12. & 13. Amennorrhea and Secondary Amenorrhea.pptx

Clinical Medicine Amenorrhea Kraig Smith MD Primary Amenorrhea • Reading Reference: Beckmann, pp. 380-384 • Learning Objectives: a.Define normal menstruation including anatomic requirements, hormonal requirements. b.Define primary amenorrhea. c.Categorize primary amenorrhea into basic types: i. H...

Clinical Medicine Amenorrhea Kraig Smith MD Primary Amenorrhea • Reading Reference: Beckmann, pp. 380-384 • Learning Objectives: a.Define normal menstruation including anatomic requirements, hormonal requirements. b.Define primary amenorrhea. c.Categorize primary amenorrhea into basic types: i. Hypogonadotropic Hypogonadism ii.Hypergonadotropic Hypogonadism iii.Eugonadotrophic Amenorrhea a.List the etiology of each type of amenorrhea based on clinical presentation. b.List pertinent lab tests and imaging studies useful in defining types of primary amenorrhea. c.Recall the management of each type of primary Primary Amenorrhea a. Define how embryology plays a role in primary amenorrhea. b. Compare and contrast Mullerian dysgenesis and androgen insensitivity. • Definitions • Primary amenorrhea: 1. No menses by age 13 in the absence of secondary sexual characteristics 2. No menses by age 15 in the presence of secondary sexual characteristics • Secondary amenorrhea >3-6 months of amenorrhea (or absence of 3 cycles) in a woman who has previously menstruated • Oligomenorrhea Menses at intervals >40 days but less than 6 months Primary Amenorrhea Primary amenorrhea ANATOMIC REQUIREMENTS FOR MENSTRUATION ) Gonadotropins FSH, LH Primary amenorrhea ANATOMIC REQUIREMENTS FOR MENSTRUATION HYPOTHALAMUS pulsatile GnRH ANTERIOR PITUITARY OUTFLOW TRACT OVARY (uterus, vagina) FSH LH Estrogen Progestero ne Menses Primary amenorrhea What is it called when something goes wrong in the….. ANATOMIC REQUIREMENTS FOR MENSTRUATION HYPOTHALAMUS Hypo, Hyper or Eu Gonadotropic hypogonadism?? ANTERIOR PITUITARY OVARY OUTFLOW TRACT Hypo, Hyper or Eu Gonadotropic hypogonadism?? Hypo, Hyper or Eu Gonadotropic?? Primary amenorrhea ANATOMIC REQUIREMENTS MENSTRUATION HYPOTHALAMUS ANTERIORPITUITARY Hypogonadotropic Hypogonadism OVARY Hypergonadotropic hypogonadism OUTFLOW TRACT Eugonadotropic Primary amenorrhea ANATOMIC REQUIREMENT S MENSTRUATIO N HYPOTHALAMU S Hypogonadotropic Hypogonadism PITUITARY OVARY OUTFLOW TRACT Hypergonadotropic hypogonadism Eugonadotropic Primary amenorrhea ANATOMIC REQUIREMENT S MENSTRUATIO N HYPOTHALAMU S Hypogonadotropic Hypogonadism •Stress •Kallmann Syndrome •Hypothyroidism •Pituitary Adenomas •Pituitary and CNS tumors PITUITARY OVARY OUTFLOW TRACT Hypergonadotropic hypogonadism Gonadal dysgenesis X0 XX XY Enzyme deficiencies Eugonadotropic •Mullerian dysgenesis •Intrauterine scar • Surgery • Infection •AIS (elevated gonadotropins)* Hypogonadotropic hypogonadism (secondary hypogonadism) • Stress Increases CRH, decreases pulsatile GnRH • Kallman Syndrome failure of olfactory axonal and GnRH neuronal migration poorly defined secondary sexual characteristics (mutation Chromosome X) • Pituitary dysfunction KEY: elevated prolactin interferes with pulsatile GnRH • Hypothyroidism • Elevated TRH stimulates prolactin from anterior pituitary • Pituitary adenomas • Other CNS lesions compressing pituitary stalk Hypergonadtropic Hypogonadism (Primary hypogonadism…… Think “primarily” an ovarian problem) • Turner syndrome (XO) • Ovaries replaced with fibrous tissue • XX gonadal dysgenesis • non-functional streak ovaries • Swyer syndrome (XY) • Testes do not develop: • no testosterone • no anti-mullerian substance • Uterus, vagina present • KEY: needs orchiectomy! (boards!) Eugonadopropic (think outflow track obstruction) • Mullerian dysgenesis • Intrauterine scarring • Surgery • Infection: Tuberculosis • Androgen insensitivity syndrome • Defective testosterone receptors • MIS present, thus