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Prenatal Form and Function – The Making of an Earth Suit

  

Introduction:   Prefertilization

  Closer Look: 
  Applying the Science: 
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Introduction

The dynamic process by which the single-cell human embryo (called a zygote (zi’got),1 becomes a 100 trillion-cell (1014) adult2 is perhaps the most remarkable phenomenon in all of nature.3 We invite you to join us as we review the beginning of this remarkable process.

Long before we are born, most body parts found in the adult and all body systems are present and most routine body functions are operative.4 By studying human development from fertilization to birth, we will see these body parts and body systems emerge and learn when many routine body functions begin.5 Human development is a continuous process beginning with fertilization and continuing throughout pregnancy, birth, childhood, adolescence, adulthood, and into old age.


 

Promoting a Lifetime of Health

 

A Note to Students

We hope you will remember the following analogy as you study the wonders of early human development:

teens in the city friends

The human body has been likened to an “Earth Suit.” Just as every astronaut must have a space suit to survive in space and every deep sea diver must have a diving suit to survive in the depths of the ocean, each of us must have an “Earth Suit” to survive on this planet. Earth Suits come in many wonderful varieties. Some Earth Suits are female and some male. Some are taller, some shorter, some younger, some older. Earth Suits also come in a variety of attractive shades. No matter what type of Earth Suit you may have inherited, certain realities apply to everyone. Each of us gets one and only one Earth Suit. If your Earth Suit is damaged by harmful substances, it may not perform very well. If part of your Earth Suit must be removed surgically, it will not grow back and, if your Earth Suit dies, you can’t stay here at all.

Learn the facts.
Take care of your Earth Suit!
And help others do the same.

smiling babies, Earth Suits come in a variety of attractive shades.

A woman’s health and well-being before and during pregnancy is vitally important to the life-long health of her embryo or fetus. Human development is so complex, it’s not surprising that things sometimes go wrong; rather, it’s amazing that things go so right so often. Pregnant Woman Breathing ExerciseWe can promote “things going right” by giving the mother and the fragile embryo or fetus the special prenatal care they need. We can also promote "things going right" by providing students with prenatal development-based health education which communicates a visual appreciation of early human development and explains the life-long consequences of exposure to harmful substances during pregnancy. With this approach, we can help prevent many of the devastating birth defects and learning disabilities occurring in the United States and around the world.


Thinking Smart

Healthy WomanDoctors can detect pregnancy as early as 8 or 9 days after fertilization.1 Most women, however, have no idea they are pregnant for weeks! By the time a woman discovers she is pregnant, many important structures in the growing embryo have long since developed. What she allows into her body during this time directly affects the growing embryo in her womb. Everything from what she eats and drinks to what substances she uses plays a role in how her fetus develops. For this reason, a woman who has even the slightest possibility of becoming pregnant should already be thinking about how her lifestyle choices affect pregnancy.

1 F. Gary Cunningham, Paul C. MacDonald, Norman F. Grant, et al., Williams Obstetrics, 20th ed. (Stamford: Appleton and Lange, 1997), 26.

During the amazingly complex process of human prenatal development, body parts and body systems appear in the embryo at a remarkably young age and surprisingly small size. From fertilization through old age, this process (and our health) is impacted by our personal choices, the choices of those around us, and our environment. For example, when we choose proper nutrition and get regular exercise, our health is generally enhanced. Likewise, if we choose to use harmful substances such as alcohol and tobacco, our health is generally impaired. Because the prenatal period is a time of preparation, pregnant women who avoid exposing themselves and their fetuses to harmful substances promote a lifetime of health for their children.



 

Terminology and Definitions

The study of early human development is best begun by becoming familiar with the basic language of the field. Investing the time and effort to master these basic terms and definitions will prepare you to understand the descriptions that follow and enable you to explain them to others.

These terms describe stages, events, and time periods during pregnancy and early human development.

