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Crushing the Creogs Rapid Primer.

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Presentation on theme: "Crushing the Creogs Rapid Primer."— Presentation transcript:

1 Crushing the Creogs Rapid Primer

2 High Yield Amenorrhea Abnormal puberty (delayed and precocious)

3 Embryonic Sexual Determination
XY SRY XX No SRY Normal female Embryo bipotent at 5 wks Karyotype XY vs XX SRY Gene (TDF) Normal Male

4 Embryonic Sexual Determination
XX XY (with SRY) Ovary Testes at 6 weeks Leydig Sertoli Anti Mullerian Hormone Testosterone DHT Dev Ext Male Ispilateral regressesion Dev. Int. Male, ipsilaterally

5 Ovaries develop separately
“Default” pathway Still requires transcription factors such as DAX1, Wnt4 and products of other SOX9 genes. Ovaries develop separately

6 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. This is a simplified summary of sex determination events. There are many potential disruptions to this system.

7 Prepubertal Physiology
+ - Gonadotropin Fetal, neonatal, and prepubertal H-P-O axis capable of full Fetal/Neonatal Period 20 wk fetal FSH and LH levels > or = reproductive age levels Feedback inhibition not established Neonatal FSH > or = reproductive age FSH 2° to release of inhibition by maternal and placental E2 and P Early Childhood: ~ 5mos and 4 years Gonadostat is extremely sensitive to steroid feedback, maintaining suppression of FSH and LH. FSH production in Agonadal children is not suppressed. Age Increasing weight, fat mass

8 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. 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. .

9 Timing of puberty is largely genetic
Estrogen  Breast Development and Androgens  Pubic Hair Bone Growth

10 Measurement of Puberty: Tanner Stages
i c H S g 1 E l v o n f p N h 2 d , m - 9 . 8 y 5 ( ) 3 F D k 4 A R 6 7 There is NO stage Zero!

11 Order of Pubertal Events
Growth spurt / Breasts Pubic hair Maximum growth velocity Menses aka “Boobs, pubes/pits and pads”

12 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. 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

13 The Menstrual Cycle

14 Endocrinology FSH LH IU/L Inh-A/B E pg/ml P ng/ml LH P FSH Inh-A Inh-B
2 20 500 10 18 9 LH 16 400 8 P 14 7 12 300 6 FSH 10 5 8 200 4 Inh-A 6 3 At 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-B E2 4 100 2 2 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Menses Ovulation

15 Preantral Follicle Initiation of Follicular Growth
Continuous process Occurs in “waves” Stimulus/mechanism unknown Independent of gonadotropins Occurs in prepubertal ovary Uninterupted by pregnancy, OCP Ends with follicular depletion The 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.)

16 FSH LH IU/L E2 pg/ml P ng/ml LH P FSH E2 Menses Ovulation 20 500 10 18
9 LH 16 400 8 P 14 7 12 300 6 FSH 10 5 8 200 4 6 3 This 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. E2 4 100 2 2 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Menses Ovulation

17 Preantral Follicle In Delicate Balance
Growth Atresia Timely gonadotropin stimulation can promote further growth Intercycle rise in FSH crucial for continued development Without gonadotropin support, doomed to atresia As 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.)

18 The “Two Cell, Two Gonadotropin Concept”
LH THECA CELL LH Receptor Cholesterol P450scc ATP cAMP Pregnenolone P450c17 Androstenedione Testosterone Basement Membrane The 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…. Androstenedione Testosterone cAMP < P450arom > FSH ATP Estrone Estradiol GRANULOSA CELL

19 Dominant Follicle Selection Mechanisms
Normal ovulatory quota = 1 Rising estrogen levels positive feedback locally negative feedback centrally Rising inhibin levels further negative feedback Declining FSH levels withdraw growth support Atresia in lesser follicles atresia The 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 cells b) more FSH receptors c) more aromatase It 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.

20 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 This shows the characteristics of the dominant follicle. Local autocrine/paracrine mechanisms Activin (granulosa) Production stimulated by FSH; augments FSH actions IGF-I (theca) Stimulates granulosa proliferation, aromatase AMH limits recruitment of small follicles TNF levels are suppressed in dominant follicles – which allows for survival.

