Sonic Hedgehog (SHH) gene

Wnt-7 gene

FGF gene

Homeobox (Hox) gene

Produced at base of limbs in zone of polarizing activity

Involved in patterning along anterior-posterior axis

Involved in CNS development

(mutation can cause holoprosencephaly)

Produced at apical ectodermal ridge

(thickened ectoderm at distal end of each developing limb)

Necessary for proper organization along dorsal-ventral axis

Produced at apical ectodermal ridge

Stimulates mitosis of underlying mesoderm, providing for lengthening of limbs

Involved in segmental oganization of embryo in craniocaudal direction

Hox mutation > appendages in wrong locations

Early Fetal Development

(Day 0)

Early Fetal Development

(Within Week 1)

Early Fetal Development

(Within Week 2)

Bilaminar disc

(epiblast, hypoblast)

2 weeks = 2 layers

Early Fetal Development

(Within Week 3)

Trilaminar disc

(3 weeks = 3 layers)

Gastrulation

Begin to form:

- Pimitive streak

- Notochord

- Mesoderm and its organization

- Neural plate

Early Fetal Development

(Within Weeks 3-8)

(Embryonic Period)

Neuroectoderm > Neural tube and closes by week 4

Organogenesis

Extremely susceptible to teratogens

Early Fetal Development

(Week 4)

Heart begins to beat

Upper and lower limb buds begin to form

(4 weeks = 4 limbs)

Early Fetal Development

(Week 6)

Early Fetal Development

(Week 10)

process that forms the trilaminar embryonic disc

Establishes the ectoderm, mesoderm, and endoderm germ layers

Starts with the epiblast invaginating to form the primitive streak

Surface ectoderm

Neuroectoderm

Neural crest

1) Adenohypophysis

(from Rathke pouch)

2) Lens of eye

3) Epithelial linings of oral cavity

4) Sensory organs of ear

5) Olfactory epithelium

6) Epidermis

7) Anal canal below the pectinate line

8) Parotid, sweat, and mammary glands

Benign Rathke pouch tumor with cholesterol crystals and calcifications

(Surface ectoderm derivative)

1) Brain

(Neurohypophysis, CNS neurons, oligodendrocytes, Astrocytes, Ependymal cells, Pineal gland)

2) Retina and Optic nerve

3) Spinal cord

1) PNS

(Dorsal root ganglia, Cranial nerves, Celiac ganglion, Schwann cells, ANS)

2) Melanocytes

3) Chromaffin cells of adrenal medulla

4) Parafollicular (c) cells of thyroid

5) Pia and Arachnoid

6) Bones of the skull

7) Odontoblasts

8) Aorticopulmonary septum

1) Muscle

2) Bone

3) Connective tissue

4) Serous linings of body cavities

(Peritoneum)

5) Spleen

(derived from foregut mesentery)

6) Cardiovascular structures

7) Lymphatics

8) Blood

9) Wall of gut tube

10) Vagina

11) Kidneys

12) Adrenal cortex

13) Dermis

14) Testes and Ovaries

Notochord induces ectoderm to form neuroectoderm (neural plate). Its only postnatal derivative is the nucleus pulposus of the intervertebral disc

VACTERL

- Vertebral defects

- Anal atresia

- Cardiac defects

- Tracheo-Esophageal fistula

- Renal defects

- Limb defects (bone and muscle)

1) Gut tube epithelium

(including anal canal above pectinate line)

2) Most of urethra

(derived from urogenital sinus)

3) Luminal epithelial derivatives

(Lungs, Liver, Gallbladder, pancreas, Eustachian tube, Thymus, Parathyroid, Thyroid Follicular cells)

Incomplete organ development

(primordial tissue present)

Extrinsic disruption

Occurs after embryonic period

Secondary breakdown of a previously normal tissue or structure

(e.g., amniotic band syndrome)

Intrinsic disruption

Occurs during the embryonic period

(weeks 3-8)

Abnormalities result from a single primary embryological event

(oligohydramnios > Potter Sequence)

Most susceptible in 3rd-8th weeks of pregnancy

(Embryonic period > Organogenesis)

Before week 3: all-or-none effects

After week 8: growth and function affected

Teratogens

(Medications)

1) ACE Inhibitors

2) Alkylating Agents

3) Aminoglycosides

4) Carbamazepine

5) Diethylstilbestrol (DES)

6) Folate antagonists

7) Lithium

8) Methimazole

9) Phenytoin

10) Tetracyclines

11) Thalidomide

12) Valproate

13) Warfarin

Teratogens

(Substance Abuse)

1) Alcohol

2) Cocaine

3) Smoking

(Nicotine, CO)

Teratogens

(Other)

1) Iodine

(Lack or Excess)

2) Maternal Diabetes

3) Vitamin A

(Excess)

4) X-rays

ACE Inhibitors

(Effects on Fetus)

Alkylating Agents

(Effects on Fetus)

Absence of digits

Multiple anomalies

Aminoglycosides

(Effects on Fetus)

Carbamazepine

(Effects on Fetus)

Neural tube defects

Craniofacial defects

Fingernail hypoplasia

Developmental delay

IUGR

Diethylstilbestrol [DES]

(Effects on Fetus)

Vaginal clear cell adenocarcinoma

Congenital Mullerian anomalies

Folate Antagonists

(Effects on Fetus)

Lithium

(Effects on Fetus)

Ebstein anomaly

(atrialized right ventricle)

Methimazole

(Effects on Fetus)

Phenytoin

(Effects on Fetus)

Fetal Hydantoin Syndrome

- Microcephaly

- Dysmorphic craniofacial features

- Hypoplastic nails and distal phalanges

- Cardiac defects

- IUGR

- Intellectual disability

Tetracyclines

(Effects on Fetus)

Discolored teeth

(Teethracyclines)

Thalidomide

(Effects on Fetus)

Limb defects

(Phocomelia/Micromelia - "flipper" limbs)

Limb defects with "thalimbdomide"

Valproate

(Effects on Fetus)

