Amenorrhea

AMENNORHEASALWA NEYAZICOSULTANT OBSTETRICIAN GYNECOLOGISTPEDIATRIC & ADOLESCENT GYNECOLOGIST

AMENORRHEAWHAT IS 1RY AMENORRHEA? Lack of the onset of menses by the 16 Y in a with 2ry sexual chct or by the age of 14 Y in without 2ry sexual development WHAT IS 2RY AMENORRHEA? Cessation of menses for a period of 6 months in a who previously had initiation of menses

CLASSIFICATION OF 1RY AMENORRHEA

A-BREAST ABSENT UTERUS PRESENT GONADAL DYSGENESIS1-TURNER SYNDROME 45XOVariations of Turner s syndrome 2-Mosaicism XO/XX not always shortThey will have menses , get pregnant then develop premature menopause3-Structural abnormalities of the X chromosome Deletion of the short arm of the X chromosome Short statureDeletion of the long arm normal HT, 2ry Amen, streak gonads

TURNER SYNDROMEFEATURES1ry amenorrhea No breast development Normal genital organs (external /internal)Streak gonads (ovaries are replaced by white nonfunctioning tissue)Short statureWebbed neck (Short broad neck) with a low hair lineCubitus vulgusShield chest / Widely spaced nipplesHigh arched palateShort 4th metacarpalCoarctation of the aorta or VSDHorse shoe kidney or single kidneyLymphedema

GONADAL DYSGENESIS

4-Pure gonadal dysgenesis 46XX Mutation in an autosomal gene Accelerated germ cell loss Streak gonads genetalia , normal Mullerian structuresRarely Turners Stigmata 5- Pure gonadal dysgenesis 46 XY genitalia Streak gonads risk of malignancy N Mullerian structures

GONADAL DYSGENESIS

6- 17- 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

HYPOTHALAMIC FILURE8-Isolated GnRH deficiency (Kalmans Syndrome)

Anosmia & Hypogonadotropic Hypogonadism X linked ----Mutation in the KAL geneMore common in > Midline defects Cleft lip & PalateSomatic defects color blindness, renal agenesis, retinitis pigmentosa, neurosensory deafness Lack 2ry sexual chct & the ability to smellHT & bone age appropriate for age

HYPOTHALAMIC FILURE9-Hypogonadotropic AmenorrheaCNS tumors GnRH pulses LH & FSH estradiolHypothalamic Lesions Craniopharyngioma granuloma, aqueduct stenosis , & the sequelae of encephalitis CNS tr interfere with the ve feedback of Dopamine on Prolactin Prolactin Other causes of HypoGonadotropic Amen hypothyroidism Prader Willi & Laurence Moon Biedl syndromes

HYPOTHALAMIC FILURE10-Anorexia Nervosa, Malnutrition, Excessive Exercise & Chronic Illness Functional GnRH deficiency May present with or without Breast developmentPhysical stress delay menarcheEach year of athelitic training before menarche delayed menarche 5 MOsteoporosis could occur with prolonged periods of Amenorrhea, low body Wt

B-BREAST PRESENT , UTERUS PRESENT

1-HYPOTHALAMIC CAUSES CNS lesions (tumors) Stress, Excessive exercise & low body Wt2-PITUITARY CAUSES Hyperprolactinemia Hypothyroidism TRH prolactin3-OVARIAN CAUSES PCO 4-OUTFLOW TRACT OBSTRUCTION Imperforate hymen Transverse vaginal septum

C-BREAST PRESENT , UTERUS ABSENT1-Testicular feminization/ Androgen insensitivityXY Karotype produce MIF Mullerian structures are absentComplete/ Partial absence of androgen receptorsX linked recessive or dominant Female external genitalia with Short blind vaginaTestosterone normal rangeBreast development due to periferal conversion of androgens to estrogensSexual hair is absent due to absence of androgen receptorsGonadectomy after puberty risk of malignancy (gonadoblastoma, dysgerminoma)

C-BREAST PRESENT , UTERUS ABSENT2- 5 reductase deficiencyAutosomal recessive Formation of the external genitalia requiers 5 REDUCTASE testosterone dihydrotestosterone

Formation of the internal wollfiane structures respond directly to testosterone

External genitalia with mild musculinizationAbsent uterusAt puberty testosterone secretion virilization

C-BREAST PRESENT , UTERUS ABSENT3-Mulerian Agenesis/ Mayer Rokitansky-Kuster-Huser syndromeEtiology ?Failure of mullerian duct development absence of the upper vagina, cx & uterus (uterine reminants may be found)The ovaries & fallopian tubes are presentNormal 46XX with normal exrenal genitaliaPt present with 1ry amenorroea47% have asociared urinary tract anomalies12% skeletal anomaliesRx psychological counseling surgical - vaginoplasty - excision of utrine reminant (if it has fuctioning endometrium) -vaginal dilators

D-BREAST ABSENT, UTERUS ABSENT

The least common presentation of 1ry AmenAll Pt are 46 XYTestosterone or NFSH/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 Insufecient estrogens for breast development