21 Ovulation LH stimulates meiosis, luteinization, and PG production
LI LH PG Smooth Muscle Fibers OMI LH LH PG FSH FSH P Plasmin Collagenase LH stimulates meiosis, luteinization, and PG production P enhances proteolytic enzymes FSH stimulates expansion of cumulus and plasmin to stimulate collagenase Many 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

22 Corpus Luteum Progesterone 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 There 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. Estradiol Progesterone

23 Corpus Luteum Requirements for Normal Luteal Function
Optimal preovulatory follicular development - luteal cell mass Adequate follicular phase FSH Tonic LH stimulation LDL cholesterol substrate A 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.

24 Ovarian Cycle Conception
FSH LH IU/L E2 pg/ml P ng/ml 20 500 10 18 9 LH 16 400 8 P hCG 14 7 12 300 6 FSH 10 5 8 200 4 If hCG appears then P and E continue at high levels and FSH & LH stays suppressed. 6 3 E2 4 100 2 2 1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Menses Ovulation

25 Normal menses 24-35 days 2-7 days of flow
35ml (mean) <80 cc of non-clotting debris.

26 Abnormal Puberty

27 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

28 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.

29 Etiologies of Precocious Puberty
GnRH Dependent female male Idiopathic 74% 41% CNS problem % 26% GnRH Independent Ovarian (cyst or tumor) 11% n/a Testicular n/a 10% McCune-Albright 5% 1% Adrenal feminizing % 0% Adrenal masculinizing 1% 22% Ectopic gonadotropin % % Hypothyroidism Exogenous Steroids Hepatoblastoma, chorioepithelioma, dysgerminoma all can secrete hCG CNS Causes Hypothalamic Tumor Hamartoma (secretes GnRH), Craniopharyngioma, Glioma, Ependymomas, Neurofibroma Congenital malformation Hydrocephalus, Rickett’s (skull malformation) Pineal tumor Trauma (brain injury stims TGF-a which stims GnRH) Encephalitis

30 1° Gonadotropin Elevation
CNS Causes Hypothalamic Tumor Hamartoma (secretes GnRH), Craniopharyngioma, Glioma, Ependymomas, Neurofibroma Congenital malformation Hydrocephalus, Rickett’s (skull malformation) Pineal tumor Trauma (brain injury stims TGF-a which stims GnRH) Encephalitis

31 1° Steroid Elevation Tumor Ovary Feminizing Adrenal Tumor
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

32 McCune Albright Syndrome
aka polyostic fibrous dysplasia Mechanism: 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 scan cafe au lait spots sexual precocity In What other disease do pts have cafe au lait spot and often pp? Neurofibromatosis Only tissues with defect are affected.

33 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 Why would I treat with GnRH agonist?

34 Findings in Various Disorders
Gonadal Size Basal FSH & LH E or T Levels DHEAS GnRH Response Idiopathic Increased Pubertal LH>FSH Cerebral Gonadal Unilat enlarged Decreased Flat* McCune- Albright Adrenal Small

35 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 Isolated Premature Thelarche usu. first few yrs. of life may be unilateral may wax and wane or persist to puberty mechanism unknown but pts have normal growth puberty Isolated Premature Menarche very rare - suspect trauma, foreign body, ingestion, local tumor Isolated Premature Adrenarche consider CAH 17OH-P baseline and androgens ? ACTH-stimulation sparse non-progressive hair growth on labia may be nl variant

36 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

37 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

38 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

39 Delayed Puberty Hypergonadotropic Hypogonadism 43%
Ovarian failure – abnormal karyotype (26%) Turner’s Syndrome Ovarian failure – normal karyotype 46XX (15%) 46XY ( 2%) Other (rare) 17-a hydroxylase deficiency (HTN, sexual infantilism, high P) Sickle Cells Disease, Torsion, Resistant Ovary Syndrome Ovarian failure – normal karyotype 17alpha hydroxylase deficiency (not failure)

