- Bipotential gonad --> Default pathway is to ovaries

- SRY gene --> Bipotential gland becomes a testis

- Testis then produce Leydig cells and Sertoli Cells

- Leydig cells: Produce SF-1 --> Testosterone --> Induces formation of male internal genitalia

- Sertoli cells: Produce WT1 and SF-1 --> Produce MIS-R --> Induces regression of Mullerian duct

- External genitalia: Formed via DHT production and effect

- Default pathway

- Bipotential gonads --> Ovary

- Mullerian ducts --> Fallopian tubes and both ducts fuse to form the uterus, cervix and vagina

- Proper fusion and resorption must occur in order to form a proper uterus

- 2-4% of fertile and infertile women

- Higher incidence in women with recurrent miscarriage and preterm delivery

- Unknown etiology

- Clinical findings: Dysmenorrhea, amenorrhea, hematocolpos, and recurrent miscarriage/preterm deliver --> Uterus is simply not large enough to hold baby to term

- Diagnosis: 3D ultrasound, hysterosalpingogram, and MRI

- Must also evaluate for renal anomalies and hearing disorders (high frequency hearing loss)

- Agenesis of one or both Mullerian ducts --> Uterine agenesis (bilateral) or unicornuate uterus (unilateral)

- Failure of lateral fusion --> Bicornuate or didelphys uterus

- Failure of vertical fusion --> Transverse vaginal septum or imperforate hymen

- Failure of resorption --> Septate uterus --> Fetus implants in the avascular septum --> Miscarriage

- DES drug related anomaly --> Higher risk of clear cell vaginal cancer

- Initially used to prevent miscarriages

- Teratogenic

- Anomalies: uterine hypoplasia, T-shaped uterine cavity, cervical hood, transverse vaginal ridge, cockscomb cervix, and adenosis of the vagina with 40x risk of vaginal clear cell carcinoma

- Poorer reproductive outcomes

- Earlier menopause

- Females with excessive androgen --> 46, XX masculinized female --> Congenital adrenal hyperplasia, excessive androgen exposure in utero, or androgen-producing tumor

- Males with deficient androgen action --> undermasculinized male or 46, XY female --> Swyer syndrome, AIS, and 5-a-reductase deficiency

- Autosomal recessive

- Hyperandrogenism due to defect in the steroid pathway

- 21-Hydroxylase deficiency (most common)

- 11 B-Hydroxylase deficiency

- 3 B-Hydroxysteroid dehydrogenase deficiency

- Classic CAH: Most severe form due to 21-hydroxylase deficiency --> Adrenal insufficiency with or without salt-losing neonatally, early virilization of males in early adulthood, and ambiguous genitalia in females

- Nonclassic CAH: Late onset 21-hydroxylase deficiency --> Premature pubic hair growth and hirsuitism, irregular menses, infertility, or acne in adolescent/adult women

- Mutation of SRY --> No testes, no MIS or testosterone

- Streak gonads --> Very small and non-functional gonad

- Uterus, female external genitalia present

- Delayed puberty

- Immediate gonadectomy due to high risk of gonadoblastoma --> Testes at body temp poses a high risk of cancer

- MIS present but lack of testosterone action

- Undescended testes

- Female external genitalia

- No uterus --> Blind vaginal pouch

- Gonadectomy after puberty to allow for female secondary sexual development --> Low risk of gonadoblastoma

- X-linked recessive trait

- Andorgen receptor gene mutation

- Female breasts present but no axillary or pubic hair

- Breasts are usually large too

- Partial Androgen Insensitivity Syndrome

- Ambiguous external genitalia

- Partial virilization at puberty with female breasts

- Autosomal recessive mutation in chromosome 2p

- Lack of DHT

- Undermasculinized external genitalia

- Normal internal/Wolffian system

- Guevedoces/Eggs at Twelve --> At puberty, increase in 5-alpha-reductase Type 2 leads to sufficiency DHT production --> Virilization 

- XO female

- Streak gonads --> Increased oocyte atresia

- Uterus and female external genitalia are present

- 1 in 5,000 live births

- Most common cause of primary amenorrhea

- Stigmata --> Short stature, high arched palate, webbed neck, shield-like chest, aortic coarctation, and cubitus valgus

- Fertility can be present in mosaics --> Not present in true XO patients

- Gender identity at 2.5-3 years old

- Hormonal influences on the brain developed independent of socialization

- Most Guevedoces assume male gender identity and sex role

- Swyer syndrome and androgen insensitivity assume female gender identity

- Hormone diffuses freely into the cell

- Hormone binds receptor --> Receptor forms dimer or heterodimer

- Dimer acts as transcription factor

- Estrogen receptor is normally kept in the cytoplasm via binding to heat shock protein 90

- P130: Scaffolding protein --> Sets up structure and binding

- Activated by P450 enzyme within mitochondria

- Enzyme is only in steroid-producing cells

- Pregnenolone then moves to cytoplasm for further processing

- DHEA --> Androstenedione --> Estrone via aromatase

- Androstenedione --> Testosterone --> DHT via 5-a-reductase

- Main secretory product of the ovary

- Main estrogen in pre-menopausal women

- 17-B-estradiol --> Most potent

- Testis is the source of estradiol in men

- Normal mid cycle: 25-100 mcg

- 1st trimester: 30 mg/day

- Menopause: 5-10 ug

- Men: 2-25 ug

- Main estrogen in men and post-menopausal women

- Derived from estradiol

- 1/10th as potent

- Also produced by the liver

- peripheral aromatization of adrenal adrostenedione in non-ovarian tissue to estrone --> 25% of estrogen in the body

- Main estrogen found in the urine

- Also produced in the liver

- Produced only in the fetus

- Absorbed readily through GI tract

- High first pass effect 

- Absorption: Skin, mucous membranes, vaginal administration, and injection

- Weakly bound in plasma to albumin

- Tightly bound to sex hormone binding globulin (SHBG) --> Only unbound fraction is active

- Diffuses freely and rapidly into cells

- Converted enzymatically to active form in target tissues

- Testosterone --> DHT via 5-a-reductase in prostate

- Testosterone --> estradiol via aromatase --> Brain and liver

- Reinstates sexual maturation

- Prevent osteoporosis

- Side effects: Hot flashes, inappropriate sweating, mood changes, and vaginitis

- Reduce risk of coronary heart disease --> Increased ration of HDL/LDL

- Forms: Estrogen only, estrogen with progesterone, and progestins

- No hysterectomy treatment: Estrogen and progesterone

- Hysterectomy treatment: Estrogen alone

- Cyclic sequential use: Progestin every 10-14 days

- Continuous: Estrogen and progestin daily

- Non-steroidal

- Fertility agent

- Effective at the hypothalamus and pituitary

- Blocks feedback inhibition of gonadotropin secretion

- Inhibits estrogen binding in the pituitary --> Partial estrogen agonist

- Induces ovulation

- Bound to albumin

- Medroxyprogesterone acetate --> Treatment of metastatic endometrial cancer

- Inhibits PR synthesis and ER synthesis

- Inactive or weakly active --> Competes for receptors

- Tamoxifen/non-steroidal/estrogenic on plasma lipids, endometrium, and bone/anti-estrogenic in the breast

- Preventative for high-risk cases

- Raloxifene: Antagonists also in the uterus and breast --> Agonist in bone and plasma lipids

- Lack of cross-resistance with other treatments

- At least as effective as aromatase inhibitors in post-menopausal women

- Used when other therapies become resistant

- Fulvestrant: Antagonizes estrogen physiology by downregulating both estrogen and progesterone receptors

- Impairs the dimerization and promotes degradation

- Inhibits proliferation of cultured human breast cells

- Reduces tumor size

- Stimulates endometrial cells causing endometrial thickening

- Decreases total cholesterol and LDL --> Doesn't increase HDL

- Prevents bone loss

- 2-3x incresae in DVTs and PE

- Side effects: Cataracts, nausea, vaginal dryness, hot flashes and muscle cramps

- Elimiation: 7-14 hours and 4-11 days --> Takes 3-4 weeks to reach steady state

- Excretion: Feces

- Elimination: N-demethylation

- Treatment efficacy decreases after 5 years --> Drug resistance

- Anastrozole and letrozole

- Used to treat post-menopausal women

- Letrozole after completed tamoxifen --> Significantly improves disease-free survival

- Side effects: Memory defects --> Due to crossing BBB

- For prostate cancer treatment --> Prostate cancers respond to DHT

- Flutamide: Inhibits release of LH: Binds to the androgen receptor

- Finasteride: 5-a-reductase II inhibitor

- 6.4 million pregnancies per year

- 29% --> Unintended and occur earlier than desired

- 20% --> Unintended and occur after women have reached desired family size

- 51% --> Intended pregnancies

- Delaying the birth of the first child until a woman's late 20s or 30s contributes to a family's economic stability

- Half of the unintended pregnancies occur while a couple was using some form of contraception

- Women generally only want to get pregnant for 5 years of their reproductive lives --> Need to use contraception for ~30 years

1. Non-hormonal

- Sterilization

- Copper IUD

- Barrier methods --> Diaphragm, condoms and female condom

- Spermicides

- Behavioral methods

2. Combined estrogen-progestin methods

- Pill, patch and ring

3. Progestin-only methods

- Progestin IUD

- DMPA injection

- Implant

- Progestin-only pill

- >99% efficacy with both perfect and typical use

- Mechanism: Mechanical blockage of sperm transport

- Permanent form of contraception

- Advantages: Permanent and few side effects

- Disadvantages: Surgical risks and regret about procedure

- Contraindications: Desire for future fertility

1. Female: Laparoscopic, mini-laparotomy, and hysteroscopic --> Placing coils into tubes or having tubes tied

- Cautery, silastic rings, or filshie clips

- Performed by making 2 incisions

- Under general anesthesia

2. Male: Much simpler procedure --> Performed with local anesthesia --> Ligation, division, cautery, suture, clips, or removal of vas deferns

- Highest patient satisfaction among methods

- Rapid return to fertility after removal

- Safe

- Immediately effective

- Long-term protection

- Highly effective

- Both non-hormonal and hormonal forms are available

- Paragard

- Polyethylene T-frame and contains barium sulfate

- 380 mm2 copper surface area

- Monofilament polyethylene thread for removal of the device

- Efficacy: >99%

- Mechanism: Spermicidal, inhibits fertilization, and alters endometrium

- Effective for 10 years

- Side effects: Dysmenorrhea, heavier bleeding, or decrease in Hb by 1.2g/L at 1 year

- Risks: Expulsion, perforation, malposition, and infection

- Contraindications: Pregnancy

- Mirena: 52 mg levonorgestrel + barium sulfate --> 4.75 mm inserter diameter

- Skyla: 13.5 mg levonorgestrel + barium sulfate --> 3.8 mm inserter diameter

- Efficacy: >99%

- Mechanism: Thickens cervial mucus, endometrial thinning, and inhibits sperm

- Efficacy: 3 years for Skyla and 5 years for Mirena

- Side effects: Irregular bleeding and usually lighter periods

- Risks: Expulsion, perforation, malposition, and infection

- Contraindications: Pregnancy

- Non-contraceptive benefits: Improves menorrhagia, dysmenorrhea, and endometriosis pain

- Nexplanon: 4 cm by 2 mm --> 60-70 mcg/day but decreases to 25-30 mcg/day by 3 years

- Advantages: Discreet, reversible, long acting, and highly acceptable

- Insertion: Local anesthesia --> Subdermal in the bicipital groove

- Efficacy: >99%

- Mechanism: Ovulation suppression, alteration of endometrium, and cervical mucus changes

- Effective: 3 years

- Side Effects: Bleeding abnormalities

- Risks: Rare insertion and removal complications

- Contraindications: Few

- Intramsucular injection

- Efficacy: 97% with typical use

- Mechanism: Ovulation suppression, thickening of cervical mucus, and alteration of endometrium

- Schedule: Injections every 3 months

- Side effects: Bleeding changes --> Some women stop bleeding, some women don't

- Risks: Weight gain and slow return to fertility after stopping

- Contraindications: Few

- Increases bone turnover and deminerilization --> Reverses 4 years after stopping DMPA use

- Efficacy: >99% with perfect and 92% with typical use

- Mechanism: Ovulation inhibition and thickening of cervical mucus

- Schedule: Daily pill, weekly patch, or monthly ring

- Side effects: Unscheduled bleeing and other variable symptoms

- 21/7, 24/4, 84/7, and 365/0 cycles are possible --> Later cycles are better at preventing escape ovulation

- 

- First generation: Norethindrone, norethindrone acetate, and ethynodiol diacetate

- Second generation: Levonorgestrel and norgestrel

- Third generation: Desogestrel and norgestimate

- Fourth generation: Drosperinone

- Norelgestromin 150 mcg/day and ethinyl estradiol 20 mcg/daily

- Outer polyester layer, middle medicated layer, and clear liner

- Used for 7 days --> 3 consecutive patches then 1 week off

- No hepatic first-pass --> N/V rates are the same and VTE risk are the same

- Etonogestrel 120 mcg/day and ethinyl estradiol 15 mcg/day

- Flexible ring containing ethylene vinyl acetate copolymer

- One ring used for 21 days --> 7 days off

- May use the ring for 28 consecutive days if desired

- Can be removed  for intercouse --> No longer than 3 hours though or contraceptive effects are reduced

- Lower serum ethinyl estradiol levels than the pill or the patch

- Decreases menstrual flow

- Decreases the risk of iron deficiency anemia

- Protects against ovarian cancer and endometrial cancer

- Improves endometriosis pain

- Reduces the risk of ectopic pregnancy

- Improves acne and hirsuitism

- Less than 3 weeks post partum

- Arterial vascular disease --> Smoker >35 years old, long standing diabetes with vascular disease, hypertension, migraines, and ischemic heart disease

