1. Amenorrhea & Anovulation Andrea Chymiy, MD Swedish Family Medicine

2. Amenorrhea Transient, intermittent, or permanent Results from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina

3. Primary vs. Secondary Amenorrhea Primary: Absence of menarche by the age of 16. Secondary: absence of menses for more than three cycle intervals or six months in women who were previously menstruating

4. Causes of Primary Amenorrhea  Chromosomal abnormalities — 45%  Physiologic delay of puberty — 20%  Müllerian agenesis — 15%  Transverse vaginal septum or imperforate hymen — 5%  Absent hypothalamic production of GnRH - 5%  Anorexia nervosa — 2%  Hypopituitarism — 2%

5. Diagnostic Evaluation for Primary Amenorrhea: Normal pubertal development? Was pt’s neonatal/childhood health normal? Family history of delayed/absent menarche? Any symptoms of virilization? Any galactorrhea? (hyperprolactinemia)

6. More history questions… Any recent increase in stress, or change in weight, diet, or exercise habits? Is pt taking any meds or drugs? Short stature compared to family members? Any symptoms of other hypothalamic-pituitary disease (headaches, visual field defects, fatigue, polyuria or polydipsia?)

7. Physical Exam: Evaluation of pubertal development - including height, weight, & Tanner staging. Pelvic exam to check for presence of cervix, uterus, ovaries (may need ultrasound) Check skin for signs of androgen excess (acanthosis nigras, hirsutism, acne, & striae) and vitiligo (thyroid disorders) Check for physical features of Turner syndrome (low hair line, web neck, shield chest, and widely spaced nipples)

8. Tanner staging

9. Acanthosis nigrans

10. Striae

11. Vitiligo

12. Typical features of Turner Syndrome

13. If uterus not found on exam… If normal vagina or uterus not obviously present on PE, a pelvic U/S is performed to confirm the presence or absence of ovaries, uterus, and cervix. If no uterus found, further evaluation should include a karyotype and measurement of serum testosterone.

14. If patient does have a uterus… …and no evidence of an imperforate hymen, vaginal septum, or congenital absence of the vagina is found, an endocrine evaluation should be performed. Check serum B-HCG, FSH, TSH, & prolactin. If signs or symptoms of hyperandrogenism, serum testosterone & DHEA-S should be measured to assess for an androgen- secreting tumor.

15. Correcting the underlying pathology Surgery is often required in patients with either congenital anatomic lesions or Y chromosome material. In those patients with Y chromosome material, gonadectomy should be performed to prevent the development of gonadal neoplasia. Gonadectomy should be delayed until after puberty in patients with complete androgen insensitivity syndrome.

16. Treatment of PCOS Hirsutism: removal of hair by electrolysis or laser treatment. Slowing of hair growth by administration of an oral contraceptive alone or in combination with an antiandrogen (eg: Sprironolactone) Endometrial protection: OCPs Anovulation & Infertility: Clomiphene, GnRH, Metformin

17. Hypothalamic amenorrhea We’ll discuss treatment options after we talk about Secondary Amenorrhea!

18. Secondary Amenorrhea First, second & third cause is pregnancy, followed by…. Ovarian disease — 40% Hypothalamic dysfunction — 35% Pituitary disease — 19% Uterine disease — 5% Other — 1%

19. Ovarian causes of amenorrhea Hyperandrogenism (from internal or external sources) Ovarian failure due to normal or early menopause

20. Diagnosing the etiology of secondary amenorrhea Rule out pregnancy!

21. Pertinent history in work-up of secondary amenorrhea  Recent stress, wt loss, diet or exercise changes, or illness?  Meds (Recent OCP initiation, danazol, meto- clopramide, anti-psychotics?)  Symptoms of other hypothalamic-pituitary disease, including headaches, visual field defects, fatigue, or polyuria and polydipsia?

22. Other important stuff in the history…  Symptoms of estrogen deficiency, including hot flashes, vaginal dryness, poor sleep, or decreased libido? Galactorrhea, hirsutism, acne, and/or a history of irregular menses? An history of obstetrical catastrophe, severe bleeding, dilatation and curettage, or endometritis or other infection that might have caused scarring of the endometrial lining ?

