-

Taking the metabolic effects of estradiol and progesterone into account, it can be assumed that the changing ratio of these hormones during the menstrual cycle effects different physiological responses of women under the influence of anaerobic exercise [80]. The presence of estrogen receptors in the human skeletal muscle [81] and the correlation between strength and high concentrations of 17β-estradiol and progesterone have been found [82]. Furthermore, buffering capacity during the 10-s rowing sprint was greater at a higher concentration of 17β-estradiol [83]. Research suggests that ovarian hormones may influence the rate of PCr resynthesis after eutrophic luteal efforts in eumenorrheic women [84]. Other studies also indicate a faster rate of PCr regeneration after anaerobic efforts in the luteal phase due to the greater work performed in this phase of the menstrual cycle during a series of ten 6-s sprints [85]. This indicates the potential for generating more anaerobic power during the luteal phase of the menstrual cycle (high concentration of 17β-estradiol and progesterone) or just before ovulation (high concentration of 17β-estradiol) compared to the follicular phase. In the literature, however, there is little information on the effect of different levels of hormones on the size of the developed strength or the level of anaerobic power indicators during the menstrual cycle, and their results are not consistent.-

While some studies show better results during the luteal phase for single and multiple sprints [85, 86], in others, there were no interphase differences in single or repeated anaerobic cycling tests [87, 88]. Bale and Nelson [89], examining 20 women training swimming, found that they achieved the best results for a distance of 50m in the follicular phase. Also, Parish and Jakeman [90] found that in comparison with the ovulation period and the luteal phase, the highest maximal and average anaerobic power values were obtained by women in the follicular phase.-

However, it should be emphasized that the choice of experiment day in some studies was not hormonally confirmed [86–90]. In many experiments on this subject, the research dates were chosen only by calendar or thermal method. Anovulatory cycles may occur without disturbing the length of the menstrual cycle, while in the case of using the calendar method, this may lead to an erroneous indication of the day of laboratory examination. In turn, a reliable diagnosis of the course of the sexual cycle, based on the measurement of basic body temperature, is possible only after the measurements have been performed in at least three consecutive cycles. The erroneous conclusions concerning the division of the cycle into follicular and luteal phases with the use of the thermal method may additionally be caused by factors such as incorrect method of core temperature measurement, night sleep less than 6hours, disease states, or the use of hypnotics. Inference based on the results obtained by the authors using the calendar method or thermal method is therefore limited [16].-

#### *3.2.1. Research based on hormonal verification of menstrual cycle-*

The results of research based on hormonal verification of the division of the menstrual cycle into phases indicate lack of significant impact of sex hormones on the values of the developed strength [91] and generated anaerobic power [73]. Nonetheless, other studies [76] show that muscle strengthreturns to the baseline level faster after strenuous stretch-shortening cycle exercise during the ovulatory phase, when the estrogen level is high, compared with the follicular phase. However, the differences in exercise-induced muscle damage markers (CK, soreness, and low-frequency fatigue) between the two menstrual cycle phases were small.-

In the research by Wiecek etal. [75], determining the size of the maximal anaerobic power, a 20-secondcycle sprint was used (Wingate test version) [92]. The energy medium of this type of effort regards mainly anaerobic processes consisting in the resynthesis of ATP at the expense of PCr and muscle glycogen. According to the research review, participation of these two processes in ATP synthesis starts from the first seconds of effort, with the participation of the phosphagen energy source in favor of anaerobic glycolysis in subsequent seconds [79]. To obtain fully reliable results, Wiecek etal. [75] performed initial assessment of the correctness and regularity of the menstrual cycle on the basis of the registration of basic body temperature. The correctness of experiment day selection was always verified by hormonal assays. In addition, the studies were repeated in two subsequent menstrual cycles. Each woman performed an anaerobic effort twice in the middle of the follicular phase (days 6–9 of the cycle) and two times in the middle of the luteal phase (5–8days after ovulation). The first day of menstruation was adopted as the first day of the menstrual cycle. The studies concluded that there are no significant differences in the level of indicators determining anaerobic capacity of women in the follicular and luteal phases of the menstrual cycle. No interphase differences were found in the maximal level or average anaerobic power. The time of obtaining and maintaining maximal power and the rate of decrease in anaerobic power were not different either. The effect of anaerobic metabolism during a 20-second effort at supramaximal intensity is a significant increase in blood lactate concentration, which entails changes in the level of acidbase balance parameters. In both phases of the menstrual cycle, the anaerobic effort caused similar disturbances in the acid-base balance [75].-

Also, in the research by Tsampoukos etal. [77], the days for exercise were carefully selected. Eumenorrheic women performed a test comprised of two, 30-s sprints separated by a 2-min break. The test was conducted during the follicular phase, just before ovulation and in the luteal phase.-The mutual ovarian hormone system was characterized by adequately low levels of progesterone and 17β-estradiol, low progesterone levels and high levels of 17β-estradiol, and high levels of progesterone and 17β-estradiol. It was found that there are no interphase differences in the maximal level or average anaerobic power. Menstrual cycle hormones also did not affect postexercise changes in metabolic parameters (blood lactate and pH, plasma ammonia) or the rate of regeneration between sprints [77].-

Furthermore, during the 6-s cycling sprint, there were no interphase differences in the amount of generated anaerobic power and changes in blood lactate or in the sympatho-adrenergic response tested by the measurement of adrenaline and noradrenaline in the blood [93]. The lack of influence of sex hormones on different exercise responses in the follicular and luteal phases was also demonstrated by studies in which no interphase differences were found in maximal accumulated oxygen deficit and sprint performance in repeated sprint cycling, i.e., three times at 120% VO2maxwith 20-minute resting periods between consecutive sprints [78]. Also, the 40-yd running time preceded by a 15-minute warm-up (jogging, skipping by moving the legs in various directions, and sprinting alternating with jogging), performed at an ambient temperature of about 32.5°C, did not differ between the early-follicular and middleluteal phases [94]. Regardless of the menstrual cycle phase, the warm-up triggered an increase in the core temperature of about 1°C, which resulted in a better result during the run [94].-

Similar results were also obtained in earlier studies [74]. Domagala etal. [74] obtained results indicating a tendency for smaller increases in lactate concentration and changes in acid-base balance parameters in the luteal phase of the menstrual cycle. In the luteal phase, they also noted a slightly higher rate of lactate concentration restitution after exercise with a supramaximal load; however, the interfacial differences were not statistically significant [74].-

However, in the research by Redman and Weatherby [83], in which rowers performed a test of anaerobic power (10-s all-out effort) and capacity (1000-m row), it was found that the peak

 power output was higher and the 1000-m rowing ergometer time was faster when the concentration of progesterone and estradiol was low (quasi-follicular phase), in contrast to when the levels of both hormones were high (quasi-luteal phase). The concentration of sex hormones was regulated by oral contraceptive pills [83]. Julian etal. [95], by examining female soccer players who performed the Yo-Yo intermittent endurance test, multiple jumps, and 3-×-30m sprints in the early-follicular phase and in the middle of the luteal phase, showed a reduction in maximal endurance performance during the middle-luteal phase. This effect was not observed for jumping or sprint performance.-

#### **3.3. Thermoregulation**

An important factor conditioning the possibility of performing physical exercise is the efficient functioning of thermoregulation mechanisms. During rest, in thermoneutral conditions, the heat balance of the body is stabilized by the exchange of heat produced in metabolic processes. Heat is exchanged with the environment through conduction and convection, radiation, and evaporation. By these means, approximately 20, 60, and 20%, respectively, of heat is eliminated from the body [96].-

During physical exercise, as a result of the intensification of metabolic processes, the thermal balance of the body and the stimulation of thermoregulation systems are disturbed. We observe an increase in the core temperature of the body, depending on the relative load expressed as % VO2max, which during efforts at constant intensity is stabilized at an elevated level. The main role in the elimination of excess endogenous heat during physical exercise is played by evaporation of perspiration from the body's surface, constituting about 80% of heat loss [96]. The effectiveness of exercise-based thermoregulation depends on the rate of sweat secretion and external conditions affecting the efficiency of its evaporation, as well as the correct functioning of the circulatory system, on which the heat transfer from the muscles to the surface of the skin depends [96]. After core temperature exceeds the so-called vasodilation threshold, blood flow through the cutaneous vessels steadily increases along with the increase of exercise intensity to about 60–70% VO2max, after which it gradually decreases due to the increase in muscular flow [97]. Thermoregulatory reactions also depend on hydration status of the body, the concentration of sodium and calcium ions in body fluids, the degree of acclimation to the conditions under which physical exercise is performed, and the level of physical fitness [96].-