  • Birth — the process of the fetus passing from the uterus into the outside world
  • Conception — the act of conceiving or becoming pregnant; synonymous with fertilization6
  • Embryo — means “growing within” and refers to the “human offspring in the first eight weeks following fertilization” 7
  • Embryonic Period — the first 8 weeks of human development starting with fertilization; characterized by the formation of most major body systems8
  • Fertilization — the process that starts with the sperm entering the egg or oocyte, and ends with the joining of the female and male DNA within the single cell zygote9
  • Fetal Period — the time from the end of eight weeks through the end of pregnancy; during this time the body grows larger and its systems begin to function10
  • Fetus — means "unborn offspring" and refers to human offspring from 8 weeks after fertilization until birth11
  • Perinatal Period — the period of time around birth, from week 28 of pregnancy until 7 days after birth12
  • Postnatal — the period of time following birth
  • Pregnancy — the condition of a female from the time of fertilization of her oocyte until birth,13 normally lasting 38 weeks for humans (or 40 weeks if measured from a woman’s last menstrual period)14
  • Prenatal Development — human development occurring between fertilization and birth
  • Prenatal Period — the period of time from fertilization until birth; ’pre’ means before, ’natal’ means ’relating to birth’15
  • Trimesters — three month periods used to divide pregnancy into three stages of approximately equal length
  • Zygote — the single-cell embryo16 that results from the joining of the sperm and oocyte; means "yoked or joined together"17

Note: All embryonic and fetal ages on this website refer to the time since fertilization.18




 

Pregnancy Timeline


Pregnancy Timeline, prenatal period, embryonic period, fetal, infancy, postnatal, first trimester, second trimester, third trimester, pregnancy timeline, fertilization, conception, birth

Figure 0.1 - Pregnancy Timeline and Terminology     Copyright © 2005 EHD, Inc. All rights reserved.



 

The Female Reproductive System

A woman’s reproductive system includes two ovaries, two uterine tubes (previously called Fallopian (fa-lo’pe-an) tubes), the uterus, or womb, and the vagina, as shown in Figure 0.2.

The ovaries contain immature reproductive cells called primary oocytes. A woman’s menstrual cycle is under the ultimate control of hormones released by her brain. Each month, a primary oocyte matures into a secondary oocyte and is released during ovulation into one of the uterine tubes.19

 
See labels of FIG 0.2, Female Reproductive System, Fallopian Tubes, Ovary, Ovaries, Uterus
Figure 0.2 - The Female Reproductive System
Copyright © 2006 EHD, Inc.
All rights reserved.

The day-to-day operation of much of the female reproductive system is highly sensitive to cyclical hormones which direct functions as diverse as maturation of oocytes, ovulation, muscle contractions of the walls of the uterine tubes and uterus, uterine wall thickness, and glandular secretions. Incredibly, hormones direct the ovarian end of the uterine tubes to draw close to the ovary in time for ovulation,20 and cause the number and types of cells lining the uterine tube and uterus to change cyclically.

Each uterine tube measures about 10 to 13 centimeters in length21 and has an inside diameter between22 1 and 2 millimeters. As shown in Figure 0.2 above, one end of the uterine tube is near each ovary and is open to the abdominal cavity while the other end opens into the inner cavity of the uterus. The uterine tubes are lined with several cell types, one of which has small projections, called cilia, which work to direct the oocyte (or embryo) down the uterine tube toward the uterus. The wall of each uterine tube contains two muscle layers which contract in rhythmic fashion to further direct transport of the oocyte, or in the case of fertilization, the embryo, toward and into the uterus.23

The uterus is a small, muscular structure which, in the event of pregnancy, serves to house, nourish, and protect the embryo and fetus until birth and then expel the fetus during childbirth.24 The size of the adult uterus varies widely depending on pregnancy status. For example, the adult uterus prior to a first pregnancy measures about 6 to 8 centimeters in length and weighs about 70 grams. By the end of full-term pregnancy, the uterus weighs approximately 1100 grams and displaces a volume of about five liters.25

The uterus is divided into distinct regions (Fig. 0.2). The upper corners of the uterus where the uterine tubes enter are called the cornu. The upper two thirds of the uterus is called the body and the uppermost part of the body between the insertion sites of both tubes is called the fundus. The cervix refers to the lower third of the uterus and is separated from the body by a narrowing called the isthmus. Within the cervix lies the cervical canal which has an upper, internal opening called the internal os and a lower opening (into the vagina) called the external os.26

The wall of the uterus contains 3 distinct sections called the endometrium, myometrium, and perimetrium.27

The endometrium forms the inner lining of the uterus and undergoes dramatic cyclical changes as part of the menstrual cycle. Its thickness varies from about .5 millimeters to as much as 5 or 6 millimeters.28 Each month (in sexually mature females prior to menopause), the endometrium grows many blood vessels and tube-shaped glands which degenerate and are expelled if pregnancy does not occur.29

The myometrium is the middle layer of the uterine wall and is composed of smooth muscle and connective tissue. The myometrium is 12 to 15 millimeters thick,30 makes up the vast majority of the uterine wall, and expands greatly during pregnancy. The muscle component is most prominent in the body of the uterus and least prominent near the cervix.31

The perimetrium is the thin outer covering of the uterus32 and is not of particular interest in this discussion.

