Presentation on theme: "Crushing the Creogs Rapid Primer. High Yield Amenorrhea Abnormal puberty (delayed and precocious) Embryology."— Presentation transcript:
Crushing the Creogs Rapid Primer
High Yield Amenorrhea Abnormal puberty (delayed and precocious) Embryology
Embryonic Sexual Determination Embryo bipotent at 5 wks Karyotype –XY vs XX –SRY Gene (TDF) XX No SRY Normal female Normal Male XY SRY
Embryonic Sexual Determination XX XY (with SRY) Ovary Testes at 6 weeks Sertoli Leydig Anti Mullerian Hormone Testosterone DHT Dev Ext Male Ispilateral regressesion Dev. Int. Male, ipsilaterally
“Default” pathway Ovaries develop separately
Summary of Sex Determination Embryo is bipotent at 5 weeks. If male (SRY, AMH, Testosterone/DHT) starts male differentiation at 6 weeks. If no male differentiation female is default pathway.
Age GonadotropinGonadotropin Prepubertal Physiology + - Increasing weight, fat mass
Normal Puberty - Gonadarche Suppression of the gonadostat decreases.* Nocturnal pulses in GnRH lead to: Increasing FSH (then increasing LH) levels lead to: Increasing androgens and estrogen, leading to: –Everything we associate with puberty.
Timing of puberty is largely genetic Estrogen Breast Development and Androgens Pubic Hair Bone Growth
Measurement of Puberty: Tanner Stages There is NO stage Zero!
Order of Pubertal Events Growth spurt / Breasts Pubic hair Maximum growth velocity Menses aka “Boobs, pubes/pits and pads”
Normal Puberty - Adrenarche Independent of HPO axis. Trigger unclear Generally precedes changes associated with puberty. Increase adrenal androgens: DHEAS and A. Mechanism: increased 17,20 lyase activity. Appearance of Pubic Hair
Continuous process Occurs in “waves” Stimulus/mechanism unknown Independent of gonadotropins –Occurs in prepubertal ovary –Uninterupted by pregnancy, OCP Ends with follicular depletion Preantral Follicle Initiation of Follicular Growth
FSHLHIU/L E 2 pg/ml Png/ml LH FSH E2E2E2E2 P OvulationMenses
GrowthAtresia Timely gonadotropin stimulation can promote further growth –Intercycle rise in FSH crucial for continued development Without gonadotropin support, doomed to atresia Preantral Follicle In Delicate Balance
Dominant Follicle Selection “Survival of the Fittest” Selected follicle –More and larger cells –more FSH receptor and greater sensitivity to falling FSH –more aromatase Advanced vascular development provides preferential delivery of FSH and LDL substrate
LH FSH P Plasmin Collagenase PG PB Smooth Muscle Fibers Ovulation OMI PG LI LH LH stimulates meiosis, luteinization, and PG production P enhances proteolytic enzymes FSH stimulates expansion of cumulus and plasmin to stimulate collagenase
Estradiol Progesterone Corpus Luteum Follicle wall becomes convoluted Luteal cells enlarge, acquire lutein pigment and lipid Capillary network penetrates granulosa Production of large amounts of both E & P E & P act centrally and locally to suppresses new follicular growth
Corpus Luteum Requirements for Normal Luteal Function Optimal preovulatory follicular development - luteal cell mass –Adequate follicular phase FSH Tonic LH stimulation LDL cholesterol substrate
FSHLHIU/L E 2 pg/ml Png/ml LH FSH E2E2E2E2 P OvulationMenses Ovarian Cycle Conception hCG
Normal menses days 2-7 days of flow 35ml (mean) <80 cc of non-clotting debris.
Terminology of Precocious Puberty GnRH - Dependent aka True Precocious Puberty aka Central Precocious Puberty GnRH - Independent aka Precocious Pseudopuberty aka Peripheral Precocious Puberty Isolated Precocious Development
Precocious Puberty Bone Age guides therapy. Bone age, bone age, bone age Typically, once menses have started, growth is limited to 6 cm more. Mature Axis: GnRH stim test LH > FSH rise. Prepubertal: GnRH stim test FSH > LH rise.