The increase in resting body temperature during the luteal phase of the menstrual cycle by about 0.3–0.5°C, as compared to the level during the follicular phase, is the result of the antagonistic effect of progesterone and estradiol on the thermoregulatory system in the hypothalamus [12]. Observations of many authors indicate the relationship between thermoregulatory responses in women and the course of the menstrual cycle [29, 39, 41, 98–100].-

#### *3.3.1. Core temperature and sweating*

The average temperature measured in the esophagus (Tes), in thermoneutral conditions, during a 30-minute exercise at an intensity of 40 and 70% VO2max, was higher in the luteal phase [101]. The increase in Tesobtained in these studies was the same in both phases of the menstrual cycle [101]. In other studies [102], the temperature measured in the auditory canal (Tty), at rest and during exercise tests (60-minute 50% VO2maxand during the graded test), was significantly higher in the luteal phase of the menstrual cycle, and Ttyincreases were slightly higher in follicular phase.-

The increases in core temperature, similar in both phases, during submaximal efforts performed in thermoneutral conditions and in conditions of elevated temperature, were also observed in the studies presented by other authors [12, 94, 100, 103]. These results are only partially consistent with the results of this study, during which a higher level of rectal temperature (Tre) was observed in the luteal phase of the menstrual cycle while performing a 60-minute effort at constant intensity of about 60% VO2max-(ambient temperature 22°C) [41]. However, Treincrements were comparable in both phases of the menstrual cycle only during the initial minutes of exercise, after which the differences between phases increased due to stabilization of Trein the follicular phase at the level of 38.3°C and its continuous increase to 38.9°C (despite the constant load) in the luteal phase [41].-

During a 15-minute exercise at a constant intensity of 70% VO2max, performed in an ambient temperature of 18°C, significantly higher Treincrements were observed in the follicular phase of the menstrual cycle [39]. In conditions of passive overheating or physical exertion, activation of sweat secretion and dilation of cutaneous blood vessels were observed at higher temperatures as well as a higher intensity of perspiration secretion in the luteal phase [12, 28, 29, 39, 98–102]. There was also later occurrence of perspiration production during exercise tests in the follicular phase [28].-

Despite the different course of Trechanges in the follicular and luteal phases, the sweat rate was similar in both phases of the menstrual cycle [41]. The authors suggest that this may be related to lower sensitivity of sweat secretion in the luteal phase (sweating rate—increase of core temperature dependency) [41]. However, these results are not confirmed by other laboratory tests, which indicate a slightly higher value in the luteal phase [28, 39, 98] or a similar sensitivity of the perspiration mechanism in both phases [12, 99, 100, 103]. The results obtained during submaximal physical exercise in thermoneutral conditions showed that the increase in rectal temperature in women was lower during the luteal than follicular phase, while the dynamics of sweating were higher in the luteal phase [104].-

Tests during which women performed two different stress tests (graded test "to refusal" and 60-minute with 50% intensity of VO2max) show that the temperature threshold for starting the perspiration release reaction is higher in the luteal phase and does not depend on the type of exercise [102]. In contrast, the sensitivity of the perspiration production reaction is independent of the menstrual cycle and is higher during the graded test [102]. According to other authors, the effectiveness of perspiration is greater in the luteal phase of the menstrual cycle [104, 105].-

Lower core temperature during exercise in the follicular phase may be due to interphase differences in the value of dermal flow and skin temperature. Some studies [39, 98] show that in thermoneutral conditions, at rest and during submaximal efforts, blood flow through the forearm reaches significantly higher values in the luteal phase. The temperature level at which the cutaneous blood vessels dilate, determined on the basis of temperature measurements, Tes, Tty, and Tre, shifted toward higher values in the luteal phase by about 0.5°C [39]. However, in other studies, resting blood flow in the forearm did not differ during the menstrual cycle [29]. The exercise-based (30 minutes 80% VO2max) increase in cutaneous flow coincided with the increase in core temperature (Tes) to the level of 37.0°C in the follicular phase and 37.4°C in the luteal phase and stabilized at a significantly higher level during the latter phase [29].-

#### *3.3.2. Skin temperature*

According to some authors, the average skin temperature (Tsk) is significantly higher in the luteal phase at rest and during submaximal efforts in thermoneutral conditions [100] at the time of heat exposure [99, 103] and during passive overheating [99]. The lack of differences between phases in the Tskvalues measured at rest as well as during the exercise tests (30 minutes 40% VO2maxand 30 minutes 70% VO2max) performed in thermoneutral conditions was also demonstrated [101]. Cutaneous flow tended to be higher in the luteal phase, but the resulting interphase differences were not statistically significant [101]. Other studies also showed similar resting values and a comparable course of Tskexercise changes in both phases of the menstrual cycle [12, 41, 106]. Cutaneous flow assumed lower values in the luteal phase [106].-

#### **3.4. Oxidative stress**

The body maintains homeostasis in the scope of redox reactions (prooxidation and antioxidative balance), which affects the proper course of biochemical intracellular processes and intercellular signaling. The condition of redox homeostasis is to maintain balance between the level of reactive oxygen and nitrogen species (RONS) and antioxidant defense. Antioxidative defense is provided by nonenzymatic low-molecular and macromolecular antioxidants and antioxidant enzymes, which together determine total antioxidant capacity. Physical activity gives health benefits by improving, among others, cardiovascular and respiratory system functioning, and metabolic processes as well as by increasing antioxidant capacity [107–109].-

#### *3.4.1. Exercise-based sources of oxygen and nitrogen-*

Research has shown that physical exercise influences prooxidation and antioxidative balance [110–114]. The mechanism of RONS formation depends on the duration, intensity of effort, and type of muscle work. An increase in ATP consumption during aerobic efforts results in an increase in the rate of oxidative phosphorylation and, consequently, increased electron leakage in the internal mitochondrial membrane. As a result, amounts larger than at rest of the superoxide anion (O2 •−), hydrogen peroxide (H2 O2 ), and hydroxyl radical (•OH), which belong to the reactive oxygen species, are formed [109]. The superoxide anion radical is also formed by the reaction of NADPH oxidase in the sarcoplasmic reticulum and transverse tubules (T-tubules) of the sarcolemma, as well as in the reaction of xanthine oxidase, the activity of which increases after anaerobic efforts [108]. The formation of RONS is promoted by the increase in lactate dehydrogenase activity, lowering the pH value, increasing the concentration of catecholamines, as well as increasing intramuscular temperature [108, 109]. Contractile activity also leads to increased nitric oxide (NO) synthesis by induced nitric oxide synthase (iNOS). The consequence of increased NO synthesis, at a high level of O2 •−, is the formation of peroxynitrite (OONO− ). Peroxynitrite is a reactive form of nitrogen. Excessive RONS production during exercise can also be the result of myocyte micro-injury associated with activation of the leukocytic system [107, 115].-

#### *3.4.2. Markers of oxidative stress-*

Oxidative stress is determined by changes in the level of many, various markers (**Table 1**). Different oxidation rates and different antioxidants are evaluated in the research, the changes of which are not always unidirectional [107].-

#### *3.4.3. The significance of reactive oxygen and nitrogen species-*

The formation of RONS in low concentrations (intracellular signaling) is necessary for the regulation and integration of biochemical processes. They activate primary signaling pathways depending on redox status. The main transcription factor, sensitive to redox status, is the nuclear factor erythroid 2-related factor (Nrf2). Nrf2 activation affects the strengthening of antioxidative defense and cytoprotection. It has been shown that as a result of regular exercise, upregulation of gene expression for peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) occurs,which upregulates Nrf2in order to regulate the mitochondrial biogenesis. The upstream signals that regulate PGC-1α expression as mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) are also redox-sensitive. RONS, through

**Table 1.** Examples of indicators of oxidative stress and antioxidants.-

MAPK, activate the NF-κB signaling pathway and, thus, affect the expression of antioxidant enzyme genes such as superoxide dismutase (SOD), catalase (CAT), or glutathione peroxidase (GPx) or glutathione reductase (GR). Therefore, they are responsible for maintaining an appropriate level of endogenous antioxidant defense [107–109, 115].-

At high concentrations (oxidative damage level), RONS exhibits inhibitory and damaging effects [107]. Excessive production of RONS with low antioxidant capacity may be the reason for shifting the prooxidation and antioxidant balance toward oxidation and oxidative stress. The consequence of oxidative stress is increased lipid peroxidation, oxidation of thiol groups of proteins, damage to DNA and carbohydrates. Oxidative damage to macromolecules is the cause of disturbance in enzyme activity and permeability of biological membranes [107].-