Inhibition of maternal folate absorption > Neural tube defects

Valproate inhibits folate absorption

Warfarin

(Effects on Fetus)

Bone deformities

Fetal hemorrhage

Abortion

Ophthalmologic abnormalities

Do not wage warfare on the baby; keep it heppy with heparin (does not cross placenta)

Alcohol

(Effects on Fetus)

Common cause of birth defects and intellectual disability

Fetal Alcohol Syndrome

Cocaine

(Effects on Fetus)

Abnormal fetal growth

Fetal addiction

Placental abruption

Smoking [Nicotine/CO]

(Effects on Fetus)

A leading cause of low birth weight in developed countries

Associated with:

- Preterm labor

- Placental problems

- IUGR

- ADHD

Iodine [Lack or Excess]

(Effects on Fetus)

Congenital goiter

Hypothyroidism

(cretinism)

Maternal Diabetes

(Effects on Fetus)

Caudal Regression Syndrome

(anal atresia to sirenomelia)

Congenital heart defects

Neural tube defects

Vitamin A

(Effects on Fetus)

Extremely high risk for spontaneous abortions and birth defects

- Cleft palate

- Cardiac abnormalities

X-rays

(Effects on Fetus)

Microcephaly

Intellectual disability

One of the leading causes of congenital malformations in the US

Increased incidence of:

- Intellectual disability

- Pre- and postnatal developmental retardation

- Microcephaly

- Holoprosencephaly

- Facial abnormalities

(smooth philtrum, thin upper lip, small palpebral fissures, hypertelorism)

- Limb dislocation

- Heart Defects

Twinning

(Dizygotic Twins)

80%

Arise from 2 eggs that are separately fertilized by 2 different sperm (always 2 zygotes), and will have 2 separate amniotic sacs and 2 separate placentas (chorions)

Dichorionic Diamniotic

Twinning

(Monozygotic Twins)

20%

Arise from 1 fertilized egg (1 egg + 1 sperm) that splits into 2 zygotes in early pregnancy

Degree of separation depends on when egg splits

(timing determies number of chorions and number of amnios)

Twinning

(Monozygotic Cleavage)

2-cell stage (25%; 0-4 days) = Dichorionic Diamniotic (fused vs. separate placenta)

Morula (75%; 4-8 days) = Monochorionic Diamniotic

Blastocyte (< 1%; 8-12 days) = Monochorionic Monoamniotic

Formed Embryonic Disc (> 13 days) = Monochorionic Monoamniotic conjoined twins

Placenta

(Fetal Components)

Cytotrophoblast

Syncytiotrophoblast

Placenta

(Mother Component)

Inner layer of chorionic villi

(Cytotrophoblast makes Cells)

Outer layer of chorionic villi

Secretes hCG

(structurally similar to LH; stimulates Corpus Luteum to secrete progesterone during first trimester)

Derived from the endometrium

Maternal blood in lacunae

2 Umbilical Arteries = return deoxygenated blood from fetal Internal Iliac a. to placenta

1 Umbilical Vein = supplies oxygenated blood from placenta to fetus; drain into IVC via liver or via Ductus Venosus

Single Umbilical a. associated with congenital/chromosomal anomalies

Umbilical a. and v. are derived from allantois

In the 3rd week the yolk sac forms the Allantois > extends into urogenital sinus

Allantois > Urachus (duct between fetal bladder and yolk sac)

Failure of urachus to obliterate

Urine discharge from umbilicus

Partial failure of urachus to obliterate

Fluid-filled cavity lined with uroepithelium, between umbilicus and bladder

Can lead to infection or adenocarcinoma

Failure of urachus to obliterate

Outpouching of bladder

Failure of Vitelline duct to close

Meconium discharge from umbilicus

Partial closure of Vitellin duct with patent portion attached to ileum

(true diverticulum)

May have ectopic gastric mucosa and/or pancreatic tissue

- Melena

- Periumbilical pain

- Ulcers

Part of Maxillary a.

(branch fo External Carotid)

1st arch is maximal

Stapedial a. and Hyoid a.

Second = Stapedial

Common Carotid a. and Proximal part of Internal Carotid a.

C is the 3rd letter of the alphabet

On left, Aortic Arch

On right, proximal part of Right Subclavian a.

4th arch (4 limbs) = Systemic

Proximal part of Pulmonary aa. and (on left only) Ductus Arteriosus

6th arch = Pulmonary and the Pulmonary-to-systemic shunt (Ductus Arteriosus)

Right = loops around proximal Right Subclavian a.

Left = loops around Ductus Arteriosus/Ligamentum Arteriosum

Also called Pharyngeal apparatus.

Composed of clefts, arches, and pouches

Clefts = Derived from Ectoderm (also called grooves)

Arches = derived from Mesoderm (muscles, arteries) and Neural Crest (bones, cartilage)

Pouches = derived from Endoderm

CAP covers from outside to inside:

Clefts = Ecto

Arches = Meso

Pouches = Endo

1st = External Auditory Meatus

2nd - 4th = Temporary cervical sinuses > obliterated by proliferation of 2nd arch mesenchyme

Persistent cervical sinus = Branchial cleft cyst

(within lateral neck)

1st Branchial Arch

(Cartilage)

Meckel cartilage:

- Mandible

- Malleus

- Incus

- Spheno-Mandibular ligament

2nd Branchial Arch

(Cartilage)

Reichert Cartilage:

- Stapes

- Styloid process

- Lesser horn of Hyoid

- Stylohyoid ligament

3rd Branchial Arch

(Cartilage)

4th - 6th Branchial Arches

(Cartilage)

Thyroid

Cricoid

Arytenoids

Corniculate

Cuneiform

1st Branchial Arch

(Muscles)

Muscles of Mastication

(Temporalis, Masseter, lateral and Medial Pterygoids)

Mylohyoid

Anterior belly of Digastric

Tensor Tympani

Tensor Veli Palatini

2nd Branchial Arch

(Muscles)

Muscles of Facial Expression

Stapedius

Stylohyoid

Platysma

Posterior belly of Digastric

3rd Branchial Arch

(Muscles)

