Amenorrhea

1. Amenorrhea UNC School of Medicine Obstetrics and Gynecology Clerkship Case Based Seminar Series

2. Objectives for Amenorrhea • Define amenorrhea and oligomenorrhea • Explain the pathophysiology and identify the etiologies of amenorrhea and oligomenorrhea • Describe the symptoms and physical examination findings of amenorrhea and oligomenorrhea • Discuss the steps in the evaluation and management of amenorrhea and oligomenorrhea • Describe the consequences of untreated amenorrhea and oligomenorrhea

3. Definition • Amenorrhea – absence of menses • Primary amenorrhea – absence of menarche • Absence of menarche by age 14 without secondary sexual characteristics • Absence of menarche by age 16 with secondary sexual characteristics • Secondary amenorrhea – absence of menses in a previously menstruating woman • Absence of menses for > 6 months or duration of 3 menstrual cycles • Oligomenorrhea – reduction in frequency of menses • Cycle lengths > 35 days, but < 6 months

4. Primary Amenorrhea: Etiology • Pregnancy • Thyroid disease • Hyperprolactinemia • Prolactinoma • Hypergonadotropic hypogonadism • Gonadal dysgenesis (i.e. Turner syndrome) • Premature ovarian failure • Hypogonadotropic hypogonadism • Constitutional delay of puberty • Congenital GnRH deficiency (Kallman syndrome) • Functional hypothalamic amenorrhea (i.e. Anorexia or Bulimia nervosa) • CNS tumor (i.e. Craniopharyngioma) • Normogonadotropic • Congenital (i.e. Mullerian agenesis, Androgen Insensitivity syndrome) • Outflow tract obstruction (i.e. Imperforate hymen, Transverse vaginal septum) • Hyperandrogenic anovulation (i.e. PCOS, Cushing’s disease)

5. Primary Amenorrhea: Etiology • Most common etiologies: • Chromosomal abnormalities causing gonadal dysgenesis – 50% • Hypothalamic hypogonadism – 20% • Absence of the uterus, cervix, or vagina – 15% • Transverse vaginal septum or imperforate hymen – 5% • Pituitary disease – 5%

6. Primary Amenorrhea: History

7. Primary Amenorrhea: Physical Exam • Evaluation of pubertal development (height, weight) and growth chart • Breast development (Tanner staging) • Evaluation for features of Turner’s syndrome • Webbed neck, low hair line, shield chest, widely spaced nipples • Examine skin for hirsutism, acne, striae, increased pigmentation, and vitiligo • Pelvic exam • Clitoral size • Intactness of hymen • Depth of vagina • Presence of vaginal septum • Presence of cervix, uterus, and ovaries

8. Tanner Stages Stage 1: Prepubertal, no palpable breast tissue or pubic hair. Stage 2: Development of breast bud; sparse, straight pubic hair. Stage 3: Enlargement of breast; pubic hair darker, coarser, and curlier. Stage 4: Areola and papilla project above the breast; pubic hair adult-like in appearance. Stage 5: Recession of areola to match contour of breast; pubic hair extends to thigh. Figure from: Roede, MJ, van Wieringen, JC. Growth diagrams 1980: Netherlands third nation-wide survey. TijdschrSocGezondheids 1985; 63:1. Reproduced with permission from the author.

9. Primary Amenorrhea: Evaluation Secondary sexual characteristics present? No Yes Measure FSH Perform ultrasound of uterus FSH < 5 FSH > 20 Uterus absent or abnormal Uterus present or normal Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism Karyotype analysis Outflow obstruction • Hypothalamic amenorrhea • Constitutional delay of puberty • Kallman syndrome • CNS tumor Karyotype analysis 46,XY 46,XX No Yes 46,XX 45,XO Müllerian agenesis Evaluate for 2° amenorrhea Androgen insensitivity syndrome Imperforate hymen Transverse vaginal septum Premature ovarian failure Turner’s syndrome • PCOS • Cushing’s

10. Secondary Amenorrhea/Oligomenorrhea: Etiology • Pregnancy • Thyroid disease • Hyperprolactinemia • Prolactinoma • Breastfeeding, Breast stimulation • Medication (i.e. Antipsychotics, Antidepressants) • Hypergonadotropic hypogonadism • Postmenopausal ovarian failure • Premature ovarian failure • Hypogonadotropic hypogonadism • Functional hypothalamic amenorrhea (i.e. Anorexia or Bulimia nervosa) • CNS tumor (i.e. Craniopharyngioma) • Sheehan’s syndrome • Chronic illness • Normogonadotropic • Outflow tract obstruction (i.e. Asherman’s syndrome, Cervical stenosis) • Hyperandrogenic anovulation (i.e. PCOS, Cushing’s disease, CAH)

