1. Dr. Hazem Al-Mandeel, M.D Assistant Professor & Consultant Obstetrics & Gynecology College of Medicine King Saud University OB/GYN Rotation-course 481 GYN

2. 1ry Amenorrhea: is the lack of onset of menses by age 16 in female with 2ry sexual characteristics OR by age of 14 in female without 2ry sexual development 2ry Amenorrhea: is the cessation of menses for a period of 6 months in a female who previously had initiation of menses

3. Gonadal Failure 43% Congenital Absence of the vagina 14% Constitutional delay 10%

4. Chronic anovulation 39% Hypothyroidisim/Hyperprolactinemia 20% Weight loss/anorexia 16%

5. Primary Sexual characteristics AbsentPresent PE 5 -Reductase def. 17-20 Desmolase def. 17 Hydroxylase Def. (All XY Karyotype) UterusAbsent Normal FSHHigh Normal Kallman’s Syndrome Physiologic Delay Karyotype XX Y line Turner (XO) HCG + Pregnancy HCG -ve Primary No Yes PE Secondary R/O Asherman’s Cx Stenosis Normal TSH, PRL, FSH Mullerian Abn AIS True Hemaphrodite

6. TSH, PRL, FSH TSH Normal Abnormal HypoThyroidism HyperThyroidism ProlactinHighHyperprolactenemia Normal FSHHigh Ovarian Failure Radiation Chemo Infection Autoimune Galacrosemia Idiopathic Normal Estrogen LowNormal CNS Exam PCOS Idiopathic Ovarian Neoplasms Obesity Cushing’s CAH Pituitary Hypothalamic Lesions: Tumors Infection Infarction Failure Toxic Chronic Disease

7. 1-TURNER SYNDROME: 45XO 2-Mosaicism of Turner’s: XO/XX  not always short, they will have menses, get pregnant then develop premature menopause 3-Structural abnormalities of the X chromosome: deletion of the short arm of the X chromosome  Short stature deletion of the long arm  normal Ht., 2ry Amenorrhea, & streak gonads

8. 1ry amenorrhea No breast development ♀ Normal ♀ genital organs (external /internal) Streak gonads (ovaries are replaced by nonfunctioning tissue) Short stature Webbed neck (Short broad neck) with a low hair line Cubitus vulgus Shield chest / Widely spaced nipples High arched palate Short 4 th metacarpal Coarctation of the aorta or VSD Horse shoe kidney or single kidney Lymphedema

9. 4-Pure gonadal dysgenesis : 46XX, mutation in an autosomal gene  accelerated germ cell loss  streak gonads. Features: ♀ genetalia with normal mullerian structures 5- Pure gonadal dysgenesis : 46 XY. Features: normal ♀ genitalia and mullerian structures with streak gonads  ↑ risk of malignancy

10. 6- 17-α hydroxylase deficiency (rare)  ovarian synthesis of estrogens  1ry Amen Sexual immaturity  cortisol  ↑ ACTH ↑ Na  K ↑ BP ↑ Progestrone as it is not converted to cortisol 7- Galactosaemia (rare) galactosaemia is toxic to oocytes

11. Anosmia & Hypogonadotropic Hypogonadism X linked ----Mutation in the KAL gene More common in ♂ > ♀ Midline defects  Cleft lip & Palate Somatic defects  color blindness, renal agenesis, retinitis pigmentosa, neurosensory deafness Lack 2ry sexual chct & the ability to smell HT & bone age appropriate for age

12. CNS tumors   GnRH pulses  LH & FSH   estradiol Hypothalamic Lesions  Craniopharyngioma granuloma, aqueduct stenosis, & encephalitis CNS tumors  interfere with the –ve feedback of Dopamine on Prolactin  ↑ Prolactin Other causes of HypoGonadotropic Amen  hypothyroidism

13. Functional GnRH deficiency May present with or without Breast development Physical stress delay menarche Each year of athelitic training before menarche delayed menarche 5 M Osteoporosis could occur with prolonged periods of Amenorrhea, low body Wt

14. 1. HYPOTHALAMIC CAUSES: CNS lesions (tumors) Stress, Excessive exercise & low body Wt 2. PITUITARY CAUSES: Hyperprolactinemia Hypothyroidism  ↑ TRH  ↑ prolactin 3. OVARIAN CAUSES: Polycystic ovarian disease/syndrome 4. OUTFLOW TRACT OBSTRUCTION: Imperforate hymen Transverse vaginal septum

15. XY Karotype  produce MIF  Mullerian structures are absent Complete/ Partial absence of androgen receptors X-linked recessive or dominant Female external genitalia with Short blind vagina Testosterone  normal ♂ range Breast development due to peripheral conversion of androgens to estrogens Sexual hair is absent due to absence of androgen receptors Gonadectomy after puberty  ↑ risk of malignancy (gonadoblastoma, dysgerminoma)

