2High Yield Amenorrhea Abnormal puberty (delayed and precocious) Embryology
3Embryonic Sexual Determination XYSRYXXNo SRYNormal femaleEmbryo bipotent at 5 wksKaryotypeXY vs XXSRY Gene (TDF)Normal Male
4Embryonic Sexual Determination XXXY (with SRY)OvaryTestes at 6 weeksLeydigSertoliAnti Mullerian HormoneTestosteroneDHTDev Ext MaleIspilateral regressesionDev. Int. Male, ipsilaterally
5Ovaries develop separately “Default” pathwayStill requires transcription factors such as DAX1, Wnt4 and products of other SOX9 genes.Ovaries develop separately
6Summary 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.This is a simplified summary of sex determination events. There are many potential disruptions to this system.
7Prepubertal Physiology +-GonadotropinFetal, neonatal, and prepubertal H-P-O axis capable of full Fetal/Neonatal Period20 wk fetal FSH and LH levels > or = reproductive age levelsFeedback inhibition not establishedNeonatal FSH > or = reproductive age FSH2° to release of inhibition by maternal and placental E2 and PEarly Childhood: ~ 5mos and 4 yearsGonadostat is extremely sensitive to steroid feedback, maintaining suppression of FSH and LH.FSH production in Agonadal children is not suppressed.AgeIncreasing weight, fat mass
8Normal 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.Is this weight?Is this leptin?Initially, pulse frequencies are spaced out and of low magnitude, throughout the pubertal process, these pulses become more frequent and stronger, leading to normal adult patterns of GnRH q60-90 minutes..
9Timing of puberty is largely genetic Estrogen Breast Development andAndrogens Pubic HairBone Growth
10Measurement of Puberty: Tanner Stages icHSg1ElvonfpNh2d,m-9.8y5()3FDk4AR67There is NO stage Zero!
11Order of Pubertal Events Growth spurt / BreastsPubic hairMaximum growth velocityMensesaka “Boobs, pubes/pits and pads”
12Normal Puberty - Adrenarche Independent of HPO axis.Trigger unclearGenerally precedes changes associated with puberty.Increase adrenal androgens: DHEAS and A.Mechanism: increased 17,20 lyase activity.Adrenarche and gonadarche are independent processes,therefore girls w/adrenal failure have normal thelarche and menarche and girls w/ gonadal failure experience normal pubarche.If you lack pubic hair, you either don’t make much adrenal and ovarian androgens OR you don’t respond to them.Appearance of Pubic Hair
14Endocrinology FSH LH IU/L Inh-A/B E pg/ml P ng/ml LH P FSH Inh-A Inh-B 22050010189LH164008P147123006FSH10582004Inh-A63At first glance the menstrual cycle can be intimidating. I don’t expect you to memorize this graph of how the various hormones fluctuate during normal ovulation. However, by understanding the basic principles which guide ovulation, you should be able to diagram this hormonal interplay.Inh-BE24100221246810121416182022242628MensesOvulation
15Preantral Follicle Initiation of Follicular Growth Continuous processOccurs in “waves”Stimulus/mechanism unknownIndependent of gonadotropinsOccurs in prepubertal ovaryUninterupted by pregnancy, OCPEnds with follicular depletionThe ovary releases eggs like a time-release capsule. A certain number emerge in waves from the reserve.This emergence is continuous and what controls it is not known. Nothing that we know of can stop it and it occurs whether women ovulate or not. (Multiparity and OCP use do not delay menopause.)
16FSH LH IU/L E2 pg/ml P ng/ml LH P FSH E2 Menses Ovulation 20 500 10 18 9LH164008P147123006FSH1058200463This shows the general pattern of what happens to follicles.Waves initiate growth. (As represented by the thick white arrows.)If FSH levels are high enough, and if the follicle can respond, a follicle is prevented from going into atresia.Late in the luteal phase when FSH begins to rise, is when a group of follicles is rescued from atresia.This graph shows that at times of elevated FSH (late luteal and early follicular) are emerging follicles spared from atresia.The one that becomes dominant likely emerged just at the right time and was the most responsive to FSH.E24100221246810121416182022242628MensesOvulation
17Preantral Follicle In Delicate Balance GrowthAtresiaTimely gonadotropin stimulation can promote further growthIntercycle rise in FSH crucial for continued developmentWithout gonadotropin support, doomed to atresiaAs the follicle emerges from its quiescent state and gains FSH receptors, it has reached a critical point in it’s development.It will become either grow or undergo atresia.It’s fate depends on the presence of FSH. If FSH is present, the follicle will grow. Without it, it fades.(This is one reason birth control pills work. If you suppress FSH early enough, you don’t rescue any follicles. Note that birth control pills work as long as they are started early enough in the cycle. If started too late, the dominant follicle may not require FSH.)
