**Introductory Chapter: Regulation of Ovarian-Menstrual Cycle as a Systemic Problem of Physiology of Humans**

Olena Lutsenko

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.85065

## **1. Introduction**

One of the main manifestations of the vital activity of the female body is the menstrual cycle, which begins during puberty and has a rhythmic (monthly) character.

Endocrine relationships in the hypothalamic-pituitary-ovarian system are formed throughout the period of puberty. This process is regulated by certain neuroendocrine processes, which have different activities depending on age. The determinants of this regulation are the hypothalamus,- pituitary gland, gonads, thyroid gland, and adrenal cortex; therefore, a certain interest is the study of the peculiarities of the formation of the hypothalamic-pituitary-ovarian hormonal system.

 Back in the late nineteenth century, leading scholars D. O. Ott, S. S. Zikharev, and A. V. Reperov found that menstrual cycle is not a local process, but a wavelike reaction of the organism associated with changes in the system of the hypothalamus-pituitary-ovaries-uterus, which appears from the outside of uterine bleeding. These changes in vital processes in the body of women were called "menstrual wave" [1, 2].

So, the normal menstrual cycle is a finely coordinated cyclic process of stimulating and inhibiting effects that lead to the release of one mature egg. Various factors involved in the regulation- of this process, including hormones, paracrine, and autocrine factors, are identified so far [3].

The regulation of the menstrual function passes through a complex neurohumoral path [4–6]. According to modern concepts [7–9], cyclic changes in the body of a woman are related to the implementation menstrual function and occur with the obligatory participation of five levels (or levels) of regulation. Each of them is regulated by the structures located above according to the mechanism of feedback.

© 2019 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.

The levels (links) of regulating the menstrual (reproductive) function:


Nowadays, leading scientists insist that the multilateral morphological features are closely related to the functional manifestations of sexual dimorphism [10, 11], which, in its turn, causes the sexual specificity of the processes of adaptation of the organism to external influences and, in particular, to physical activity. For women, the role of estrogen and progestogens is predominant, and for men, androgens. The degree of saturation of the body by sex hormones determines their biological effect [12–16].

Estrogens are an important link in the chain of adaptive-trophic reactions in the body [17, 18]; they have an anabolic effect but are slightly weaker than androgens, determine the degree and- nature of the distribution of fatty tissue by female type, increase the growth of pelvic bones,- create a female type of body proportions [19, 20], contribute to the closure of epiphyseal bone growth zones, and hinder the development of osteoporosis (resorption of bone tissue). Estrogens suppress erythropoiesis (red blood cells), reduce thrombocytopenia, promote growth of shock and minute volume of the heart, increase cardiac output, increase the volume of circulating blood, and have a positive effect on myocardial tropism and vascular tone [21, 22].

Progesterone, like estrogens, increases systolic and temporal volumes of blood and the frequency of heart contractions. Progesterone has a sodium diuretic effect and reduces the peripheral resistance of the blood vessels, which contributes to lowering blood pressure [23, 24].

Estrogens cause narrowing of the lumen of bronchioles by increasing the release of histamine and serotonin, increasing pulmonary resistance. Its direct effect increases the excitability of the respiratory center; improves the patency of bronchioles by increasing their lumen; decreases the overall pulmonary resistance; as a consequence, increases alveolar ventilation; and decreases the tone of the respiratory muscles [18, 25].

The change in the balance of steroid hormones, in particular the deficiency of progesterone and the excess of estrogens involved in the regulation of water-salt metabolism, increases reabsorption (reabsorption) of sodium in the kidneys while increasing osmotic pressure. As a result, in order to maintain homeostasis, the water is delayed in the body to compensate for the homeostasis, and, as a consequence, the body weight increases in the premenstrual and menstrual phases of the cycle. Scientists have established the influence of sex hormones on the emotional state of women [22, 26]. All of the above suggests that reproductive and exogenital functional systems are closely interrelated, and the reproductive system, in turn, has a different effect on the organs and tissues of other functional systems, which correlates the adaptation, resistance, and reactivity of the female body. In recent years, the distribution and extension theory has intensified, according to which the influence of sex steroids to one degree or another extends to the functional state of all organs and systems [10, 27, 28].

The functional state of the cardiovascular system in women has a number of features due to hormonal changes that accompany the menstrual cycle [29]. In recent years, the study of the role of estrogens and progestogens in the regulation of the function of the cardiovascular system [30].

The increased resistance of women in comparison with men to cardiovascular diseases is associated with the dynamics of cardiodynamics parameters in stressed women [23], which is determined by the sexual characteristics of the nervous and humoral regulation of the cardiovascular system. During stress, more catecholamines are released in the female body [31, 32], and their influence on the heart rhythm becomes more pronounced, but pressor responses are less prolonged than in men, which suggests that the control of the sympathetic adrenal system is more effective in the female body [33]. The factors limiting its activity include the presence of estrogens, which enhance the tone of the parasympathetic nervous system and reduce sympathetic effects on the cardiovascular system. The influence of estrogens on the vegetative level of regulation, along with their peripheral effects on the heart and blood vessels, is the basis of cardioprotective properties of estrogens. Information on the influence of androgens on the cardiovascular system and the mechanisms of its regulation are few and contradictory. Testosterone contributes to the development of hypertension and has an atherogenic effect [34]. At the same time, testosterone improves coronary blood flow in coronary arteries [35] and positively affects the mechanical function of the heart by activating the expression of heavy α chains of myosin [36]. Sexual features in cardiovascular stress reactivity are largely due to differences in the autonomic regulation of the cardiovascular system in the female and male body. Investigation of the mechanisms that determine the differences in the activity of the autonomic nervous system departments convinces in the need to study the role of sex hormones. The scarcity and contradictory nature of research data on the role of autonomic regulation of the cardiovascular system in the female and male organisms, as well as the influence of sex hormones on the autonomic balance, justify the carrying out of complex studies of the revealed phenomenon [37, 38].

Significant are the effective attempts to decipher the mechanism of the influence of sex hormones on the central nervous system that are highlighted in the works of well-known scientists [33]. The beginning of puberty is marked by a significant increase in the threshold of the sexual centers of the central nervous system (gonadostat) to steroids in the feedback system, which was first noticed by Hohlweg and Dohin (1932) and then Donovan and van der Werff- Ten Bosch (1965) [38]. Further animal studies and human observation fully confirmed this assumption. The enhancement of the inhibitory effect of sex steroids on the hypothalamus has been linked with a change in the puberty of the spectrum of sex hormones—the shift in the ratio of estrogen to testosterone in favor of the latter, which is allegedly less effective in suppressing the production of gonadotropins. However, this is unlikely.-

The scientific assumptions about the importance of changing the metabolism of testosterone and other androgens during puberty have been supported. So, in an experiment in many species of animals, it was discovered and demonstrated that the metabolic activity of the liver and kidneys, aimed at inactivating androgens, increases with age. Small amounts of sex hormones produced by gonads of immature animals give a more pronounced inhibitory effect due to the fact that in adult animals the inactivation of hormones is more pronounced [38]. However, this hypothesis was subjected to devastating criticism, as the androgenic effect on other target organs during puberty does not decrease but increases.

An important role in the onset of puberty may be played by not only inhibiting but also stimulating effects of sex hormones, in particular estrogens. We have convincing evidence of the- leading role of estrogens in the formation of systems of the hypothalamic neurons responsible for regulating the gonadotropic function of the pituitary gland. This process begins during the period of sexual differentiation of the hypothalamus, but its final stage falls on the puberty- period. It has been experimentally shown that the administration of small doses of sex hormones can cause premature puberty. Although the role of estrogens is particularly significant- in the formation of pubertal in girls, however, in boys, estrogens are also an effective stimulator- for secretion of gonadotropin and gonadotropins, since central nervous structures do not lose their ability to respond to the stimulating effect of estrogens during sexual differentiation [33].

During the menstrual cycle, there are significant changes in the hypothalamic-pituitary system and in the body as a whole. Cyclical changes in the structures of the hypothalamus and in the anterior lobe of the pituitary gland regulate all processes that ensure the reproductive function of the woman.

Fluctuations in mental processes and functional state during the menstrual cycle have been proven by many researchers, and the association of these oscillations with the nature of secretion of sex hormones is evident. These changes were detected in the attitude of emotional and motivational behavior [39], the electrical activity of the cerebral cortex [23, 40], the autonomic tone [41], the activity of the cerebral hemispheres [42], and the physical and mental performance [80].

However, the clear dependence of the change in the psycho-functional state, depending on the phases of the menstrual cycle, cannot be identified, and the results of the research are mainly controversial (especially concerning the premenstrual and menstrual phases). Thus, the follicular phase is considered by most researchers as a period of high mental and physical working capacity. As for the phase of ovulation, as a period of poor performance, researchers have quite controversial thoughts. At the same time, some scholars tend to believe that the menstrual cycle does not affect the psycho-functional state of the woman [43], and there are those who record a significant deterioration or improvement [26] of mental and physical performance in the premenstrual and menstrual periods.

Investigating the indicators of the functional state of the soccer players in various phases of the ovarian menstrual cycle, Buzzin VR (2009) [44] concluded that the dependence of the level of physical performance in the first phase of CMC depends mainly on the state of central hemodynamics, in stages II and V (from repolarization of the ventricles), in the IV phase (the state of the atrium), and in the III phase (from the general state of the organism). Body mass swims on the studied indicators of the body of soccer players throughout the entire biological cycle. Given that it is an integral indicator of the general state of the organism, the data obtained can be evidenced by the fact that the pursuit of football contributes to the coherence in the activity of the studied systems of the body of athletes. Perhaps, this is due to the individual nature of the body's response to the fluctuations of sex hormones during the menstrual cycle, depending on many variables of psychophysiological factors, mediating the influence of hormones on the central nervous system and higher nervous activity.-

The factors that may affect the condition of women in the premenstrual phase include age, type of constitution, level of health, and typological peculiarities of higher nervous activity. Confirmation of the influence of the identified factors can be, in particular, significant differences in the level of sex hormones between people with different typological peculiarities: type of constitution [12], functional asymmetry [23], temperament [45], as well as differences between adolescent and adolescent girls [41].

The study of Naumova [71] illustrates the different effects of the phases of the ovarian-menstrual cycle on the psychomotor quality and properties of the nervous system of women. The author measured these indices during the premenstrual phase (1–3 days before menission), the menstrual phase (1–2 days), and the postmenstrual phase (1–2 days) during the 3-month period. The obtained data were compared with each other and with the background (from the beginning of menstruation on the 10th–12th day). The premenstrual phase is characterized by deterioration of psychomotor performance. Compared with the background (the period between menstruations), muscle strength and maximum frequency of movements decreased much more often than they increased. Endurance in relation to static forces varied slightly during this period and in the direction of increase [47, 48].

