Causative factors of congenital nephrotic syndrome (CNS) in 0–3 months of age.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
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\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Nephrotic syndrome is a general type of kidney disease seen in children. Historically, Roelans is credited with the first clinical description of nephrotic syndrome in the late fifteenth century. Nephrotic syndrome is appropriate to excessive hypoalbuminemia, proteinuria, and edema, although additional clinical hyperlipidemia is also usually present. The beginning of adrenocorticotropic hormone and cortisone in the 1950s contributed to an even greater decrease in mortality (to 9%), which was noted to occur in association with dramatic resolution of proteinuria.
The childhood nephrotic syndrome is principally idiopathic or primary, though a limited number of cases are secondary to glomerular and inclusive diseases and other infectious agents. Age reliant is also the etiology factor of nephrotic syndrome. Maximum cases presenting in the first 3 months of lifespan are mentioned as CNS (congenital nephrotic syndrome) and are caused by genetic diseases. While in the remaining of the first year of lifecycle (3–12 months) there has been no effective study of the etiology of nephrotic syndrome reported cases, there are a number of stats shows that up to 40% of reported cases meanwhile this time may also be due to genetic factors [1]. At the time of first year and in the first decade of life, maximum presenting cases are due to primary or idiopathic nephrotic syndrome, at the time of first 10 years of lifecycle the number of secondary nephrotic syndrome cases increases.
Congenital nephrotic syndrome is the type of nephrotic syndrome which occurs in first 3 months of life and is due to genetic causes mostly by alterations in the gene encrypting nephrin, a podocyte opening diaphragm protein. For the first time, these mutations were expressed in the Finnish, from then the name congenital nephrotic syndrome of the Finnish type (CNF) [1]. Though the incidence of CNF is high in Finland it also occurs in other populations also. Congenital nephrotic syndrome is not either equivalent with CNF, reason is that alterations in other genes encrypting podocyte opening diaphragm proteins, early-onset nephrotic syndrome can also be caused by proteins such as podocin. Upto 40% of all cases of nephrotic syndrome occurring in the first 3 months of life are due to alterations in a sequence of podocin gene [2] in the earliest 3 months of life. Nephrotic syndrome may also be part of multisystemic syndromes such as nail-patella syndrome, Pierson syndrome, Denys-Drash syndrome, and others or a sequence of congenital infections such as cytomegalovirus and syphilis (Table 1).
Genetic | Mutation in nephrin (NPHS1) gene leads to congenital nephrotic syndrome of the Finnish type (CNF) Mutation in podocin (NPHS2) gene results Autosomal recessive FSGS Mutation in WT1 gene results Autosomal dominant diffuse mesangial Sclerosis (DMS) Mutation in laminin β2 gene leads Congenital nephrotic syndrome |
Syndromes | Nail-patella syndrome due to mutation in LIM homeodomain protein (LMX1B) Jeune’s syndrome Galloway Mowat syndrome Denys-Drash syndrome due to WT1 mutation with DMS Pierson syndrome Schimke immunoosseous dysplasia with FSGS due to mutation in SMARCAL1 Cockayne syndrome |
Idiopathic | Nonsyndromic DMS Minimal change nephrotic syndrome FSGS |
Infections | Congenital toxoplasmosis Congenital cytomegalovirus (CMV) infection Congenital syphilis |
Causative factors of congenital nephrotic syndrome (CNS) in 0–3 months of age.