GnRH Dependent female male Idiopathic74%41% CNS problem 7%26% GnRH Independent Ovarian (cyst or tumor)11% n/a Ovarian (cyst or tumor)11% n/a Testicular n/a10% McCune-Albright 5% 1% Adrenal feminizing 1% 0% Adrenal masculinizing 1%22% Ectopic gonadotropin 0.5% 0.5% Hypothyroidism Hypothyroidism Exogenous Steroids Etiologies of Precocious Puberty
1° Steroid Elevation Tumor –Ovary may produce estrogens, androgens, hCG - typically causing heavy irreg. bleeding 80% have palpable mass granulosa, theca, gonadoblastomas, teratomas, lipoid cell, cystadenomas, epithelial cancer –Feminizing Adrenal Tumor very rare, usu. associated with DHA-S
McCune Albright Syndrome aka polyostic fibrous dysplasia Mechanism: –Activating mutation of G s resulting in unregulated cAMP formation. –Somatic mosaic mutation, therefore not lethal and variable phenotype. Classic Triad: –cystic bone lesions causing easy fracture - Tc bone scan –cafe au lait spots –sexual precocity
McCune-Albright How to tell it from true precocious puberty? –Elevated E with low FSH and LH –Poor response to GnRH-agonists –No nocturnal GnRH pulsatility. Treatment: aromatase inhibitor +/- GnRH agonist
Findings in Various Disorders Gonadal Size Basal FSH & LH E or T Levels DHEAS GnRH Response IdiopathicIncreasedIncreasedIncreasedIncreased Pubertal LH>FSH CerebralIncreasedIncreasedIncreasedIncreased Gonadal Unilat enlarged DecreasedIncreasedIncreasedFlat* McCune- Albright IncreasedDecreasedIncreasedIncreasedFlat* AdrenalSmallDecreasedIncreasedIncreasedFlat*
Isolated Premature Development Isolated Thelarche –May be unilateral, may wax and wane –Normal growth Isolated Premature Menarche –VERY rare: suspect trauma or foreign body, tumor. Isolated Premature Adrenarche –Rule out CAH
Treatment Objectives Dx and Rx any intracranial disease Dx and surgically treat peripheral tumors Arrest maturation until appropriate age Lessen established precocious characteristics Maximize adult height Avoidance of abuse, treat emotional problems, and consider contraception
Treatment of Central Precocious Puberty GnRHa therapy – –monitor growth, 2° sexual characteristics, bone age, and keep E2 < 10 or maintain negative GnRH stim test –GnRH may be used in the case of hamartoma
Delayed Puberty Most girls in USA enter puberty by age 13 Workup when –no 2° sex characteristics by age 13 –absence of menarche by age 16 –5 years between onset thelarche and menarche Delayed puberty is rare in girls and is commonly associated with pathology
Three Cases of Amenorrhea and Blind Pouch Three Cases of Amenorrhea and Blind Pouch MRKH –Normal pubic hair & breasts. No cyclic pain. AIS –Scant pubic hair, normal breast. No pain. –Androgen Receptor Defect (can’t respond to Androgens, develop breasts because unopposed E, have testes/AMH therefore don’t develop uterus.) Transverse Septum –Normal pubic hair & breasts. Cyclic Pain!
Idiopathic Precocious Puberty Spontaneous increase in GnRH. Diagnosis of exclusion. Treat with GnRH-agonist.
Know for CREOGS Order of pubertal stages. Genetics = #1 determinant of timing. Average age of menarche is 12.8 Precocious puberty: prior to age 8 Delayed puberty: absence of 2 ndary chars by age 13 McCune-Albright Syndrome Clinical Differences between AIS, Transverse Septum and Mullerian Agenesis
Amenorrhea Primary: –No menses by 16 in the presence normal growth and secondary sex characteristics –No menses by 14 without secondary sex characteristics Secondary: –H/o previous menses. –No menses in for past three expected cycles or past 6 months.
