REI Flashcards
What is congenital adrenal hyperplasia?
most common cause of ambiguous genitalia. also causes hirsutism.
46 XX, clitoral enlargement, labial fusion, urogenital sinus.
-AR inheritance. 2/2 21 hydroxyls deficiency. obstructs cortisol production and no negative feedback to switch off ACTH. excessive precursor “sidetracks” in direction of androgen production.
-mild to severe disease.
ddx: high 17-OHP.
In new borns, causes shock 2/2 insufficient cortisol. salt-wasting in severe forms 2/2 inadequate aldosterone.
What is puberty?
2 main events:
- gonadarche: FSH/LH activate ovaries
- adrenarche: incr androgen production by adrenal cortex.
What are the stages of puberty in chronological order?
Growth spurt
thelarche - breasts
Pubarche: pubic hair
Adrenarche: onset of androgen dependent changes - axillary and pubic hair growth, body odor, acne
Menarche: Tanner IV or 2-3 years after thelarche.
- normal cycle takes 2-3 yrs to become regular after menarche but can take up to 6.
What are situations to evaluate amenorrhea?
No menses within 3 years of thelarche
No secondary sex development by age 13
Age 14 w/ hx eating disorder
age 14 w/ hirsutism
Age 15 regardless of development
>90 days without menses in menstruating adolescent.
Precocious puberty: occurs 2.5 standard deviations earlier than mean age. age 7 in whites and age 6 in blacks.
Delayed puberty: no breasts by age 12-13
What is life cycle of hair follicle?
ACT!
Anagen - active phase of hair growth
Catagen - involution of epithelial cells surrounding dermal papilla
Telogen - resting phase (hairs fall out with initiation of anlagen)
What is differential diagnosis of hirsutism and what is workup?
familial, PCOS, CAH,
Tumor (ovary or adrenal)
drugs (androgens, danazol)
Hypothyroid, elevated prolactin
Cushings
Workup:
- total testosterone (r/o ovarian/adrenal issues)
- DHEAS (r/o abnormal adrenal function)
- 17-OHP (r/o CAH)
What is treatment of hirsutism?
- OCP (decr androgen and incr SHBG so less free androgen)
- spironolactone (blocks androgen receptor and inhibits 5-alpha reductase)
- Finasteride (5-alpha reductase inhibitor inhibits conversion of testosterone to DHT)
- Flutamine (competitively androgen R antagonist -blocks androgen receptor)
- Vaniqua/eflornithine - blocks ornithine decarboxylase
- laser hair removal
-weight loss : increases SHBG
What is primary amenorrhea?
No menses by age 13 w/o secondary sex characteristics
- No menses by 15 WITH secondary sex
- no menses before age 15 w/ secondary sex + cyclic pelvic pain (r/o outflow tract obstruction)
Causes are divided into :
1. presence or absence of breast development (marker of estrogen/ovarian function)
2. presence/absence of uterus
3. FSH level (POI)
- pregnancy, PCOS, thyroid or prolactin issue, stress-induced, non-congenital CAH
Causes of primary amenorrhea w/ uterus present
- Breast present (estrogen present)
- hypothalamic
-pituitary (prolactinoma)
- ovarian causes
- uterine causes/outflow tract obstruction - Breast absent (estrogen absent)
- Gonadal failure (hypergonadotrophic hypogonadism): Turner’s, mosacisim (X/XX), pure XX/XY gonadal dysgenesis (usually tall), 17-alpha hydroxylate deficiency (rare)
- CNS-hypothalamic-pituitary (hypogonadotrophic hypogonadism): CNS lesions (pituitary adenoma), Kallman’s (hypothalamic failure 2/2 inadequate GnRH), isolated gonadotrophin deficiency, constitutional delay
Causes of primary amenorrhea w/ uterus absent
+breasts:
- vaginal agenesis (Rokitansky-Hauser syndrome): nl pubic hair
- androgen insensitivity (XY): remove gonads after puberty, short/absent vagina, sparse pubic hair.