- Risk for venous thromboembolism --> Previous history, known thrombophilia, or prolonged immobilization

- Acute liver disease

- Active breast cancer --> Estrogen stimulates growth

- Low dose of norethindrone or levonoregestrel

- Taken daily --> Must be taken at the same time of day

- Higher failure rate --> 1-3% when used perfectly

- Mechanism: Suppression of ovulation

- Side effects: Irregular menses

- No contraindicated in women with vascular disease --> Risk is elevated by estrogens not progestins

- Advantages: Non-hormonal, non-presciption, and decrease sperm and STD exposure

- Disadvantages: Require partner cooperation, may require a spermicide for optimal effectiveness, not as effective as hormonal methods --> 5-15% failure rates

- Female methods: Diaphragm and female condom

- Efficacy: 82% (perfect) and 71% (typical)

- Mechanism: Surfactant and destroys sperm cell membrane

- Schedule: Must be used every time you have intercourse

- Side effects: Irritation, rare allergy, and UTI

- Risks: >2x/day use --> Vaginal epithelial disruption

- Contraindications: Few

- Efficacy: 95% (perfect) and 73% (typical)

- One of the most important methods of contraception

- Depends on the male partner being able to control ejaculation

- Exclusive breastfeeding

- Woman must not have experienced postpartum menses

- Within 6 months of birth

- 98% protection within first 6 months

- Milk expression by hand or pump is not sufficient --> Frequent suckling is necessary

- Used after intercourse and hopefully before ovulation

1. Plan B --> Levonorgestrel 1.5 mg --> Labeled up to 72 hours after sex

- Effectiveness: 60-80% depending on timing

2. Ella: Single dose of ulipristal acetate

- Antiprogestin --> Up to 5 days post intercourse

- Prescription only

- Effectiveness is higher

3. Paragard insertion --> Extremely effective up to 1 week after intercourse

- Termination of a pregnancy by medical means

- Doesn't include: spontaneous abortion, medical or surgical management of a non-viable pregnancy, or illegal abortion

- Legal abortion is safer than term delivery

- Not associated with future miscarriage, future infertility, or breast cancer

- Depression is not directly associated with abortion --> Depression is assocated with unintended pregnancy though

- 1.2 million abortion/year in the US

- Women more likely to have abortions: Young, old, unmarried, and poor

- Abortion before 12-14 weeks --> 90% of abortions

- Both medical and surgical techniques are extremely safe --> 10x safer than term pregnancy

- Provided by dedicated free-standing clinics

1. Medical: One tablet of mifepristone 200 mg

- Up to 9 menstrual weeks

- Followed 24 hours by misoprostol 800 mcg usually buccal

- 80-90% of women will abort within 24 hours

- 3-5% of women will have a uterine aspiration for bleeding, incomplete abortion, or lack of expulsion

- 0.2-0.5% of women will continue pregnancy

2. Surgical: Performed under local or general anesthesia

- 4-14 weeks of pregnancy

- Mechanical cervical dilation

- Uterine aspiration with hand-held syringe or electic suction --> Takes 5-10 minutes

- Contraception can be started immediately

- ~1% repeat procedures

- Reasons: Pregnancy not diagnosed earlier, finances, access, ambivalence, denial, and fetal anomaly

- Requires more skill, more resources and carries more risk --> Still safer than term pregnancy

1. Medical: Hospital based

- Misoprostol used to induce uterine contractions

- Uterus may be prepared with mifepristone --> May induce fetal demise first

- Intact delivery of the fetus

- 5-15% of patients retain the placenta --> Requires extraction

2. Surgical

- Ages 14 weeks and up

- Needs pre-procedure cervical dilation --> Osmotic dilators over 1-2 days

- Needs sedation or anesthesia

- Extraction of fetal parts and placenta with forceps and suction --> Ultrasound guidance

- Complications are rare but may be serious

- Free/Unbound --> 2%

- Albumin binding --> 50-60% in men and 25% in women

1. Men

- Testes: 3-10 mg/day of Testosterone --> 10-20x more than women

- Normal rage: 300-1000 ng/dL

- Diurnal rhythm --> Highest levels are between 6-9 am

2. Women

- Testosterone: 300 mcg/daily --> Ovaries and adrenals

- Normal range: 2-45 ng/dL

- Diurnal rhythm

- Menstrual variation --> Slightly increased levels during the ovulatory phase with LH surge

- Change of 1-2% can actually greatly influence andorgenic effects on the body

1. Increased SHBG

- Estrogens

- Hyperthyroidism

- Hepatitis

- Androgen deficiency

- Aging

- GH deficiency

- Porphyria

2. Decreased SHBG

- Androgens

- Obesity

- Hyperinsulinemia/Insulin resistance

- Metabolic syndrome

- Type II diabetes

- Progestins

- Hypothyroidism

- Glucocorticoids

- GH excess

- Familial

- Failure to produce sufficient Testosterone

- Failure to produce sufficient sperm (infertility) --> Oligospermia (<3 M/mL) and azoospermia (0 sperm)

1. Primary --> Primary gonadal failure and hypergonadotropic hypogonadism

2. Secondary --> Central hypogonadism and hypogonadotropic hypogonadism

- Klinefelter's Syndrome --> 47, XXY

- Sertoli Cell only syndrome

- LH resistance

- Cryptorchidism

- Varicocele

- Testicular trauma, torsion, or radiation

- Infiltration/Leprosy

- Mumps orchitis

- Muscular dystrophy

- Isolated GnRH Deficiency/Kallmann's Syndrome --> 46, XY:KAL1 Xp22.3

- Idiopathic Hypogonadotropic hypogonadism --> LH/FSH Deficiency

- Hemochromatosis --> HFE gene 6p21.3

- Hyperprolactinemia --> Pituitary tumor, stalk compression/transection, medications inducing prolactin release, and primary hypothyroidism

- Glucocorticoids

- Opioids

- Acute sickness or stress

- Chronic systemic illness

- 1st Trimester: Complete deficiency --> Female genitalia and partial deficiency --> Hypospadias and bifid scrotum

- 3rd Trimester: Normal sexual differenation with micropenis

- Testes <5 cc

- Penis <5cm

- Hypopigmented scrotum

- Lack of rugae on scrotum

- Small prostate

- Gynecomastia

- Little body hair

- High pitched voice

- Low hair line

- Eunuchoid proportions --> long extremities

- Decreased libido

- Erectile dysfunction/impotence

- Osteoporosis

- Decreased muscle mass

- Normal skeleton, penile length, pubic hair, voice, and prostate size

- Testes <15 cc

- Gynecomastia

- Decreased rate of facial/body hair growth

- Decreased muscle mass

- Osteoporosis

- Decreased libido

- Erectile dysfunction and impotence

- Galactorrhea --> Bilateral implies systemic cause

- Visual field defects

- Intramuscular: Testosteron esters

- Transdermal --> Scrotal and non-scrotal forms

- Buccal patch

- Must be sure that children and spouses don't come in contact with the gel applied

- ~$300 monthly --> Pricey

- Increased fat-free/lean body mass

- Increased strength

- Decreased total fat mass

- Adverse effects: Acne, oily skin, breast tenderness, erythrocytosis, peripheral edema, and possible sleep apnea

-Absolute Contraindications: History of prostate and breast cancer, HCT >55%, and allergy

- Relative Contraindications: HCT 52-55%, severe obstructive BPH symptoms, advancement of CHF, and untreated severe obstructive sleep apnea

- Ensures andorgenization

- Does NOT improve spermatogenesis --> hCG, rFSH, and rGnRH does stimulate

- T should not be tested during an acute illness --> Will be low

- T should be checked early in the morning

- T should be checked twice to confirm

- Also measure gonadotropins (LH and FSH)

- Treatment: Directed at raising T levels and transdermal preparations are the most physiologically active

- Monitor clinical efficacy by measuring T levels along the way

- Inability of the male to attain and/or maintain an erection that is sufficient for satisfactory sexual intercourse

- Associated with CAD/PVD

- Medical management: PDE5 inhibitors and testosterone replacement --> Depends on the cause of ED

- Evaluation: History, physical and labs

- Treatment: Psychosexual counseling, PDE5 inhibitors, testosterone supplements, and second line therapies

- PDE types 2,3,4 and 5 are present in the penis

- PDE5 is specific to the NO-cGMP pathway

- Adverse effects: Headache, flushing, nasal congestion, gastric upset, blue haze (PDE6), backache (PDE11), and priapism

- Priapism is a medical emergency when it lasts >4 hours

- Sildenafil: 3-4 hour half life and 30-60 min onset

- Vardenafil: 4-5 hour half life and 15-45 min onset

- Tadalafil: 17-22 hour half life and 20-30 min onset

- Sildenafil and vardenafil --> Specific for PDE6 --> blue haze

- Tadalafil --> Specific for PDE11 --> Backache

- Contraindicated in men taking nitrates --> CANNOT take within 24 hours of eachother

- Decreased sex drive/desire

- Causes: Androgen deficiency, medications, systemic illness, depression, stress, and relationship problems

- Low T can cause but decreased libido and ED

- Vacuum constriction devices

- Widely used since the 1970s

- No tests required beyond the initial evaluation

- High success rates in motivated patients

- Adverse effects: Ecchymosis, petechiae, pain, numbness, and blocked ejaculation due to the structure of the device

- Intracavernosal therapy

- Synthetic formulations of prostaglandin E1

- Injected into the corpus cavernosa

- PGs increase cAMP within the penis --> Stimulates  the formation of an erection

- Other injections: Papaverine and phentolamine

- Intraurethral pharmacotherapy (MUSE): Alprostadil is directly delivered into the urethra --> Indicated for patients who fear needles --> 30-45% efficacy

- Penile prostheses

- Selected patients with severe damage or who have failed all previous treatments

- Design changes have improved function, reliability, and safety

- 77-90% patient and partner satisfaction

- Mechanical pump resides in the testicles

- Pumps saline directly into two tubes placed in the penis to produce erection

- Due to HPV infection --> Sexually transmitted

- Genital warts or venereal warts

- Potentially can transform to malignancy --> HPV 16,18, 31, 33, 35, and 39

- Podophyllin: Cytotoxic topical agent used to treat

- Imiquimod: Immune modulator that enhances NK cell activity

- Surgical excision

- Asssociated with circumcision status, hygiene, phimosis, number of sexual partners, smoking, and HPV infection

- Neonatal circumcision virtually eliminates risk

- HPV 16 --> Commonly associated

- Prevention: Good hygiene and neonatal circumcision

- Treatment: Microsurgery excision, partial penectomy, total penectomy, and chemotherapy

- Metastatic disease has a very poor survival

- 20% due to male alone

- 30% male and female both

- 50% of cases --> Male factor is present

- Evaluation: History, physical exam, semen analysis, hormonal evaluation, genetic analysis, and testis biopsy

- Dilated pampiniform plexus of spermatic veins

- Can reduce seme quality and quantity

- Increased testicular temperature

- Surgical repair--> Improves semen parameters

- No sperm production by the testis

- Obstructive: Obstruction of the vas deferens or the ejaculatory ducts --> Surgical correction

- Non-obstructive: Failure of sperm production

- Requires genetic testing to determine cause

- Important to determine etiology

- Chemotherapy can cause azospermia

- Congential absence of vas deferens --> CFTR gene mutation

- Klinefelter's syndrome --> XXY

- Kallmann's Syndrome --> Hypogonadotropic hypogonadism --> Anosmia

- Kartagener's Syndrome --> Poor sperm mobility due to improper cilia formation

- Y Chromosome Microdeletions --> AZFa, AZFb, and AZFc mutations

- Most common in men 15-35 years old

- 7,000 new cases a year

- Highly effective chemotherapy --> Even metastatic disease has a VERY high cure rate --> 95%

- Diagnosis: History, physical, and scrotal ultrasonography

- Surgical excision of the testicle through inguinal approach --> RLND also to stop lymph node metastasis

- Tumors can secrete tumor markers --> AFP, bHCG, and LDH

- Very common in males >50

- Increased transitional zone prostate volume

- Due to impaired apoptosis

- DHT sensitive

- African American men are at higher risk

- Medications: 5-alpha reductase inhibitors, alpha blockers to inhibit smooth muscle, and anticholinergics to relax detrusor muscle

- Surgery: Transurethral resection, laser removal, prostate stents, and microwave therapy

- Most common solid cancer in males

- 2nd most frequent cause of cancer deaths in men

- 1 in 6 men will develop

- Risk factors: Age, African Americans, Family history, high fat diet, and HPC1 gene

- Diagnosis: History, rectal exam, PSA, transrectal prostate ultrasound, prostate biopsy, and CT scan/bone scan

- PSA: Protease that helps to liquefy semen

- Treatment: Surveillance (PSA every 6 months), radiation (external beam and brachytherapy), surgery (laproscopic or robot assisted), hormonal therapy, and chemotherapy

- Surgical castration --> Removal of testes

- Lupron (GNRH agonist) --> Shuts down LH and FSH production --> Reduced T and DHT production

- GNRH antagonists also possible

- Estrogen --> Possible antagonistic receptors in the prostate

- Antiandrogens

- Side effects: Sexual dysfunction, reduced libido, osteoprosis, muscle wasting, fatigue, weakness, and hot flashes

- Used for cancers that are "castration resistant"

- Patients with rising PSA despite hormonal therapy

- Docetaxel: Induces apoptosis in prostatic cells

- Immunotherapy: Provenge --> Prostate cancer vaccine --> 4 month increased survival and EXTREMELY expensive