23. Physical exam findings Height & weight, BMI Any evidence of systemic illness or cachexia Breast exam – check for galactorrhea Check for hirsutism, acne, striae, acanthosis nigricans, vitiligo, skin thickness or thinness, and easy bruisability

24. Initial lab evaluations for secondary amenorrhea Urine or serum B-HCG Serum prolactin, TSH, FSH DHEA-S and testosterone if indicated

25. High serum prolactin  Screen twice before ordering imaging  Goal of imaging is to rule out a hypothalamic or pituitary tumor. CT is frequently adequate, but MRI provides a better view of the hypothalamic-pituitary area  In the case of a prolactinoma, the image will allow determination of whether it is a microadenoma ( 1 cm)

26. High serum FSH Indicates the presence of ovarian failure. This test should be repeated monthly on three occasions to confirm persistent elevation. A karyotype should be considered in most women of secondary amenorrhea age 30 years or younger to r/o complete or partial deletion of the X chromosome, or presence of any Y chromosome material

27. High serum androgen concentrations A high serum androgen value may solidify the diagnosis of PCOS, or may raise the question of an androgen-secreting tumor of the ovary or adrenal gland. initiate evaluation for a tumor if the serum concentration of testosterone is greater than 150 to 200 ng/mL or that of DHEA-S is greater than 700 µg/dL

28. Normal or low serum gonadotropin concentrations and all other tests normal One of the most common outcomes of laboratory testing in women with amenorrhea. Women with hypothalamic amenorrhea have normal to low FSH values, with FSH typically higher than LH Cranial MRI is indicated in all women without an a clear explanation for hypogonadotropic hypogonadism No further testing is required if the onset of amenorrhea is recent or is easily explained and there are no symptoms suggestive of other disease

29. Normal serum prolactin & FSH with history of uterine instrumentation Evaluation for Asherman's syndrome should be performed. Many clinicians start with a progestin challenge (Provera 10 mg qD x 10 d) If withdrawal bleeding occurs, an outflow tract disorder has been ruled out.

30. Evaluating for Asherman’s syndrome If bleeding does not occur, estrogen and progestin should be administered (conjugated estrogen x 35 d with medroxyprogesterone for last 10 d) failure to bleed upon cessation of this therapy strongly suggests endometrial scarring. In this situation, a hysterosalpingogram or direct visualization of the endometrial cavity with a hysteroscope can confirm the diagnosis of Asherman syndrome

31. Treatment for functional hypothalamic amenorrhea For athletic women, adequate caloric intake to match energy expenditur31e is often followed by resumption of menses (70-80%) All women athletes with amenorrhea should be encouraged to take 1200 to 1500 mg of calcium daily and supplemental vitamin D (400 IU daily)

32. Basal BMI vs probability of resumption of menstruation

33. Treatment for functional hypothalamic amenorrhea Nonathletic women who are underweight or who appear to have nutritional deficiencies - should have nutritional counseling - Can be referred to a multidisciplinary team specializing in the assessment and treatment of individuals with eating disorders.

34. Hyperprolactinemia Can be corrected with a dopamine agonist in most women (cabergoline, bromocriptine, pergolide) Other options include surgery, radiation therapy and estrogen

35. Treatment of ovarian causes of secondary amenorrhea No treatment available for primary ovarian failure, but women should take supplemental calcium and vitamin D. All the texts and journal articles also recommend HRT… PCOS can be treated as described previously

36. Treatment of Asherman’s syndrome Therapy consists of hysteroscopic lysis of adhesions followed by long-term estrogen administration to stimulate regrowth of endometrial tissue

39. Case 1: 17 yo female with primary amenorrhea Normal pubertal development Normal health No family history of delayed puberty Not involved in athletics Does well in school Not taking any meds

40. Case 1: Physical Exam  Thin young woman (10% below IBW)  Normal genitalia  No galactorrhea  Tanner stage 4 Laboratory values  Urine and serum B-HCG negative  Prolactin, FSH, TSH all normal

41. Case 1: Further history Patient’s parents concerned about her eating habits (very low fat intake and restricting calories)

42. Diagnosis: Hypothalamic Amenorrhea  Etiology is most likely inadequate caloric and fat intake.  Patient should be referred for evaluation for an eating disorder.  Chances of normal menstruation are very good if patient takes in adequate calories.

43. Case 2: 24 yo woman with secondary amenorrhea Menarche at age 12 Periods have always been irregular Now c/o amenorrhea x 10 months Overweight Wants to get pregnant

44. Case 2: Physical Exam Obese female Acne Normal genitalia Mild hirsutism

45. Case 2: Laboratory findings Urine B-HCG negative TSH, FSH and Prolactin wnl Testosterone 180 ng/dL Pelvic U/S findings show polycystic ovaries

46. U/S findings in PCOS

47. Case 3: 29 yo woman with 18-month h/o amenorrhea Normal development No family history of amenorrhea Does not exercise excessively or restrict diet Denies galactorrhea Has h/o SAB with subsequent D & C

48. Case 3: Physical Exam WDWN young woman Normal exam No galactorrhea

49. Case 3: Laboratory findings Urine B-HCG negative Prolactin wnl TSH, FSH, LH all wnl

50. Case 3: Further work-up Fails Provera challenge Fails 1-month trial of estrogen + progesterone Pelvic U/S shows no uterine stripe Hysteroscope confirms diagnosis of…Asherman’s Syndrome

51. Thank you !