ORGAN SYSTEMS │ 6. The Endocrine System Thyroid
►►Physiologic Actions of Thyroid Hormone
Metabolic rate ↑ metabolic rate: high O2 consumption, mitochondrial growth, ↑ Na+/K+-ATPase activity, ↑ food intake,
thermogenesis, sweating, ↑ ventilation
Energy substrates Mobilization of carbohydrates, fat and protein; ↑ ureagenesis; ↓ muscle and adipose mass
Growth Required after birth for normal brain development and bodily growth (protein anabolic)
Circulation ↑ cardiac output (linked to metabolism), ↑ β-adrenergic receptors on heart
►►Control of Thyroid Hormone
TRH Cold, stress
TSH Stimulates TRH = thyrotropin-releasing hormone (hypothalamus)
Inhibits
TSH = Thyroid-stimulating hormone (anterior pituitary);
T4 & T3 is also trophic (increases gland mass)
T4 = thyroxine (tetraiodothyronine); 90% of production,
but low biologic activity (thyroid)
T3 = triiodothyronine; 10% of production, very potent (thyroid)
►►Synthesis and Storage
Process Mechanism Result
Uptake of I– Active transport ↑ follicular cell iodide
Oxidation Peroxidase Produce oxidized iodine
Iodination Peroxidase Produces MIT and DIT within thyroglobulin
Coupling Peroxidase Links MITs and DITs to form T4 and T3
Exocytosis Exocytosis into lumen Storage of thyroglobulin
Definition of abbreviations: DIT, diiodotyrosine; MIT, monoiodotyrosine.
386
►►Secretion Mechanism Result ORGAN SYSTEMS │ 6. The Endocrine System
Endocytosis Colloid taken up by follicular cells
Process Lysosomes and colloid fuse Incorporation in lysosomes
Transport Lysosomal enzymes Cleave thyroglobulin into T3, T4, MITs, and DITs
Fusion Simple diffusion Lipid-soluble T3 and T4 diffuse into extracellular fluid to plasma
Proteolysis Deiodinase Removes iodide from MITs and DITs to recycle it
Secretion
Deiodination
►►Regulation of Thyroid Activity
Transport 99% bound to thyroid binding globulin, 1% free; represents a pool to prevent rapid change of
thyroid level
Peripheral Conversion T4 converted to more active T3 by 5´-monodeiodinase or to inactive reverse T3 by
5-monodeiodinase; occurs in most tissues giving local control of hormone action
Mechanism of action Binding to nuclear receptors: T4 has low affinity, T3 has high affinity, so is responsible for most
thyroid hormone effects
Degradation Successive deiodination steps to thyronine, also sulfates and glucuronides
►►Thyroid Disorders T4 TSH TRH Gland Mass
↑, goiter possible
Disorder ↓↑ ↑ ↓, due to low TSH
Primary hypothyroidism ↓, due to low TSH
↓↓ ↑
Pituitary hypothyroidism ↑, goiter likely
↓↓ ↓ ↑, goiter possible
Hypothalamic hypothyroidism ↓, due to low TSH
↓↑ ↑ ↑, goiter possible
Iodine deficiency (prolonged, severe)
↑↑ ↓
Pituitary hyperthyroidism
↑↓ ↓
Primary hyperthyroidism (tumor)
↑↓ ↓
Graves disease
(autoimmune production of thyroid-stimulating
immunoglobulins [TSIs])
387
ORGAN SYSTEMS │ 6. The Endocrine System ►►Disorders of the Thyroid Gland
Hyperthyroidism • Seen most often in Graves disease, toxic multinodular goiter, toxic adenoma
Graves disease • C linical: tachycardia, cardiac palpitations (β-adrenergic effect), skin warm and flushed, ↑ body temperature,
heat intolerance, hyperactivity, tremor, weight loss, osteoporosis, diarrhea and oligomenorrhea, eyes show a
wide stare with lid lag; exophthalmos seen only in Graves disease
• Thyrotoxic storm: severe hypermetabolic state with 25% fatality
• Lab values: low TSH and elevated T4; low TSH is most important
• N ote: in pregnancy, ↑ in TBG secondary to high estrogen levels elevates total serum T4, but not free serum T4
• Peaks in the third and fourth decades; more common in women; associated with other autoimmune
diseases (including Hashimoto thyroiditis)
• Type II non-cytotoxic hypersensitivity
• Production of TSI and TGI bind and activate TSH receptors
• Pathology: diffuse, moderate, symmetric enlargement of gland
• Microscopic appearance: hypercellular with small follicles and little colloid
Hypothyroidism • Clinical features depend on age group
Infants • Lab values: elevated TSH and low T4
• Develop cretinism; major effects are on skeletal and CNS development; once apparent, syndrome
is irreversible; neonatal screening for elevated TSH for early detection
• C linical: protuberant abdomen, wide-set eyes, dry rough skin, broad nose, delayed epiphyseal closure
Older children Short stature, retarded linear growth (GH deficiency caused by thyroid hormone deficiency), delayed onset of
puberty
Adults • Lethargy, weakness, fatigue, decreased appetite, weight gain, cold intolerance, constipation
• M yxedema: associated with severe hypothyroidism; periorbital puffiness, sparse hair, cardiac enlargement,
pleural effusions, anemia
Hashimoto • Chronic lymphocytic thyroiditis featuring goitrous thyroid gland enlargement
thyroiditis • A utoimmune; may be autoantibodies to the TSH receptors, T3 and T4; antimicrosomal antibodies also
seen
• Type IV hypersensitivity
• Most common type of thyroiditis; highest incidence in middle aged females
• Pathology: painless goiter, gland enlarged and firm
• M icroscopic appearance: lymphocytic and plasma cell infiltrate with Hürthle cells (follicular cells with
eosinophilic granular cytoplasm), evidence of cell-mediated cytolysis
Diffuse nontoxic Diffuse enlargement of gland in euthyroid patients; high incidence in certain geographic areas with iodine-
goiter deficient diets
de Quervain • Self-limited disease; seen more often in females in the second to fifth decades
granulomatous • Follows viral syndrome, lasts several weeks with a tender gland
subacute thyroiditis • May initially have mild hyperthyroidism later, usually euthyroid
Riedel thyroiditis • Rare, chronic thyroid disease, possibly of immune origin, that causes dense fibrosis of the thyroid gland
leading to hypothyroidism
• Presents with a hard, fixed, painless goiter
• May be associated with idiopathic fibrosis in other sites such as the retroperitoneum
Thyroglossal • May communicate with skin or base of tongue
duct cyst • Remnant of incompletely descended midline thyroid tissue
Ectopic thyroid Usually at the base of tongue; prior to removal, it must be documented that patient has other functioning
nests thyroid tissue
Definition of abbreviations: GH, growth hormone; TBG, thyroid-binding globulin; TGI, thyroid growth immunoglobulin; TSI, thyroid-stimulating
immunoglobulin; TSH, thyroid-stimulating hormone.
388
►►Drugs for Thyroid Gland Disorders ORGAN SYSTEMS │ 6. The Endocrine System
Class Mechanism Comments/Agents
Hyperthyroidism These agents are used for short-term or long-term treatment of hyperthyroid states. The most common
Agents adverse effects are related to signs and symptoms of hypothyroidism.
Thioamides • Inhibit synthesis of thyroid hormones • Examples: PTU, methimazole
• They do not inactivate existing T4 and T3 • I ndications: long-term hyperthyroid therapy, which may
• P ropylthiouracil is able to inhibit peripheral lead to disease remission and short-term treatment
before thyroidectomy or radioactive iodine therapy
conversion of T4 to T3
• Side effects: skin rash (common), hematologic effects
(rare)
Iodides • Inhibit the release of T4 and T3 (primary) • E xamples: Lugol’s solution (iodine and potassium
• I nhibit the biosynthesis of T4 and T3 and ↓ iodide) and potassium iodide alone
the size and vascularity of thyroid gland • I ndications: preparation for thyroid surgery; treatment
of thyrotoxic crisis and thyroid blocking in radiation
emergency
• Note: therapeutic effects can be seen for as long as 6
weeks
Beta-Blockers Nonselective β-receptor blockers used for • Examples: nadolol, propranolol
Radioactive Iodine palpitations, anxiety, tremor, heat intolerance; • Used to treat the signs and symptoms of
[131I] partially inhibit peripheral conversion of T4 to
T3 hyperthyroidism
Ablation of thyroid gland • Indications: first-line therapy for Graves disease;
treatment of choice for recurrent thyrotoxicosis in adults
and elderly
Hypothyroidism These agents are used as thyroid replacement therapy. The most common adverse effects are related to
Agents signs and symptoms of hyperthyroidism.
Thyroid Hormones Acts by controlling DNA transcription and Examples: synthetic T4, synthetic T3, or combination of
protein synthesis synthetic T4:T3 in 4:1 ratio
Definition of abbreviation: PTU, propylthiouracil.
►►Thyroid Neoplasms
Adenomas • Follicular adenoma is most common; may cause pressure symptoms, pain, and rarely thyrotoxicosis
• Pathology: usually small, well-encapsulated solitary lesions
Papillary • Most common thyroid carcinoma
carcinoma • Incidence higher in women
• Pathology: papillary branching pattern; 40% have tumors containing psammoma bodies
• Spread to local nodes is common; hematogenous spread rare
• Resection curative in most cases
Follicular • More malignant than papillary cancer
carcinoma • Pathology: may be encapsulated, with penetration through the capsule; colloid sparse
• Local invasion and pressure → dysphagia, dyspnea, hoarseness, cough
• Hematogenous metastasis to lungs or bones common
Medullary • Arises from parafollicular C cells
carcinoma • Secretes calcitonin
• May be associated with MEN IIa and IIb
Anaplastic • Rapid growing, aggressive with poor prognosis; affects older patients
carcinoma • Pathology: tumors usually bulky and invasive with undifferentiated anaplastic cells
• Clinical: early, widespread metastasis and death within 2 years
389
ORGAN SYSTEMS │ 6. The Endocrine System Growth Hormone
►►Control of Growth Hormone
GHIH GHRH Secretion of GH
Growth hormone Hypoglycemia, sleep • Pulsatile, ↑ during sleep
Somatomedins stress, androgens, • Moderate in childhood
estrogens, amino acids • Increases at puberty
• Lower in adults
• Secretion requires thyroid hormone
• Increased by sex steroids
Hyperglycemia, free fatty acids Stimulates
β - adrenergic Inhibits
►►Biologic Actions of Growth Hormone
GH
Adipose tissue Liver Muscle
Glucose uptake RNA synthesis
Lipolysis Protein synthesis Glucose uptake
Adiposity Gluconeogenesis Amino acid uptake
IGFBP Protein synthesis
Lean body mass
IGFs
Increases plasma glucose
IGFs
Bone, heart, lung Chondrocytes
Protein synthesis Amino acid uptake
RNA synthesis Protein synthesis
DNA synthesis RNA synthesis
Cell size and number DNA synthesis
Organ size Collagen
Chondroitin sulfate
Cell size and number
Linear growth
390
►►Childhood Disorders ORGAN SYSTEMS │ 6. The Endocrine System
Dwarfism • Caused by:
– ↓ GH or ↓ liver production of IGF (Laron syndrome)
– Defective GH receptors
• Mental development normal
• Reversible with GH treatment
Gigantism • Caused by ↑ GH prior to epiphyseal closure
• Increased height, increased body mass
Definition of abbreviation: GH, growth hormone; IGF, insulin-like growth factor.
►►Adult Disorders of Growth Hormone
Acromegaly ↑ GH • Enlargement of hands and feet
• Protrusion of lower jaw, coarse facial features
• ↑ lean body mass
• ↓ body fat
• ↑ size of visceral organs
• Impaired cardiac function (related to mass)
• Abnormal glucose tolerance with tendency to hyperglycemia
Deficiency ↓ GH • Tendency to hypoglycemia when fasting
• Susceptible to insulin-induced hypoglycemia
• Significance of other effects disputed
Definition of abbreviation: GH, growth hormone.
►►Treatment of Growth Hormone Disorders
Class Mechanism Comments/Agents
GH Stimulation of linear/skeletal growth (pediatric patients • S omatropin and somatrem (recombinant forms
only); potentiation of cell and organ growth; enhanced of human GH)
protein, carbohydrate and lipid metabolism
• Indications: growth failure, Turner syndrome,
Octreotide • Long-acting octapeptide that mimics somatostatin cachexia, somatotropin deficiency
• Inhibits release of GH, glucagon, gastrin, thyrotropin, • I ndications: acromegaly, carcinoid, glucagonoma,
insulin gastrinoma, other endocrine tumors
Definition of abbreviation: GH, growth hormone.
