Chapter 9: Reproductive Physiology

Overview

The male and female gonads and the genitalia develop from common precursors in the first weeks of embryonic life, but the final stages of sexual differentiation are not completed until puberty. Human reproduction and sexuality are unique in that they are defined by recreation and pleasure in addition to procreation; physiological and psychological satisfaction are both of central importance. In sexually mature males, millions of gametes (spermatozoa) are continually produced by the testes, whereas in females, fertility is cyclical and yields a single gamete (oocyte) approximately once per month. If intercourse occurs at the appropriate time, ejaculation of sperm into the female reproductive tract enables the fertilization of the oocyte by a single sperm. Implantation of the developing embryo occurs in the uterus, and is rapidly followed by development of the placenta. The normal gestation period of 40 weeks ends with labor and parturition (childbirth). The final differentiation of the female breast occurs during pregnancy to allow lactation and breast-feeding. The complex events in male and female reproductive physiology are orchestrated by the pituitary, the gonadal, and (during pregnancy) the placental hormones.

Sexual differentiation refers to the transformation of the undifferentiated gonads of the early embryo into functional male and female reproductive systems. Anatomic differentiation occurs in utero, but the final maturation that produces fully functional reproductive organs is not completed until puberty.

Reproductive Embryology

The process that determines whether male or female reproductive organs develop depends on the complement of sex chromosomes present; female gametes (oocytes) all have the same 22X chromosomal makeup, whereas male gametes (spermatozoa) are either 22X or 22Y. The chromosomal sex of the fetus is determined at fertilization when the male and female gametes combine; XX is female and XY is male.

The default phenotypic sex is female if the fetus does not have a Y chromosome. The presence of a Y chromosome directs the undifferentiated gonad to become a testis rather than an ovary. A single gene (SRY), located in the sex-determining region of the Y chromosome, is required for male sexual differentiation.

Before sexual differentiation begins, the fetus has developed two parallel duct systems located near the undifferentiated gonads: the mesonephric (wolffian) duct and the paramesonephric (müllerian) duct (Figure 9-1). By week 10 of gestation, the fetal gonads can be distinguished as either testes or ovaries.

• In males, the primordial germ cells have given rise to precursors of male gametes called spermatogonia, which, together with support cells called Sertoli cells, form the germinal epithelium that will later generate male gametes. The mesenchyme surrounding the germinal epithelium gives rise to interstitial cells called Leydig cells, which secrete testosterone.

• In females, the primordial germ cells give rise to precursors of female gametes called oogonia. The epithelium surrounding the oogonia differentiates into granulosa cells, and the surrounding ovarian mesenchyme becomes thecal cells. In the sexually mature female, estrogens and progestins are secreted by the granulosa and theca cells.

Differentiation of the genitalia depends only on the presence or absence of hormones secreted by the testes. In the male fetus, the secretion of testosterone by Leydig cells directs each mesonephric duct to develop into an epididymis, a vas deferens, and a seminal vesicle (Figure 9-1). Leydig cells produce testosterone in response to the hormone human chorionic gonadotropin (hCG), which is secreted by the placenta. At the same time, the developing Sertoli cells are directed by SRY to secrete müllerian-inhibiting substance, causing regression of the müllerian duct system. Fetal ovaries are not necessary for the development of the female genitalia, which are able to continue to develop due to the high concentration of maternal estrogens that are present during pregnancy. The absence of the müllerian-inhibiting substance in the female fetus allows the müllerian duct system (instead of the wolffian duct) to develop, forming the fallopian tubes, the uterus, and the upper vagina (see Figure 9-1).

Undifferentiated external genitalia consist of a genital tubercle and a urogenital slit, bounded by two lateral genital folds and two labioscrotal swellings (Figure 9-2A). In males, the conversion of testosterone to dihydrotestosterone, via the enzyme 5 α-reductase within these target tissues, is necessary for formation of the prostate gland and the male external genitalia. The genital folds fuse to form the penis, and the enlargement and fusion of the labioscrotal swellings form the scrotum (see Figure 9-2B). Descent of the fetal testes into the scrotum requires the secretion of the fetal gonadotropins and occurs during the last trimester of pregnancy.

Cryptorchidism is the incomplete descent of the testis from the abdominal cavity to the scrotum, and is associated with testicular malignancy and infertility. In the setting of unilateral cryptorchidism, the fully descended testis may remain at risk of impaired sperm production or of becoming malignant.

In females, the urogenital slit remains open to form the introitus (vaginal opening); the labia minora are formed from the genital folds, and the clitoris forms anterior to the urethral opening. The labia majora are formed from the labioscrotal swellings. Exposure of the female fetus to androgens at this critical time of sexual differentiation can result in masculinization of the fetus, regardless of the genetic or gonadal sex.

Virilization of a fetus refers to a genetic female with normal ovaries and müllerian duct structures (e.g., fallopian tubes, uterus, and upper vagina), but with masculinization of the external genitalia (e.g., clitoromegaly, large phallus, and fusion of the labioscrotal folds to form a scrotum) due to excessive in utero exposure to androgens.

Male Pseudohermaphroditism

Sexual differentiation can be abnormal in genetically male or female infants. Male pseudohermaphroditism occurs when the testes are present and the external and possibly internal genitalia have a female phenotype.

Complete androgen insensitivity (testicular feminization) results from the lack of functional androgen receptors. This condition illustrates the role of steroids in sexual differentiation.

• Dihydrotestosterone cannot direct the wolffian duct to develop into male genitalia; the testes remain undescended.

• Müllerian-inhibiting substance continues to be secreted from the Sertoli cells, resulting in the absence of the female internal genitalia. Patients have a short, blind-ended vagina without a cervix, uterus, or ovary.

• Failure of masculinization during puberty is due to the lack of androgen receptors. The low levels of estrogens present cause breast development at puberty, but there is only a small amount of pubic hair. Diagnosis is often determined following failure of the onset of the menstrual cycle.

A cause of male pseudohermaphroditism is deficiency of the enzyme 5 α-reductase, which prevents the conversion of testosterone to dihydrotestosterone. The weaker androgenic effects of testosterone produce varying degrees of failure of the genital and labioscrotal folds to close. The presence of masculinization at puberty distinguishes this condition from complete androgen insensitivity.

Female Pseudohermaphroditism

Ambiguous genitalia in a genetically female infant most commonly results from congenital adrenal hyperplasia. The most common example of congenital adrenal hyperplasia is deficiency of the enzyme 21α-hydroxylase in the steroid synthesis pathway, which results in excessive production of adrenal androgens and virilization of a female fetus (see Chapter 8, Adrenal Glands).

Puberty

Puberty is the final stage in the process of sexual differentiation and results in the mature individual, with the development of physical and behavioral attributes that allow reproduction. Adrenarche, which precedes puberty, is the stage of maturation when the contribution of the adrenal glands occurs before the visible onset of puberty, with increased secretion of adrenal androgens in both males and females. Adrenarche occurs at about 6 to 8 years of age and is independent of adrenocorticotropic hormone (ACTH) or gonadotropins. Increasing levels of the adrenal androgens initiate axillary and pubic hair growth during this time.