11. Secondary Amenorrhea/Oligomenorrhea: Etiology • Most common etiologies: • Ovarian disease – 40% • Hypothalamic dysfunction – 35% • Pituitary disease – 19% • Uterine disease – 5% • Other – 1%

12. Secondary Amenorrhea/Oligomenorrhea: History

13. Secondary Amenorrhea/Oligomenorrhea: Physical Exam • General • Evaluation of height, weight, and BMI • Examine skin for hirsutism, acne, striae, acanthosis nigricans, thickness or thinness, and easy bruisability • Thyroid exam • Breast exam • Express for galactorrhea • Pelvic exam • Atrophy • Vaginal dryness

14. Secondary Amenorrhea/Oligomenorrhea: Evaluation Negative urine pregnancy test Check TSH and prolactin Normal prolactin, Abnormal TSH Normal TSH, Abnormal prolactin Both normal Progestin challenge test Prolactin < 100 ng/mL Prolactin > 100 ng/mL Thyroid disease Withdrawal bleed No withdrawal bleed • Medication MRI to evaluate for prolactinoma Normogonadotropic hypogonadism Estrogen/progestin Challenge test Negative MRI Consider other causes • Hyperandrogenic anovulation • PCOS • Cushing’s No withdrawal bleed Withdrawal bleed • Medication Outflow obstruction Check FSH FSH > 20 IU/L Hypergonadotrpoic hypogonadism • Asherman’s • Cervical stenosis • Ovarian failure • Hypothalamic amenorrhea • Chronic illness MRI to evaluate for pituitary tumor Normal MRI Hypogonadotropic hypogonadism FSH < 5IU/L

15. Secondary Amenorrhea/Oligomenorrhea: Evaluation • Progestin challenge test • Medroxyprogesterone acetate 10 mg daily for 10 days • IF withdrawal bleed occurs – Not outflow tract obstruction • IF no withdrawal bleed occurs – Estrogen/Progestin challenge test • Estrogen/Progestin challenge test • Oral conjugated estrogen 0.625 – 2.5 mg daily for 35 days • Medroxyprogesterone acetate 10 mg daily for 26-35 days • IF no withdrawal bleed occurs – Endometrial scarring • Hysterosalpingogram or Hysteroscopy to evaluate endometrial cavity

16. Secondary Amenorrhea/Oligomenorrhea: Evaluation • Evaluation of hyperandrogenism • Symptoms: hirsutism, acne, alopecia, masculinization, and virilization • Differential diagnosis: • Adrenal disorders: Atypical congenital adrenal hyperplasia (CAH), Cushing’s syndrome, Adrenal neoplasm • Ovarian disorders: PCOS, Ovarian neoplasms • Lab: Testosterone, DHEA-S, 17α-hydroxyprogesterone

17. Amenorrhea/Oligomenorrhea: Management • Treatment should be directed at… • Correcting the underlying pathology • Helping woman to achieve fertility (IF desired) • Preventing the complications of disease process • Consequences of untreated amenorrhea/oligomenorrhea: • Hypoestrogenism – Osteoporosis, Infertility • Hyperestrogenism – Heart disease, Stroke, Diabetes Mellitus, Breast cancer (controversial), Endometrial hyperplasia and Endometrial cancer

18. Amenorrhea/Oligomenorrhea: Management *Causes of primary amenorrhea only

19. Bottom Line Concepts • A thorough history and physical examination as well as laboratory testing can help narrow the diagnosis of amenorrhea. • In patients with primary amenorrhea, the presence or absence of sexual development should direct evaluation. • Constitutional delay of puberty is a diagnosis of exclusion. • The definitive method to identify hypothalamic-pituitary dysfunction is to measure FSH and prolactin levels. • If the patient has abnormal uterine development, a karyotype analysis should be performed to diagnose müllerian agenesis versus chromosomal abnormalities. • In a patient with secondary amenorrhea, pregnancy should be ruled out prior to further workup. • Treatment goals of amennorrhea and oligomenorrhea include prevention of complications such as osteoporosis, endometrial hyperplasia and heart disease; preservation of fertility; and in primary amenorrhea, progression of normal pubertal development.

20. References and Resources • APGO Medical Student Educational Objectives, 9th edition, (2009), Educational Topic 43 (p92-93). • Beckman & Ling: Obstetrics and Gynecology, 6th edition, (2010), Charles RB Beckmann, Frank W Ling, Barabara M Barzansky, William NP Herbert, Douglas W Laube, Roger P Smith. Chapter 35 (p315-319). • Hacker & Moore: Hacker and Moore's Essentials of Obstetrics and Gynecology, 5th edition (2009), Neville F Hacker, Joseph C Gambone, Calvin J Hobel. Chapter 32 (p355-363). • Master-Hunter T, Helman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006 Apr 15; 73(8): 1374-82.