Above the infancy and above the first year of life, maximum of the nephrotic syndrome cases are idiopathic. MCNS (Minimal-Change Nephrotic Syndrome) is the most usual deviation, and is responsible for more than 80% of all cases [3]. Focal segmental glomerulosclerosis (FSGS), Membranoproliferative glomerulonephritis (MPGN), and mesangial multiply glomerulonephritis are the other less common histopathologic types in this age group (Table 2). For a few cases in this age group genetic disease is also responsible. 10–25% of all cases of familial and sporadic SRNS were caused by mutations in NPHS2, inherited in an autosomal genetic mode, because it was exposed in one series. Beginning of nephrotic syndrome in untimely childhood, not response to steroid treatment, strong findings of focal segmental glomerulosclerosis (FSGS) on histopathology renal biopsy, progress to ESRD in 5 years of finding, and comprehensively decreases the risk of disease recurrence following renal transplantation are by the phenotype typically associated with NPHS2 mutations [4, 5]. Additional genetic factors consists autosomal dominant transmitted causes such as α-actinin 4, mutations in the Wilms’ tumor suppressor gene (WT1), TRPC6 and CD2AP [6, 7, 8, 9, 10]. Individually from those in WT1, maximum of these mutations go to result in adult-onset disease. To a number of systemic diseases in children, nephrotic syndrome may also be secondary. Pediatric diseases such as Henoch-Schönlein purpura; diabetes mellitus; systemic lupus erythematosus, especially membranous (WHO Class V) SLE; and sarcoidosis may all exist with nephrotic syndrome. Infective factors can also cause nephrotic syndrome and can be bacterial, viral, or parasitic. Despite it is not so far fully known how these factors cause nephrotic syndrome, it is maybe due to an bizarre immune response to them in the majority of the reported cases, occurring in the progression and aggregation of immune complexes in the glomerulus. The interpretation of these factors as a cause of nephrotic syndrome turn to parallel their prevalence in demanding regions of the world. For example, in Hong Kong and countries in Africa, hepatitis B and C are important causes of nephrotic syndrome [11, 12]. In areas where malaria is endemic, Malaria, particularly quartan malaria, is also an important cause. Eighteen nephrotic syndrome in both adults and children can be caused by Human immunodeficiency virus (HIV).despite the renal abrasion linked with HIV can be changeable, FSGS is the most common histologic finding affiliated with HIV is, particularly the breakdown is different. Despite the result of treatment of the underlying infection on the nephropathy is not well known, but there are details that hepatitis B-associated nephrotic syndrome may be cooperative to treatment of the hepatitis [13]. A list of infective factors associated with nephrotic syndrome is shown in Table 2. Drugs such as angiotensin converting enzyme inhibitors (ACEIs), penicillamine, gold, nonsteroidal antiinflammatory drugs (NSAIDs), sickle cell disease, bee stings, lymphoma, leukemia, and various types of food allergies are the other less common causes of nephrotic syndrome. Moreover, in children with obesity the nephrotic syndrome is being seen further recurrently. The histologic scrape most frequently occurs in this setting is FSGS.
Idiopathic | C1q nephropathy IgM nephropathy Membranous nephropathy (MN) Membranoproliferative glomerulonephritis (MPGN) Minimal change nephrotic syndrome (MCNS) Focal segmental glomerulosclerosis (FSGS) Mesangial proliferative glomerulonephritis |
Hereditary | Mutation in WT1 gene results autosomal dominant diffuse mesangial Sclerosis (DMS) Mutation in gene encoding transient receptor potential cation channel 6 (TRPC6) results Autosomal dominant FSGS Mutation in gene encoding CD2-associated protein (CD2AP) results autosomal dominant FSGS Mutation in gene encoding α-actinin 4 leads to autosomal dominant FSGS Mutation in podocin(NPHS2) gene results autosomal recessive FSGS |
Drugs | NSAIDs Penicillamine ACEIs Pamidronate Gold Lithium Mercury Interferon Heroin |
Metabolic diseases | Glutaric acidemia Mitochondrial cytopathies Glycogen storage disease Fabry’s disease |
General diseases | Systemic lupus erythematosus Sarcoidosis Diabetes mellitus Henoch-Schönlein purpura |
Blood and oncologic diseases | Lymphoma (Hodgkin’s most likely can lead to minimal change) Leukemia Sickle cell disease |
Infections | HIV Malaria Filariasis Schistosomiasis Hepatitis B and C |
Others | Food allergies Obesity (usually with FSGS) Bee stings (MCNS) Pregnancy Oligomeganephronia |
Causative factors of nephrotic syndrome above 3 months of life.
The development of massive proteinuria is the central abnormality in all cases of nephrotic syndrome. Some of the literature shows the evidence in that nephrotic syndrome may be a significance of glomerular defect, circulating factors, and defect in immunological system.