Stylopharyngeus

(think of Stylopharyngeus innervated by glossopharyngeal nerve)

4th  Branchial Arch

(Muscles)

Most Pharyngeal Constrictors

Cricothyroid

Levator Veli Palatini

6th  Branchial Arch

(Muscles)

1st Branchial Arch

(Nerves)

CN V2 and V3

Chew

2nd  Branchial Arch

(Nerves)

CN VII

(facial expression)

Smile

3rd Branchial Arch

(Nerves)

CN IX

(stylopharyngeus)

swallow stylishly

4th Branchial Arch

(Nerves)

CN X

(superior laryngeal branch)

Simply swallow

6th Branchial Arch

(Nerves)

CN X

(recurrent laryngeal branch)

Speak

1st Branchial Arch

(Abnormalities/Comments)

Treacher Collins Syndrome

1st arch neural crest fails to migrate:

- Mandibular hypoplasia

- Facial abnormalities

2nd Branchial Arch

(Abnormalities/Comments)

Congenital Pharyngocutaneous Fistula

Persistence of cleft and pouch > fistula between tonsillar area and lateral neck

3rd - 4th  Branchial Arches

(Abnormalities/Comments)

1 = Chew

2 = Smile

3 = Swallow Stylishly

4 = Simply Swallow

6 = Speak

Develops into:

- Middle ear cavity

- Eustachian tube

- Mastoid air cells

Contributes to endoderm-lined structures of ear

Dorsal Wings = Inferior parathyroids

Ventral Wings = Thymus

3rd pouch makes 3 structures

(Thymus, Left and Right inferior Parathyroids)

3rd pouch structures end up below 4th pouch structures

Ear, Tonsils, Bottom-to-Top

1 = ear

2 = tonsils

3 dorsal = bottom parathyroids

3 ventral = thymus

4 = top parathyroids

Aberrant development of 3rd and 4th pouches

- T-cell deficiency (Thymic aplasia)

- Hypocalcemia (failed parathyroid development)

Associated with cardiac defects

(Conotruncal anomalies)

Mutation of germline RET

(neural crest cells)

1) Adrenal medulla (Pheochromocytoma)

2) Parathyroid (Tumor) = 3rd/4th pharyngeal pouch

3) Parafollicular cells (Medullary Thyroid Cancer) = derived from neural crest cells; associated with 4th/5th pouches

Failure of fusion of the maxillary and medial nasal processes

(formation of primary palate)

Often occurs with cleft palate

Failure of fusion of the two lateral palatine processes

or

Failure of fusion of lateral palatie processes with the nasal septum and/or median palatine process

(Formation of secondary palate)

Often occurs with cleft lip

Genital Embryology

(Female)

Default development

Mesonephric duct degenerates

Paramesonephric duct develops

Genital Embryology

(Male)

SYR gene on Y chromosome = produces testis-determining factor 

(Testes development)

Sertoli cells secrete Mullerian inhibitory factor (MIF) > suppresses development of Paramesonephric ducts

Leydig cells secrete androgens > stimulate development of Mesonephric ducts

Genital Embryology

(Paramesonephric [Mullerian] Duct)

Develops into female internal structures

1) Fallopian tubes

2) Uterus

3) Upper portion of vagina

(lower portion from Urogenital sinus)

Abnormalities > anatomical defects that may present as 1^o amenorrhea in females with fully developed 2^o sexual characteristics

(indicator of functional ovaries)

Genital Embryology

(Mesonephric [Wolffian] Duct)

Develops into male internal structures (except prostate)

SEED

1) Seminal vesicles

2) Epididymis

3) Ejaculatory duct

4) Ductus deferens

Results from incomplete fusion of the Paramesonephric ducts

(Complete failure of fusion = Double uterus and vagina)

Can lead to anatomic defects > recurrent miscarriages

Develop both male and female internal genitalia

+

Male external genitalia

Inability to convert testosterone into DHT

- Male internal genitalia

- Ambiguous external genitalia until puberty

(increased testosterone levels cause masculinization)

Genital Tubercle

(Estrogen)

Glans clitoris

Vestibular bulbs

Urogenital Sinus

(Estrogen)

Greater vestibular glands (of Bartholin)

Urethral and Paraurethral glands (of Skene)

Urogenital Folds

(Estrogen)

Labioscrotal Swelling

(Estrogen)

Genital Tubercle

(DHT)

Glans penis

Corpus cavernosum and spongiosum

Urogenital Sinus

(DHT)

Bulbourethral glands (of Cowper)

Prostate gland

Urogenital Folds

(DHT)

Ventral shaft of penis

(Penile urethra)

Labioscrotal Swelling

(DHT)

Abnormal opening of penile urethra of inferior (ventral) side of penis

(Hypo is below)

Cause = failure of urethral folds to close

More common than Epispadias

Fix to prevent UTIs

Abnormal opening of penile urethra on superior (dorsal) side of penis

(when you have Epispadias, you hit you Eye when you pEE)

Cause = faulty positioning of genital tubercle

Association = Exstrophy of the bladder

Band of fibrous tissue

Male Remnant = anchors testes within scrotum

Female Remnant = Ovarian ligament + Round ligament of Uterus

Evagination of peritoneum

Male Remnant = forms tunica vaginalis

Female Remnant = obliterated

Left ovary/testis = Left Gonadal v. > Left Renal v. > IVC

Right ovary/testis = Right Gonadal v. > IVC

Left Spermatic v. enters Left Renal v. at a 90^o angle > flow is less continuous of the left than on the right

1) Left venous pressure > Right venous pressure

2) Varicocele more common on the left

Ovaries/Test > Para-aortic lymph nodes

Distal Vagina/Vulva/Scrotum > Superficial Inguinal nodes

Proximal Vagina/Uterus > Obturator, External Iliac, and Hypogastric nodes

Infundibulopelvic Ligament

(Connects)

Infundibulopelvic Ligament

(Structures Contained)

Infundibulopelvic Ligament

(Notes)

Also called Suspensory Ligament of the Ovaries

Ligate vessels during oophorectomy to avoid bleeding

Ureter courses retroperitoneally, close to gonadal vessels. At risk of injury during ligation of ovarian vessels.