#### *3.4.4. Antioxidant effect of estradiol activity-*

In women, the antioxidative role is attributed to estrogen. Animal experiments have shown that the amount of H2 O2 formed in the mitochondria of females is lower than in the mitochondria of male rats. The positive effect of estradiol on oxidative stress has also been demonstrated in women. It was found that estradiol reduces the level of reactive oxygen species, and in postmenopausal women, it intensifies oxidative stress, which is counteracted by hormone replacement therapy. Estradiol, acting indirectly through the estrogen receptor, increases antioxidant capacity, affecting activation of the NF-κB signaling pathway, which consequently results in an increase in enzymatic antioxidant capacity [116–119].-

#### *3.4.5. Redox balance in the menstrual cycle-*

An interesting research model was carried out by Massafra etal. [120]. Young women (aged 20–27) participated in the study, declaring a regular menstrual cycle, the length of which ranged from 28 to 30days. The first day of menstruation was accepted as the first day of the menstrual cycle. Changes in ovarian hormones were monitored based on the daily determinations of 17β-estradiol and progesterone. A preovulatory peak of 17β-estradiol concentration was determined for each woman, which was the "0" point. In relation to the "0" point, three tests were determined in the follicular phase (early, from bleeding to −10; middle, from days −8 to −4; late, from days −2 to 0) and in the luteal phase (early, from days 2 to 4; middle, from days 6 to 10; late, from days 12 to 14). Significant changes in the menstrual cycle were found in erythrocyte GPx activity, with higher values in the period from late follicular to early luteal phases compared to early-follicular phase. This coincided with the elevated level of 17β-estradiol, and the correlation coefficient was 0.8. In this study, there was no effect of 17β-estradiol, progesterone, and LH or FSH on the activity of CAT and SOD in erythrocytes, which were similar throughout the menstrual cycle [120].-

In turn, in another study [121] involving 259 regularly menstruating women aged 18–44, it- was found that the level of antioxidants in blood serum is dependent on ovarian hormones.- Similar appointments for assays were determined as in previous studies [120]. Among others,- antioxidant fat-soluble vitamins and carotenoid micronutrients (α-tocopherol, γ-tocopherol,- β-carotene, retinol, lutein, lycopene) and ascorbic acid were determined. The concentration of- F2-isoprostane was determined as an indicator of lipid oxidation. In most women, the assayswere conducted during two menstrual cycles. Among others, it was found that the concentrations of fat-soluble vitamins and ascorbic acid are lower during menstruation. The concentration of fat-soluble vitamins positively correlated with the concentration of 17β-estradiol. The- concentration of ascorbic acid also correlated positively with the concentration of 17β-estradiol- and progesterone, while it was lower when the concentration of LH was higher. Women with- higher ascorbic acid concentrations had lower F2-isoprostane concentrations. In this study, the- ratio of α- to γ-tocopherol was associated with an increased risk of anovulatory cycles [121].-

While regularly maturing young women (cycle length 26–31days) were divided into two groups, i.e., ovulating and non-ovulating, it was found that plasma TBARS (lipid oxidation index), whole blood GSH concentration, and CAT, GPX, and GR activity in erythrocytes are similar in both groups in the first (7–9days) and in the second (22–25days) mid-menstrual cycle [122]. However, the activity of SOD in erythrocytes, in both measurements, was significantly higher in the non-ovulating group. In ovulating women, there was a significant negative correlation between the concentration of 17β-estradiol in the blood plasma and the activity of SOD in erythrocytes. Research has shown that the lack of ovulation in menstruating women does not affect increased lipid peroxidation. In contrast to previous studies [120], there was no effect of GSH-dependent erythrocyte antioxidant defense, while it was found that lower plasma estradiol resulted in attenuated erythrocyte SOD inhibition and elevated enzyme activity [122].-

There are also studies in which it was concluded that women are subjected to oxidative stress for most of the menstrual cycle. In these studies, oxidative stress was assessed on the basis of the reactive oxygen metabolites-derived compound test (d-ROMs), the results of which correspond to the hydroxyperoxide level. The measurement in the blood was performed every 3 days, starting from the first day of menstruation up to the last day of the menstrual cycle (the day before the next menstruation). The level of dROMs was significantly elevated between days 9 and 24 of the menstrual cycle, when there was a peak of 17β-estradiol at low progesterone concentration, as well as when the levels of both hormones were elevated. However, there was no correlation between 17β-estradiol concentration and the level of dROMs; thus, it can be assumed that other factors influenced the increased lipid oxidation [123].-

Other studies do not confirm the relationship between oxidative stress and the course of- the menstrual cycle. There were no differences in the level of 8-OHdG in the urine (oxidative DNA damage index) between follicular phase, ovulation, and the luteal phase of the menstrual cycle [124]. There were also no differences between TBARS [34, 125] and MDA [125, 126], i.e., lipid oxidation indices, as well as H2 O2 and nitrite/nitrate levels [127], nor in total GSH, GSH, and GSSG concentrations [125]. The effect of hormones during the menstrual cycle on the total activity of SOD and the activity of extracellular superoxide dismutase (EC-SOD) [34] or the total antioxidant capacity were not demonstrated [126]. Also, in older postmenopausal women who did not use hormone replacement therapy, there were no higher levels of dROMs or lower antioxidant capacity compared to premenopausal women of similar age (46–55years). On the basis of dROM values in both groups of women, the middle oxidative stress level was found, and a slight deficit in antioxidant defense was detected [127]. However, the level of lipid oxidation in older women was higher compared to the young (25–35years), properly menstruating women who did not use contraceptive pills [127].-

It was shown that oral contraception (monophasic pills containing 0.02mg ethinyl estradiol and 3mg drospirenone) affects the prooxidative and antioxidant status of young women [128]. Compared to women who do not use oral contraception, they cause a decrease in GSH and glutathione S-transferase (GST), GR, and GPx in the blood while increasing CAT activity and lowering GSSG concentration, resulting in the GSH/GSSG oxidative stress index to not change. These studies show that external modification of the concentration of sex hormones causes catalase to play a main antioxidative role, which confirms the positive correlation between CAT activity and MDA concentration. Increased CAT activity may be the result of accumulation of H2 O2 and other radicals. Detoxification of reactive oxygen species by the GSH system is weakened in this situation [128].-

#### *3.4.6. Exercise-induced changes in redox balance-*

Studies show that high levels of 17β-estradiol in non-training young women with normal- biphasic menstrual cycles favor easier elimination of free radicals formed during exercise [34].- Despite the lack of interphase differences in resting TBARS level and SOD activity, after a- 30-minute cycling effort with 60% intensity VO2max, it was found that the TBARS level decreased- in the follicular phase when the 17β-estradiol concentration was higher than during menstruation and the luteal phase. In the luteal phase, however, the activity of SOD in the blood- decreased after the effort. Although in none of the phases (menstruation, follicular phase, luteal- phase), neither at rest nor after exercise, was there any correlation between the concentration of- 17β-estradiol and oxidative stress markers, it was nonetheless found that along with the higher- concentration of this hormone, the decrease in SOD activity was lower [34].-

In another study [125], in which young women also performed a 30-minute moderate-intensity exercise (about 75–80% VO2max) in the follicular and luteal phases of the menstrual cycle, a significant postexercise increase in GSSG concentration was noted during the luteal phase (by 28%), while the concentration of total GSH decreased significantly after exercise only in the follicular phase (by 8%). The concentration of GSH after exercise, regardless of the phase of the menstrual cycle, significantly decreased by about 16–17%. These results show that at higher concentrations of 17β-estradiol (late follicular phase), exercise causes slightly less disturbances of redox homeostasis due to more efficient scavenging free radicals with the participation of glutathione [125].-

Amenorrheic and eumenorrheic athletes underwent a 90-minute effort at an intensity of 60% VO [129]. The level of 17β-estradiol was significantly lower in amenorrheic women both 2max- before and during exercises (30, 60, and 90minutes) and at 15-minute recovery. In these studies, there was a greater effect of the effort on the oxidative stress markers in amenorrheic women. In this group, at rest and during exercise, GPx activity was higher. Before the effort, GR activity in both groups of women was comparable, but as a result of the effort, it also significantly increased in amenorrheic women. Plasma lipid peroxidation concentration and CAT activity were similar in both groups and did not change in response to physical effort. Contrary to other studies [120], there was a negative correlation between GPx activity and 17β-estradiol concentration, but, simultaneously, GPx activity depended positively on cortisol concentration, which was elevated in the group of amenorrheic women [129].-