The most important possible functions of the kidney is the filtration of blood and blood products at glomeruli, which permits the fluid and dirty products while retaining the greater part of blood proteins and all blood cells within the vasculature. These types of process of filtration is made potential by the (GFB), which is made up of specific glomerular epithelial cells (podocytes), endothelial cells, and GBM these distal bottom actions are attached to the GBM (Figure 1) [14]. Adjacent podocyte bottom actions are associated to each one other by networks of specific cell-cell junctions called as opening diaphragms. Additionally, the GBM (glomerular basement membrane) has a plentiful supplies of negatively charged molecules of heparin sulfate proteoglycan, resultant in these negatively charged heparin sulfate proteoglycan controlled from passage than positively charged molecules with same particles [15]. General healthy system, particle more than 42 Å in diameter is not capable to enter into the GFB [16]. This kind of restrictions based on mostly structural reliability of the podocyte bottom actions and opening diaphragms, by means of the charge of GBM. Loss of negative charge of the GBM occurs in nephrotic syndrome [17, 18, 19]. The confirmation, swelling and diffusion podocyte binds to bottom actions, dislocation of opening diaphragms, occurrence of filling junctions, vacuole formation, and deficiency of inclusion of podocytes from the GBM, these type of morphologic changes in podocytes that occur during progress of nephrotic syndrome [20, 21, 22, 23]. Mutations in genes encoding some of the opening diaphragms proteins or their transcription factors can cause SRNS and/or FSGS. This mechanism of nephrotic syndrome is additional reinforced by recent observations in humans and experimental animals [4, 10, 11, 14, 24, 25, 26]. The subject of many recent reviews in the literature this type of result have been discussed [27, 28, 29]. In infants mutations in the gene encoding the opening diaphragms protein nephrin (NPHS1) mostly causes CNF. In addition, in children mutations in NPHS2 are estimated to be responsible for up to 25% of cases of sporadic familial and Steroid resistant nephrotic syndrome (SRNS) [10, 25]. Frasier syndrome and Denys rash syndrome in children occurs due to Mutations in the transcription factor suppressor gene WT1 [30, 31, 32]. Mutations in (1) CD2-associated protein (CD2AP); (2) the LIM-homeodomain protein (encoded by LMX1B), which leads to in nail-patella syndrome; (3) the actin-bundling protein α-actinin 4, which leads to adult-onset FSGS; which results in adult-onset FSGS; (4) laminin β2, which results in Pierson syndrome and (5) the chromatin regulator encoded by SMARCAL1. [25, 33, 34, 35].
Components of the glomerular filtration barrier (GFB) during normal glomerular filtration, electron micrographic view.
Some of soluble mediators that may alter capillary wall permeability in nephrotic syndrome proved by investigational data to carry the existence [37, 38, 39] show to be true for this includes (1) scared decrease of proteinuria subsequent treatment with protein A immunoadsorption in of primary nephrotic syndromes [24], (2) progress of nephrotic syndrome in child babies born to mothers with nephrotic syndrome who actually transferred a soluble factor to their fetuses in utero [39], (3) decrease of repeated disease induced by treatment with protein A immunoadsorption due to presumed removal of circulating factors in the reappearance of FSGS in transplanted kidneys in patients with primary FSGS [40], and (4) FSGS recurrence in transplanted kidney patients serum injected in to the experimental animals leads to causing of enhanced glomerular permeability [32] serum of children with FSGS and recognized as components of apolipoproteins, from the suggestive of that an imbalance involving serum permeability factors and permeability inhibitors may have a pathogenic role in FSGS. Moreover, inhibitors of glomerular permeability have also been isolated [33].
For more than 30 years nephrotic syndrome may be because of abnormalities of the immune system has existed. Both the humoral and cellular immune responses are abnormal during relapse of nephrotic syndrome. Still, have a thought that relationship between the nephrotic syndrome and T lymphocyte function was first proposed by Shalhoub and his colleagues and concluded that abnormalities in cellular immune responses [36] proves for this includes (1) sensitivity of most forms of primary nephrotic syndrome to mycophenolate mofetil, corticosteroids, calcineurin inhibitors, and alkylating agents, these drugs all are inhibitors of T lymphocyte purpose, (2) mostly measles and malaria, diseases well-known to slow down the cell-mediated immunity following remission of nephrotic syndrome, and (3) detection of Minimal-Change Nephrotic Syndrome (MCNS) as a paraneoplastic manifestation of lymphoreticular malignancies and other Hodgkin’s disease. Latest reported cases have also suggested and vital role of the cell-mediated immune system in nephrotic syndrome, collectively with depressed cell-mediated immunity during relapses of MCNS alterations in T cell subsets during relapses and increased cell surface expression of IL-2 receptors on T cells, reflective of T cell activation [34, 41]. Additionally, a number of cytokines, released in part by T lymphocytes, have been recommended to be erratically changed throughout nephrotic syndrome (NS) [42, 43].