The vagina receives the male reproductive cells and serves as the birth canal through which the fetus passes during childbirth.

 

Oocyte and Primordial Follicle Production

The process of forming female reproductive cells, called oocytes, is called oogenesis.33

Female reproductive cells form in the ovaries, which contain four important cell types called oocytes, follicular cells, granulosa cells, and theca cells.

Each oocyte and its surrounding cells form a functional unit called a follicle. The type, size, structure, and complexity of follicles will be further described below.

Primary germ cells are the source of oocytes. In the human embryo, about 1000 to 2000 primary germ cells34 travel to the developing ovaries from the yolk sac (See UNIT 5) during the 5th week of embryonic development.35 They form oogonia which divide by mitosis until midpregnancy. Between 3 and 4 months, the oogonia begin to enlarge and start their first meiotic division and are called primary oocytes.36 The number of oocytes peaks at approximately 7 million by midpregnancy at which time their numbers begin to decrease dramatically. By birth, only 2 million are present.37 Note: all oocyte production occurs before birth.38

 
See labels for FIG 0.3, Primordial Follicle
Figure 0.3 - Primordial Follicle
Copyright © 2006 EHD, Inc.
All rights reserved.

During the fetal period, each primary oocyte achieves a diameter of 20 micrometers and is surrounded by a single layer of flat epithelial cells called follicular cells.39 The primary oocyte and its surrounding cells are collectively called a primordial follicle.40 (Fig. 0.3) [Primordial follicle = primary oocyte + single layer of flat follicular cells] Before the prenatal period ends, the ovaries produce a lifetime supply of primordial follicles each containing a primary oocyte "frozen" at an early stage of meiosis I. Little change occurs in these follicles until puberty when the menstrual cycles begin as described below.41

The Cyclic Changes of the Female Reproductive System

The pituitary gland is located just underneath the brain and produces a total of 8 hormones which control numerous vital functions of the human body.42 Acting under the influence of a hormone called GnRH (gonadotropin releasing hormone) released from the hypothalamus (the master gland control center of the brain),43 the pituitary gland releases 2 hormones called LH (luteinizing hormone) and FSH (follicle-stimulating hormone) that cause tremendous changes to occur in the ovaries.44




 
See lables for FIG 0.4, Ovary
Figure 0.4 - Changes in the Ovary During the Menstrual Cycle
Copyright © 2006 EHD, Inc.
All rights reserved.



 
See labels for FIG 0.5, Primary Follicle
Figure 0.5 - Primary Follicle
Copyright © 2006 EHD, Inc.
All rights reserved.

Changes in the Ovaries (Fig. 0.4)

As each menstrual cycle begins, FSH and LH activate between 6 and 20 primordial follicles to begin a rapid growth phase.45 FSH and LH also cause several types of cells around each follicle to rapidly increase in number.46 Cells of the once-flat single layer assume a cuboidal shape and then multiply, forming several cell layers around the oocyte. An acellular material called the zona pellucida forms between the oocyte and the granulosa cells.47 This functional unit is now called a primary follicle.48 [Primary follicle = primary oocyte + several layers of granulosa cells + zona pellucida + theca cells] See Figure 0.5. The cells surrounding the oocyte are now called granulosa cells and the cells surrounding the granulosa cells are called theca cells. Note: The primary oocyte now has a diameter of 50 to 80 micrometers.49

 
See labels for FIG 0.6, Secondary Follicle
Figure 0.6 - Secondary Follicle
Copyright © 2006 EHD, Inc.
All rights reserved.

During this process, granulosa cells and theca cells gain the ability to produce a hormone called estrogen.50 As these cells grow in number, they produce fluid containing estrogen, which collects inside each follicle creating a central cavity called the antrum.51 The follicle is now called a secondary or antral follicle.52 Estrogen causes the follicles to become even more sensitive to the effects of FSH and LH, which results in further rapid growth of the follicles. During this process, these antral follicles (including the oocyte within) grow substantially in size adjacent to the antrum and are sometimes called vesicular follicles53 (Fig. 0.6).