- Most common gyn cancer in the US

- 50,000 new cases --> 8,600 deaths

- 2.6% lifetime risk

- Most commonly diagnosed at age 61

- Symptoms: Post-menopausal bleeding

- Usually symptomatic at an early stage

1. Type I/Endometrioid: 80% of cases

- Preceeding lesion --> Endometrial hyperplasia

- Risk factor: Excess endrogen

- Endogenous sources: PCOS, obesity, nulliparity, diabetes type II, and late menopause

- Exogenous sources: Unopposed estrogen contraceptives, tamoxifen, estrogen with intermittent progesterone

- Protective: Estrogen with daily progesterone, OCPs, and progesterone IUDs

- Hereditary risks: HNPCC/Lynch Syndrome, BRCA1, and PHx

2. Type II Endometrial Cancer: 20% of cases

- Poorly differentiated, endometrioid, clear cell, and serous types

- Not associated with endometrial hyperplasia

- Arises from an atrophic endometrium

-  Risk factors: Multiparity, advanced age, and black race

- Diagnosis: Biopsy and pelvic ultrasound

- Stage 1: Uterus only --> 80-90%

- Stage 2: Uterus and cervix --> 70-80%

- Stage 3: Uterus and serosa,adnexa, vagina, pelvic lymph nodes, or para-aortic lymph nodes --> 30-60%

- Stage 4: Distant metastasis to the lung, bladder, or bowels --> 20%

- Excess growth of endometrial glands --> High and prolonged levels of estrogenic stimulation

- Simple --> Cystic dilation of the ducts

- Complex --> Back-to-back glands with minimal stroma

- May have nuclear atypia present --> Presence increases risk of developing cancer

- Atypical complex hyperplasia --> 17-5% --> Recommend hysterectomy

- Causes: Menopause, persistent anovulation, PCOS, granulosa cell tumors, estrogen replacemnt therapy and obesity

- Treatment: Oppose the unopposed estrogen stimulus with medicines and weight loss, or remove the uterus

- Pts >40 years old with abnormal vaginal bleeding

- Pts 30-40 years old with abnormal uterine bleeding and risk factors

- Pts who fail to respond to medical treatment

- Pts with uterus in situ receiving unopposed estrogen replacement therapy

- Atypical glandular cells on cervical cytology >35 years old

- Presence of endometrial cells on cervical cytology in menopausal women

- Pts with HNPCC

- 2nd most common gynecological malignancy in the US

- 1.4-1.8% lifetime risk

- Average age of diagnosis is mid 50s

- 70% of cases asymptomatic until late stage

- Most common cause of death from gyn cancers

- Risk factors: Family history, nulliparity, infertility, early menarche (age <12) and late menopause (age >50)

- Genes: BRCA1, BRCA2, and Lynch syndrome/HNPCC (mismatch repair genes)

- Factors reducing risk: OCPs, tubal ligation, multiparity, breast feeding, and possibly progesterone use

- Treatment: Surgery for histological diagnosis, staging, and possible resection

- Stage I: 15% diagnosed --> 83-90%

- Stage II: 10% diagnosed --> 65-70%

- Stage III: 65% diagnosed --> 33-47%

- Stage IV: 10% diagnosed --> 19%

- Most common gyn malignancy worldwide

- 83% of cervical cancer from developing countries

- 55% mortality in developing countries

- 1.8 RR for Hispanic women and 1.5 RR for A-A women

- 70% squamous cell

- 25% adenocarcinoma carcinoma

- 5% adenosquamous carcinoma

- Risk factors: Early onset of sexual activity, multiple high risk sexual partners, high parity, immunosuppression, low soioeconomic status, prolonged OCP use, and smoking

- Highly associated with HPV infeciton --> 99.7% have detectable HPV infections

- Prognosis: 58% for stage IIB but down to 32-32% for Stage III and 15 or 16% for Stage IV

- 80% of infections are transient

- 70% cleared in one year

- 91% cleared within 2 years

- HPV 16 and 18 are more likely to persist

- Diagnosis: Cytological evidence on pap smear, DNA testing for different strains, mRNA tests (E6/E7)

- Requires persistent infection for CIN-1 to form

- CIN-1 may develop in a couple months

- CIN-3 --> Develops 15-20 years later

- Only 30% of CIN-3 lesions will become cancerous if left untreated --> <1% if treated

- Invasive carcinoma develops 20-30 years after infection

- Quadrivalent Vaccine (Gardasil): HPV 6,11,16, and 18

- Bivalent Vaccine (Cervarix): HPV 16 and 18

- Height more than 2 SD below the mean for age and sex

- ~3% of all children

- Growth velocity rapidly declines after birth

- People should grow at least 2 inches a year

- Rapid and highly variable growth

- Growth due to increased production of adrenal and gonadal hormones --> Puberty and growth spurt

- Pubertal development is around 10 years old in girls and 12 years old in boys

- Pubertal growth spurt occurs at the beginning of puberty and ends mid-puberty

- Growth spurt occurs in the middle of puberty and peaks at the end

- Growth rate declines markedly after puberty

- Bone growth ceases

- Epiphyseal plates fuse

- Height is stable --> Unless there is a presence of degenerative disease/condition of trauma

- Accurate height and weight measurements --> More accurate height measurements in an endocrinologist office

- Record and plot data

- Really need a solid growth pattern to analyze data

- Growth and weight plots crossing multiple growth standard lines implies endocrine problem

- WHO growth charts: Babies predominantly breast fed --> Grow faster but later on don't weigh as much

- Most babies diagnosed with failure to thrive end up being fine in the future

- Family history of short stature

- Normal birth weight and length

- Height <3rd percentile for age

- Normal annual growth rate

- Predicted adult heigh is <3rd percentile

- Normal onset of puberty

- No other causes of growth failure present

- Can be different from chronological age

- Growth can be based more effectively off of bone age

- 11 year 5 month old with a bone age of 9 years 4 months --> Explains low height and weight

- AKA late bloomer --> Intrinsic short stature 1

- Slow gorwth during the first 2-3 years of life

- Normal growth rate after that time

- Family history of similar growth pattern

- Delayed bone age closer to height age

- Height age: Age at which a child's height would be 50th percentile

- Normal predicted adult weight --> Context of family growth pattern

- XO female

- Multiple nevi

- Low posterior hairline

- Increased carrying angle of the forearms (when at side)

- Dysplastic nails

- Webbed neck --> Result of lymphangiomas

- Widely spaced nipples

- Cardiac abnormalities --> Aortic coarctation and left-sided defects

- Renal abnormalities --> Horseshoe kidney and duplicated collecting system

- Different chart for growth and height expectations for Turner's patients --> Classical pattern of growth

- Intrinsic short stature 2

- Intrauterine growth retardation

- Genetic disorders: Turners syndrome, Down syndrome, Noonan syndrome, Prader-Willi syndrome (young obese boys), and Russell-Silver syndrome

- Disproportionate short stature: Skeletal dysplasias and post skeletal radiation therapy

- Height and weight drop off rapidly at one point

- Descreased weight-to-height ratio

- Indicates systemic illness

- Absolute or relative nutritional deficiency

- Decrease in rate of weight gain or weight loss prior to decrease in linear growth

- Causes: IBD and celiac disease --> Often otherwise asymptomatic

- Hypocaloric disorders: Malnutrition, GI disease, and poorly control IDDM

- Metabolic: Renal tubular acidosis, nephrogenic diabetes insipidus, renal failure, hepatic, congenital heart disease, chronic anemias (hematologic), CF, severe asthma, and chronic infections

- Symptoms: Fatigue, cold intolerance, and constipation

- Signs: Myxedema, dry, course skin and nails, decreased heart rate, decreased deep tendon relfexes

- Decreased growth velocity --> Rapidly once T4 supplementation is initiated

- Permanent height deficit may remain based on when diagnosed 

- GH is required for bone and soft tissue growth --> Stimulates the production of IGF-1 by the liver

- GH receptor: Class I cytokine receptor: GH binds receptor, dimer activates JAK2 --> Activates STAT proteins and stimulates production of IGF-1 

- IGF-1 is produced directly in cartilage and bone also

- IGFBP-3: Main binding protein for growth hormone in plasma --> Levels are age dependent but varies only modestly with age --> Less nutritionally dependent than IGF-1

- 1/4,000-10,000 live births

- Normal birth weights and lenghts

- Immature appearance

- Large calvarium/Frontal bossing --> Looks like an infant

- Underdeveloped nasal bridge

- "Ripply" abdominal fat

- Severe: Multiple pituitary deficits --> Hypoglycemia, conjugated hyperbilirubinemia, neonatal hepatitis, and small phallus in booys

- Mild: Presents after 6 months with subnormal growth rate

1. Congenital Causes

- Syndromes: Septo-optic dysplasia, cleft lip/palate, and empty sella syndrome --> Midline defects

- CNS abnormalities: Holoprosencephaly, anencephaly, pituitary aplasia, hypoplasia, thin or absent pituitary stalk, and hydrocephalus

- IGF-1 deficiency --> Abnoralities in GH receptor signaling leading to primary GH deficiency

2. Acquired Causes

- Trauma: Perinatal events and head injury

- Infections: Meningitis and granulomatous disease

- Infiltrative: Histiocytosis and sarcoidosis

- Neoplasms: Craniopharyngioma, germinoma, and hypothalamic astrocytoma/optic glioma

- Cranial irradiation

- Craniopharyngioma --> Completely obliterating the hypothalamic/pituitary area

- Bridging period of growth where endocrine axes become active in order to initiate and complete secondary sexual development

- Helps attain the potential capacity for reproductive maturity

- Second wave of skeletal growth to reach adult stature

- Transitional phase from the sexually immature to potentially fertile

- Psychosocial maturity doesn't necessarily corellate with sexual maturity

- Girls undergo puberty between the ages of 8 and 13

- Average age of menarche is 12.5 years old

- Boys undergo puberty between the ages of 9 and 14.5

- Thelarche: Breast development --> ~9 years for AA girls and ~10 years for White girls

- Adrenarche: Pubic hair development --> Associated with increased DHEA levels

- Gonadarche: Maturation of the gonads --> Due to increased GnRH, LH and FSH production --> Increased sex steroids in both males and females

- Menarche: Onset of first menstrual period --> Average age of 12.2 for AA girls and 12.9 years for white girls

- Thelarche begins puberty for girls --> Should undergo menarche within at least 3 years

- Increased growth velocity associated

- LH stimualtes Leydig cells --> T in males

- LH has little effect in females until after ovulation --> Progesterone produced by the corpus luteum

- FSH stimualtes ovarian follicle growth in females --> Estrogen production by granulosa cells --> Transported into follice to theca cells

- FSH has little effect on males until spermarche --> Supports development of sperm

- Inhibit: Ovaries and testes both produce --> Negative feedback action on FSH secretion

- Various different states for breast, pubic hair, and penile growth during puberty

- First sign of puberty in the male is enlargement of the testes --> Then penile growth

- Based on 2.5x SDs from the mean

- Signs of secondary sexual development before age 8 in girls and before age 9 in boys

- 10:1 female predominance --> Parents are more worried about earlier onset of puberty in girls than boys

- New criteria: Before age 6 in black girls and before age 7 in white girls

- Puberty onset: Appearance of either breast development or pubic hair growth

- Central

- Normal sequence leading to menarche unless treated

- Diagnosis: GnRH challenge test --> LH surgei is always higher than the FSH surge

- Family tendency --> Family history of early onset of puberty

- No neurological disease

- Isolated/premature adrenarche

- Isolated/premature thelarche

- Isolated/premature menarche

- Ex. 4 year old girl with breasts

- Consistent with the sex of the child

- Due to exogenous sources of sex hormones --> In this case estrogen

- Premature adrenarche in girls

- Thelarche in boys

- Due to excess exposure to androgens in girls or estrogen in boys

1. Major Criteria:

- Breast development <8 years (Tanner stage 2)

- Pubic Hair <8.5 years (Tanner 2)

- Menarche <9.5 years

2. Minor Criteria:

- Increased growth velocity (>2.0 SD)

- Increased skeletal maturation (>2.0 SD)

- Apocrine body odor

- Leukorrhea

- Emotional lability --> Fighting with parents/moody

- Pubertal levels of estradiol

- Pubertal vaginal maturation

1. Major Criteria

- Pubic hair <9.5 years (Tanner 2)

- Testicular enlargement <9.0 years

- Penile enlargement <9.0 years

2. Minor Criteria

- Increased Growth Velocity (>2 SD)

- Increased skeletal maturation (>2 SD)

- Apocrine body odor

- Emotional lability

- Pubertal levels of testosterone

1. Absolute Criteria

- Evidence of pubertal gonadotropin secretion

- Pubertal LH response to GnRH stimulation

- Pubertal amplitude/frequency of pulsatile LH secretion

- Early morning LH level >0.3 iu/L

- Pubertal urinary gonadotropin excretion

- The younger the girl --> Higher the possibility of finding a brain tumor

- Increased incidence in international adoptees

- Causes: Hypothalamic hamartomas, etc

- Treat underlying cause --> CAH, hypothyroidism, hyperinsulinism, obesity, brain tumor, etc

- Suppress axis with central PP

- Address psychosocial and behavioral issues --> Think about the ability for a 4 year old to comprehend and deal with menses or breast development

- 13 year old girl or 14 year old boy without secondary sexual changes

- Presentation: Complete lack of pubertal development, abnormal tempo, or abnormal sequence

- No menarche by 15-16 years

- Menstruation should follow thelarche by 3 years at the most

- The later the onset of puberty --> Shorter the time until menarche

- Temporary causes: Late bloomers/constitutional delay and delayed bone age

- Permanent causes: Hypothalamic hypogonadism and isolated gonadotropin deficiency