absent uterus, upper vagina Scarring from tuberculosis infection To summarize types of primary amenorrhea *If FSH and LH are low  hypogonadotropic hypogonadism (secondary hypogonadism) *If FSH and LH are high  hypergonadotrophic hypogonadism (primary hypogonadism) • * FSH/ LH are normal eugonadotropic (outflow obstruction) • DEMO Case Presentation Chief complaint “My stomach hurts and feels full.” Ms. JM A 15-year-old G0P0 female with no prior medical complaints is brought to the emergency department by her mother. She complains of low, midline abdominal pain. Our patients’ stories • History   • Physical Exam • Labs/Imaging • Assessment • Plan         History of present illness GYN history OB history Medical history Surgical history Medications Allergies Social history Family history Case Presentation History of present illness • JM reports that the pain began approximately 48 hours ago. It increased slowly at first but in the last 4 hours, has increased dramatically. She has had prior episodes of pain for the last year, but none as severe. • The last episode was approximately 1 month ago. The pain is dull and creates a sense of fullness in her lower abdomen. Case Presentation History of present illness What other questions do you have? Case Presentation History of present illness What other questions do you have? • • • • • • • • Nausea, vomiting? Fevers? Chills? Change in bowel habits? Dysuria? Frequency? Menstrual history Using contraceptives? Sexually active? Vaginal discharge? Others? Gyn and obstetric history Gynecologic History • Menstrual history: • Not reached menarche yet • PAP history: N/A • Sexual history • Has never been sexually active • Contraceptive history: N/A Obstetric History: • Never been pregnant Does our patient meet criteria for primary amenorrhea? Case Presentation History • Medical history: no medical diseases • Surgical history: no prior surgeries • Medications: daily vitamin • Allergies: No known drug allergies • Social history: • Lives with parents • No use of tobacco or alcohol • Denies family violence Case Presentation Physical exam: • Vital signs: T = 98.4 HR=90, BP =110/80 • General: Appears uncomfortable but in minimal distress • Breasts: SMR 4 • Abdominal exam • Soft, no rebound or guarding fullness in lower abdomen, slightly tender • Pelvic exam • Normal external genitalia • Patient and parents decline internal exam What is your current differential? Remember Our patients’ stories • History • Physical Exam • Labs/Imaging • Assessment • Plan What laboratory studies/imaging do you want to order next? Case presentation Laboratory Tests for abdominal pain • Pregnancy test • CBC with differential • Liver Function tests • Urinalysis Imaging studies: • Ultrasound • CT Tests for amenorrhea      TSH Prolactin Estrogen FSH Karyotype Laboratory results • • • • BHCG = negative HCT= 39, WBC= 8.0 UA= negative for leukocyte esterase, blood Liver function tests = WNL (with-in normal limits) • • • • • TSH 2.0 mIU/mL (normal) Prolactin 5 mcg/mL (normal) Estrogen 50 pg/mL (normal) FSH (normal) Karyotype: XX What imaging study do you want? Ultrasound Transabdominal ultrasound results Pelvic exam findings Assessment: Vaginal septum with hematocolpus http://www.netterimages.com/images/vtn/000/000/002/2704150x150.jpg Embryology Prior to 8 weeks Male/female embryo has two pairs of genital ducts -Mesonephric (Wolffian) -Paramesonephric (Mullerian) Male: Mesonephric duct (Wolffian ducts) Week 5-6 testes develop Sertoli cells produce MIS(Mullerian Inhibiting substance) Paramesonephric ducts regress Female: Paramesonephric duct Embryology • IN The Female  Mullerian ducts fuse  Septum degnerates  Mullerian ducts merge with urogenital ridge and septum degenerates Embryology key: IMPORTANT • Mullerian ducts form the • • • • Upper 2/3 of vagina Cervix Uterus Fallopian tubes • Urogenital ridge forms