Fig. 3.1
Hormonal events of the menstrual cycle showing the direct ovulatory stimulus to be P4. FSH follitropin, LH leuteotropin, E2 estradiol-17β, P 4 progesterone. (Modified from [88, pp. 987–1000] with permission from Elsevier)
Progesterone and Ovulation of a Mature Ovum
The importance of progesterone for (1) creating a secretory endometrium that accepts the fertilized ovum and (2) maintaining pregnancy has been understood for many decades. The assessment of serum progesterone in normal pregnancy was accomplished from 1950 through 1970, while most of the assessment of pregnancy complications relating to progesterone was between 1963 and the early 1980s. The first use of progesterone as a contraceptive was reported by C. J. Andrews from Norfolk, Virginia, in 1936 [89]. However, the importance of progesterone in ovulation has not been conclusively confirmed in the literature, although this role has been implied over the past several decades. As seen in Fig. 3.1, the observation of high P4 levels in the preovulatory follicle hinted at a role in ovulation but did not spark much interest in the research community. The importance of its role as the direct mediator of ovulation becomes evident when reading the effects of exercise on P4 levels with a negative [90–95] or positive [96–97] effect on the menstrual cycle, which can be linked to the secondary effect of LH release from the anterior pituitary [98]. One author, in a review article [99], credits ovulation induction exclusively to P4 while rejecting any role of a positive feedback mechanism for E2 on LH as the primary cause of ovulation. The mistake of failing to factor in this E2 feedback mechanism has been addressed in hundreds of articles that clearly link rising E2 as the primary stimulus for the LH surge, rising LH as the primary stimulus for P4 secretion, and rising P4 in the follicular antrum as the primary causal factor for ovulation. The effect of this P4 production, while not initially great enough to give a large increase in blood serum levels, is seen later as the GCs become luteal cells. However, early P4 production is clearly high enough to cause the GCs to produce the enzyme milieu to bring about the events necessary for ovulation to take place.
LH works through the second messenger system to initiate P4 synthesis. LH and FSH are both potent stimulators of steroid synthesis and thus control E2 and P4. One major role of steroids is to bind to the nuclear receptors on DNA and transcribe mRNA molecules for protein transcription in the cytoplasm. Over the space of 5–10 h these proteins will produce the necessary thinning of the follicular wall, degrade the ovum maturation inhibitor (OMI), increase the antral colloid osmotic pressure, and begin the transition of GCs to luteal cells of the CL.
In Dr. Swanson’s lab a total of 56 rabbits were mated with a buck to elicit ovulation in this coitus-induced ovulator species. The ovaries were then exposed with a flank incision and Graafian follicles were divided randomly into equal numbers of experimental anti-P4 antiserum (a-Pas) or control normal rabbit serum (NRS) follicles to be injected with 2 µL of one or the other compounds. Rabbits ovulate predictably approximately 12 h after coitus. When injected with a-Pas within 4 h postcoitally, only 20 % of injected follicles ovulate and have entrapped MII ova in the antrum (Fig. 3.2a). When injected after 5 h postcoitally, there is no difference between a-Pas and normal rabbit serum (NRS) injected follicles; 80 % ovulation (Fig. 3.2b).
Fig. 3.2
Illustrates the results of microinjecting either (a) antiprogesterone antiserum (a-Pas) or the diluent (b), normal rabbit serum (NRS), into the rabbit Graafian follicular antrum. (From unpublished research; R.J. Swanson)
These results illustrate the driving force of P4 in the ovulatory event (Fig. 3.3). This highlights the importance in recognizing the effects of strenuous exercise on the female reproductive cycle. Not only can perturbation of P4 have a detrimental effect on embryo implantation and pregnancy maintenance, but low P4 can negate the release of an egg on any cycle so that there would be no chance for fertilization. When the normal female reproductive cycle is clearly understood, a person can play a major controlling role in monitoring and managing her reproductive health in relation to exercise regimens, diet, and ingested recreational substances, all of which can improve or ravage the body with devastating effects on the reproductive system.