In children with nephrotic syndrome facial or general edema, is the basic symptom due to accumulation of fluid in the interstitial compartment. In nephrotic syndrome the edema is usually causes disproportionate proteinuria, which leads to retention of sodium and water, hypoalbuminemia to recompense for intravascular volume depletion. The pathogenesis of edema can be well explained by analysis of the classic Starling equation, which explains the regulation of fluid movement across capillary walls [44].
Net filtration = LpS (Δ hydraulic pressure − Δ oncotic pressure).
= LpS [(Pcap − Pif) − s(πcap − πif)].
where:
Lp = the capillary permeability.
S = the surface area of the capillary wall.
Pcap = the capillary hydrostatic pressure.
Pif = the interstitial fluid hydrostatic fluid pressure.
s = the reflection coefficient for proteins (0 = complete permeability and 1 = complete impermeability).
πcap = the capillary oncotic pressure.
πif = the interstitial fluid oncotic pressure.
The formation of edema is prevented in healthy patients by a balance between forces favoring edema (capillary hydrostatic pressure [Pcap]) and those opposing it (capillary oncotic pressure [πcap]). The slight tendency toward fluid accumulation is counterbalanced by the lymphatics in the interstitial space. In nephrotic patients hypoalbuminemia results when the liver fails to synthesize the loss of albumin through urine. The hypoalbuminemia results leads to low down capillary oncotic pressure (πcap), which leads to relatively unopposed capillary hydrostatic pressure (Pcap) and subsequent edema formation. Relative intravascular volume reduction is due to edema formation the intravascular volume which triggers neurohumoral compensatory mechanisms. Which includes sympathetic nervous system (SNS), arginine vasopressin (AVP), and the renin angiotensin aldosterone system (RAAS), with the net causes being sodium and water retention by the kidney. In the background of nephrotic syndrome, aortic arch, left ventricle, mechanoreceptors in the carotid sinus, and afferent arterioles in the glomeruli detect reduced pressure distension. This produce (1) SNS outflow increases from the central nervous system, (2) RAAS activation, and (3) nonosmotic release of AVP from the hypothalamus. These three changes lead to peripheral vasoconstriction (increased SNS and angiotensin II), sodium retention (angiotensin II, aldosterone, and increased SNS), and water retention.
As a result of these mechanisms, it is greatly accepted that patients with nephrotic syndrome have an excess of total body water and sodium. The condition of their intravascular volume is to some amount controvertible. Intravascular state in nephrotic is demonstrated by the following hypothesis: so-called overfill hypothesis and underfill hypothesis. The continuation of a reduced effective circulating blood volume in nephrotic syndrome is explained by underfill hypothesis (Figure 2). Due to activation of the RAAS with resultant of reduction in urinary sodium excretion and elevation of aldosterone levels, is most expectedly promoted by findings of low urine sodium in the presence of edema. The low urinary sodium [45] is due to reduction of atrial natriuretic peptide (ANP). Evidence, additionally for the underfill hypothesis includes betterment in sodium excretion with albumin infusion or head-out water immersion, and reduced cardiac output and increased vascular evaluated. It is possible that the overfilled state may be major in the chronic phase during which patients may have long-lasting sodium retention due to unrelenting low-grade hypoalbuminemia. But the underfilled state may be major in the acute setting in which excessive proteinuria causes rapid development of hypoalbuminemia and a gradual drop in plasma oncotic pressure.
Under fill hypothesis proposes the continuation of a reduced effective circulating blood volume in nephrotic syndrome. Pathophysiologic events leading to the formation of edema in nephrotic syndrome.
Supposed to be intravascularly volume-expanded as different to degree-constricted, founding whether a child is underfilled versus overfilled can be clinically important in the edema in children with nephrotic syndrome may be different. Depends upon the below urinary estimations comparison with elevated plasma vasopressin, renin, norepinephrine, aldosterone levels they are Single group has support to estimate the relative urinary potassium excretion [UK/(UK + UNa and)] absolute excretion of sodium (FENa) to elucidate the distinction. Nephrotic patients who are with high urinary potassium excretion (>60%) and a low FENa (<1%) would be probable to have a low intravascular load [46].