the: • Lower 1/3 of vagina • Renal anomalies are often associated Mullerian anomalies Treatment http://www.netterimages.com/images/vtn/000/000/002/2704150x150.jpg www.pharmacy2u.co.uk/product.asp?id=AM VD1 Vaginal Septum Androgen Insensitivity Syndrome Androgen Insensitivity Syndrome (AIS) (another condition with absent uterus, vagina) • Karyotype: XY • Androgen receptors cannot respond to androgen • Testes present, Mullerian Inhibiting Substance produced therefore no Mullerian structures are present (absent uterus, fallopian tubes, upper vagina). • Lower vagina is present, but may be only a dimple • Orchiectomy is indicated Let’s compare Mullerian dysgenesis Breast tissue Uterus and vagina Testosterone Karyotype Complications Androgen Insensitivity Let’s compare Mullerian agenesis Androgen Insensitivity Breast tissue Normal Normal Uterus and vagina Various anomalies Absent uterus, blind vagina Testosterone Normal Male ranges, high Karyotype 46 XX 46 XY Complications Renal anomalies Needs gonadectomy Case presentation #2 • A 15-year-old female is referred to your office for never having menstruated. She has no prior medical history. On exam, she is 50 in tall, weighs 100 lbs . Her breast and pubic hair are both Tanner stage 1. The abdominal examination reveals no masses. The pelvic exam is consistent with a prepubescent female. http://www.tsregistry.org/images/ Mom.jpg Laboratory results • BHCG negative • • • • • TSH 2.0 mIU/mL (normal) Prolactin 5 mcg/mL (normal) Estrogen (low) FSH > 86 IU/mL (elevated) Karyotype: XO •What is the diagnosis? Turner Syndrome  Most common genotype X,O - Mosaicism possible (45X/46 XX)  Ovaries replaced with fibrous tissue - Amenorrhea because little estrogen. Phenotype: - External female genitalia - Uterus and fallopian tubes develop normally until puberty when estrogen induced maturation fails to occur - Short stature, webbed neck, shield chest. Associated with cardiovascular and renal anomalies http://www.biology.ualberta.ca/people/mike_harrington/genet418/handouts/ Treatment • Estrogen and progesterone replacement at puberty normal pubertal development including pubic and axillary hair, breast development, cyclic vaginal bleeding • Growth hormone prior to administration of gonadotropins will help women with Turner’s syndrome to gain height. • Pregnancy??? • possible with oocyte donation. Another type of gonadal dysgenesis: Swyer Syndrome • Defective SRY region • The early stages of testicular formation require the action of several genes, including the SRY (Sex determining Region of the Y chromosome). Mutations of the SRY account for most cases of Swyer syndrome. • Testes fail to develop in genetically male (XY) fetus • No testosterone • No antimullerian substance • Mullerian ducts develop into normal internal female organs uterus, fallopian tubes, cervix and vagina. • Orchiectomy is indicated! Workup for Delayed Puberty FSH, LH Bone age Consider TSH, free T4 and sex hormones (estradiol, testosterone) Serum Prolactin Workup for any suspected chronic conditions (CBC, ESR, CMP) A karyotype should be performed in every patient with primary hypogonadism to evaluate the possibility of Klinefelter syndrome in boys and Turner syndrome in girls • Consider MRI to visualize hypothalamic region and sella turcica • • • • • • Question 1 • 1. Which of the following groups of patients with gonadal atresia will need a gonadectomy because of an increased risk of malignancy? A. B. C. D. E. Turner syndrome (XO) and AIS (XY) AIS (XY) and Swyer syndrome (XY) Swyer syndrome (XY) and Turner (XO) Gonadal dysgenesis (XX) and AIS (XY) None of the above Question 2 • 2. Which of the following patients will not menstruate even with exogenous estrogen and progesterone. A. B. C. D. E. Turner syndrome (XO) Swyer syndrome (XY) AIS (XY) Gonadal dysgenesis (XX) Pituitary microadenoma Question 3 • 3. 