391
The Reproductive System
Chapter 7
Reproductive System Female Reproductive System Pathology
Male and Female Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Diseases of the Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Male and Female Reproductive Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . 395–396 Diseases of the Vagina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Diseases of the Cervix/Fallopian Tubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Male Reproductive System Diseases of the Uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Diseases of the Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414–415
Male Reproductive Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Gestational Trophoblastic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Agents for Erectile Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Partial Moles Versus Complete Moles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Diseases of the Penis and Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397–398
Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 Breast Pathology
The Testes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398–399
Spermatogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .400 Fibrocystic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
Hormonal Control of Steroidogenesis and Spermatogenesis . . . . . . . . . . . . . . . 401 Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
Inflammatory Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Carcinoma of the Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
Testicular Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Breast Carcinoma Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
Fibrocystic Disease Versus Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
Female Reproductive System Miscellaneous Breast Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
Hormonal Control of Steroidogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Genitourinary System Disease
Folliculogenesis and Ovulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
Uterine Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Infections and Sexually Transmitted Diseases (STDs) . . . . . . . . . . . . . . . . . 419–421
Menstrual Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .406
Fertilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Early Embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Implantation and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
Diseases of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Infectious Agents That Cross the Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Female Reproductive Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410–411
393
ORGAN SYSTEMS │ 7. The Reproductive System Reproductive System
►►Male and Female Development
Adult Female and Male Reproductive Structures Derived From Precursors of the Indifferent Embryo
Adult Female Indifferent Embryo Adult Male
Ovary, follicles, rete ovarii Gonads Testes, seminiferous tubules, rete testes
Uterine tubes, uterus, cervix, and upper Paramesonephric ducts Appendix of testes
part of vagina
Duct of Gartner Mesonephric ducts Epididymis, ductus deferens, seminal
vesicle, ejaculatory duct
Clitoris Phallus Glans and body of penis
Labia minora Urogenital folds Ventral aspect of penis
Labia majora Labioscrotal swellings Scrotum
Congenital Reproductive Anomalies
Female Pseudointersexuality
• 46,XX genotype
• Have ovarian (but no testicular) tissue and masculinization of the female external genitalia
• Most common cause is congenital adrenal hyperplasia, a condition in which the fetus produces excess androgens
Male Pseudointersexuality
• 46,XY genotype
• Testicular (but no ovarian) tissue and stunted development of male external genitalia
• M ost common cause is inadequate production of testosterone and müllerian-inhibiting factor (MIF) by the fetal testes; due to
a 5α-reductase deficiency
5α-reductase 2 • C aused by a mutation in the 5α-reductase 2 gene that renders 5α-reductase 2 enzyme underactive in
deficiency catalyzing the conversion of testosterone to dihydrotestosterone
• Clinical findings: underdevelopment of the penis and scrotum (microphallus, hypospadias, and bifid scrotum)
and prostate gland; epididymis, ductus deferens, seminal vesicle, and ejaculatory duct are normal
• At puberty, they undergo virilization due to an increased T:DHT ratio
Complete androgen • O ccurs when a fetus with a 46,XY genotype develops testes and female external genitalia with a rudimentary
insensitivity vagina; the uterus and uterine tubes are generally absent
(CAIS, or testicular
feminization • Testes may be found in the labia majora and are surgically removed to circumvent malignant tumor
syndrome) formation
• I ndividuals present as normal-appearing females, and their psychosocial orientation is female despite their
genotype
• Most common cause is a mutation in the androgen receptor (AR) gene that renders the AR inactive
394
►►Male and Female Reproductive Anatomy ORGAN SYSTEMS │ 7. The Reproductive System
Male
Peritoneum
Ureter Skin
Rectovesical M Urinary bladder Ischiocavernosus Dartos fascia
pouch PA muscle (cut)
Ductus deferens Deep (Buck) fascia
Seminal Superficial transverse Corpus spongiosum
vesicle Prostate gland perineal muscle (covered by Buck fascia)
Median lobe (M)
Ejaculatory Anterior lobe (A) Corpus cavernosum
duct Posterior lobe (P) (covered by Buck fascia)
Kaplan Author ISBN # UrethraAuthor's review External anal
(if needed) sphincter muscle
Urogenital Fig. # Document name OK Correx Levator ani muscle
diaphragm PenIniistials Date
03.03.24 Gluteus maximus
Bulbourethral CE's review OK Correx
gland EpididymiAsrtist Date 1/30/02 Date
Initials
Rich LaRocco Check if revision
TesticBlxeW X 2/C 4/C
Figure III-3-24. Male Pelvis
Female
Oviduct Ureter Peritonium Bulbospongiosus Clitoris
muscle Crus of clitoris
Uterus Suspensory Round
ligament ligament Ischiocavernosus Vestibular bulb
Fundus of ovary Vesicouterine muscle Bartholin gland
pouch
Rectouterine Urinary Superficial Ischial tuberosity
pouch (Pouch bladder transverse
of Douglas) perineal muscle External anal
Urethra sphincter muscle
Posterior Clitoris Levator ani muscle
fornix Anococcygeal ligament
Coccyx
Cervix
Vagina
Urogenital
diaphragm
Figure III-3-25. Female Pelvis
Pelvic Floor and Perineum
• The floor of the pelvis is formed by the pelvic diaphragm (two layers of fascia with a middle layer of skeletal muscle).
• T he muscles forming the middle layer are the levator ani and coccygeus. The levator ani acts as a muscular sling for the rectum and
marks the boundary between the rectum and anal canal.
• T he region below the pelvic diaphragm is the perineum, which contains the ischioanal fossa, the fat-filled region below the pelvic
diaphragm surrounding the anal canal.
• The urogenital diaphragm is in the perineum and extends between the two ischiopubic rami. The urogenital diaphragm (like the
pelvic diaphragm) is composed of two layers of fascia with a middle layer of skeletal muscle.
(Continued)
395
ORGAN SYSTEMS │ 7. The Reproductive System ►►Male and Female Reproductive Anatomy (Cont’d.)
Perineal Pouches
Deep perineal The deep perineal pouch is the middle (muscle) layer of the urogenital diaphragm. It contains:
pouch (space) • Sphincter urethrae muscleserves as external sphincter of the urethra
• Deep transverse perineal muscle
• Bulbourethral (Cowper) gland (in the male only)duct enters bulbar urethra
Superficial The superficial perineal pouch is the region below the urogenital diaphragm and is enclosed by the superficial
perineal pouch perineal (Colles) fascia. It contains:
(space)
• Crura of penis or clitoriserectile tissue
• Bulb of penis (in the male)erectile tissue; contains urethra
• Bulbs of vestibule (in the female)erectile tissue; in lateral walls of vestibule
• Ischiocavernosus muscleskeletal muscle that covers crura of penis or clitoris
• Bulbospongiosus muscleskeletal muscle that covers bulb of penis or bulbs of vestibule
• Greater vestibular (Bartholin) gland (in female only)homologous to Cowper gland
Pelvic Innervation
The pudendal nerve (S2, S3, S4 ventral rami) and its branches innervate the skeletal muscles in the pelvic and urogenital
diaphragms, the external anal sphincter and the sphincter urethrae, skeletal muscles in both perineal pouches, and the skin that overlies
the perineum.
Male Reproductive System
►►Male Reproductive Physiology
Penile Erection
Erection occurs in response to parasympathetic stimulation (pelvic splanchnic nerves). Nitric oxide is released, causing relaxation of the
corpus cavernosum and corpus spongiosum, which allows blood to accumulate in the trabeculae of erectile tissue.
Ejaculation
• S ympathetic nervous system stimulation (lumbar splanchnic nerves) mediates movement of mature spermatozoa from the
epididymis and vas deferens into the ejaculatory duct.
• A ccessory glands, such as the bulbourethral (Cowper) glands, prostate, and seminal vesicles, secrete fluids that aid in sperm survival
and fertility.
• Somatic motor efferents (pudendal nerve) that innervate the bulbospongiosus and ischiocavernous muscles at the base of the penis
stimulate the rapid ejection of semen out the urethra during ejaculation. Peristaltic waves in the vas deferens aid in a more complete
ejection of semen through the urethra.
Clinical Correlation
• I njury to the bulb of the penis may result in extravasation of urine from the urethra into the superficial perineal space. From this space,
urine may pass into the scrotum, into the penis, and onto the anterior abdominal wall.
• Accumulation of fluid in the scrotum, penis, and anterolateral abdominal wall is indicative of a laceration of either the membranous or
penile urethra (deep to Scarpa fascia). This can be caused by trauma to the perineal region (saddle injury) or laceration of the urethra
during catheterization.
396
►►Agents for Erectile Dysfunction ORGAN SYSTEMS │ 7. The Reproductive System
Drug Mechanism Comments
PDE 5 inhibitors + nitrates (which ↑ cGMP production) →
Selective phosphodiesterase Inhibits the enzyme severe hypotension
(PDE) 5 inhibitors phosphodiesterase (PDE) 5, which
inactivates cGMP, leading to ↑ cGMP Administered via transurethral or intracavernosal injection
(sildenafil, vardenafil, tadalafil) → vasodilation, more inflow of blood Contraindications: intercourse with pregnant women
→ better erection
(can stimulate uterine contractions unless used with a
Synthetic prostaglandin E1 ↑ cAMP (via adenylate cyclase) → condom); conditions that might predispose a patient to
(PGE1) agents smooth muscle relaxation priapism (e.g., sickle cell anemia, multiple myeloma,
leukemia)
(alprostadil) Used if diminished libido is a significant patient complaint
Testosterone Replacement/supplementation
for males whose serum androgen
concentrations are below normal
►►Diseases of the Penis and Prostate
Noninfectious Disorders of the Penis
Hypospadias and With hypospadias, urethra opens onto the ventral surface of penis
epispadias Often associated with a poorly developed penis that curves ventrally, known as chordee
With epispadias, urethra opens onto dorsal surface; often associated with exstrophy of bladder
Either of these malformations may cause infertility
Phimosis Prepuce orifice too small to be retracted normally
Interferes with hygiene; can also predispose to bacterial infections; if foreskin retracted over the glans, it
may lead to urethral constriction → paraphimosis
Treatment: circumcision
Penile carcinoma
Bowen disease Carcinoma in situ; can be associated with visceral malignancy
Men >35 years; tends to involve shaft of the penis and scrotum
Gross: thick, ulcerated plaque
Micro: squamous cell carcinoma in situ
Squamous cell 1% of cancers in men in the United States, usually age 40–70.
carcinoma Usually slow growing and non-painful; patients often delay seeking medical attention.
Circumcision decreases the incidence.
Human Papilloma virus (types 16 and 18) infection is closely associated.
Gross: Plaque progressing to an ulcerated papule or fungating growth.
Metastases can go to local lymph nodes.
Peyronie disease Curved penis due to fibrosis of the tunica albuginea
(Continued)
397
ORGAN SYSTEMS │ 7. The Reproductive System ►►Diseases of the Penis and Prostate (Cont’d.)
Diseases of the Prostate
Prostatic • Most common cancer in men; usually occurs after age 50, and the incidence increases with age
carcinoma • Associated with race (more common in African Americans than in Caucasians, relatively rare in Asians)
• May present with urinary problems or a palpable mass on rectal examination
• Prostate cancer more common than lung cancer, but lung cancer is bigger killer
• Metastases may occur via the lymphatic or hematogenous route
• Bone commonly involved with osteoblastic metastases, typically in the pelvis and lower vertebrae
• Elevated PSA, together with an enlarged prostate on digital rectal exam, highly suggestive of carcinoma
• Most patients present with advanced disease and have a 10-year survival rate of <30%
• Treatment: surgery, radiation, and hormonal modalities (orchiectomy and androgen blockade).
Benign prostatic • Formation of large nodules in the periurethral region (median lobe) of the prostate
hyperplasia • May narrow the urethral canal to produce varying degrees of urinary obstruction and difficulty urinating
• It is increasingly common after age 45; incidence increases steadily with age
• Can follow an asymptomatic pattern, or can result in urinary symptoms and urinary retention
Prostatitis • Results from a bacterial infection of the prostate
Acute • Pathogens are often organisms that cause urinary tract infection
• Escherichia coli most common
Chronic • Bacteria spread by direct extension from the posterior urethra or the bladder; lymphatic or hematogenous
spread can also occur
• Common cause of recurrent urinary tract infections in men
• Two types: bacterial and nonbacterial
• Both forms may be asymptomatic or may present with lower back pain and urinary symptoms
►►Antiandrogens
Drug Mechanism Clinical Uses
Flutamide Androgen receptor antagonist Prostate cancer
Spironolactone Androgen receptor antagonist (also a potassium-sparing Hirsutism (also used for primary
diuretic) hyperaldosteronism, edema, hypertension)
Leuprolide GnRH analog Kaplan Author ISBN # Au(tihf onre'sedreevdi)ew Depot form is used for prostate cancer
Finasteride
OK Correx Benign prostatic hypertrophy (BPH), male pattern
Ketoconazole baldness
5α-reductase inhibitor (pFigr0.3e#.0v3.e05ntsDoccumoennt navmeersion oIniftialstestDoatesterone
Artist Date 1/30/02 CE's review Androgen receptor−positive prostate cancer
to DHT) Rich LaRocco Check if revision
OK Correx
B x W X 2/C 4/C Initials Date
Inhibits steroid synthesis (also an antifungal agent)
Definition of abbreviation: DHT, dihydrotestosterone.
►►The Testes Descent of the Testes
Testes Peritoneum The processus vaginalis is an evagination of parietal
peritoneum that descends through the inguinal canal
A BC during fetal life. The tunica vaginalis is a patent
remnant of the processus vaginalis that covers the
398 Gubernaculum Processus anterior and lateral parts of the testis.
vaginalis
A hydrocele is an accumulation of serous fluid in the
D tunica vaginalis or in a persistent part of the processus
vaginalis in the cord.