- CNS tumors: Craniopharyngiomas, histiocytosis, germinomas, and astrocytomas

- Congenital anomalies: Septo-optic dysplasia with ACTH and GH deficiency

- Idiopathic hypopituitarism

- Acquired lesions: Closed head injuries, radiation treatment, and weight loss

1. Primary gonadal failure with no feedback inhibition

- Ovaries or testes don't respond to LH and FSH

2. Androgen insensitivity syndrome

3. Swyer syndrome --> SRY mutations

- Gonadotropin levels are very high

- Precocious puberty, cafe-au-lait spots and lytic bone lesions

- GNAS1 gene mutation

- Involved in the actions of multiple hormones

- Hyperthyroidism, acromegaly, and Cushing's syndrome

- Only chimeric individuals survive

- Predominantly in females

- Autosomal dominant condition

- AKA Familial testostoxicosis

- Mutation in LH receptor gene --> Constitutive activation

- Precocious puberty by age 4 years with moderate enlargement of the testes

- Female carriers are asymptomatic --> Both LH and FSH are needed for development in girls

- Adrenal disorders: Adenomas, carcinomas, CAH, etc

- CAH: 21-hydroxylase deficiency

- Aromatase excess syndrome: Familial gynecomastia and conrasexual precocity in males

- Van Wyk-Grumbach syndrome: Large accumulation of TSH levels exerting a weak FSH effect

- Ovarian cysts: Transient or intermittent breast development and vaginal bleeding

- Individual who is phenotypically and genotypically one sex but has a very strong psychological conviction that they are the other sex

- Crucial to identify early

- Early intervention with psychological, social, and medical support

- Oophorectomy in genetic female early enough to prevent pubertal development of breasts

- Early castration in males and estrogen therapy to prevent tall and muscular structure

- Non-cyclic pain of >6 months duration

- Localized to the anatomical pelvis, anterior abdominal wall, below the umbilicus, and the lumbosacral back or buttocks

- Sufficient severity to cause funcitonal disability

- Prevalence: 2.1-24% of patients

- About 1/3 of women with chronic pelvic pain seek medical care

- Etiologies: Gynecologic, urologic, GI, MSK, neurologic, and psychological/psychiatric

- Endometriosis

- Chronic pelvic inflammatory disease

- Pelvic adhesions

- Pelvic congestion/varicosities

- Adenomyosis

- Ovarian remnant/residual ovary syndrome

- Leiomyoma

- Malignancy

- Tubal disorders --> Endosalpingiosis, post-hysterectomy tubal prolapse, and tuberculous salpingitis

- Adnexal/postoperative peritoneal cysts

- Interstital cystitis

- Recurrent urinary tract infection

- Ureteral/bladder stones

- Urethral diverticulum

- Urethral syndrome

- Malignancy

- Radiation cystitis

- Irritable bowel syndrome

- Inflammatory bowel disease

- Diverticular disease

- Chronic intermittent bowel obstruction

- Malignancy

- Chronic constipation

- Celiac disease/sprue

- Myofascial pain and pelvic floor myalgia

- Joint disease of back, hips, or pubic symphysis

- Abdominal hernia

- Abnormal posture

- Fibromyalgia

- Neuralgia

- Disk disease

- Malignancy

- Nerve entrapment/neuropathic pain

- Abdominal epilepsy/migraine

- Depression/anxiety

- Somatization

- Hypochondriasis

- Substance abuse

- Physical and sexual abuse

- Sleep disorders

- Porphyria

- Sickle cell disease

- Hyperparathyroidism

- Heavy metal poisoning --> Lead and mercury

- Tabes dorsalis

- Presentation: Pelvic pain, infertility, and bowel obstruction

- Diagnosis: Surgical visualization

- Treatment: Surgical lysis of adhesions

- Prevention: good surgical technique and use of adhesion barriers

- Presence of endometrial glands and stroma outside the endometrial cavity

- Prevalence: 5-10%

- Pathogenesis: Retrograde menstruation, coelomic metaplasia, dissemination through vessles/lymphatics, altered immunity, and overexpression of ERb --> Suppressing PR levels

- Estrogen-dependent condition --> Incessant ovulation

- Decreased risk with multiparity

- Rare prior to menarche and post menopause

- Associated with a higher risk of endometrioid ovarian cancer

- Presentation: Pelvic pain, dyspareunia, dysmenorrhea, and infertility

- Histology: endometrial glands, stroma, and hemosiderin macrophages seen on biopsy

- Endometrial cyst/Chocolate cyst --> Specific presentation of ovarian endometriosis

- Diagnosis: Surgical visualization

- Treatment: Hormone suppression with OCPs, GnRH analogs, and progestins or surgical removal/ablation

- Leiomyomas/myomas --> Benign mesenchymal tumors

- Most common pelvic tumor in females

- Benign monoclonal growth

- Incidence: >70% at 50 years --> 2-3x higher in black women

- Unclear pathophysiology

- Estrogen dependent --> Shrink at menopause

- Increased risk with early menarche and low parity

- Presentation: Menorrhagia, pelvic pressure, pain, and reproductive dysfunction

- Diagnosis: Pelvic evaluation, pelvic ultrasound, MRI and hysterosalpingogram

- Treatment: Surgery (myomectomy and hysterectomy), uterine artery embolization, and medical therapy with GnRH analogs

- Reduces uterine arterial blood flow --> Fibroid infarction and size reduction

- Side effects/compliations: Pain, fever, allergy, vaginal passage of fibroid, readmission, and need for unplanned procedure

- More serious complications: Misdiagnosis of leiomyosarcoma and post-procedural ovarian dysfunction and infertility

- Contraindication: Postmenopausal women and premenopausal women with pedunculated/submucosal fibroids, extensive adenomyosis, very large fibroids, and plans for future pregnancy

- Localized hyperplastic overgrowth of endometrial glands and stroma around vascular core --> Benign hyperplasia

- Sessile or pedunculated

- 70% benign, 26% hyperplasia, 3% hyperplasia with atypia and 0.8% cancer

- Incidence peaks in 5th decade --> 10-24% prevalence

- Pathogenesis: Monoclonal endometrial hyperplasia, overexpression of aromatase in endometrium, and cytogenetic abnormalities

- Absence of progesterone receptor --> Progesterone acts as an anti-proliferative stimulus

- Presentation: Abnormal uterine bleeding, metrorrhagia (uterine bleeding at irregular intervals) or post menopausal bleeding

- Diagnosis: Hysterosalpingography, sonohysterography, or hysteroscopy

- Treatment: Hysteroscopically guided removal --> Only if symptoms are present

- Endometrial glands and stroma present within the myometrium --> Non-functional glands --> Benign lesion

- Adenomyomas --> Nodules

- Prevalence: 15-25% of uteri examined

- Hypertrophy of myometrium and globular enlargement of the uterus

- Pathogenesis: Endomyometrial invagination of endometrium and metaplasia of Mullerian nests

- Estrogen-dependent

- More common in parous than nulliparous women and patients with prior uterine surgery

- Presentation: Menorrhagia, dysmenorrhea, dyspareunia, and chronic pelvic pain --> Typically between ages 40 and 50

- Histology: Stratum basalis layer of the endometrial present deeper in the myometrium

- Diagnosis: Histological examination and pelvic MRI

- Treatment: Hysterectomy, short term progestins, GnRH analogs, or aromatase inhibitors, and uterine artery embolization

- Asherman syndrome

- Intrauterine adhesions --> Uterine scarring

- May develop after pregnancy related curretage for heavy bleeding or infection, or other uterine surgery

- Curettage: Removes deep endometrial layers and destroys basal crypts/glands needed for endometrial regeneration

- Presentation: Amenorrhea/hypomenorrhea, infertility, recurrent pregnancy loss, and cyclic pelvic pain

- Diagnosis: Hysterosalpingography, sonohysterography, or hysteroscopy

- Treatment: Hysteroscopic resection

- Blockage of Fallopian Tube due to hydrosalpinx and tubo-ovarian abscess

- Etiologies: Infection and adhesions

- Presentation: Infertility, pelvic pain, and ectopic pregnancy --> Very painful

- Diagnosis: Hysterosalpingogram or ultrasound

- Treatment: Surgical correction followed by recurrence of tubal adhesions

- Prevention: Reduce STDs

- History: Pain characteristics, previous diagnostic tests, Ob/Gyn history, PMHx, surg. Hx, and sexual Hx

- Physcial Exam: Abdominal and pelvic exam and straight leg raising test (Carnett's sign)

- Labs: Pregnancy test, CBC, Urinalysis and cervical cultures

- Imaging: Pelvic ultrasound and MRI

- Empiric therapy: NSAIDs, OCPs, progestin therapy, danazol, and GnRH agonist

- Therapy: Laparoscopy, hysterectomy, local heat/ice, psychological counseling, antidepressants, pelvic physical therapy, acupuncture, and electric nerve stimulation

- Anovulation/PCOS (30-35%) --> States of chronic anovulation

- Hypothalamic amenorrhea (20-25%): Structural and functional disorders --> Marathon runners/stress

- Gonadal dysgenesis (10-12%)

- Prolactin tumors (7-10%)

- Asherman's syndrome/Uterine scarring (5-10%)

- Hypothyroidism (1%) --> Very uncommon

- Compression or destruction of hypothalamus

- Craniopharyngioma --> Common in young women

- Germinoma (ectopic pinealoma)

- Glioma of the optic chiasm or hypothalamus

- Hand-Shuller-Christian disease (Histiocytosis or eosinophilic granuloma)

- Midline dermoid cyst and teratoma

- Endodermal sinus tumor (yolk-sac carcinoma)

- Tuberculosis and sarcoidosis

- Metastatic carcinoma

- Head trauma: Prolactinoma removal, etc --> Changes in pituitary area

- Post-irradiation damage to pituitary

- Isolated GnRH deficiency (Kallman's syndrome)

- Exercise, anorexia/bulimia, and athletic female triad

- Low FSH, low LH and low estradiol levels

- Whole pituitary axis shut down

- Exercising women can have normal spiking estrogen but very low progestin levels --> Anovulation results

- Diagnosed between ages 10-30

- Weight loss of 25%, weight 15% below normal for age and height

- Attitudes: Denial, distorted body image and unusual hoarding or handling food

- Defining characteristics: Lanugo (soft, unpigmented, downy hair), bradycardia, overactivity, bulimia/overeating, and vomiting

- Amenorrhea

- No other known medical illness or psych. disorder

- Other characteristics: Constipation, low BP, hypercarotenemia, and diabetes insipidus

- Prolactin-producing pituitary adenoma --> Sign is galactorrhea

- Non-prolactin producing pituitary tumor

- Empty sella syndrome --> Squashed by CSF or other sources of pressure

- Sheehan's syndrome: Pituitary necrosis --> Severe blood loss at birth

- Autoimmune disease --> Lymphocytic hypophysitis --> Very rare

- Begins as luteal phase insufficiency --> Oligomenorrhea --> Amenorrhea/anovulation

- Levels of prolactin >25 --> Reduces estrogen levels in the body

- Reduces follicular maturation and ovulation

- Medicines: Phenothiazones, haloperidol, other antipsychotics, and alpha-methyldopa

1. Congenital --> Primary amenorrhea

- Gonadal dysgenesis --> Turner's (45,XO) --> Many Turner's patients will ovulate for some time but will stop

- Gonadal agenesis (46,XY or 46,XX) --> Primary amenorrhea

- Results in very high FSH levels (>20) with very low estradiol levels

2. Acquired

- Premature ovarian failure --> Autoimmune disorder, enzymatic defects (galactosemia), irradiation, chemotherapy, endometriosis, and tubo-ovarian abscesses

- Idiopathic

- Ovarian resistance to hormones --> Improper response to pituitary hormones

- Functioning ovarian tumors (Germ cell/sex cord tumors)

- Disorders of the thyroid gland --> Hypo or hyperthyroidism

- Disorders of the adrenal gland --> Addison's disease/hypocortisolism (rare), Cushing's syndrome/hypercortisolism (rare), and congenital adrenal hyperplasia (much more common)

- Congenital: Mullerian agenesis, transverse vaginal septum, and imperforate hymen

- Acquired: Asherman's syndrome --> Removal of stratum basalis of the endometrium --> Two sides of the uterus fuse --> Infertile

- Complex syndrome of ovarian dysfunction

- Features of hyperandrogenism and polycystic ovaries

- 4-6% of women --> Now may be closer to 10-15% due to increased levels of obesity

- Symptoms: Oligomenorrhea, hirsuitism, endocrine abnormalities, anovulation, and amenorrhea

- Endocrine abnormalities: Elevated LH, elevated LH:FSH ratio, or elevated testosterone/androstenedione

- Highly associated with insulin resistance, obesity, and diabetes

- Insulin resistance --> High insulin --> High LH levels and high androstenedione levels --> High testosterone --> Hirsuitism

- High androstenedione --> High estrone levels in fat --> Low FSH but high LH levels (estrone inhibits FSH but stimulates LH) --> Impaired follicular maturation --> Anovulation

- Chronic anovulation or clinical/biochemical signs of hyperandrogenism

- Oligo or anovulation

- Clinical/biochemical hyperandrogenism

- Polycystic ovaries seen on ultrasound --> No other etiology for cysts

- Presence of 12 or more follicles in each ovary --> Follicles 2-9 mm in diameter or volume >10 mL

- Only one ovary needs to be involved to diagnose

- This criteria does NOT apply to women on OCPs

- Not necessary for diagnosis

- Can be helped to confirm diagnosis

- FSH, E2 levels --> Usually low

- TSH, and PRL levels --> May be high or low depending on etiology of anovulation/PCOS