15 year-old female presents to the office who has never begun her menses. On physical exam the pubic and axillary hair is Tanner stage 2, breast development may be stage 2. Upon further questioning she reports she has a poor sense of smell. Her urine pregnancy test is negative, LH and FSH are low. Her karyotype is XX. Normal ovaries and uterus visualized on ultrasound. What is the most likely A.are Kallman syndrome diagnosis. B. • C. D. E. Gonadal dysgenesis Mullerian agenesis AIS Stress Clinical Medicine Secondary Amenorrhea Kraig Smith MD Secondary Amenorrhea • learning Objectives: • Define secondary amenorrhea and oligomenorrhea. • Identify the primary causes of secondary amenorrhea including pregnancy, anovulation, premature ovarian failure and outflow obstruction. • Discuss the prevalence of polycystic ovarian syndrome (PCOS) and the diagnostic criteria. • List treatment options for PCOS and discuss potential long-term consequences of the syndrome. Secondary Amenorrhea • List treatment options for PCOS and discuss potential long-term consequences of the syndrome. • Recall and apply the algorithm for evaluating secondary amenorrhea. • Recognize treatment options for secondary amenorrhea for each etiology. • Define hirsutism and virilization. • Identify etiologies of hirsutism. • Describe the steps in the evaluation and initial management for hirsutism and virilization. Secondary Amenorrhea Definition Secondary Amenorrhea: Absence of a menstrual period for greater than 3 months in a woman with regular cycles or greater than 6 months in a woman with irregular cycles. Oligomenorrhea: fewer than 9 menstrual cycles per year or cycle length greater than 35 days Secondary Amenorrhea Secondary amenorrhea CASE #1 • CC : “My periods have stopped” • HPI: Pt is a 29-year-old who presents to the office with a history of no menstrual cycle for a consecutive 8 months. Prior to this she had regular cycles approximately 29 days apart. Each cycle lasted approximately 5 days with heavier flow on the first two days. Secondary amenorrhea CASE #1 • What other questions do you need to ask? Secondary amenorrhea • Most common causes of Secondary Amenorrhea • Pregnancy • Anovulation • PCOS • Premature ovarian failure(menopause) • Outflow obstruction Secondary Amenorrhea Work-up • Important History • Hypothalamic Causes • - stress, changes in weight, changes in diet or excercise (eating disorders)? • -medications? • -signs or symptoms of PCOS? • Pituitary Disease • Headaches, visual field defects,galctorrhea • Ovarian Deficiency • -signs of Estrogen deficiency (hot flashes ,night Secondary Amenorrhea Work-up Uterine Any history of uterine trauma ( D and C,Csection, instrumentation of uterus) Secondary Amenorrhea • Physical Examination • Body Measurements Height and Weight • Exam for Hirsuitism,acne,acanthosis nigricans • Look for evidence of estrogen deficiency Secondary amenorrhea CASE #1 • ROS : Denies - visual changes, negative neuro changes • : Admits - recent facial acne, increase in facial hair growth • : Admits - recent weight gain 30 lbs. in last year • :Admits – Hair growth over chest and thighs • PMH: • Chronic Illness – none • PSH-none • Hospitalization- none Secondary amenorrhea CASE #1 • FH-Mother age 56 living Diabetes type 2 Father living age 58 history of hypertension Secondary amenorrhea CASE #1 • Physical Exam • VS---P 89, BP 130/80 RR 18 Weight 208lb ht. 5’5” 02 sat 96%ra • HEENT- PERRLA, Facial hair noted around chin and face Acanthosis nigricans on neck • Pulmonary-BBS present and equal No wheezes or rales or dullness to percussion • CV—RRR no M,G,R • Abdomen -no lesions BS present in 4 quads no percussion tenderness no rebound and nontender to deep palpation Secondary amenorrhea CASE #1 • Physical Exam continued • Pelvic Exam—External Genitalia without lesions no clitoromegaly, • _Speculum- cervix appears nulliparous no