Amenorrhea

1. Amenorrhea Brittany Greene, MS3 Nikita Malhotra, MS3

2. Objectives • Review relevant findings on history, physical, laboratory tests and diagnostic imaging used in evaluation of amenorrhea, and how they point to the etiology of amenorrhea • Formulate a Differential Diagnosis • Describe the pharmacological, non-pharmacological and surgicaltreatment options for amenorrhea

3. The Case A 17 yo nulliparous female complains that she has not yet started menstruating. She denies weight loss or excessive exercise. Each of her sisters achieved menarche by age 13 years. The patient’s mother recalls a doctor mentioning that her daughter had a missing right kidney on an abdominal x-ray film. On examination, she is 5 feet 6 inches ( cm) and weigh 65 kg. Her blood pressure is 110/60. Her thyroid gland is normal on palpation. She has Tanner stage IV breast development and female external genitalia. She has Tanner stage IV axillary and pubic hair. There are no skin lesions.

4. Amenorrhea Primary Amenorrhea • no menses by age 14 in absence of 2 sexual characteristics OR no menses by age 16 with 2 sexual characteristics. Secondary Amenorrhea • no menses for >6 mo or 3 cycles after documented menarche Oligomenorrhea • Episodic vaginal bleeding occurring at intervals >35 d

5. Primary Amenorrhea *Always rule out pregnancy first • With 2ry Sexual Characteristics • Normal breast and pelvicdevelopment • Hypothyroidism • Hyperprolactinemia • PCOS • Hypothalamic dysfunction • Normal breast, ABNORMAL uterine development • Androgen insensitivity (XY) • Anatomic abnormalities (Müllerianagenesis, uterovaginal septum, imperforate hymen) • Without 2ry Sexual Characteristics • High FSH (hypergonadotropichypogonadism) • Gonadal dysgenesis • Abnormal sex chromosome (Turner’s XO) • Normal sex chromosome (46XX, 46XY) • Low FSH (hypogonadotropichypogonadism) • Constitutional delay (most common) • Congenital abnormalities (isolated GnRHdeficiency, pituitary failure (Kallman syndrome, head injury, pituitary adenoma, etc.) • Endocrine disorders (T1DM) • Pituitary tumors • Systemic disorders (IBD, JRA, chronic infections, etc.)

6. Secondary Amenorrhea *Always rule out pregnancy first SYSTEMS-BASED APPROACH • Hypothalamic-Endocrine • Functional hypothalamic amenorrhea • Clues: eating disorder, excessive exercise, stress • Hypothyroidism, hyperthyroidism • Clues: symptomatic thyroid disease • Hyperprolactinemia • Clues: galactorrhea • Adrenal androgen-secreting tumour, Late onset or mild CAH • Clues: hyperandrogenism

7. Secondary Amenorrhea *Always rule out pregnancy first SYSTEMS-BASED APPROACH • Pituitary • Sheehan syndrome (infarction of pituitary), pituitary adenoma, infiltration (sarcoidosis), head injury • Clues: hx of PPH, visual Sx, injury hx • Ovarian • Premature Ovarian Failure • Clues: symptomatic hypoestrogenemia • Polycystic Ovarian Syndrome, Ovarian tumour (Sertoli-Leydig) and hyperthecosis • Clues: hirsutism, obesity, insulin resistance • Uterine • AshermanSyndrome (uterine adhesions) • Clues: hx of D&C, endometrial trauma, radiation to pelvis, etc.; no progesterone withdrawal bleed • Iatrogenic • cyclophosphamide drugs, radiation

8. Approach to Amenorrhea: History and Physical • History • IDand HPI • ROS (Thyroid Sx, Pituitary Sx, hirsutism) • Family Hx of menarche • Exercise, diet, drugs, alcohol, sexually active • Physical Exam • Height, weight • Tanner Staging • Pelvic/vaginal exam

9. Approach to Amenorrhea: Investigations • Always do a βhCg! • U/S (anatomy, identify ?PCOS) • Hormonal workup (TSH, prolactin, FSH, LH, androgens, estradiol) • TSH • Prolactin • FSH • Androgens • Progesterone challenge to assess estrogen status • karyotype indicated if premature ovarian failure or absent/abnormal anatomy

10. Sexual Characteristics? Approach to Amenorrhea: Primary LH/FSH? Normal uterine/pelvic development? History & Physical Hypothyroidism Hyperprolactinemia PCOS Hypothalamic dysfunction Anatomic abnormalities (Müllerian agenesis, uterovaginal septum, imperforate hymen) Gonadal dysgenesis (Turners, 46XX, 46XY) AIS (XY) Constitutional delay (most common), Isolated GnRH deficiency, Pituitary failure/tumour, T1DM, Systemic disorders No Yes LH/FSH Pelvic & U/S No Low Yes No High Karyotype, high T Karyotype Pelvic & U/S Hormone panel: TSH, Prolactin Hormone panel: TSH, Prolactin, GnRH; work up for systemic disorders

11. Prolactin Normal Abnormal (high if >20ng/dL) Approach to Amenorrhea: Secondary Uterine defect Asherman’ssyndome HP axis dysfunction FSH / LH Hypothyroidism Pituitary adenoma Progestin challenge TSH CT head if > 100 ng/dL Withdrawal bleed No withdrawal bleed Pelvic U/S Hysterosalpingogram / Hysteroscopy Normal / Low High HP axis dysfunction Weight loss / excessive exercise Systemic diseases POF PCOS Hx & Physical Exam +/- U/S Hx & Physical Exam

12. Management • Primary AMENORRHEA • Hypothyroid, Hyperprolactinemia – correct underlying etiology • AIS • Gonadal resection after puberty • Psychological counselling • Creation of neo-vagina • Anatomical (imperforate hymen, transverse vaginal septum, cervical agenesis) • Surgical management • Mülleriandysgenesis (MRKH syndrome) • Psychological counselling • Creation of neo-vagina with dilation • Diagnostic study to confirm normal urinary system, spine, and heart

13. Management • Secondary AMENORRHEA • Functional hypothalamic amenorrhea • Reverse inciting factor • Hypothyroidism • Treat with synthetic thyroid hormone • Hyperprolactinemia • MRI/CT head to rule out lesion  surgery if lesion • If no lesion – bromocriptine, cabergoline if fertility desired; combined OCP if no fertility • Sheehan syndrome • Treat like primary deficiencies of respective target glands due to hypopituitarism • Premature Ovarian Failure • Hormonal therapy – estrogen + progestin • Polycystic Ovarian Syndrome • Weight loss, OCP, ovulation induction (clomiphene citrate) if fertility desired • Asherman Syndrome • Surgical – hysteroscopy to lyse adhesions

14. Back to the case… • 17 yo nulliparous female • denies weight loss or excessive exercise • sisters achieved menarche by age 13 years • missing right kidney on Abdo x-ray • 5 feet 6 inches, 65 kg • thyroid gland normal • Tanner stage IV development and female external genitalia • Tanner stage IV axillary and pubic hair • no skin lesions

15. Back to the case… • Primary amenorrhea • βhCg –ve, • Pelvic and U/S • Absent right kidney • Absent uterus/cervix, short vagina • Karyotype • XX Mülleriandysgenesis (MRKH syndrome)! • Psychological counselling • Creation of neo-vagina with dilation • Diagnostic study to confirm normal urinary system, spine, and heart

16. Thank you! Questions? References: Toronto Notes 2014, Case Files Obstetrics and Gynecology