18The “Two Cell, Two Gonadotropin Concept” LHTHECA CELLLH ReceptorCholesterolP450sccATPcAMPPregnenoloneP450c17AndrostenedioneTestosteroneBasement MembraneThe two cell, two gonadotropin theory works on the principle that FSH is the main stimulator of Granulosa cells and LH stimulates Theca cells.Each has specialized function. Androgens are made in the theca cells and cross the basement membrane to the granulosa cells.LH Theca begins to express P450c17 to make androgens. (P450c17 is a dual enzyme which has 17a hydroxylase and 17,20-lyase activity. It is the 17,20-lyase which converts 21-carbons into 19-carbon steroids (androgens).)FSH Granulosa division and expression of P450Arom to convert the androgens to estrogens.Of note: Even without LH, FSH can promote early growth, because of adrenal androgens.Let’s see how this two-cell theory works through the menstrual cycle….AndrostenedioneTestosteronecAMP<P450arom>FSHATPEstroneEstradiolGRANULOSA CELL
19Dominant Follicle Selection Mechanisms Normal ovulatory quota = 1Rising estrogen levelspositive feedback locallynegative feedback centrallyRising inhibin levelsfurther negative feedbackDeclining FSH levelswithdraw growth supportAtresia in lesser follicles atresiaThe dominant follicle is selected by cycle day 5-7.Most likely, it emerged late in the luteal phase and therefore had a slight advantage over other follicles in that it had:a) more granulosa cellsb) more FSH receptorsc) more aromataseIt also has a richer blood supply which delivers more blood, therefore more FSH and more nutrients.Estrogen rises within the atrum of the follicle where it potentiates all the effects of FSH.Estrogen begins to have negative feedback on the hypothalmus and pituitary where it reduces the signal (FSH) available for other follicles.The GC also produce inhibin, which also limit FSH production.This loss of FSH causes atresia of follicles which are not as sensitive to FSH.
20Dominant Follicle Selection “Survival of the Fittest” Selected follicleMore and larger cellsmore FSH receptor and greater sensitivity to falling FSHmore aromataseAdvanced vascular development provides preferential delivery of FSH and LDL substrateThis shows the characteristics of the dominant follicle.Local autocrine/paracrine mechanismsActivin (granulosa)Production stimulated by FSH; augments FSH actionsIGF-I (theca)Stimulates granulosa proliferation, aromataseAMHlimits recruitment of small folliclesTNF levels are suppressed in dominant follicles – which allows for survival.
21Ovulation LH stimulates meiosis, luteinization, and PG production LILHPGSmooth MuscleFibersOMILHLHPGFSHFSHPPlasminCollagenaseLH stimulates meiosis, luteinization, and PG productionP enhances proteolytic enzymesFSH stimulates expansion of cumulus and plasmin to stimulate collagenaseMany hormones and peptides reside in antral fluid. These keep a break on ovulation.With the LH surge:OMI (Ovulation Maturation inhibitor) is reduced.Lutienization inhibitor is reduced.Prostaglandins lead to increase in proteolytic enzymes.There is rapid expansion of the follicle which coincides with thinning of the wall. This is not a high-pressure situation. The wall simply erodes and the oocyte is extruded.PB
22Corpus Luteum Progesterone Follicle wall becomes convoluted Luteal cells enlarge, acquire lutein pigment and lipidCapillary network penetrates granulosaProduction of large amounts of both E & PE & P act centrally and locally to suppresses new follicular growthThere is also invasion of blood vessels into the CL. This delivers high blood flow and lots of LDL cholesterol to serve as substrate for steroid synthesis.EstradiolProgesterone
23Corpus Luteum Requirements for Normal Luteal Function Optimal preovulatory follicular development - luteal cell massAdequate follicular phase FSHTonic LH stimulationLDL cholesterol substrateA key point here is that normal CL function requires adequate stimulus before ovulation. The machinery must be built in the follicular phase which will support a normal CL. A poor stimulation produces a weak CL.
24Ovarian Cycle Conception FSHLHIU/LE2pg/mlPng/ml2050010189LH164008PhCG147123006FSH10582004If hCG appears then P and E continue at high levels and FSH & LH stays suppressed.63E24100221246810121416182022242628MensesOvulation
25Normal menses 24-35 days 2-7 days of flow 35ml (mean) <80 cc of non-clotting debris.