The first endocrine event of puberty is an increase in the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which occurs during sleep. This increase is due to the loss of inhibition of the gonadotropin-releasing hormone (GnRH) pulse generator within the central nervous system. Toward the beginning of puberty, there is a marked diurnal cycle of LH and FSH secretion, which disappears after puberty. Figure 9-3 shows the typical time course of changes that occur in males and females between the ages of 6 and 21 years. Puberty visibly begins in males between 9 and 14 years of age, with enlargement of the testes; in females, visible puberty begins between 8 and 10 years of age, with breast enlargement (thelarche). Other secondary sexual characteristics appear over the next 2.5 years. In males, the first ejaculation (thorarche) occurs between the ages of 12 and 14 years; in females, the first menstrual cycle (menarche) occurs between the ages of 11 and 14 years.

Pubertal changes in males include:

• Increased size and maturation of the testes, involving secretion of testosterone by Leydig cells and spermatogenesis in the seminiferous tubules. Enlargement of the testes in puberty results from FSH secretion and can be used as a clinical indicator of normal function in the developing hypothalamic-pitu­itary axis.

• Enlargement of the scrotum and penis.

• Male secondary sexual characteristics develop as testosterone levels increase, and include increased and thickened hair on the axilla, face, trunk, and pubis. Bone mass and the mass and strength of skeletal muscle also increase. There is deepening of the voice and enlargement of the larynx.

Gynecomastia, or enlargement of the male breast, can be a pathologic condition. However, normal physiologic gynecomastia occurs when estrogen levels are elevated, such as occurs during the neonatal period (due to high maternal estrogen levels) or during normal male puberty (due to increased testosterone secretion, which is converted to estrogen). Gynecomastia may also occur in elderly men due to increased conversion of testosterone to estrogen.

Pubertal changes in females include:

• Breast development, which is mainly a response to the increasing levels of ovarian estrogen secretion. Breast development is characterized by growth of the lactiferous duct system and deposition of fat. Final differentiation and development of the breast only occurs during pregnancy.

• Establishment of the monthly ovarian cycle requires maturation of the hypothalamic-pituitary-ovarian axis (see Menstrual Cycle). First, there is an increase in FSH and LH secretion; next, ovarian steroid secretion occurs in response to gonadotropin; and finally, there is development of a midcycle positive feedback response to estrogen, causing an LH surge that initiates ovulation. Initial menstrual cycles may be anovulatory and are often irregular as the hormonal axis matures.

• Secondary sexual characteristics in females include enlargement of the uterus, the labia minora, and the labia majora, and keratinization of the vaginal mucosa. There is widening of the pelvis and deposition of fat on the hips and thighs.

Pubertal Growth Spurt

A dramatic growth spurt occurs in both males and females during puberty. Somatic growth is primarily controlled by the growth hormone (GH)–insulin-like growth factor (IGF)-1 axis (see Chapter 8). Increased LH and FSH secretion at the beginning of puberty occurs together with increased GH secretion. The increase in GH secretion is caused by increasing estrogen levels in both sexes; in males, estrogen is produced from testosterone via the enzyme aromatase. The highest rates of GH secretion occur during puberty because the strength of negative feedback inhibition of GH secretion by IGF-1 is weak. After puberty, the rate of GH production declines with age.

Sex steroids are responsible for closure of the epiphyseal growth plates in long bones. Early exposure to sex steroids is likely to result in short adult stature. On average, men are 10–15 cm taller than women, which can be attributed to two phenomena:

1. Growth during the pubertal growth spurt is more rapid in males than in females.

2. Puberty occurs later in males, allowing about 2 additional years of prepubertal growth before closure of the epiphyseal plate is stimulated by sex steroids. Linear growth is completed in females by about age 17 and in males by about age 21.

Precocious puberty refers to early pubertal development, often before 8 years of age in girls and before 9 years of age in boys. In addition to early sexual maturation, increased linear growth and skeletal maturation are also common features in both boys and girls. As a result, children who experience precocious puberty are often tall for their age during childhood, but short for their age during adulthood.

The major components of the male reproductive system are shown in Figure 9-4. The reproductive function of the penis is vaginal penetration during sexual intercourse, allowing ejaculation of semen into the vagina. Semen contains spermatozoa (male gametes), which are produced in the testis. Most of the volume of semen is seminal plasma, which is composed of secretions from the seminal vesicles and the prostate gland. Spermatozoa contribute about 10% of semen volume, producing a final sperm count of approximately 20–50 million spermatozoa per mL of semen.

The Testis

The paired testes are located outside the abdominal cavity, in the scrotum. The two major functions of the testis are:

1. Spermatogenesis (production of spermatozoa), which occurs in numerous coiled tubes called seminiferous tubules (see Figure 9-4B). The testes are located outside the abdominal cavity within the scrotum and are maintained at a temperature about 2°C below normal body temperature, which is necessary for spermatogenesis to occur. Spermatogenesis is strongly inhibited by heat.

2. Testosterone secretion. Steroid-producing Leydig cells are interstitial cells scattered between seminiferous tubules.

The Epididymis and the Vas Deferens

The ducts of the seminiferous tubules exit the testis and converge to form a comma-shaped structure that lies behind the testis, called the epididymis. The duct of the epididymis is a single, highly coiled tube, about 6-m long. It is formed from the convergence of the seminiferous tubules at the upper pole of the testis; the tail of the epididymis is continuous with the vas deferens at the lower pole of the testis. Final maturation of spermatozoa occurs during their storage in the epididymis.

Cystic fibrosis affects the lungs and pancreas and also the genitourinary tract. More than 95% of males diagnosed with cystic fibrosis have azoospermia due to obliteration of the vas deferens by thick, tenacious fluid secretions. Approximately 20% of women with cystic fibrosis are infertile due to abnormal fluid transport in the cervix and fallopian tubes.

The vas deferens is a muscular tube that expels spermatozoa to the urethra during ejaculation. It passes up behind the testis, enters the abdomen via the inguinal canal, and follows a course around the abdominal and pelvic walls. The vas terminates by joining the duct of the seminal vesicle to form the ejaculatory duct. The ejaculatory ducts on each side pierce the prostate gland and empty into the first portion of the urethra, just below the bladder. At ejaculation, spermatozoa combine with secretions from the seminal vesicles.

The Seminal Vesicles and the Prostate Gland

The paired seminal vesicles are glandular outpouchings of the vas deferens, located behind the bladder. Seminal vesicles secrete about 70% of semen by volume and produce an electrolyte fluid, rich in fructose, for the nourishment of ejaculated spermatozoa within the female reproductive tract.

The prostate gland surrounds the first portion of the urethra and consists of lobules that drain directly into the urethra through small ducts. Prostate secretion is an electrolyte fluid, rich is acid phosphatase. The prostate gland contains smooth muscle, which contracts to deliver secretions into the urethra during a phase called emission, just prior to ejaculation.

Benign prostatic hyperplasia (BPH) causes enlargement of the prostate, typically in the periurethral zone. Impedance of urinary flow is a common finding in BPH. In contrast, prostate cancer most commonly arises in the peripheral (outer) zone of the prostate; urinary obstruction becomes a late complication.

Male External Genitalia

The functions of the penis are urination and (after puberty) intercourse. The penis is composed of three columns of erectile tissue: two corpora cavernosa and the corpus spongiosum. The penile urethra traverses the corpus spongiosum, which ends as the expanded glans penis; urine and semen exit via the external urethral meatus of the glans. The prepuce, or foreskin, is a retractable fold of skin covering the glans penis, which is often surgically removed by circumcision.