The menstrual phase is characterized by an increase in the muscle strength of the majority of the girls studied (but only to the background level) and the maximum frequency of movements (excess of the background level), but the endurance is somewhat reduced. At the same time, the secondcomponent of endurance attracts attention—maintaining the effort against the background of increasing fatigue [46–49]. The postmenstrual phase was accompanied by a variety of changes in the studied parameters. The maximum frequency of movements increases even more, and muscle strength and endurance are greatly reduced.

In the premenstrual phase, the mobility of the nervous processes has increased. These changes indicate an increase in the emotional and motor reactivity of women in the premenstrual phase, which corresponds to the findings of the researchers in the literature on increasing the irritability of women before menstruation [50, 51]. It is explained by the fact that thyroid gland swelling is observed in the premenstrual phase of CMC and there are symptoms of thyrotoxicosis, that is, increased production of thyroid hormones [52]. In the postmenstrual phase, the return of the neurodynamics to the background level is observed. Excitement increases, and mobility of nervous processes decreases somewhat.

The strength of the nervous system in various phases of the OMC did not undergo significant and logical changes. Consequently, as can be seen from the data presented, in different phases of the CMC, the psychomotor functions change unevenly and differently, so that the deterioration of performance on one indicator may be accompanied by an improvement in the ability to work after another [53–55]. Thus, the indicators of "external" and "internal" balances in certain phases of CMC vary in a different direction [56]. The effect of phases of the CMC on functional parameters, well-being, and mood should be taken into account in studies related to the female contingent [23, 57, 58].

The revealed neurovegetative and endocrine regularities of regulation of the ovarian-menstrual cycle are realized through individual-typological peculiarities of the hormonal status and morphology of the female body.

#### **1.1 Individual features of central hemodynamics and cardiac rhythm variability in women of reproductive age**

The variability of the heart rate (HRV) is a fundamental physiological property of the human body and reflects the state of regulating mechanisms, in particular the autonomic tone of the autonomic nervous system; its study contributes to the development of quality diagnosis, prognostication, and prevention of various diseases [43].

In recent years, the number of studies on the variability in the duration of the interval RR [31, 32, 34, 59, 60], blood pressure [60, 61], shock volume of blood [35, 60], respiratory arrhythmia [31, 32, 40], and communication wave changes in various hemodynamic parameters. This is due to the wide introduction of information technologies to medicine and physiology, as well as to the confirmed or highly diagnostic value of parameters of- regulatory rhythms of hemodynamics.

On the adaptive-trophic role of the sympathetic department of the VNS, including in the- reproduction, one of the first pointed academician Orbeli [27]. However, until now, the study- of the state of the VAS, including heart rate activity, in women during the normal menstrual- cycle and in the physiological and complicated pregnancy, remains insufficient. A number- of review papers [43, 62] provide data on age and gender changes in some HRV indices.- However, they relate mainly to short (2–5min) records of RR intervals and performed on contingents of persons with different pathologies. At the same time, the characteristics of the wave- structure of oscillation of hemodynamic indices in healthy women in different physiological- conditions and loads in the ontogenesis process are insufficiently analyzed. Studies by Ketel- et al. [12], conducted in randomized tubes for 149 men and 137 middle-aged women, revealed that HRV levels were inversely related to age and heart rate in both sexes. The level of LF in- men is significantly higher in women than in women and is negatively related to the level of- triglycerides, insulin. The power of the R-R interval for women is higher than that of men.

The widespread introduction of the ECG Holter monitoring method into the clinical practice allowed the evaluation of HRV values in the course of the day and at certain intervals and also used this method for studying the state of autonomic regulation of the cardiac rhythm [64]. Extreme values of total power of the spectrum and power in the range of very low and low frequencies in Holter monitoring of women compared to men were also recorded in Fluckiger et al. [65]. At the same time, the power in the ranges of low and high frequencies was negatively correlated with age. The total power of the spectrum decreased relatively between 20–29 years and 60–69 years by 30%.

The same gender and age characteristics of the wave structure of the cardiac rhythm were also confirmed in measurementsof 302 men and 312 women conducted by Bai etal. [36], with 653 persons performed by Aubert et al. [66], and on 276 persons conducted by Barrett etal. [67]. The gender differences of HRV are measured at the sixth decade of a person's life cycle. Changes in the heart rhythm and its spectral components during orthopedic trial at this age did not have sexual differences.-

There are significant differencesin the reactivity of fluctuations in the duration of the R-R interval and the peripheral pressure of men and women on physical, mental, and cold loads. So in studies OV Peshakova [68] shows that women under these conditions have a greater centralization of mechanisms of regulation of the cardiovascular system, and for men—an increase in the activity of the sympathetic link of the autonomic nervous system.

Many researchers [39, 69] point out that cardiovascular analysis is more appropriate to detect minor fluctuations of the VNS activity during the menstrual cycle than the use of traditional- indicators such as heart rate and arterial pressure. However, the results of studies of changes in- cardiac rhythm in different phases of the menstrual cycle are still controversial. It should be noted- that significant changes in HRF in women of reproductive age, whether alone or in psycho-emotional stresses, may be due to the ovarian cycle [70]. SDNN in young women was highest during- the follicular phase of the menstrual cycle [26]. According to Kravchenko and co-authors [71] in women during the luteal phase compared with the follicular showed an increase in the activity of the sympathetic department of the autonomic autonomy of the autonomy according to the HRV- indices. However, a group of researchers Grossman etal. [70] insists on the absence of differences- in the parameters of the wave structure of blood pressure and heart rate when performing orthopedic and stimulating carotid sinus in women in different phases of the ovarian cycle.-

Japanese scientists [39] demonstrate a significant increase in sympathetic and decreased parasympathetic activity in the luteal phase compared to follicular, as evidenced by an increase in LF/HF and LF values, as well as a decrease in HF in the luteal phase. The facts of the increase in the level of LF/HF in the early and middle luteal phase are presented in Hirshoren etal. [72], with the late lutein phase showing a tendency to decrease the level of LF/HF.-At the same time, some researchers, Princi et al. [69] and Sato etal. [39], refute this assumption, indicating that there is no significant change. Although some researchers point to an increase in the level of HF in the follicular phase compared with the luteal and menstrual phase, measurements were made only one [15] or twice a week [73] during the cycle. Since hormonal and physiological changes during the menstrual cycle are complex, they cannot be characterized by two measurements, indicating the need for long-term research.

In studies [45], with ten completely healthy women, it was found that spontaneous baroreceptor sensitivity increases during the luteal phase compared to the follicular phase. It was stated that there were certain differences in the logRSA fluctuations during the menstrual cycle, which were related to the average NSC indices.-

According to Fleischman [28], there are significant changes in both the wave structure of the cardiac rhythm and its reactivity to the burden on women in the first 20weeks of pregnancy. So, normally in this period, the power of OT components increases, and often the synchronization of respiratory and baroreflector waves is observed. In pathological development of pregnancy, there is an inversion of such regulatory relations.

The variability of the cardiac rhythm during the physiological course of pregnancy is reduced, which indicates an increase in the activity of the sympathetic department of the autonomic nervous system [12, 13]. In women with gestosis, HRV is more pronounced. Revealed by scientists the facts of changes in HRV with other hypertensive states in pregnant women, as well as in normal and complicated childbirth, are few and controversial. The emphasis is on the prospect of further study of sympathetic activity in relation to the change in HRV in pregnant and childbearing women, as well as on the need for widespread introduction of cardiointervalography in obstetrics.

Many scientists [13, 64, 74] note that in the second and third trimesters of pregnancy, the activity of the VNS is higher (by characteristics of the wave structure of the cardiac rhythm) than in nonpregnant women. The analysis of these works shows that the decrease in HRV during pregnancy is manifested in the reduction of the values of the mathematical expectation, the mod, the mean square deviation, the variational magnitude, the variation coefficient, the power of the OT waves, the normalized power of the OT waves, and the pHN50, as well as in the increase of the amplitude of the mod, index voltage, autonomic equilibrium index, LF wavelengths, normalized LF wavelengths, VLF wavelengths, and LF/HF ratios.-

At the same time, it should be noted that until now scientists have not agreed on the change in HRV at the beginning of pregnancy. Thus, Vae etal. [36] investigated that in the first trimester the HRV increases and in the second and third trimesters it decreases. According to other scholars [45, 63], HRV progressively decreases, starting with the first trimester. According to Klinkenberg etal. [75], HRV in the first trimester remains unchanged. The question remains as to the nature of the changes in BCR before delivery: according to some data [64], it increases and it contributes to the normal course of labor, and for the other [1, 13]—does not change.

The reasons for increasing the excitability of VNS during pregnancy are still not studied. Some scientists believe that increased activity occurs under the influence of chronic stress, which is considered pregnancy; others regard it as a compensation in response to systemic vasodilatation, which occurs under the influence of NO, whose production will increase significantly in pregnancy. According to Klinkenberg etal. [75], the increase in VNS activity during pregnancy is the result of a true increase in the activity of higher sympathetic centers under the influence of changes in the production of various hormones during pregnancy, as well as the result of an increase in the effectiveness of b-adrenergic effects on the heart (or a decrease in the effectiveness of M-cholinergic effects). The latter is due to an increase in the content of endogenous b-adrenergic agonists (b-AP) and endogenous b-AP sensitizers or endogenous M-cholinoreceptor blockers (M-HRP) in the blood. Previously, it was shown that in pregnancy, indeed, the content in the blood b-AP increases, while the content of M-HRP does not change. Most likely, in general, the increase in sympathetic activity is a manifestation of adaptation to pregnancy and is aimed at the formation of mechanisms that ensure the growth and development of the fetus, including inhibition of contractile activity of the uterus, increased pumping function of the heart, and gas transport function of the blood.

Studying the health of women during menopause is of great interest, both for practitioners and for theoretical scholars. This is a separate branch of health care that is socially important in all countries of the world, because in connection with the prolongation of life expectancy, the number of women over 50 years old has increased threefold [76, 77], and more than onethird of her life, a woman holds in postmenopausal care [78].