27Terminology of Precocious Puberty GnRH - Dependent aka True Precocious Puberty aka Central Precocious PubertyGnRH - Independent aka Precocious Pseudopuberty aka Peripheral Precocious PubertyIsolated Precocious Development
28Precocious Puberty Bone Age guides therapy. Bone age, bone age, bone ageTypically, 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.
29Etiologies of Precocious Puberty GnRH Dependent female maleIdiopathic 74% 41%CNS problem % 26%GnRH IndependentOvarian (cyst or tumor) 11% n/aTesticular n/a 10%McCune-Albright 5% 1%Adrenal feminizing % 0%Adrenal masculinizing 1% 22%Ectopic gonadotropin % %HypothyroidismExogenous SteroidsHepatoblastoma, chorioepithelioma, dysgerminoma all can secrete hCGCNS CausesHypothalamic TumorHamartoma (secretes GnRH), Craniopharyngioma, Glioma, Ependymomas, NeurofibromaCongenital malformationHydrocephalus, Rickett’s (skull malformation)Pineal tumorTrauma (brain injury stims TGF-a which stims GnRH)Encephalitis
311° Steroid Elevation Tumor Ovary Feminizing Adrenal Tumor may produce estrogens, androgens, hCG - typically causing heavy irreg. bleeding80% have palpable massgranulosa, theca, gonadoblastomas, teratomas, lipoid cell, cystadenomas, epithelial cancerFeminizing Adrenal Tumorvery rare, usu. associated with DHA-S
32McCune Albright Syndrome aka polyostic fibrous dysplasiaMechanism:Activating mutation of Gs resulting in unregulated cAMP formation.Somatic mosaic mutation, therefore not lethal and variable phenotype.Classic Triad:cystic bone lesions causing easy fracture - Tc bone scancafe au lait spotssexual precocityIn What other disease do pts have cafe au lait spot and often pp?NeurofibromatosisOnly tissues with defect are affected.
33McCune-Albright How to tell it from true precocious puberty? Elevated E with low FSH and LHPoor response to GnRH-agonistsNo nocturnal GnRH pulsatility.Treatment: aromatase inhibitor +/- GnRH agonistWhy would I treat with GnRH agonist?
34Findings in Various Disorders Gonadal SizeBasal FSH & LHE or T LevelsDHEASGnRH ResponseIdiopathicIncreasedPubertal LH>FSHCerebralGonadalUnilat enlargedDecreasedFlat*McCune- AlbrightAdrenalSmall
35Isolated Premature Development Isolated ThelarcheMay be unilateral, may wax and waneNormal growthIsolated Premature MenarcheVERY rare: suspect trauma or foreign body, tumor.Isolated Premature AdrenarcheRule out CAHIsolated Premature Thelarcheusu. first few yrs. of lifemay be unilateralmay wax and wane or persist to pubertymechanism unknown but pts have normal growth pubertyIsolated Premature Menarchevery rare - suspect trauma, foreign body, ingestion, local tumorIsolated Premature Adrenarcheconsider CAH17OH-P baseline and androgens? ACTH-stimulationsparse non-progressive hair growth on labia may be nl variant
36Treatment Objectives Dx and Rx any intracranial disease Dx and surgically treat peripheral tumorsArrest maturation until appropriate ageLessen established precocious characteristicsMaximize adult heightAvoidance of abuse, treat emotional problems, and consider contraception
37Treatment of Central Precocious Puberty GnRHa therapy –monitor growth, 2° sexual characteristics, bone age, and keep E2 < 10 or maintain negative GnRH stim testGnRH may be used in the case of hamartoma
38Delayed Puberty Most girls in USA enter puberty by age 13 Workup when no 2° sex characteristics by age 13absence of menarche by age 165 years between onset thelarche and menarcheDelayed puberty is rare in girls and is commonly associated with pathology
43Three Cases of Amenorrhea and Blind Pouch MRKHNormal pubic hair & breasts. No cyclic pain.AISScant 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 SeptumNormal pubic hair & breasts. Cyclic Pain!
44Idiopathic Precocious Puberty Spontaneous increase in GnRH.Diagnosis of exclusion.Treat with GnRH-agonist.