Congenital anomalies of the penis include hypospadias and epispadias. Hypospadias is an abnormality in which the urethral opening is on the ventral surface of the penis and occurs when the urethral folds fail to fuse during development. Epispadias is a malformation in which the urethral opening is on the dorsal surface of the penis.

Spermatogenesis

The three phases of spermatogenesis are:

1. Proliferation of spermatogonia to produce a large population of cells. Once a spermatogonium undergoes its final mitotic division, it becomes a primary spermatocyte.

2. Generation of genetic diversity by meiosis. After the first meiotic division, the developing gametes are called secondary spermatocytes; after the second (final) meiotic division, gametes are called spermatids.

3. Maturation of sperm with specializations that allow the journey to the oocyte within the female reproductive tract. Dramatic cellular remodeling of spermatids produces sper­matozoa in a process called spermiogenesis.

The seminiferous epithelium consists of cells in the various stages of spermatogenesis. Moving from the periphery of a seminiferous tubule toward the lumen, germinal cells are progressing in their development from spermatogonia to spermatozoa (Figure 9-4B). Developing spermatocytes are embedded in cytoplasmic extensions from the large nongerminal Sertoli cells, which provide support and nutrition. The process of spermiation involves the release of spermatids from contact with Sertoli cells into the tubule lumen as spermatozoa.

Approximately 74 days are needed to produce mature spermatozoa from spermatogonia. Spermatozoa remain in the seminiferous tubule for about 60 days but have not yet acquired the motility needed to swim to the ovum within the female reproductive tract. Final maturation of spermatozoa in the epididymis takes approximately 2 weeks. Mature spermatozoa have a head region containing the nucleus, which is surrounded by a large secretory vesicle, the acrosome; there is a middle connecting section, which is rich in mitochondria, and a tail region, which provides a swimming action (Figure 9-5).

Endocrine Control of Spermatogenesis

LH and FSH are secreted from the anterior pituitary under the control of GnRH from the hypothalamus. LH stimulates Leydig cells to produce testosterone, which enters the systemic circulation and also diffuses locally into the seminiferous tubules. FSH stimulates the Sertoli cells, resulting in the secretion of androgen-binding protein into the lumen of the seminiferous tubule. The function of androgen-binding protein is to increase the local concentration of testosterone at the site of spermatogenesis (Figure 9-6). FSH stimulates the secretion of inhibin from the Sertoli cells, which exerts negative feedback on FSH secretion by the anterior pituitary. Testosterone exerts negative feedback on the secretion of both FSH and LH.

Erection, Emission, and Ejaculation

Penile erection is necessary for intercourse to occur and is controlled by the parasympathetic nervous system. Erotic stimuli increase efferent parasympathetic activity, causing relaxation of vascular smooth muscle and vasodilation of penile blood vessels. Nitric oxide (NO) is the most important transmitter causing vasodilation in erectile tissue through the second messenger cyclic guanosine monophosphate (cGMP). NO may be released directly from parasympathetic nerve endings, or it may be produced in response to acetylcholine release. Erection can occur via a spinal reflex, by stimulation of the glans penis, or the perineum. It can be induced (or suppressed) by psychogenic stimuli from higher centers at the level of midbrain and amygdala. An erection results when vasodilation causes the sinusoidal spaces within erectile tissue to fill with blood. Expansion of the corpora cavernosa compresses venous outflow, further increasing rigidity of the penis. The corpus spongiosum does not contribute significantly to penile rigidity because the urethra must remain patent for passage of the ejaculate.

Impotence or erectile dysfunction can be related to many conditions, including endocrine disorders (e.g., diabetes mellitus or low testosterone levels due to hypogonadism), drugs (e.g., antihypertensives or antidepressants), vascular disease, or psychogenic causes (e.g., stress). Sildenafil (Viagra) is a drug that is taken orally and can be used to treat some types of erectile dysfunction. Sildenafil inhibits phosphodiesterase type V, the enzyme responsible for breaking down cGMP. By inhibiting this key enzyme, sildenafil potentiates the effects of cGMP, prolonging vasodilation of the erectile tissues.

As ejaculation approaches, there is sequential contraction of smooth muscle in the vas deferens, the prostate, and the seminal vesicles, which results in spermatozoa and seminal plasma moving into the urethra. This is called the emission phase and is coordinated by sympathetic nerves. At ejaculation, semen is ejected forcefully from the urethra; contraction of the internal bladder sphincter (by sympathetic neural stimulation) prevents retrograde ejaculation. Ejaculation is largely an involuntary spinal reflex that occurs after the entry of semen into the urethra during emission. Forceful contractions of the perineal musculature and pelvic floor are coordinated through somatic innervation via the pudendal nerve. Orgasm is the pleasurable sensation, which, in males, accompanies ejaculation.

If the internal bladder sphincter does not contract properly, the ejaculate can travel up the urethra and into the bladder, a condition known as retrograde ejaculation. Dysfunction of the internal bladder sphincter can result as a complication of diabetes mellitus, use of drugs (e.g., antidepressants), or prostate surgery (e.g., transurethral resection of the prostate, a surgical treatment for benign prostatic hyperplasia).

The major components of the upper female reproductive tract are shown in Figure 9-7. The ovaries normally release a single oocyte (ovum or egg) into the reproductive tract, which occurs approximately once per month. The oocyte travels along a fallopian tube to a hollow muscular organ, the uterus. The fallopian tube is the normal site where fertilization of the ovum by a single sperm cell occurs; the uterus is the site of implantation and development of the embryo.

The lower reproductive tract consists of the vagina and the vulva (external genitalia). The functions of the vagina are to receive the penis during intercourse and to temporarily retain semen. The vagina and vulva also comprise the lowest part of the birth canal.

The Ovaries and the Fallopian Tubes

The paired ovaries are the female gonads. There is one ovary located laterally on each side of the pelvis. The ovary is the site of gametogenesis (oogenesis) and the major source of the sex steroids. The histologic appearance of the ovary varies throughout the ovarian cycle; oocytes in various stages of development within follicles, as well as a temporary endocrine gland, the corpus luteum, may be seen (Figure 9-8).

The fallopian tubes transport the ovum and sperm to the site of fertilization, and transport the zygote to the site of implantation in the uterus. There is one fallopian tube associated with each ovary and each one has four areas (Figure 9-7):

1. The most distal part of a fallopian tube is funnel-shaped and bears finger-like projections called fimbria, which receive the ovum when it is released from the ovary at ovulation. A ciliated epithelial lining propels the ovum along the fallopian tube toward the uterus.

2. The usual site of fertilization of the oocyte is a dilated area called the ampulla.

3. A narrow portion, called the isthmus, helps to retain the early embryo within the tube for 2–3 days after fertilization. During this time, there is final maturation of the endometrium (lining of the uterus) to facilitate implantation of the embryo.

4. Each fallopian tube has an intramural portion, where it joins the hollow uterus. The point of entry of the fallopian tube is called the cornua of the uterus.

Pelvic inflammatory disease (PID) is caused by an ascending sexually transmitted disease. PID is most commonly due to chlamydia and gonorrhea, and ascends from the cervix to the endometrium, to the fallopian tubes, and to the pelvic cavity. As a complication, the fallopian tubes can become scarred, increasing the risk of an ectopic tubal pregnancy, which is a potentially fatal condition! The most common site of implantation of an ectopic pregnancy is the ampulla of the fallopian tube.