Cardinal Ligament

(Connects)

Cardinal Ligament

(Contains)

Cardinal Ligament

(Notes)

Round Ligament of the Uterus

(Connects)

Round Ligament of the Uterus

(Contains)

Round Ligament of the Uterus

(Notes)

Derivative of Gubernaculum

Travels through Round Inguinal canal

Above the artery of Sampson

Broad Ligament

(Connects)

Broad Ligament

(Contains)

Ovaries

Fallopian tubes

Roung Ligaments of uterus

Broad Ligament

(Notes)

Components:

- Mesosalpinx

- Mesometrium

- Mesovarium

Ovarian Ligament

(Connects)

Ovarian Ligament

(Contains)

Ovarian Ligament

(Notes)

A derivative of the Gubernaculum

Ovarian Ligament Latches to Lateral uterus

Vagina

(Histology)

Ectocervix

(Histology)

Endocervix

(Histology)

Transformation Zone

(Histology)

Squamocolumnar junction

Most common area for cervical cancer

Uterus

(Histology)

Fallopian Tube

(Histology)

Simple columnar epithelium

Many ciliated cells

A few secretory (peg) cells

Outer Surface of Ovary

(Histology)

Simple cuboidal epithelium

(Germinal epithelium covering surface of ovary)

1) Phase of excitement

(Uterus elevates; Vaginal lubrication)

2) Plateau

(Expansion of inner vagina)

3) Orgasm

(Contraction of uterus)

4) Resolution

Mediated by Autonomic Nervous System

Also causes tachycardia and skin flushing

SEVEN UP

- Seminiferous tubules

- Epididymis

- Vas deferens

- Ejaculatory ducts

- (Nothing)

- Urethra

- Penis

Autonomic Innervation of Male Sexual Response

(Erection)

Parasympathetic nervous system

(Pelvic n.)

Point and Shoot

(Erection = Parasympathetic; Emission = Sympathetic)

NO > increase cGMP > smooth muscle relaxation > vasodilation > proerectile

NE > increases [Ca2+]_in > smooth muscle contraction > vasoconstriction > antierectile

Autonomic Innervation of Male Sexual Response

(Emission)

Sympathetic nervous system

(Hypogastric n.)

Point and Shoot

(Erection = Parasympathetic; Emission = Sympathetic)

Autonomic Innervation of Male Sexual Response

(Ejaculation)

Visceral and Somatic nerves

(Pudendal n.)

Seminiferous Tubules: Spermatogonia/Germ Cells

(Function)

Maintain germ pool

Produce 1^o spermatocyctes

Seminiferous Tubules: Sertoli cells [Non-germ Cells]

(Function)

1) Secrete inhibin > inhibit FSH

2) Secrete androgen-binding protein > maintain local levels of testosterone

3) Tight junctions between adjacent Sertoli cells form blood-testis barrier > isolate gametes from autoimmune attack

4) Support and nourish developing spermatozoa

5) Regulate spermatogenesis

6) Produce MIF

7) Temperature sensitive; decrease sperm production and decrease inhibin with increased temperature

(Seen in Varicocele, Cryptorchidism)

Sertoli cells Support Sperm Synthesis

Seminiferous Tubules: Leydig Cells

(Function)

Secrete testosterone in the presence of LH

(production unaffected by temperature)

Seminiferous Tubules: Spermatognoa [Germ Cells]

(Location/Notes)

Seminiferous Tubules: Sertoli Cells [Non-germ Cells]

(Location/Notes)

Line seminiferous tubules

Convert testosterone and androstenedione to estrogen via Aromatase

Seminiferous Tubules: Leydig Cells [Endocrine Cells]

(Location/Notes)

Interstitium

Also contain aromatase

Estrogen

(Source)

Ovary

(17B-estradiol)

Placenta

(estriol)

Adipose tissue

(estrone via aromatization)

Estrogen

(Potency)

Estrogen

(Function)

1) Development of genitalia and breast

2) Female fat distribution

3) Growth of follicle

4) Endometrial proliferation

5) Increased myometrial excitability

6) Upregulation of estrogen, LH, and progesterone receptors

7) Feed back inhibition of FSH and LH

8) LH surge

9) Stimulation of prolactin secretion

10) Increase transport proteins (SHBG)

11) Increase HDL

12) Decrease LDL

Estrogen

(Pregnancy)

50-fold increase in estradiol and estrone

1000-fold increase in estriol

(indicator of fetal well-being)

Estrogen

(Receptors)

Expressed in the cytoplasm

Translocate to the nucleus when bound by ligand

Estrogen

(Pathway)

Pulsatile GnRH > stimulates FSH and LH

LH > Theca cell > increased Desmolase activity > Cholesterol to Androstenedione

FSH > Granulosa cell > increased Aromatase activity > Androstenedione to Estrogen

Progesterone

(Source)

Corpus luteum

Placenta

Adrenal cortex

Testes

Progesterone

(Function)

1) Stimulation of endometrial glandular secretions and spiral artery development

2) Maintenance of pregnancy

3) Decreased myometrial excitability

4) Production of thick cervical mucus > inhibits sperm entry into uterus

5) Increased body temperature

6) Inhibition of gonadotropins (LH, FSH)

7) Uterine smooth muscle relaxation (preventing contractions)

8) Decreased estrogen receptor expressivity

9) Prevents endometrial hyperplasia

Progesterone is pro-gestation

Progesterone

(Delivery/Ovulation)

Fall in progesterone after delivery disinhibits prolactin > lactations

Increase in progesterone indicative of ovulation

Progesterone is pro-gestation

Prolactin is pro-lactation

Assigned independently to genitalia, pubic hair, and breast

(can have stage 2 genitalia and stage 3 pubic hair)

1) Childhood (prepubertal)

2) Pubic hair appears (pubarche); Breast buds form (thelarche)