- breasts:
- XY, agondaism, 17 alpha hydroxylate deficiency
What is the workup of primary amenorrhea?
physical exam: absence of breasts/uterus, hirsutism
HCG
FSH
TSH
PRL
E2/FT4
Pelvic US
MRI in complex cases
What is secondary amenorrhea and causes?
no menses for >3 months in females w/ normal menstrual cycles or >6 months if irregular cycles
- pregnancy!
- Thyroid (hypo OR hyper)
- hyperprolactinemia (lactation, prolactinoma, meds)
- PCOS
-CAH - Stress/exercise
- weight loss/anorexia
- meds (psychotropics)
- POI + fragile X premutation
- androgen secreting tumors
ACTH/GH secreting tumors
hypothalamic lesions: cranioipharyhgioma/TB - Sherman’s syndrome
What is workup of amenorrhea?
- r/o pregnancy
- History: stress/nutrition/weight/meds/sx of hypo estrogen. If galactorrhea: TSH/PRL
- Exam: mullerian structures present?
– short/blind ending vagina: Mullerian agenesis (Mayer Rokitansky), androgen insensitivity (Total testosterone and karyotype), vaginal agenesis/transverse vaginal septum. Cervical atresia (pain/hematometra)
– Normal vagina + cervix:
- TSH/prolactin
- FSH/estradiol
- progesterone withdrawal challenge: 10mg provera (medroxyprogesterone acetate) for 10d:
– if +bleed and nl labs=anovulation (have endogenous estrogen and no outflow tract obstruction)
– If no bleed and nl labs: low estrogen or outflow tract issue (adhesions or scarring)—> E+P challenge.
- E+P challenge: estrogen x 14d then estrogen + progesterone x 10d. If bleeds, not making adequate estrogen. If no bleed, abnormal outflow (Asherman’s, anomaly).
What are FSH/LH/estradiol levels?
FSH: nl 5-30.
LH: nl 5-20.
Estradiol: low is <50
What is workup of primary ovarian insufficiency?
POI: depletion of ovarian follicles w/ cessation of menses before age 40.
2 random tests 1 month apart (CANNOT DO IF ON OCPs):
- elevated FSH/LH and E2 <50 | Typical FSH 30-40, E2<50
- neg pregnancy test
- nl PRL, TSH
If age <30, get karyotype
- 50% is 45 XO=Turner’s
- 25% = 46 XX=Gonadal dysgenesis/agenesis
-25%= 46 XX/XY=Y mosaics (need gonadectomy 2/2 incr cancer risk w/ Y chromosome. eg. gonadoblastoma, dysgermimoma, choriocarcinoma)
If age 30+:
- autoimmune (thyroid, RA, SLE, myasthenias)
- fragile X premutation
- galactosemia
- 17-hydroxylase deficiency (absent secondary sex characteristics)
- perimenopause: incr FSH, nl LH. rpt assays
What is workup of normal FSH/LH assays in amenorrhea?
Workup of low FSH/LH assays?
presentation same as pituitary/hypothalamic failure.
For low: suspect pituitary/hypothalamic issue
- MRI pituitary positive: manage tumor/empty sella syndrome
- MRI normal: hypothalamic amenorrhea (suppression of GnRH pulsatile secretion)- stress/weight/exercise/psychiatric/kallaman syndrome.
What is primary ovarian insufficiency?
What are causes and workup?
cessation of menses by age 40
- Chromosomal (gonadal dysgenesis +/- Turner’s)
- damage from chemo/radiation
- Endocrinopathies: hypoPTH, hypoadrenalism
- Autoimmune
prior pelvic surgery
If confirmed ddx:
- karyotype, FMR1 permutation, adrenal antibodies (if pos, yearly corticotrophin stem test due to risk of adrenal insufficiency), pelvic US, TSH/TPO Ab (20% develop Hashimoto’s)
What is treatment of POI?
- goal: preserve bone, cardiovascular and sexual health
Risks: hypoestrogenism -> osteoporosis, CVD, cognitive impairment, all-cause mortality, genital atrophy, vasomotor sx.