Fig. 3.3
Antiprogesterone antiserum injected into Graafian follicles 1–8 h postcoitally. Normal rabbit serum-injected follicles ovulated at 80 % for all hours of injection postcoitally. (From unpublished research; R.J. Swanson)
Beginning of Pregnancy
Human pregnancy starts with embryo implantation into the uterine wall at approximately day 6 or 7 postfertilization and is a very delicate mechanism that requires embryo–endometrium dialog. The time period during which implantation can occur (the implantation window) generally ranges from day 6 to day 10 post-ovulation (days 20–24 in a 28-day cycle). By day 10, the blastocyst has become totally encased within the endometrium and embryo development has started.
The Placenta
The human placenta is a highly specialized organ which plays a number of important roles, including embryonic/fetal nutrition and growth, endocrine function, and acting as a physical and immunological barrier. Furthermore, during gestation, the human fetus depends on the placenta for its pulmonary, hepatic, and renal functions.
Placental Barrier
During the early stages of pregnancy the placental barrier comprises four layers, namely the syncytiotrophoblast, the cytotrophoblast, connective tissue, and the endothelium of the capillary vessels, whereas at term only a hemo-monochorionic structure comprising the trophoblast and the fetal endothelium remains. Although the placental barrier separates fetal blood from maternal blood, this separation is not absolute, and a number of substances are able to either passively or actively cross the placental barrier.
Placental Transfer
The placenta plays a pivotal role in providing the fetus with the oxygen, water, and nutrients it needs while transporting the CO2 and other metabolites resulting from fetal catabolism from the fetus to the mother. These different compounds cross the placenta by a number of mechanisms, including simple diffusion (gases, water, and the majority of electrolytes), facilitated diffusion (glucose and lactate), active transport (some cations, water-soluble vitamins, and amino acids), pinocytosis (lipoproteins and phospholipids), or by direct passage through a placental barrier’s solution of continuity (for example red blood cells under both normal and abnormal conditions, such as placental abruption) [100].
The exchange of substances between the mother and the fetus depends on the characteristics of the exchange membrane, the hydrostatic or oncotic pressure on both sides of the membrane, the dynamics of placental maternal and fetal circulation and its spatial configuration, the concentration of the different compounds on both sides of the placental membrane, and the placental metabolism [100].
Placental Respiration
Although the placenta is the first lung for the fetus , its respiratory efficiency is considerably lower than in the lung (1/5 per tissue weight unit). Both O2 and CO2 cross the placenta by simple diffusion, and the fact that the maternal blood reaching the intervillous space has a higher pO2 than that in the villous capillaries results in a flow of O2 to the fetal circulation . The direction of flow for CO2 is the opposite since the pCO2 is higher on the fetal side. Moreover, various unique characteristics of fetal blood favor O2 uptake by the fetus: (a) higher hemoglobin concentration than in maternal blood, (b) the higher O2 affinity of fetal hemoglobin, (c) the fact that O2 transfer is facilitated by CO2 transfer, (d) CO2 transfer is 20 times quicker in the placenta and is facilitated by O2 transfer [100].
Placental Endocrine Function
The placenta synthesizes a number of molecules, the function of many of which is still not well understood. These include:
1.
Human chorionic gonadotropin (hCG)
This is a glucopeptidic hormone produced by the syncytiotrophoblast that comprises two subunits (α and β). The α unit is very similar to the α unit of LH, TSH, and FSH, whereas the β unit bears some resemblance to the β unit of LH, thus meaning that they share some of the same biological functions. Its main role is to maintain the CL during the first weeks of pregnancy. hCG levels are detectable soon after implantation and increase sharply up until the 10th week of gestation, at which point they begin to decrease.
2.