3) Pubic hair darkens and becomes curly; Penis size/length increases; Breasts enlarge

4) Penis width increases; Darker scrotal skin; Development of glans; Raised areolae

5) Adult; areolae are no longer raised

Menstrual Cycle

(Follicular/Proliferative Phase)

Can vary in length

Follicular growth fastest during 2nd week of proliferative phase

Estrogen stimulates endometrial proliferation + maturation of graafian follicle

Menstrual Cycle

(Secretory/Luteal Phase)

Is usually a constant 14 days

(Ovulation + 14 days = menstruation)

Progesterone maintains endometrium to support impantation

(from Corpus Luteum)

Decreased progesterone > Decreased fertility

Menstrual Cycle

(Ovulation)

Menstrual Cycle

(Menstruation)

Intermenstrual bleeding

Frequent but irregular menstruation

Heavy menstrual bleeding

> 80 mL blood loss or > 7 days of menses

Menstrual Cycle

(Pathway)

Oogenesis

(Characteristics)

1^o oocytes begin meiosis I during fetal life and complete meiosis I just prior to ovulation

Meiosis I is arrested in prOphase I for years until Ovulation (1^o oocytes)

Meiosis II is arrested in metaphase II until fertilization (2^o oocytes)

[An egg met a sperm]

If fertilization does not occur within 1 day, the 2^o oocyte degenerates

- Increased estrogen

- Increased GnRH receptors on anterior pituitary

Estrogen surge > stimulate LH release > ovulation (rupture of follicle)

Increased temperature

(progesterone induced)

Transient mid-cycle ovulatory pain

Classically associated with peritoneal irritation

(Follicular swellin/rupture; Fallopian tube contraction)

Can mimic appendicitis

Fertilization:

Most commonly occurs in upper end of fallopian tube (the ampulla)

Occurs within 1 day of ovulation

Implantation:

Within the wall of the uterus

Occurs 6 days after fertilization

Detectable:

Syncytiotrophoblasts secrete hCG

- Detectable in blood 1 wk after conception

- Detectable in urine 2 weeks after conception

After labor, decrease in progesterone and estrogen > disinhibits lactation

Suckling required to maintain mild production

(increased nerve stimulation > increased oxytocin and prolactin)

Induces and maintains lactation

Decreased reproductive function

Assists in milk letdown

Promotes uterine contractions

Breastmilk is ideal nutrition for infants < 6 months old

Contains:

- Maternal immunoglobulins

(conferrs passive immunity; mostly IgA)

- Macrophages

- Lymphocytes

Reduces infant infections and associated with decreased risk in infants for:

- Asthma

- Allergies

- DM

- Obesity

Exclusively breastfed > requires Vitamin D supplementation

Breastfeeding decreases maternal risk of breast/ovarian cancer and facilitates mother-child bonding

hCG

(Source)

hCG

(Function)

Maintains the Corpus Luteum (and thus progesterone) for the 1st trimester by acting like LH

(otherwise no Luteal cell stimulation > abortion)

In 2nd and 3rd trimesters, placenta synthesizes its own estriol and progesterone and the corpus luteum degenerates

Used to detect pregnancy because it appears early in the urine

a-subunit structurally identical to a-subunits of LH, FSH, and TSH. B-subunit is unique (pregnancy tests detect this).

Increased in multiple gestations and pathologic states

(Hydatidiform mole; Choriocarcinoma)

Menopause

(Hormonal Changes)

1) Decreased estrogen

(due to age-linked decline in number of ovarian follicles)

2) Increased FSH

(loss of negative feedback due to decreased estrogen; more increased than LH; specific for menopause)

3) Increased LH

(less increased than FSH; no surge)

4) Increased GnRH

Menopause

(Characteristics)

Average age at onset = 51 years

(earlier in smokers; before age 40 indicates premature ovarian failure)

Usually preceded by 4-5 years of abnormal menstrual cycles

(peripmenopause)

Source of estrogen (estrone) after menopause becomes peripheral conversion of androgens

(increased androgens > hirsutism)

Menopause

(Symptoms)

Menopause causes HAVOCS

- Hot flashes

- Atrophy of the Vagina

- Osteoporosis

- Coronary artery disease

- Sleep disturbances

Begins at puberty with spermatogonia

Full development takes 2 months

Location = Seminiferous tubules

Produces spermatids that undergo spermiogenesis (loss of cytoplasmic contents + gain acrosomal cap) to form mature spermatozoon

Gonium is going to be a sperm; Zoon is Zooming to egg

Androgens

(Types)

Testosterone

Dihydrotestosterone

(DHT)

Androstenedione

Androgens

(Source)

Testis = DHT and Testosterone

ADrenal = AnDrostenedione

Androgens

(Potency)

Androgens

(Testosterone Function)

1) Differentiation of epididymis, vas deferens, seminal vesicles (genitalia, except prostate)

2) Growth spurt

(Penis, Seminal vesicles, Sperm, Muscle, RBCs)

3) Deepening of voice

4) Closuing of epiphyseal plate

(via estrogen converted from testosterone)

5) Libido

Androgens

(DHT Function)

Early = differentiation of:

- Penis

- Scrotum

- Prostate

Late:

- Prostate growth

- Balding

- Sebaceous gland activity

Androgens

(Production)

Testosterone > DHT by 5a-reductase

(inhibited by Finasteride)

In the male, androgens > estrogen by cytochrome P-450 aromatase

(primarily in adipose and testis)

Androgens

(Exogenous Testosterone)

Klinefelter Syndrome

(Genotype, Phenotype, Epidemiology)

Male

XXY

1:850

Klinefelter Syndrome

(Characteristics)

Symptoms:

1) Testicular atrophy

2) Eunuchoid body shape

3) Tall with long extremities

4) Gynecomastia

5) Female hair distribution

6) May present with developmental delay

Presence of inactivated X chromosome

(Barr body)

Common cause of hypogonadism seen in infertility work-up

Klinefelter Syndrome

(Pathway)

Dysgenesis of seminiferous tubules > decreased inhibin > increased FSH

Abnormal Leydig cell function > decreased testosterone > increased LH > increased estrogen

Turner Syndrome

(Genotype, Phenotype)

Female

XO

("hugs and kisses" [XO] from Tina Turner)

Can be complete monosomy (45,XO) or mosaicism (45,XO/46,XX)

Turner Syndrome

(Characteristics)

Symptoms:

1) Short stature (if untreated)

2) Ovarian dysgenesis (Streak ovary)

3) Shield chest

4) Bicuspid aortic valve

5) Preductal coarctation (Femoral < Brachial pulse; Notched ribs)

6) Lymphatic defects (result in webbed neck or cystic hygroma; lymphedema in feet, hands)

7) Horshoe kidney

Most common cause of 1^o amenorrhea.