These results are contrary to those of other researchers [130] who found a positive relationship between GPx activity and estradiol levels both before and after physical exercises. Nontraining, young women, during menstruation and the preovulatory phase, performed three isokinetic efforts to exhaustion, consisting of performing maximum alternating concentric and eccentric work of the knee extensor muscles of the dominant lower limb, preceded by a 15-minute submaximal bicycle effort at an intensity of 50% VO2max. The concentration of MDA in the blood plasma did not change after exercise, but the activity of SOD and GPx in erythrocytes decreased significantly. The effort-induced changes were lower when the estradiol concentration was higher, what is more, the α-tocopherol supplementation (antioxidant vitamin) did not affect this [130].-

Another study [131] showed that a low carbohydrate diet for 3days (5% carbohydrate, 52%- fat, 43% protein), preceded by exertion of glycogen depletion, supports the antioxidant- defense system in healthy eumenorrhoeic women, both at rest and during graded exercises- performed "until exhaustion," compared to women using a balanced diet at this time (59%- carbohydrate, 27% fat, 14% protein). It seems reasonable to assume that the higher daily- intake of heme iron, selenium, and α-tocopherol provided with a low carbohydrate diet- contributed to the increase of antioxidative capacity by increasing the activity of CAT and- increasing the concentration of selenium and α-tocopherol in the plasma, which gave better- protection of the cell membranes against peroxidative damage caused by physical effort. This- is reflected in the limited release of creatine kinase into the blood, which is an indicator of sarcolemma damage. Physical effort was repeated twice in the follicular phase (6–8days), when- the concentration of 17β-estradiol was low, and twice during the luteal phase (4–6days after- ovulation), when both the concentrations of 17β-estradiol and progesterone in the blood were- high. In this study, the phase of the menstrual cycle had only a small effect on antioxidant- defenses of blood [131].-

#### *3.4.7. Sex differences in exercise-induced oxidative stress-*

 It can be assumed that due to differences in estradiol concentration, disturbances in prooxidative-oxidative balance of the blood after exercise are higher in men than women. In the research carried out by Wiecek etal. [111] among young individuals, it was found that the changes in the prooxidative-antioxidative balance of the blood induced by maximum intensity exercise (graded test) differ in women and in men. In men, there was a significant shift in prooxidant-antioxidant balance toward oxidation without increasing the total plasma antioxidant capacity (TAC). In women, the postexercise changes in total plasma oxidation status (TOS) were low due to the increase in TAC.-Exercise-induced changes in TOS concentration depended on VO2maxand simultaneously, on the increase in lactate concentration- [111]. The lack of such relationships in women may indicate the influence of other factors on postexerciseoxidative stress in this group of subjects, such as damage to muscle fibers. Continuing research with the participation of young individuals, it was found that the result of physical effort at maximum intensity is significant, independent of VO2maxand VO2 as well as the work intensity (% VO2max) at the level of the second ventilatory threshold, increase in concentration of ox-LDL and 3-nitrotyrosin in the blood serum, testifying to similar lipid and protein damage in women and men. The significant increase in TAC after exercise at

maximum intensity was the result of micro-damage of muscle fibers that occurred in women [114]. However, when young people performed an anaerobic effort, it was found that with similar disturbances of acid-base balance, changes in TAC, TOS, and oxidative stress index (TOS/TAC) in the blood were the same in both women and men. The changes in concentration of low-molecular nonenzymatic antioxidants induced by this effort were also the same in both sexes. The level of the tested markers was indicative of oxidative stress persisting for at least 24hours after the end of the work [110]. There was no evidence that anaerobic exercise caused muscle damage [113]. During the first hour after completing anaerobic exercise, there were no changes in the activity of xanthine oxidase (XO) in the blood plasma of men or women. The significant increase in the activity of this enzyme was found 24hours after the completion of anaerobic exercise. The increase in XO activity in the blood after anaerobic exercise was greater in women than men. At the same time, the postexercise increase in XO activity was negatively correlated with the amount of total work performed during anaerobic exercise and with mean and peak anaerobic power, which were significantly lower in women [113]. In turn, the 45-minutesubmaximal (50% VO2max) effort ending with a 15-minute eccentric exercise [downhill run (−4.5°)] caused oxidative damage to lipids only in women [112]. An increase in ox-LDL concentration indicated redox balance disturbances. In men, regardless of the type of muscle work (eccentric, concentric), submaximal running efforts did not cause oxidative stress. The probable cause of these gender differences was the higher antioxidant capacity of men's blood dependent on greater physical performance [112]. In the above studies, however, the phase of the menstrual cycle was not taken into account; women performed the exercise either during the follicular phase or in a randomly selected phase. Nonetheless, the results indicate that changes in redox balance among women depend on the intensity of the effort and on the type of muscle work involved.-

#### **4. Conclusion**

Despite many years of interest in this subject, the current research does not allow to draw unambiguous conclusions about the impact of the changing level of sex hormones during individual phases of the menstrual cycle on the exercise capacity of women. There are indications that in the luteal phase, the capacity to perform efforts based mainly on aerobic energy transformations does increase. For example, in one of recent studies [132], an increase in cardiac and respiratory efficiency in the luteal phase of the menstrual cycle for normal-weight females was found, where as in overweight and obese individuals, there was an overall decrease in fitness capacity along with an increase in body mass index (BMI). However, the differences between groups noted by one researcher in the measured effects of the applied test are not confirmed by observations of other authors [133]. Often, however, differences in the results obtained by women in the pre- and postovulatory phase are small. According to a review of studies on women's exercise capacity, in most experiments, efforts were applied with constant submaximal intensity or gradually increasing until the oxygen uptake was achieved. However, there is little information on intergroup variation in response to typical anaerobic efforts. These studies, as one of the most recent [134], indicate a lack of hormone influence in the menstrual cycle on anaerobic efficiency indices. But these tests also provide divergent results.-

The question arises as to why there are still no studies that explicitly determine the exercise capacity of women depending on the phase of the menstrual cycle [135].-

Difficulties in undertaking research on exercise-related reactions in women lie, inter alia, in- obtaining volunteers for research, especially those non-training ones if the experiment requires- the implementation of very high intensity efforts. No physical examinations involve large- groups of women. Usually, the research group consists of several to a dozen people. The problem is also obtaining the right motivation of the studied women to fully carry out their potential capabilities during laboratory exercise tests. The reason for the discrepancy of some results- may be the determination of test date based on measurements of basic body temperature without hormonal determinations. On the other hand, the source of often conflicting results, given- by different authors using sex hormone markers, may be the terminology used to determine- the location of the performed laboratory test in the course of the menstrual cycle. Some authors- use the division of menstrual cycle into follicular and luteal phases, without specifying the- days on which the tests were performed and/or concentrations of estradiol and progesterone- determined. Considering the changing ratio of these hormones during the menstrual cycle, the- following division seems to be more appropriate: early-follicular (low estradiol and progesterone), late-follicular (elevated estradiol and low progesterone), and middle-luteal (high estradiol and progesterone levels) [16] or to reference the day of testing to the day of ovulation [120].- Difficulties in comparing the results obtained by different authors also result from significant- differences in the age and level of physical activity of the surveyed women, or from the variety- of applied stress tests and performed assays, which mainly concern markers of oxidative stress.- Different methodological approaches and inconsistent presentation of data are a limitation- when comparing the results of women obtained by them depending on the changing hormone- concentrations of the menstrual cycle. So far, it has not been specified whether it is necessary to- take the phase of the menstrual cycle into account in sports diagnostics, e.g., during stress tests- that check the physical performance of women training different sports. Also, comparisons- between exercise reactions of men and women may be imprecise due to methodological differences. A comprehensive and multi-aspect study of the exercise should be carried out, involving training and non-training women of all ages, in the pre- and postmenopausal period, as- well as those using and not using hormonal contraceptives or hormone replacement therapy,- which would precisely characterize whether there are differences in biochemical-physiological- adaptation to the efforts of varying intensity and type of work and the course of changes in the- recovery period, related to the level of hormones in the menstrual cycle.-

#### **Acknowledgements**

This work was supported by the Faculty of Physical Education and Sports, University of Physical Education in Krakow, (Poland) under Grant 153/BS/INB/2018.-