lesions • - Bimanual---uterus is normal size and shape and anterior • - Adnexa without masses but slightly enlarged bilaterally • Extremities –no lesions no edema Secondary amenorrhea CASE #1 Secondary amenorrhea CASE #1 Secondary Amenorrhea Case #1 • What Labs / Tests do we want?? Secondary Amenorrhea Work-up • Must Rule Out Pregnancy First! Secondary Amenorrhea Case #1 • What Labs / Tests do we want?? • TSH • Prolactin • FSH • Progesterone Withdrawal • Testosterone,DHEAS • Ultrasound?? Secondary Amenorrhea Case #1 • Lab Findings • TSH—normal • FSH__normal • Prolactin---normal • DHEAS—normal Testosterone –elevated slightly • Secondary Amenorrhea Case #1 •Menses after progesterone challenge?? • YEP! Diagnostic criteria for PCOS Rotterdam Criteria 2003 Two of following required for diagnosis: • Menstrual irregularity due to anovulation or oligo-ovulation * can be oligo or metrorrhagia • Hyperandrogenism Evidence may be clinical or laboratory • Polycystic ovaries (by ultrasound) Etiology of PCOS= UNKNOWN! But some thoughts… PCOS originates at the time of puberty possibly due to interplay of: (1)obesity & excess availability and production of androgens (BUT….20% of patients with PCOS normal BMI!) (2) intrauterine environment (3) genetic factors (X-linked, autosomal dominant, no current genetic tests) Ultimately, disruption in the H-P-O axis Obesity and PCOS Obesity often the common factor (50%), with PCOS originates at the time of increased acquisition of body fat Compensatory hyperinsulinemia can directly ↓ hepatic SHBG production Decreased SHBG results in more bioavailable circulating free androgens (this increase in free androgens may be a tropic stimulus to androgen production in the adrenal gland too!) Androstenedione is aromatized to estrone with-in adipocytes Estrone has positive feedback on pituitary LH secretion Increased LH stimulates theca lutein cells to increase androstenedione With increased androstenedione , there is an increase in testosterone production which causes acne and hirsutism Secondary Amenorrhea PCOS • After diagnosis is made must also evaluate for cardiovascular risks: • Blood Pressure and BMI • Fasting Lipid Profile • 2 hour GTT or Fasting Blood glucose and HGB A 1 c Secondary Amenorrhea PCOS-Management • Aimed at the individual Components of the Syndrome • Weight-loss strategies • Menstrual Dysfunction • -OCPs • -Ovulation induction • Hyperandrogenic Symptoms • - OCPs • -Spironolactone • Type2 Diabetes and Lipid disoreders • -treat accordingly Hirsutism • Affects 5-10 % of pre-menopausal women • Diagnosis-clinical diagnosis defined as dark coarse hairs in androgen sensitive areas • Measured using Ferriman and Gallwey scale • Usually has an underlying endocrine disorder (PCOS) most common • Contrast with virilization---more severe form with masculinizing features Hirsutism Causes • PCOS • NCCAH-non classic congenital hyperplasia (21 hydroxylase deficiency) • Ovarian and adrenal androgen secreting tumors Hirsutism Diagnosis • Clinical features • Lab evaluation • Total Testosterone (ovarian source) • DHEAS (adrenal) • 17-OHP (NCCAH) • Elevated androgens-next step is imaging US and MRI r/o androgen secreting tumors Hirsutism Hirsutism • Idiopathic • -normal serum androgens • -no menstrual irregularities • no identifiable cause virilization • More severe for of hyperandrogenism with masculinizing features - Baldness -Clitoromegaly -Deep voice -Muscle growth Usually results from androgen secreting tumor! virilization Secondary ammenorrhea References 1. Hacker and Moore. Essentials of Obstetrics and Gynecology, Fifth Edition 2. UpToDate Online, 3. Precis; Reproductive Endocrinology, ACOG 1998 4. Association of Professors of Gynecology and Obstetrics. APGO Medical Student Educational Objectives, 9th edition. 2009. Crofton, MD. 5. Beck, W. NMS Obstetrics and Gynecology. 4th edition 6. CDC.gov