Causes of nephrotic syndrome are also age reliant. The majority of the cases reported in the first 3 months of life is referred to as congenital nephrotic syndrome (CNS) and are because of genetic diseases. While there has been no efficient study of the etiology of nephrotic syndrome presenting in the rest of the first year of life (3–12 months), there are data telling that up to 40% of cases during this time may also be due to genetic causes. While it is extensively accepted that patients with nephrotic syndrome have an excess of total body sodium and water as a result of these remunerative mechanisms, the status of their intravascular volume is to some extent controversial. Nephrotic syndrome was a variety of disease processes with heavy proteinuria and hypoalbuminemia at its main symptoms. Although ongoing research hard work in the mechanism of disease, first-line therapy has stay over relatively unaffected for decades, and corticosteroids drugs are the basis of treatment Most children have MCNS, which come through a good prognosis; renal failure is uncommon in patients with MCNS. The manner of patients with nephrotic syndrome is changeable, but most patients will have periods of relapse and remission. Guidelines published by the American Academy of Pediatrics and the KDIGO can guide the pediatrician in the treatment of MCNS. There are alternative to corticosteroid therapy that has had success in induction and/or maintenance of reduction, although findings are conflicting, necessitating additional multicenter trials to contrast these medications head to head. Hypotheses concerning the mechanisms of proteinuria and the possible association of glomerular structure to the nephrotic syndrome are discussed (Figure 3).
Pathophysiologic events leading to the formation of edema in nephrotic syndrome according to the overfill hypothesis.
None declared.
I am very much thankful to Dr. Manish Kumar Thimmaraju for his guidance, kind help and constant encouragement during progress of my work. I am also very thankful to my colleagues for the completion of this work.
NS | nephrotic syndrome |
CNS | congenital nephrotic syndrome |
CNF | congenital nephrotic syndrome of the Finnish type |
ESRD | end-stage renal disease |
GBM | glomerular basement membrane |
SRNS | steroid-resistant nephrotic syndrome |
MPGN | membranoproliferative glomerulonephritis |
FSGS | focal segmental glomerulosclerosis |
MCNS | minimal-change nephrotic syndrome |
RAAS | renin angiotensin aldosterone system |
SNS | sympathetic nervous system |
AVP | arginine vasopressin |
GFB | glomerular filtration barrier |
SRNS | steroid resistant nephrotic syndrome |
Menstrual cycle lasts 28 ± 7 days. Just a third of patients have cycles every 28 days and 82% fluctuations among 22 and 32 days [1].
\nA 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.
\nCycles 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.
\nThe 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.
\nThe 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.
\nIf there is no embryo implantation, the endometrium is detached giving rise to menstrual flow, which has normal volume parameters, up to 80 mL, in duration, 3–8 days, content, absence of clots and symptoms, and absence of pain.
\nIt is considered that the conserved cyclicity expresses that the hypothalamic-pituitary-gonadal axis is healthy. The ovaries do not alternate to ovulate.
\nOvarian 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.
\nWhen 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.
\nIn a woman fertility, among 38–40 years is lower than at 25–30 years. Atresia of oocytes is a continuous process that never stops not even with the use of anovulatory or pregnancy.
\nOocyte 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).
\nAt 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).
\nThe 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 37–38 years and near 500 during the postmenopause.
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.
\nOf the estrogens, the most potent is estradiol. The actions they develop are:
Female genital apparatus: they stimulate the growth and development of the female sexual organs and the proliferation of the endometrium during the sexual cycle.
Breast: they favor the growth of the mammary ducts and are, in part, responsible for the development of the mammary gland during puberty.
Bone: they regulate the osteoclastic activity and stimulate the osteoblastic activity, in such a way that they are essential to maintain adequate bone mineralization.
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.
\nFollicular 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).
\nThe 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 beta-estradiol concentrations of progesterone and estradiol decrease, menstruation begins a new cycle, unless a pregnancy has been established.
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].
\nDynamic scheme of follicular activity and the changes in gonadotropins, steroids, and inhibins during follicular phase of menstrual cycle.