#### **Conflict of interest-**

No conflict of interest was reported.-

## **Author details**

Magdalena-Wiecek-

Address all correspondence to<EMAIL_ADDRESS>
Department of Physiology and Biochemistry, Faculty of Physical Education and Sport, University of Physical Education, Krakow, Poland-

## **References**

## **Chapter 6**

## **Premature Ovarian Insufficiency**

## Abdelhamid Benmachiche and Amel Dammene Debbih

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80090

#### **Abstract**

Premature ovarian insufficiency (POI) is a heterogeneous disorder, affecting approximately- 1% of women before the age of 40. Heterogeneity of POI is reflected by various causes.- The known causes are genetic defects, autoimmune ovarian damage, metabolic, iatrogenic- following surgery, cancer therapy, and environmental factors. However, in most cases, the- cause remains unknown (idiopathic POI). The main symptom is the absence of regular menstrual cycles, and the diagnosis is confirmed by the raised gonadotropins and low estradiol.- The disorder usually leads to infertility and has long-term comorbidities such as cardiovascular diseases, osteoporosis, and cognitive impairments. Management includes the use of- hormone replacement therapy till the age of natural menopause. In women having fertility- issues, the spontaneous conception varies between 5 and 10%, and in vitro fertilization with- donor oocytes remains the treatment of choice. Moreover, fertility preservation options can- be offered to some patients with cancer and those at risk of early menopause, such as those- with familial cases of POI. Further research is clearly needed, to identify new mechanisms- which may improve the prediction of the early onset of the disease.-

**Keywords:** premature ovarian insufficiency, irregular menstrual cycle, estrogen deficiency, hormone replacement therapy, infertility treatment-

#### **1. Introduction**

Premature ovarian insufficiency (POI) is a heterogeneous condition defined by the presence of menopausal-level serum gonadotropins in repeated blood tests with menstrual disturbance (oligomenorrhea or amenorrhea) in adolescent girls or women under 40years of age [1]. Several different terms have been used to describe this condition, such as premature menopause, premature ovarian insufficiency (POI), or premature ovarian failure (POF). Confusion exists concerning nomenclature, namely, the use of POF or POI. The term POI has

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 been adopted recently by the European Society of Human Reproduction and Embryology (ESHRE) consensus instead of "failure" [2]. Because it was found to more accurately describe the fluctuating nature of the condition. The POF is best considered as the only final stage of POI [3, 4]. The incidence of spontaneous POI has been estimated to affect 1in 100 women before 40years of age and 1in 1000 women before 30years of age [1, 5]. Although the incidence of spontaneous POI appears to have remained stable, of increasing concern is the rising incidence of iatrogenic POI [6]. Improved survival following malignant diseases has led to increasing numbers of women experiencing the long-term effects of cancer treatments. A recent cohort study estimated the incidence of POI, both spontaneous and iatrogenic, at 7.4% [7]. The risk of POI varies by ethnicity, ranging from 0.1% in Japanese to 1% in Caucasian and 1.4% in African American and Hispanic groups [8]. Environmental factors such as cigarette smoking and poverty were associated with an increased risk of idiopathic POI.-In contrast, certain factors related to ovulation, such as late menarche, irregular menstruation, and longer breastfeeding seem to reduce the risk of POI [9]. The familial form of POI is rare, representing 4–31% of all cases of POI [10–12]. Morris DH etal. (2011) reported that women were around six times more likely to have early menopause if their mother (odd ratio [OR], 6.2; p-<-0.001) or older sister (OR, 5.5; p-<-0.001) also experienced early menopause [13].-

### **2. Objective**

In this comprehensive review, we aim to provide an overview of the current knowledge of the- identifiable causes leading to POI development and the recent advances in the management of- its consequences in terms of long-term complications as well as in terms of infertility concerns.-

### **3. Methods**

*Literature search strategy*: Using the MEDLINE database and Google Scholar, we conducted a comprehensive literature search to identify relevant publications on menstrual cycle disorders associatedwith premature ovarian insufficiency. The keyword combinations include "premature ovarian insufficiency," "primary ovarian failure," "hypergonadotropic amenorrhea," "hypergonadotropic hypogonadism," and "early menopause."-

*Selection criteria*: The search was restricted to articles that were published up to May 2018in English language and that assessed at least one of the following aspects of the condition: "epidemiology," "diagnosis," "etiology," "long-term consequences," "hormonal replacement therapy," "infertility management," and "prediction."-

*Data synthesis and analysis*: The conclusions and the interpretationof the findings were based on our personal experience. In addition, we provided some clinical recommendations and guidelines about the management of patients experiencing premature or early menopause based on the expertise of prestigious scientific societies such as the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM). Statistical testing was not conducted.-

## **4. Diagnosis**

Current studies have failed to determine specific biomarkers or signs/symptoms of POI that will accurately predict when menopause will occur. Some women with POI may not experience any specific symptoms particularly in the idiopathic form of the largest etiology, which may delay the establishment of the diagnosis.-

One study reported that over 50% of patients with POI had seen at least three clinicians- before the diagnosis was made, and in 25% the diagnosis took more than 5years [14]. Before- puberty, the clinical picture is characterized by absent menarche, and pubertal delay results- in absent sexual maturation. After puberty, the typical disorder is characterized by the loss- of menstrual regularity (oligomenorrhea or amenorrhea) in young women for 3 or more- consecutive months and often associated with symptoms of estrogen deficiency such as- vasomotor symptoms which are similar to those observed with the onset of menopause,- such as hot flushes, insomnia, nervousness, irritability, loss of libido, vaginal dryness, dyspareunia, etc. Female infertility is a common concern, as only 5–10% of the patients will- conceive spontaneously [15]. POI may be part of other syndromic features: autoimmune- polyendocrinopathy-candidiasis-ectodermal dystrophy, blepharophimosis-ptosis-epicanthus inversus syndrome, carbohydrate-deficient glycoprotein syndromes, galactosemia,- Turner syndrome, and PHP I [16].-

 Additionally, patients can experience long-term consequences of hypoestrogenism, including low bone density (osteoporosis) [17], cardiovascular diseases [18], and neurocognitive disorders [19]. For the biochemical confirmation, follicle-stimulating hormone (FSH) levels are used as the gold standard in establishing a diagnosis of POI.-Two serum FSH levels in the menopausal range should be obtained at least a month apart (**BOX 1**) [27]. However, there is a lack of consensus on adequate cutoff levels used to define hypergonadotropism. No follicles were found in ovarian biopsies when FSH levels are above 33 and 40 mIU/ml in women with primary and secondary amenorrhea, respectively [20]. Some women with POI express FSH levels lower than these proposed cutoff values, particularly women with autoantibodies. La Marca etal. (2009) found that women with POI due to steroidogenic cell autoimmunity had significantly lower FSH levels (n-=-26, median 37 mIU/ml) compared with idiopathic POI (median 99 mIU/ml) (P-=-0.001) [21]. Furthermore, estradiol (E2) levels are typically low, with a level of 50pg/ml in women with absent or nonfunctioning follicles [22]. Antimullerian hormone (AMH) is currently the most convenient predictor of ovarian reserve. Very low AMH levels seem to play a role in predicting age at menopause [23, 24].

**Box 1.** Criteria to establish the diagnosis of premature ovarian insufficiency.-

Younger than 40 years of age-

Oligo/amenorrhea for at least 4 months-

Two FSH levels in the menopausal range, obtained at least a month apart-

Data from [27].-

1 not at present indicated in women with POI, unless there is evidence suggesting a specific mutation (e.g. BPES).- 2 POI of unknown cause or if an immune disorder is suspected.- Data from [25].-

**Table 1.** Summary of diagnostic workup.-

The differential diagnosis is based on the exclusion of other causes of primary and secondary amenorrhea, for example, pregnancy, polycystic ovarian syndrome, hypothalamic-pituitary disease (pituitary tumors, hyperprolactinemia, Kallmann syndrome), hypothalamic amenorrhea (induced by stress, intensive exercise, anorexia, weight loss, fasting, and severe diseases), endocrine disorders (hyperthyroidism, hypothyroidism, and Cushing syndrome), and vaginal/uterus anatomical abnormalities, such as Rokitansky syndrome or Asherman syndrome. Once the diagnosis has been confirmed, second-line investigations to look for an underlying cause should be considered which may have implications for the individualization of the management **Table 1** [25].-

#### **5. Etiology**

Three potential mechanisms can be associated with POI, that is, a congenital decrease in primordial follicles, accelerated follicular atresia, and an inability to recruit primordial follicles [26]. The known causes of POI are wide ranging and can be divided into spontaneous and iatrogenic categories.-