0.1 mg/day transdermal estradiol + cyclic progesterone x 10-14d/month
- 5-10% can spontaneously conceive. still need contraception
- if adolescent, specialist for hormone therapy for puberty.
- treat until 51-52 years of age.
When does fertility decrease?
What is change of live birth for IVF with own eggs for age 40+? With donor eggs
Risk factors associated with premature decline in fertility?
Fecundity decreases at age 32! Accelerates at age 37.
40+ can be referred immediately
12% with own eggs, 51% if egg donor.
What if using eggs from egg donor? 51%
Smoking, prior ovarian surgery, chemo/radiation, family history of early menopause, endometriosis
What is risk of miscarriage if iVF preg? 30%
What is mechanism of increase in autosomal trisomy in older women?
Incr risk non-disjunction due to changes in meiosis.
What is workup for infertility
infertility is failure to achieve pregnancy within 12 months of unprotected intercourse or donor insemination. affects 15% of couples (male factor is 40% of infertile couples).
at any age if anovulatory, male hx infertility or <40
- age <35, 12mo of attempting w/o success. age >35, 6 mo.
- can start workup immediately if 40+
- history (menses, intercourse, counseling on costs/multiple visits/REI), PMH, fam hx -genetic issues. any STI, recent US? Any prior form of contraception. How long trying to get pregnant
Partner testing for infertility.
- TEST OVULATORY DYSFUNCTION:
- mid luteal (day 21) progesterone: nl>3
- urine LH kit : some false pos/neg - TEST TUBAL STATUS
- HSG
- laparoscopy w/ chromopertubation - TEST SEMEN
- semen analysis (Volume – 1.4 mL, total # 40 million, morphology 4% normal) - TEST OVARIAN RESERVE
- day 2-3 FSH >10 or E2>60-80
- AMH: <1 abnormal - perform anytime - predicts response to ovarian stimulation. secreted by ganulosa cells of follicle.
- antral follicle count day 2-5: <3 abnormal
- clomid challenge test day 10. If FSH >22, abnormal - UTERINE FACTOR
- TVUS, HSG, hysteroscopy, saline SIS. look for polyps, synchiae, mullein anomalies.
What are risk factors for decreased ovarian reserve?
- age > 35
- Fam hx early menopause
- genetic condition (i.e. 45 XO turner)
- FMR-1 permutation
- prior ovarian surgery
- oophorectomy
- hx chemo/RT
- smoking
means less response to ovarian stimulation.
- onset of LH surge to ovulation: 36hrs
- LH peak to ovulation: 12 hrs.
What is mechanism of action of methotrexate?
dihydrofolate reductase inhibitor
- cofactor for DNA and RNA synthesis.
- acts on rapidly dividing trophoblast cells
What is mechanism of action for tamoxifen?
SERM
anti-estrogen and pro estrogen in different parts of body
- Anti-estrogen in breast
- pro estrogen in bones and endometrium
What is mechanism of action of clomiphene
anti-estrogen (SERM). competes w/ estrogen-binding R.
- partial agonist in hypothalamus, incr GnRH release and FSH/LH to stimulate follicle development
- dose: 50mg for 5d on day 5. If no ovulation, increase to 100mg/d for 5 days. monitor ovulation by predictor kit or mid-luteal progesterone. Once ovulated, continue dose for 4-6 cycles.
sex every other day starting 5d after last dose. for 5-7d. - ovulation occurs 5-10d after last tablet.
- test ovulation w/ menses or with serum progesterone
- 70% will ovulate, of those who ovulate, 30-40% will conceive.
- SE: vasomotor sx, HA, dizziness, blurred vision (STOP bc could be optic neuropathy), decreased cervical mucous and thin endometrium
What is mechanism of letrozole?
What is dosing?
Aromatase inhibitor
- blocks synthesis of estrogen which reduces feedback at pituitary and increases FSH.