To date, some research on HSR has been devoted to the study of this phenomenon in women engaged in physical exercise and sports. Thus, the specific features of the female body and its response to intensive, often extreme, training and competitive loads, characteristic of certain sports, are rather negligible. It is believed that this circumstance does not allow to accurately formulate the extent of the impact of occupations on various sports and the desire for the highest sports results in the condition of the female body [60, 79]. However, in the HSR studies on women-tongue-men in comparison with the group of men of masters of sports and masters of the international class, it was found that men had more frequencies of HRV, in particular TP, VLF, LF, LF/HF but less HF and HF percentage (%). Thus, we see that the women of single fighters in comparisonwith men are noticeable strengthening of the sympathetic link of the VNS.-

In the study of the variability of the heart rate in the mode of the training day in the gymnasts, it was established that the relationship between the cardiovascular system and the degree of centralization in the management of cardiac rhythm not only is preserved but also varies. At the same time, the dynamics of integral indicators of the functional state of the circulatory system in gymnasiums is rather informative for the assessment of "urgent" training effect [31, 32].

It should be noted that many researchers point out that the athlete's affiliation with a particular sports specialization determines his "vegetative portrait," which is related to the nature of the exercise, which can be offset by gender differences in HRD [78].

## **Author details**

Olena-Lutsenko-

Address all correspondence to: olena85lutsenko@gmail.com

Department of Theory and Methods of Teaching of Natural Sciences, Hlukhiv National Pedagogical University of Alexander Dovzhenko, Ukraine

#### **References**


## **Normal Menstrual Cycle**

Barriga-Pooley Patricio and Brantes-Glavic Sergio

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79876

#### **Abstract**

 Normal menstrual cycle represents a coordinated serial event, repeated month by month, at regular intervals, in which the hypothalamus participates along with the secretion of GnRH, the pituitary gland secreting follicle stimulating hormone and luteinizing hormone (LH), and the ovary which responds to those hormones, recruiting a dominant follicle and secreting estradiol and inhibin A. Estradiol stimulates endometrial proliferation and production of cervix mucus. A peak of estradiol triggers discharge of LH, responsible for ovulation and posterior secretion of progesterone by the corpus luteum, which in turn, involutionates 14 days later if it does not receive the stimulation of hCG (pregnancy). Normal menstrual cycles last 28-±-7days, being accepted a fluctuation of ±2days in the same woman, as a normal pattern, what is described as a regular cycle. Normality of these events would allow to achieve a successful embrionary implantation in the case of looking for pregnancy. For this it is required that an adequate ovule to be fertilized is reached by a capacitated spermatozoon, during the ovulatory stage. Spermatozoon can survive as long as 5 days at feminine genital tractum, but the ovum is possible to be fecundated only during 12–24 hours. Fecundation occurs at the distal third of the fallopian tube and the fecundated zygote arrives in the state of a morula, to be implanted at the endometrium 4 days later. Once the state of blastocyst is reached, it is detached from its shaggy area (hatching) and it is implanted in a receptive endometrium when the window of implantation is open (days 7–9) postovulation. The first marker of pregnancy is the detection in maternal blood of β-hCG. No more than the 25% of fertile couples exposed to pregnancy can achieve gestation at the month of exposure.

**Keywords:** menstrual cycle, fertility, concepcional cycle

#### **1. Definition of normality-**

 Menstrual cycle lasts 28 ± 7 days. Just a third of patients have cycles every 28 days and 82% fluctuations among 22 and 32days [1].

© 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 cycle is known as regular when the frequency has a variation of no more than 2 days. The lasting of each cycle is calculated since the first day of menstruation until the previous day of next menstruation. The cycle frequency is regulated by the hypothalamus-pituitary-gonadal axis; hormones such as follicle stimulating hormone (FSH) and luteinizing hormone (LH) must reach their effectors at the ovarian level where a dominant follicle must be recruited and developed, secrete estradiol, in enough amounts to obtain endometrial receptivity but also participating directly in a feedback-regulated control of the cycle.

Cycles show more irregularity in the extremes of the reproductive lifespan, during the first 2 years from the menarche and during the perimenopausal transition. The ovarian cycle has two stages separated by ovulation, the first, from the beginning of the cycle to ovulation, is called the follicular or proliferative phase. The second, between ovulation and the next menstruation, is called the luteal phase or secretory phase.

The follicular phase is characterized by the maturation of the follicle containing an ovule and a retinue of follicular cells, which are responsible for transforming androstenedione into estradiol, which in turn is released and, among many other actions, stimulates endometrial renewal.

The luteal phase, named because the follicular cavity that left the ovule after hatching, is transformed into a corpus luteum and continues to produce estrogen, but it also releases important amounts of progesterone. The luteal phase is preceded by a significant increase in LH, and ovulation marks its onset; then, it lasts ±14 fairly constant days when comparing different women. During this phase, the average total body temperature of women is constantly 0.5°C higher than in the follicular phase.

If there is no embryo implantation, the endometrium is detached giving rise to menstrual flow, which has normal volume parameters, up to 80mL, in duration, 3–8days, content, absence of clots and symptoms, and absence of pain.

It is considered that the conserved cyclicity expresses that the hypothalamic-pituitary-gonadal axis is healthy. The ovaries do not alternate to ovulate.

#### **2. Important concepts-**

**Ovarian reserve**: *it corresponds to the number of follicles that a woman has and it is defined during fetal life and then the number of follicles goes slowing down gradually.-*

When is born, each woman counts with a fixed number of ova, which are getting lost with the past of years (atresia) Delaying maternity is nonrecommendable, since at higher age the risk of not having ovum of a good quality at the moment when a pregnancy is planned.

In a woman fertility, among 38–40years is lower than at 25–30years. Atresia of oocytes is a continuous process that never stops not even with the use of anovulatory or pregnancy.

**Oocyte atresia:***it is the mechanism of follicular apoptosis that seems to contribute to the selection of optimal ovules.* During the early fetal stage, about 7,000,000 oocytes are formed in the ovary. Before birth, the ovular reserve has been reduced to one-third by mechanisms of apoptosis (programmed death).

At birth, only 1–2 million oocytes remain in the ovary and during puberty, there are usually 300,000 available for eventual ovulation. In fact, they will only ovulate between 400 and 500 throughout the lifespan. Then, through the female reproductive life, between the periods of puberty and menopause, about 250,000 follicles will be destined to die, reaching less than 1000 during perimenopause (**Figure-1**).

**Sex steroids—estrogens and progesterone:** Estrogens are steroid hormones produced by the granulosa follicle, the corpus luteum, and the placenta (if there is pregnancy). Its synthesis comes from cholesterol molecules. Progesterone is synthetized by corpus luteum and placenta, if there is pregnancy.

Of the estrogens, the most potent is estradiol. The actions they develop are:


**Figure-1.-**The number of oocytes in any woman comes defined at the moment of birth and slow down inevitably during her life during her life from 1 to 2 million at the moment of birth at 300,000 to go decreasing through her life 25,000 at 37–38years and near 500 during the postmenopause.-

• *Cardiometabolic*: estrogen relaxes the smooth muscle of arterioles, increases HDL cholesterol, and lowers LDL cholesterol, which has been associated with the lower incidence of cardiovascular disease that women have in relation to men, especially before menopause.

Progesterone is also a steroid hormone. It is responsible for the progestational changes of the endometrium. On the breasts, progesterone stimulates the development of the lobes, being its action complementary to that of the estrogens. Progesterone is thermogenic and contributes to the increase in basal temperature experienced by some women after ovulation.

#### **3. Follicular phase-**

Follicular phase begins the very first day of menstruation. The development of ovarian follicles, named folliculogenesis, begins at the last days of menstrual cycle before the release of mature follicle during ovulation (**Figure-2**).

When a pregnancy did not occur, the release of inhibin A and sex steroids are reduced by the end of the functional period of the corpus luteum. Both falls contribute to reduce the release of FSH by feedback at the central level, which is dependent on pulsatility of hypothalamic GnRH. This is how FSH increases during the last days of the menstrual cycle (**Figures-3** and **4**) [2].

**Figure-2.-**The menstrual cycle has two phases, follicular phase and luteal phase. The follicular phase begins with menstruation. The follicle stimulating hormone (FSH) increases released by the anterior pituitary gland and stimulates follicular growth and estradiol production. The 17 beta-estradiol produced by the follicles exerts negative feedback on the FSH. Estradiol continues to increase due to the growth of the dominant follicle. The LH increases sharply to trigger ovulation. Immediately after ovulation, the luteal phase begins. The corpus luteum produces progesterone and 17 betaestradiol concentrations of progesterone and estradiol decrease, menstruation begins a new cycle, unless a pregnancy has been established.

**Figure-3.-**Dynamic scheme of follicular activity and the changes in gonadotropins, steroids, and inhibins during follicular phase of menstrual cycle.

**Figure-4.-**The level of inhibin changes through menstrual cycle. Inhibin B dominates follicular phase during the cycle while inhibin A dominates luteal phase.

The progressive elevation of FSH allows many follicles to be recruited simultaneously. Nevertheless, only some persist, in such a way that an approximate 99% of the cycles, only a dominant follicle will be destined to ovulate, during the next menstrual cycle.

The remaining 1% has codominance, that is two dominant follicles, which eventually can generate a double ovulation at the risk of a multiple pregnancy.

In women from 19 to 42 years, follicular phase has an average duration of 14.6 days, however, to be precise on each woman in what step of the cycle she is very difficult because of the following reasons:

• Duration of menstrual cycle is very changing, even among young women of similar ages, with variations described from 25 to 34days.-


At the development of dominant follicle (DF), three steps have been described namely, **recruiting, selection,** and **dominance** (**Figure-6**). Recruiting stage is developed during the days 1–4 of menstrual cycle.

 **Figure-5.-**Menstrual cycle lasting variation according to age. Graphic shows the average lasting of the cycle and the range (percentiles 95 and 5) yrs. = years, d = days. Triangles indicate the group of age in the percentage of women with more than14 days of variation of a cycle during a year. From Mihm etal. [3].

**Figure-6.-**Time lapse of recruiting, selection, and ovulation of dominant follicle (DF) with the beginning of atresia in the other follicles of the group. Adapted from Hodgen [4].

During the follicular phase, FSH is responsible for recruitment among those follicles that remain available. Between days 5 and 7 of the cycle, follicular selection normally occurs, to allow only one follicle, the dominant follicle (FD) to ovulate and the rest to experience atresia. Anti-müllerian hormone (AMH), which is secreted in the granular layer, also participates in the selection of FD. On day 8 of the cycle, the FD promotes its own growth, suppressing the maturation of the other ovarian follicles.