Primary Amenorrhea Increased FSH Gonadal Failure Most common cause is genetic: XO or mosaic (XO/XX), or XY –Turners: Short stature, webbed neck, wide spaced nipples, increased arm carrying angle, coarctation, low posterior hair line, renal abnormalities, streak gonads. Galactosemia: failure to thrive, abnormal FSH and LH and failure of germ cells to migrate to ovary. 17 hydroxylase deficiency (HTN, hypokalemia) with high 17-OHP
Steroid Synthesis Start with cholesterol (27C) Rate limiting reaction is side chain cleavage 27C 21C Pregnenolone 21 Carbons: progestins, glucocorticoids, mineralocorticoids mineralocorticoids 19 Carbons: Androgens 18 Carbons: Estrogens
Cortisol levels are regulated tightly, others are not. –if cortisol synthesis is limited, ACTH increases to overcome blockage. –precursors build up
CAH Hydroxlase Most common enzyme deficiency leading to congenital adrenal hyperplasia. Name is confusing: (named backwards) –It adds on –OH group to C21 –Named this way because, scientists were working back from cortisol and aldosterone. The product names confuse people, for the same reasons.
CAH – 11 hydroxylase deficiency CAH – 11 hydroxylase deficiency Presentation more variable Hypertension –Incr 11DOC Na + overload Hypo K + Female masculinized Addisons possible with stress
17 Hydroxylase Deficiency Female pubertal delay Male ambiguous genitalia HTN due to mineralocorticoid affect of 11-DOC Hypokalemia 17-OHP is low. Renin low due to Na retension and water expansion. Aldosterone is also low Low urinary 17 keto-steroids
CAH Diagnosis Screening Test is 17- OHP Diagnosis made with ACTH stimulation test. Measure cortisol and precursors before and after.
CAH Summary The Cortisol, Aldo enzymes are named backwards. 21-hydroxylase def. is most common cause of CAH. 11-hydroxylase is 2 nd Blockages lead to buildup of precursors and androgens.
Rotterdam Diagnostic Criteria Need two of three Rotterdam Diagnostic Criteria Need two of three Chronic Oligo-Anovulation Hyperandrogenism Polycystic Ovaries Rule out other causes
PCOS Treatment Management of menses –OCP (35mcg EE), Mirena, Cyclic P Management of hirsuitism –OCP, Spironolactone, Finasteride, Vaniqa, Laser Management of insulin resistance –Weight loss, metformin, exercise. –Metformin most useful if patient overweight. Fertility –Ovulation induction: clomid, letrozole, metformin Clomid = anti estrogen (increases FSH) Letrozole = aromatase inhibitor (increases FSH) Require functioning hypothalmus/pituitary!!!
Hirsuitism Hirsuitim –Excess terminal hair in male pattern. Midline chest, face, back, lower midline abdomen. Arm and leg hair get darker. Virilization –Deepening voice, clitoromegally, breast atrophy and loss of feminine contour.
Causes of Hirsuitism Ethnicity Idiopathic (intrinsic 5a reductase activity) Insulin stimulates pilosebaceous unit, ovarian androgen production and decreases SHBG PCOSCAH Ovarian tumor Adrenal tumor Cushings, hyperprolactinemia
Hirsuitism Workup Androgen assays not very reliable in women. Rapid change associated with pathology –Free T – most sensitive, rarely needed. –Total T – used to rule out ovarian tumor, or follow treatment –DHEAS – used to rule out adrenal tumor –17-OHP – screen for CAH –PRL – can lead to increased DHEAS Consider Insulin Resistance, Cortisol, GH
Hirsuitism Treatments Takes 6 months to arrest new hair growth. Lifestyle changes, as needed Cosmetic treatments: Laser, Electrolysis Eflornithine (Vaniqa) – arrests new hair growth – twice a day x 4 hours. 58% had overall improvement.