#### **5.1. Spontaneous POI**

Most cases of spontaneous POI are idiopathic despite the diagnostic advances [27] but may be also due to genetic causes, autoimmune disorders, metabolic dysfunction, enzyme deficiencies, toxins, or infections [27–29].-

#### *5.1.1. Genetic causes of POI*

The normal ovarian function requires the presence of many intact genes functionally normally and in a coordinated fashion. Chromosomal abnormalities are found in around 10–12% of women with POI, of which the majority is X chromosomal abnormalities [30]. An increasing number of studies have documented autosomal involvement. The incidence of chromosomal abnormalities is higher in women with primary amenorrhea (21%) than in those presenting with secondary amenorrhea (11%) [31].-

#### *<IP_ADDRESS>. X Chromosome defects*

Both the short and long arms of the X chromosome appear to play important roles.-

X Chromosome defects usually involve either complete deletion of one X (Turner syndrome) or partial deletions, duplications, and balanced translocations between the X and- autosomal chromosomes. Females lacking an X chromosome as well as those showing- an extra X chromosome are predisposed to developing POI.-Monosomy X (45X), known- as Turner syndrome, is due to the loss of the second sex chromosome and affects 1in 2500 live-born female infants and has a frequency of 4–5% in POI [32]. In phenotypic- women, Turner syndrome is associated with short stature, gonadal dysgenesis, and primary amenorrhea. In women with Tuner syndrome, oocyte loss usually begins early in- childhood as a result of accelerated follicle atresia [33]. The vast majority of pregnancies- with this karyotype end in spontaneous miscarriage, and it is argued that the surviving- individuals most likely carry some degree of mosaicism [34]. In mosaic Turner syndrome- (45X/46XX), patients have a milder phenotype and may present later with secondary- amenorrhea and hypergonadotropic hypogonadism. Trisomy X (47XXX) is caused by- nondisjunction of the X chromosome during meiosis. It is the most common form of- aneuploidy, occurring in 1:900 women. About 1.5–3.8% patients with POI had the triple- X [30, 35] and may manifest in many mosaic forms, that is, 45X/47XXX, 46XX/47XXX, or- 47XXX/48XXXX [36]. The presence of three X chromosomes presumably leads to meiotic disturbance and, secondarily, ovarian failure. X Chromosome deletions associated- with POI are more common than translocations. At present, the microdeletions are not- normally identified by conventional karyotyping and so often go unrecognized. Krauss- etal. reported in 1987 a family in which one woman and two girls, with early menopause,- had a deletion of the long arm of the X chromosome (Xq21–Xq27) [37]. Cytogenetic and- molecular analyses of POI women carrying a balanced X-autosome translocation allowed- the identification of a "critical region" for the ovarian development and function on the- long arm of the X chromosome from Xq13.3 to q27. Various deletions or translocations- occurring within this region and also on the short arm of the X chromosome have been- associated with POI [38, 39]. POI can also be associated with the Xq isochromosome- which occurs when the centromere splits abnormally in the transverse plane instead of- the longitudinal plane. The resulting chromosome pair contains structurally identical- arms with identical genes. The isochromosome for the long arm (q) is the most common X- structural abnormality. These patients present with streak gonads and Turner-like characteristics which are rare causes of POI [40].-

#### *<IP_ADDRESS>. Single-gene defects*

The fragile X syndrome is an X-linked dominant genetic disorder that is a leading cause of mental retardation and autism. Women exhibiting extended repeats of the CGG trinucleotide sequence may be classified as having the permutation (55–199 repeats) or the full condition (>200 repeats). There is an association, although nonlinear, between the number of repeats and the severity of the condition. The fragile site of the X chromosome contains a (CGG) repeat in the 5′ region of the gene. In normal variants, the trinucleotide repeat ranges from 6 to 55 repeats.-

The syndrome occurs when the number of the repeats exceeds 200, being denominated as full mutation alleles. The fragile X mental retardation 1 (FMR1) gene premutation, mapped at position Xq27.3 on the X chromosome, is the most frequently identified single-gene mutation associated with POI outside the Xq POI critical region. It has been shown that females carrying a premutation have up to 23% rate of POI and experience menopause 5years earlier than average [41]. The FMR1 premutation has been identified in 11% of familial POI and 3% of sporadic cases [42–44], and therefore, screening for the FMR1 premutation is usually recommended in women diagnosed with POI to identify those patients and family members who may be at risk of having children with fragile X syndrome. Those with identified premutation should be referred for family genetic counseling. *The bone morphogenetic protein 15 gene (*BMP15) *is a member of transforming growth factor beta (TGF-ß) superfamily and is located on the short arm of the X chromosome (Xp11.2) within the Xp POI critical region* [45, 46]. It is an *oocyte-specific folliculogenesis growth differentiation factor (GDF) and appears to have a vital role in folliculogenesis and granulosa cell growth.*

Approximately 1.5–12% of POI is associated with *BMP15* gene mutation [47–50].-

Fragile site, folic acid type, rare (*FRAXE*)/fragile site mental retardation 2 gene (*FMR2*) has been described in patients who have the cytogenetic changes of fragile X syndrome but who are *FMR1* mutation negative. It was found at Xq28 and found to be folate sensitive [51].-

#### *<IP_ADDRESS>. Autosomal genetic defects*

While several genes relevant to ovarian function lie on the X chromosome, autosomal genes also appear to be involved in the development of POI [26].-

In recent years, attention has focused on genes that are known to play a role in folliculogenesis and ovarian function. Oocyte-specific gene expression is necessary for primordial- follicle formation and their subsequent differentiation into primary follicles. A number- of autosomal genes have been suggested as a causative factor of POI.-For some of these- genes, mutations are identified, while others are listed as candidate genes with a need- for further investigation. The genes with identified mutations that could result in POI are- genes involved in folliculogenesis (NR5A1, NOBOX, FIGLA, and FOXL2), folliculogenesis growth factors (GDF9 and inhibin A), sex hormone function (*CYP17A1, CYP19*, FSH/- luteinizing hormone (LH) receptors, and *NR5A1*) [26, 38], or genes identified in syndromes- often associated with POI such as Bloom syndrome BLM 15q26.1 [52], Ataxia telangiectasia,- A-T.-ATM 11q22-q23 [53], Werner syndrome WRN 8p12 [54], and Rothmund-Thomson syndrome RTS 8q24.3 [55]. Given that the conventional approaches have had limited success in- finding causative genes, further research and new techniques on the genetic background of- POI including genome-wide analysis in affected families may change this recommendation- in the near future.-

#### *5.1.2. Autoimmune causes of POI*

Anti-ovarian antibodies are reported in POI by several studies, but their specificity and- pathogenic role are questionable. Autoimmune diseases are estimated to be involved in the- pathogenesis of up to 5% of POI cases. Adrenal autoimmunity is thought to account for- 60–80% of autoimmune POI [56], and there is a strong association between the presence of- adrenal antibodies and a diagnosis of autoimmune lymphocytic oophoritis [57]. The evidence- of oophoritis is rare (<3%) in POI in the absence of adrenal involvement [16]. The presence- of many other autoantibodies has been investigated such as ovarian and other steroidogenic- cell autoantibodies; however, reliable markers to diagnose non-adrenal autoimmunity are- yet to be identified [56]. POI can be associated with endocrine (thyroid, hypoparathyroid,- diabetes mellitus, and hypophysitis) and non-endocrine diseases (chronic candidiasis, idiopathic thrombocytopenic purpura, vitiligo, alopecia, autoimmune hemolytic anemia, pernicious anemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, Crohn's disease,- Sjogren syndrome, primary biliary cirrhosis, and chronic active hepatitis) (**Table 2**) [16, 58, 59]. POI may be part of the autoimmune polyglandular syndromes (APS) when accompanied- by other autoimmune endocrinopathies. POI is more common with APS types I and III than- with APS type II [60].-

#### *5.1.3. Metabolic causes of POI*

A number of inherited enzymatic pathway disorders have been associated with ovarian- follicular dysfunction leading to POI such as galactose-1-phosphate uridylyltransferase- deficiency (galactosemia) [61], 19, carbohydrate-deficient glycoprotein deficiency [62], 17α-hydroxylase/17,20 desmolase deficiency [63], and aromatase mutations [64] where- there is biochemical damage of the ovary and autoimmune regulator which triggers autoimmune damage. However, the strength of evidence linking each anomaly with POI is- variable.-