The Uterus

The uterus is a pear-shaped muscular organ within the pelvis, located between the bladder and rectum. The function of the uterus is to support the growing fetus during pregnancy. There is dramatic growth of the uterus during pregnancy, occurring by a process of both muscle cell hyperplasia and production of new muscle cells from the resident stem cells. During parturition (childbirth), the uterine smooth muscle contracts powerfully to expel the fetus. The uterus is supported in position by several connective tissue ligaments. Damage to the uterine ligaments (e.g., during childbirth) may result in prolapse of the uterus downward into the vagina.

Pelvic relaxation most commonly results from mechanical trauma related to childbirth. Complications of pelvic relaxation include uterine prolapse, cystocele (bulging of the anterior vaginal wall and bladder into the vagina), rectocele (bulging of the posterior vaginal wall and rectum into the vagina), enterocele (herniation of the pouch of Douglas containing small intestine into the vagina), and urinary stress incontinence (leakage of urine during coughing, sneezing, or laughing).

The structure of the uterus includes three areas:

1. The fundus is the area above the openings of the fallopian tubes.

2. The corpus is the main body of the uterus. The lower third of the corpus is called the lower uterine segment. Contraction of this area draws the dilated cervix (lowest part of the uterus) upward during labor.

3. The cervix is about 4-cm long and is mainly composed of connective tissue; this contrasts with the corpus, which is mainly composed of smooth muscle. Approximately half of the cervix protrudes into the upper vagina. The cervical canal joins the vaginal lumen and uterine cavity, and is lined by a mucous-secreting epithelium. The properties of cervical mucus change significantly during the menstrual cycle. About the time of ovulation at midcycle, under the influence of high estrogen and low progesterone, the mucus is thin and readily allows passage of sperm. A sample of cervical mucus placed on a microscope slide at this time dries in a fern-like pattern, hence the term ferning of cervical mucus. Later in the menstrual cycle, high concentrations of progesterone promote the secretion of thicker mucus, which resists the passage of sperm.

Cervical cancer most commonly occurs at the squamocolumnar junction, which is the transition zone between vaginal epithelium and cervical epithelium. The most effective screening tool for the detection of cervical cancer was developed by George Papanicolaou and is known as the Pap smear. Cells collected from the cervical squamocolumnar junction are stained with the multichromatic Papanicolaou's stain and examined under the microscope for signs of dysplasia. Infection with human papillomavirus (HPV), including types 16 and 18, plays an important etiologic role in the development of cervical cancer. HPV viral proteins have the capacity to inactivate tumor-suppressor genes, which may explain the carcinogenic effects of the virus. The recent development of an HPV vaccine (Gardasil) protects women from persistent infection with the virus and may significantly alter the epidemiology of cervical cancer in the future.

Endometrium

The endometrium is the epithelial lining of the uterus and undergoes dramatic changes during the monthly cycle. There are three phases of the monthly menstrual cycle:

1. The proliferative phase occurs in the first half of the cycle prior to ovulation and is under the influence of high estrogen levels. During this time, there is marked thickening of the endometrium, growth of the endometrial glands, and the appearance of spiral arteries.

2. The secretory phase occurs after ovulation, during the second half of the monthly cycle when there is progesterone dominance. There is copious secretion of progesterone from the endometrial glands in preparation for implantation of an embryo at this time.

3. The menstrual phase occurs if implantation of an embryo does not occur; progesterone levels decrease toward the end of the cycle, causing the uterine spiral arteries to spasm. Tissue necrosis and bleeding (menses) occurs, usually over a period of 4–5 days, as the endometrial lining sloughs off.

The Vagina and the Vulva

The vagina is a tube that extends from the vaginal opening (introitus) to the cervix. Many mucus-secreting glands line the introitus and are stimulated during intercourse to provide lubrication. The largest and most important of these glands is Bartholin's gland, which is located posterolaterally. The vulva is the collective name for the female external genitalia and comprises the lower third of the vagina, the labia, and the clitoris (Figure 9-9). The clitoris is the female homologue of the penis and consists of erectile tissue of the paired corpora cavernosa, ending in the highly sensitive glans clitoris. The urethral opening lies between the clitoris and the introitus.

Condyloma acuminatum (or genital warts) can occur in men or women. HPV types 6 and 11 have been associated with this contagious venereal disease.

Oogenesis

Oogenesis is the process through which the mature female gamete is formed. Oogenesis begins in fetal life but is not completed until the time of fertilization. The proliferation of oogonia by mitosis ends midway through fetal life, at which time oocytes are arrested in the first meiotic division. Thereafter, the number of oocytes gradually declines with age; there are about 1–2 million oocytes at birth and about 100,000 at puberty. Oocytes may be stimulated to develop for release at ovulation, or they will die through a process called atresia.

Oogenesis occurs in the ovary within structures called follicles. Each unstimulated follicle contains a single primary oocyte surrounded by a single layer of granulosa cells, which in turn are associated with thecal cells. With each monthly menstrual cycle, several follicles are stimulated to develop, but only one will become the dominant follicle that continues to ovulation.

• The oocyte and granulosa cells in developing follicles enlarge.

• A clear gelatinous ring of extracellular matrix appears around the oocyte, called the zona pellucida.

• The dominant follicle becomes a graafian follicle (Figure 9-10). After the LH surge, the oocyte within a graafian follicle completes the first meiotic division to become a secondary oocyte.

• Rupture of the graafian follicle at ovulation expels the oocyte into the peritoneal space near the fimbria of the fallopian tube.

• The ruptured follicle collapses and granulosa cells proliferate to fill the space. Under the influence of LH, structural transformation to the corpus luteum occurs.

Trisomy (e.g., trisomy 21, also known as Down syndrome) is associated with increased maternal age. The mechanism that causes trisomy is thought to be related to prolonged arrest of the first meiotic division and age-dependent degradation of the meiotic proteins in the primary oocyte. The first meiotic division is arrested during fetal life and is not completed until that particular oocyte is “chosen” to become the dominant follicle for ovulation.

The Menstrual (Ovarian) Cycle

The cyclic activity of the hypothalamic-pituitary-ovarian axis results in ovulation and the simultaneous development of a uterine environment that is capable of supporting pregnancy, should fertilization occur. The terms menstrual cycle and ovarian cycle are both used to describe a sequence of events that recurs approximately every 28 days. The first day of menstrual bleeding defines day 1 of a menstrual cycle. From the perspective of events taking place in the ovary, the cycle is divided into three phases (Figure 9-11):

1. The follicular phase (days 1–14). The follicular phase is the first half of the menstrual cycle. Toward the end of the previous cycle, the corpus luteum dies, resulting in a sharp decrease in the blood levels of progesterone, estrogen, and inhibin. The loss of negative feedback inhibition of FSH secretion allows plasma FSH concentration to increase. Under the influence of FSH, a cohort of primary follicles develops (a process that begins in the final 2–3 days of the previous cycle).

   • Granulosa cells secrete estrogen and inhibin under the influence of FSH, accounting for the increase in plasma concentration of these hormones during the follicular phase (Figure 9-11). Granulosa cells rely on a supply of androgens from thecal cells as a substrate for estrogen production. By the midfollicular phase, FSH secretion is suppressed, preventing the recruitment of more follicles.