Human placental lactogen (hPL)
This single-chain polypeptidic hormone is also produced by the syncytiotrophoblast and is very similar to the growth hormone (GH) produced by the anterior pituitary. hPL levels increase steadily throughout pregnancy, reaching a peak at the end of pregnancy, and correlate with placental weight. The biological role of this hormone is to guarantee the availability of glucose as an energetic substrate for the fetus . In the event of maternal fasting, the resulting hypoglycemia induces hPL production, which in turn triggers lipolysis in the mother, thereby increasing the level of free fatty acids, which cross the placenta and can be used as an energetic substrate. It also increases amino acid placental transfer by restricting protein use by the mother [100, 101].
3.
Steroid hormones
The placenta produces huge amounts of progesterone and estrogens from precursors obtained from the mother. Progesterone is mainly synthesized from maternal cholesterol. However, since placental tissue lacks 17-hydroxylase activity, it is not able to synthesize estradiol or estrone from progesterone or pregnenolone. As a result, the aforementioned estrogens are synthesized from the dehydroepiandrosterone sulfate (DHEA-S) synthesized by the adrenal glands of both the mother and the fetus. Placental sulfatase reacts with DHEA-S to form DHEA, which is converted into androstenedione and testosterone, and subsequently into estrone and estradiol by placental aromatization.
The Amniotic Fluid
The embryo/fetus is immersed in the amniotic cavity, which is filled with amniotic fluid. The main functions of this fluid include protecting the fetus and the umbilical cord from external injury and the pressure resulting from uterine contractions, allowing the fetus to move freely (at least during the first part of pregnancy), which is necessary for normal fetal development, contributing to fetal thermoregulation, participating in fetal lung development, and, at labor , promoting cervical dilation. The mean volume of amniotic fluid at term is 800 mL, although this value can vary over a wide range (400–1200 mL).
The Fetus
Intrauterine life can be considered to comprise three stages: (a) the differentiation period (conception to week 12 of amenorrhea) , during which organogenesis takes place, (b) the growth period (weeks 12–28), which is characterized by cell proliferation, and (c) the weight increase period (week 28 until the end of pregnancy), during which functional maturation of the organs occurs. The mean newborn weight at term is 3200 g (normal weight ranging from 2500 to 4000 g).
Fetal Circulation
Maternal/placental circulation begins once uterine spiral arteries penetrate the intervillous space. From that moment, these spiral arteries inject oxygenated blood into this space, where exchange with the chorionic plate occurs, and then this blood returns to the maternal circulation via the veins located in the placental septa [101]. Fetal blood reaches the placenta through two umbilical arteries that branch into the dividing villi.
Fetal oxygenation occurs via the placenta , which receives a significant proportion (close to 40 %) of cardiac output, whereas the lungs, which lack a respiratory function, receive only 8 %. Another peculiarity is that oxygenated and less oxygenated blood circulates through the same vessels in the fetal circulation . Oxygenated blood from the placenta reaches the abdominal wall of the fetus via the unique umbilical vein from where it penetrates into the liver. The majority of this blood passes to the inferior vena cava via the ductus venosus, with the remainder passing into the left hepatic lobule, which subsequently drains into the inferior vena cava via the left hepatic vein. The inferior vena cava contains two different blood flows, namely less oxygenated blood from the lower extremities and the abdomen (O2 saturation 40 %) and more oxygenated blood from the ductus venosus (O2 saturation 83 %) and the left hepatic vein (O2 saturation 73 %). These two blood flows almost do not mix [100, 101].
Blood from the inferior vena cava flows into the left atrium very close to the interauricular communication, where a septum allows differential conduction of the flow, with oxygenated blood (from the ductus venosus and left hepatic vein) flowing to the left atrium and then on to the left ventricle and less oxygenated blood, together with blood from the superior vena cava, flowing directly to the right ventricle. The oxygenated blood leaving the left ventricle flows into the ascending aorta, from where it reaches the fetal encephalon. In contrast, the majority of the less oxygenated blood leaving the right ventricle flows into the descending aorta (via the ductus arteriosus), with a small proportion reaching pulmonary circulation. This means that whereas the fetal encephalon is only irrigated with more oxygenated blood, the lower part of the body receives a mix of oxygenated and less oxygenated blood.