(menopause before menarche)

No Barr body

Pregnancy is possible in some cases

(Oocyte donation; Exogenous estradiol-17B and progesterone)

Turner Syndrome

(Cause)

Decreased estrogen > increased LH and FSH

Can result from mitotic or meiotic error

XYY

1:1000

Phenotypically normal

- Very tall

- Severe acne

- Antisocial behavior

(seen in 1-2% of XYY males)

Normal fertility

Small percentage diagnosed with autism spectrum disorders

46,XX or 47,XXY

Also called ovotesticular disorder of sex development

Both ovary and testicular tissue present (ovotestis)

Ambiguous genitalia

Very rare

Diagnosing Disorders of Sex Hormones:

Increased Testosterone

Increased LH

Diagnosing Disorders of Sex Hormones:

Increased Testosterone

Decreased LH

Testosterone-secreting Tumor

Exogenous steroids

Diagnosing Disorders of Sex Hormones:

Decreased Testosterone

Increased LH

Diagnosing Disorders of Sex Hormones:

Decreased Testosterone

Decreased LH

XX

Ovaries present, but external genitalia are virilized or ambiguous

Cause = excessive and inappropriate exposure to androgenic steroids during early gestation

(Congenital Adrenal Hyperplasia; Exogeneous steroid administration during pregnancy)

XY

Testes present, but external genitalia are female or ambiguous.

Most common form is androgen insensitivity syndrome

(testicular feminization)

46,XX

Inability to synthesize estrogens from androgens

Masculinization of female infants

(ambiguous genitalia)

Increased serum testosterone and androstenedione

Can present with maternal virilization during pregnancy

(fetal androgens cross the placenta)

46,XY

Defect in androgen receptor

- Normal-appearing female

- Female external genitalia with rudimentary vagina

- Uterus and fallopian tubes generally absent

- Scant sexual hair

- Develops testes (often found in Labia Major; surgically removed to prevent malignancy)

Increased testosterone, estrogen, and LH

(vs. sex chromosome disorders)

46,XY

Autosomal recessive

Inability to convert testosterone to DHT

Ambiguous genitalia until puberty, when increased testosterone causes masculinization and incerased growth of external genitalia

Testosterone + Estrogen = Normal

LH = Normal or increased

Internal genitalia are normal

Failure to complete puberty

A form of hypogonadotropic hypogonadism

- Defective miration of GnRH cells

- Defective formation of olfactory bulb

- Decreased synthesis of GnRH in the hypothalamus

- Anosmia

- Decreased GnRH, FSH, LH, Testosterone

- Infertility

(low sperm count in males; amenorrhea in females)

Cystic swelling of chorionic villi and proliferation of chorionic epithelium

(only trophoblast)

Treatment = Dilation and curettage + Methotrexate

Monitor B-hCG

2 Types:

- Complete Mole

- Partial Mole

Complete Mole

(Karyotype)

Complete Mole

(hCG)

Complete Mole

(Uterine Size)

Complete Mole

(Convert to Choriocarcinoma)

Complete Mole

(Fetal Parts)

Complete Mole

(Components)

Enucleated egg + Single sperm

(subsequently duplicates paternal DNA)

Empty egg + 2 sperm is rare

Complete Mole

(Risk of Complications)

Complete Mole

(Symptoms)

Vaginal bleeding

Enlarged uterus

Hyperemesis

Pre-eclampsia

Hyperthyroidism

Complete Mole

(Imaging)

Honeycombed uterus or "clusters of grapes"

"Snowstorm" on ultrasound

Partial Mole

(Karyotype)

69,XXX

69,XXY

69,XYY

Partial Mole

(hCG)

Partial Mole

(Uterine Size)

Partial Mole

(Convert to Choriocarcinoma)

Partial Mole

(Fetal Parts)

Yes

(partial = fetal parts)

Partial Mole

(Components)

Partial Mole

(Risk of Complications)

Low risk of malignancy

(< 5%)

Partial Mole

(Symptoms)

Vaginal bleeding

Abdominal pain

Partial Mole

(Imaging)

Gestational Hypertension

(Pregnancy-Induced Hypertension)

BP > 140/90 mmHg after the 20th week of gestation

No pre-existing HTN

No proteinuria or end-organ damage

Treatment:

1) Antihypertensives

- a-methyldopa

- labetalol

- Hydralazine

- Nifedipine

2) Deliver at 29 weeks

Preeclampsia

(Definition)

Hypertension

(> 140/90 mmHg)

Proteinuria

(> 300 mg/24 hrs)

After 20th week of gestation to 6 weeks postpartum

(< 20 weeks suggests molar pregnancy)

Preeclampsia

(Severe Features)

BP > 160/110 mmHg with or without end-organ damage

- Headache

- Scotoma

- Oliguria

- Increased AST/ALT

- Thrombocytopenia

Preeclampsia

(Cause)

Preeclampsia

(Associations)

Preexisting HTN

Diabetes

Chronic renal disease

Autoimmune disorders

Preeclampsia

(Complications)

Placental abruption

Coagulopathy

Renal failure

Uteroplacental insufficiency

Eclampsia

Preeclampsia

(Treatment)

Antihypertensives

Deliver at 34 weeks (severe) or 37 weeks (mild)

IV Mg Sulfate

(to prevent seizure)