Tunica
vaginalis
(Continued)
►►The Testes (Cont’d.) ORGAN SYSTEMS │ 7. The Reproductive System
Normal Anatomy and Anatomic Abnormalities
Deep inguinal ring The inguinal canal is formed by four of the eight
tissue layers of the anterior abdominal wall;
Inferior epigastric outpocketings of three of these layers give rise
3. artery & vein to spermatic fasciae, which cover the testis and
structures in the spermatic cord.
The spermatic cord contains the:
2. • Ductus deferens, which conveys sperm from
the epididymis to the ejaculatory duct in the male
1. pelvis
1. External oblique fascia Superficial 1. • T esticular artery, which arises from the
External spermatic fascia inguinal ring abdominal aorta between the L2 and the L3
2. vertebrae
2. Internal oblique muscle 3.
Cremaster muscle and fascia • Artery to the ductus deferens, which arises from
a branch of the internal iliac artery
3. Transversalis fascia
Internal spermatic fascia • Pampiniform plexus of the testicular vein
• Right testicular vein, which drains into the
inferior vena cava
• Left testicular vein, which drains into the left
renal vein.
• Lymphatic vessels that drain the testis. Testicular
lymphatic vessels pass through the inguinal canal
and drain directly to lumbar nodes in the posterior
abdominal wall.
Cremasteric Reflex
The cremasteric reflex utilizes sensory and motor fibers in the ventral ramus of the L1 spinal nerve. Stroking the skin of the superior
and medial thigh stimulates sensory fibers of the ilioinguinal nerve. Motor fibers from the genital branch of the genitofemoral nerve
cause the cremaster muscle to contract, elevating the testis.
Abnormalities
Cryptorchidism • Failure of normal descent of intra-abdominal testes into the scrotum
• Most common location of a cryptorchid testis is in the inguinal canal
• Unilateral or bilateral, more often on right side
• Bilateral cryptorchidism can cause infertility
• Maldescended testes are associated with a greatly increased incidence of testicular cancer, even once
repositioned within scrotum
Torsion • Precipitated by sudden movement, trauma, and congenital anomalies
• Twisting of spermatic cord may compromise both arterial supply and venous drainage
• Sudden onset of testicular pain and a loss of the cremasteric reflex are characteristic
• If not surgically corrected early, may result in testicular infarction
Hydrocele • Congenital hydrocele occurs when a small patency of the processus vaginalis remains so that peritoneal fluid
can flow into the processus vaginalis; may occur later in life, often inflammatory causes (e.g., epididymitis)
• Results in fluid-filled cyst near testes
Varicocele • Results from dilatations of tributaries of the testicular vein in the pampiniform plexus
• Varicosities of the pampiniform plexus are observed when the patient is standing and disappear when the
patient is lying down
Spermatocele • Retension cyst containing sperm in the rete testes or head of the epididymis
399
ORGAN SYSTEMS │ 7. The Reproductive System ►►Spermatogenesis
Cross section of Spermatogenesis occurs in the seminiferous tubules between
seminiferous tubules the Sertoli cells, which extend from the seminiferous tubule
basement membrane to the lumen and are separated
Area of detail by tight junctions (blood−testis barrier) and germ cells
in varying stages of spermatogenesis. The blood−testis
Spermatids barrier protects the spermatocytes and spermatids from the
immune system
Secondary Spermatozoa
spermatocyte Three Stages of Spermatogenesis
Tight Primary
junction spermatocyte 1. S permatocytogenesis begins at puberty adjacent
to the basement membrane of the Sertoli cell.
Spermatogonium Sertoli cell Spermatogonia first undergo spermatocytogenesis,
during which mitosis divides the spermatogonia into
Basement spermatocytes.
membrane
Connective 2. M eiosis reduces the diploid spermatocytes into haploid
tissue spermatids.
Leydig cell 3. S permiogenesis is the maturation of spermatids into
mature spermatozoa.
Acrosome Head Spermiogenesis
Nucleus
Mid- During spermiogenesis, the spermatids undergo chromatin condensation and nuclear
Mitochondria piece elongation, which forms the head of the spermatozoa.
Microtubules
The acrosome, a hydrolytic enzyme-containing region on the sperm cell head, also forms during
Flagellum this time.
Principal Tail The midpiece of the sperm has as a mitochondrial sheath that contains much of the ATP
piece necessary for sperm movement. The flagellum contains an array of 9 + 2 microtubular pairs
linked by dynein for sperm motility. Patients with defective or absent dynein in Kartagener
End syndrome have reduced sperm motility, as well as reduced mucus clearance in the respiratory
piece pathways, leading to bronchiectasis.
Spermatozoon Once formed, spermatozoa detach from the Sertoli cells and combine with a fluid that aids in
the movement of spermatozoa into the epididymis. In the epididymis, the fluid is reabsorbed,
thereby concentrating sperm, and sperm interact with forward motility factor, a protein that
aids in sperm motility. Ejaculated sperm must undergo capacitation in the uterus before
fertilization can occur.
Fertilization
Fertilization is a three-step process:
1. Acrosome reaction: Sperm close to the corona radiata release hyaluronidase, which
dissolves material between corona radiata cells, allowing sperm to reach the zona pellucida.
2. Z onal reaction: Sperm bind to a glycoprotein of the zona and release acrosin, which
facilitates penetration of the zona by the sperm head.
3. Cortical reaction: The first sperm to penetrate the zona fuses with the plasma membrane
of the ovum and induces a calcium-dependent release of cortical granules that prevents
polyspermy.
400
►►HormonHaOlRMCOoNAnLtCrOoNTlRoOLfOSF StTeErRoOIiDdOoGEgNEeSnISeANsDisSPEaRnMAdTOSGEpNeESrISmatogenesis ORGAN SYSTEMS │ 7. The Reproductive System
Negative fb to hypothalamus
GnRH
Negative fb to pituitary (LH) LH Negative fb to pituitary (FSH) GnRH is synthesized in the
FSH preoptic nucleus and is
1 Leydig cell 2 released in a pulsatile man-
LH FSH ner into the hypophysial
portal system. Binding of
Sertoli cell Aromatase Inhibin GnRH to its receptor on the
anterior pituitary stimulates
Cholesterol 3 Testosterone Estradiol the release of LH and FSH.
Testosterone Androgen
Note: If the gonadotrophs
binding are subjected to constant
protein GnRH stimulation, the
receptors will undergo
Nucleus downregulation.
Nucleus Growth
factors
Spermatogenesis
Blood Blood
1 LH binds to the Leydig cell and stimulates the conversion of cholesterol into testosterone. Testosterone diffuses into blood and
feeds back to inhibit hypothalamic GnRH and pituitary LH. Testosterone diffuses into the Sertoli cell and increases transcription of
androgen-binding protein and growth factors that mediate spermatogenesis.
2 FSH binds to the Sertoli cell and stimulates transcription of androgen-binding protein, the conversion of testosterone to estradiol,
and the secretion of inhibin. Inhibin feeds back to inhibit further production of pituitary FSH.
3 Sertoli cell-derived androgen binding protein provides an important reserve of testosterone in the testes. Because
spermatogenesis is dependent on intratesticular testosterone rather than systemic testosterone, these reserves are important to
normal spermatogenesis.
►►Inflammatory Lesions
Mumps • Orchitis develops in approximately 25% of patients over age 10, but is less common in patients under 10
• Rarely leads to sterility
Gonorrhea • N eglected urethral gonococcal infection may spread to prostate, seminal vesicles, and epididymis,
but rarely to testes
Syphilis • Acquired or congenital syphilis may involve the testes
• Two forms: gummas or a diffuse interstitial/lymphocytic plasma cell infiltrate
• Can lead to sterility
Tuberculosis • TB usually spreads from epididymis; this is almost always associated with foci of TB elsewhere
401
ORGAN SYSTEMS │ 7. The Reproductive System ►►Testicular Neoplasms
Germ Cell Tumors
Most common malignancy in men 15 to 34 years of age
Seminoma • Rare in infants, incidence increases to a peak in the fourth decade
• 10% are anaplastic seminomas; show nuclear atypia
• Prognosis: with treatment; 5-year survival rate exceeds 90%
• Highly radiosensitive; metastases rare
Embryonal carcinoma • Most commonly in the 20–30-year-age group
• Aggressive, present with testicular enlargement
• 30% metastatic disease at time of diagnosis
• Serum AFP: elevated
• 5-year mortality rate 65%
• Less radiosensitive than seminomas
• Often metastasize to nodes, lungs, and liver
• May require orchiectomy and chemotherapy
Choriocarcinoma • Most common in men 15–25 years of age, highly malignant
• May have gynecomastia or testicular enlargement
• Elevated serum and urine hCG levels
• Tends to disseminate hematogenously, invading lungs, liver, and brain
• Treated with orchiectomy and chemotherapy
Yolk sac tumor • Most common testicular tumor in children and infants, although rare overall in adults
• Elevated alpha fetoprotein (AFP)
• Very aggressive; exhibiting a 50% 5-year mortality rate
Teratoma • Can occur at any age, but are most common in infants and children
• Appears as a testicular mass
• Exhibit a variety of tissues, such as nerve, muscle, cartilage, and hair
• Benign behavior during childhood, malignant in adults
• 2-year mortality is 30%
• Treatment: orchiectomy, followed by chemotherapy and radiation
Non−Germ Cell Tumors
Leydig cell tumor • Usually unilateral
• Can produce androgens or estrogens
• Children: present with masculinization or feminization; adults: gynecomastia
• Usually benign and only 10% are invasive; surgery may be curative
Sertoli cell • Usually unilateral
• C an produce small amounts of androgens or estrogens, usually not enough to cause endocrinologic
changes
• Present with testicular enlargement
• Over 90% are benign
Lymphoma • Lymphomas are the most common testicular cancer in elderly men
• The tumors are rarely confined to the testes (often disseminated)
Note: Testicular neoplasms tend to metastasize to the lumbar nodes, whereas scrotal disease affects superficial inguinal nodes.
402
Female Reproductive System ORGAN SYSTEMS │ 7. The Reproductive System
►►Hormonal Control of Steroidogenesis
Negative fb to hypothalamus
GnRH
Negative fb to pituitary (LH & FSH) LH Negative fb to pituitary (FSH) GnRH is synthesized in
FSH the preoptic nucleus and
is released in a pulsatile
Theca cell **LH 2 FSH 3 manner into the hypophysi-
Granulosa cell al portal system. Binding of
LH 1 GnRH to its receptor on the
4 anterior pituitary stimulates
the release of LH and FSH.
Cholesterol Inhibin
Note: If the gonadotrophs
Cholesterol Progesterone Aromatase are subjected to constant
Androgen Androgen GnRH stimulation, the
Nucleus receptors will undergo
downregulation.
Nucleus Estradiol
5
Blood
1 L H binds receptors on theca cells, resulting in production of androstenedione or testosterone. Androgens produced by
the theca cells enter the granulosa cells to be converted into estrogens.
2 LH also binds receptors on granulosa cells during the luteal phase and stimulates production of progesterone, which enters the
theca cells. During the luteal phase, progesterone is required to maintain pregnancy if fertilization/implantation occur.
3 F SH binds receptors on granulosa cells, resulting in aromatization of androgens to estradiol and synthesis of new LH receptors on
the granulosa cells. Estradiol can be released into the blood or can act locally to increase granulosa cell proliferation and sensitivity
to FSH.
4 FSH also stimulates the production of inhibin, which negatively feeds back to inhibit further FSH secretion.
5 Estradiol secreted into the blood negatively feeds back to inhibit hypothalamic and pituitary secretion of GnRH, and LH
and FSH, respectively. This action does not occur near the ovulatory period.
Definition of abbreviations: LH, luteinizing hormone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone.
403
Fig. # Document name
01.10.01 Initials Date
CE's review OK Correx
Artist Date 9/10/01
Rich LaRocco Check if revision
B x W X 2/C 4/C Initials Date
ORGAN SYSTEMS │ 7. The Reproductive System ►►Folliculogenesis and Ovulation Graafian follicle
Follicular Development
14 days 1
2
Primary Developing Secondary
follicle follicles oocyte Mature (graafian) 3
4
Primordial follicle
follicle 5
6
Secondary oocyte 7
arrested in
metaphase 5. Corona radiata
of meiosis II 6. Follicular antrum
7. Granulosa cells
Corpus Mature Ruptured 1. Theca externa
albicans corpus luteum follicle 2. Theca interna
3. Cumulus oophorus
Early 4. Zona pellucida
corpus luteum
Follicular Development
• At puberty, there are about 400,000 follicles present in the ovarian stroma, but only about 450 of these will develop
(remaining follicles undergo atresia).
• T he immature or primordial follicle (an oocyte surrounded by pregranulosa cells) is arrested in prophase I of meiosis
until maturation.
• Starting at puberty, during each cycle, a primordial follicle becomes the primary follicle when the oocyte enlarges and the granulosa
cells mature and proliferate. The granulosa cells secrete mucopolysaccharides, creating the zona pellucida, which protects the
oocyte and provides an avenue for the oocyte to receive nutrients and chemical signals from the granulosa cells.
• A s the follicle matures, additional granulosa cell layers are added and a layer of androgen-producing theca cells known as the theca
interna surround the now secondary follicle. The secondary follicle continues to grow, and a fibrous theca externa surrounds the
follicle. A follicular cavity (antrum) forms from granulosa cell secretions.