45Know for CREOGS Order of pubertal stages. Genetics = #1 determinant of timing.Average age of menarche is 12.8Precocious puberty: prior to age 8Delayed puberty: absence of 2ndary chars by age 13McCune-Albright SyndromeClinical Differences between AIS, Transverse Septum and Mullerian Agenesis
46Amenorrhea Primary: Secondary: No menses by 16 in the presence normal growth and secondary sex characteristicsNo menses by 14 without secondary sex characteristicsSecondary:H/o previous menses.No menses in for past three expected cycles or past 6 months.
49Primary Amenorrhea Increased FSH Gonadal FailureMost common cause is genetic: XO or mosaic (XO/XX), or XYTurners: 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.17a hydroxylase deficiency (HTN, hypokalemia) with high 17-OHP
50Steroid Synthesis Start with cholesterol (27C) Rate limiting reaction is side chain cleavage 27C 21C Pregnenolone21 Carbons: progestins, glucocorticoids,mineralocorticoids19 Carbons: Androgens18 Carbons: Estrogens
51Cortisol levels are regulated tightly, others are not. if cortisol synthesis is limited, ACTH increases to overcome blockage.precursors build up
52Adrenal Steroid Disorders CAH (% nomal genitalia vs & ambiguous)21 hydroxylase deficiency (90% of cases)11b hydroxylase deficiency (5% of cases)3b dehydrogenase deficiency (rare)Pubertal Disorders (&) vs Ambiguous Genitalia (%)17a hydroxylase deficiency17b dehydrogenase deficiencyAffects boys and girls differently
53CAH HydroxlaseMost common enzyme deficiency leading to congenital adrenal hyperplasia.Name is confusing: (named backwards)It adds on –OH group to C21Named this way because, scientists were working back from cortisol and aldosterone.The product names confuse people, for the same reasons.
54CAH – 11b hydroxylase deficiency Presentation more variableHypertensionIncr 11DOCNa+ overloadHypo K+Female masculinizedAddisons possible with stress
5517a Hydroxylase Deficiency Female pubertal delayMale ambiguous genitaliaHTN due to mineralocorticoid affect of 11-DOCHypokalemia17-OHP is low.Renin low due to Na retension and water expansion.Aldosterone is also lowLow urinary 17 keto-steroids
56CAH Diagnosis Screening Test is 17-OHP Diagnosis made with ACTH stimulation test.Measure cortisol and precursors before and after.
57CAH Summary The Cortisol, Aldo enzymes are named backwards. 21-hydroxylase def. is most common cause of CAH.11-hydroxylase is 2ndBlockages lead to buildup of precursors and androgens.
62Pathogenesis PCOS iSHBG Increased Converted to DHT androgens Insulinresistance& obesityiSHBGHirsutismIncreasedandrogensConverted to DHTPCOSAnovulationiFSHIncreased LHPolycystic ovariesAcyclic, elevatedestrogenAmenorrhea
63‘Metabolic Syndrome’ Insulin Resistance Abdominal Obesity Diabetes mellitusHypertensionDyslipidemiaHigh triglyceridesLow HDLAtherosclerosisPCOSPCOS is associated with metabolic derangements.No one knows if these translate into higher mortality. This has not been demonstrated; however, due to the negative consequences of PCOS, be careful with your diagnosis. Use it only if you’re sure.Insulin ResistanceAbdominal Obesity
64PCOS Treatment Management of menses Management of hirsuitism OCP (35mcg EE), Mirena, Cyclic PManagement of hirsuitismOCP, Spironolactone, Finasteride, Vaniqa, LaserManagement of insulin resistanceWeight loss, metformin, exercise.Metformin most useful if patient overweight.FertilityOvulation induction: clomid, letrozole, metforminClomid = anti estrogen (increases FSH)Letrozole = aromatase inhibitor (increases FSH)Require functioning hypothalmus/pituitary!!!
65HirsuitismHirsuitimExcess terminal hair in male pattern.Midline chest, face, back, lower midline abdomen. Arm and leg hair get darker.VirilizationDeepening voice, clitoromegally, breast atrophy and loss of feminine contour.
66Causes of Hirsuitism Ethnicity Idiopathic (intrinsic 5a reductase activity)Insulin stimulates pilosebaceous unit, ovarian androgen production and decreases SHBGPCOSCAHOvarian tumorAdrenal tumorCushings, hyperprolactinemia
67Hirsuitism Workup Androgen assays not very reliable in women. Rapid change associated with pathologyFree T – most sensitive, rarely needed.Total T – used to rule out ovarian tumor, or follow treatmentDHEAS – used to rule out adrenal tumor17-OHP – screen for CAHPRL – can lead to increased DHEASConsider Insulin Resistance, Cortisol, GH
68Hirsuitism Treatments Takes 6 months to arrest new hair growth.Lifestyle changes, as neededCosmetic treatments:Laser, ElectrolysisEflornithine (Vaniqa) – arrests new hair growth – twice a day x 4 hours. 58% had overall improvement.