   • A dominant follicle emerges, which has high sensitivity to FSH, and continues to develop and to secrete estrogen, despite the now low levels of circulating FSH. The less dominant follicles undergo atresia and die, leaving a single oocyte for release at ovulation.

2. The ovulatory phase (days 13–15). Ovulation occurs at the midpoint of a normal menstrual cycle. It is triggered by an LH surge and occurs about 12 hours after the peak LH concentration (Figure 9-11). The dominant follicle signals its maturity to the pituitary gland by a rapid increase in estrogen secretion, which exerts positive feedback on the anterior pituitary by sensitizing it to GnRH.

   • When the LH surge occurs, the primary oocyte completes the first meiotic division to form a larger secondary oocyte, which stops in the second meiotic division until fertilization.

   • Ovulation occurs due to thinning and rupture of the dominant follicle, under the influence of LH, progesterone, and locally released prostaglandins.

   • The released oocyte is surrounded by the zona pellucida and granulosa cells. The oocyte is guided into the fallopian tube by fimbria and is propelled toward the uterus by the ciliated epithelial lining cells of the fallopian tube.

3. The luteal phase (days 15–28). After ovulation, the corpus luteum is formed, under the influence of LH by differentiation of both theca and granulosa cells, into theca-lutein and granulosa-lutein cells, respectively. Progesterone is the major secretory product of these cells, although both estrogen and inhibin are also secreted. During the luteal phase, high levels of estrogen are unable to induce another LH surge in the presence of high progesterone levels.

   • If pregnancy does not occur, the corpus luteum spontaneously degenerates. Continued progesterone secretion by the corpus luteum is essential to early pregnancy. If implantation of an embryo occurs, the trophoblast cells of the developing placenta secrete the LH analogue hCG, which supports the corpus luteum until the developing placenta assumes the production of progesterone.

Menopause

Menopause is a normal stage of life—the physiologic effects of menopause can be viewed as a syndrome of “ovarian failure.” Cessation of menstruation is a universal feature of menopause. Withdrawal of estrogen is particularly important in accounting for the symptoms of menopause, which include insomnia, hot flushes, variable degrees of vaginal atrophy, and decreased breast size. Estrogen deficiency causes bone loss and increases the risk of osteoporosis.

During menopause, there is marked reduction of estrogen and progesterone concentrations. The loss of ovarian function removes negative feedback on GnRH, producing high serum concentrations of FSH and LH. FSH levels are particularly high in postmenopausal women because inhibins, which exert selective negative feedback on FSH secretion, are no longer produced by the ovary.

Despite the proposed cardioprotective effects of estrogen, the leading causes of death are similar in men and women: (1) cardiovascular disease, (2) cancer, and (3) stroke. The Women's Health Initiative studied the effects of hormone replacement therapy (combined use of estrogen and progestin, known as HRT) on postmenopausal women. The results showed that, compared to women in the placebo group, women on HRT had higher rates of breast cancer, coronary heart disease, stroke, and pulmonary embolism. The only benefits noted were reduced rates of hip fracture and colon cancer. These findings from the Women's Health Initiative have contributed to the controversy surrounding the use of combined estrogen and progestin.

Endometrial cancer is the most common malignant tumor of the female genital tract. It is primarily a disease of postmenopausal women and typically presents clinically as postmenopausal vaginal bleeding. Exposure to unopposed estrogen plays a critical etiologic role. Risk factors include obesity, nulliparity (no pregnancies), late menopause, chronic anovulation (e.g., polycystic ovarian syndrome), and use of estrogen replacement therapy.

Andropause occurs in men; there is reduced testosterone secretion, but the effects of andropause are usually mild compared to the effects of menopause in most women.

The physiology of human sexual responses is categorized in four phases as excitement, plateau, orgasm, and resolution. Physiologic changes during the human sexual response include vascular congestion, generalized muscle tension, and increased cardiorespiratory activity.

The Male Sexual Response

The four phases of the male sexual response are as follows (Figure 9-12A):

1. Penile erection is the first response to effective sexual arousal in the excitement phase, and can occur through psychogenic or reflexogenic stimulation.

2. During the plateau phase, there is a small increase in penile erection, the testes enlarge due to vascular congestion, and the scrotum contracts to draw the testes upward toward the perineum. Emission occurs shortly before ejaculation, depositing spermatozoa and seminal plasma into the posterior urethra.

3. With adequate stimulation, orgasm and ejaculation occur simultaneously. There is an intense subjective sensation of pleasure and release of sexual tension.

4. During the resolution phase, penile detumescence (return to the flaccid state) occurs in two stages. In stage 1, the penis quickly returns to about half its erect size and is totally refractory to further stimulation. In stage 2, the penis returns to its flaccid size over a longer period of time and is in a relative refractory state, when another full cycle of excitement through to orgasm may be possible.

The Female Sexual Response

The four phases of the female sexual response are as follows (Figure 9-12B):

1. Psychogenic and reflexogenic pathways function similarly in males and females during sexual arousal. Clitoral erection is a variable response in the excitement phase. Vaginal lubrication is a more consistent response. There is expansion of the upper vagina, and the labia minora enlarge, moving outward away from the vaginal introitus.

2. Engorgement and reddening of the labia minora are characteristics of the plateau phase.

3. Female orgasm produces rhythmic contractions of the perineum and reproductive organs. Intense subjective sensations of pleasure are followed by release of general skeletal muscle tone. Female orgasm differs from male orgasm in that there is no ejaculation response; female orgasm can last longer and there is no refractory period before additional orgasms can occur.

4. The resolution phase involves relaxation of the vagina and vascular decongestion of the reproductive organs.

Dysfunction of the sexual response cycle can occur at any stage; examples include desire disorders (more common in women), excitement disorders (e.g., inadequate vaginal lubrication), erectile dysfunction, anorgasmia (e.g., inadequate clitoral stimulation), dyspareunia (i.e., painful intercourse), and vaginismus (i.e., painful reflexive spasms of the paravaginal muscles inhibiting any vaginal penetration).

At ejaculation, 100–600 million sperm are deposited into the vagina. After a few minutes, a small number of sperm have already reached the fallopian tube. Sperm transport results from the sperm's swimming motion and is assisted by contractions of the uterus and fallopian tubes during female orgasm (if it occurs). The oocyte is propelled along the fallopian tube by the action of cilia. The sperm and egg usually meet in the dilated ampulla of the fallopian tube. Successful fertilization occurs within a short time window, several hours after ovulation. The fertilized egg is usually retained in the fallopian tube for about 3 days, where it divides into a solid mass of 12 or more cells called a morula. The morula develops into a blastocyst during the proceeding 3 days as it floats freely in the uterine cavity. Implantation of the blastocyst into the uterine endometrium occurs 6–7 days after ovulation.

Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. Approximately 17% of infertility is unexplainable, and 25% relates to male factors and about 58% relates to female factors.

Capacitation of Spermatozoa

Sperm must undergo a final maturation event to acquire the ability to penetrate the zona pellucida and fertilize the egg. This process is called capacitation and involves the removal of a protein coat that alters the membrane properties of the sperm. Capacitation occurs physiologically within the female reproductive tract, but it can also occur in vitro.

Stages of Fertilization

There are eight defined stages during fertilization of the egg by a sperm (Figure 9-13):

1. The sperm head penetrates the layer of follicular cells surrounding the egg and binds to specific proteins in the zona pellucida.