40 Frequency of Delayed Puberty Etiologies
Hypogonadotropic Hypogonadism 31% Reversible (18%) Physiologic delay 10% Weight loss/anorexia 3% Prolactinoma % 1° hypothyroidism 1% CAH % Cushing’s %

41 Frequency of Delayed Puberty Etiologies
Hypogonadotropic Hypogonadism 31% Irreversible (13%) GnRH deficiency 7% Kallman’s, Prader Willi GP54R, Leptin Receptor deficiency Irradiation, infiltrating disease Hypopituitarism 3% Craniopharyngiomas 1% Congenital CNS defects % pituitary adenomas % Malignant pituitary tumor % Kallman’s, hyperprolactin

42 Frequency of Delayed Puberty Etiologies
Eugonadism % Mullerian agenesis 14% Inappropriate + feedback % (PCOS) Vaginal septum 3% Androgen insensitivity 1% Imperforate hymen %

43 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!

44 Idiopathic Precocious Puberty
Spontaneous increase in GnRH. Diagnosis of exclusion. Treat with GnRH-agonist.

45 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 2ndary chars by age 13 McCune-Albright Syndrome Clinical Differences between AIS, Transverse Septum and Mullerian Agenesis

46 Amenorrhea Primary: Secondary:
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.

47 Primary Amenorrhea Pearls
Physical Exam is essential. Breasts = Estrogen exposure. Normal height = Estrogen exposure. Uterus = Eliminates AIS, MRKH, Transverse Septum. Broad DDx Hypergonadotropic (ovarian failure) Hypogonadotropic (CNS, Pituitary issue) Eugonadal (Secondary amenorrhea w/u)


49 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. 17a hydroxylase deficiency (HTN, hypokalemia) with high 17-OHP

50 Steroid Synthesis Start with cholesterol (27C)
Rate limiting reaction is side chain cleavage 27C  21C Pregnenolone 21 Carbons: progestins, glucocorticoids, mineralocorticoids 19 Carbons: Androgens 18 Carbons: Estrogens

51 Cortisol levels are regulated tightly, others are not.
if cortisol synthesis is limited, ACTH increases to overcome blockage. precursors build up

52 Adrenal 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 deficiency 17b dehydrogenase deficiency Affects boys and girls differently

53 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.

54 CAH – 11b hydroxylase deficiency
Presentation more variable Hypertension Incr 11DOC Na+ overload Hypo K+ Female masculinized Addisons possible with stress

55 17a 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

56 CAH Diagnosis Screening Test is 17-OHP
Diagnosis made with ACTH stimulation test. Measure cortisol and precursors before and after.

57 CAH Summary The Cortisol, Aldo enzymes are named backwards.
21-hydroxylase def. is most common cause of CAH. 11-hydroxylase is 2nd Blockages lead to buildup of precursors and androgens.


59 Rotterdam Diagnostic Criteria Need two of three
Chronic Oligo-Anovulation Hyperandrogenism Polycystic Ovaries Rule out other causes

60 Differential Diagnosis
Late-onset congenital adrenal hyperplasia Idiopathic (constitutional) hirsutism Hypothalamic amenorrhea Premature ovarian failure Prolactin Thyroid

61 Differential Diagnosis
Cushing’s Syndrome Androgen producing tumors Acromegaly Anabolic drugs

62 Pathogenesis PCOS iSHBG Increased Converted to DHT androgens
Insulin resistance & obesity iSHBG Hirsutism Increased androgens Converted to DHT PCOS Anovulation iFSH Increased LH Polycystic ovaries Acyclic, elevated estrogen Amenorrhea

63 ‘Metabolic Syndrome’ Insulin Resistance Abdominal Obesity Diabetes
mellitus Hypertension Dyslipidemia High triglycerides Low HDL Atherosclerosis PCOS PCOS 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 Resistance Abdominal Obesity

64 PCOS Treatment Management of menses Management of hirsuitism
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!!!

65 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.

