1. APPROACH TO PATIENTS WITH AMENORRHEA Enrico Gil C. Oblepias, MD, FPOGS Associate Professor University of the Philippines Philippine General Hospital

2. INTRODUCTION Menstruation is the: physical herald to physiologic capacity for conceiving monthly prepares the uterus for implantation shedding of the uterine lining at the end of the reproductive cycle

3. Amenorrhea is the: absence of menstruation is met with some extent with anxiety. INTRODUCTION

4. FIRST STEP Ask when the last menses were. This will systematically cut down differentials to a more manageable and economical number. Dichotomously dividing these into primary and secondary cases of amenorrhea.

5. AMENORRHEA Never had menses? Primary amenorrhea: Failure of menarche to occur when expected in relation to the onset of pubertal development.  No menarche by age 16 years with signs of pubertal development.  No onset of pubertal development by age 14 years.

6. Secondary amenorrhea: Absence of menstruation for 3 or more months in a previously menstruating women of reproductive age. Used to have menses? AMENORRHEA

7. HPO AXIS The menstrual cycle is actually 3 different inter-related cycles synchronously taking place at the same time. These are: (1) the ovarian cycle (2) the hormonal cycle (3) the endometrial cycle.

8. Amenorrhea is only a manifestation of the problem. HPO AXIS Problem may be endocrinologic or embryologic: +/- secondary sexual characteristics +/- female internal genitalia

9. PRIMARY AMENORRHEA Quick Rules to Remember No breast – no or low estrogen < FSH, LH – hypothalamic or pituitarian > FSH, LH – ovarian No uterus 46XX –Mullerian agenesis 46XY – Pseudohermaphroditism

10. PHYSICAL EXAM

11. Primary Amenorrhea Without breast With breast Without uterus Category 3 Category2 With uterus Category 1 Category 4 PHYSICAL EXAM

12. Category 1: Breasts Absent and Uterus Present – Think low estrogen, check FSH A. Gonadal failure: High FSH (hypergonadotropic) 1. 45X (Turner’s Syndrome) 2. 46X; abnormal X (Deletion Disorders) 3. Mosaicism (X/XX, X/XX/XXX) 4. Pure XX (PGD, 46XX or Perrault syndrome ) 5. 17 alpha-hydroxylase deficiency (46XX) PRIMARY AMENORRHEA

13. Category 1: Breasts Absent and Uterus Present – Think low estrogen, check FSH B. CNS-hypothalamic pituitary disorders: Low FSH (hypogonadotropic) 1. CNS lesions 2. Inadequate GnRH – Kallmann’s 3. Isolated gonadotrophin insufficiency PRIMARY AMENORRHEA

14. High Blood Pressure Normal High 45 X 46 X, abn X Mosaic Pure gondal Dysgenesis w/ 26 XX or 46 XY 17 alpha Hydroxylase Deficiency (Congenital Adrenal Hyperplasia) Karyotype Serum FSH Hypergonadotropic Hypogonadism CT scan, Prolactin Hypogonadotropic Hypogonadism NormalHigh Non-prolactin Secreting tumor of the CNS Inadequate GnRH Pituitary Adenoma Low or Normal Category 1: Breasts Absent and Uterus Present

15. Category 2: Breasts Present and Uterus Absent – Think (+) estrogen, (?) MIF: check karyotype A.Mayer Rokitansky Kuster Hauser Syndrome (46XX) vaginal agenesis and no uterus caused by random birth defect B.Androgen Insensitivity Syndrome (46 XY) cells are not receptive to testosterone thus patient has intra-abdominal testes and no uterus or vagina PRIMARY AMENORRHEA

16. Karyotyping Testosterone 46XX Normal 46XY High Congenital Absence of the Uterus Androgen Insensitivity (Testicular Feminization) Category 2: Breasts Present and Uterus Absent