Maternal Changes During Pregnancy
Pregnancy leads to a number of changes in almost every maternal organ and tissue . Although the majority of these changes are more evident at the end of pregnancy , many of them can also be detected in its earlier stages.
Gynecological Changes
Uterus
Perhaps the most remarkable of the local changes is the enlargement of the uterus , which increases progressively in size mainly due to the hypertrophia and hyperplasia of uterine smooth-muscle cells. At term, the uterus has a weight of 1100 g and a capacity of 5000 mL compared to its normal weight of around 70 g and capacity of 5 mL outside pregnancy. This increase in uterine size and weight is partially responsible for some of the compression-related effects on neighboring structures. Throughout pregnancy some irregular and painful contractions (known as Braxton-Hicks contractions) can occur, which are frequently misinterpreted as the beginning of labor at the end of pregnancy.
Cervix
Immediately after conception, the cervix is closed by a mucous plug, which forms a protective barrier against microorganism.
Ovaries
The CL enlarges during early pregnancy and remains active for 8–10 weeks, producing huge amounts of estrogens and progesterone.
Breasts
There is a remarkable increase in breast size as a consequence of adipose tissue hypertrophy, acini neoformation, and dilation of the lactiferous ducts during pregnancy. Breast vascularization also increases. Colostrum is produced from around week 12.
Systemic Changes
Cardiovascular Changes
A number of cardiovascular modifications, which are depicted in Table 3.1 [102], occur as a consequence of the need to irrigate a larger area (placenta, larger uterus, and breasts). Likewise, a number of symptoms and signs, such as asthenia, dyspnea, mild systolic murmurs, and peripheral edema, which outside pregnancy would suggest heart disease, can be completely normal during pregnancy [103]. Similarly, when the woman lies in the supine position, especially at the end of pregnancy, the enlarged uterus can obstruct blood flow to the inferior vena cava, thereby decreasing cardiac output, causing hypotension, and resulting in “supine hypotensive syndrome” or “aortocaval compression syndrome.” This condition can affect fetal well-being and produce maternal lipothymy.
Table 3.1
Cardiovascular changes during pregnancy—Stages of labor and relationship between fetal descent and cervical dilation pattern
Start (week) | Maximum (week) | Increase (%) | |
|---|---|---|---|
Blood volume | 8 | 32–35 | + 40 |
Plasma volume | 8 | 32 | + 50 |
Erythrocyte volume | 8 | 40 | + 25 |
Cardiac output | 10 | 24–32 | + 40 |
Heart rate | 12 | 40 | + 22 |
Respiratory rate | 8 | 40 | + 45 |
Oxygen consumption | 14 | 40 | + 22 |
Blood pressure | 1st trimester | − 20 | |
3rd trimester | + 40 | ||
Vascular resistance | 8 | 22 | − 45 |
Venous varicosities are also common, especially in the legs, vulva, and rectum (hemorrhoids).
Hematological Changes
Pregnancy results in an increase in maternal erythropoiesis. However, the increase in plasma volume is higher than the increase in total erythrocyte volume, thus leading to a decrease in hematocrit values and resulting in the so-called “physiologic anemia of pregnancy” or “pseudoanemia of pregnancy.” As a result, the cutoff for defining anemia in pregnancy is a hemoglobin level of 10.5 g/dL instead of the 12 g/dL used outside of pregnancy. A number of changes in the coagulation system, including a 50 % increase in fibrinogen values, an increase in clotting factors VII, VIII, IX, X, and XII, a decrease in factor XI, and a 50 % decrease in factor XIII, also occur [100, 101, 103].
Respiratory Changes
A number of changes occur in the respiratory function [104], all of which are aimed at obtaining a more efficient respiratory function in order to provide oxygen supply to the fetus (Fig. 3.4 [104]). One common finding during normal pregnancy is dyspnea, although its cause is not well established.
Nephro-Urological Changes
There is a 40 % increase in both renal blood flow and the glomerular filtration rate, and anatomical changes, such as an increase in renal size and urethral dilation, also occur.