By about 1 week into the cycle, 1 of the follicles distinguishes itself by growing the fastest and the others begin to shrink.54 The mechanism for "choosing" a single dominant follicle is not well understood but this process (when successful) prevents ovulation of multiple oocytes and prevents formation of nonidentical twins/triplets, etc. (Note: Nonidentical twins occur when 2 follicles release their oocytes nearly simultaneously and both become fertilized and implanted.)

 
See labels for FIG 0.7, Mature Follicle
Figure 0.7 - Mature Follicle
Copyright © 2006 EHD, Inc.
All rights reserved.

Ovulation is preceded by a 6- to 10-fold increase in LH levels, a 2- to 3-fold increase in FSH, a fall in estrogen levels, and a rise in progesterone levels (Figure coming soon). Note that without the LH peak (about 16 hours prior to ovulation - some authorities report the LH surge precedes ovulation by up to 36 hours), ovulation will not occur.55 The LH surge stimulates the completion of meiosis I, resulting in cell division. This division creates 2 very unequal daughter cells - 1 large cell which contains most of the cell contents and is destined to begin meiosis II, and 1 cell called a polar body destined to degenerate.56 The oocyte is now referred to as a secondary oocyte and the follicle is called a preovulatory follicle or mature follicle. (Fig. 0.7) Finally, just prior to ovulation, the secondary oocyte becomes free floating within the single preovulatory follicle. The follicle is now ready to release its oocyte during ovulation. The preovulatory follicle has a diameter between 1 and 1.5 centimeters.

Ovulation is marked by a breakdown in the wall of the follicle at the surface of the ovary.57 The oocyte and its surrounding fluid is released and captured by the "fingers" of the end of the uterine tube called fimbriae. The oocyte (Figure coming soon) is bordered by a cell membrane which is surrounded by a specialized membrane called the zona pellucida which, in turn, is surrounded by granulosa cells called the corona radiata.58 The corona radiata and the zona pellucida are the final barriers a spermatozoon must overcome to join the oocyte.

Following ovulation, during the Secretory Phase, theca cells and granulosa cells in the mature follicle transform to produce significant quantities of progesterone59 into the blood and the follicle is called a corpus luteum.60 The purpose of this hormone production is to further prepare and maintain the uterine lining for implantation in the event that fertilization occurs. In the absence of fertilization, by about 12 days after ovulation, the corpus luteum begins to degenerate, hormone levels fall, and the corpus luteum becomes nonfunctional.

Changes in the Uterine Tubes

During the Proliferative Phase, under the influence of estrogen released by the maturing follicles in the ovary, the number of ciliated cells lining the uterine tube increases significantly. Cilia protrude into the canal of the uterine tube and act to create a "flow" within the uterine tube toward the uterus. Additionally, the fimbriae of the uterine tube move close to, and then partially envelope, the ovary and move back and forth across its surface.61

As the Secretory Phase begins following ovulation, the fimbriae capture and direct the oocyte into the uterine tube. Cilia lining the inside of the uterine tube sweep the oocyte toward the uterus. Mild muscle contractions further encourage transport down the tube.62 Glands in the uterine tube, under the influence of progesterone, release basic nutrients into the canal which sustain the oocyte and, in the event of pregnancy, sustain the the early embryo.63

In the absence of fertilization, the oocyte reaches the uterus within about 4 days and degenerates within a short time.64

Changes in the Uterus

During the Follicular or Proliferative Phase, under the influence of estrogen released by the maturing follicles in the ovary, the inner surface of the uterus forms a new lining of cells, develops many additional blood vessels, numerous glands, and grows to about 5 millimeters in thickness.65

During the Secretory or Luteal Phase, primarily under the influence of progesterone released by the corpus luteum, the lining thickens to about 6 millimeters.66 The uterine glands become coiled and produce nutrients, some of which are released into the uterine cavity to nourish the free floating embryo. The remaining nutrients are stored in the uterine wall. The cervix develops thick mucous which effectively closes the cervical canal from the vagina.67 All these events prepare the uterus for the possibility of fertilization and then implantation.

If fertilization does not occur, the Menstrual Phase begins as the corpus luteum begins to degenerate, progesterone and estrogen levels fall dramatically, and the uterine lining separates and is expelled from the uterus. This process is referred to as a woman’s menstrual period and is accompanied by mild muscle contractions of the uterus, bleeding and cramping.68


 

The Male Reproductive System


Spermatozoa Production

(A full description of the male reproductive system and reproductive cell formation is beyond the scope of this article.)

The male reproductive system is under the hormonal control of FSH and LH released by the pituitary gland in similar fashion as the female reproductive system, as outlined above.