- LH levels --> usually high --> Prevents proper maturation

- Testosterone, DHEA-S, 17-OH progesterone levels --> High levels

- HbA1c to determine if patient also has type II diabetes --> Most patients are obese

- 50-70% of obese and non-obese PCOS patients have insulin resistance

- 30% have impaired glucose tolerance

- 5-10% have diabetes mellitus (type II)

- Obese women have a greater risk for insulin resistance and metabolic syndrome

- Careful history --> Menstrual history, hair growth, eating habits, exercise habits, etc

- Physical exam

- bhCG, FSH, PRL, and TSH

- Androgen levels, LH, HbA1c, estradiol levels

- Others: Pelvic ultrasound, progesterone withdrawl bleed, MRI, and bone density tests

- Intact H-P-O axis --> Synchronize oocyte release and endometrial preparation

- Adequate number of follicles with an adequate occyte/ovarian reserve

- Healthy female anatomy --> Patent fallopian tubes, uterus, cervix, and vagina

- Adequate cervical mucus production --> Alot of the sperm ends up in the cervical mucus so need proper production

- Proper sperm production and transport --> Proper flagella formation, etc

- Ability of a couple to have intercourse --> Erectile dysfunction

- Egg usually lasts 24 hours after ovulation and sperm lasts 2-3 days after ejaculation in the vagina

- Inability to conceive after 1 year of regular unprotected sex

- Age <30 --> 10% of couples are infertile

- Age 30-35 --> 15% of couples are infertile

- Age 40-44 --> 30-40% of couples are infertile --> Maybe more like 40-50% in reality

- Started after 1 year of regular unprotected sex without the ability to concieve

- Earlier evaluation if mother is >35 years old, has a history of oligo/amenorrhea, known/suspected tubal disease or endometriosis, or partner is known to be subfertile

- 50% female origin --> 40% tubal disease, pelvic adhesions, and uterine abnormalities, 40% oligo-amenorrhea, ovulatory facotr, and 20% due to cervical factors

- 35% male origin --> Unknown etiology

- 10-15% both

- 10-15% of couples have no known abnormality --> Unexplained infertility

- History and physical exams for both mother and father

- Evaluation of ovarian reserve

- Rule out hormonal abnormalities --> Day 3: FSH, E2, antral follicle count (>12 is ideal), TSH, and prolactin levels

- Hysterosalpingogram

- Semen analysis

- Age --> Crucial for likelihood of infertility --> Fertility drastically declines between the ages of 35 and 40

- Menstrual history

- Obstetric history

- Pelvic and STD history

- Past surgical history --> Especially abdominal and pelvic surgery

- History of systemic illness

- Results from prior evaluation for infertility

- Prior or current medication use

- Life style factors --> Weight, diet, physical exercise, alcohol consumption, smoking, and use of recreational drugs

1. No evidence of hirsuitism

- Careful history with sexual and menstrual history

- Physical exam

- Labs --> FSH, prolactin, and TSH levels

- Progesterone withdrawal bleed test

2. Evidence of hirsuitism

- Careful history and physical

- Labs --> Prolactin, TSH, testosterone, DHEA, 17-OH progesterone, fasting glucose, insulin, and HbA1c

- Progesterone withdrawal bleed test

- Normal volume is 2-5 mL --> <1 mL is abnormal

- Sperm concentration --> Normal is 20-100 mill/mL --> <10 mill/mL is abnormal

- Motility (%) --> Normal is >50% --> Abnormal <40%

- Morphology (%) --> Normal is >50% --> Abnormal is <40%

- Treat thyroid disease if present --> Hypothyroid treated with synthroid

- Treat hyperprolactinemia with dopamine agonist --> Parlodel

- Clomiphene citrate with/without glucophage to stimulate ovulation in anovulatory patients

- 2nd line therapy: Injectable gonadotropins (rFSH) --> 2-3 cycles

- In vitro fertilization as 3rd line treatment

1. Causes: Mild tubal disease, endometriosis, mild pelvic adhesions, mild male factor (low sperm count), cervical factor, and unexplained

2. Treatment

- Clomid with intraurterine insemination of washed sperm for 2-3 cycles --> Washed with millions of sperm instead of the hundreds through normal intercourse

- Injectable gonadotropins with IUI for 2-3 cycles --> Stimulates proper ovulation plus washing with more sperm

- In vitro fertilization --> covered by all insurance in MA so available to almost all women

- Used to treat infertility due to severe disease

1. rFSH, oocyte retrieval and embryo transfer

2. Standard insemination: 25,000 sperm/oocyte in petridish --> Used for tubal blockage or unexplained fertility --> Only inject 2 oocytes per IVF treatment

- Intracytoplasmic sperm injection (ICS): Used for men with <5 mill/mL of sperm --> Directly injects a single sperm into the egg

- 90% success rate with flash freezing eggs now --> Can preserve fertility before chemo or removal of ovaries

- Donor oocytes for FSH levels >16 --> Shows low oocyte reserve

- Host uterus/surrogate for severe Asherman's disease

3. Fertilized egg is incubated in petridish until day 5 --> Blastocyst stage

- Implanted at this stage

- Can also take a section of this stage for analysis to determine if embryo has any genetic abnormalities

- Caused by Neisseria gonorrhoeae --> G- coccus, can grow and multiply in warm, moist areas --> Mouth, troat, eyes, and anus

- Requires a mucosal surface to gain access to the body

- Movement to subendothelial sites

- Anaerobic bacteria --> Not easily detected via culture, need PCR

- Presentation in men: Urethritis and purulent penile discharge

- Presentation in women: Asymptomatic --> Pain or burning on urination, vaginal discharge, and vaginal bleeding

- Etiology: Disease of youth (18-24 years old) --> Poverty, urban residence, unmarried, non-white, MSWM, and prostitutes

- Disseminated --> Joint/blood infection

- Newborn infection --> Opthalmia --> Blindness if untreated --> All children are given antibiotic eye drops at birth in the US

- Ceftriaxone 250 IM once --> Resistance is a big problem though

- Azithromycin 1g PO once --> Limited activity for gonorrhea but necessary to cover chlamydia since pt is also likely infected with both

- Dual therapy --> Coinfection, antibiotic resistance, and enhanced treatment for pharyngeal infection

- Caused by Chlamydia trochamatis --> G- like obligate intracellular pathogen --> Reticulate bodies are infective form

- Most common STD

- Gain access to the body by invading epithelial cells of the endocervix, urethra, endometrium, Fallopian tubes, rectum, and conjunctivae

- Presentation in men: Asymptomatic or urethritis --> Risk of transmission

- Presentation in women: Asymptomatic --> Cervicitis or endometritis --> PID, chronic pain, infertility, and ectopic pregnancy

- Neonatal disease: Pneumonia or conjunctivitis leading to blindness

- Diagnosis: PCR of cervial/vaginal or urine samples because culture is difficult and wet mount --> Sheets of white cells

- Azithromycin 1 gm PO once

- Reinfection is possible in the future

- Rescreen patients 3-4 months afterwards to follow up on successful treatment

- Doxycycline is an alternative --> Requires a longer treatment regimen (1 week) and not as effective

- Recommended for patients who have a suspected incidence of >4%

- Screening --> Decreased PID incidence

- PCR/LCR methods are best

- Infection of the upper genital tract

- Includes endometritis, salpingitis, and peritonitis

- PID --> Most commonly polymicrobial but also commonly caused by gonorrhea or chlamydia

- Can lead to chronic pelvic pain, infertility, and ectopic pregnancies (tubal)

- Presentations: Acute pelvic infection and tubal damage (gonorrhea) and subsequent infections due to chlamydia can cause PID

- Complications: Fitzhugh Patrick Curtis Syndrome --> Chlamydial perihepatitis

- Symptoms: Fever, mucopurulent discharge, WBCs seen in vaginal fluid, elevated ESR and CRP, and cervical, uterine or adnexal tenderness

1. Diagnosis

- Endometrial biopsy --> Evidence of endometritis

- Sonography or MRI --> Thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex

- Abnormalities seen laparoscopically

2. Treatment

- Outpatient --> Ceftriaxone/Cefoxitin IM plus probenecid and doxycycline po BID for 14 days --> With or without metronidazole po BID for 14 days

- Inpatient --> Cefotetan or Cefoxitin IV plus doxycyline

- Can also substitue clindamycin and gentamycin IV for inpatient treatment

- Possible complication of PID

- May follow primary infection but most likely after secondary or polymicrobial

- Symptoms: Pelvic tenderness, fever, N/V, ileus, and leukocytosis

- Diagnosis: Ultrasound

- Treatment: Antibiotics but surgical drainage with laparotomy after 24-48 hours

- Overtreatment of viral infections, GI illness, and strained muscles with antibiotics --> Resistance

- Often overdiagnosed because women are extremely worried about PIDs consequences on fertility

- Condoms --> Prevention of gonorrhea and chlamydia

- Hormonal contraceptives --> Prevention of PID
- Women who don't live with their partner have higher rates of PID --> Partner sleeps elsewhere and may be sleeping around 

- Spirochete --> Treponema pallidum

- Enters the body through miniscule breaks in  the skin of external genitalia that occurs during sexual intercourse

- Four stages --> Primary, secondary, latent, and tertiary syphilis

- Treatment: Penicillin --> used in all but highly allergic patients --> Can prevent life-threatening sequelae

- Presents with a painless chancre --> Small painless lesions

- Lasts 1-2 months

- Heals spontaneously

- Systemic disease

- Spirochetes populate the dermis

- Widespread papular rash --> Includes palms and soles

- Resolves over 4-12 weeks if untreated

- Progresses into latent disease

- Latent period --> May last months to years after secondary syphilis occured

- Cardiovascular and nervous systems --> Gummas, etc

- Half the patients with symptomatic tertiary syphilis will die as a result of disease --> Cardio complications

- Maternal infection with syphilis during pregnancy

- Transplacental infection is possible

- Adverse outcomes --> Stillbirth, perinatal death, permature delivery, low birth weight, and congenital anomalies

- Early treatment can decrease severity of infection

- Primary: Darkfield microscopy of fresh mixed slide

- Serology --> 2-phase test for primary phase --> Will remain positive for years --> Lower titer though

- Universal screening for pregnant women

- Targeted testing for non-pregnant people with other STIs, high occupational risk, and high risk sexual practices

- DNA virus --> HPV 6, 11, 16, and 18 --> High risk

- Induces chronic infections with no systemic sequelae

- HPV 6 and 11 --> Genital warts/condyloma acuminata --> On the penis in men and vaginal introitus and labia in women

- HPV 16 and 18 --> Cervical neoplasia

- Epidemiology: Up to 75% of sexually active women will acquire latent HPV infection --> Most infections are transient

- Neonate infection is possible but very rare

- Condyloma acuminata

- Flesh-colored, pink or pigmented papules with a frond-like surface

- More common in immuncompromised patients and during pregnancy

- HPV may say quiescent for years

- Treatment: Topical --> Podophylline, TCA, imiquinone, crytotherapy, cautery, and excision

- Prevention: HPV vaccines

- Establishes a latent infection in the sacral dorsal root ganglia

- Oral or genital muco-cutaneous lesions

- Disseminated neonatal infection --> Acquired during delivery

- Immunocompromised --> Disseminated infection

- HSV-1 --> Oral lesions --> 80-90% prevalence

- HSV-2 --> Genital disease --> 25% prevalence --> More likely to develop latent infection

- Primary lesion: May be asymptomatic or may present with symptomatic vesicle on the penis, vulva or cervix --> No HSV antibodies detected initially

- Recurrent lesions: May be asymptomatic --> Less severe and shorter duration if symptomatic

- Diagnosis: Direct culture, smear, or serum antibody assay

- Treatment: Valcyclovir (anti-virals)

- 90% of women with HSV-2 genital infections shed virus from the cervix during acute infection

- Only 12-20% of women with recurrent disease shed virus from the cervix

- 50% of pregnant women with primary lesions during delivery will transmit infection to their child

- Only 5% of pregnant women with recurrent lesions transmit infection

- Should receive prophylaxis

- Neonatal herpetic infections --> Life-threatening so may require caesarean delivery to prevent

- 70% via heterosexual transmission

- More readily transmitted from males to females

- Acute infection: Fever, malaise, muscle aches, headache, fatigue, generalized rash, sore throat, and lymphadenopathy --> High levels of virus shedding

- Symptoms of acute infection persists for 2-3 weeks before resolving

- Asymptomatic phase --> Lasts several months to many years

- Prevention: Condoms during intercourse and clean needles with IVDU

- 25% of children born to untreated HIV+ mothers will become HIV+

- Prenatal screening can identify asymptomatic women

- <1-2% of children born to treated HIV+ mothers will become HIV+

- Single dose therapy is sufficient to treat HIV+ mothers

- Anti-retroviral therapy --> Low rates of transmission during breastfeeding

- Therapy started once mother goes into labor --> Largest risk of transmission

- One celled organism with multiple flagellae --> Frequently confused with bacterial vaginosis

- Symptoms: Vaginal discharge, cervicitis, and possible urethritis

- Men --> Frequently asymptomatic

- Diagnosis: Microscopically

- Treatment: 2 gm metronidazole once --> Resistance possible

- Partner treatment is necessary

- Chlamydia --> Annual screening for all sexual active females <25 years old

- Gonorrhea --> At risk women <25 years old

- HIV --> Sexual active women or IVDUs

- Cervical cancer: Beginning at age 21

- HIV

- Syphilis

- Chlamydia

- Gonorrhea in high risk areas

- Hepatitis B and C

1. Men who have sex with men

- HIV

- Syphilis

- Gonorrhea and chlamydia --> Urethral, rectal or pharyngeal testing

- Hep. B

2. Women who have sex with women

- Should not be presumed to be low risk

- Screen for STDs like general population

- Routine pap smear

- 10-15% of couples fail to conceive after one year

- 10-20% of pregnancies are spontaneously aborted

- 2-4% of deliveries are stillbirths

- 2-3% of live newborns exhibit a defect

- 5-10% of defects may be due to a teratogen

1. Men

- Spermatogenesis --> chemo and industrial chemicals (phthalate esters, lead, and dibromochloropropane)