66 Causes of Hirsuitism Ethnicity
Idiopathic (intrinsic 5a reductase activity) Insulin stimulates pilosebaceous unit, ovarian androgen production and decreases SHBG PCOS CAH Ovarian tumor Adrenal tumor Cushings, hyperprolactinemia

67 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

68 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.

69 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.

70 Hyperprolactinemia Elevated prolactin:
May interfere with GnRH secretion to cause: Short luteal phase Oligomenorrhea Amenorrhea Galactorrhea Hirsuitism Bone loss Decreased libido in men

71 Hyperprolactinemia Inhibitors Stimulators
Dopamine (primary regulator via portal system) Prolactin Stimulators TRH Estrogen VIP (food) Oxytocin (sex, nipple stimulation) Many drugs

72 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.

73 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.

74 PRL and Rx Antipsychotics Antidepressants Opiates & Cocaine Verapamil
Methyldopa Metoclopramide H2 blockers ranitidine and cimetidine Estrogen Dilantin PRL levels usually return to normal within 2-4 days of stopping Rx

75 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)

76 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.

77 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.

78 Menopause

79 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.

80 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.

81 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 Layered clothing Avoiding cues Better sleep through estrogen Micronized progesterone Adjunctive medicine only if other methods fail. Antidepressants Hypnotic agents

82 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.

83 Management Protect bone. Protect against hyperplasia.
Alleviate symptoms. Promote healthy living.

84 Menopause-Associated Bone Loss
Bone Mass by Age and Sex Bone Mass Age (years) Men Women Menopause-Associated Bone Loss This 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:

85 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)

86 When to Measure BMD in Postmenopausal Women
One or more risk factors 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) Hypothyroidism Immobility* Poor nutrition Medications (steroids and heparin) I’ve added the list of medications to the end of this talk, for your own edification.

87 Treatment Options Calcium Vit D supplementation SERMs (raloxifene)
mg daily Vit D supplementation Sunshine IU/daily SERMs (raloxifene) HRT (oral or patch) Bisphosphonates (Etidronate, Alendronate) Weight bearing exercise

88 Affects of Various Treatments
Decreases Hip Fracture Rates Increases in BMD (%)† Decreases Vertebral Fracture Rates ERT/HRT Alendronate|| Risedronate|| Raloxifene|| Calcitonin Yes§ Yes¶ Yes No 5 - 6 5 - 8 1 - 2 Yes‡ Most Common Side Effect Breakthrough bleeding Gastric ulceration Upper GI symptoms Hot flushes Nasal irritation

89 WHI Results Absolute and Relative Risk or Benefit of HRT Heart attacks
Increased Absolute Risk per 10,000 Women/Yr Increased Absolute Benefit per 10,000 Women/Yr Relative Risk vs Placebo at 5. Years Health Event Heart attacks Strokes Breast cancer VTEs Colorectal cancer Hip fractures 1.29 1.41 1.26 2.11 0.63 0.66 7 8 18 6 5 But 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:

90 WHI E-only Arm What’s different What’s the similar
No increased CVD risk. No increased breast cancer risk. What’s the similar Increased risk of DVT Small increase risk of stroke Bone protection.

91 WHI NIH Recommendations
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. National Heart, Lung, and Blood Institute, National Institutes of Health. New facts about: estrogen/progestin hormone therapy. Available at:

92 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

93 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.

94 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

95 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.

96 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.

97 Infertility 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.

98 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.

99 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.

100 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

101 RPL: GEISHA Genetic 5% Endocrine 20% Infections 5% (controversial)
Immune 20% Structural 20% Anybody’s guess (unknown) 30%

102 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.

103 RPL -- Genetic Normal

104 6 possible gametes, only two can produce unaffected offspring.
RPL -- Genetic Robertsonian balanced translocation account for 2/3 genetic etiologies. 6 possible gametes, only two can produce unaffected offspring.

105 RPL -- Genetic Balanced recipricol translocation
Normal Abnormal Balanced Abnormal Four possible combinations with two unaffected gametes

106 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

107 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.

108 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

109 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 a Indicates HPA axis in fetus. marker of fetal well being? b/c DHEAS  Estriol


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