- 1st line for oligo-ovulatory w/ PCOS.
- SE: hot flashes, fatigue, dizziness
- benefits: higher rate mono follicular development (less multiples), no direct anti-estrogen effects on endometrium.
- dose 2.5mg/d for 5d on day 3 of cycle, increase at 2.5mg increments.
What is mechanism of action of gonadotropin?
FSH or combination of FSH and LH
- acts on fSH receptors to stimulate follicular growth
- use LH w/ hypothalamic amenorerhea
what is mechanism of action of leuprolide (lupron)?
GnRH agonist produces CONTINUOUS exposure (not pulsatile) of GnRH -> reduces FSH.
Indications:
- tx endometriosis or CPP, shrink fibroids pre-surgery, increase blood count pre surgery, precocious puberty to switch off stimulation, thin out endometrium prior to ablation.
- SE: osteoporosis if use >6 mo, vasomotor sx, vaginal dryness.
What is mechanism of action of GnRH antagonists
competitively and reversibly bind GnRH-R in pituitary, block FSH and LH.
- SE: hypoestrogenic sx
-Indications: endometriosis, fibroids, infertility for SUBQ injection
What are the copper and progesterone IUD?
Copper: 10yrs, inhibits sperm migration, +emergency contraception
Progesterone: Levonorgestrel 52mg, use for 8 years. SE: hormonal (breast tenderness, nausea, depression). inhibits sperm migration, alters cervical mucus, suppresses endometrium.
– decreases HMB, dysmenorrhea, anemia, endometriosis pain, risk of PID, risk of endometrial cancer, treats endometrial hyperplasia.
CONTRAINDICATIONS: pregnancy, PID, undiagnosed vaginal bleeding, genital tract malignancy, uterine anomalies, copper allergy, any of this in past 3 months (PP endometritis, septic AB, PID).
What are the non-contraceptive benefits of the OCP?
regular menses
less blood loss esp w/ fibroids
decr IDA
decr PID
decr dysmenorrhea
decr endometrial and ovarian cancer
decr functional ovarian cysts and benign breast disease
tx for endometriosis
tx for hyperandrogenism
What are recs for OCPs w/ common medical issues?
OK to use to age 50-55 if no contraindications
- HTN: not if >160/100 or vascular disease. POPs ok.
- lipid disorder: low dose (<35mcg ) ok if well controlled. monitor lipids frequently. oral estrogen incr TG
- DM acceptable unless microvascular disease. avoid depo
- migraine w/ aura: stroke risk increased. use pOP or IUD
- fHx breast cancer: okay! doesn’t incr risk for BRCA 1 and 2.
What are absolute contraindications for OCP?
- breast cancer
- any estrogen sensitive tumor
- pregnancy
- unexplained vaginal bleeding
- known inherited thrombophilia.
- thrombosis
- smoker age 35+
- liver disease
- CHD
- first 21days postpartum
- migraines w/ aura
- severe HTN
- DM w/ vascular dz or disease <20yr duration
- SLE w/ APL Ab
How do you counsel on elevated FSH in infertility?
ovarian reserve is decreased, decreases ability to respond to ovarian stimulation.
What is workup for primary ovarian insufficiency?
rule out genetic causes: karyotype, FMR1 premutation, adrenal Ab
- Pelvic US
If Turner’s, pregnancy contraindicated 2/2 high cardiac risks.
Donor egg IVF best option or adoption.
what is the evaluation for primary amenorrhea?
H&P
Confirm normal vagina, cervix, uterus (US or MRI)
- If blind vagina, obtain karyotype and testosterone (Mullein agenesis vs androgen insensitivity
- If normal outflow tract: hormonal eval (HCG, TSH, FSH, PRL)
- If hyperandrogenism: testosterone, DHEA-S, 17-OHP
- If normal/low FSH: central hypothalamic or pituitary process: consider cranial MRI
- If high FSH: karyotype for Turner’s, FMR1 permutation and adrenal Ab for POI
Treatment:
- remove gonads if Y chromosome 2/2 cancer risk
- correct outflow tract obstruction (transverse vaginal septum)
- hormone replacement for gonadal dysgenesis
- correct underlying abnormality: TSH, PRL.