The process of forming male reproductive cells, called spermatozoa (singular spermatozoon), is called spermatogenesis.69

Male reproductive cells form in the testis which contain 3 important cell types called spermatogonia, Leydig cells, and Sertoli cells all described briefly below.

Spermatogonia are the source of male reproductive cells. Spermatogonia develop from primary germ cells which travel to the developing testes from the yolk sac (See UNIT 5) during the 5th week of embryonic development.70 They remain inactive until perhaps 12 or 13 years of age, when the process of sexual maturity called puberty occurs.

Once sexual maturity is reached, spermatogonia divide by mitosis throughout life. They produce cells to replace themselves as well as cells which will become spermatogonia called primary spermatocytes. Each primary spermatocyte completes the first meiotic division and forms 2 secondary spermatocytes, which then complete the 2nd meiotic division, forming 4 nonidentical spermatids. These spherical, nonmobile cells contain 23 chromosomes characteristic of human reproductive cells. They undergo a process called spermiogenesis and eventually become highly mobile, long cylindrically shaped spermatozoa. Note that each spermatid and/or spermatozoon contains either a male (Y) chromosome or a female (X) chromosome which will determine the sex of the embryo should fertilization occur.71

Leydig cells, acting under the influence of LH, produce and release testosterone,72 a hormone which greatly impacts a wide range of tissues throughout the body including spermatozoa production.

Sertoli cells (sometimes called sustentacular cells) facilitate most steps in the process of spermatozoa production73 in response to the male hormone testosterone. Sertoli cells are also regulated by FSH to produce certain proteins and fluid.74

Spermatozoa Structure

The spermatozoon is uniquely equipped to to fertilize an oocyte. The head is surrounded by a cell membrane (Figure coming soon). Just beneath the surface around much of the of the head is a compartment called the acrosome which contains enzymes used to break down the physical barriers represented by the corona radiata and the zona pellucida.75 The chromosomal material is stored in a highly condensed form within the rest of the head as shown and the long midpiece and tail provide locomotion for swimming toward the oocyte.76

The specialized function of the spermatozoon will be discussed briefly in the next unit as we review fertilization.

Spermatozoa Transport and Maturation

Spermatozoa placed in the vagina during sexual intercourse must overcome many obstacles to reach the oocyte located in the uterine tube. The chemical properties of mucous in the cervix of the uterus vary according to the phase of the menstrual cycle. During the time period immediately preceding ovulation, this cervical mucous facilitates transport of spermatozoa while at other times in the cycle, it presents a nearly impenetrable barrier.77 Once in the uterus, mild muscle contractions of the uterus deliver a select number of spermatozoa into the lower part of the uterine tubes.78

Once in the isthmus portion of the uterine tube, many spermatozoa attach to the wall. Chemical entities near the surface of the uterine tube wall remove several substances from the membrane overlying the acrosome. This enables these spermatozoa to significantly increase their mobility and to release acrosomal enzymes during fertilization.79 This process, called capacitation, is an absolute requirement for successful fertilization and requires 6 to 8 hours (some authors report capacitation is not completed until further interaction occurs with the cells of the corona radiata and that the process takes up to 72 hours80) before the spermatozoa are released and ready to continue their journey.81

The fully mature spermatozoa travel from the isthmus to the ampulla through a series of muscle contractions of the uterine tube and by swimming.82 The ampulla of the uterine tube has a very complex series of folds.83 The daunting task of finding a single oocyte in this maze is made possible because the oocyte releases a factor communicating its presence which the spermatozoa detect and follow (Figure coming soon).84