During the follicular phase, estradiol plasma levels are higher along with the growth of the number of granulosa cells and the growth of the DF. FSH receptors are found exclusively in the cell membrane of granulosa cells. The increase in FSH during the late luteal phase induces its own FSH receptors and eventually increases the secretion of estradiol by the granulosa cells by transforming androstenedione, which diffuses from the theca cells (**Figure-7**).

It is important to point out that the increase in the numbers of receptors of FSH is due to an increase in the population of granulosa cells and not to an increase of the concentration of receptors of FSH on them. Each granulosa cell has 1500 receptors of FSH at secondary stage of follicular development, and the number of receptors of FSH stays constant during the rest of DF growing.

The increase in estradiol secretion also upregulates their own receptors, increasing the total of estradiol receptors (ER) in the granulosa cells. On the other hand, in the presence of estradiol, FSH stimulates the formation of LH receptors in the same cells, which allows the secretion of small amounts of progesterone and 17-hydroxyprogesterone (17 OHP) that would exert positive feedback on the pituitary gland. Already sensitized by the increase of estrogen, thus allowing the release of luteinizing hormone (LH) and achieve its peak. FSH also stimulates many steroidogenic enzymes such as aromatase and 3β-hydroxysteroid dehydrogenase (3β-HSD).

**Figure-7.-**Diameter of dominant follicle (DF) days prior to LH peak and plasma concentration of estradiol per follicle diameter (curved lines are 95th and 5th percentiles). Adapted from Macklon and Fauser [5].

There are other signaling pathways that impact the differentiation of theca cells, not only LH but also insulin-like 3 (INSL3) that appear to modulate LH-mediated androgen biosynthesis and increased follicle cell apoptosis and luteal regression, bone morphogenetic proteins (BMPs) produced by granulosa cells, and/or oocytes who antagonized the effects of LH and INSL3, the circadian clock genes, androgens, and estrogens and (2) theca-associated vascular, immune and fibroblast cells, as well as the cytokines and matrix factors that play key roles in follicle growth [6].

At **Table-1**, production rates are presented for sexual steroids during follicular phase, luteal phase at the moment of ovulation.

Differently from granulose cells, LH receptors are localized at theca cells during all of the- stages of menstrual cycle. LH receptors stimulates granuloma's cells. LH stimulates the production of androstenedione and at a lesser level the production of testosterone at the theca cells.


Androstenedione is then transported to the cells of granulosa where it is aromatized, and finally, it becomes estradiol 17-β-hydroxysteroid dehydrogenase type I. This is known as the

\*Values are expressed in milligrams or micrograms per 24 hours. From Baird and Fraser [7].

**Table-1.-**Production rate of sex steroids in women at different stages of the menstrual cycle.- hypothesis of two cells and two gonadotropins of the regulation of synthesis on the ovary (**Figure-8**).

The normal follicular phase has been divided in two stages: (a) early and (b) middle and (c) late, to allow a better comprehension of the endocrine events that will be finally responsible of ovulation.

**Early follicular phase (days 1–4):**it begins with the first day of menstruation. Follicular recruitment occurs due to the elevation of FSH, as a consequence of the decrease in estradiol, progesterone, and inhibin A released by the corpus luteum of the previous cycle, allowing the number of LH receptors to increase in the cells of the teak and the granulosa. The plasma levels of estradiol tend to remain low at this stage (**Figure-1**).

**Medium follicular phase (days 5–7):** as the recruitment and growth of follicles induced by FSH progress, estradiol increases slowly in a progressive manner thanks to the increased activity of CYP19, an FSH-dependent aromatase that is present in granulosa cells. The follicle that achieves the highest number of FSH receptors may aromatize more estradiol and become the dominant follicle. The other follicles, with fewer receptors for FSH, suffer- atresia. For estrogen synthesis, it is necessary for the thecal cells to produce androgens, under the stimulus of LH, and for these to diffuse to the granulosa cells. Simultaneously,- two glycoproteins, activin and inhibin, are produced in the theca and granulose, with local actions. Inhibin B exerts a negative hypophyseal feedback effect, where it potentiates the- effect of estradiol and inhibits the synthesis and release of FSH [9, 10]. This would be a mechanism to achieve dominance giving an advantage to the follicle that has greater

**Figure-8.-**Two cells and two gonadotropins, on the regulation and the synthesis of estrogens at the ovary. From: Doshi and Agarwal [8].

development. The estrogen take-off (ETO) marks the successful establishment of the dominance of a follicle.

The FD develops its internal theca and increases receptivity to LH, which stimulates the production of androgens by degrading molecules of cholesterol to progesterone and from this to dehydroepiandrosterone, androstenedione, and testosterone.

At the end of this phase, the granulosa-theca complex of the FD has almost complete functionality to enter the late follicular phase.

**Late follicular phase (days 8–12):** this period is characterized by the elevation of estrogens that come from the DF, reaching its maximum values between 40 and 50 hours, before an elevation of FSH that precedes the ovulatory peak of LH. This preovulatory follicle reaches an average diameter of 15–20 mm.

#### **3.1. Follicular phase and fertility-**

The moment of greatest likelihood of successful fertilization is intercourse on the day before ovulation. However, the potentially fertile period, which depends on sperm survival, can extend from 5 days before ovulation. Those pregnancies that have been obtained after day 14, are associated with later ovulation, a normal variability in the duration of the follicular phase depending on the time of the ETO.

 It is believed that cycles of 30–31days and 5days of bleeding would have a higher probability of pregnancy [11], perhaps due to better quality of the DF, good function of the corpus luteum and optimal endometrial receptivity. The moment of the fertile window is quite variable. It has been reported that a significant number of women with regular menstrual cycles can be in their fertile window before day 10 or after day 17, of their menstrual cycle [12]. However, it seems that the possibility of pregnancy is low when the cycles are short, less than 25days [13].

In clinical practice, to determine the fertility potential of a given cycle, indirect methods are used, which require observing at least one of the three primary signs of fertility (basal body temperature, cervical mucus and position of the cervix), known as methods based on symptoms.

There are kits to detect the increase in LH, which occurs 24–36hours before ovulation named ovulation predictor kits (OPK). Those urine-based ovulation test kits are available in versions standard OPKs, digital OPKs or advanced digital OPKs, but some saliva-based ovulation tests are available also.

Computerized devices that interpret basal body temperature, urinary test results, or changes in saliva are called fertility monitors, and there are different types: urine-based fertility monitors, perspiration-based fertility monitors and saliva-based fertility monitors.

In the monitoring of assisted fertility procedures, effective follicular follow-up with ultrasonography is preferred.

In infertility treatments, ovulation inducers are used that increase endogenous levels of FSH or eleven therapeutically by administering FSH parenterally, which manages to rescue multiple follicles from atresia. So, this patient has a higher risk of multiple ovulation. It is interesting to note that when rescuing follicles from atresia, the follicular endowment remains the same, so that follicles will not be depleted in an accelerated manner.

#### **3.2. Follicle types-**

At born, woman count with primordial follicles (PF), each surrounded by one layer of cells of granulosa and are detained at the pro phase of the first meiotic division.-

 During adolescence, the woman has antral follicles that depend on FSH. On average, this follicle takes 14 days to mature to preovulatory FD. They are derived from a recruitment process that is independent of FSH and is mainly regulated by the anti-müllerian hormone (AMH), which is produced by the granulosa cells of the follicles in early development and inhibits the transition from the primordial to the primary follicular stage [14]. AMH levels can be measured in serum and used to measure the follicular reserve (**Figures-9and-10**).

Primordial follicles (PF) are independent of FSH. Their average life is 60–65 days, then they are transformed in to preantral follicles (PAF), also independent of FSH, and are surrounded by many layers of granulosa's cells and also by theca cells. In this process, many primordial follicles suffer atresia (**Figure-11**).

Due to the presence of 5α-reductase, the early preantral and antral follicles produce more androstenedione and testosterone compared to the estrogen rate. 5α-reductase is the enzyme responsible for converting testosterone to dihydrotestosterone (DHT). Once testosterone has been reduced by 5α, DHT cannot be aromatized.

**Figure-9.-**AMH is involved in the paracrine control of recruitment in the first stage, when the process is still independent of gonadotropins. AMH can not only reflect the number of early antral follicles in the process of development, but also those in earlier stages. Adapted from Ref. [1].

**Figure-10.-**Clinical witnesses of the follicular development in stage pre- and postdependence of FSH: AMH and ultrasound, respectively. Adapted from Ref. [15].

**Figure-11.-**Follicular dynamics and illustration of folliculogenesis process.

With the increase in age in women, the involution of granulosa cells decreases the levels of inhibin production. Because of this, when a woman approaches menopause her FSH levels become higher, a sign that her ovarian reserve has decreased. On the other hand, the perimenopausal follicles are of the worst quality, half have chromosomal alterations.

As mentioned, the development of the preantral follicle is independent of FSH, so any follicle that grows beyond this point will require an interaction.

Secretion of gonadotropin is regulated by the releasing hormone of gonadotropin (GnRH), steroidal hormones, and diverse peptides released by dominant follicle.

Among substances that can be found al follicular liquid there are steroids, pituitary hormones, plasmatic proteins, proteoglycans, and ovarian factors nonsteroidal, which regulate the micro environment of the ovary and the steroidogenesis of the granulosa.

Factors of growing such as the insulin growth factors 1 and 2 (IGF1, IGF2) and the epidermal growth factor (EGF) would have an important role at the development and maturity of oocytes. Concentration of ovarian steroids is higher at follicular liquid compared to plasmatic concentrations.

There are two population of antral follicles: **big follicles**, which measure more than 6 mm diameter, and **little follicles**, less than 8 mm. In big follicles, concentrations of FSH are higher. Estrogen and progesterone are higher as well, while prolactin concentration is lower. Inside little follicles, prolactin and androgen levels are higher in comparison to big- antral follicles.

In addition, as mentioned, FSH increases during the early follicular phase and then begins to decrease until the ovulation phase, except in the short preovulatory peak. In contrast, LH is low in the early follicular phase and begins to increase in the middle follicular phase due to positive feedback of increasing levels of estrogen.

 To achieve positive feedback of LH release, plasma estradiol should be greater than 200 pg/ml, for at least 48 hours. The gonadotropins are secreted in a pulsatile manner in the anterior pituitary, with a frequency and widening of pulses that change according to the phase of the menstrual cycle (**Figure-12**).