Hirsuitism Treatments OCPs are off-label and no studies of adequate power to show benefit. –Decrease LH (decrease androgens) –Increase SHBG Spironolactone (need contraception) –Directly blocks androgen receptor and mildly inhibits 5a reductase –Cheap and more affective than finasteride. –More side effects: polyuria, hypotension, fatique, hyperK Finasteride (need contraception) –5a reductase inhibitor –Non-toxic Flutamide (need contraception) –Androgen receptor blocker, but liver tox limits use.
Hyperprolactinemia Elevated prolactin: May interfere with GnRH secretion to cause: –Short luteal phase –Oligomenorrhea –Amenorrhea GalactorrheaHirsuitism Bone loss Decreased libido in men
Hyperprolactinemia Galactorrhea is bilateral and white. May be seen with normal prolactin levels. –Assay does not reflect biologic activity. –May not detect nocturnal PRL secretion. Fat seen on smear. #1 cause of hyperprolactinemia is idiopathic. The higher the prolactin, the greater the chance of having an adenoma. Renally and hepatically cleared, so increased with renal failure and liver disease.
HyperPRL – CNS Issues Microadenoma <10mm, usually does not grow. Macroadenoma > 10mm (may secrete GH, ACTH, TSH, FSH or nothing) Infiltrating disorders (sarcoid, TB) Radiation Empty Sella Syndrome (herniation of CNS fluid into sella and compresses stalk) Rathke’s cyst or other stalk tumors.
PRL and Rx AntipsychoticsAntidepressants Opiates & Cocaine VerapamilMethyldopaMetoclopramide H2 blockers ranitidine and cimetidine EstrogenDilantin PRL levels usually return to normal within 2-4 days of stopping Rx
Prolactin Variants PRL = normal bioactive form Big PRL (macro-PRL dimers which are connected, can lyse and become bioactive) Big-Big PRL (little bioactivity, but cross react with assay)
When to image for PRL? Debatable. No clear answer. –Some say any elevation is indication. –Levels > 100 ng/ml in absence of drug is universally accepted. –Antipsychotics my raise PRL into 300 range. (Still no one would fault you for imaging.) MRI with and without contrast is image of choice.
HyperPRL Tx Remove offending agent Bromocriptine (DA agonist) (FDA+) –Ergot deriv. Usually req 2-3x/day dose –12% nausea, headache, syncope, dizziness and orthostatic hypotension –PO or PV route good. Cabergoline (DA agonist) (Off label) –Long t 1/2, give 2 x per week –Few side effects Both lead to tumor shrinkage. Except in cases of neurologic emergency, Rx therapy is always first choice.
Menopause Definitions Menopause: cessation of menses for 12 months due to loss of ovarian function. –Average age 51 –Younger if smoker, Hispanic, African American. Climacteric (perimenopause begins 5-6 years prior) symptoms appear (vasomotor and irregular cycles.) –Natural menopause: gradual decline, characterized by fluctuating E and FSH. –Increase FSH due to loss of inhibin! Premature ovarian failure/menopause <40 –Under 30 should get karyotype to look for Y chromosome. –Consider Fragile X gene mutation testing (FMR1) Surgical menopause: sudden drop in E.
Managing Perimenopause Standard HRT doses will not prevent pregnancy and should not be used as first line agents unless a patient is surgically sterile or cannot take OCP. The patch: –Low dose patch mg will reduce hot flashes by 85%. –If the patient has a uterus, you must give progestin therapy for 14 days q month.
Hot Flash Alternative Approaches Lifestyle changes, cool environment Biofeedback Vitamin E, dong quai, and black cohosh—no difference compared with placebo Phytoestrogens Clonidine (patch or pill) Megestrol SSRI/SNRI therapy
Menopausal Changes Symptoms: hot flashes (catecholamine mediated) hot and cold, night sweats, mood changes, insomnia, vaginal atrophy, possibly skin changes. Bone loss (most in first 5 years), especially trabecular bone. Increased central obesity. Lipid abnormalities. –Latter two increase HTN, CAD risk.