Preeclampsia + Maternal seizures

Maternal death due to stroke > intracranial hemorrhage or ARDS

Treatment:

- Antihypertensives

- IV Mg Sulfate

- Immediate delivery

Hemolysis

Elevated Liver enzymes

Low Platelets

A manifestation of severe preeclampsia, although may occur without HTN

Treatment = Immediate delivery

Placental Abruption

(Abruptio Placentae)

Premature separation (partial or complete) of palcenta from uterine wall before delivery of infant

Risk Factors:

- Trauma (MVC)

- Smoking

- HTN

- Preeclampsia

- Cocaine abuse

Presentation:

- Abrupt, painful bleeding (concealed or apparent) in 3rd trimester

- Possible DIC

- Maternal shock

- Fetal distress

Life threatening for mother and fetus

Defective decidual layer > abnormal attachment and separation after delivery

Risk Factors:

- Prior C/S

- Inflammation

- Placenta previa

Types distinguishable by depth of penetration

Presentation = no separation of placenta after delivery > massive bleeding

(life threatening for mother)

Placenta attaches to myometrium without penetrating it

Most common type

Placenta penetrates ("perforates") through the myometrium into uterine serosa (invades entire uterine wall)

Can result in placental attachment to rectum or bladder

Attachment of placenta to lower uterine segment

Lies near (marginal), partially covers (partial), or completely covers (complete) internal cervical os.

Risk Factors:

- Multiparity

- Prior C/S

May cause postpartum hemorrhage

Increased risk of infection

Most often in ampulla of fallopian tube

Pain with or without bleeding

Suspect with history of:

- Amenorrhea

- Lower-than-expected rise in hCG based on dates

- Sudden lower abdominal pain

Confirm with US

Often clinically mistaken for appendicitis

Risk Factors:

- History of infertility

- Salpingitis (PID)

- Ruptured appendix

- Prior tubal surgery

> 1.5-2 L of amniotic fluid

Associations:

1) Fetal malformations (esophageal/duodenal atresia, anencephaly; both > inability to swallow amniotic fluid)

2) Maternal Diabetes

3) Fetal anemia

4) Multiple gestations

< 0.5 L of amniotic fluid

Associations:

1) Placental insufficiency

2) Bilateral renal agenesis

3) Posterior urethral valves (in males) > inability to excrete urine

Any profound oligohydramnios can cause Potter sequence

Cervical Pathology:

Dysplasia and Carcinoma in situ

(Definition)

Disordered epithelial growth

Begins at basal layer of squamocolumnar junction (Transition Zone) and extends outward

Classified as CIN 1, CIN 2, or CIN 3 (severe dysplasia or carcinoma in situ) depending on extent of dysplasia

Cervical Pathology:

Dysplasia and Carcinoma in situ

(Associations)

HPV 16 and 18

Produce:

E6 > inhibits p53 suppressor gene

E7 > inhibits RB suppressor gene

Cervical Pathology:

Dysplasia and Carcinoma in situ

(Presentation)

Typically asymptomatic or presents as abnormal vaginal bleeding (often postcoital)

Detection = Pap smear

(Koilocytes - wrinkled, raisin-like nuclei with perinuclear halo)

May progress slowly to invasive carcinoma if left untreated

Cervical Pathology:

Dysplasia and Carcinoma in situ

(Risk Factors)

Multiple sexual patners (#1)

Smoking

Early sexual intercourse

HIV infection

Cervical Pathology:

Invasive Carcinoma

Often squamous cell carcinoma

Pap smear can catch cervical dysplasia (koilocytes) before it progresses to invasive carcinoma

Lateral invasion can block ureters > renal failure

Inflammation of the endometrium

(with plasma cells and lymphocytes)

Association:

- Retained products of conception following delivery/miscarriage/abortion

- Foreign body such as an IUD

Retained material in uterus > promotes infection by bacterial flora from vagina or intestinal tract

Treatment = Gentamicin + Clindamycin with or without Ampicillin

Endometriosis

(Definition)

Non-neoplastic endometrial glands/stroma outside of the endometrial cavity

Can be found anywhere; most common sites are:

- Ovary

- Pelvis

- Peritoneum

In ovary, appears as an endometrioma (blood-filled "chocolate cyst")

Endometriosis

(Cause)

Retroglade flow

Metaplastic transformation of multipotent cells

Transportation of endometrial tissue via lymphatics

Endometriosis

(Presentation)

1) Cyclic pelvic pain

2) Bleeding

3) Dysmenorrhea

4) Dyspareunia

5) Dyschezia

(pain with defecation)

6) Infertility

7) Normal sized uterus

Endometriosis

(Treatment)

NSAIDs

OCPs

Progestins

GnRH agonists

Surgery

Extension of endometrial tissue (glandular) into uterine myometrium

Cause = hyperplasia of the basalis layer of the endometrium

Presentation:

- Dysmenorrhea

- Menorrhagia

- Uniformly enlarged, soft globular uterus

Treatment = Hysterectomy

Adenomyoma

(Polyp)

Well-circumscribed collection of endometrial tissue within the uterine wall

May contain smooth muscle cells

Can extend into the endometrial cavity in the form of a polyp

Abnormal endometrial gland proliferation

Cause = usually excess estrogen stimulation

Increased risk for endometrial carcinoma

Presentation = postmenopausal vaginal bleeding

Risk Factors:

- Anovulatory cycles

- Hormon replacement therapy

- Polycystic ovarian syndrome (PCOS)

- Granulosa cell tumor

Most common gynecologic malignancy

Peak occurrence = 55-65 years old

Presentation = vaginal bleeding

Typically preceded by endometrial hyperplasia

Risk Factors:

- Prolonged use of estrogen without progestins

- Obesity

- Diabetes

- HTN

- Nulliparity

- Late menopause

Increased myometrial invasion > worse prognosis

Leiomyoma

(Fibroid)

Most common tumor in females

Often presents with multiple discrete tumors

Increased incidence in blacks

Benign smooth muscle tumor

(does NOT progress to leiomyosarcoma)