**Table 2.** Endocrine and non-endocrine diseases associated with premature ovarian failure.-

#### **5.2. Induced POI**

The induced POI may result from damage to the ovaries, such as that caused by iatrogenic agents like chemotherapy, radiotherapy, pelvic surgery, and also environmental toxic agents.-

#### *5.2.1. Cancer therapy*

There is an overall increase in cancer prevalence followed by an increase in long-term survival of the affected patients these days compared to the past. The 5-year survival rate for childhood, adolescent, and young adult cancer currently exceeds 80% [65]. Medical treatment for neoplastic conditions can be associated with POI.-Chemotherapy and radiotherapy are welldocumented causes of POI.-

Chemotherapy induces apoptosis of mature ovarian follicles, and histological studies have- shown fibrosis, vascular damage, and reduced follicle numbers. The gonadotoxic effect of- chemotherapy is drug and dose dependent [66]. Alkylating agents have been shown to be- gonadotoxic [67]. The prepubertal ovary is relatively resistant to this form of gonadotoxicity- [67]. The risk of developing POI after radiotherapy is dependent on the radiation therapy field- (abdominal pelvic, total body irradiation) and on dose and age [68–70]. Transposition of the- ovaries in young women requiring pelvic irradiation helps in preserving their ovarian function.-

#### *5.2.2. Pelvic surgery-*

Aside from surgical menopause due to bilateral oophorectomy, limited evidence suggests that pelvic surgery is maybe associated with POI such as hysterectomy [71], tubal sterilization [72], or both ovarian surgery for endometrioma and endometriosis [73] presumably due to damage to ovarian blood vessels as a result of the surgical procedure. Research has now also linked ovarian drilling for polycystic ovary syndrome and removal of endometriotic cysts to an earlier age at menopause [74, 75].-

#### *5.2.3. Toxins*

The increasing prevalence of POI in recent years might be also due to an increase in presently unidentified environmental toxic agents. However, studies examining the cause and effect of the chemical substances and POI in humans are rare.-

 Chang etal. (2007) found that cigarette smoking was associated with an increased risk of POI (OR-=-1.82 [1.03–3.23]) [76]. Many other endocrine-disrupting substances have been also suggested to be ovotoxic and influencing the age of menopause such as 2-bromopropane [76], vinylcyclohexene diepoxide (VCD) [77], polycyclic aromatic hydrocarbons (PAHs) [77], etc., but they are not readily considered as diagnosable causes of POI.-Further research is warrantedto clarify in which toxicants affect human reproduction and how insufficiency with FSH values is found in the menopausal range [78].-

#### *5.2.4. Infections*

It has been indicated that many viral infections can be followed by POI, but only mumps oophoritis has been directly linked to POI, explaining 3–7% of POI cases [79]. Other potential causes of POI include tuberculosis, malaria, varicella, and *Shigella* [80]. More recently, there has been suggestion that human immunodeficiency virus (HIV) infection (or antiviral therapy) can lead to POI.-However, a recent systematic review revealed nonconclusive evidence due to a significant methodological limitation with available data [81].-

#### **6. Management**

Patients must be provided with adequate information (education, understanding, and- counseling). Management should address the following aspects: psychology support, ovarian hormone replacement for the prevention of long-term complications, and therapy for- fertility.-

#### **6.1. Psychologic support**

The diagnosis of POI is an extremely devastating psychologic disturbance [35]. Some will experience a range of emotions such as high levels of depression and low levels of self-esteem with negative effects on sexuality [82], and providers should offer support regarding infertility, altered self-image, and sexual dysfunction. Patients may benefit from referral to a psychologist and support groups [83].-

#### **6.2. Hormone replacement therapy**

Hormone replacement therapy (HRT) remains the cornerstone of treatment for relief of menopausal symptoms (including vasomotor instability, sexual dysfunction, mood, fatigue, and- skin issues) and prevention of long-term morbidity and earlier mortality related to prolonged- estrogen deficiency [84]. The results of Women's Health Initiative (WHI) study should not be- applied to young women with POI [85, 86]. In contrast with women older than 50s, POI is a pathologic condition in which young women have low serum E2 levels compared with their peers.-  Physiological- replacement of ovarian steroid hormones until the age of 50years (the average age of natural- menopause) is generally accepted as routine, unless a specific contraindication exists, such- as an estrogen-dependent malignancy. At present, very little evidence exists regarding the- optimum method of hormone replacement, and options include both the combined oral contraceptive pill (COC)and hormone replacement. Data regarding the optimal estradiol levels- in POI are lacking; however, the average serum estradiol level during the menstrual cycle- in normal women is approximately 100pg/ml [87]. Transdermal and transvaginal replacement of 100μg/day of estradiol achieves physiologic blood levels in this range and provides- adequate symptomatic relief. The transdermal route has the advantage of avoidance of firstpass hepatic metabolism and appears to be free of an excess risk of thrombosis compared with- oral estrogen [88–90]. To reduce the risk of endometrial hyperplasia, 5–10mg of medroxyprogesterone acetate should be given for 12days of the month, provided that the uterus- is present and intact [90, 91]. However, the optimum type of progestogen is unclear. With- the use of this regimen, most of women will develop monthly withdrawal bleeding, which-

 maybepsychologicallyimportantto the patient. The COC is also commonly used as hormone replacement in POI.-However, they should not be recommended as first-line hormone- replacement. Indeed, they result in supraphysiological doses of sex steroid hormones and- are associated with an increased risk of thromboembolic events related to the first-pass effect- on the liver [27]. Androgen replacement could be carefully considered for women who have- persistent fatigue and low libido despite optimized estrogen replacement [92]. Transdermal- testosterone administration and dehydroepiandrosterone treatment are two of the options for- androgen replacement in these women [93]. Importantly, this should be performed with great- caution and for relatively short periods until more data are available. When there has been- no spontaneous start to puberty or progression of breast development, many options for HRT- are suggested for puberty induction. However, systemic administration of increasing doses- of estradiol, preferably by transdermal application, is the only form of therapy to achieve- natural levels of estradiol in blood and mimic normal estradiol physiology in adolescence- and adulthood [94, 95]. Patients who do not want to get pregnant should be offered contraception due to the 5–10% chance of spontaneous conception. Women with untreated POI- are at increased risk of developing long-term comorbidities such as cardiovascular disease- [96], metabolic syndrome [97], osteoporosis, dementia, cognitive impairment, Parkinsonism,- reduced sexual function, and psychological well-being. Untreated POI can induce specific- increase in mortality rate due to complications of the prolonged estrogen deficiency compared- to those with a menopause after the age of 50years [98]. The main reason for shortened life- expectancy in women with POI is cardiovascular disease. The Framingham study was one of- the first to show a higher incidence of cardiovascular disease among postmenopausal women- than age-matched women who were premenopausal [99]. A number of studies have subsequently demonstrated higher rates of coronary artery disease, higher rates of heart failure,- and higher rates of mortality in women reaching menopause before 40–45years of age, and- it has been demonstrated that this impairment was reversed by estrogen replacement [100].- Compared with control women, women with premature ovarian insufficiency have reduced- bone mineral density. The prevalence of osteoporosis in POI appears to be in the range of- 8–14% [101]. Multiple studies have shown that the lower bone mineral density (BMD) seen- in women with POI is associated with significantly higher overall fracture risk, and this has- been associated with the presence, degree, and duration of estrogen deficiency. Studies on- fracture risk in early menopause compared to natural menopause have demonstrated that- fracture rates are reduced among women with POI or early menopause who are treated with- the use of HRT [101–103]. Early data demonstrate an increased risk of cognitive impairment- [104]. Some studies suggest that estrogen is neuroprotective. The Mayo Clinic Cohort Study- of Oophorectomy and Aging demonstrated that women who underwent either unilateral or- bilateral oophorectomy before the onset of the menopause had an increased risk of cognitive- impairment or dementia [105] and Parkinsonism [104] compared to controls and that this- risk increased with younger age at oophorectomy. They also demonstrated a protective role- for estrogen replacement in women with bilateral oophorectomy when taken until at least- 50years of age. A similar finding was noted in a Danish cohort study, revealing an increased- risk of dementia in women undergoing oophorectomy prior to the age of 50years, with a- similar trend of increasing risk with earlier age at oophorectomy [106].-

#### **6.3. Fertility**

#### *6.3.1. Spontaneous conception and POI*

For many women with POI, infertility is the most devastating aspect of the diagnosis.-