Bone Mass by Age and Sex Bone Mass Age (years) MenWomen Menopause-Associated Bone Loss Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999; Riggs BL, Melton LJ III. N Engl J Med. 1986;314:
Osteoporosis DEXA scan = gold standard (Dual Energy Xray Absorptiometry) T score = StDev from healthy 30yo woman. – Osteopenia = T -1 to -2.5 – Osteoporosis = T < -2.5 Z score = StDev from same age woman. –Used in premenopausal women. T & Z scores correlate with fracture risk. –DEXA less reliable in Obese (artificially low T score) and osteoarthritis (artificially high T score) Error range of DEXA = ~7% and repeat test not valid at <1 year, more valid at 2 years. Urinary and serum markers of bone turnover measure cancellous bone. (Telopeptides most commonly used, if at all)
When to Measure BMD in Postmenopausal Women Non-Modifiable Age > 65 Caucasian Race Female Family history History of fracture History of falls Bad Eyesight Modifiable Smoking Cigarettes Low Body Weight ETOH Not on HRT (low E) HypothyroidismImmobility* Poor nutrition Medications (steroids and heparin) One or more risk factors
Treatment Options Calcium – mg daily Vit D supplementation –Sunshine – IU/daily SERMs (raloxifene) HRT (oral or patch) Bisphosphonates (Etidronate, Alendronate) Weight bearing exercise
Affects of Various Treatments Increases in BMD (%) † DecreasesVertebralFractureRates ERT/HRT Alendronate || Risedronate || Raloxifene || Calcitonin Yes § Yes ¶ Yes No Yes ‡ Yes MostCommon Side Effect Breakthrough bleeding Gastric ulceration Upper GI symptoms Hot flushes Nasal irritation Decreases Hip Fracture Rates
WHI Results Absolute and Relative Risk or Benefit of HRT Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: Heart attacks Strokes Breast cancer VTEs Colorectal cancer Hip fractures Relative Risk vs Placebo at 5. Years Increased Absolute Risk per 10,000 Women/Yr Health Event Increased Absolute Benefit per 10,000 Women/Yr
WHI E-only Arm What’s different –No increased CVD risk. –No increased breast cancer risk. What’s the similar –Increased risk of DVT –Small increase risk of stroke –Bone protection.
WHI Use HRT for shortest period of time needed, to treat symptoms. HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: –lifestyle changes –cholesterol- and blood pressure-lowering drugs For osteoporosis prevention: –weigh the benefits against their personal risks for heart attack, stroke, blood clots, and breast cancer; alternate treatments are available to prevent osteoporosis and fractures. NIH Recommendations
Endometriosis/Adenomyosis Endometriosis = endometrial tissue outside the uterus. Adenomyosis = endometrium within muscle. Endometriosis Incidence: –3-10% of general population –30% of infertile population –50% of pelvic pain –70% of pelvic pain and infertility LEFT ovary is most common site of endometrioma. Disease stage correlates with ~fertility, but not pain. Genetic (7% of first degree relatives) Etiology: genetic, environmental, autoimmune. Tissue has abnormal regulation (altered responsiveness to progesterone: resistant to apoptosis; excess aromatase.) Also assoc with: premenstrual spotting, poor egg quality
Endometriosis Treatment Infertility Surgery benefits stage I-II disease. –NNT = 12 –More advanced disease, role of surgery mainly limited to diagnosis. GnRH-agonist –Modest benefit, if any for fertility All forms of fertility have decreased efficacy with endometriosis (IVF, COH/IUI) –Likely related to poorer egg quality.
Endometriosis Treatment (pregnancy, pseudopregnancy or pseudomenopause) OCPs (60-90% get relief in first year) –Promote decidualization (progestin effect), pseudopregnancy –10% recurrence risk/year Depo Provera/Progestins –Promote decidualization (pseudopregnancy) Depot Lupron (75-90% get relief in first year) –Decapeptide, long-acting GnRH promotes pseudomenopause by decreasing ovarian E. –50% recurrence upon stopping. –Bone loss at 6 months Addback regimens: 25 ug E patch q week, mg CEE QD, or norethindrone acetate 5mg QD. Levonorgestrel IUD –Decrease severity of symptoms (pseudopregnancy). Danazol (95% relief) –Androgen side effects: hirsuitism, loss of female contour, liver tox
Endometriosis Surgery Hysterectomy/BSO: 90% cure. Presacral neurectomy: risks constipation, helps midline pain. Laparoscopic Uterosacral Nerve Ablation (LUNA): no proven benefit. Cystectomy vs ablation of cyst wall –Both superior to simple drainage.