17. Category 3: Breasts Absent and Uterus Absent – This is rare. – Think low estrogen and (+) MIF: check a karyotype A. 17, 20-Desmolase deficiency (46 XY) B. 17 alpha hydroxylase deficiency (46 XY) C. Pure XY (PGD, 46XY or Swyer’s Syndrome) D. Agonadism PRIMARY AMENORRHEA

18. Karyotype (XY) Laparoscopy testes present testes absent Enzyme Deficiency: 17, 20 desmolase 17 - Hydroxylase (with XY karyotype) Agonadism Category 3: Breasts Absent and Uterus Absent

19. Category 4: Breasts Present and Uterus Present –Think (+) estrogen, (-) MIF – Evaluate like secondary amenorrhea A. Hypothalamic causes B. Pituitary causes C. Ovarian causes D. Uterine causes and outflow tract causes (?) PRIMARY AMENORRHEA

20. Prolactin Normal High Hypothalamic causes Pituitary causes Ovarian causes Uterine causes Outflow tract disorders Pituitary Lesion (Prolactinoma) Category 4: Breasts Present and Uterus Present

21. Cryptomenorrhea Despite the absence of menstrual flow, withdrawal bleeding does take place – albeit concealed. intermittent abdominal pain possible difficulty with micturition possible lower abdominal swelling -imperforate hymen -transverse vaginal septum with functioning uterus -isolated vaginal agenesis with functioning uterus -isolated cervical agenesis with functioning uterus

22. Cryptomenorrhea

23. CNS; HP Disorder Gonadal Failure History and physical examination completed for a patient with primary amenorrhea Secondary sexual characteristics present NoYes Measure FSH and LH levels Uterus absent or abnormal Uterus present or normal Karyotype analysis Outflow obstruction FSH and LH < 5 IU/ L Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism Karyotype analysis 46, XY46, XX Mullerian Agenesis Androgen Sensitivity Syndrome NoYes Evaluate for secondary amenorrhea Imperforate hymen or transverse vaginal septum Perform ultrasonography of uterus Evaluation of Primary Amenorrhea FSH > 20 IU/ L and LH > 40 IU/ L

24. SECONDARY AMENORRHEA

25. In women of reproductive age, pregnancy is the most common cause of secondary amenorrhea. Pregnancy The reality of this must be ascertained before any intervention is instituted for non-obstetric amenorrhea.

26. Give them a progestin challenge to induce menstruation. Dichotomously dividing secondary cases of amenorrhea to those with and without estrogen priming of the endometrium SECONDARY AMENORRHEA

27. 10mg of progesterone orally for 5- 10 days A withdrawal bleed occurring within ten days of a progesterone challenge is a positive result and a diagnosis of anovulation may be established. PROGESTERONE CHALLENGE TEST (PCT)

28. POSITIVE HP Dysfunction Hyperthyroidism PCOS PROGESTERONE CHALLENGE TEST (PCT) NEGATIVE Hyperprolactenemia Hypothyroidism Hypopituitarism POF Asherman’s

29. Hypothalamic-Pituitary Dysfunction can result from any condition that disturbs the HPO axis the immediate cause is a decrease or lack of GnRH pulses this may be idiopathic, or may be the result of stress or weight loss anorexia (most common cause of secondary amenorrhea in teenagers) POSITIVE PCT

30. Hyperthyroidism although the sex binding globulin is increased, testosterones and estrogen are also increased relatively, compared to normal, there is more circulating free estrogen and free testosterone with testosterone being converted further peripherally to estrogen the elevated estrogen concentration then leads to state similar to anovulation POSITIVE PCT

31. Polycystic Ovaries Syndrome a persistent anovulatory state result in a steady supply of estrogen and the lack of progesterone’s anti-estrogen effect brings about continuous stimulation of the receptive endometrium the most common endocrinopathy in reproductive- age women and amenorrhea or oligomenorrhea is quite frequent POSITIVE PCT