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Intro
Footnotes

1 Gasser, 1975. 1.
2 Guyton and Hall, 2000. 2; Lodish et al., 2000. 12.
3 Cunningham et al., 1993. 165.
4 Vindla and James, 1995. 598.
5 O'Rahilly and Müller, 1987. 2.
6 Spraycar, 1995. 377, 637.
7 Ayto, 1990. 199; O'Rahilly and Müller, 1987. 9; O'Rahilly and Müller, 2001. 87; Spraycar, 1995. 377.
8 Moore and Persaud, 2003. 3; Saunders, 1970. 1.
9 Spraycar, 1995. 1134.
10 Cunningham FG et al., 2001. 226; Moore and Persaud, 2003. 2; Moore and Persaud, 2003. 3; O'Rahilly and Müller, 2001. 87.
11 Moore and Persaud, 2003. 3.
12 O'Rahilly and Müller, 2001. 87.
13 Ayto, 1990. 199.
14 Cunningham FG et al., 2001. 226; Moore and Persaud, 2003. 3; O'Rahilly and Müller, 2001. 87; O'Rahilly and Müller, 2001. 92.
15 Moore and Persaud, 2003. 3.
16 Spraycar, 1995. 1177.
17 Spraycar, 1995. 1329.
18 Mall, 1918. 400; O'Rahilly and Müller, 1999b. 39; O'Rahilly and Müller, 2001. 88, 91.
19 Kacsoh, 2000. 508; Guyton and Hall, 2000. 933; O'Rahilly and Müller, 2001. 30.
20 Carlson, 2004. 28.
21 Kacsoh, 2000. 509.
22 Moore, 1980. 389-390.
23 Cunningham FG et al., 2001. 46-47.
24 Carlson, 2004. 17.
25 Cunningham FG et al., 2001. 39-40.
26 Moore, 1980. 385.
27 Moore and Persaud, 2003. 22.
28 Guyton and Hall, 2000. 936.
29 Cunningham FG et al., 2001. 41-42.
30 Moore, 1980. 385.
31 Cunningham FG et al., 2001. 43.
32 Moore, 1980. 385.
33 Moore and Persaud, 2003. 16.
34 Carlson, 2004. 409.
35 Sadler, 2004. 28.
36 O'Rahilly and Müller, 2001. 25.
37 O'Rahilly and Müller, 2001. 323; Sadler, 2004. 20; Moore and Persaud, 2003. 21.
38 Moore and Persaud, 2003. 21.
39 Borysenko et al. 1979. 205.
40 Sadler, 2004. 20.
41 Guyton and Hall, 2000. 930.
42 Guyton and Hall, 2000. 846.
43 Guyton and Hall, 2000. 848 & 929.
44 Guyton and Hall, 2000. 846-847; Carlson, 2004. 17.
45 Moore and Persaud, 2003. 25; Sadler, 2004. 23; Carlson, 2004. 20; Sadler, 2004. 31.
46 Guyton and Hall, 2000. 930.
47 Bloom and Fawcett, 1975. 863.
48 Moore and Persaud, 2003. 20.
49 Borysenko et al. 1979. 205.
50 O'Rahilly and Müller, 2001. 25 & 27.
51 Guyton and Hall, 2000. 931.
52 Borysenko et al. 1979. 205; Sadler, 2004. 21 & 23.
53 Guyton and Hall, 2000. 931; O'Rahilly and Müller, 2001. 25.
54 Sadler, 2004. 23; O'Rahilly and Müller, 2001. 25.
55 Guyton and Hall, 2000. 932; Carlson, 2004. 27.
56 Sadler, 2004. 23-24.
57 Moore and Persaud, 2003. 26.
58 Carlson, 2004. 27.
59 Guyton and Hall, 2000. 932.
60 Moore and Persaud, 2003. 28.
61 Carlson, 2004. 28; Carlson, 2004. 21; Sadler, 2004. 35.
62 Carlson, 2004. 29.
63 Guyton and Hall, 2000. 936.
64 Sadler, 2004. 35; Carlson, 2004. 29-30.
65 Guyton and Hall, 2000. 936; Carlson, 2004. 21.
66 Guyton and Hall, 2000. 936.
67 Carlson, 2004. 21.
68 Guyton and Hall, 2000. 937.
69 Moore and Persaud, 2003. 16.
70 O'Rahilly and Müller, 2001. 25; Sadler, 2004. 28.
71 Guyton and Hall, 2000. 916; Carlson, 2004. 13-14; O'Rahilly and Müller, 2001. 23-24; Sadler, 2004. 24-27; Moore and Persaud, 2003. 20.
72 Sadler, 2004. 26; Moore and Persaud, 2003. 307.
73 Moore and Persaud, 2003. 20.
74 Sadler, 2004. 26.
75 Guyton and Hall, 2000. 919; Carlson, 2004. 14-15.
76 Moore and Persaud, 2003. 21.
77 Carlson, 2004. 31.
78 Carlson, 2004. 31; Moore and Persaud, 2003. 30.
79 Guyton and Hall, 2000. 919.
80 O'Rahilly and Müller, 2001. 24.
81 Sadler, 2004. 38.
82 Moore and Persaud, 2003. 30.
83 Carlson, 2004. 16; Cunningham FG et al., 2001. 47.
84 Moore and Persaud, 2003. 31.