Infertility No pregnancy after 1 year of adequate, unprotected intercourse. 15% of all couples. Increases with age. Roughly equal between male and female causes. 20% of cases are isolated male factor. 10% are unexplained.
Infertility Basic workup Ovulation? –Tests of ovulation: history, BBT (.5 degree rise), urinary LH detection, timed serum P. Sperm? –Volume 2ml, concentration 20m/ml, motility 40%, morphology 14% (30% WHO III) Anatomy? –HSG (pretty reliable if says tubes are patent 85% specific, only fair if tubes are blocked 54% sensitive) –Not the greatest test for endometriosis. Ovarian reserve? –Elevated CD3 FSH ( abnormal if >10 IUm/L) –Elevated CD3 Estradiol (abnormal if >75 pg/ml) –Predicts outcomes with IVF, reliability not established for general public. Post coital test. –Not predictive.
Fertility Septate uteri do not cause infertility. Fibroids involving the cavity decrease fertility. Polyps >2cm decrease fertility Endometriosis decreases fertility via egg quality. Obesity and cigarette smoking decrease fertility.
Normal fertility Fecundity –approximately 20% per cycle during 20s and early 30s. –Approximately 10% at age 40. –Most couples infertile by age 45. –At age 44-45, age is more predictive of fertility than is ovarian reserve.
RPL 3 consecutive losses with same partner If no prior livebirths: –70% chance of livebirth in next pregnancy. –40% livebirth after 4 losses. If prior livebirths: –70% livebirth until 6 losses. Increases risk of ectopic, neural tube defects
RPL Thrombophilia ACOG says the only definitive ones are immune mediated: –Anticardiolipin antibodies and Lupus anticoagulant. –These two are the best characterized. These are the only two, for which treatment has been demonstrated.
RPL -- Genetic Normal
Robertsonian balanced translocation account for 2/3 genetic etiologies. 6 possible gametes, only two can produce unaffected offspring.
RPL -- Genetic Balanced recipricol translocation Normal Abnormal Balanced Abnormal Four possible combinations with two unaffected gametes
Endocrinology of Pregnancy Maternal Recognition of Pregnancy –Progesterone is secreted by CL exclusively for 5-7 weeks, due to hCG –After 6-7 weeks, placenta produces large amounts. –After 9th week, removal of ovaries has no effect on pregnancy. –Progesterone production peaks at term. –hCG quits doubling at 6-7 weeks gestation or at about 10K –hCG peaks at 10 weeks
Endocrinology of Pregnancy Function of P4 (summary) –Pregnancy maintenance. –Uterine quiescence –Immune modulation Is a fall in P associated with partuition? –No. Does P have a role in partuition? –Yes Explain: –Receptor changes cause decreased function of P.
Endocrinology of Pregnancy Placenta and steroid hormone production What does the mother contribute to placental steroid production? –Cholesterol from LDL. What does the baby contribute? –DHEAS Which enzymes does placenta lack? –17hydroxylase/17,20lyase and 21 hydroxylase Consequence –Placental steroid production stops at P (No androgens or cortisol) –E3 is produced by conversion of DHEAS
Endocrinology of Pregnancy What is primary precursor for E?DHEAS from fetal adrenal. Primary E of pregnancy?Estriol aka E3 (90%) What organ makes E3?Placenta converts fetal precursors to E3 Role of placental estrogens?Increase uteroplacental bloodflow. Are Es required for pregnancy maint?Does not seem so. E is mainly a sink to prevent excess androgens. Conditions associated with low E?Anencephally Congenital adrenal lipoid hyperplasia Aromatase and sulfatase deficiencies Why has estriol been used as aIndicates HPA axis in fetus. marker of fetal well being?b/c DHEAS Estriol marker of fetal well being?b/c DHEAS Estriol