**Figure-12.-**Pulses of LH throughout a normal cycle. Number of pulses per 24 h decreases, but total daily secretion and LH half-life are stable. The intersecretory burst interval becomes longer as the cycle progresses, being very long in the luteal phase, whereas the pulse amplitude of LH shows a dichotomous behavior, with small and high waves. Adapted from data of Sollenberger etal. [16].

During early follicular phase, secretion of LH occurs to a frequency of pulse from 60 to 90 minutes with a widening of pulse constant but variations on number of pulses intersecretory burst interval and pulse amplitude [16]. During late follicular phase, previous to ovulation, frequency of pulse increases and widening may be beginning to increase. Most of women have widening of pulse of LH beginning to increase after ovulation.

Once menstruation is produced, levels of FSH begin to decrease due to negative retro alimentation on inhibin B produced by developing follicle.

#### **4. Ovulation-**

Hatching occurs 10–12 hours after peak of LH (**Figure-8**). Augmentation of LH is generated by significative raising of estradiol, with levels between 200 and 450pg/mL, produced at the preovulatory follicle.

The critical concentration of estradiol needed to initiate positive feedback requires that the dominant follicle reach a size >15mm in diameter. The increase in LH occurs 34–36hours before ovulation and is a very reliable predictor of ovulation (**Figure-9**). This increase in LH is responsible for the luteinization of granulosa cells that stimulates the synthesis of progesterone and also estradiol. In addition, the LH increase resumes the second meiotic division and the chromosomal reduction in the oocyte with the release of the first polar corpuscle.-

Estradiol levels decrease abruptly immediately before peak of LH. This can be due to regulation to down of LH from its own receptor or due to direct inhibition of estradiol synthesis because of progesterone.

Progesterone also participates in the stimulation of the increase in FSH in the middle of the cycle (**Figure-13**).

This increase in FSH would produce the release of oocytes from their follicular junctions, to stimulate the plasminogen activator and increase the LH receptors in the granulosa. The exact mechanism responsible for the post ovulatory fall is unknown.

Decrease in LH would occur as the consequence of the loss of positive retro alimentation of estrogens the inhibitory retro alimentation of progesterone (**Figure-14**).

It takes 36hours from the peak of estrogen until ovulation occurs. The time to ovulation measured from the peak of LH is 12 hours; considering the time of detection in urine, ovulation will take place at 24 hours since LH is measured in the urine. The hormone hCG is similar to LH and can be used as an exogenous hormone to trigger ovulation, which will occur 36hours after administration.

During the ovulatory period, progesterone and prostaglandins are secreted inside the follicle, as well as proteolytic enzymes. This results in digestion and rupture of the follicular wall allowing hatching, commonly called ovulation [18].

**Figure-13.-**Increase of LH precedes ovulation in 36 hours. Peak, on the other side, precedes ovulation in 10–12hours.-

**Figure-14.-**Changes in ovarian gonadotropins and steroids in the middle of the cycle, just before ovulation. The beginning of the increase of LH is at time. 0 time. Abs: E2, estrogen; P, progesterone. Adapted from Hoff etal. [17].

Proteolytic enzymes and prostaglandins are activated in response to LH and progesterone and digest collagen in the follicular wall, which leads to an explosive release of the cumulusoocyte complex. Prostaglandins can also stimulate the release of oocytes, stimulating the smooth muscle within the ovary.

The point of the dominant follicle closest to the ovarian surface where the rupture occurs is called a "stigma."

All the mechanisms are still not elucidated. The concentrations of prostaglandins E and F and hydroxyeicosatetraenoic acid (HETE) reach a maximum level at the follicular level just before ovulation.

Prostaglandins stimulate proteolytic enzymes, whereas HETE stimulates angiogenesis and hyperemia. The use of high doses of prostaglandin inhibitors could hinder the follicular rupture, causing what is known as luteinized unruptured follicle syndrome, and can be observed in fertile and infertile women.

Consequently, it should be recommended to women in search of pregnancy and especially that with fertility problems, avoid the intake of inhibitors of prostaglandin synthesis, and inhibitors of cyclooxygenase (COX), in fact, are being investigated as an alternative to morning after pill in emergency contraception [19, 20].

For ovulation to occur, a series of complex molecular mechanisms that commence after the gonadotrophin surge must be given. These include intracellular signaling, gene regulation, and remodeling of tissue structure in each of the distinct ovarian compartments, which can be summarized in (a) ovulatory mediators that exert effects through the cumulus cell complex,- (b) convergence of ovulatory signals through the cumulus complex co-ordinates the mechanistic processes that control oocyte maturation and ovulation, and (c) other multiple inputs, including

**Figure-15.-**Proposed mechanisms at follicular rupture. LH stimulates the expression of genes in granulosa cells (PR, PGS-2) that control the activation of matrix metalloproteinases (MMPs), leading to the breakdown and remodeling of extracellular matrices and the surface epithelium to allow rupture of the follicle and extrusion of the oocyte (ovulation). Modified from Richards etal. [22].

endocrine hormones, immune and metabolic signals, as well as intrafollicular paracrine factors from the theca, mural and cumulus granulosa cells, and the oocyte itself. Therefore, healthy and meiotically competent oocytes and the coordination and synchronization of endocrine, paracrine, immune, and metabolic signals acting mainly through the cumulus compartment exert control on oocyte maturation, developmental, and ovulation process [21].

Mechanisms suggested implied in follicle rupture [22] are shown in **Figure-15**.

#### **5. Luteal phase-**

This phase lasts 14 days in most women after ovulation. The granulosa cells that are not released with the oocyte acquire a vacuolated appearance and a characteristic yellow color due to the concentration of a carotenoid called lutein and the incorporation of fat drops. No other function has been described for lutein than being a powerful antioxidant.

The luteinized cells combine with the newly formed theca-lutein cells together with the surrounding stroma; thus, originates the transitory endocrine organ that secretes progesterone, known as the corpus luteum, whose main function is to prepare the endometrium, already proliferated by the action of follicular phase estrogens, for the implantation of the fertilized egg.

The endometrium expresses adhesion molecules that make it receptive to the blastocyst and between days 7 and 9 from ovulation, a period of maximum efficiency known as the window of implantation is established; after day 9, implantation is not possible, which is why it is called the refractory phase.

Eight or nine days after ovulation, at the time when implantation is expected, maximum vascularization is reached, the basal lamina dissolves, and the capillaries invade the granulosa cell layers in response to the secretion of angiogenic factors, both from the granulosa and from the theca cells, in harmony with the maximum levels of plasma progesterone and estradiol.

The survival of the corpus luteum depends on the continuous stimulation of LH, but estradiol metabolites, acting via paracrine-autocrine pathways, affect angiogenesis or LH-mediated events also [23].

The function of the corpus luteum decreases at the end of the luteal phase unless chorionic gonadotropin appears due to an eventual pregnancy. If pregnancy does not occur, the corpus luteum undergoes luteolysis. Under the action of estradiol and prostaglandins, it forms a scar tissue called *corpus albicans* [24].

As noted, estrogen levels increase and decrease twice during the menstrual cycle, increase during the middle follicular phase, and then decrease rapidly after ovulation, followed by a further increase during the middle luteal phase, in parallel with the increase in serum levels of progesterone and 17α-hydroxyprogesterone, all falling at the end of the menstrual cycle (**Figure-1**).

The mechanism of how the corpus luteum regulates steroid secretion is not known exactly. It may be determined in part by the pattern of LH secretion, changes in its receptor, or variations in the levels of enzymes that regulate the production of steroid hormones. The amount of granulosa cells formed during the follicular phase and the levels of LDL cholesterol that surround it may also play a role in the regulation of steroid synthesis by the corpus luteum.

There are at least two types of luteal cells, large and small.

Both produce progesterone but with differences. Large cells come from granulosa, are more active- in steroidogenesis, produce large amounts of progesterone, and although they have numerous LH receptors, they do not elevate progesterone secretion in response to LH or cAMP. Instead, they possess receptors for PGF2a and respond to this hormone with activation of at least two second messengers. Activation of protein kinase C (PKC) decreases progesterone's secretion.

As a result of the binding of PGF2a to its receptor, the concentration of free intracellular calcium increases, which seems to be related to the induction of apoptosis and cell death.

The large cells are influenced by other autocrine and paracrine factors, such as inhibin, relaxin, and oxytocin (**Figure-16**). The small cells are derived from the theca, contain receptors for LH, and respond to LH or cAMP by increasing the secretion of progesterone by 5–15 times [25, 26].

The synthesis of progesterone by the corpus luteum is essential for the establishment and maintenance of pregnancy.

**Figure-16.-**Regulation of small luteal cells (left) and large (right). In small luteal cells, the binding of LH to its receptor activates the second messenger protein kinase A (PKA) pathway, which stimulates the synthesis of progesterone. In large cells, the LH that binds to its receptor does not increase the intracellular concentrations of cAMP nor the synthesis of progesterone, but the binding of PGF2a to its receptor activates PKC, which inhibits the synthesis of progesterone and causes an influx of calcium that leads to cell degeneration. AC: adenylate cyclase, DAG: diacylglycerol, IP3: inositol 1,4,5-trisphosphate, PIP2: phosphatidylinositol 4,5-bisphosphate, and PLC: phospholipase C.-From Niswender [25].

In addition to luteinization, that is, the conversion of an ovulatory follicle into the corpus luteum and luteal regression to allow a new cycle, there are also mechanisms of luteal maintenance and rescue to sustain pregnancy.

Humans preferably use circulating LDL cholesterol for steroidogenesis although the corpus luteum has the ability to synthesize its own cholesterol, in smaller amounts [27].

Inside the cells, lipid steroid precursors are found as free cholesterol. There is also esterified cholesterol that accumulates within the rough endoplasmic reticulum and as cytoplasmic lipid droplets or lipoprotein particles. These fatty acid esters of cholesterol cannot replace free cholesterol as a structural ingredient of the plasma membrane nor serve as direct substrates for the production of steroids. They are hydrolyzed by a neutral cholesterol ester hydrolase (NCEH), also known as hormone-sensitive lipase, because their activity is tightly regulated in steroidogenic tissues by FSH, LH, and hCG.

Progesterone secretion and estradiol during luteal phase is tightly connected with the pulses of secretion of LH (**Figure-12**). The frequency and widening of secretion of LH during follicular phase regulates the function of the posterior luteal phase and is concordant with the function of LH during luteal phase.

The frequency and widening of the pulses of secretion of pituitary LH affect the secretion of progesterone and estradiol during the luteal phase (**Figure-12**).

The half-life of the corpus luteum can be reduced with the continuous administration of LH during any of the phases, follicular or luteal, as if the LH concentration is lower or its pulses are reduced.