• T he mature follicle, the graafian follicle, is now ready for ovulation. At the time of the LH surge, the oocyte resumes meiosis,
completes the first meiotic division, and is arrested in metaphase of meiosis II prior to ovulation. Meiosis produces a
nonfunctional first polar body, which degenerates, and a larger secondary haploid oocyte.
• I f it is fertilized, the secondary oocyte completes meiosis II to form a mature oocyte and polar body.
Ovulation
• As the antral fluid increases, the pressure becomes greater until the follicle ruptures and the oocyte is extruded.
• Following ovulation, the theca cells enlarge and begin secreting estrogen and the granulosa cells enlarge and secrete progesterone.
This new endocrine organ is called the corpus luteum and reaches maximal development about 7 days
after ovulation.
• If fertilization does not occur, the corpus luteum degenerates.
• If fertilization does occur, the corpus luteum continues to grow for about 3 months and is maintained by human chorionic
gonadotropin (hCG) from the embryo. Once the placenta is functional, the corpus luteum is no longer necessary to
maintain pregnancy.
404
►►Uterine Cycle ORGAN SYSTEMS │ 7. The Reproductive System
Anterior pituitary
Follicle stimulating
hormone (FSH)
Luteinizing
hormone (LH)
1 2 Corpus luteum Corpus albicans The uterine cycle can be
Oocyte Graafian follicle divided into four phases:
Estrogen Progesterone 1 menstruation
2 proliferative phase
Spiral 3 secretory phase
Vein artery 4 premenstruation
Gland
As with the menstrual cycle, Day
Bleeding 1 of the uterine cycle begins
at the onset of menses. This
time period corresponds with
the degeneration of the corpus
luteum.
Days 1 3 4 14 28
Menses Ischemic
Proliferative phase Secretory phase 4
1 2 3 phase
Proliferative Phase 2
• The proliferative phase follows menses, corresponding to the latter portion of the follicular phase of the menstrual cycle
and ending near ovulation.
• D uring this time, elevated estrogen levels stimulate the proliferation of endometrial cells, an increase in length and number of
endometrial glands, and increased blood flow to the uterus.
• T he endometrium increases in thickness sixfold and becomes contractile. Estrogen also stimulates a marked increase in progesterone
receptors in the endometrium to prepare it for fertilization. Edema develops in the uterus toward the end of the proliferative phase and
continues to develop during the secretory phase.
Secretory Phase 3
• T he secretory phase corresponds with the luteal phase of the menstrual cycle and is characterized by endometrial cell
hypertrophy, increased vascularity, and edema.
• P rogesterone levels are elevated during this phase and lead to a thick secretion consisting of glycoprotein, sugars, and amino
acids. Like estrogen, progesterone increases cell proliferation and vascularization, but unlike estrogen, progesterone depresses
uterine contractility.
Premenstrual Phase 4
• T he premenstrual phase consists of constriction of arteries, causing ischemia and anoxia. The superficial layer of the
endometrium degenerates, and blood and tissue appear in the uterine lumen.
405
ORGAN SYSTEMS │ 7. The Reproductive System►►Menstrual Cycle Ovulation 400
Progesterone 300
mIU/mL60 Ovulation ng/mL 200
ng/mLFollicle-10 Estrogen pg/mL 100
pg/mL
50 stimulating 5
hormone
40 Luteinizing
hormone
30
20
10
5 10 Day 20 25 5 10 Day 20 25
Overview
• There are four phases in the menstrual cycle: menses, follicular phase, ovulation, and luteal phase.
• The average cycle length is 28 days, but can vary widely. The period from ovulation to the onset of menses is always
14 days, so any variation from 28 days occurs during the follicular phase.
Menses
• The onset of menses marks Day 1 of the menstrual cycle and is triggered by a decrease in estrogen (decreased estrogen synthesis
by granulosa cells and decreased LH) and progesterone. The decrease in estrogen and progesterone support for the endometrium
results in tissue necrosis and arterial rupture, leading to sloughing of the superficial layer of the endometrium and bleeding.
• T he elevated levels of progesterone in the luteal phase act to negatively feed back and decrease LH production. Also, luteal cells
become less responsive to LH about 1 week following ovulation.
Follicular Phase
• T he follicular phase begins on about Day 5 of the menstrual cycle and lasts an average of 9 days.
• W hen progesterone and estrogen levels decrease, the negative feedback on the hypothalamus and pituitary is removed, allowing
an increase in the frequency of GnRH pulses. This, in turn, stimulates FSH secretion, thereby stimulating follicular growth (and
estrogen production from proliferating granulosa cells).
• O ne follicle will secrete more estradiol than the others and will become the dominant follicle while the others undergo atresia.
Estrogen levels continue to increase until they reach a critical point, at which estrogen changes from negative to positive feedback
to increase GnRH pulse frequency and LH and FSH secretion. This rapid rise in GnRH pulse frequency results in a surge of both LH
and FSH.
Ovulation
• T he LH surge and high estrogen levels trigger ovulation on about Day 14 of the cycle.
• The follicle ruptures about 24 to 36 hours after the LH surge, during which the oocyte resumes meiosis and the first polar body is
extruded.
Luteal Phase
• The luteal phase begins after ovulation around Day 14 and extends to about Day 28.
• During this time the follicular cells form the corpus luteum and secrete high levels of progesterone and a lower level of estrogen
(even without LH stimulation). Progesterone negatively feeds back to slow the frequency of GnRH pulses, so LH and FSH levels
remain low.
• I n the absence of fertilization, the corpus luteum undergoes luteolysis, causing progesterone and estrogen levels to decrease until the
hormonal support for the endometrial lining declines and the cells undergo apoptosis. Menses occurs and the cycle
is back at the beginning.
406
►►Fertilization Fallopian tube Ampulla ORGAN SYSTEMS │ 7. The Reproductive System
Isthmus
Uterus Infundibulum
Fimbria
The ovulated oocyte is picked
Perimetrium up from the intraperitoneal
Endometrium cavity by fimbria of the fallopian
Myometrium tube. Peristaltic contractions
of the fallopian tube move the
oocyte into the ampulla, where
fertilization usually occurs 8 to 25
hours after ovulation.
Fertilization
• Semen ejaculated into the vagina quickly coagulates and neutralizes the acidic vaginal fluids to permit sperm survival. About
100,000 of the approximately 60 million sperm that enter the vagina will make it through the cervix. Elevated estrogen before
ovulation thins the cervical mucus, allowing for easier transit of sperm to the uterus.
• U terine fluid solubilizes the glycoproteins coating the sperm in a process called capacitation. Capacitation aids in fertilization by
increasing energy metabolism, enhancing motility, and allowing the acrosome reaction that occurs at the zona pellucida. Sperm
movement through the uterus is primarily accomplished by contraction of the female reproductive tract, primarily the uterus.
• S perm are capable of fertilizing for as long as 72 hours after ejaculation. Once sperm reach the oocyte, they bind to the zona
pellucida and undergo the acrosome reaction. This reaction releases hydrolytic enzymes stored in the acrosome cap, which
dissolve the zona pellucida. Sperm motility is important to push the sperm head toward the oocyte. When the sperm reach the oocyte,
the two membranes fuse and the contents of the sperm cell enter the oocyte. At this point, a cortical reaction occurs, during which
the zona pellucida hardens and prevents additional sperm from entering the oocyte.
• Prior to fusing of the male and female pronucleus, the oocyte undergoes a second meiotic division, producing the second polar body
and the female pronucleus. The contents of the sperm form the male pronucleus, which fuses with the female pronucleus,
forming the embryo.
Early Embryogenesis
• The embryo remains in the ampulla several days, during which time rising levels of progesterone relax the uterine and fallopian tube
musculature, making it easier for the embryo to pass into the uterus.
• T he embryo usually arrives in the uterus by about the third day following fertilization, but does not implant in the uterus for
about 3 more days. During the latter 3 days, the embryo develops a vascular system that aids in taking up nutrients it receives from
uterine secretions.
407
ORGAN SYSTEMS │ 7. The Reproductive System ►►Implantation and Pregnancy
Implantation
Umbilical arteries (2) At the time of implantation, the trophectoderm cells of
the embryo contact the maternal epithelium, resulting in
Umbilical vein (1) Maternal increased vascular permeability in the embryo, edema in
blood the intracellular matrix, swelling of the stromal cells with
addition of glycogen granules, and sprouting and ingrowth
Syncytiotrophoblast of capillaries. This reaction is called decidualization and
prepares the decidua for the embryo. Within about 12 days
Chorionic after fertilization, the embryo is completely embedded in
plate the decidua.
Villus Between 8 to 12 days after fertilization, human chorionic
gonadotropin (hCG) is synthesized by the blastocyst
Fetal and is structurally and functionally similar to LH. It acts
on the ovary to stimulate luteal growth and to suppress
Maternal Decidua Myometrium luteolysis.
basalis Perimetrium
Uterine vein
Uterine artery
Placenta
• The placenta allows for the exchange of nutrients and waste products between the maternal and fetal circulations. By about
5 weeks postfertilization, the placenta is developed and functional, although not fully mature.
• The placenta consists of villi from cell columns of chorionic syncytiotrophoblast, which have fetal blood vessels throughout. The villi
branch and penetrate the maternal stroma, forming a mass of terminal villi that is separated from fetal capillaries by the thin layer of
the villi.
Lactation
• During pregnancy, estrogen and progesterone stimulate the development of the mammary glands for lactation while preventing
milk production.
• Following delivery, estrogen and progesterone levels decline and milk production is permitted.
• The production of milk requires prolactin, a hormone produced by the anterior pituitary. Prolactin is normally inhibited by
hypothalamic dopamine, but suckling decreases dopamine release.
• T he ejection of milk requires oxytocin, a hormone produced in the hypothalamus and released from the posterior pituitary. Oxytocin
is released in response to suckling or baby crying and acts on the myoepithelial cells to stimulate contraction (milk let-down). Milk
is then ejected from the nipple.
408
►►Diseases of Pregnancy ORGAN SYSTEMS │ 7. The Reproductive System
Pregnancy-induced Hypertension
Preeclampsia Preeclampsia: Hypertension, proteinuria, and edema
and eclampsia Symptoms can include headache, blurred vision, mental changes, facial and extremity edema, and abdominal
pain
Preeclampsia is common (>5% of pregnancies) from 20 weeks’ gestation onward
Can cause Hemolysis, Elevated Liver function tests, and Low Platelets (HELLP syndrome)
Best treatment is delivery of fetus if possible; or manage with bed rest, salt restriction, IV magnesium sulfate,
antihypertensives, and diazepam if needed for treatment and/or prevention of seizures.
Eclampsia = Preeclampsia and seizures
Rare because of aggressive management of preeclampsia
Placental Abnormalities
Abruptio placentae Placenta detaches prematurely from the endometrium, with risk of death for the fetus and DIC in
the mother
Placenta previa Placenta overlies the cervical os; the baby must be delivered by Caesarian section to prevent life-threatening
maternal or fetal hemorrhage due to tearing of the placenta during delivery
Placenta accreta Placenta implants directly in the myometrium rather than the endometrium; following delivery, hysterectomy is
usually performed to be sure all of the placenta was removed
Amniotic Fluid Abnormalities
Polyhydramnios Very large amount of amniotic fluid; usually due to severe abnormalities in the fetus such as anencephaly,
esophageal atresia, or duodenal atresia
Oligohydramnios Very small amount of amniotic fluid; usually due to severe abnormalities in the fetus such as bilateral renal
agenesis or posterior urethral valves (males) that prevent urination
Miscellaneous
Ectopic pregnancy Embryo lodges in an abnormal site (most commonly in a fallopian tube, but can also be on pelvic organs or in
the abdomen)
Typically because of fallopian tube pathology that prevents the egg from reaching the uterine cavity
Risk of potentially fatal hemorrhage to the mother
►►Infectous Agents That Cross the Placenta
(Mnemonic: TORCH) Miscellaneous:
Toxoplasma Listeria monocytogenes
Other (Syphilis) Parvovirus B19
Rubella Coxsackie B
CMV Polio
Herpes and HIV
409
ORGAN SYSTEMS │ 7. The Reproductive System ►►Female Reproductive Pharmacology
Class Mechanism Comments/Agents
Contraception
The most common methods of reversible contraception include oral contraceptives, long-acting injectable or implantable progestins,
condoms, spermicides, withdrawal, diaphragm and intrauterine devices, and timely abstinence.
Estrogens and Suppresses production of FSH and LH, • Commonly used estrogens: ethinyl estradiol and mestranol
progestins which leads to inhibition of ovulation
and alteration of cervical mucus and the • C ommonly used progestins: norgestrel, norethindrone, and
endometrium. medroxyprogesterone
• A re available orally as monophasic, biphasic, and triphasic
combinations; also available as progestin-only preparations
• Are available in many other forms, including transdermal
patches, vaginal rings, IUDs, and long-acting injections
• Can cause nausea, breast tenderness, headache, depression,
thromboembolism, and weight gain
• Absolute contraindications include thrombophlebitis,
thromboembolic disorders, cerebral vascular disease, coronary
occlusion, known or suspected pregnancy, smokers over the
age of 35; dramatically impaired liver function, and suspected
breast cancer
• O ther uses: female hypogonadism, HRT, dysmenorrhea,
uterine bleeding, and acne
Postcoital Prevents pregnancy if used within 72 Different types include estrogens alone, progestins alone,
contraceptives hours of unprotected intercourse combination pills, mifepristone (RU486)
Intrauterine devices “Devices” that create a hostile Examples: Copper-T 380 (IUD) and Progesterone T (IUD)
(IUD) environment in the endometrium through
low-grade intrauterine inflammation
and increased prostaglandin formation;
therefore interfere with the implantation of
the fertilized ovum
Hormone Replacement Therapy (HRT)
• Used in the treatment of menopause, which is defined as a permanent cessation of menstruation secondary to a loss of ovarian
follicular activity. HRT is used to prevent hot flashes, atrophic changes in the urogenital tract, and osteoporosis.