- Erection and ejaculation --> SSRIs and antihypertensive agents

2. Women

- Ovulation

- Blastocyst development and implantation

- Fetus --> Teratogenic effects on differentiation and growth and pharmacologic effects like in adults

- Placental function

- Uterine contractility

- A: No feal risk based on human studies

- B: Fetal risk in animals but not in humans

- C: Fetal risk in animals and risk in humans unknown

- D: Fetal risk but benefit>risk

- X: Lethal effect or fetal risk>benefits

- FDA requires data from two species --> Rat/mouse and rabbit studies

- Predictability from animal studies --> 37/38 sensitivity and 67/165 specificity

- Inhibition of cholesterol biosynthesis

- Perturbation of transcription factors in tissues --> Sonic hedgehog morphogenetic pathways, HOX genes, and blockade of promoter regions

- Inhibition of folate synthesis

- Inhibition of cell replication

- Reduced birth weight

- Skeletal malformations

- Delayed ossification

- Reduced survival of fetal rats at highest dose tested

- Decreased fetal viability and maternal mortality in rabbits at human dose equivalent

- Rare CNS and limb defects

- Fetal risk> maternal benefits

- Genetics --> Species dependence in risk

- Dose and access to fetus --> Placental diffusion greater with low MW lipophilic drugs

- Exposure time in gestation --> Higher risk in first trimester in general --> Organ formation

- Low birth weight --> Increased risk of growth retardation during 3rd trimester and increased risk of preterm delivery

- First trimester effects --> Possible heart defects

- 12.2% of pregnant women in 2000 were smokers --> Older teenagers

- Low birth weight

- Microcephaly

- Characteristic facial abnormalities

- Mental retardation

- Dose-dependent --> Higher amount of alcohol intake leads to increased risk and effects

- Found in commonly consumed fish --> Tuna and salmon

- Impaired brain development

- 1st trimester: Category C --> Risk of CV and CNS malformations

- 2nd & 3rd trimester: Category D --> Renal failure, oligohydramnios (low amniotic fluid), and fetal/neonatal death

- Necessary for some others to maintain seizure control

- 2x risk of teratogenic effects with the use of antiepileptic drugs

- Less information for newer drugs

- Valproic acid --> Category D --> Neural tube defects --> 1-2% spina bifida

- Requires folate acid supplementation in order to reduce the risk of neural tube defects

- Cell replication inhibitors --> Infertility in both men and women, abortion in 1st trimester, and teratogenic abnormalities

- Ex: Methotrexate --> Cat. X --> Skull and limb abnormalities

- Methotrexate is used in high doses to induce termination of ectopic pregnancy

- Craniofacial, heart, thymus, and CNS defects

- Critical role of retinoids bound to RAR/RXR receptors --> Transcription factors

- RAR/RXR --> Regulates cephalic neural crest cells during organogenesis --> Affects HOX genes involved in embryonic patterning

- Isotretinoin --> Cat. X

- Etretinate --> Cat. X

- Tretinoin --> Cat. C (topical)

- Cat. X

- Early pregnancy/1st Trimester --> Skeletal defects, facial anomalies, CNS abnormalities, and mental retardation

- Unfractionated or low molecular weight heparin is used instead of warfarin

- Based on scienfic evidence --> NONE

- Classified as Cat. X --> No reason to be taking during pregnancy but NO real risk to fetus

- Risk of prematurity increases with the number of fetuses

- Risks are based on the number of fetuses and chorionicity (number of placentae)

- No in vitro fertilization --> 1.2% twins, 0.015% triplets, and 0.00017% higher order

- Clomiphene --> 8-10% twins, and <1% triplets

- Gonadotropins --> 15% twins, 5% triplets, and 0.6% higher order pregnancies

- ART: 27.9% twins, 5.9% triplets, and 1% higher order pregnancies --> All depends on the number of embryos transferred to mom

- Diamniotic, dichorionic (Di-Di) twins --> 2 sacs and 2 placentae --> Dizygotic/Fraternal twins

- Diamniotic, monochorionic (Di-mono) twins --> 2 sacs and 1 placenta --> Monozygotic/identical twins

- Monoamniotic, dichorionic --> Doesn't occur

- Monoamniotic, monochorionic (mono-mono) twins --> 1 sac and 1 placenta --> Monozygotic/identical twins 

1. Di-di

- Increased risk of poor fetal growth

- Increased risk of preterm labor

2. Di-mono

- Same di-di risks

- Increased risk of congenital malformations

- Increased risk for twin-twin transfusion syndrome --> Based on the fact that both twins share placenta

3. Mono-mono

- Same di-mo risks --> Congenital malformations and twin-twin transformation syndrome

- Increased risk of cord entanglement

1. Twins --> Mean gestational age at delivery is 36.5 +/- 3 weeks

- ~5% risk of delivery <30 weeks

- 1-2% risk of delivery <27 weeks

- 50% risk of pre-term labor

2. Triplets --> Mean gestational age at delivery is 33.2 +/- 3 weeks

- ~33% risk of delivery <30 weeks

- 5% risk of delivery <27 weeks

- 80-90% risk of preterm labor

3. Quadruplets --> Mean gestational age at delivery is 30 +/- 3 weeks

- 50% risk of delivery <30 weeks

- 33% risk of delivery <27 weeks

- 90-100% risk of preterm labor

- Loss of a pregnancy <20 weeks --> 50% of women will have one

- ~15% of recognized pregnancies result in spontaneous abortion

- >80% of miscarriages occur in the 1st trimester

- >60% of 1st trimester miscarriages are chromosomally abnormal --> 52% trisomic, 18% are 46X, 17% are triploid, 6% are tetraploid, and 3% have unbalanced translocation

- Risk: Approaches 100% by age 40-45 (nearing menopause)

- Pathophysiology: Oocytes remain in prophase I since fetal development --> Longer they remain there, higher the chance of non-disjunction, crossing over, or failure of the mitotic spindle to occur

- hCG levels --> Levels drop off at ~30 days

- Having one miscarriage is normal, but having multiple is not

- 2 consecutive losses in nulliparous women or 3 consecutive losses in parous women

- Causes of recurrent abortion

1. Parental chromosome translocations

2. Structural uterine abnormalities --> Septate uterus/avascular septum

3. Antiphospholipid antibodies --> Associated with SLE and multiple miscarriages

4. Thyroid disorders --> Hyperthyroid leads to miscarriage

5. Poorly controlled diabetes mellitus --> HbA1c ~10 leads to 25% miscarriage rate

- Any pregnancy that implants outside of the corpus of the uterus

- Incidence --> Hard to quantify --> 1-2% depending on the specific population

- Incidence with IUD use --> If you get pregnant on an IUD, it is an ectopic pregnancy until proven otherwise

- Risk factors: PHx (10x), smoking, and IUD usage

- Locations: 94% Fallopian tube, 3% ovary, 2% interstitial/uterine cornua and 1% abdominal

- Due to conditions that delay or prevent passage of the zygote/embryo into the uterine cavity --> 90% due to tubal pathology

- Causes: Chronic salpingitis or salpingitis isthmica nodosa

- Factors inherent in the embryo that result in premature implantation --> No difference in karyotypic abnormalities

- Induced by mother

- Preterm --> <37 weeks

- Includes preterm births from preterm labor and premature membrane rupture

- Excludes births resulting from pre-eclampsia, fetal growth restriction, and other maternal/fetal conditions

- Risk factors: Emotional or physical stress, excessive/impaired uterine distension, cervical factors, infection, placental pathology, and fetal abnormalities

- Single women

- Low socioeconomic status

- Anxiety

- Depression

- Adverse life events --> Divorce/separation and death in the family

- Long periods of standing and physical exertion

- Abdominal surgery during pregnancy

- Stress induces excessive glucocorticoid secretion

- Multiple gestation

- Polyhydramnios --> Too much amniotic fluid

- Uterine anomaly --> Bicornuate uterus (smaller cavity)

- Uterine fibroids

- Prenatal DES exposure

- Myometrial stretch induces labor

- History of 2nd trimester pregnancy termination

- History of cervical surgery

- Permature cervicacl dilation or effacement

- Prenatal DES exposure --> Incompetent cervix --> Completely silent dilation of the cervix around 16-18 weeks

- Sexually transmitted infections --> Conceived with active inflammatory process in the vagina or uterus

- Urinary tract infections --> Bacteruria --> Cystitis --> Pyelonephritis (Progesterone from pregnancy relaxes the smooth muscle to allow bacteria to migrate up)

- Systemic infections

- Periodontal disease

- Appendicitis

- Pneumonia

- Infections stimulate the production of prostaglandins, which induce labor

- Placenta previa --> When uterus contracts, puts pressure on the placenta and induces bleeding

- Placental abruption --> Normally implanted placenta separates from the wall of the uterus

- Vaginal bleeding --> Blood coming out is mom's --> Region where blood is flowing can't heal --> Reduced blood flow to baby

- Bleeding produces thrombin which is a potent activator of labor

- Previous preterm birth

- Cocaine use

- Smoking

- Extremes in maternal age --> Very young or very old

- African-Americans

- Inadequate prenatal care

- Fetal anomalies

- Onset of labor is a molecular collaboration between mother and baby

1. Pituitary and Adrenal Axis

- Adrenal gland is one of the last fetal organs to develop

- Once adrenal gland is formed --> Produces enough glucocorticoids to stimulate labor

- Placental CRH is also key --> Secreted into maternal and fetal circulation

- CRH stimulates ACTH --> More glucocorticoids to be produced by maternal and fetal adrenals

- Maternal effects --> Adrenal production of glucocorticoids and DHEA-S

- Fetal effects --> Adrenal production of glucocorticoids for lung surfactant and DHEA to promote uterine contractility

- Preterm labor occurs when premature elevation of CRH and glucocorticoids occurs

2. Progesterone and Uterine contractions

- Change in myometrial progesterone receptors --> Become resistant to progesterone

- Altered progesterone metabolism

- Determined by the placenta

- Assures that fetus is ready for extrauterine life

- Intiated by glucocorticoid levels, prostaglandins, and myometrial stretch once the baby is mature enough

- Dependent on Ca-dependent transport 

- Transport is activated by prostaglandins E2 and F2a and oxytocin

- Stimulated by stretch

- Occurs via synchrony --> Waves of contraction and relaxation that push baby down and out of the uterus

- Waves are electrically excited and prostaglandin mediated

- Tocolysis: Inhibition of uterine contractions

- Most common are magnesium sulfate and parenteral NSAIDs

- Risks: Maternal side effets and the possible fetal side effects of leaving fetus in a hostile environment (cytokine soup) --> Not really sure how severe these might be

1. Interrupt Ca++ homeostasis

- Magnesium sulfate and calcium channel blockers (nefidipine)

2. Interrupt myosin phosphorylation

- B-adrenergic agonists

- Not very well tolerated --> Tachycardia in mom

3. Interrupt prostaglandin synthesis

- Cyclooxygenase inhibitors --> Parenteral NSAIDs

4. Preventing oxytocin binding to receptor

- Oxytocin antagonists

- Normal term weight --> 5.5-9 lbs

- 15 weeks --> 5g/day

- 20 weeks --> 10 g/day

- 34 weeks --> 30-35 g/day

- Term --> 20 g/day

- > 90th percentile for genstational age OR >4,000-4,5000 g --> Really only affects term birth weight

- Increased risk of birth injury --> Erb's palsy

- Increased risk of neonatal hypoglycemia

- Glucose is the preferred fuel for fetus

- hPL --> Induces insulin resistance in mom

- Fetal hyperglycemia due to hyperglyemic or diabetic mom induces insulin secretion

- Insulin stimulates IGF release --> Stimulates fetal growth

- Results in overgrowth of the skeleton and adipose tissue

- Occurs when the head delivers by the body doesn't follow

- Injury can pull on the brachial plexus --> Erb's plasy in 10% of cases --> 10% will be permanent

- Fetus specifically has truncal overgrowth in macrosomia

- Only have 4 minutes to get the baby out before asphyxia and hypoxia occurs --> Shoulder compresses umbilical cord

- Increased risk with increased birth weight

- Commonly seen in diabetic moms

- Physicians recommend cesarean delivery in infants >4250-4500 g --> Not for >4,000 though

- Secondary to hyperinsulinemia at birth

- Greaterst risk with maternal diabetes

- Can also be seen without maternal diabetes though

- Can result in neonatal seizures and death

- Treatment: Early formula feeds or glucose containing IV fluids

- Any fetus that fails to reach its growth potential

- <10%th percentile for gestational age with signs of compromised intrauterine environment or signs of fetal compromise/abnormalities

1. Fetal causes

- 5-15% --> Genetic

- 1-2% --> Fetal anomalies

- 2-3% --> Multiple gestation

- 2-5% --> Congenital infection (CMV and malaria) --> Malaria colonizes maternal side of the placenta

2. Maternal causes

- 2-3% --> Malnutrition

- 5-15% --> Drug/toxin exposure

3. Uteroplacental --> ~50% of cases

- Chronic hypertension

- Pre-eclampsia

- Antepartum abruptio placenta --> Reduced blood flow based on the amount of placenta that has lifted up