Estrogen sensitive

(increase tumor size with pregnancy, decreased with menopause)

Peak occurrence = 20-40 yrs old

Presentation:

- May be asymptomatic

- Abnormal uterine bleeding

- Miscarriage

- Severe bleeding > iron deficiency anemia

Histology = Whorled pattern of smooth muscle bundles with well-demarcated borders

Incidence:

Endometrial > Ovarian > Cervical

(data pertains to US; Cervical cancer most common worldwide)

Worst prognosis:

Ovarian > Cervical > Endometrial

premature atresia of ovarian follicles in women of reproductive age

Presentation = signs of menopause after puberty but before age 40

Hormones:

- Decreased estrogen

- Increased LH and FSH

1) Pregnancy

2) PCOS

3) Obesity

4) HPO axis abnormalities

5) Premature ovarian failure

6) Hyperprolactinemia

7) Thyroid disorders

8) Eating disorders

9) Female athletes

10) Cushing syndrome

11) Adrenal insufficiency

Polycystic Ovarian Syndrome

(Definition)

Also called Stein-Leventhal Syndrome

Hyperandrogenism due to deranged steroid synthesis by Theca cells + Hyperinsulinemia

Estrogen > increased steroid hormone-binding globulin (SHBG) and decreased LH > decreased free testosterone

Insulin and Testosterone > decreased SHBG > increased free testosterone

Pituitary/Hypothalamus dysfunction > increased LH

Polycystic Ovarian Syndrome

(Presentation)

Enlarged, bilateral cystic ovaries

Amenorrhea/oligomenorrhea

Hirsutism

Acne

Infertility

(most common cause in women)

Polycystic Ovarian Syndrome

(Associations)

Associated with obesity

Increased risk of endometrial cancer 2^o to increased estrogens from the aromatization of testosterone and absence of progesterone

Polycystic Ovarian Syndrome

(Hormones)

Increased LH and FSH

(LH:FSH = 3:1)

Increased Testosterone

Increased Estrogen

(from aromatization)

Polycystic Ovarian Syndrome

(Treatment)

Hirsutism and Acne:

1) Weight reduction

2) OCPs

(Estrogen > increased SHBG and decreased LH > decreased free testosterone)

3) Antiandrogens

Infertility:

1) Clomiphene citrate

(blocks negative feedback of circulating estrogen)

2) Metformin

(increased insulin sensitivity > decreased insulin levels > decreased testosterone; enables LH surge)

Endometrial protection = Cyclic Progesterones

(antagonizes endometrial proliferation) 

Ovarian Cysts

(Follicular)

Distention of unruptured graafian follicle

May be associated with Hyperestrogenism and Endometrial Hyperplasia

Most common ovarian mass in young women

Ovarian Cysts

(Corpus Luteum)

Hemorrhage into persistent corpus luteum

Commonly regresses spontaneously

Ovarian Cysts

(Theca-Lutein)

Often bilateral/multiple

Due to gonadotropin stimulation

Associations:

- Choriocarcinoma

- Moles

Ovarian Cysts

(Hemorrhagic)

Blood vessel rupture in cyst wall

Cyst grows with increased blood retention

Usually self-resolves

Ovarian Cysts

(Dermoid)

Mature teratoma

Cystic growths filled with various types of tissue such as fat, hair, teeth, bits of bone, and cartilage

Ovarian Cysts

(Endometrioid)

Endometriosis within ovary with cyst formation

Varies with menstrual cycle

When filled with dark, reddish-brown blood it is called a "chocolate cyst"

Ovarian Neoplasms

(Characteristics)

Most common adnexal mass in women > 55 yrs

Can be benign or malignant

Arise from:

- Surface epithelium

- Germ cells

- Sec cord stromal tissue

Majority of malignant arise from epithelial cells; Majority of all (95%) are epithelial

(Serous cystadenocarcinoma most common)

Ovarian Neoplasms

(Risk)

Increases:

- Advanced age

- Infertility

- Endometriosis

- PCOS

- Genetic predisposition (BRCA-1/2, HNPCC, strong family history)

Decreases:

- Previous pregnancy

- History of breastfeeding

- OCPs

- Tubal ligation

Ovarian Neoplasms

(Presentation)

1) Adnexal mass

2) Abdominal distension

3) Bowel obstruction

4) Pleural effusion

Diagnose surgically

Monitor progression by measuring CA-125 levels

(not good for screening)

1) Serous cystadenoma

2) Mucinous cystadenoma

3) Endometrioma

4) Mature cystic teratoma (dermoid cyst)

5) Brenner Tumor

6) Fibromas

7) Thecoma

Most common ovarian neoplasm

Thin-walled

Uni- or multilocular

Lined with fallopian-like epithelium

Often bilateral

Multiloculated and large

Lined by mucus-secreting epithelium

Mass arising from growth of ectopic endometrial tissue

Complex mass on US

Presents with:

- Pelvic pain

- Dysmenorrhea

- Dyspareunia

Mature Cystic Teratoma

(Dermoid Cyst)

Germ cell tumor

Most common ovarian tumor in women 20-30 yrs

Can contain elements from all 3 germ layers

(teeth, hair, sebum are common components)

Can also contain functional thyroid tissue > present as hyperthyroidism

(Struma Ovarii)

Presents with pain 2^o to ovarian enlargement or torsion

Looks like a bladder (Brenner)

Solid tumor that is pale yellow-tan in color and appears encapsulated

"Coffee bean" nuclei on H&E stain

Bundles of spindle-shaped fibroblasts

Meigs Syndrome

- Ovarian fibroma

- Ascites

- Hydrothorax

Pulling sensation in groin

Like granulosa cell tumors, may produce estrogen

Usually present as abnormal uterine bleeding in a postmenopausal woman

1) Immature Teratoma

2) Granulosa Cell tumor

3) Serous Cystadenocarcinoma

4) Mucinous Cystadenocarcinoma

5) Dysgerminoma

6) Choriocarcinoma

7) Yolk sac (Endodermal Sinus) Tumor

8) Krukenberg Tumor