16. Autosomal recessive Formation of the ♂ external genitalia requires 5 α REDUCTASE testosterone     dihydrotestosterone Formation of the internal wolfiane structures respond directly to testosterone External genitalia ♀ with mild musculinization Absent uterus At puberty   testosterone secretion  virilization

17. Etiology ? Failure of mullerian duct development  absence of the upper vagina, cx & uterus (uterine reminants may be found) The ovaries & fallopian tubes are present Normal 46XX ♀ with normal exrenal genitalia Pt present with 1ry amenorroea 47% have asociared urinary tract anomalies 12% skeletal anomalies  Rx  psychological counseling surgical treatments: vaginoplasty, excision of utrine reminant (if it has fuctioning endometrium)

18. The least common presentation of 1ry Amenorrhea All patients are 46 XY Testosterone   or N FSH/LH  ↑ A. 17-20 DESMOLASE DEFICIENCY The enzyme required for the synthesis of Androgens   androgens   estrogen The testes produce MIF therefore no mullerian structures ♀ external genitalia Insufficient estrogens for breast development

19. B. 17 α HYDROXYLASE DEFICIENCY Similar to 17-20 desmolase deficiency. Cortisol synthesis also   ↑ BP, hypernatraemia & hypokalaemia C. AGONADISM Degeneration of the testes (in utero) after the production of the MIF

20. History & Physical examination to place the Pt in one of the four categories

21. CNS / HP DISORDER Gonadal Dysgenesis  FSH ↑↑FSH Karyotype XY Gonadectomy XX ↑Na  K ↑ Progestrone 17α hydroxylase deficiency XO CT / MRI HEAD CNS TUMORS ↑ TSH Prolactin  N  Wt ↑Exercise Stress 1-BREAST ABSENT UTERUS PRESENT TSH  N PROLACTIN  ↑ /N Hypothyroidism Kallman’s Syndrome  Wt ↑Exercise Stress  Wt ↑Exercise Stress

22. TREATMENT 1-BREAST ABSENT UTERUS PRESENT Gonadal Dysgenesis XY XXXO Gonadectomy Estrogen Progestrone Replacement Breast development / Menses Improve Bone Min Density 17αOH-Dif Cortisol Kallman’s Syndrome Estrogen Progestrone Replacement  Wt ↑Exercise Stress Psychiatric Help Treat thecause Hypothyroidism  Thyroxin CNS Tmr Treat accordingly

23. ↑Prolactin TSH  N MRI/CT Pituitary Prolactin  N TSH  N +Progestrone chalange Anovulatory cycle -Progestrone chalange  FSH Hypoth/ pituit Failure ↑FSH Ovarian Failure MRI/CT R/O CNS TMR Karyotyping ↑ TSH Hypothyroid 2-BREAST PRESENT UTERUS PRESENT Out flow Tract Obstruction ↑ TSH Hypothyroid ↑Prolactin TSH  N ↑ TSH Hypothyroid

24. TREATMENT 2-BREAST PRESENT UTERUS PRESENT Hypoth/ pituit Failure Ovarian Failure Out flow Tract Obstruction ↑Prolactin TSH  N ↑ TSH Hypothyroid Anovulatory cycle HRT Progestin D16-25 Bromocriptin Surgery Thyroxin

25. Testosterone  N♀ 3-BREAST PRESENT UTERUS ABSENT ↑Testosterone  N♂ Karyotyping XY Testicular Feminization Gonadectomy Karyotyping XX Mullerian Agenesis U/S Pelvis U/S MRI  Gonads U/S Pelvis U/S KIDNEY IVP

26. 3-BREAST PRESENT UTERUS ABSENT XY Testicular Feminization XX Mullerian Agenesis Vaginoplasty Vaginal dilators Gonadectomy HRT

27. 4-BREAST ABSENT UTERUS ABSENT All 46 XY Pysical Exam U/S MRI for Gonads Gonadectomy HRT

29. WHAT IS 2RY AMENORRHEA? Cessation of menses for a period of 6 months or 3 consecutive menstrual cycles in a ♀ who previously had initiation of menses WHAT IS THE PREVELANCE OF AMENORRHEA? 1.8-3% WHAT IS THE CLASSIFICATON OF 2RY AMENORRHEA? Hypergonadotropic Hypogonadotrpic Euogonadotrpic Hperprolactinemia Anatomic defects

30. Stress  ↑ β-endorphins  GnRH   FSH  LH   Estrogens Exercise  Excessive streneous exercise  e.g.: runners Mechanism  Similar to stress Wt. loss “ Anorexia nervosa ”  More frequent in adolescent & young adults  0.5-1% of women aged 15 – 30 years  15% < Ideal Body Wt. Functional “ Non of the above causes ”  No LH pulses or persistent pulse frequency of “ Luteal Phase ” 2ry to neurotransmitter abnormality of the CNS (? ↑ Opioid activity)