• When ERT is administered alone, it may induce endometrial growth and cancer; concomitant progesterone use prevents this. HRT
has been associated with an increased breast cancer and stroke risk and is no longer as widely used.
(Continued)
410
►►Female Reproductive Pharmacology (Cont’d.) ORGAN SYSTEMS │ 7. The Reproductive System
Class Mechanism Comments/Agents
Selective Estrogen Receptor Modulator (SERM)
These drugs act as estrogen agonists, partial agonists, or antagonists, depending on the target tissue.
Tamoxifen • Estrogen antagonist in breast • Used in hormone-responsive breast CA; reduces risk of
• Estrogen agonist in endometrium breast CA in very high risk women
• Estrogen agonist in bone
• Increases risk of endometrial CA
• Prevents osteoporosis in woman using it for breast CA
• Causes hot flashes and increases risk of venous
thrombosis
Raloxifene • Partial estrogen agonist in bone • Prevents osteoporosis in postmenopausal women
• Estrogen antagonist in breast
• Estrogen antagonist in uterus • Reduces risk of breast CA in very high risk women
• No increased endometrial CA risk
• Causes hot flashes and increases risk of venous
thrombosis
Miscellaneous Agents
Clomiphene Fertility agent; nonsteroidal agent that Most common side effect: multiple birth pregnancy
selectively blocks estrogen receptors in
the pituitary, reducing negative feedback
mechanism and thereby increasing FSH and
LH and stimulation of ovulation
Danazol Inhibits ovarian steroid synthesis Used in endometriosis and fibrocystic breast disease
Anastrozole Aromatase inhibitor (decrease in estrogen Used in breast CA in postmenopausal women
Exemestane synthesis)
Mifepristone Progesterone and glucocorticoid antagonist Used as postcoital contraceptive and abortifacient
(RU 486)
Dinoprostone PGE2 analog Used to induce labor, causes cervical ripening
and uterine contractions; also an abortifacient
Terbutaline β2 agonists Relax uterus, have been used to suppress
premature labor
Definition of abbreviations: CA, cancer; ERT, estrogen replacement therapy; FSH, follicle-stimulating hormone; HRT, hormone-replacement
therapy; LH, luteinizing hormone.
411
ORGAN SYSTEMS │ 7. The Reproductive System Female Reproductive System Pathology
►►Diseases of the Vulva
Disease Description Distribution Etiology/Comments
Vulva, perineum, Associated with human
Condyloma Verrucous, wartlike lesions vagina, and cervix
acuminatum Koilocytosis, acanthosis, hyperkeratosis, papillomavirus (HPV) serotypes 6
Occur along the milk and 11
and parakeratosis line Greatly increased risk of cervical
Labia majora carcinoma
Papillary Benign tumor similar to an intraductal
hidradenoma papilloma of the breast Not associated with underlying tumor
Extramammary Erythematous, crusted rash
Paget disease of the Intraepidermal malignant cells with
vulva
pagetoid spread
Candida Erythema, thick white discharge Vulva and vagina Extremely common, especially in
vulvovaginitis diabetics and after antibiotic use
Note: See also Sexually Transmitted Diseases, pages 419–421.
►►Diseases of the Vagina
Vaginal Adenosis and Clear Cell Adenocarcinoma
• Rare in the general population, but greatly increased risk in females exposed to diethylstilbestrol (DES) in utero (1940−1970)
• Vaginal adenosisbenign condition thought to be a precursor of clear cell carcinoma
Embryonal Rhabdomyosarcoma (Sarcoma Botryoides)
• Rare tumor affecting female infants and young children (age <4)
• Polypoid, “grapelike,” soft tissue mass protruding from the vagina
• Spindle-cell tumor, may show cross-striations, positive for desmin, indicating skeletal muscle origin
►►Diseases of the Cervix/Fallopian Tubes
Disease Description Etiologies Disease Manifestations Clinical
Pelvic Ascending infection Neisseria gonorrhoeae Cervicitis, endometritis, • V aginal discharge/
inflammatory from cervix to (Gram − diplococcus) salpingitis, peritonitis, pelvic bleeding
disease endometrium, abscess, perihepatitis
fallopian tubes, and Chlamydia (Fitz-Hugh-Curtis syndrome), • Midline abdominal pain,
pelvic cavity trachomatis chandelier sign bilateral lower abdominal
(intracytoplasmic and
inclusions in mucosal Complications: tubo-ovarian pelvic pain
cells) abscess, tubal scarring,
infertility, ectopic pregnancy, • Abdominal tenderness
intestinal obstruction and peritoneal signs
Cervical Third most common Associated with early Begins as cervical • Fever
carcinoma malignant tumor first intercourse, multiple intraepithelial neoplasia (CIN)
of the female sexual partners, infection → carcinoma in situ → invasive May be asymptomatic,
genital tract in by HPV types 16, 18, squamous cell cancer or may have postcoital
United States; peak 31 and 33, smoking, and bleeding, dyspareunia,
incidence in the 40s immunosuppression discharge
Early detection possible
with Papanicolaou (Pap)
smear – koilocytic cells
412
►►Diseases of the Uterus ORGAN SYSTEMS │ 7. The Reproductive System
Disease Description Location Pathology Clinical
Endometritis Ascending infection Endometrium and Ureaplasma, Associated with pregnancy or
from the cervix decidua Peptostreptococcus, abortions (acute)
Gardnerella, Bacteroides,
Group B Streptococcus, Associated with PID and
Chlamydia trachomatis, intrauterine devices (IUDs)
Actinomyces (yellow, (chronic)
granular filaments on IUD)
Chronic pelvic pain linked to
Endometriosis • Presence of Ovary Red-brown serosal menses
Leiomyoma endometrial glands nodules (“powder Dysmenorrhea and
Leiomyosarcoma and stroma outside Ovarian and uterine burns”) dyspareunia
the uterus ligaments Rectal pain and constipation
Endometrioma: ovarian Infertility
• M ost commonly Pouch of Douglas “chocolate” cyst
affects women of Menorrhagia
reproductive age Serosa of bowel and Adenomyosis = Abdominal mass
bladder endometrial glands in the Pelvic pain, back pain, or
• Benign smooth myometrium suprapubic discomfort
muscle tumor that Peritoneal cavity Infertility
grows in response
to estrogen. May occur in Well-circumscribed, Increased incidence in blacks
subserosal, rubbery, white-tan Aggressive tumor that
• H igher incidence in intramural, or “whorled” masses
African Americans submucosal tends to recur
locations in the Often multiple May present with cervical
Malignant variant: myometrium
leiomyosarcoma bleeding
Myometrium Gross: Bulky tumor
Smooth muscle with necrosis and Postmenopausal vaginal
sarcoma of the uterus Begins in hemorrhage bleeding
endometrium
Endometrial Most common and may invade Micro: Malignant smooth Risk Factors:
adenocarcinoma malignant tumor of the myometrium muscle cells, often with Early menarche and late
female genital tract nuclear pleomorphism
and increased mitotic menopause
Most commonly affects rate Nulliparity
postmenopausal Hypertension and diabetes
women Gross: Obesity
Tan polypoid endometrial Chronic anovulation
Estrogen-producing
mass
Invasion of myometrium is ovarian tumors, estrogen
replacement therapy and
prognostically important tamoxifen
Endometrial hyperplasia
Micro: endometrioid Lynch syndrome (colon,
adenocarcinoma (most endometrial, and ovarian
common type) cancers = HNPCC)
Definition of abbreviations: HNPCC, hereditary nonpolyposis colorectal cancer.
413
ORGAN SYSTEMS │ 7. The Reproductive System ►►Diseases of the Ovary
Disease Presentation Laboratory/Pathology Etiology Treatment
Polycystic • Young, obese, • E levated luteinizing Increased LH stimulation Oral contraceptives or
ovary disease hirsute females of hormone (LH) leads to increased medroxyprogesterone,
(Stein-Leventhal reproductive age androgen synthesis and metformin, surgical
syndrome) • L ow follicle stimulating anovulatory cycles wedge resection
• O ligomenorrhea hormone (FSH)
or secondary
amenorrhea • Elevated testosterone
• Infertility Bilaterally enlarged ovaries
with multiple follicular cysts
Epithelial Tumors
Cystadenoma Most common benign ovarian tumor
Cystadeno- Pathology: Unilocular cyst with simple serous or mucinous lining
carcinoma
Most common malignant CA-125- marker for Genetic risk factors: Surgery,
Borderline tumor ovarian tumor. cystadenocarcinoma of antineoplastic drugs
Brenner tumor ovary. Used to monitor • BRCA-1: breast and
Less common Often asymptomatic recurrence, measure ovarian cancers
tumors until far advanced response to therapy.
Teratoma (presenting symptoms • Lynch syndrome
may be increased Complex multiloculated cyst
Dysgerminoma abdominal girth due to with solid areas
ascites, bowel or bladder
problems) • Serous (serous
cystadenocarcinoma)
Can produce or mucinous (mucinous
pseudomyxoma cystadenocarcinoma)
peritonei lining with tufting,
papillary structures with
psammoma bodies
• Spreads by seeding
pelvic cavity
Tumors of low malignant potential
Rare tumor that resembles transitional carcinoma; can be benign or malignant
• Y olk sac tumor: may have structures resembling primitive glomeruli
• C horiocarcinoma (see table below) and embryonal carcinoma: very aggressive tumors
Germ Cell Tumors
• Most are benign Ovarian cyst containing May be due to abnormal Surgical
hair, teeth, and sebaceous differentiation of fetal
• Occur in younger material germ cells that arise from
women the fetal yolk sac
• C ontain elements
from all three germ
layers (ectoderm,
mesoderm,
endoderm)
• I mmature teratoma-
contains primitive cells
– higher malignant
potential
• Malignant Similar to seminoma in Risk factors: Radiosensitive, so good
appearance prognosis
• A ffects mainly young Turner syndrome,
adults pseudohermaphroditism (Continued)
414
►►Diseases of the Ovary (Cont’d.) ORGAN SYSTEMS │ 7. The Reproductive System
Sex Cord-Stromal Tumors
Ovarian fibroma Common tumor. Associated with Meigs syndrome = fibroma + ascites + pleural effusion
Granulosa cell Potentially malignant, produces estrogen and can produce precocious puberty, irregular menses, or
tumor dysfunctional uterine bleeding.
Microscopic: made of polygonal tumor cells with formation of follicle-like structures (Call-Exner bodies)
Complications: endometrial hyperplasia and cancer
Sertoli-Leydig • Androgen producing tumor, presents with virilization
cell tumor
(androblastoma)
►►Gestational Trophoblastic Disease
Hydatidiform Mole (Molar Pregnancy)—tumor of placental trophoblast
Incidence 1:1,000 pregnancies
Clinical “Size greater than dates,” vaginal bleeding, passage of edematous, grape-like tissue, elevated
β-hCG, invasive moles invade myometrium
Treatment Curettage, follow β-hCG levels
Types
Complete mole Results from fertilization of an ovum that lost 90% 46,XX; 10% contain a Y chromosome
all its chromosomal material; all chromosomal
material is derived from sperm
Partial mole Results from fertilization of an ovum by two Partial moles are triploid = 69, XXY (23,X [maternal] +
sperm, one 23,X and one 23,Y 23X [one sperm] +23Y [the other sperm])
Choriocarcinoma • Malignant germ cell tumor derived from trophoblast
• Gross: necrotic and hemorrhagic mass
• Micro: proliferation of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblasts
• Hematogenous spread to lungs, brain, liver, etc.
• Responsive to chemotherapy
►►Partial Moles Versus Complete Moles
Properties Partial Mole Complete Mole
Diploid
Ploidy Triploid 46 (All paternal)
Elevated (+++)
Number of chromosomes 69 All are hydropic
Marked
β-hCG Elevated (+) Absent
10%
Chorionic villi Some are hydropic 2%
Trophoblast proliferation Focal
Fetal tissue Present
Invasive mole 10%
Choriocarcinoma Rare
415
ORGAN SYSTEMS │ 7. The Reproductive System Breast Pathology
►►Fibrocystic Disease
• Most common breast disorder, affecting approximately 10% of women; may be mistaken for CA
• Develops during reproductive life, distortion of the normal breast changes associated with the menstrual cycle
• Patients often have lumpy, tender breasts
• Pathogenesis: possibly due to high estrogen levels, coupled with progesterone deficiency
• Pathology: several morphologic patterns recognized
Fibrosis • Women 35 to 49 years of age; not premalignant
• Gross: dense, rubbery mass; usually unilateral, most often in the upper outer quadrant
• Histology: increase in stromal connective tissue; cysts are rare
Cystic disease • Women 45 to 55 years of age; not premalignant
• Gross: serous cysts, firm to palpation, may be hemorrhagic; usually multifocal, often bilateral
• Histology: cysts lined by cuboidal epithelium, may have papillary projections
• May be an accompanying stromal lymphocytic infiltrate (chronic cystic mastitis)
Sclerosing • Women 35 to 45 years of age; mild increased risk of CA
adenosis • Gross: palpable, ill-defined, firm area most often in upper outer quadrant; usually unilateral.