The luteal phase can suffer shortening also if the levels of FSH are inadequate or low, during the follicular phase, conditioning the development of a smaller corpus luteum.

The function of the corpus luteum begins to decrease 9–11 days after ovulation. The mechanism by which the corpus luteum undergoes involution (luteolysis) is partially elucidated. Prostaglandin F2α would have a luteolytic action, through the synthesis of endothelin-1 that inhibits steroidogenesis and stimulates the release of a growth factor, the tumor necrosis factor alpha (TNFα) oxytocin, and vasopressin and would produce a luteotropic effect through an autocrine/paracrine mechanism.

The ability of LH to negatively regulate its own receptor may also play a role at the end of the luteal phase; thereby, the involution of the corpus luteum must be caused by a decrease in the sensitivity of the LH receptors, rather than by a pulsatile secretion of it. Finally, the matrix metalloproteinases would also play a role in luteolysis and, therefore, in the fall of progesterone levels.

#### **6. Menstruation-**

In the absence of pregnancy, the levels of progesterone and estradiol begin to decrease as a result of the corpus luteum decreasing. The fall of progesterone increases in degree of coiling and the constriction of the spiraled arterioles. This finally produces tissue ischemia due to decreased blood flow from the superficial, spongy, and compact endometrial layers. After the fall of serum concentrations of ovarian steroids, matrix metalloproteinases play a key role in the onset of menstrual bleeding in the human endometrium, by inducing the degradation of the extracellular matrix of this mucosa [28]. Endometrial prostaglandins cause contractions of the uterine smooth muscle and detachment of degraded tissue.

The release of prostaglandins may appear due to instability of the lysosomal membranes in the endometrial cells. The magnitude of this effect is such that inhibitors of prostaglandin synthesis can be used as a therapy in women with excessive uterine bleeding. Menstrual flow is composed of detachment of endometrial tissue, red blood cells, inflammatory exudates, and proteolytic enzymes.

Two days after the start of menstruation and while the shedding of the endometrium still occurs, the estrogen produced by the new growing follicles begins to stimulate the regeneration of the superficial layers of the endometrium. The estrogen secreted by the growing follicles causes a long constriction of the vessel facilitating the formation of a veil over the denuded endometrial vessels.

The average duration of menstruation is 4–6 days, but the normal range can be 2–8 days. As mentioned above, the average amount of bleeding loss is 30ml and more than 80ml is considered abnormal. A few years ago, a classification has been generalized to describe the abnormalities of bleeding suggested by the International Federation of Gynecology and Obstetrics [29].

#### **6.1. Types of endometrium at echographies-**

The characteristics of the endometrium in gynecological ultrasound change depending on the period of the menstrual cycle, presenting different thicknesses according to the stage of the menstrual cycle (**Figure-17**).

**Endometrium type 0, postmenstrual:**it is characterized because only a fine refractive line can be seen. It is the endometrium typical of postmenopause, postpartum, or after a uterine scraping. Most postmenopausal women are between 3 and 5mm thick, but it is normal up to 8 mm if there has been no unexpected bleeding.

**Endometrium type 1, preovulatory:** trilaminar endometrium, refers to the observation of three refractive lines. This stage corresponds to the proliferative or estrogenic phase. In an early follicular stage, the size of the endometrium is between 3 and 4mm thick, while in the stage close to ovulation, it can reach 9–11 mm.

**Endometrium type 2, postovulatory:** in this stage, the progesterone matures the already proliferated endometrium, especially in its glandular and vascular structures, thickening the endometrium. The ultrasound image becomes whiter to the extent that it contains more water and glycogen. This layer of refringency represents most of the endometrium toward the end of the luteal phase.

**Figure-17.-**The main substrate for human steroidogenesis is LDL cholesterol: it is incorporated by endocytosis and stored as free cholesterol or as ester. Esterified cholesterol is hydrolyzed cholesterol esterases (CE) and transported as free cholesterol to the mitochondria. It passes from the outer mitochondrial membrane to the internal membrane, with the concurrence of the steroidogenic acute regulatory protein (StAR), peripheral type benzodiazepine receptors and endozepine. In mitochondria, cholesterol is converted to pregnenolone by cytochrome P450scc, which is transported out of the mitochondria and converted to progesterone by 3b-hydroxysteroid dehydrogenase, D5, D4 isomerase (3b-HSD), which is present in the smooth endoplasmic reticulum (The cell nucleus is not shown.)

**Endometrium type 3, premenstrual:** in this stage, there is only one large refractive line and corresponds to the late secretory phase.

#### **6.2. Endocrine regulation of the menstrual cycle-**

When the gonadal axis has reached maturity, the neurons of the preoptic area and the infundibular and arcuate nuclei in the hypothalamus secrete GnRh in a pulsatile fashion, every 60–90 minutes, to the pituitary portal system.

Frequency and amplitude are essential to produce and maintain the effect on the gonadotropic cells of the anterior part of the pituitary gland, which consists of releasing both LH and FSH. The secreted amounts of each will depend not only on the pulsatility of GnRH, but also on the positive and negative feedbacks mechanisms of sex steroids.

In general, estrogen sensitizes and counter-regulates FSH, at both levels, the hypothalamus and the adenohypophysis, selectively modulated by other factors such as inhibins A and B. LH is sensitive to positive feedback, while there are estrogens in the late follicular phase and in the luteal phase, but the feedback becomes negative when estrogen levels fall at the end of the cycle.

Recent evidence indicates that the administration of progesterone in the late well-estrogenized follicular phase does not prevent the LH surge, which is of great importance because it would have no interference with ovulation [30, 31].

Relatively, low levels of estradiol, in early follicular and luteal phases, decrease kisspeptin expression, which reduces the amplitude of GnRH pulses [32]. On the other hand, progesterone would increase the dynorphin expression, which in turn reduces that of kisspeptin. These changes have been associated with the lower frequency of GnRH pulses in the luteal phase.

Other modulators that stimulate the pulsatile secretion of GnRH are glutamate and norepinephrine, while GABA and endogenous opioids inhibit it.

Neurokinin B and dynorphin neuropeptides act in an auto-synaptic fashion in the arcuate/ infundibular nucleus, so that an increase in the expression of neurokinin B (NKB) stimulates the secretion of and, therefore, of GnRH, while an increase in dynorphin (Dyn) expression decreases kisspeptin secretion by inhibiting the pulsatility of GnRH. This system is known as KNDy [33].

At the beginning of the menstrual cycle, estradiol levels are low and FSH levels are slightly elevated. This ratio manages to recruit follicles and as that happens, not only estradiol increases but also inhibin A, due to the empowerment of FD, which generates a continuous decrease in FSH in the follicular phase.

The concentrations of FSH reach the maximum levels on the day when the FD is defined, followed by a slow decrease during the follicular phase, from day 5 to 13, reaching a nadir and then a peak just before ovulation (**Figure-14**). There comes a time when estradiol levels are such that they trigger the peak of FSH and LH, producing ovulation.

**Figure-18.-**Types of endometrium in transvaginal ultrasound. The endometrium was classified into four types (0, 1, 2, and 3)- according to the appearance of the myometrium-endometrium and endometrium-endometrium interfaces, the texture, and the thickness of the functional layer. Type 0: smooth, thin as a pencil line; type 1: trilaminar structure with an iso- or hypoechoic functional layer; type 2: also trilaminar, but the myometrium-endometrium interfaces are thicker than those of type 1; and type 3: thick and homogeneous echogenic image. The type of endometrium correlates with the day of the- menstrual cycle. Ultrasound is defined on day 0 as the day of the follicle break. Type 0 is usually found on day −11, during and immediately after menstruation. Type 1 is observed during the middle follicular phase and until day +2. Types 2 and 3 are observed after the ovulatory days. The endometrium increases more thickness during the preovulatory phase- (average +5.5 mm), and in the luteal phase, the average is +2.6 mm.

As the luteal phase advance in time, inhibin A, estradiol, and progesterone fall together with the increase in activin A. FSH increases in the transition from the luteal phase to the next follicular phase, beginning 4 days before menstruation, a stage in which inhibin B increases during follicular recruitment.

The concentration of activin A secreted by the follicles increases in the second half of the luteal phase [34] (**Figure-18**), decreases at the beginning of the follicular phase, increases during the early follicular phase, and then increases during the middle follicular phase in parallel with estradiol and inhibin A (**Figure-19**).

In older women, FSH is higher, even during nadir, and the increase occurs early during the luteal phase. Recruitment of a group of follicles begins early, but the selection of DF is altered and can either advance or delay. The result is the variability of the cycle at the expense of a variable follicular phase, called "lag phase," which ends when the ETO is produced [35].

The ETO is when the estradiol overt elevation is achieved, which marks the selection of the FD. If an FD capable of ovulating was not achieved, the woman can go through a hyperestrogenic state without establishing a corpus luteum, so at the endometrial level, the cycle is hormonally monophasic. This is the pathophysiological basis that explains the monophasic hyperestrogenism that affects approximately one-third of women in perimenopause- (**Figure-20**).

 **Figure-19.-**Scheme composed shows luteal events, follicular ones and hormonals during luteal phase of woman CL-=corpus luteum; DF-=dominant follicle; WEM1–3-=wave emergency 1, 2, or 3 at the cycle; the waves of follicle of light gray color indicates the low frequency of the principal waves (selection of DF) during luteal phase or early follicular ones in women of 2 or 3 waves. The estradiol rise in the follicular phase begins after the emergence of the ovulatory DF and becomes more rapid following DF selection, and occurs earlier in women with 2 versus 3 follicle waves per cycle. After ovulation, estradiol concentrations increase to the mid-luteal phase (days 7–9 after ovulation) and then decline, and this is due to luteal estradiol secretion and is unaffected by minor or major anovulatory waves. Adapted from Macklon and Fauser [5].

**Figure-20.-**The variability in perimenopause depends on the lag phase, a delayed recruitment process. Adapted from Hale etal. [35].

A chronic negative energy imbalance reduces the pulsatility of LH, generates atresia of FD and, consequently, anovulation and amenorrhea. Weight loss is associated with a reduction in LH pulses, which generates functional, reversible hypothalamic amenorrhea. On the contrary, the pulsatility of LH is increased in adolescents with irregular cycles or in women with polycystic ovary syndrome, associated with anovulation also, but here the selection of DF is absent.