2. The sperm undergoes the acrosome reaction. The acrosome is a large secretory vesicle containing hydrolytic enzymes, located in the head of the sperm. Binding of the sperm head to the zona pellucida produces an increase in intracellular [Ca²⁺] in the sperm, resulting in exocytosis of the contents of the acrosome on to the zona pellucida.

3. The sperm penetrates the zona pellucida to reach the oocyte membrane.

4. The cell membranes of the sperm and egg fuse, releasing the sperm nucleus and cytoplasm into the egg cytoplasm. This event causes depolarization of the egg cell membrane, which deters binding of other sperm heads to the egg.

5. The egg undergoes the cortical reaction in which enzymes are released by the egg, via exocytosis, and results in hardening of the zona pellucida. The cortical reaction is caused by entry of the sperm nucleus, triggering a large inositol triphosphate-dependent increase in intracellular [Ca²⁺] in the egg. Together, with the egg cell membrane depolarization, hardening of the zona pellucida prevents entry of further sperm (polyspermy).

6. The Ca²⁺ signal of the cortical reaction triggers completion of the second meiotic division by the secondary oocyte. Unfolding of chromosomes occurs to produce the female pronucleus.

7. Chromosomes in the sperm nucleus decondense, producing the male pronucleus.

8. Male and female pronuclei fuse. The union of chromosomes from the male and female, called syngamy, marks the end of fertilization. A zygote is formed with 23 chromosomes from each parent. The chromosomal sex of the fetus has also been determined, depending on whether the sperm is 22X or 22Y.

Hydatidiform mole is a benign molar pregnancy that can be classified as either complete (most common) or incomplete. A complete hydatidiform mole results from fertilization of an empty egg with a single sperm, resulting in only paternally derived chromosomes. An incomplete hydatidiform mole results from fertilization of a normal egg with two sperm, resulting in triploidy (three sets of chromosomes). Molar pregnancies are incompatible with life.

Implantation

The fertilized egg develops for 6–7 days before implantation. Synchronized development of the fertilized egg and the endometrium are required for successful implantation. The endometrium is in the secretory phase, under the influence of progesterone from the corpus luteum. Endometrial secretions nourish the developing embryo within the lumen of the uterus prior to implantation. Fluid within the uterine cavity is gradually absorbed via finger-like projections of the endometrium, called pinopodes, which appear only at this time. Fluid absorption brings the embryo closer to the endometrium to facilitate contact and implantation.

During the time when the developing embryo is floating in the uterine cavity, a process called “hatching” occurs, in which the zona pellucida and the follicular cells surrounding the blastocyst degenerate to expose the underlying embryonic cells. The blastocyst stage of a developing embryo is spherical; a fluid-filled cavity is surrounded by a layer of cells called the trophoblast (Figure 9-14). The inner cell mass is a collection of cells on one side of the cavity that will develop into the embryo. Once hatching is complete, the trophoblast cells are able to come into direct contact with the endometrium.

Implantation occurs in the following three stages:

1. Apposition is the formation of a loose connection between the trophoblast and the endometrium.

2. Adhesion occurs through specific ligand-receptor interactions when microvilli extend from the trophoblast cells. Adhesion is followed by rapid proliferation of trophoblast cells and differentiation into two layers: an inner cytotrophoblast cell layer and an outer multinucleated layer facing the endometrium, called the syncytiotrophoblast.

3. Invasion of the endometrial stroma by the syncytiotrophoblast causes the embryo to become completely embedded in the endometrium.

After invasion by the syncytiotrophoblast, the entire endometrium undergoes further biochemical and morphologic change, called decidualization (decidual reaction), and forms the “membranes of pregnancy” called the decidua. Decidualization begins at the site of implantation and spreads in a concentric wave around the entire endometrium.

Choriocarcinoma is a malignant molar pregnancy that consists of both cytotrophoblasts and syncytiotropho­blasts. Due to the natural invasive nature of the syncytiotropho­blastic cells, it is of no surprise that this tumor is very invasive and hemorrhagic. The most common site of metastasis is hematogenous spread to the lung.

The Placenta

The placenta is formed by elements from both the mother and the fetus. The two general functions of the placenta are:

1. It is a transporting epithelium. Materials needed for fetal growth and development must pass across the placenta from the maternal to the fetal circulation.

2. It is an endocrine gland, secreting several hormones required for the maintenance of pregnancy.

The syncytiotrophoblast develops spaces within it called lacunae, as it invades deeper into the endometrium. When maternal blood vessels in the endometrial wall are invaded, these spaces fill with maternal blood (Figure 9-14). Lacunae eventually coalesce into a single blood-filled space, called the intervillous space. Chorionic villi begin to grow from the cytotrophoblast into the syncytiotrophoblast to make contact with lacunae. The intervillous space behaves like a giant capillary, with fresh maternal arterial blood entering from the uterine spiral arteries and leaving via the placental veins. Mature chorionic villi contain fetal blood capillaries at their core (Figure 9-15). Numerous chorionic villi project into the intervillous space, resembling a forest of trees “rooted” to a discrete area called the chorionic plate. Fetal blood flowing through the chorionic villi arrives via two umbilical arteries, which branch repeatedly as they enter the chorionic plate. Blood returns from the chorionic villi to the fetus via the umbilical veins. The maternal-fetal exchange barrier between fetal and maternal blood consists of the following three components:

1. The fetal capillary endothelium.

2. A layer of cytotrophoblast and fetal mesenchymal cells.

3. A layer of syncytiotrophoblast facing the maternal blood pool.

The most common cause of bleeding during the third trimester is due to separation of the placenta from the uterine wall, a condition known as placenta abruptio. This potentially fatal condition classically presents as painful vaginal bleeding in the third trimester.

Placental Transport

Transport across the placenta occurs by a combination of active and passive mechanisms. Oxygen and carbon dioxide move by simple diffusion; glucose is transported to the fetus by facilitated diffusion; and amino acids are mostly transported by secondary active transport. Large molecules such as low-density lipoproteins (LDL), antibodies, and other peptides (e.g., transferrin) are taken up by the syncytiotrophoblast via receptor-mediated endocytosis. Transport rates increase significantly in the final weeks of gestation, reflecting the accelerating growth rate of the fetus at this time.

Antibodies transported across the placenta augment the fetal immune system. The immune system of a newborn predominately consists of maternal IgG. However, at approximately 6 months of age, the infant's immune system must begin to assume the major role in defense against infection due to the degradation of the maternal IgG over time. Thus, immunodeficiency disorders (e.g., severe combined immunodeficiency [SCID]) do not begin to manifest until after 6 months of age.

Gas Exchange Across the Placenta

Umbilical arteries carry deoxygenated blood from the fetus to the placenta, and gas exchange with blood in the maternal intervillous space results in the return of oxygenated blood to the fetus via the umbilical veins. The average Po₂ of blood in the intervillous space is about 30–35 mm Hg, which, in adults, would only produce about 60% saturation of hemoglobin and would result in severely impaired arterial oxygen content (see Chapter 5). Fetal hemoglobin has a higher oxygen affinity than adult hemoglobin, allowing 80–90% saturation of hemoglobin with a Po₂ of only about 30 mm Hg in the umbilical venous blood (Figure 9-16).