• Histology: glandular patterns of cells in a fibrous stroma; may be difficult to distinguish from cancer
Epithelial • Women over 30 years of age, mild increased CA risk
hyperplasia • Gross: variable with ill-defined masses
• Histology: ductal epithelium is multilayered and produces glandular or papillary configurations
• Atypical hyperplasia has a moderate risk of CA
►►Tumors • Most common benign breast tumor
• Single movable breast nodule, often in the upper outer quadrant; not fixed to skin
Fibroadenoma • Occurs in reproductive years, generally before age 30, possibly related to increased estrogen sensitivity
• May show menstrual variation and increased growth during pregnancy; postmenopausal regression usual
Phyllodes tumor • Gross: round and encapsulated with a gray-white cut surface
(cystosarcoma • Histology: glandular epithelial-lined spaces with a fibroblastic stroma
phyllodes) • Surgery required for definitive diagnosis
Intraductal • Fibroadenoma-like tumors that have become large, cystic, and lobulated
papilloma • Distinguished by the nature of the stromal component
• Malignant fibrous, cartilaginous; bony elements may be present
• Gross: irregular mass; often fungating or ulcerated
• Histology: myxoid stroma with increased cellularity, anaplasia, and increased mitoses
• Tumor initially localized but may spread later, usually to distant sites but not to local lymph nodes
• Most common in women 20–50 years of age; solitary lesion within a duct
• May present with nipple discharge (serous or bloody), nipple retraction, or small subareolar mass
• Gross: small, sessile or pedunculated, usually close to the nipple in major ducts
• Histology: multiple papillae
• Single intraductal papillomas may be benign, but multiple papillomas associated with an increased risk of CA
416
►►Carcinoma of the Breast ORGAN SYSTEMS │ 7. The Reproductive System
General features • Most common cause of CA in women
• Lung CA causes more deaths
• Rare in women under age 25
• Lifetime risk of breast CA for the average woman with no family history: 8 to 10%
Risk factors • Increasing age (40+ years) • Fibrocystic disease
• Nulliparity • Previous history of breast cancer
• Family history • Obesity
• Early menarche • High-fat diet
• Late menopause
Clinical features • 50% in the upper outer quadrant
• Ninety percent arise in ductal epithelium
• Slightly more common in the left breast; bilateral or sequential in 4% of cases
• Breast mass usually discovered after self-examination or on routine physical
Tumor suppressor Mutated BRCA1
genes: BRCA1 and • Almost 100% lifetime risk for breast CA, often in the third and fourth decades of life
BRCA2 • Also at increased risk for ovarian CA (men may be at increased risk for prostate CA)
Mutated BRCA2
• Increased incidence of breast CA in both women and men
• Smaller risk of ovarian CA compared with BRCA 1
Invasion • May grow into the thoracic fascia to become fixed to the chest wall
• May extend into the skin, causing dimpling and retraction
• May cause obstruction of subcutaneous lymphatics, causing an orange-peel consistency to skin called
“peau d’orange”
• May invade Cooper ligaments within ducts to cause nipple retraction
Metastases • Most breast CAs disseminate via lymphatic or hematogenous routes
• Involve axillary, supraclavicular, and internal thoracic nodes
• Can also involve nodes of the contralateral breast
417
ORGAN SYSTEMS │ 7. The Reproductive System ►►Breast Carcinoma Types
Noninfiltrating • Gross: focus of increased consistency in breast tissue
intraductal • Histology: typical duct epithelial cells proliferate and fill ducts, leading to ductal dilatation
carcinoma • Often called “comedocarcinomas” because cheesy, necrotic tumor tissue may be expressed from ducts.
• Rarely have a papillary pattern
Infiltrating ductal • Most common breast CA
carcinoma • Gross: rock hard, usually 2 to 5 cm in diameter, foci of necrosis and calcification common (may be seen on
mammography)
• Histology: malignant duct epithelial cells appear in masses or ducts, invading the stroma
• Fibrous reaction responsible for the hard, palpable mass
Paget disease of the • Older women; poor prognosis
breast • Form of intraductal carcinoma involving areolar skin and nipple
• Gross: skin of the nipple and areola ulcerated and oozing
• Histology: ductal carcinoma, as well as large, anaplastic, hyperchromatic “Paget cells”
Medullary • Better prognosis than infiltrating ductal carcinoma
carcinoma
• Gross: fleshy masses, often 5 to 10 cm in diameter, little fibrous tissue, although foci of hemorrhage and
necrosis common
• Histology: sheets of large, pleomorphic cells with increased mitotic activity and a lymphocytic infiltrate
Colloid (mucinous) • Older women, slow growing, has a better prognosis than infiltrating ductal carcinoma
carcinoma • Gross: soft, large, gelatinous tumors
• Histology: islands of tumor cells with copious mucin
Lobular carcinoma • Multicentric; usually have estrogen receptors, arise from terminal ductules
• Gross: rubbery and ill-defined (result of their multicentric nature)
• Histology: tumor cells small and may be arranged in rings
►►Fibrocystic Disease versus Breast Cancer
Fibrocystic Disease Breast Cancer
• Often bilateral • Often unilateral
• May have multiple nodules • Usually single nodule
• Menstrual variation • No menstrual variation
• Cyclic pain and engorgement • No cyclic pain and engorgement
• May regress during pregnancy • Does not regress during pregnancy
►►Miscellaneous Breast Conditions
Acute mastitis • Fissures in nipples during early nursing predispose to bacterial infection; usually unilateral with pus in
ducts; necrosis may occur
• Usual pathogens: Staphylococcus aureus and Streptococcus
• Antibiotics and surgical drainage may be adequate therapy
Mammary duct ectasia • Occurs in fifth decade in multiparous women
(plasma cell mastitis) • Presents with pain, redness, and induration around the areola with thick secretions; usually unilateral
• Skin fixation, nipple retraction, and axillary lymphadenopathy may occurmust be distinguished from
malignancy
Gynecomastia • Enlargement of the male breasts; most often unilateral, but may be bilateral
• Secondary to Klinefelter syndrome, testicular tumors, puberty, or old age
• Associated with hepatic cirrhosis (cirrhotic liver cannot degrade estrogens)
• May be important signal that patient has high-estrogen state
418
Genitourinary System Disease ORGAN SYSTEMS │ 7. The Reproductive System
►►Infections and Sexually Transmitted Diseases (STDs)
Type Infection Case Vignette/ Most Pathogenesis Diagnosis Treatment
Key Clues Common
Causative
Agent(s)
Urethritis Gram − diplococci Neisseria Invasive; pili assist Growth on Thayer- Ceftriaxone
in PMNs in urethral gonorrhoeae adherence; have Martin agar, DNA
exudate antigenic variation; are probes
antiphagocytic; IgA
protease
Culture − , glycogen Chlamydia Obligate intracellular Tissue culture; Tetracyclines,
inclusion bodies in trachomatis in epithelial cells; glycogen-containing macrolides
cytoplasm, tissue CMI and DTH cause inclusion bodies in
culture scarring cytoplasm
Urease ⊕, no cell Ureaplasma Urease raises pH Not gram staining; Tetracyclines,
wall, ↑ urine pH, urealyticum of urine → struvite diagnosed by macrolides
non-Gram staining stones exclusion, urinary pH
Flagellated Trichomonas Unknown, PMN filtrate Flagellated Metronidazole
protozoan with vaginalis protozoan,
corkscrew motility corkscrew motility
Cystitis Painful urination, E. coli #1, other Pili, adhesins, motility, Culture of urine ≥105 Fluoroquinolones,
hematuria, fever, gram − enterics many are β hemolytic CFU/ml of gram − sulfonamide
rods in urine
As above, in young, Staphylococcus Sexual intercourse Culture of urine, Fluoroquinolones
newly-sexually saprophyticus introduces normal gram + cocci
active female flora organisms into
(honeymoon urethra
cystitis)
As above with Proteus spp. Urease raises urinary Culture of urine, Fluoroquinolones,
increased urinary pH, predisposes to lactose non- TMP-SMX
pH struvite stones fermenting gram −
bacilli with swarming
motility
Pyelonephritis As above with flank E. coli, Strictures, urinary Culture of urine Fluoroquinolones,
stasis allow 3rd gen
pain and fever Staphylococcus colonization cephalosporin,
ampicillin-
sulbactam
Cervicitis Friable, inflamed Neisseria Invades mucosa, PMN Gram − diplococci, Ceftriaxone
cervix with gonorrhoeae infiltration, pili, IgA Thayer-Martin agar
mucopurulent protease Tetracyclines,
discharge Chlamydia macrolides
trachomatis Obligate intracellular, Tissue culture,
CMI and DTH → cytoplasmic
scarring inclusions
Herpes simplex Vesicular lesions, dsDNA, nuclear Acyclovir,
virus painful envelope, valacyclovir,
icosahedral; Tzanck famciclovir
smear, intranuclear
inclusions (Continued)
419
ORGAN SYSTEMS │ 7. The Reproductive System ►►Infections and Sexually Transmitted Diseases (STDs; Cont’d.)
Type Infection Case Vignette/ Most Pathogenesis Diagnosis Treatment
Key Clues Common Metronidazole
Causative
Agent(s) Nystatin,
miconazole
Vulvovaginitis Adherent yellowish Bacterial Overgrowth of Clue cells, gram −
discharge, pH >5, vaginosis Gardnerella vaginalis, rods Metronidazole
fishy amine odor in anaerobes
KOH, clue cells, Ceftriaxone +
gram − cells doxycycline
dominate (doxycycline given
for presumed
Vulvovaginitis, Candida spp. Antibiotic use → Germ tube test, coinfection with
pruritus, erythema, overgrowth, gram ⊕ yeasts in Chlamydia)
discharge with immunocompromised vaginal fluids Doxycycline,
consistency of macrolides
cottage cheese
Podophyllin,
“Strawberry cervix,” Trichomonas Vaginitis with Pear-shaped imiquimod
foamy, purulent vaginalis discharge trophozoites with
discharge; many corkscrew motility Acyclovir,
PMNs and motile valacyclovir,
trophozoites famciclovir
microscopically
(corkscrew motility) (Continued)
Pelvic Adnexal Neisseria Pili and IgA protease Gram − diplococci
inflammatory tenderness, gonorrhoeae production in PMNs or culture
disease bleeding, on Thayer-Martin
dyspareunia, Chlamydia
vaginal discharge, trachomatis Intracellular in Tissue culture,
fever, chandelier mucosal epithelia; intracytoplasmic
sign, onset often causes type IV inclusions in
follows menses hypersensitivity mucosal cells
damage
Condyloma Lesions are Human HPV proteins E6 and dsDNA, naked,
acuminatum papillary/wart-like, papilloma virus E7 inactivate cellular icosahedral,
(genital warts) may be sessile (HPV; most antioncogene intranuclear
or pedunculated, common U.S. inclusion bodies
koilocytotic atypia is STD) Associated with
present, anogenital cervical CA
Genital herpes Multiple, painful, Herpes simplex Latent virus in sensory Virus culture,
vesicular, ganglia reactivates intranuclear
coalescing, inclusions,
recurring syncytia (Tzanck
smear), dsDNA
enveloped (nuclear),
icosahedral
420
►►Infections and Sexually Transmitted Diseases (STDs; Cont’d.) ORGAN SYSTEMS │ 7. The Reproductive System
Type Infection Case Vignette/ Most Pathogenesis Diagnosis Treatment
Key Clues Common
Causative
Agent(s)
Syphilis Painless chancre Treponema 3-week incubation Biopsy/scraping Penicillin,
Primary forms on glans, pallidum during which viewed with dark- doxycycline is
penis (or vulva/ spirochetes spread field microscopy an alternative
cervix) and heals throughout the body shows spirillar
within 1 to 3 months organisms
Secondary Local or generalized Develops 1 to 2 SerologyVDRL ⊕
rash lasting 1 to 3 months after primary (nonspecific); FTA-
months, can involve stage ABS (specific)
the palms and soles
Tertiary Affects central Develops in one-third Serology – FTA-Abs,
nervous system, of untreated patients; non-specific tests
heart, and skin; neurosyphilis: may be negative
characteristic lesion including
is gumma, may be meningovascular,
single or multiple; tabes dorsalis, and
most common in general paresis;
the liver, testes, and obliterative endarteritis
bone of vasa vasorum of
the aorta can lead
thoracic aneurysm
Chancroid Nonindurated, Haemophilus Unknown Gram − rods, Cefotaxime,
painful ulcer, ducreyi chocolate agar ceftriaxone
suppurative with (requires NAD and
adenopathy; slow hemin)
to heal
Lymphogranuloma Soft, painless Chlamydia Obligate intracellular Cell culture, Tetracyclines,
venereum papule heals, lymph trachomatis glycogen-containing erythromycin
nodes enlarge serotypes L1–3 inclusions
and develop
fistulas, genital
elephantiasis may
develop
Definition of abbreviations: CA, cancer; CMI, cell-mediated immunity; ds, double-stranded; DTH, delayed type hypersensitivity;
PMNs, polymorphonuclear leukocytes.