Fertility of women with POI is severely diminished, but unlike menopause, POI may be- accompanied with spontaneous ovarian activity and natural pregnancies in approximately 5–10% [107]. Currently, no fertility treatment has been found to effectively increase fertility in women with POI including estrogens [108–110], 5-dehydroepiandrosterone (DHEA) [111], corticosteroids [112], and azathioprine [113].-

#### *6.3.2. Assisted reproductive technology (ART) and POI-*

#### *<IP_ADDRESS>. Oocyte donation*

The only proven therapy for obtaining a pregnancy in patients with POI is fertilization of a donor oocyte. At present IVF with donor oocytes confers the highest chance of pregnancy for women with POI with high success rates of around 40–50% per cycle.-

The pregnancy rate from oocyte donation is not greatly affected by the recipient's age [114, 115].-

#### *<IP_ADDRESS>. Fertility management of the Turner syndrome*

There are special considerations regarding oocyte donation in women with Turner syndrome. If pregnancy is desired, hormone replacement therapy can be initiated to increase uterine size, followed by assisted reproductive technology, namely, invitro fertilization with an oocyte donor. However, coexisting cardiac abnormalities associated with Turner syndrome may increase the risk of pregnancy for the mother, and therefore this type of approach to achieve pregnancy is strongly discouraged [116, 117]. Should a Y chromosome be identified with or without an SRY gene mutation, the patient should be counseled about the risk of development of a gonadal tumor, and gonadectomy should be advised [118, 119].-

#### *<IP_ADDRESS>. Fertility preservation and POI-*

Fertility preservation may also be considered for women at risk of POI; in young women who require cancer treatments, including chemotherapy, radiotherapy, and surgery; or for those who have a strong family history of POI.-Options for fertility preservation include ovarian transposition, oocyte or embryo cryopreservation, and ovarian tissue cryopreservation. Ovarian transposition remains the standard of care for women undergoing pelvic radiation, although it has been suggested that it may be combined with ovarian tissue cryopreservation. Embryo cryopreservation remains the most successful technique, with success rates approaching that of fresh embryo transfer [120, 121]. Live birth rates of approximately 30% per embryo transfer have been reported, depending on the age of the patient [120]. The success of oocyte cryopreservation has also improved significantly in recent years, and birth rates similar to that of fresh oocytes have been reported [122]. Oocyte cryopreservation is a potential option for women without a partner. Since the initial report of successful pregnancy following ovarian tissue cryopreservation and subsequent transplant in 2000 [123], there has been increasing success with the technique [124, 125].-

### **7. Prediction and genetic counseling**

Contrary to the induced POI occurring in cancer survivors, the spontaneous POI particularly the idiopathic form is still difficult to be predicted in the general population. Low circulating AMH level is currently thought to be the most reliable measure of reduced ovarian reserve and may play a role in predicting age at menopause [23]. Sowers etal. (2008) have shown that AMH starts declining 5years before the final menstrual period. All these observations suggest a potential role for AMH in screening women at high risk for POI and in well woman screening programs [24]. Autoantibody screening, for anti-adrenal, anti-ovarian, and antithyroid antibodies, is also recommended [25]. Genetic counseling is nowadays recommended for several reasons, when a genetic form of POI is suspected or identified. The prevalence of familial POI has been reported to be between 4 and 31% of cases in various series [126–129]. The early diagnosis of familial POI will provide the opportunityto predict the likelihood of early menopause and allow other reproductive choices to be made, such as freezing embryos or having children earlier. Karyotyping and screening for the FMR1 gene permutation are especially important in younger patients with or without mental retardation or when a female is born from a family with female members affected with POI.-The review of McConkie-Rosell states that approximately 13–24% of women who are fragile X premutation carriers (identified through families with fragile X syndrome) have POI [130].-

#### **8. Future**

Continued advances in DNA sequencing techniques will facilitate finding additional genes responsible for POI in other portions of the genome. Besides, the future holds the possibility of restoring ovarian function with ovarian or oogonial stem cell (OSC) therapy which may open the door to novel fertility preservation strategies for women with both age-related and POI [131]. More recently, Kawamura etal. (2013) have successfully promoted follicle growth, retrieved mature oocytes, and performed IVF.-Following embryo transfer, a healthy baby was delivered [132]. This invitro activation (IVA) approach has been reproduced by a group in Zhengzhou University, China, with two cases [133]. Up to the summer of 2018, there were more than one dozen of successful cases.-

#### **9. Summary**

The POI represents a continuum of declining ovarian function with intermittent ovulation in- women below the age of 40years resulting usually in an earlier than average menopause. Its- incidence is gradually increasing secondary to the improved survival of young women withcancer. In most cases, the etiology is unknown, but known causes include genetic disorders,- particularly involving the X chromosome, associations with autoimmune diseases, cancer- therapy, pelvic surgery, and also environmental toxic agents. A timely diagnosis of POI is- the main challenge. The typical disorder is characterized by the loss of regular menstrual- cycles, and the diagnosis is confirmed by the detection of menopausal-level serum gonadotropins in repeated blood tests. Second-line investigations should be directed by specific- clinical indications. Regardless of the etiology, patients with POI are estrogen deficient. The- aims of HRT extend beyond simply symptom relief to levels that support cardiovascular,- bone, and cognitive health. Only 5–10% of women with POI may conceive spontaneously.- Currently, there are no proven treatments to improve ovarian function, and only the use- of donor eggs with IVF confers the highest chance of pregnancy. However, in women with- Turner syndrome, this approach is strongly discouraged. To date, the prediction of POI is- difficult in the general population. However, in women at risk of POI particularly those who- have a strong family history of POI, or require cancer treatments, a screening program will- provide the opportunity to predict the likelihood of early onset menopause and to consider- fertility preservation as well. Further research is needed particularly in idiopathic POI to- identify mechanisms and specific molecular defects which may offer a better opportunity- for early therapeutic interventions.-

#### **Conflicts of interest-**

There are no conflicts of interest.-

## **Financial support and sponsorship**

Nil.-

#### **Author details**

Abdelhamid-Benmachiche1 \* and Amel Dammene-Debbih2

\*Address all correspondence to<EMAIL_ADDRESS>
1-Center for Reproductive Medicine, Clinique Ibn Rochd, Constantine, Algeria,-

2-Faculty of Medicine of Algiers, Bologhine University Hospital Center, Algiers, Algeria-

#### **References-**

[1] Coulam CB, Adamson SC, Annegers JF.-Incidence of premature ovarian failure.- Obstetrics and Gynecology. 1986;**67**(4):604-606-

expressed in oocytes during early folliculogenesis. The Journal of Clinical Endocrinology and Metabolism. 1999;**84**:2744-2750-

**Chapter 7**

**Provisional chapter**

**Standardization of Menstrual Cycle Data for the**

**Standardization of Menstrual Cycle Data for the**

DOI: 10.5772/intechopen.81504

Daily diary methodology is becoming popular in human menstrual cycle (MC) research. However, variations in MC length makes it difficult to examine fluctuations in dependent variables (e.g., substance use levels), across the MC. Existing analytic approaches collapse data across MC phases, examining phase-related changes; however, a loss of potentially vital information can result when data is collapsed across phase. Additionally, current phase designation methods (phase designation and days within each phase) vary substantially across studies, making it difficult to interpret/compare results across studies. To address these problems, two methods were developed to standardize intensive longitudinal data collected via daily diary methodologies—phasic and continuous standardization. Phasic standardization accounts for individual variability in MC length by allowing luteal phase length differences while remaining phases are fixed, enabling the analysis of phasic variations. Alternatively, continuous standardization accounts for individual variability in MC length by standardizing the luteal phase to a seven-day phase, while remaining phases are fixed, allowing for the exploration of continuously reported variables across MC day. This chapter will discuss how to standardize daily diary data collected across the MC using phasic and continuous standardization methods and demonstrate the two standardization

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Historically, females have been omitted from addictions research. One reason for this omission is that ovarian hormones fluctuate rhythmically across females' menstrual cycles and may impact their addictive behavior. As a result of this sex bias, theory and evidence pertaining to

**Keywords:** addiction, substance use, behavioral addiction, mood, menstrual cycle

**Analysis of Intensive Longitudinal Data**

methods using two clinically-relevant hypothetical examples.

**Analysis of Intensive Longitudinal Data**

Kayla M. Joyce and Sherry H. Stewart

Kayla M. Joyce and Sherry H. Stewart

http://dx.doi.org/10.5772/intechopen.81504

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Chapter 7**