- Maternal thrombophilia --> Factor V Leiden and Prothrombin mutations (double heterozygote) 

- Chromosomal abnormalities --> Trisomes (18>13>21), triploidy, and sex chromosome abnormalities

- Single gene defects --> Dwarfism and maternal metabolic diseases

- Confined placental mosaicism --> Rare but possible

- Cardiovascular anomalies

- Bilateral renal agenesis (Potter's syndrome)

- Multiple gestation --> Risk increases with fetal number and worse in monochorionic twins than dichorionic --> Twin-twin transfusion syndrome

- One twin gets more blood flow than the other

- Amniotic fluid discrepancy too

- Can crush and cut off the blood supply to the other twin

- Neither babies end up doing well

- Abruptio placenta

- Velamentous insertion of the umbilical cord --> Implanted at one edge of the placenta instead of right in the middle

- Single umbilical artery --> Reduced blood flow --> Signifies more anomalies --> Keep looking

- Thrombophilia-related uteroplacental insufficency --> Double heterozygotes (Factor V Leiden and Prothrombin)

1. Normal

- Umbilical cord inserted in the center

- Warton's jelly in the cord keeps it from being compressed all the time

- Reduces the risk of kinking of the cord too

2. Velamentous

- Cord is inserted right at the edge of the placenta

- Warton's jelly only on one side --> Compression can occur on one side

- Can precipiate twin-twin transfusion syndrome

- Can kink the umbilical cord of the other twin --> Not a true twin-twin transfusion syndrome

- Placenta detaches prematurely

- Patient may or may not have vaginal bleeding

- Small abruptions can cause FGR

- Large abruptions can be fatal for fetus and occasionally even mother

- Mother would likely go into DIC afterwards

- CMV

- Rubella

- Varicella

- HIV

- Malaria

- Caused when virus is acquired in the first trimester of pregnancy --> Cell dropout --> Virus kills fetal cells

- Gestational malnutrition superimposed on pre-pregnancy malnutrition

- Cyanotic heart disease

- Chronic and severe pulmonary disease --> Asthma

- Severe anemia --> Sickle cell and malaria

- Uncontrolled hyperthryoidism --> Baby loses all calories via hyperthryoidism instead of growing properly

- Heavy cigarette smoking --> Smoking matters more when mom is older

- Cocaine

- Alcohol

- Coumadin

- Dilantin

- Chemotherapy

- Fetal asphyxia and death

- Prematurity

- Antecedent for adult disease in the future --> Hypertension, hyperlipidemia, CAD, and diabetes

- Being small and having to use calories wisely has long term effects --> Adult disease

- Unique to human pregnancy

- 3-5% of pregnancies

- Causes at least 50,000 deaths/year worldwide

- Cured by delivery of baby --> Caused by placenta

- Diagnosis: Hypertension (<140/90) in a previously normotensive mom, proteinuria, and excessive weight gain

- Edema of the feet and face, anasarca, ascites, and flash pulmonary edema possible

- HELLP Syndrome: Hemolysis, elevated liver enzymes, and low platelets

- Occipital edema --> Visual symptoms and headaches

- Swelling of Glissen's capsule --> Epigastric pain

- Abruptio placenta --> Hypertension in mom can blow placenta off

- Oliguria/anuria --> <600 mL urine/24 hours

- Fetal growth restriction

- Endpoint is usually hepatic rupture and maternal death

- Grand mal seizures caused by pre-eclampsia

- Very hard on the fetus --> Mother holds her breath and baby can become anoxic

- Nulliparity/Primapaternity

- Extremes of maternal age

- Vascular disease

- Insulin resistance

- Thrombophilia --> Double heterozygotes for Factor V Leiden and Prothrombin mutations

- Multiple gestations

- Molar pregnancy --> Placenta causes pre-eclampsia and molar pregnancies are primarily placental pathologies

- Ethnicity

- Prior history or family history of pre-eclampsia

- Results either from increased demand from baby or reduced ability to deliver by mom

1. Placental factors

- Abnormal implantation --> Abnormal production/availability of placental growth factor

- Placental abnormalities --> Failure of cytotrophoblasts to invade the spiral arteries of the maternal decidua, molar pregnancy, and fetal hydrops (fetal edema)

2. Fetal factors --> Multiple gestations

3. Maternal factors --> Reduced ability to supply fetus

- Hypertension, diabetic vasculopathy, or anemia

- Thrombophilia --> Anticardiolipin antibodies, lupus anticoagulant, Factor V Leiden mutation, Prothrombin mutation, etc

- Genetic predisposition --> Ethnicity, FHx, insulin resistance, and dyslipidemias

- Decreased prostacyclin (PGI2) and NO --> Vasodilators

- Increased thromboxane, TNF-a, and Interleukin-1 (IL-1) --> Vasoconstrictors --> Leads to hypertension etc --> Placenta and baby are trying to say give me more but mom can't

- Lots of similarities between maternal vascular pathology and the pathology of pre-eclampsia

- Don't really know the true etiology though

- Mismatch between fetal needs and maternal ability to supply

- Vasospasm --> Hypertension

- Capillary leak --> Edema

- Renal cell damage --> Proteinuria

- Microcoagulation --> Tissue ischemia and thrombocytopenia

- Evaluate the patient --> Physical exam, BP monitoring, lab tests, 24 hour urine collection

- Deliver if term pregnancy or pre-term with severe disease

- Administer magnesium sulfate --> Stops pre-term labor and prophyalxis for seizures

- Magnesium sulfate reduces eclampsia risk by 75%

- Mangesium sulfate is also neuroprotective for fetus --> First line to stop labor now

- Differentiation between complete and partial mole via p57 immunostaining --> Partial mole presents with p57 staining (maternal chromosomes present)

1. Complete Mole --> Only placental tissue results

- 90% 46,XX diploid --> Empty oocyte fertilized by diploid XX sperm

- 10% 46,XX or 46,XY --> Empty oocyte fertlized by two haploid sperm

- Histology: Diffuse edematous villi with cavitation and trophoblastic proliferation

- Significantly elevated serum hCG levels

- 2% progression to choriocarcinoma

2. Partial Mole --> Triploid or tetraploid zygote results

- Both fetal and placental tissue is present

- Chromosomally normal oocyte fertilized by two haploid sperm or one diploid sperm --> 69, XXY or 69,XXX

- Histology: Mixed normal and abnormal villi, focal syncytiotrophoblast proliferation, and stromal trophoblast inclusions --> No cellular atypia of the trophoblastic layer

- Elevated but lower hCG elevation from complete mole

- Very low risk of transition to choriocarcinoma

- Complex tumors

- Contains hair, sebum, bone, teeth, and skin

- No neural elements

- Typically found in the ovary

- May be present at birth

- 46,XX --> All of maternal origin

- Spermatogonia constantly arise from stem cell population

- Many cell divisions occur over time

- Risk of mutation --> 1 x 10-6

- Autosomal dominant single gene defects --> Increase with advancing paternal age --> Achondroplasia and Marfan's syndrome

- Human chorionic gonadotropin (hCG) --> Should increase 50% every 2 days

- Progesterone

- Estrogens --> Estrone (E1), Estradiol (E2), and Estriol (E3)

- Placental lactogen (hPL or hCS) --> Rises slower than hCG but ends up being higher later on

- Cholesterol transported into placenta

- Placental enzymes convert cholesterol to progesterone

- Progesterone is then transported back to mom or to baby

- Progesterone pool is then formed in both mom and baby

- Progesterone is produced in the corpus luteum for the first 6-8 weeks

- Then produced in the placenta for the rest of pregnancy

1. Estrone (E1) and estradiol (E2) production

- DHEA-s from mom and baby transported to placenta

- Sulfatase produces DHEA in placenta

- Aromatase produces E1 and E2 from DHEA

- E1 and E2 then transported to mom and baby

2. Estriol (E3) production --> Not produced by mom

- Fetal adrenal produces DHEA-S

- DHEA-S is transported to the liver --> 16a-OH DHEA-S produced in the livery

- 16a-OH DHEA-S transported to placenta

- Sulfatase produces 16-OH DHEA in the placenta

- Aromatase produces estriol in the placenta

- Estriol transported back into mom and baby

- Readjusts mom's metabolism

- Stimulates insulin resistance in mom --> Shunts glucose and amino acids to fetus instead of mom

- Negative feedback on the pituitary for GH release

- hPL secretion is directly proportional to placental weight

- Both CRH and POM-C genes are expressed in the placenta

- CRH acts at the level of placenta, fetal, and maternal pituitary

- Glucocorticoids have a positive feedback on placental CRH --> Higher levels --> Higher CRH release

- Stimulates placental growth and fetal growth

- Volume support for the fetus and amniotic fluid

- Nutrition for the fetus and placenta in the form of glucose, amino acids and oxygen

- Clearance of fetal waste

- Protection of the fetus from perturbations in the system

- Failure of adequate intravascular volume expansion --> Increased risk of having poor pregnancy outcome

- Greatest risk --> Renal disease and hypertension

- Pre-existing heart disease --> Predisposes to difficulty compensating for the normal increase in circulating blood volume

- Dangerous abnormalities --> Mitral valve stenosis and pulmonary hypertension/Eisenmenger's syndrome

- Tidal volume, minute ventilatory volume, and minute O2 uptake all increase

- Fetal Hb kinetics favor O2 unloading to the fetus

- Increased pO2 (95-105 mmHg) and pH (7.44-7.45)

- Decreased pCO2 (28-32 mmHg) and HCO3 (18-22 meq/L)

- Many pregnant women have the sensation of shortness of breath

- GFR and RPF increase during pregnancy

- 60-70% increase in filtered sodium load

- Decreased glucose resorption in the proximal tubule

- Urine volume in renal pelvis and ureters can double

- Renal disease and hypertension --> Poor volume expansion during pregnancy

- Glycosuria --> Even in the absence of glucose intolerance

- Pyelonephritis occurs in 40% of women

- Relative hyperinsulinemia --> Peripheral insulin resistance develops

- Increase in hepatic protein synthesis and P450 activity

- Increased calcium absorption 

- Entire GI tract relaxes

- Hypercoagulable state

- Increased thyroxine synthesis due to increased circulating thryoid binding globulin

- Nausea, vomiting, heart burn and constipation are common

- Mild dilutional anemia --> Fluid overload

- Modest leukocytosis --> Demargination and reduced diapedesis of WBCs into tissue

- Increased coagulability --> DVT/VTE most common in late pregnancy and postpartum

- Significant challenge for women with hemoglobinopathies

- Increased circulating thyroid hormone due to increased thyroid binding globulin

- Increased intestinal Ca absorption --> Increased active Vit. D

- Increased aldosterone and cortisole secretion

- Increased prolactin secretion and production by the pituitary

- Increased decidual prolactin production

- Cellular immunity decreases --> Specifically T-cell mediated response

- IgG crosses to fetus --> IgG receptor-mediated transport system

- Demargination for WBCs in peripheral blood

- Increased melanotrophic hormone (MSH) from POM-C cleavage

- Pigment changes occur

- Melasma --> Tan or dark skinned discoloration (papules/patches)

- Linea nigra --> Dark vertical line that shows up on the abdomen during the first 3/4 of pregnancy --> Disappears a few months after delivery

- Cervix thins, becomes effaced and dilates to 4-5 cm

- Some dilation and effacement occurs before labor actually begins --> Last few weeks of pregnancy

- Contractions usually last 30-45 seconds --> 5-30 minutes apart and much less severe

- Typically lasts 6-12 hours but can last a day or more

- Usually not necessary to be in the hospital at this point

- Contractions become more severe and more intense

- Cervix dilates 5-8 cm --> Labor usually progresses faster after 6 cm

- Should come to the hospital once contractions last 1 minute and are 3-4 minutes apart

- Contractions are 45-60 seconds and 3-5 minutes apart

- Stage lasts 3-5 hours

- Baby starts internal rotation at this point --> Anterior position or posterior position

- Posterior position can cause severe back pain in mother so try changing positions to get baby to turn

- Most intense part of labor but usually the fastest

- Occurs right before mom begins pushing

- Forceful contractions cause the top of the uterus to become thick to begin to push baby down

- Cervix dilates from 8-10 cm

- Common symptoms: Hot flashes, shaking, chills, nausea, and vomiting

- Quickly intensifies --> Contractions may have 2 peaks, last 60-90 seconds and are usually only 1-2 minutes apart

- Lasts 30 minutes to 2 hours

- Pushing stage of labor --> Birth of child

- Once cervix is fully dilated

- May fell the urge to push right away or the contractions may ease for 30 minutes or so

- Contractions last 60-90 seconds and are 3-5 minutes apart

- Lasts 20 minutes to 3 hours

- Uterus pushes the baby down --> Baby descends within the vaginal canal

- Negative to positive stations in relation to the body of the pelvis --> +5 station --> Babies head pushes out and then slips back out of the cervix

- Once the head is through the cervix --> Baby crowns and the labia squeeze the head so it doesn't slide back into the uterus

- Birth of the head --> Baby lifts it's head and extends chin --> Head turns to line up with the shoulders

- Top shoulder comes out then bottom shoulder --> Rest of the baby

- After birth

- Lay baby on mom's bare skin if baby is healthy --> Helps temp and blood pressure equalize

- Breast feeding within the first hour leads to better outcomes and better ability to breast feed in the future

- Intense labor contractions end with birth --> Milder contractiosn begin 5-20 minutes afterwards

- Placenta is then delivered and examined by the doctor

- Doc will then massage the top of the uterus --> Can be very painful but helps shrink the uterus and reduces bleeding

- Week 4-6: Mesenchymal milk crest and milk lines --> Accessory nipples may develop