421
The Musculoskeletal System, Skin,
and Connective Tissue
Chapter 8
Structure, Function, and Pharmacology of Muscle Musculoskeletal Disorders
Features of Skeletal, Cardiac, and Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . 424 Skeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442–443
Skeletal Muscle Fiber Morphology and Function . . . . . . . . . . . . . . . . . . . . . . . . . 425 Microbiology of Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
Red Versus White Skeletal Muscle Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Musculoskeletal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
Smooth Muscle Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 Joint Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
Skeletal Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Infectious Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Rheumatoid Arthritis Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
Head and Neck Embryology and Anatomy Drugs Used in the Treatment of Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Tumors Involving Joint Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Skeletal Muscles Innervated by Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . .428 Muscle Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Pharyngeal Pouches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Palate and Face Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Skin
Cavernous Sinuses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Skin and Skin Appendages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
Upper Extremities and Back Skin Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451–453
Infectious Diseases of the Skin, Mucous Membranes, and
Brachial Plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Lesions of Roots of the Brachial Plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 Underlying Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453–456
Upper and Lower Brachial Plexus Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 Selected Rashes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457–458
Lesions of Nerves of the Brachial Plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432–433
Cutaneous Innervation of the Hand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Back Muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Movements of the Pectoral (Shoulder) Girdle on the Trunk . . . . . . . . . . . . . . . . 434
Movements at the Shoulder (Glenohumeral) Joint . . . . . . . . . . . . . . . . . . . . . . . 434
Rotator Cuff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Movements at the Elbow Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Movements at the Radioulnar Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Movements at the Wrist Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Movements of the Fingers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Movements of the Thumb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Effects of Lesions to Roots and Nerves of the Lumbosacral Plexus . . . . . . . . . . . 438
Sensory Innervation of the Foot and Leg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Movements at the Hip Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Movements at the Knee Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Common Knee Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Movements at the Ankle Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Movements at the Tarsal (Transverse Tarsal and Subtalar) Joints . . . . . . . . . . . . 441
Movements of the Toes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
423
ORGAN SYSTEMS │ 8. The Musculoskeletal System Structure, Function, and
Pharmacology of Muscle
►►Features of Skeletal, Cardiac, and Smooth Muscle
Characteristics Skeletal Cardiac Smooth
Nonstriated, fusiform fibers
Appearance Striated, unbranched fibers Striated, branched fibers No Z lines; have dense bodies
Z lines Z lines Single nucleus
Multinucleated Single nucleus
T tubules Form triadic contacts with Form dyadic contacts with Absent; have limited SR
SR at A-I junction SR near Z line
Cell junctions Absent Junctional complexes between Gap junctions
fibers (intercalated discs),
including gap junctions
Innervation Each fiber innervated Electrical syncytium Electrical syncytium
Action potential Inward Na+ current • Inward Ca2+ current Inward Na+ current
Upstroke No plateau (SA node) No plateau
Plateau • I nward Na+ current (atria,
ventricles, Purkinje fibers)
• No plateau (SA node)
• P lateau present (atria,
ventricles, Purkinje fibers)
Excitation-contraction AP → T tubules → Ca2+ • Inward Ca2+ current during • AP → opens voltage-gated Ca2+
coupling released from SR plateau → Ca2+ release from channels in sarcolemma; hormones
SR
and neurotransmitters → open IP3-
• cAMP increases Ca2+ and gated Ca2+ channels in SR
force in myocytes
• c AMP and cGMP inhibit smooth
muscle contraction
Calcium binding Troponin Troponin Calmodulin
Definition of abbreviations: AP, action potential; IP3, inositol triphosphate; SR, sarcoplasmic reticulum.
424
►►Skeletal Muscle Fiber Morphology and Function ORGAN SYSTEMS │ 8. The Musculoskeletal System
Skeletal muscle connective tissue (see right): Epimysium
Perimysium
E pimysium: dense connective tissue that surrounds the
entire muscles
P erimysium: thin septa of connective tissue that extends
inward from the epimysium and surrounds a bundle (fas-
cicle) of muscle fibers
E ndomysium: delicate connective tissue that
surrounds each muscle fiber
Subcellular components (see below): Fibers IA
H
M yofibrils: long, cylindrical bundles that fill the Myofibrils
sarcoplasm of each fiber Z
M yofilaments: actin and myosin; are within each myofi-
bril and organize into units called sarcomeres
During contraction: I band: shortens Nucleus Endomysium
A band: no change Z lines: move closer together Sarcolemma
H band: shortens
The Crossbridge Cycle
HZ AI
band line band band
Myofibril
Sarcomere
H band
I band A band
Myosin filament F-Actin filament
G-Actin
molecules
Myosin filament
Heavy Light
meromyosin meromyosin
►►Red versus White Skeletal Muscle Fibers
Red Fibers (Type I) White Fibers (Type II)
Slow contraction Fast contraction
↓ ATPase activity ↑ ATPase activity
↑ Capacity for aerobic metabolism ↑ Capacity for anaerobic glycolysis
↑ Mitochondrial content ↓ Mitochondrial content
↑ Myoglobin (imparts red color) ↓ Myoglobin
Best for slow, posture-maintaining muscles, e.g., back (think Best for fast, short-termed, skilled motions, e.g., extraocular
chicken drumstick/thigh) muscles of eye, sprinter’s legs, hands (think chicken breast
meat and wings)
425
ORGAN SYSTEMS │ 8. The Musculoskeletal System ►►Smooth Muscle Function
Types of Smooth Muscle
Multiunit • Acts as individual motor unit
• Little or no electrical coupling
• Is densely innervated; contraction controlled by autonomic nervous system
• In iris, ciliary muscle of lens, and vas deferens
Unitary • Extensive electrical coupling, allowing coordinated contraction
(single unit)
• Has a resting tone; spontaneously active (slow waves), has pacemaker activity; activity is
modulated by neurotransmitters and neurohormones
• Found mainly in the walls of hollow viscera, e.g., GI tract, uterus, bladder, ureters
Vascular • Has properties of both multiunit and single-unit smooth muscle
Smooth Muscle Contraction
[Ca2+ ] 1. ↑ intracellular Ca2+
2. Ca2+ binds calmodulin
calmodulin Ca2+–calmodulin 3. Ca2+-calmodulin binds to and activates
myosin light Ca2+–calmodulin– myosin light chain kinase (MLCK)
chain kinase myosin light chain
(inactive) kinase (active) 4. Myosin is phosphorylated
AT P ADP 5. Myosin-P binds actin and shortening occurs
6. Dephosphorylation of myosin → relaxation
myosin myosin-P
(inactive) (active)
Bridge to Pharmacology
α1 and M3 stimulation: ↑ IP3 → ↑ intracellular Ca2+ → smooth muscle contraction
β2 stimulation: ↑ cAMP → inhibits MLCK → smooth muscle relaxation
426
►►Skeletal Muscle Relaxants ORGAN SYSTEMS │ 8. The Musculoskeletal System
There are two general classes of skeletal muscle relaxants: neuromuscular blockers and spasmolytics. Neuromuscular blockers are used
during surgical procedures and act on skeletal muscle nicotinic cholinergic receptors. There are two classes of neuromuscular blockers:
nondepolarizing (competitive) and depolarizing. Spasmolytics are used for CNS disorders and acute muscle spasm and have varying
mechanisms of action.
Neuromuscular Blockers
Nondepolarizing Blockers
These agents are competitive antagonists at the nAChR (NM) on skeletal muscle and can be therefore be reversed by acetylcholinesterase
inhibitors (e.g., neostigmine, pyridostigmine).
Drug Duration Elimination Notes
Atracurium Intermediate Spontaneous Safer in renal and hepatic disease
Cisatracurium Intermediate Spontaneous Safer in renal and hepatic disease
Doxacurium Long Renal
d-Tubocurarine Long Renal Also blocks autonomic ganglia and causes histamine release
Mivacurium Short Plasma ChE
Pancuronium Long Renal Blocks muscarinic receptors
Rocuronium Intermediate Hepatic
Vecuronium Intermediate Hepatic
Depolarizing Blockers:
These agents act as nicotinic agonists and depolarize skeletal muscle. Patients often initially have fasciculations. Continuous
depolarization of the motor end-plate leads to flaccid paralysis. When given continuously, two phases occur:
Phase I block (depolarizing)fasciculations, flaccid paralysis; this phase is augmented by AChE inhibitors
Phase II block (desensitizing)the end-plate repolarizes, but is unresponsive to ACh; reversed by AChE inhibitors
Succinylcholine Ultrashort Plasma ChE Stimulates autonomic ganglia and muscarinic receptors; can →
hyperkalemia; postoperative muscle pain
Spasmolytics
The spasmolytics reduce excessive muscle tone in CNS disorders (e.g., cerebral palsy, multiple sclerosis, stroke, spinal cord injury) or
in acute muscle injury.
Drug Mechanism of Action Location of Action Clinical Uses
Baclofen GABAB receptor agonist CNS Spasticity of central or spinal origin
Diazepam Benzodiazepine, potentiates GABAA CNS Spasticity and acute muscle spasm
receptors
Tizanidine α2-receptor agonist CNS Acute muscle spasm
Botulinum toxin Blocks ACh release Muscle
Locally injected to relieve spasticity,
e.g. in CP; used for cosmetic
purposes
Dantrolene Blocks ryanodine receptors on SR to Muscle Malignant hyperthermia; neuroleptic
prevent Ca2+ release malignant syndrome
Cyclobenzaprine CNS Acute muscle spasm
Carisoprodol
Metaxalone
Definition of abbreviation: CP, cerebral palsy; SR, sarcoplasmic reticulum.
427
ORGAN SYSTEMS │ 8. The Musculoskeletal System Head and Neck Embryology and Anatomy
►►Skeletal Muscles Innervated by Cranial Nerves
Muscles Derived from Cranial Nerve Muscles Skeletal Elements
a Pharyngeal Arch (from neural crest)
Mandibular process
First arch—mandibular Trigeminal Four muscles of mastication: Maxillary process
mandibular nerve (V3) • Masseter
(Mandibular hypoplasia is seen • Temporalis Malleus
in Treacher Collins syndrome • Lateral pterygoid Incus
and in the Robin sequence. • Medial pterygoid
Both involve neural crest cells.) Plus: Hyoid (superior part)
• Digastric (anterior belly) Styloid process
• Mylohyoid Stapes
• Tensor tympani
• Tensor veli palatini Hyoid (inferior part)
Thyroid cartilage
Second arch—hyoid Facial (VII) Muscles of facial expression:
• Orbicularis oculi
• Orbicularis oris Cricoid, arytenoid,
• Buccinator and others corniculate, cuneiform
Plus: cartilages
• Digastric (posterior belly)
• Stylohyoid
• Stapedius
Third arch Glossopharyngeal (IX) Stylopharyngeus
Fourth arch Vagus (X) superior laryngeal Cricothyroid
(external branch)
Fifth arch Vagus (X) pharyngeal Levator veli palatini
Sixth arch branches Uvular muscle
Pharyngeal constrictors
Lost Salpingopharyngeus
Vagus (X) recurrent Palatoglossus
laryngeal Palatopharyngeus
Lateral cricoarytenoid
Posterior cricoarytenoid
Transverse arytenoid
Oblique arytenoid
Thyroarytenoid (vocalis)
Muscles of myotome origin Accessory (XI) Trapezius
Sternocleidomastoid
Hypoglossal (XII) Genioglossus
Hyoglossus
Styloglossus
Oculomotor (III) Superior, inferior, and medial
rectus; inferior oblique, levator
palpebrae superioris
Trochlear (IV) Superior oblique
Abducens (VI) Lateral rectus
428
►►Pharyngeal Pouches Foregut ORGAN SYSTEMS │ 8. The Musculoskeletal System
Auditory Tube and 1 Foramen
Middle Ear Cavity Cecum
(Pharyngeal Pouch 1)
External Auditory Meatus 2
(Pharyngeal Groove 1)
Tympanic Membrane Path of Thyroglossal Duct
(Pharyngeal Membrane 1) 3
SP 4
Thyroid
UB Gland
IP
T
Adult Structures Derived from the Fetal Pharyngeal Pouches
Pouch Adult Derivatives Clinical Correlate
1 Epithelial lining of auditory tube and middle The DiGeorge sequence occurs when pharyngeal
ear cavity pouches 3 and 4 fail to differentiate into the
2 Epithelial lining of crypts of palatine tonsil parathyroid glands and thymus. Patients have
3 Inferior parathyroid gland (IP) immunologic problems, hypocalcemia, and may have
Thymus (T) cardiovascular defects (persistent truncus arteriosus),
4 Superior parathyroid gland (SP) abnormal ears, and micrognathia.
Ultimobranchial body (UB)
The thyroid gland does not develop in a pharyngeal pouch; it develops from midline endoderm of the oropharynx and
migrates inferiorly along the path of thyroglossal duct. Neural crest cells migrate into the UB to form parafollicular C
cells of the thyroid.
The external auditory meatus is the only postnatal remnant of a pharyngeal groove or cleft.
►►Palate and Face Development
Lateral Nasal Medial Nasal Frontonasal The face develops from the frontonasal
Prominence Prominence Prominence prominence, the pair of maxillary prominences,
Maxillary Maxillary and the pair of mandibular prominences.