#### **7. Conclusion-**

Human reproduction depends on the integrity of a system of intracrine and paracrine signals within the ovaries, in which those recruited follicles that have reached a level of differentiation that make them sensitive to the endocrine control of the other distant and great actor, the hypothalamus axis participate pituitary. Once a dominant follicle has been achieved, the elevations of the circulating levels of estradiol and inhibin B produced by it will modulate FSH levels and will allow, on the one hand, the atresia of the other follicles, and on the other, they will facilitate the LH surge, necessary to trigger ovulation. After hatching, the surrounding theca and granulosa cells from the follicular bed abandoned by the newly ovulated egg interact to produce a corpus luteum, which retains sufficient steroidogenic properties to produce progesterone at the concentration required to regulate the endometrium, till the implantation of a fertilized egg. If pregnancy does not occur, since the end of the luteal phase, gonadotropic changes are prepared to allow the development of a follicular recruitment phase.

Being such a complex process, dependent on so many variables and exposed to so many actions, reactions and interferences, the sequences of the menstrual cycle are remarkably predictable within not very wide ranges of variability. In general, the duration standards of each cycle, 25–35days, coincide with the ovulation presumption criteria accepted for women with ovulatory anomalies such as in the polycystic ovarian syndrome. The detailed understanding of the mechanisms allow to improve the efficiency in the clinical management when it is intended to give assistance to obtain a pregnancy, as well as to avoid it when the goal is contraception, or to correct bleeding anomalies that may result from ovulatory disorders with luteal insufficiency. There are still many aspects to investigate.-

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

The authors declare no conflict of interest in relation to this publication.-

#### **Author details-**

Barriga-Pooley Patricio1 \* and Brantes-Glavic Sergio2

\*Address all correspondence to: pbarriga@uft.cl

1 Obstetrics and Gynaecology Department, School of Medicine, Finis Terrae and San Sebastian Universities, Santiago, Chile

2 Depto Ginecología y Obstericia, Universidad de Chile, Santiago, Chile

#### **References-**


#### **Chapter 3**

## **Pre Menstrual Syndrome**

Preye Fiebai, Avwebo Ochuko Ukueku and Rosemary Ogu

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80492

#### **Abstract**

Approximately 80–90% of women experience some symptoms in the premenstrual period at some point in their reproductive years. Teenagers often present with moderate to severe symptoms, while women in the fourth decade of life appear to have worse symptoms with the severity of the disease worsening with increasing age up until menopause. Obesity and smoking have also been identified as risk factors. Symptoms could be physical, psychological, emotional, environmental and/or behavioral and affect the ability to perform normal daily activities as well as adversely affect interpersonal relationships. Though several theories have been propounded, the exact cause of premenstrual syndrome is unknown. Management of this disorder requires a multi-disciplinary approach involving the general practitioner, the general gynecologist or a gynecologist with a special interest in PMS, a mental health professional (psychiatrist, clinical psychologist or counselor), physiotherapist and dietician.

**Keywords:** menstruation, psychosomatic menstrual syndrome, girls

#### **1. Introduction**

A syndrome is a group of symptoms and/or signs associated with a medical disease or disorder, often occurring concurrently. Premenstrual syndrome (PMS) can be defined as a group of physical and emotional symptoms and signs usually occurring within the last 14 days of the menstrual cycle, that is, from ovulation to the onset of menstruation, of sufficient severity to result in deterioration of interpersonal relationships and affect normal activities [1]. The symptoms span a range of medical specialties; from the gynecological to the psychiatric. PMS is included as a diagnostic category in the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD) with its' more "severe" form,

© 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.

Premenstrual Dysphoric Disorder (PMDD), included in the 5th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM) [1, 2].

Premenstrual syndrome became a recognized medical disorder over the last century. It was initially thought to be an 'imagined' disease all in the heads of 'crazy' women [3]. Later it was presumed that the female reproductive organs had complete control over the woman and energies diverted from reproductive organs caused suboptimal functioning as such women involved in manual labor required more treatments than those who only exercised their brains [4]. Till date, symptoms of PMS are often viewed with skepticism or used in mockery of the female sex or the idealism of gender equality such that many females who suffer from this condition are unwilling to seek help or even admit to having difficulty managing the psychological symptoms associated with their menstrual cycles. This chapter methodology derives from a synthesis of the available literature under the MESH search term premenstrual and focus group discussion of women attending a tertiary health facility in Southern Nigeria.-

Premenstrual syndrome was named by a British physician Katharina Dalton in 1953 [5]. PMS psychological symptoms had been described as early as the time of the ancient Greeks, but it wasn't until 1931 that this disorder was recognized by the medical community. This diagnosis was made popular by a paper presented at the New-York Academy of Medicine by Robert T. Frank titled "Hormonal Causes of Premenstrual Tension" [6]. Robert Frank theorized that excess estrogen levels were the cause of symptoms experienced by affected women. In 1981, Dalton served as the chief defense medical expert in a murder trial in London. She successfully argued that the defendant was not responsible for murdering her lover because she suffered from severe PMS.-This trial caught the attention of different viewers in the United States and brought publicity to PMS.-PMS or the "disease of the 1980s" became a media event. More importantly, PMS acquired medical legitimacy, "after years of telling women their problems were 'all in the head,' the proportion of doctors who accepted PMS as a real disease reached critical mass" [7].

## **2. Epidemiology**

Approximately 80–90% of women experience some symptoms in the premenstrual period at some point in their reproductive years. However, only 20% of these women meet the diagnostic criteria for PMS, of these; 10% are severely affected and 3–8% have PMDD [1].

Teenagers often present with moderate to severe symptoms, 14–88% of teenage girls are affected, with the older teenagers more likely to have symptoms than the younger teenagers.- PMS and PMDD are associated with a higher risk of Anorexia nervosa, Bulimia nervosa and- substance abuse. It is also more likely to occur in women who have suffered some form of- abuse (emotional, physical or sexual) in early life or are presently in abusive relationships [8, 9].

Women in the fourth decade of life appear to have worse symptoms, and the severity of the disease tends to worsen with increasing age up until menopause. There is also an increased risk of hypertensive disorders in affected patients later in life.-

There is evidence of genetic predisposition to the disease as women whose mothers suffered from PMS are at higher risk of having the disease, and also monozygotic twins have a 93% rate of PMS compared with 44% in dizygotic twins [9]. Symptoms also vary with race; while black women often experience a higher prevalence of food cravings than white women, the white women often experience a higher prevalence of mood swings and weight gain [10].

Obesity and smoking have also been identified as risk factors for this condition. Women with body mass index more than 30, are three times more likely to have PMS than non-obese women and women who smoke are more than two times likely to present with severe symptoms [10, 11].

## **3. Clinical presentation**

PMS symptoms tend to occur in a cyclic pattern from ovulation to onset of menstruation. Symptoms could be physical, psychological/emotional, environmental and/or behavioral [12, 13]. Over 200 symptoms have been described. Symptoms and signs tend to affect a patient's ability to perform normal daily activities and adversely affect their interpersonal relationships. Occasionally it results in violence in the home and broken marriages as well as loss of a woman's economic means in society. In a focus group discussion carried out among women attending a tertiary health facility in Southern Nigeria, premenstrual syndrome was viewed as a curse because of its myriad of symptoms.

Physical symptoms include the following:

Headaches- Acne Breast tenderness Abdominal bloating Diarrhea or constipation- Joint and muscle pains Fatigue Weight gain (from fluid retention)-Swelling of the extremities- Dysmenorrhea- Change in bowel habits Frequent urination Hot flashes or cold sweatsGeneral aches or pains (malaise)- Nausea and vomiting- Allergic reactions Upper respiratory tract infections- Palpitations Unusual food cravings- Low tolerance for noise, odors or light Psychological/emotional symptoms include the following:

• Anxiety symptoms such as:

Difficulty sleeping-

Tense feelings

Irritability-

Clumsiness

Mood swings

Panic attacks-

Paranoia

• Depressive symptoms such as:-

> Depressed mood and affect-

Angry feelings for no reason

Feelings that are easily upset

Poor concentration

Memory loss

Feelings of low self-worth

Violent feelings and/or action

Crying spells

Social withdrawal-

Changes in appetite

Changes in libido

Mental health disorders are worsened or exacerbated by PMS.-These include depression and anxiety disorders. Other medical conditions whose symptoms may be worsened by PMS include; myalgic encephalomyelitis or chronic fatigue syndrome, irritable bowel syndrome and bladder pain syndrome. Health problems such as asthma, allergies and migraines may also worsen with this disease. Patients with PMS may also experience heavy menstrual bleeding and early menopause.

## **4. The pathophysiology of premenstrual syndrome**

The exact cause of premenstrual syndrome is unknown and is the subject of much ongoing research. Several theories have been proposed; from sex hormones interactions to neurotransmitters interactions in the central nervous system. Older theories that have proven to be incorrect include estrogen excess or withdrawal, progesterone deficiency (these were the initial sex hormones theories),- pyridoxine (vitamin B6) deficiency, alteration of glucose metabolism, fluid-electrolyte imbalances.- Current research provides some evidence supporting the following etiologies:

#### **4.1. Sex hormone**

Symptoms of premenstrual syndrome begin following ovulation and resolve with menses, and because they only affect women in reproductive age, it is assumed that the female gonadal hormones (estrogen and progestogen) have a role in the pathophysiology of the disease. This is underscored by the facts that symptoms are less common in women with surgical oophorectomy or drug-induced ovarian hypofunction, such as with gonadotropinreleasing hormone (GnRH) agonists. Moreover, women with anovulatory cycles rarely report PMS symptoms. For these reasons, research of PMS pathophysiology has focused on the sex steroids, estrogen and progesterone. However, no propounded theory so far has borne fruit.-

#### **4.2. Serotonin deficiency-**

It is postulated that patients with PMS suffer from lower serotonin level in the luteal phase, which may or may not be as a result of the various interactions of the sex hormones. It has been proven that patients most affected by symptoms of PMS have differences in serotonin levels when compare to others. This evidence supports a role for serotonergic system dysregulation in the pathophysiology of PMS.-Moreover, trials of serotonergic treatments have shown symptom reduction in women with PMS, symptoms respond to selective serotonin reuptake inhibitors (SSRIs), which increase the levels of circulating serotonin.-

#### **4.3. Central nervous system interaction**

Estrogen and progesterone are neuroactive steroids and influence the central nervous system (CNS) neurotransmitters: serotonin, noradrenaline, and γ-aminobutyric acid (GABA). The predominant action of estrogen is neuronal excitability, whereas progestogens are inhibitory. Women with PMS have exaggerated responses to normal levels of these hormones, and rapid changes in the levels of these hormones as is experienced in the luteal phase of the menstrual cycle promote the development of symptoms.