The Pco₂ of umbilical arterial blood is about 50 mm Hg compared to the Pco₂ of about 42 mm Hg in the intervillous space. This diffusion gradient allows carbon dioxide excretion from the fetus to the mother; the carbon dioxide produced by the fetus is excreted via the maternal lungs.

There are several hormones (e.g., peptides, amines, and steroids) that are essential to the maintenance of pregnancy. The placenta is a key endocrine organ, particularly after the first few weeks of gestation. The time course over which the plasma concentration of several hormones increases during pregnancy is shown in Figure 9-17.

Placental Peptides

The two major placental peptides, which are only secreted during pregnancy, are human chorionic gonadotropin (hCG) and human chorionic somatomammotropin (hCS).

1. hCG is the most important peptide hormone produced by the placenta because it rescues the corpus luteum from degeneration and allows continued progesterone secretion to support the early pregnancy. At about 8–9 weeks’ gestation, the placenta will assume the production of progesterone. Thereafter, the plasma hCG concentrations decrease to lower levels but continue to be important for maintaining progesterone secretion by the syncytiotrophoblast. Placental hCG secretion is controlled in a paracrine manner by locally produced GnRH.

2. Levels of hCS (also called human placental lactogen) are high during pregnancy. hCS is structurally similar to GH and prolactin. Its metabolic effects are similar to those of GH, with suppression of maternal glucose use and reduced maternal insulin responsiveness, which may preserve glucose for fetal use. Fatty acids and ketones are important energy sources in the fetus and placenta, and hCS stimulates production of these substrates. Higher concentrations of hCS found later in pregnancy also promote mammary gland development.

Pregnancy tests can detect the unique appearance of hCG in urine in early pregnancy. These tests are able to detect hCG in maternal urine 7–10 days after fertilization. hCG is produced by the syncytiotrophoblast and will be elevated in cases of twin pregnancy, hydatidiform mole, and choriocarcinoma.

Steroid Hormone Production by the Maternal-Placental-Fetal Unit

Maternal levels of progesterone and estrogens are both much higher during pregnancy than at any time during the normal menstrual cycle. High steroid levels are necessary to support pregnancy. For example, progesterone is needed in the uterus to maintain the decidua and to relax the uterine smooth muscle to prevent early expulsion of the fetus. Beyond week 9 of gestation, most of the steroids present in the maternal circulation are secreted by the placenta.

The placenta is assisted by both the mother and fetus to provide all the necessary substrates and enzymes for steroid production, giving rise to the concept of a maternal-placental-fetal unit (Figure 9-18).

• Maternally derived LDL cholesterol is necessary for placental steroidogenesis because the placenta lacks enzymes needed to produce cholesterol from acetate. The placenta can produce progesterone when provided with a supply of cholesterol.

• The placenta lacks enzymes needed to produce estrogens but has very high aromatase activity to convert androgens to estrogens. The fetal adrenal glands supply the placenta with weak androgens for conversion to estrogens. These glands produce dehydroepiandrosterone sulphate (DHEA-S), most of which is converted to 16-hydroxy-DHEA-S by the fetal liver.

• Estriol (E3) is produced by the placenta from fetal 16-OH-DHEA-S. Normally, estriol is not an important estrogen, but it is considered the major estrogen of pregnancy. Estriol has weak estrogenic properties in most maternal organs, but increases uteroplacental blood flow.

• The fetus does not produce progesterone or estrogens, thereby avoiding exposure to high concentrations of these steroids. Although the fetus produces large amounts of weak adrenal androgens, masculinization of the female fetus does not occur because the placenta acts as a large sink for fetal androgens.

Maternal Hormones

The level of activity in several maternal endocrine axes is altered during pregnancy.

• In pregnant women, the total concentration of thyroid hormones (T₃ and T₄) is increased but the concentration of free T₃ and T₄ is normal. Estrogens stimulate the maternal liver to increase the synthesis of many proteins, including thyroid hormone-binding globulin. Increased levels of thyroid-binding globulin cause an initial decrease in free thyroid hormone concentration, which produces feedback stimulation of the hypothalamic-pituitary-thyroid axis to restore free T₃ and T₄.

• There is an increase in the maternal levels of parathyroid hormone (PTH) and vitamin D, which results in increased maternal Ca²⁺ uptake from the diet. The final activation of vitamin D₃ occurs in the placenta as well as in the kidney. Changes in the PTH-vitamin D axis are necessary to support the very high demand of fetal growth on the Ca²⁺ supply.

• The renin-angiotensin-aldosterone axis is upregulated in pregnancy, allowing the maternal blood volume to increase. Sensitivity to the pressor effects of angiotensin II is reduced to prevent high blood pressure.

Preeclampsia (also known as toxemia) is defined by pregnancy-induced onset of hypertension, proteinuria, and edema. Although the precise pathogenesis is unknown, pre­eclampsia results in systemic vasospasm and endothelial injury, causing multiorgan damage. If preeclampsia progresses to include seizure, the condition is referred to as eclampsia.

Numerous physiologic demands are placed on the mother by the fetus, which result in changes in virtually all of the maternal physiologic systems.

1. Blood volume increases 40–50% during pregnancy. The increase is necessary to provide a larger preload to meet the demands for increased cardiac output, to protect maternal venous return, and to provide a reserve against blood loss during childbirth. The increased maternal cardiac output supplies the increased demand from the pregnant uterus, the placenta, the kidney (for excretion), the skin (to liberate additional heat), the breast (developing in readiness for lactation), and the heart (to support increased cardiac work). The increase in maternal blood volume reflects an increase in both plasma volume and red cell mass. Plasma volume increases due to upregulation of the renin-angiotensin-aldosterone axis in response to high levels of estrogen and progesterone. The increase in plasma volume is greater than the increase in red cell mass, producing a dilutional anemia during pregnancy.

2. Blood coagulability increases to protect the mother from hemorrhage during childbirth.

   Pregnancy is a hypercoagulable state primarily because of increases in coagulation factors VII, VIII, and IX, and protein C. The hypercoagulable state of pregnancy predisposes the mother to the development of deep vein thrombosis and pulmonary embolism.

3. Alveolar ventilation increases due to the action of progesterone on the medullary respiratory centers. Increased alveolar ventilation results from an increase in tidal volume rather than increased respiratory rate. Maternal arterial Pco₂ decreases from about 40 mm Hg to about 30–34 mm Hg. The kidney compensates for this mild respiratory alkalosis and returns the plasma pH to normal by reducing the plasma bicarbonate concentration (see Chapter 6). When compared to the nonpregnant state, pulmonary function tests show a measurable decrease in residual volume and functional residual capacity because the diaphragm is displaced upward by the enlarged uterus.

4. The glomerular filtration rate increases by 40–50% by midpregnancy, with a consequent decrease in the concentrations of plasma creatinine and urea. Glucose appears in the urine in 10–20% of pregnant women because of increased filtered glucose load and relatively fixed tubular reabsorptive capacity for glucose.

5. Nutritional demands of pregnancy include notable increases in protein intake for growth of the fetus, placenta, uterus, and breasts. Maternal iron deficiency can develop due to the demands for production of fetal and maternal hemoglobin. Folate supplementation is also needed for increased hemoglobin synthesis as well as to reduce the risk of fetal neural tube defects.

6. Suppression of cellular immunity is important to avoid fetal rejection; however, this causes pregnant women to become more susceptible to viral infections.