Prominence Mandibular Prominence
Prominence The intermaxillary segment forms when the
Philtrum two medial nasal prominences fuse together
at the midline and → the philtrum of the lip,
four incisor teeth, and the primary palate of
the adult.
Intermaxillary Segment Four Incisor Teeth The secondary palate forms from palatine
Primary Palate Incisive Foramen shelves, which fuse in the midline, posterior to
Philtrum of Lip the incisive foramen.
Secondary Primary Fused The primary and secondary palates fuse at the
Palate Palate Palatine incisive foramen to form the definitive palate.
Shelves
(maxillary (secondary
prominence) palate)
Figure III-6-7. Face and Palate DeveloCpelimneicntal Correlation
Cleft lip occurs when the maxillary prominence fails to fuse with the medial nasal prominence.
Cleft palate occurs when the palatine shelves fail to fuse with each other or the primary palate.
429
ORGAN SYSTEMS │ 8. The Musculoskeletal System ►►Cavernous Sinuses Optic chiasm
Cavernous sinus Internal carotid artery
Pituitary gland
Oculomotor nerve (III)
Trochlear nerve (IV) Sphenoidal sinus
Abducent nerve (VI) Nasopharynx
Ophthalmic nerve (V1)
Maxillary nerve (V2)
The cavernous sinuses are located on either side of the body of the sphenoid bone. Each sinus receives blood from some of
the cerebral veins, ophthalmic veins, and the sphenoparietal sinus. Each cavernous sinus drains into a transverse sinus via
the superior petrosal sinus and into the internal jugular vein via the inferior petrosal sinus.
Cavernous Sinus Thrombosis
Infection can spread from veins of the face into the cavernous sinuses, producing a thrombosis that may involve the cranial
nerves that course through the cavernous sinuses. Cranial nerves III, IV, and VI and the ophthalmic and maxillary divisions
of CN V, as well as the internal carotid artery and its periarterial plexus of postganglionic sympathetic fibers, traverse the
cavernous sinuses. All of these cranial nerves course in the lateral wall of each sinus, except for CN VI, which courses through
the middle of the sinus. Initially, patients have an internal strabismus. Later, all eye movements are affected, along with with
altered sensation in skin of the upper face and scalp.
430
Upper Extremities and Back ORGAN SYSTEMS │ 8. The Musculoskeletal System
►►Brachial Plexus
The brachial plexus is formed by an Suprascapular n. C5
intermingling of ventral rami from the C5 Superior C6
through T1 spinal nerves.
The ventral rami of the brachial plexus Lateral Middle C7
exhibit a proximal to distal gradient of Posterior Inferior
innervation. Nerves that contain fibers Medial C8
from the superior rami of the plexus (C5 Musculocutaneous n. T1
and C6) innervate proximal muscles in the Axillary n.
upper limb (shoulder muscles). Nerves Radial n. Long thoracic n.
that contain fibers from the inferior rami
of the plexus (C8 and T1) innervate distal Median n.
muscles (hand muscles). Ulnar n.
Five major nerves arise from the brachial
plexus: the musculocutaneous, median,
and ulnar nerves contain anterior division
fibers and innervate muscles in the
anterior arm, anterior forearm, and hand
that act mainly as flexors. The axillary
and radial nerves contain posterior
division fibers, and innervate muscles in
the posterior arm and posterior forearm
that act mainly as extensors.
►►Lesions of Roots of the Brachial Plexus
Lesioned Root C5 C6 C7 C8 T1
Medial forearm Medial arm
Dermatome Lateral border of Lateral forearm to Over triceps, to little finger to elbow
paresthesia upper arm thumb midforearm, middle
finger Finger flexors Hand muscles
Wrist flexors
Muscles Deltoid Biceps Latissimus dorsi Hand muscles —
affected Rotator cuff Brachioradialis Pectoralis major Lower trunk
Serratus anterior Brachialis Triceps — compression
Biceps Supinator Wrist extensors Lower trunk
Brachioradialis compression
Reflex test — Biceps tendon Triceps tendon
Causes of Upper trunk Upper trunk Cervical spondylosis
lesions compression compression Herniation of
C6/C7 disk
431
ORGAN SYSTEMS │ 8. The Musculoskeletal System ►►Upper and Lower Brachial Plexus Lesions
Upper (C5 and C6) Brachial Plexus Lesion: Erb-Duchenne Palsy
• U sually occurs when the head and shoulder are forcibly separated (e.g., accident, birth injury, or herniation of disk)
• Trauma will damage C5 and C6 roots of the upper trunk
• P rimarily affects the axillary, suprascapular, and musculocutaneous nerves with loss of function of the intrinsic muscles
of the shoulder and muscles of the anterior arm
• A rm is medially rotated and adducted at the shoulder: loss of axillary and suprascapular nerves. The unopposed latissimus dorsi
and pectoralis muscles pull the limb into adduction at the shoulder
• T he forearm is extended and pronated: loss of musculocutaneous nerve
• Sign is “waiter’s tip”
• S ensory loss on lateral forearm to base of thumb: loss of musculocutaneous nerve
Lower (C8 and T1) Brachial Plexus Lesion: Klumpke’s Paralysis
• U sually occurs when the upper limb is forcefully abducted above the head (e.g., grabbing an object when falling, thoracic
outlet syndrome, or birth injury)
• Trauma will injure the C8 and T1 spinal nerve roots of the inferior trunk
• Primarily affects the ulnar nerve and the intrinsic muscles of the hand with weakness of the median-innervated muscles
of the hand
• Sign is combination of “claw hand” (ulnar nerve) and “ape hand” (median nerve).
• M ay include a Horner syndrome
• S ensory loss on medial forearm and medial 1½ digits
►►Lesions of Nerves of the Brachial Plexus
Radial Nerve (C5, C6, C7, C8)
Axilla: (Saturday night palsy Mid-shaft of humerus at radial groove Wrist: (laceration)
or using crutches) or lateral elbow (lateral epicondyle)
• Loss of extension at the elbow, wrist • Loss of forearm extensors of the wrist • N o motor loss
and MP joints and MP joints
• S ensory loss only on dorsal aspect of
• W eakened supination • Weakened supination thumb (first dorsal web space)
• Sensory loss on posterior arm, forearm, • S ensory loss on the posterior forearm
and dorsum of thumb and dorsum of thumb
• D istal sign is “wrist drop” • D istal sign is “wrist drop”
Median Nerve (C6, C7, C8, T1)
Elbow: (Supracondylar fracture of humerus) Wrist: (carpal tunnel or laceration)
• W eakened wrist flexion (with ulnar deviation) • Loss of thumb opposition (opponens pollicis muscle);
sign is ape or simian hand
• L oss of pronation
• Loss of first two lumbricals
• L oss of flexion of lateral 3 digits, resulting in the inability to • T henar atrophy
make a complete fist; sign is “hand of benediction” • S ensory loss on the palmar surfaces of lateral 3½ digits. Note
• Loss of thumb opposition (opponens pollicis muscle); sensation on lateral palm may be spared (see figure on next
sign is ape (simian) hand page).
Note: Lesions of median nerve at the wrist present without
• L oss of first two lumbricals hand of benediction and with normal wrist flexion, digital
flexion, and pronation.
• Thenar atrophy
(Continued)
• S ensory loss on palmar surface of the lateral hand and the
palmar surfaces of the lateral 3½ digits
Note: A lesion of median nerve at the elbow results in the
“hand of benediction” and “ape hand.”
432
►►Lesions of Nerves of the Brachial Plexus (Cont’d.) ORGAN SYSTEMS │ 8. The Musculoskeletal System
Ulnar Nerve (C8, T1)
Elbow (medial epicondyle), wrist (lacerations), fracture of hook of hamate, midshaft clavicle fracture
• Loss of hypothenar muscles, third and fourth lumbricals, all interossei and adductor pollicis
• With elbow lesion, there is minimal weakening of wrist flexion with radial deviation
• Loss of abduction and adduction of digits 2–5 (interosseus muscles)
• W eakened IP extension of digits 2–5 (more pronounced in digits 4 and 5)
• Loss of thumb adduction
• A trophy of the hypothenar eminence
• Sign is “claw hand” (note that clawing is greater with a wrist lesion)
• S ensory loss on medial 1½ digits
Axillary Nerve (C5, C6)
Fracture of the surgical neck of the humerus or inferior dislocation of the shoulder
• L oss of abduction of the arm to the horizon
• Sensory loss over the deltoid muscle
Musculocutaneus Nerve (C5, C6, C7)
• Loss of elbow flexion and weakness in supination
• Loss of sensation on lateral aspect of the forearm
Long Thoracic Nerve (C5, C6, C7)
• Often damaged during a radical mastectomy or a stab wound to the lateral chest (nerve lies on superficial surface of
serratus anterior muscle)
• L oss of abduction of the arm above the horizon to above the head
• Sign of “winged scapula”; patient unable to hold the scapula against the posterior thoracic wall
Suprascapular Nerve (C5, C6)
• Loss of shoulder abduction between 0 and 15 degrees (supraspinatus muscle)
• Weakness of lateral rotation of shoulder (infraspinatus muscle)
►►Cutaneous Innervation of the Hand
Anterior (palmar) Radial n. Posterior (dorsal) The palm is supplied mainly by the median
Ulnar n. Ulnar n. and ulnar nerves. The median supplies the
lateral 3½ digits and the adjacent area of
the lateral palm and the thenar eminence.
The ulnar supplies the medial 1½ digits
and skin of the hypothenar eminence. The
radial nerve supplies skin of the dorsum
of the hand in the area of the first dorsal
webbed space, including the skin over the
anatomic snuffbox.
Median n.
433
ORGAN SYSTEMS │ 8. The Musculoskeletal System ►►Back Muscles Muscles Involved Innervation
Dorsal rami of spinal nerves
Action 1. Splenius capitis, splenius cervicis Dorsal rami of spinal nerves
Extend/Rotate vertebrae
2. Erector spinae: Dorsal rami of spinal nerves
• Iliocostalis
• Longissimus
• Spinalis
3. Transversospinalis:
• Semispinalis
• Multifidus
• Rotatores
►►Movements of the Pectoral (Shoulder) Girdle on the Trunk
Action Muscles Involved Innervation Major Segments
of Innervation
Elevation Levator scapulae Dorsal scapular C4, C5
Trapezius, upper part Accessory C1−C5
Depression Pectoralis minor Medial pectoral C7, C8
Trapezius, lower part Accessory
Protraction Serratus anterior Long thoracic C5−C7
Retraction Rhomboid major and minor Dorsal scapular C5
Trapezius, middle fibers Accessory C1−C5
Lateral (upward) rotation Serratus anterior, lower half Long thoracic C5−C7
of scapula (in abduction) Trapezius, upper and lower parts Accessory C1−C5
Medial (downward) rotation Rhomboid major and minor Dorsal scapular C5
of scapula (in adduction) Levator scapulae Dorsal scapular C4, C5
►►Movements at the Shoulder (Glenohumeral) Joint
Action Muscles Involved Innervation Major Segments
Flexion of Innervation
Pectoralis major, clavicular head Lateral pectoral
Extension Deltoid clavicular part Axillary C5−C7
Biceps short head Musculocutaneous C5, C6
Abduction C5, C6
Adduction Deltoid, posterior fibers Axillary
Latissimus dorsi Thoracodorsal C5, C6
Lateral rotation Teres major Lower subscapular C6−C8
C6
Medial rotation Deltoid, middle fibers Axillary
Supraspinatus Suprascapular C5, C6
C5
Pectoralis major, sternocostal part Medial and lateral pectoral
Latissimus dorsi Thoracodorsal C6−T1
Teres major Lower subscapular C6−C8
C5, C6
Deltoid, posterior fibers Axillary
Infraspinatus Suprascapular C5, C6
Teres minor Axillary C5, C6
C6
Pectoralis major Medial and lateral pectoral
Latissimus dorsi Thoracodorsal C5−T1
Deltoid, clavicular part Axillary C6−C8
Teres major Lower subscapular C5−C7
Subscapularis Upper and lower subscapular C5, C6
C5, C6
434
►►Rotator Cuff ORGAN SYSTEMS │ 8. The Musculoskeletal System
Coracoid process Acromion
Supraspinatus
The tendons of rotator cuff muscles strengthen the glenohumeral Glenoid cavity
joint and include the supraspinatus, infraspinatus, teres minor, Subscapularis Infraspinatus
and subscapularis (the SITS muscles). The tendons of the
muscles of the rotator cuff may become torn or inflamed. The Teres minor
tendon of the supraspinatus is most commonly affected. Inferior angle
Patients with rotator cuff tears experience pain anteriorly and
superiorly to the glenohumeral joint during abduction.
►►Movements at the Elbow Joint
Action Muscles Involved Innervation Major Segments
Flexion of Innervation
Brachialis Musculocutaneous
Extension Biceps brachii Musculocutaneous C5, C6
Brachioradialis Radial C5, C6
C5, C6
Triceps Radial
C7, C8
►►Movements at the Radioulnar Joints
Action Muscles Involved Innervation Major Segments
of Innervation
Pronation Pronator teres Median
Pronator quadratus Median (anterior C6, C7
C8, T1
Supination Supinator interosseous nerve)
Biceps brachii C6–C8
Radial (deep branch) C5, C6
Musculocutaneous
435
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