- Weeks 12-16: Nipple and areola arise from smooth muscles cells

- Weeks 16-32: Breast tissue development

- Puberty: Multiple hormones interact to promote breast development --> Estrogen, progesterone, growth hormone, prolactin, adrenal steroids, and insulin

- Early pregnancy: Alveolar development --> Stimulated by BhCG

- Late pregnancy: Secretory differentiation --> Increased number of glands and accumulation of secretions in alveoli --> Stimulated by prolactin, estrogen, progesterone, GH, glucocorticoids, and insulin

- Colostrum: + lactose, ++ milk proteins, +++ immunoprotective proteins (IgG and IgA) --> Extremely nutritional and immunoglobulin dense

- Since IgG and IgA pass into breast milk --> Mom needs to be vaccinated for pertussis and the flu 

- Pertussis is highly lethal for neonates

- Histology: Much more dense glandular structures, lots of secretions, and lots of active WBCs (plasma cells)

- Childbirth --> Secretory activation

- Requires progesterone withdrawal from the delivery of the placenta --> Progesterone inhibits milk secretion

- Occurs 30-40 hours postpartum --> Delay until new mom's milke arrives --> Colostrum in the time being

- Volume: ~30 mL/24 hours --> First day

- Baby suckles --> Stimulates 4-6th intercostal nerves

- Signal travels up to brain --> Stimulates prolactin and oxytocin secretion from the pituatary

- Prolactin --> Milk production

- Oxytocin --> Ejection/drop reflex

- Intercostal nerve damage --> Random, unilateral milk production even without pregnancy

- Hypothyroid patients --> Milk production due to decreased negative feedback for TSH

- Lactose

- Milk proteins

- Immunoprotective proteins

- Fats

- Electrolytes

- Vitamins

- Minerals

- Water

- Delivers 60-75 kcal/dL

- Immediately: Decreases postpartum blood loss --> Accelerates uterine involution

- Short-term: Weight loss and postpartum anovulation

- Long-term: Decreased risk for breast and ovarian cancer as well as diabetes

1. Direct effects

- Decreased risk of illness --> IgA and IgG transmission

- Reduces risk of diarrhea, upper and lower respiratory tract infections, acute and recurrent otitis media, and UTIs

2. Long term effects

- Decreased risk for acute illnesses

- Decreased obesity, allergies, GI infections, leukemia, and type I diabetes

- American Academy of Pediatrics strongly recommends breast feeding for at least the first 6 months postpartum

1. Maternal

- Drug or alcohol abuse

- HIV+

- Active and untreated TB

- Certain prescription drugs

- Active breast cancer treatment

- Some active infections

2. Infant

- Galactosemia --> Inability to break down galactose in breast milk

- Estrogen and progesterone withdrawal leading to:

1. Glandular atrophy

2. Decreased number of lobules

3. Accumulation of adipose tissue

4. Adipose tissue > functional tissue

- Mammograms are now easier to interpret --> Fat is black on x-ray so reading against a black background instead of a grey background

1. Engorgement

- Early --> Within 3 days of birth --> Swollen lumpy and tender breasts --> Inadequate infant latching

- Late --> Accumulated milk due to missed feeding/weaning

- Treatment: Empty breasts (feedings/pumping), cool or warm compresses

2. Sore Nipples

- Sensitivity is normal --> Usually subsides within 30 seconds and resolves within 1 week postpartum

- Traumatized nipples and significant pain can result

- Treatment: Proper latching technique, moisturizer, and nipple shield

- Any abrasions/cracking can lead to infections --> Mastitis

- 3-10% of lactating women

- Typically unilateral

- Symptoms: Pain, tenderness, erythema over infected area, and fever >101 F

- Organisms: S. aureus, Streptococci, and E. coli

- Treatment: 4 weeks of antibiotics --> Dicloxicillin 500 mg QID, Keflex 500 mg QID, and Clindamycin 300 mg QID, NSAIDs, continued breast feeding/emptying, and warm/cool compresses

- 5-10% mastitis cases develop into an abscess

- Treatment: Serial drainage with culturing and 4-6 weeks of antibiotics

- Broaden antibiotic coverage --> Augmentin 875/125 mg QID, Clindamycin 300 mg QID, or Keflex+Flagyl 500 mg TID

1. Non-proliferative

- Simple cysts, usual hyperplasia --> Doesn't increase risk of breast cancer

2. Proliferative without atypia

- Fibroadenomas --> Doesn't increase risk for breast cancer

- Ductal and intraductal hyperplasia, intraductal papillomas, radial scars, and sclerosis adenosis --> 1.5-2x breast cancer risk

3. Atypical hyperplasia --> 3.7-5.3x breast cancer risk

- Breast pain

- Minor cyclic pain related to the menstrual cycle

- Common

- DDx: Breast pathology, hormone therapy, and referred pain

- Risk of malignancy is extremely low in the presence of normal imaging and breast exam --> Most cancers don't hurt either

- Treatment: Warm compresses, NSAIDs, trial of vitamin E, evening primrose oil, and weight loss/exercise

- Avoid: Caffeine and underwire bras

- 50-80% of reproductive age women can express discharge from their nipple is they try hard enough

- Increased risk of breast cancer if discharge is:

1. Bloody

2. Unilateral/uniductal

3. Spontaneous

4. Associated with breast mass

5. Occurs in women over 40 years of age

- Evaluation: Medication review, TSH, prolactin, and BhCG levels, occult blood test, gram staining/culture, cytology, and imagin

- Abnormal milk production from the breast

- May be caused by hyperprolactinemia

- 45% of presenting women have normal prolactin levels

- Represents milk secretion following lactation and treatment for hyperprolactinemia

- Milky, green or black fluid is ok

- Bloody fluid is NOT ok

- Discoloration, scaling/crusting, ulceration, dimpling, and edema

- Paget's Disease of the Breast: Redness and ulceration of the breast are worrisome

- Requires a punch biopsy for concerning lesions

1. Proliferative Phase

- Active growth of glands, stroma and vessels --> Tubular pseudostratified glands

- Influenced by estradiol production by the granular cells in the ovary

- Multiple mitoses present and variable stromal changes

2. Ovulation

3. Secretory Phase

- Lots of mitotic activity in the pseudostratified epithelium --> Subnuclear vacuoles within cells

- Reflects the effect of the combined production of progesterone and estradiol

- Produced by the luteinized granulosa and theca cells of the corpus luteum

4. Menstrual Phase

- Dissolution of the corpus luteum

- Lack of progesterone leads to the sloughing off of the endometrial layer

1. Early Secretory Phase

- Day 17 --> Rows of subnuclear vacuoles with no mitoses

- Day 18 --> Sub and supranuclear vacuoles with apical discharge

2. Midsecretory Phase

- Basal nuclei with scattered supranuclear vacuoles

3. Late Secretory Phase

- Secretions present inside the gland lumen

- Saw-toothed glandular appearance

- Tubular glands with rare mitoses present

- Lower portion of the stratum functionalis breaksdown

- Blood escapes from the stroma marking the beginning of menstrual shedding

- Blue clusters become present within the stroma

- Surface breakdown and regeneration begins to occur

- Primary malignant epithelial tumor of the uterus

1. Endometrioid type: 80% present in menopasual women

- Estrogen dependent tumors

- Endometrial hyperplasia is the precursor lesion

- Degree of differentiation: 5% or less (G1), 6-50% (G2), and >50% (G3)

2. Non-endometrioid type: Serous, clear cell, and high grade variants present

- 20% present in older postmenopausal women --> 80% younger women

- Non-estrogen dependent tumors

- High grade/more aggressive tumors

- Papillary serous carcinoma --> High grade carcinoma --> May present with myometrial and lymph node involvement

- Etiology: STDs, pre-pubertal, post-abortion, or post instrumentation procedure

- 2-7 days: Acute inflammation with vaginal exudate is present --> Ascending spread to tubo-ovarian region --> Acute suppurative salpingitis

- Days to weeks: Fimbria of fallopian tubes seal off the opening --> Become adherent to ovaries --> Pyosalpinx, salpingo-oophoritis, and tubo-ovarian abscesses

- Etiology: Chronic PID, postpartum, intrauterine device (IUD), tuberculosis, and non-specific

- 15% due to Chlamydial infection

- Histology: Lots of plasma cells seen within the stroma

- Actinomyces infections are highly associated with IUD implantation

- Typical non-caseating granuloma formation with TB infection

- Malignant mesenchymal tumor of the uterus

- Really disorganized structure

- Less well circumscribed mass

- Nuclear and cytologic atypia present

- Lots of strange mitotic figures

- Any central necrosis is always malignant

- 50% subsequent to molar pregnancy, 25% subsequent to spontaneous abortion, 2.5% subsequent to ectopic pregnancy and 22.5% subsequent to normal pregnancy

- Highly malignant tumor of placental origin --> Cytotrophoblast and syncytiotrophoblast derived

- No villi are present

- Produces hCG

- Primary tumor in the uterus may regress quickly and may only present with metastatic disease

- Treatment: Chemotherapy --> Extremely responsive

- 12 months of amenorrhea

- Symptoms result from estrogen withdrawal

- Premature ovarian failure/insufficiency: Menopause before the age of 40

- Etiology: 90% idiopathic, genetic defects (Turner's syndrome, etc), ovarian toxins (chemo, radiation, mumps or CMV), autoimmune disease, or abnormal follicular stimulates (FSH receptor mutations)

- Evaluation: FSH, hCG, prolactin levels, thyroid hormone analysis, adrenal analysis, karytoyping, FMR1 premature screen, and baseline DEXA (bone) scan

- Treatment: Psychosocial support, prevention of osteoporosis (HRT, DEXA scans, weight bearing exercise, and supplementation), monitoring thyroid and adrenal function, contraception, and IVF if fertility is desired

- Patients with premature ovarian failure and much more likely to develop thyroid and adrenal failure --> Need yearly TSH and adrenal hormones

- 5-10% of POF patients will actually conceive naturally due to spontaneous ovulation --> Need contraception if pregnancy is not desired

- Donor oocytes if pregnancy is desired

- Average age --> 51.4

- Presents earlier in Latina women and later in Japanese-American women --> Possibly due to the increased soy consumption by Japanese

- Presents about 2 years earlier in smokers

- Presents earlier in nulliparas and regularly cycling women

- Symptoms can vary throughout cultures

- Menopause is a happy time in African culture but is a terrible thing that women have to go through in the US

- Follicular depletion in the ovary --> Precipitous loss ~ age 38-40 years

- Fall in inhibin B concentrations --> Risk in serum FSH levels

- Estradiol secretion intially is normal or high but declines over time --> Increased FSH levels initially stimulates lots of estradiol production

- Changes in CNS responsiveness --> Stimulation of Chemothermal zones --> Hot flashes

- Vasomotor symptoms --> Hot flashes (75%), night sweats, and sleep disruption

- Amenorrhea or oligomenorrhea

- Vaginal and breast atrophy with urinary symptoms

- Decreased bone mineral density --> Increased risk of osteoporosis and fracture risk

- Cardiovascular changes --> Increased risk of atherosclerosis --> Estrogen is cardio protective

1. Vasomotor symptoms: Estrogen supplementation with intermittent progesterone is uterus still present, SSRIs, gabapentin, and clonidine

- Hormone replacement therapy shows the highest efficacy when initiated shortly after menopause (within 10 years)

- Bioidentical horomones: Hormone cream compounded based on individual salivary levels of estrogen and progesterone --> Individualized so very expensive and not recommended by professional societies

2. Vaginal dryness: Vaginal estrogen preparations, lubricants, and ospemifine (vaginal SERM) --> Agonist in the vagina but antagonist in the breast and uterus so no increased risk of breast/uterine cancer

3. Decreased bone density --> Assess bone mineral density via DEXA and treat based on risk

- Low bone mass and microarchitectural deterioration

- Increase in bone fragility and susceptibility to fractures

- Epidemiology: 1.5 million fractures/year --> Costs $17 billion/year --> 1:3 lifetime risk for vertebral fracture and 1:6 lifetime risk for hip fracture in white women >50

- 1/10 - 1/5 of women with a hip fracture die within a year

- 1/4 of these patients end up in a nursing home permanently

- T score: SDs between patient and average peak young adult

- Z score: SDs between patient and average bone mass for same age and weight

- Osteoporosis: T score <-2.5

- Osteopenia/low bone mass: T score -1 - -2.5

- Fracture risk doubles with every SD decrease

- Evaluation: Dual-energy x-ray absorptiometry (DEXA) bone scan --> Scans spine and hip to predict fracture risk and monitor therapy

- Weight bearing exercise

- Quitting smoking

- Dietary modification --> Increase calcium and vitamin D intake

- Medications: Bisphosponates (first line), selective estrogen receptor modulators, and estrogen replacement therapy

- SERMs are generally not well tolerated because they cause serious hot flashes

- Monitor therapy with DEXA of spine/hip 

- 40% of women report sexual complaints

- 12% (1 in 8) have a sexual problem associated with distress

- Forms: Lack of sexual desire, impaired arousal, inability to achieve orgasm, and pain with sexual activity

- Vaginal dryness, dyspareunia, low desire and decreased arousal are more common after menopause --> More common in early menopause and normalizes over time

- Tailor management to the sexual problem

- Assess for conditions that alter sexual function

- Suggest lifestyle changes, sex therapy or psychotherapy

- Postmenopausal vaginal dryness --> Vaginal estrogen preparations, lubricants and ospemifene

- Postmenopausal women with hypoactive sexual desire --> Testosterone trial (very experimental)

- Arousal or orgasm disorder due to SSRIs --> Phosphodiesterase inhibitor