Digestive Changes
The main digestive changes result from the relaxant effects of progesterone on the smooth muscle as well as the compressive effects of the gravid uterus on neighboring structures. The consequences include heartburn and esophageal reflux, risk of Mendelsohn’s syndrome (chemical pneumonitis caused by aspiration of gastric contents), especially during general anesthesia, constipation, and hemorrhoids. The changes in liver function that occur result in alterations to the levels of many biochemical blood parameters (Table 3.2 [102]).
Table 3.2
Effect of normal pregnancy on liver function tests—Stages of labor and relationship between fetal descent and cervical dilation pattern
Test | Effect | Trimester of maximum change |
|---|---|---|
Alkaline phosphatase | 2–4× | 3rd |
Cholesterol | 2× | 3rd |
Fibrinogen | 1.5× | 2nd |
Ceruloplasmin | ↑ | 3rd |
Transferrin | ↑ | 3rd |
Alpha-globulin | S ↑ | 3rd |
Beta-globulin | S ↑ | 3rd |
Lactate dehydrogenase | S ↑ | 3rd |
GGT | S ↑ | 3rd |
Bilirubin | N or S ↑ | 3rd |
BSP | N or S ↑ | 3rd |
Prothrombin time | = | = |
SGOT | = | = |
SGPT | = | = |
Gamma globulin | N or S ↓ | 1st |
Albumin | 0.8× | 2nd |
Musculoskeletal Changes
Lumbar lordosis develops progressively as a consequence of the increased weight in the anterior part of the body due to the enlarged uterus. Moreover, the feet of pregnant woman tend to be more widely separated than usual when standing.
Metabolic Changes
One of the most evident changes during pregnancy is the increase in maternal weight. Thus, the mean increase in maternal weight at the end of pregnancy is 11 kg, with 5.1 kg of this being due to the intrauterine contents (3.5 kg for the fetus, 1 kg the amniotic fluid, and 0.6 kg the placenta), 1.1 kg the uterus, 1.6 kg the blood, 0.5 kg the breasts, and the remainder to general storage. Nutritional requirements increase during pregnancy up to an additional 20 % at term.
A remarkable volume of water is retained during pregnancy: 3.5 L for the fetus, amniotic fluid, and placenta , and a further 3 L for the increase in plasma volume, the increase in extracellular and extravascular water, and the water accumulated in the breasts and uterus.
The increased concentration of estrogens, progesterone, and especially hPL results in an increase in circulating insulin levels whose biological significance is to ensure a continual supply of glucose to the fetus. Pregnancy is a diabetes-enhancing condition and, as such, aggravates previously existing diabetes.
Labor
Term delivery in humans occurs at between 37 and 42 completed weeks. The mean gestational age is 280 days (40 weeks) after the last menstrual period if ovulation occurs 14 days after the onset of menstruation. Normal labor takes between 3 and 18 h.
The Elements of Labor
The Birth Canal
During delivery , the fetus must descend through the birth canal, which comprises a skeletal and a nonskeletal portion. The skeletal passageway of labor is constituted by the pelvis which is composed of four bones: the sacrum, coccyx, and two innominate bones. Each innominate bone is formed by the fusion of the ilium, ischium, and pubis. The innominate bones are joined to the sacrum at the sacroiliac synchondroses and to one another at the symphysis pubis [101]. The nonskeletal portion comprises the uterine cervix, the vagina and its opening, the vulva, and the surrounding structures (rectum, bladder, and levator ani and perineal muscles). The birth canal follows an anterior curve rather than a straight line. Likewise, whereas the transversal diameter is larger than the anteroposterior diameter at the beginning of the birth canal, this situation is reversed at the end .
The Object of Labor (the Passenger)
During normal delivery, the fetus is in a longitudinal lie and in cephalic presentation. In this delivery , fetal presentation has an ovoid form, with the anteroposterior diameter being larger than the biparietal. In contrast, in the larger part of the remaining fetal body (the shoulders) the transversal diameter is much larger than the anteroposterior diameter.
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