What is the differential for abdominal pain/distension?
Pregnancy, PID, fibroids, TOA, ectopic pregnancy. GI: diverticulitis, post-op ileus, constipation, IBS.
If pt had recent ovarian stimulation w/ REI, how would you manage new onset abdominal pain/distension?
Concern for ovarian hyperstimulation syndrome. Shift of serum from intravascular space to abdominal cavity 2/2 follicular stimulation
If mild: CBC, BMP, US. abdominal distension, mild N/V, diarrhea. Tx=tylenol, AVOID NSAIDS
Mod: US w/ ascites. Monitor weight and urine uOP
Severe: Hct>55, Cr>1.6, severe abdominal pain, N/V, rapid weight gain, VTE, oliguria. VTE prophylaxis. Resolves in 10-14d, longer if pregnant. Can cause stroke, loss of perfusion to extremities.
anticoagulation, correct electrolyte abnormalities. Inform their REI.
What increases risk for OHSS?
PCOS, prior episode, AMH>3, antral follicle count >8, high # oocytes retrieved, pregnancy, high estradiol level,
How many oocytes at birth?
42 y/o with desired fertility. What is chance of live birth with IVF?
What if IVF with eggs from young healthy donor?
1-2 million. Declining number as we age.
At menopause: thousands.
12%
51%
What factors affect fertility?
- Ovarian factor: prior chemo/RT
- Uterine factor: Prior pelvic surgery, Asherman’s (hysteroscopic resection then place foley to maintain cavity + vaginal estrogen to prevent adhesions), Mullerian abnormality , Leiomyoma, Endometriosis, Pelvic infection
- Tubal factor: PID
- Male factor - know specifics on semen analysis
Sperm count: 39 million is minimum for normal - Female factor: age, Smoking, obesity, meds, Fragile X
Besides fertility, what risks increased for older women attempting to conceive?
What is the mechanism by which autosomal trisomy increased in older women?
HDP, DM, SAB, fetal anomalies, CD
Changes in meiotic spindle predispose to non-disjunction
Diagnostic criteria for PCOS?
- Hyperandrogenism
- ovulatory dysfunction
- polycystic ovaries (in one or both ovaries, either 12+ follicles measuring 2-9mm or increased ovarian volume (greater than 10cm3)
What are types of uterine anomalies?
Arcuate
Septate
Bicornuate
Didelphys
Unicornuate
Arcuate: A minor irregularity in the shape of the uterus, causing a small dent in the top.
Septate: The uterus is divided by a band of muscle or tissue creating two separate cavities within the uterus.
Bicornate: Similar to a septate uterus, a bicornate uterus also known as “heart-shaped,” has two cavities created by a wall of tissue, but also has an external fundal indentation of more than 1cm.
Didelphys: Additionally known as a “double uterus”, women with this rare abnormality have two separate uteruses with smaller cavities than a normal uterus. Each uterus has its own cervix, fallopian tube, and ovary.
Unicornuate: This abnormality is classified by only one half of the uterus developing, resulting in only one fallopian tube
Pregnancy risks: SAB, PTL, malpresentation, CD
What is recurrent pregnancy loss?
What are causes?
What is workup?
> 2 spontaneous pregnancy loss
incidence: 5%
baseline incidence of SAB: 10%
Causes:
- Uterine anomalies: congenital (septate=worst), acquired (fibroids, polyps)
- genetic (balanced translocation, robertsonian translocation, mosaicism)
- Hormonal (thyroid, DM)
- Environmental (smoking, drugs, obesity)
- APLS
- unexplained: in 50% cases.
Workup:
- history (family pedigree, maternal hx, exposures)
- physical (inspect placenta, autopsy of fetus)
- Labs: a1c, TSH, APLS labs, karyotype of parents and fetus, sono-hysterogram/US