#### **4.4. Nutrient deficiencies-**

Magnesium and calcium deficiencies have been hypothesized to be causes of PMS symptoms. Studies evaluating supplemental therapies have shown improvement in symptoms.-

#### **4.5. Psychosocial theory**

The psychosocial theory postulates that PMS is a conscious demonstration of a woman's conflict with her femininity and motherhood. It suggests that the premenstrual physical changes remind the woman that she is not fulfilling her traditional role of incubating, nurturing, and rearing a child. This theory is highly subjective and scientifically unprovable.-

#### **4.6. Sociocultural theory**

The sociocultural theory postulates that PMS is a manifestation of a conflict between the societal expectation of the dual role of a woman as both a productive part of the workforce and a mother. It suggests that PMS is a cultural expression of women's dissatisfaction with their traditional roles in society.

#### **4.7. Cognitive and social learning theory**

This theory suggests that the onset of menstrual bleeding is an adverse psychological outcome for some women and PMS is a display of maladaptive coping strategies in other to reduce immediate stress.

## **5. Diagnosis of premenstrual syndrome**

Diagnosis of PMS can often be difficult because may medical and psychological conditions mimic the symptoms, and there are no laboratory tests to confirm the diagnosis. Women with PMS usually present with complaints from multiple systems, and these symptoms display temporal association with the menstrual cycle luteal phase. Symptoms must begin at least 5 days (American College of Obstetricians and Gynecologists [ACOG] criteria) [8] or 1 week (DSM-IV-TR) before menses, and remit within 4 days (ACOG criteria) or a few days (DSM-IV-TR) after menses onset [2]. Evaluation of women complaining of PMS symptoms includes prospective daily symptom rating for at least two or three menstrual cycles.

A menstrual diary could be used to record the onset and duration of symptoms of PMS- for 2–3 cycles; this not only helps the physician make the diagnosis but also increases the patient's awareness of her body and moods. She is thus, better at coping with her symptoms. The Endicott Daily Record of Problem Severity chart or the Daily Symptom Rating- are tools that can be used to assess the frequency and severity of symptoms described in the luteal phase as against those experienced in the follicular phase of the menstrual cycle [14].

 A within-cycle increase from follicular to luteal phase score of at least 20–50% is necessary- to confirm a diagnosis of PMS.-This is calculated by subtracting the follicular score from the- luteal score, divided by the luteal score and multiplied by 100 (luteal score-− follicular score/ luteal score × 100).

A physical examination may identify some of the physical symptoms and signs of the disease. In certain instances, PMS symptoms may be an exacerbation of underlying primary psychiatric condition(s). Thus, a psychiatric evaluation may help rule out other common psychiatric conditions such as depression, dysthymia, and anxiety disorders. Additionally, other medical conditions that have a multisystem presentation should be considered. These include hypothyroidism, systemic lupus erythematosus, endometriosis, anemia, fibromyalgia, chronic fatigue syndrome, fibrocystic breast disease, irritable bowel syndrome, and migraine. Laboratory studies should include complete blood count, thyroid function tests and gynecological hormone profile.-

## **6. Premenstrual dystrophic disorder (PMDD)**

This is a condition in which a woman has severe depressive symptoms, tension and irritability before menstruation. It is a more severe form of PMS that affects a small percentage of women- within reproductive age resulting in remarkable disability and loss of function. Symptoms- are of sufficient severity as to interfere with work or school, social activities, interpersonal- relationships and quality of life. Patients complain of similar symptoms as seen in PMS but- of increased severity. Most symptoms of PMDD are similar to symptoms of a major depressive disorder (MDD). These symptoms, however, are cyclic and disappear with the onset of- menses. The most common symptoms of PDMM are irritability, limited concentration, sleep- disturbance, mood lability and marked depressed mood. Similarities to MDD are highlighted- below.


#### **7. Diagnosis**

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition established 7 criteria for diagnosis of PMDD [2] (A–G).-

#### **7.1. Criterion A**

In Criterion A in most menstrual cycles during the past year, 5 out of 11 symptoms listed must be present (including one of the first four) in the last 1–2weeks before the onset of menses and disappear in the week post-menses. These symptoms are as follows:


#### **7.2. Criterion B**

One of the following symptoms must be present:


#### **7.3. Criterion C**

One or more of the following symptoms must be present additionally, to reach a total of five symptoms when combined with Criterion B.


Note: the symptoms in criteria A–C must be met for most of the menstrual cycles in the preceding year.

#### **7.4. Criterion D**

The symptoms are associated with clinically significant distress or interference with work, school, usual social activities or relationship with others (e.g. avoidance of social activities, decreased productivity and efficiency at work, school, or home).-

#### **7.5. Criterion E**

The disturbance is not merely an exacerbation of the symptoms of another disorder, such as a major depressive disorder, panic disorder, persistent depressive disorder (dysthymia) or a personality disorder (although it may occur concurrently with any of these disorders).-

#### **7.6. Criterion F**

Prospective daily ratings during at least two symptomatic cycles should confirm Criterion A. (Note: the diagnosis may be made provisionally prior to this confirmation).-

#### **7.7. Criterion G**

The symptoms are not attributable to the physiological effects of a substance, (e.g. substance abuse, a medication, or other treatment) or another medical disorder (e.g. hyperthyroidism).-

#### **8. Management**

#### **8.1. Patient education/counseling**

PMS may cause significant distress for patients especially the adolescents and as such providing patients with adequate information on the disease including alternative therapies is imperative. Management of this disorder requires a multi-disciplinary approach involving the general practitioner, the general gynecologist or a gynecologist with particular interest in PMS, a mental health professional (psychiatrist, clinical psychologist or counselor), physiotherapist and dietician.

#### **8.2. Life style and dietary changes**

Treatment of PMS is majorly according to the severity of symptoms [8, 12, 13, 15]. Regular exercise and dietary restrictions often reduce symptoms. Obese patients should be encouraged to join a weight management program. Dietary modification is often a part of the overall treatment regime. Patients are encouraged to consume smaller meal portions high in carbohydrates. Patients should be counseled to avoid salt, caffeine, alcohol and simple or refined sugars. Exercise and physical activities cause a release of endorphins which improve general health, nervous tension and anxiety.

#### **8.3. Behavioral anger and stress management therapies**

This may help patients cope and or regain control during times of heightened emotions. A variety of methods may be employed. These include; emotional support from family and friends, individual and couples' therapy, self-help support groups, anger management courses, stress management classes, as well as cognitive-behavioral therapy. Our clients described emotional support from family and friends as very helpful. Relaxation techniques such as yoga, biofeedback and self-hypnosis are also be helpful.

#### **8.4. Supplements**

These include but are not limited to calcium and magnesium supplements, vitamin E and B6, and polyunsaturated fatty acids (omega-3 and omega-6). Some alternative medicines/herbal supplements have been used to ease PMS symptoms with varying reports of success. These include; Black cohosh, Chaste berry (or vitex agnus-castus), Evening Primrose oil, St John's Wort and Dandelion. Research has shown that for these remedies to be effective, they need to be taken for at least two consecutive cycles. However, some of these remedies may be toxic and cause liver damage at high doses.

#### **8.5. Medications**

Various medications have been used to address the moderate to severe symptoms of PMS including:

*Diuretics*: These are often given to eliminate excess fluid. For example, spironolactone is widely used to treat swelling of the hands, feet and face.

*Hormonal therapies*: Some women benefit from combined oral contraceptives. The newer formulations (drospirenone-containing COCPs) control the fluctuations of the sex hormones reducing symptoms of PMS.-The Mirena Intrauterine System releases low doses of progesterone and suppresses ovulation reducing the symptoms of PMS; however, it may initially induce PMS-like symptoms. Depo-Provera has a similar mechanism of action. Percutaneous estradiol combined with cyclical progestogens has been found to be useful in managing both physical and psychological symptoms of PMS.-

*Gonadotrophin-releasing hormone (GnRH) analogues and agonists*: These are ovarian hormone suppressors, by suppressing the release of the sex hormones from the ovaries, they reduce the symptoms of PMS.-GnRH analogues are highly effective in treating symptoms of severe PMS. An- example of a GnRH analogue is danazol, and a GnRH agonist is goserelin. However, use of these- therapies for greater than 6 months is associated with increased risk of osteoporosis and irreversible virilizing effects; therefore, in women receiving GnRH analogues for more than 6 months,- add-back hormone therapy should be given. COCPs should be given or tibolone is recommended.

*Analgesics and anti-prostaglandins*: These are commonly used to treat menstrual cramps, headaches, breast tenderness and pelvic discomfort. Non-steroidal anti-inflammatory drugs like ibuprofen, naproxen and mefenamic acid have been very useful. However, long-term use may predispose patient to gastric ulcers.

*Antidepressants*: These increase levels of neurotransmitters and excitatory chemical in the brain (e.g. serotonin, GABA, opioids). They help treat mood disturbances associated with PMS.-Examples include; fluoxetine and paroxetine.-

*Selective serotonin reuptake inhibitors* (*SSRIs*) *and selective noradrenaline reuptake inhibitors*  (*SNRIs*): These are mood stabilizers with antidepressant effects. There increase the levels of serotonin and noradrenaline in the brain, both of which tend to decrease in the luteal phase in women with PMS.-

#### **8.6. Bilateral oophorectomy**

In extreme cases, especially when the patient's quality of life is affected as seen in PMDD, and knowing the disease worsen with age, patients may be counseled for a bilateral oophorectomy and hysterectomy. This is especially recommended for patients who have completed their reproductive careers or patients who have severe symptoms unresponsive to all other therapies. It, however, tilts the women into early menopause with its problems as such hormone replacement therapies (HRT) should be considered. Bilateral oophorectomy without removal of the uterus will necessitate the use of a progestogen as part of HRT which carries the risk of PMS-like symptoms.-

### **9. Conclusion**

Premenstrual syndrome is a disease very prominent among women of reproductive age. It is not to be dismissed, taken for granted or treated with skepticism. There are therapies to end the sufferings of affected women. It is essential that we treat these women in other to promote their health, the health of the family and to sustain the economic productivity of women in our communities.

## **Author details**

Preye Fiebai1,2, Avwebo Ochuko-Ukueku<sup>2</sup> and Rosemary-Ogu1,2\*

\*Address all correspondence to: rosemary.ogu@uniport.edu.ng

1 University of Port Harcourt, Port Harcourt, Nigeria-

2 University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria-

## **References**