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.
\nThe remaining 1% has codominance, that is two dominant follicles, which eventually can generate a double ovulation at the risk of a multiple pregnancy.
\nIn 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 34 days.
Changes that normally occur during the fertile lifespan, between the menarche to menopause. Some women may have long and irregular cycles, many times associated to abundant uterine bleeding, at the first 2 years after to menarche and 4–6 years that precede menopause.
Besides there is a wide range of presentation for both phases of the cycle, the follicular phase may last from 10 to 23 days and luteal phases could last between 7 and 19 days. Only 10% of women with a cycle of 28 days shows follicular and luteal phase of 14 days. The variability depends more on follicular phase, which vary ±3–7 days with time, depending on the estrogen take off (ETO), at the beginning of the middle follicular phase on each cycle, which is the main explanation for the duration of cycles.
Finally, despite of normal length in their cycles, 7% of women of 25–39 years may show anovulation, even though is more frequent to observe shorter cycles or longer ones, especially in early postmenarche and premenopause (60% between 10 and 14 years and 34% older than 50 years) as seen in Figure 5.
Other environmental, ethnic, or even socioeconomic factors may affect the duration of the cycle and bleeding.
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 et al. [3].
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.
\nTime 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.
\nDuring 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).
\nDiameter 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].
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.
\nThe 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).
\nThere 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].
\nAt Table 1, production rates are presented for sexual steroids during follicular phase, luteal phase at the moment of ovulation.
\nSex steroids* | \nEarly follicular | \nPreovulatory | \nMid-luteal | \n
---|---|---|---|
Progesterone (mg) | \n1 | \n4 | \n25 | \n
17α-Hydroxyprogesterone (mg) | \n0.5 | \n4 | \n4 | \n
17α-Hydroxyprogesterone (mg) | \n7 | \n7 | \n7 | \n
Androstenedione (mg) | \n2.6 | \n4.7 | \n3.4 | \n
Testosterone (μg) | \n144 | \n171 | \n126 | \n
Estrone (μg) | \n50 | \n350 | \n250 | \n
Estradiol (μg) | \n36 | \n380 | \n250 | \n
Production rate of sex steroids in women at different stages of the menstrual cycle.
Values are expressed in milligrams or micrograms per 24 hours.
From Baird and Fraser [7].
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.
\nAndrostenedione 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 hypothesis of two cells and two gonadotropins of the regulation of synthesis on the ovary (Figure 8).
\nTwo cells and two gonadotropins, on the regulation and the synthesis of estrogens at the ovary. From: Doshi and Agarwal [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.
\nEarly 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).
\nMedium 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 development. The estrogen take-off (ETO) marks the successful establishment of the dominance of a follicle.
\nThe 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.
\nAt the end of this phase, the granulosa-theca complex of the FD has almost complete functionality to enter the late follicular phase.
\nLate 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.
\nThe 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.
\nIt is believed that cycles of 30–31 days and 5 days 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 25 days [13].
\nIn 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.
\nThere are kits to detect the increase in LH, which occurs 24–36 hours 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.
\nComputerized 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.
\nIn the monitoring of assisted fertility procedures, effective follicular follow-up with ultrasonography is preferred.
\nIn 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.
\nAt 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.
\nDuring 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 9and10).
\nAMH 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].
Clinical witnesses of the follicular development in stage pre- and postdependence of FSH: AMH and ultrasound, respectively. Adapted from Ref. [15].
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).
\nFollicular dynamics and illustration of folliculogenesis process.
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.
\nWith 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.
\nAs mentioned, the development of the preantral follicle is independent of FSH, so any follicle that grows beyond this point will require an interaction.
\nSecretion of gonadotropin is regulated by the releasing hormone of gonadotropin (GnRH), steroidal hormones, and diverse peptides released by dominant follicle.
\nAmong 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.
\nFactors 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.
\nThere 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.
\nIn 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.
\nTo 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).
\nPulses 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 et al. [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.
\nOnce menstruation is produced, levels of FSH begin to decrease due to negative retro alimentation on inhibin B produced by developing follicle.
\nHatching 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 450 pg/mL, produced at the preovulatory follicle.