69Hirsuitism Treatments OCPs are off-label and no studies of adequate power to show benefit.Decrease LH (decrease androgens)Increase SHBGSpironolactone (need contraception)Directly blocks androgen receptor and mildly inhibits 5a reductaseCheap and more affective than finasteride.More side effects: polyuria, hypotension, fatique, hyperKFinasteride (need contraception)5a reductase inhibitorNon-toxicFlutamide (need contraception)Androgen receptor blocker, but liver tox limits use.
70Hyperprolactinemia Elevated prolactin: May interfere with GnRH secretion to cause:Short luteal phaseOligomenorrheaAmenorrheaGalactorrheaHirsuitismBone lossDecreased libido in men
72Hyperprolactinemia 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.
73HyperPRL – CNS Issues Microadenoma <10mm, usually does not grow. Macroadenoma > 10mm (may secrete GH, ACTH, TSH, FSH or nothing)Infiltrating disorders (sarcoid, TB)RadiationEmpty Sella Syndrome (herniation of CNS fluid into sella and compresses stalk)Rathke’s cyst or other stalk tumors.
74PRL and Rx Antipsychotics Antidepressants Opiates & Cocaine Verapamil MethyldopaMetoclopramideH2 blockers ranitidine and cimetidineEstrogenDilantinPRL levels usually return to normal within 2-4 days of stopping Rx
75Prolactin 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)
76When 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.
77HyperPRL Tx Remove offending agent Bromocriptine (DA agonist) (FDA+) Ergot deriv. Usually req 2-3x/day dose12% nausea, headache, syncope, dizziness and orthostatic hypotensionPO or PV route good.Cabergoline (DA agonist) (Off label)Long t 1/2 , give 2 x per weekFew side effectsBoth lead to tumor shrinkage.Except in cases of neurologic emergency, Rx therapy is always first choice.
79Menopause Definitions Menopause: cessation of menses for 12 months due to loss of ovarian function.Average age 51Younger 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 <40Under 30 should get karyotype to look for Y chromosome.Consider Fragile X gene mutation testing (FMR1)Surgical menopause: sudden drop in E.
80Managing 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.
81Hot Flash Alternative Approaches Lifestyle changes, cool environmentBiofeedbackVitamin E, dong quai, and black cohosh—no difference compared with placeboPhytoestrogensClonidine (patch or pill)MegestrolSSRI/SNRI therapyLayered clothingAvoiding cuesBetter sleep through estrogenMicronized progesteroneAdjunctive medicine only if other methods fail.AntidepressantsHypnotic agents
82Menopausal ChangesSymptoms: 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.
83Management Protect bone. Protect against hyperplasia. Alleviate symptoms.Promote healthy living.
84Menopause-Associated Bone Loss Bone Mass by Age and SexBone MassAge (years)MenWomenMenopause-Associated Bone LossThis is just to demonstrate that bone mass loss is accelerated for women during menopause. This accelerated loss lasts about 7 years, but it leads to a permanent separation of bone density between males and females which is never corrected.Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999;Riggs BL, Melton LJ III. N Engl J Med. 1986;314:
85OsteoporosisDEXA scan = gold standard (Dual Energy Xray Absorptiometry)T score = StDev from healthy 30yo woman.Osteopenia = T -1 to -2.5Osteoporosis = T < -2.5Z 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)
86When to Measure BMD in Postmenopausal Women One or more risk factorsNon-ModifiableAge > 65Caucasian RaceFemaleFamily historyHistory of fractureHistory of fallsBad EyesightModifiableSmoking CigarettesLow Body WeightETOHNot on HRT (low E)HypothyroidismImmobility*Poor nutritionMedications (steroids and heparin)I’ve added the list of medications to the end of this talk, for your own edification.