Constipation is a common problem during pregnancy because of the effects of progesterone on smooth muscle. Progesterone slows gastric and colonic motility, thereby increasing transit time and subsequent fluid absorption, which results in constipation.

The gestation period is approximately 40 weeks, and is measured from the first day of the last menstrual period. Expulsion of the fetus, its placenta, and other membranes from the uterus occurs during labor. This process is characterized by thinning and dilation of the cervix and by strong regular contractions of the uterus. The four phases of uterine activity during pregnancy and labor are:

• Phase 0 is a long phase during which the uterus remains quiescent, under the influence of progesterone. The peptide relaxin, secreted by the corpus luteum, assists in maintaining the uterus in a relaxed state.

• Phase 1 represents activation of the uterus when close to term. In the weeks preceding parturition (childbirth), there is weak, low-frequency myometrial activity called contractures (also known as Braxton-Hicks contractions or false labor). In phase 1, there is increased myometrial expression of receptors for oxytocin and excitatory prostaglandins (PGE₂, PGF_2α). The appearance of many new gap junctions promotes coordinated contraction of the myometrial smooth muscle cells. These changes are associated with a transition from contractures to true contractions.

• Phase 2 is the dramatic stage of labor when there is stimulation of the uterus, with increasing oxytocin and prostaglandin levels inducing true uterine contractions and dilation of the cervix. The products of conception are delivered at parturition, ending phase 2.

• In phase 3, the uterus returns to its normal size with the assistance of sustained contraction of the myometrium, which also assists in blood clotting.

The initiation of labor is poorly understood because of considerable species differences that limit inferences from animal studies. In humans, there is evidence that prostaglandins and estrogens produced by the maternal-fetal-placental unit are important. Production of estrogens by the placenta requires fetal androgen precursors. An increase in fetal androgen production before labor may result from the placental secretion of corticotropin-releasing hormone, leading to the secretion of adrenocorticotropic hormone (ACTH) from the fetal pituitary gland. Fetal ACTH stimulates the fetal adrenal gland to produce androgen.

Once labor is initiated, the local release of prostaglandins is important for generating powerful uterine contractions. Oxytocin is secreted in large amounts from the posterior pituitary during the expulsive stage of labor. The positive feedback stimulation of oxytocin secretion due to increasing cervical distension is known as the Ferguson reflex.

The powerful uterine contractions induced by prosta­glandins can be utilized clinically to expel a fetus during abortion or ectopic tubal pregnancy or to stop postpartum hemorrhaging due to an atonic uterus.

The gross anatomy of the lactating breast is illustrated in Figure 9-19A. The functional unit of milk production is the mammary alveolus, which consists of a lumen surrounded by alveolar epithelial cells (Figure 9-19B). Alveolar epithelial cells are capable of transcellular fluid and electrolyte secretion, receptor-mediated transport of maternal immunoglobulins, and the synthesis and transport of milk lipids and proteins. A cluster of alveoli comprise a secretory lobule. Each lobule delivers breast milk via a duct that widens at an ampulla and continues to the nipple via a lactiferous duct.

Initial breast development at puberty produces a rudimentary system of ducts. During the first weeks of pregnancy, under the influence of ovarian and placental steroids, there is rapid growth and development to produce mammary alveoli and a differentiated system of ducts. Other hormones, including insulin, cortisol, prolactin, and chorionic somatomammotropin, contribute to the final development of the breast during pregnancy.

Breast Milk

Breast milk is a complex emulsion of lipids in an isotonic solution, which contains all the minerals founds in extracellular fluid.

• Fats, mostly in the form of triglycerides, constitute 3–5% of milk.

• Proteins make up about 1% of milk; the proteins casein and lactalbumin are only found in milk.

• The major sugar in milk is lactose, comprising about 7% of milk.

Colostrum is the thin, yellowish fluid produced within the first few days after parturition, before the main milk production begins. It contains more protein than milk, including antibodies and immune cells, and provides the neonate with some immunologic protection.

Human breast milk is the preferred food for full-term infants. Breast milk is rich in immunoglobulins (mainly IgA) and maternal macrophages, which are thought to protect the infant against upper respiratory tract and inner ear infections. In addition to reduced infections, breast-fed infants also have a lower incidence of allergic diseases (e.g., food allergies and intolerances to foods). Breast-feeding also promotes bonding between the mother and the infant and hastens the return to prepregnancy weight for the mother.

Endocrine Control of Lactation

Prolactin and oxytocin are the two key hormones involved in the control of lactation; prolactin is required for milk production, and oxytocin stimulates milk ejection from the breast (see Chapter 8).

Prolactin is a peptide hormone secreted by the anterior pituitary lactotropes and is essential for milk production by the lactating breast. The control of prolactin secretion is unusual in that the dominant factor controlling prolactin secretion is inhibition by hypothalamic dopamine. Despite elevated prolactin levels during pregnancy, maternal milk production does not occur before the birth of the infant because high estrogen levels inhibit the effects of prolactin at the breast. There is a dramatic decline in estrogen levels after expulsion of the placenta at birth, which removes the inhibitory effects of estrogen on prolactin. Milk production in response to prolactin begins approximately 2 days after birth. During the first few days postpartum, the breast secretes colostrum, before lactation begins.

The Suckling Reflex

The neuroendocrine responses that occur when an infant suckles are known as suckling reflexes. The afferent limb of the reflex is neuronal, and the efferent responses are hormonal. The suckling reflexes have three major functions:

1. Suckling is the most important stimulus for prolactin secretion, acting via neural pathways to inhibit hypothalamic dopamine release. Elevated prolactin levels are sustained for as long as an infant breast-feeds. Peaks of prolactin concentration occur with each feeding session so that milk production meets the demands set by the infant. The prolactin released during a feed serves to stimulate milk production in readiness for the next feed.

2. The suckling reflex stimulates oxytocin secretion from neurons in the posterior pituitary. Oxytocin causes contraction of myoepithelial cells and milk ejection (let-down) from the breast. The reflex can be conditioned, for example, by the sound of an infant crying.

3. The suckling reflex inhibits the GnRH pulse generator, which suppresses FSH and LH release and also suppresses the menstrual cycle in most mothers who are breast-feeding. The effectiveness of this suppression depends on feeding frequency and can result in the absence of menses for over 2 years. Mothers who do not breast-feed usually resume their menstrual cycles within 2–4 months after giving birth.

Many methods of contraception have been developed and apply strategies to intervene in the physiologic mechanisms of reproduction; for example:

• Natural contraception encourages the avoidance of coitus during the woman's midcycle fertile period, about the time of ovulation.

• Barrier methods such as condoms and the cap attempt to prevent the sperm from encountering the egg.

• Intrauterine devices (IUDs) disrupt implantation of the blastocyst.

• Hormonal contraception aims to disrupt the endocrinology of the menstrual cycle. Combined oral contraceptives contain both estrogen and progesterone and inhibit the increase of FSH that is needed to induce follicular development. Progestin-only pills produce thick cervical mucus that inhibits sperm passage, and they also disrupt normal endometrial development and inhibit gonadotropin production.

Similar to pregnancy, oral contraceptives induce a hypercoagulable state and should be avoided in patients with a history of vascular disease (e.g., deep vein thrombosis or stroke). On the other hand, oral contraceptives have been associated with lower rates of ovarian and endometrial cancer.