\nThe critical concentration of estradiol needed to initiate positive feedback requires that the dominant follicle reach a size >15 mm in diameter. The increase in LH occurs 34–36 hours 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.
\nEstradiol 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.
\nProgesterone also participates in the stimulation of the increase in FSH in the middle of the cycle (Figure 13).
\nIncrease of LH precedes ovulation in 36 hours. Peak, on the other side, precedes ovulation in 10–12 hours.
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.
\nDecrease in LH would occur as the consequence of the loss of positive retro alimentation of estrogens the inhibitory retro alimentation of progesterone (Figure 14).
\nChanges 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 et al. [17].
It takes 36 hours 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 36 hours after administration.
\nDuring 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].
\nProteolytic 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 cumulus-oocyte complex. Prostaglandins can also stimulate the release of oocytes, stimulating the smooth muscle within the ovary.
\nThe point of the dominant follicle closest to the ovarian surface where the rupture occurs is called a “stigma.”
\nAll 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.
\nProstaglandins 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.
\nConsequently, 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].
\nFor 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 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].
\nMechanisms suggested implied in follicle rupture [22] are shown in Figure 15.
\nProposed 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 et al. [22].
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.
\nThe 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.
\nThe 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.
\nEight 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.
\nThe 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].
\nThe 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].
\nAs 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).
\nThe 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.
\nThere are at least two types of luteal cells, large and small.
\nBoth 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.
\nAs 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.
\nThe 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].
\nRegulation 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].
The synthesis of progesterone by the corpus luteum is essential for the establishment and maintenance of pregnancy.
\nIn 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.
\nHumans preferably use circulating LDL cholesterol for steroidogenesis although the corpus luteum has the ability to synthesize its own cholesterol, in smaller amounts [27].
\nInside 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.
\nProgesterone 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.
\nThe frequency and widening of the pulses of secretion of pituitary LH affect the secretion of progesterone and estradiol during the luteal phase (Figure 12).
\nThe 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.
\nThe 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.
\nThe 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.
\nThe 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.
\nIn 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.
\nThe 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.
\nTwo 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.
\nThe 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 30 ml and more than 80 ml 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].
\nThe 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).
\nThe 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 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 5 mm thick, but it is normal up to 8 mm if there has been no unexpected bleeding.
\nEndometrium 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 4 mm thick, while in the stage close to ovulation, it can reach 9–11 mm.
\nEndometrium 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.
\nEndometrium type 3, premenstrual: in this stage, there is only one large refractive line and corresponds to the late secretory phase.
\nWhen 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.
\nFrequency 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.
\nIn 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.
\nRecent 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].
\nRelatively, 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.
\nOther modulators that stimulate the pulsatile secretion of GnRH are glutamate and norepinephrine, while GABA and endogenous opioids inhibit it.
\nNeurokinin 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].
\nAt 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.
\nThe 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.
\nAs 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.
\nThe 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).
\nTypes 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.
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].
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].
\nThe 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).
\nThe variability in perimenopause depends on the lag phase, a delayed recruitment process. Adapted from Hale et al. [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.
\nHuman 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.
\nBeing 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, 25–35 days, 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.
\nThe authors declare no conflict of interest in relation to this publication.
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",metaTitle:"Edited Volumes",metaDescription:"The Edited Volume, also known as the InTechOpen Book, is an InTechOpen pioneered publishing product. Edited Volumes make up the core of our business - and as pioneers and developers of this Open Access book publishing format, we have helped change the way scholars and scientists publish their scientific papers - as scientific chapters. ",metaKeywords:null,canonicalURL:"/pages/edited-volumes",contentRaw:'[{"type":"htmlEditorComponent","content":"WHY PUBLISH IN AN INTECHOPEN EDITED VOLUME?
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\n\nOut of all of the publishing options available to researchers, why choose to contribute your research to an IntechOpen Edited Volume? The reasons are simple. IntechOpen has worked exceptionally hard over the past years to fine tune the Open Access book publishing process and we continue to work hard to deliver the best for all of our contributors. The quality of published content is of utmost importance to us, followed closely by speed, and of course, availability and accessibility. To view current Open Access book projects that are Open for Submissions visit us here.
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\n\nOver the years we have learned what is important. What makes a difference to the researchers that work with us, what they value. Something that is very high not only on their lists, but our own, is the quality of the published content.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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