32. Hyperprolactenemia elevated levels of prolactin inhibits GnRH by increasing the release of dopamine from the arcuate nucleus of the hypothalamus inhibiting gonadal steroidogenesis, which is the hypoestrogenism may be caused by either compression of the pituitary or excess production from a pituitary gland adenoma NEGATIVE PCT

33. Hypothyroidism alpha subunits of LH, FSH, and TSH are identical and only vary in their beta subunits a cross-reaction between the TSH, FSH, LH leads to a negative feedback suppressing the release of FSH and LH affecting follicular maturation and ovulation the endometrium fails to go through the proliferation and secretory phases resulting in the absence of menstruation. stimulation of the anterior pituitary leading to an increased release of prolactin has also been considered NEGATIVE PCT

34. Hypopituitarism caused by necrosis of the anterior pituitary due to blood loss and hypovolemic shock Sheehan’s syndrome if obstetric in origin Simmond’s syndrome if non-obstetric FSH and LH become deficient and lead to the lack of menstruation NEGATIVE PCT

35. Premature Ovarian Failure is an end organ phenomenon occurring before the age of 40 characterized by (1) lack of ovarian response to tropic stimulation; (2) lack of gonadal negative feed-back; (3) elevated circulating levels of FSH and LH pathogenesis of this disorder has not been determined it is possible that there is an autoimmune basis for this NEGATIVE PCT

36. Asherman’s Syndrome is characterized by the formation of scar tissues obliterating the endometrial cavity that prevents the occurrence of normal menstrual periods occurs most frequently after a vigorous scraping during completion curettage can also result from other pelvic surgeries like cesarean sections, myomectomies, pelvic irradiation, schistosomiasis and genital tuberculosis cervical stenosis after a cone biopsy or LEEP NEGATIVE PCT

37. Medroxyprogesterone acetate (5-10 mg BID for 5 days) Uterine Bleeding No Uterine Bleeding Step 2 Step 3 STEP 1: Evaluation of Secondary Amenorrhea

38. Uterine bleeding: positive response LH High (>25mIU/ml) Normal or Low Testosterone (Ovarian) DHEAS (Adrenal) Ultrasound Hypothalamic Dysfunction (drug, stress or exercise, weight loss) Polycystic Ovarian Syndrome Prolactin Normal High Induce bleeding monthly with progestins, oral contraceptives; Dexamethasone Spironolactone Induce uterine bleeding monthly with DMPA 10 mg/day for 12 days Work-up for hyperprolactinemia Hyperthyroidism TSH STEP 2: Evaluation of Secondary Amenorrhea

39. No uterine bleeding: negative response FSH Premature Ovarian Failure Hypothalamic Pituitary Disorder High (>30 mIU/ml) Normal or Low TSH (hypothyroidism) Prolactin (hyperprolactinemia) CT scan of CNS If < 25 years old; karyotype If < 35 years old; antinuclear antibodies, 24 hr urine cortisol test Negative Estrogen Progesterone test Asherman’s Syndrome HSG Hysteroscopy STEP 3: Evaluation of Primary Amenorrhea

40. GENERAL PRINCIPLES OF MANAGEMENT OF AMENORRHEA 1.attempts to restore ovulatory function by treating underlying cause 2.if not possible, HRT (estrogen and progesterone) is given to hypo-estrogenic amenorrheic women 3.periodic progestogen may be given instead for anovulatory women 4.if Y chromosome is present gonadectomy is indicated 5.create outflow tract or at least a sexually functional vagina 6.many cases require frequent re-evaluation

41. Amenorrhea may be caused by any of the many differentials discussed herein. The appropriate management of this will depend on the accurate diagnosis of the etiology. A logical approach makes it possible to do it systematically and in a shorter period of time. Some conditions may be correctable while others are not. Objectives of treatment may vary, but the underlying cause in each must be addressed at the very least every time. CONCLUSION