87Treatment Options Calcium Vit D supplementation SERMs (raloxifene) mg dailyVit D supplementationSunshineIU/dailySERMs (raloxifene)HRT (oral or patch)Bisphosphonates (Etidronate, Alendronate)Weight bearing exercise
88Affects of Various Treatments DecreasesHipFractureRatesIncreases inBMD (%)†DecreasesVertebralFractureRatesERT/HRTAlendronate||Risedronate||Raloxifene||CalcitoninYes§Yes¶YesNo5 - 65 - 81 - 2Yes‡MostCommonSide EffectBreakthrough bleedingGastric ulcerationUpper GI symptomsHot flushesNasal irritation
89WHI Results Absolute and Relative Risk or Benefit of HRT Heart attacks IncreasedAbsolute Riskper 10,000Women/YrIncreasedAbsolute Benefitper 10,000Women/YrRelative Riskvs Placeboat 5. YearsHealth EventHeart attacksStrokesBreast cancerVTEsColorectal cancerHip fractures1.291.411.262.110.630.66781865But they did stop the study. But in this case, the patients on placebo actually did better.While the differences were not statistically significantly different, there was no benefit.Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:
90WHI E-only Arm What’s different What’s the similar No increased CVD risk.No increased breast cancer risk.What’s the similarIncreased risk of DVTSmall increase risk of strokeBone protection.
91WHI NIH Recommendations Use HRT for shortest period of time needed, to treat symptoms.HRT should not be continued or started to prevent heart diseaseDiscuss other methods of CVD prevention:lifestyle changescholesterol- and blood pressure-lowering drugsFor 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.National Heart, Lung, and Blood Institute, National Institutes of Health. New facts about: estrogen/progestin hormone therapy. Available at:
92Endometriosis/Adenomyosis Endometriosis = endometrial tissue outside the uterus.Adenomyosis = endometrium within muscle.Endometriosis Incidence:3-10% of general population30% of infertile population50% of pelvic pain70% of pelvic pain and infertilityLEFT 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
93Endometriosis Treatment InfertilitySurgery benefits stage I-II disease.NNT = 12More advanced disease, role of surgery mainly limited to diagnosis.GnRH-agonistModest benefit, if any for fertilityAll forms of fertility have decreased efficacy with endometriosis (IVF, COH/IUI)Likely related to poorer egg quality.
94Endometriosis Treatment (pregnancy, pseudopregnancy or pseudomenopause) OCPs (60-90% get relief in first year)Promote decidualization (progestin effect), pseudopregnancy10% recurrence risk/yearDepo Provera/ProgestinsPromote 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 monthsAddback regimens: 25 ug E patch q week, mg CEE QD, or norethindrone acetate 5mg QD.Levonorgestrel IUDDecrease severity of symptoms (pseudopregnancy).Danazol (95% relief)Androgen side effects: hirsuitism, loss of female contour, liver tox
95Endometriosis 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 wallBoth superior to simple drainage.
96InfertilityNo 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.
97Infertility Basic workup Ovulation? Sperm? Anatomy? Ovarian reserve? 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.
98Fertility Septate uteri do not cause infertility. Fibroids involving the cavity decrease fertility.Polyps >2cm decrease fertilityEndometriosis decreases fertility via egg quality.Obesity and cigarette smoking decrease fertility.
99Normal 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.
100RPL 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
102RPLThrombophiliaACOG 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.
1046 possible gametes, only two can produce unaffected offspring. RPL -- GeneticRobertsonian balanced translocation account for 2/3 genetic etiologies.6 possible gametes, only two can produce unaffected offspring.
105RPL -- Genetic Balanced recipricol translocation Normal Abnormal Balanced AbnormalFour possible combinations with two unaffected gametes
106Endocrinology of Pregnancy Maternal Recognition of PregnancyProgesterone is secreted by CL exclusively for 5-7 weeks, due to hCGAfter 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 10KhCG peaks at 10 weeks
107Endocrinology of Pregnancy Function of P4 (summary)Pregnancy maintenance.Uterine quiescenceImmune modulationIs a fall in P associated with partuition?No.Does P have a role in partuition?YesExplain:Receptor changes cause decreased function of P.
108Endocrinology of Pregnancy Placenta and steroid hormone productionWhat does the mother contribute to placental steroid production?Cholesterol from LDL.What does the baby contribute?DHEASWhich enzymes does placenta lack?17hydroxylase/17,20lyase and 21 hydroxylaseConsequencePlacental steroid production stops at P (No androgens or cortisol)E3 is produced by conversion of DHEAS
109Endocrinology 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 E3Role of placental estrogens? Increase uteroplacental bloodflow.Are Es required for pregnancy maint? Does not seem so. E is mainly a sink to preventexcess androgens.Conditions associated with low E? AnencephallyCongenital adrenal lipoid hyperplasiaAromatase and sulfatase deficienciesWhy has estriol been used as a Indicates HPA axis in fetus.marker of fetal well being? b/c DHEAS Estriol