31. IS IT OF ANY CONCERN IF THESE YOUNG WOMEN BECOME AMENORRHEIC ? HYPOESTROGENISM is the main concern WHY IS IT MORE WORRYING THAN THE MENOPAUSAL WOMEN ? During adolescence estrogen plays a critical role in determining PEAK BONE DENSITY which reached in the 2 nd decade of life

32. IS THERE ANY EVIDENCE OF ITS EFFECT ON THE BONES? Amenorrheic Athletes  Bone Mineral Density (BMD) in lumbar spines, femur, tibia Athletes with menstrual irregularities  BMD but less than athletes with regular cycles Anorexia nervosa Pt  BMD (0.64) Anorexia nervosa Pt may have osteoporotic fractures

33. SHEHAN ’ S SYNDROME Pituitary failure  following sever post partum hemorrhage Deficiency of all pituitary hormones  FSH & LH  Failure of ovarian follicular development  estrogen  Amenorrhea Rx  HRT

34.  In training intensity to a level where regular menses resume HRT  Cyclic estrogen / progestrone; e.g.: Premarin continuously + Medroxyprogestrone acetate for 12 days  OCP  better compliance Anorexia nervosa  Psychiatric Rx + HRT Long term follow up  Frequent relapses after attaining ideal body wt. Functional Amennorhea  HRT / ovulation induction

35. Polycystic Ovarian Disease / Syndrome Amenorrhea / anovulatory cycles Enlarged polycystic ovaries Infertility Hyperinsulinemia / Obesity Hyperandrogenism / hirsutism ↑ LH Acyclic estrogen production / unopposed by progesrtrone  ↑ risk of endometrial hyperplasia/Ca Inheritable disorder with a complex inheritance pattern

36. TREATMENT OF PCO Amenorrhea Irrigular cycles Hirsutism Infertility OCP Anti androgens Cyclic progest -Protect endometrium -Regulate cycle -  menorrhagia  Ovarian Androgen ↑SHBG Sprinolactone Cyproterone acetate Flutamide Bind androgen receptors  Androgens  5αreductase activity + Clomid hMG Ovarian drilling Ovulation 70% Pregnancy 40% Ovulation 92% Pregnancy 70% Hyperinsulinism Obesity Gluco phage Wt  Clomid Ovulation 70% Pregnancy 40%

37. WHAT IS PREMATURE OVARIAN FAILURE (POF) ? 2ry Amenorrhea ↑ FSH & LH  Estrogen Before the age of 40 years WHAT IS THE INCIDENCE OF POF ? 1% WHAT IS THE CAUSE? Unknown / autoimmune / genetic factors Associated autoimmune disease 39%

38. WHAT ARE THE PATHOLOGICAL CHARACTERISTICS OF POF ? Ovarian sclerosis & lack of follicles Resistant ovary syndrome HOW TO MANAGE POF? R/O other autoimmune diseases  RH factor ANA, Antithyroid Antibodies, Antichromosomal Antibodies, glucose, cortisol, Ca, Ph, TSH HRT  to prevent osteoprosis Spontaneous pregnancy can occur in 8% of women with POF on HRT

39. The most common pituitary cause of 2ry Amenorrhea Causes -Pituitary adenoma -Idiopathic -Loss of inhibition by dopamine  Hypothalamic or pituitary stalk lesions -Hypothyroidism -PCOS -Medications  phenothiazines, haloperidol monoamineoxidase inhibitors, TCA, H2 receptors blockers

40. Galactorrhea  1/3 of Pt Amenorrhea/ Hyperprolactinemia Pt  at risk of osteoporosis due to  estrogen TREATMENT - Hypothyroidism  L-Thyroxin  If still amenorrheic after RX  Parlodel + Thuroxin -If no substitute for the medications that cause hyperprolactinemia  HRT -Hypothalamic or pituitary stalk lesions  Surgical excision

41. PITUITARY ADENOMA (PROLACTINOMA) *Macroadenoma  > 10 mm  Respond to medical Rx  Dopamine agonist (bromocriptin)   size of the tumor &  prolactin level  Pt not responding to medical Rx or not tolerating it  Surgery/ Irradiation *Microadenoma  < 10mm  remain stable in size Rx  Bromocriptin   prolactin level to normalize the menstrual cycle

42. IDIOPATHIC HYPERPROLACTINEMIA Rx  Dopamine agonist  Bromocriptin or Pergolide Side effects of dopamine agonists -Postural hypotension -Nausea -Headache -Nasal stuffiness Starting with a low dose & gradually ↑ it helps to avoid the side effects

43. Uncommon cause of 2ry Amenorrhea Asherman ’ s Syndrome  Hx of D/C for RPOC after abortion / puerperium or previous uterine infection Intrauterine Adhesions Normal hormones Negative progestrone chalange test Dx  HSG / HYSTROSCOPY Rx  Hystroscopic resection of the adhesions followed by estrogen therapy