D-BREAST ABSENT, UTERUS ABSENT

B- 17 HYDROXYLASE DEFICIENCYSimilar to 17-20 desmolase defCortisol synthesis also BP, hypernatraemia & hypokalaemiaC-AGONADISM Degeneration of the testes (in utero) after the production of the MIF

INVESTIGATIONS & TREATRMENTHx & Physical examination to place the Pt in one of the four categories

CNS / HPDISORDERGonadal DysgenesisFSHFSHKaryotypeXYGonadectomyXXNa KProgestrone17 hydroxylasedeficiencyXOCT / MRIHEADCNSTUMORSTSHProlactinN Wt ExerciseStress

1-BREAST ABSENT UTERUS PRESENT TSHNPROLACTIN /NHypothyroidismKallmansSyndromeWt ExerciseStressWt ExerciseStress

TREATMENT1-BREAST ABSENT UTERUS PRESENTGonadal DysgenesisXYXXXOGonadectomy

Estrogen ProgestroneReplacementBreast development / MensesImprove Bone Min Density17OH-DifCortisol KallmansSyndromeEstrogen ProgestroneReplacementWt ExerciseStressPsychiatricHelp Treat thecause HypothyroidismThyroxinCNS TmrTreat accordingly

ProlactinTSHNMRI/CTPituitaryProlactin NTSH N+ProgestronechalangeAnovulatorycycle-Progestrone chalangeFSHHypoth/ pituit FailureFSHOvarianFailureMRI/CTR/OCNS TMRKaryotyping TSHHypothyroid2-BREAST PRESENT UTERUS PRESENTOut flowTractObstruction TSHHypothyroidProlactinTSHN TSHHypothyroid

TREATMENT2-BREAST PRESENT UTERUS PRESENTHypoth/ pituit FailureOvarianFailureOut flowTractObstructionProlactinTSHN TSHHypothyroidAnovulatorycycleHRTProgestinD16-25BromocriptinSurgeryThyroxin

Testosterone N3-BREAST PRESENT UTERUS ABSENTTestosterone NKaryotypingXYTesticularFeminization GonadectomyKaryotypingXXMullerian AgenesisU/S PelvisU/S MRI GonadsU/S PelvisU/S KIDNEYIVP

3-BREAST PRESENT UTERUS ABSENTXYTesticularFeminization XXMullerian AgenesisVaginoplastyVaginal dilatorsGonadectomyHRT

4-BREAST ABSENT UTERUS ABSENTAll46 XYPysical ExamU/SMRI forGonadsGonadectomyHRT

2RY AMENORRHEA

2RY AMENORRHEAWHAT IS 2RY AMENORRHEA?Cessation of menses for a period of 6 months or 3consecutive menstrual cycles in a who previously had initiation of mensesWHAT IS THE PREVELANCE OF AMENORRHEA?1.8-3%WHAT IS THE CLASSIFICATON OF 2RY AMENORRHEA?HypergonadotropicHypogonadotrpicEuogonadotrpicHperprolactinemiaAnatomic defects

CNS / HypothalamicPituitaryOvarianOutflow Uterine Cx Vaginal

HYPOGONADOTROPIC AMENORRHEA CNS / HYPOTHALAMIC Stress -endorphins GnRH FSH LH EstrogensExercise Excessive streneous exercise Runners & Ballet dancers 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 Persistant pulse frequency of luteal phase 2ry to neurotransmitter abnormality of the CNS (? Opioid activity)

HYPOGONADOTROPIC AMENORRHEAIS 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 2nd decade of life

HYPOGONADOTROPIC AMENORRHEAIS 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 < athletes with regular cyclesAnorexia nervosa Pt BMD (0.64) < Normal controls (0.72)Anorexia nervosa Pt may have osteoporotic fractures

HYPOGONADOTROPIC AMENORRHEASHEHANS SYNDROMEPiuitary failure following sever post partum hemorrhageDeficiency of all pituitary hormonesFSH & LH Failure of ovarian follicular development estrogen AmenorrheaRx HRT hMG for ovulation induction

TREATMENT OF HYPOGONADOTROPIC AMENORRHEA In training intensity to a level where regular menses resume HRT Cyclic estrogen / progestrone Premarin 1.25 mg continuously Medroxyprogestrone acetate 5 mg /D for 12 D each cycle OCP better compliance Anorexia nervosa Psychiatric Rx Meanwhile HRT Long term follow up Frequent relapses after attaining ideal body WtFunctional HypoGt Amen HRT / ovulation induction

EUOGONADOTROPIC AMENORRHEA

PCOAmenorrhea / anovulatory cyclesEnlarged polycystic ovariesInfertilityHyperinsulinemia / ObesityHyperandrogenism / hirsutism LHAcyclic estrogen production / unopposed by progesrtrone risk of endometrial hyperplasia/CaInheritable disorder with a complex inheritance pattern

TREATMENT OF PCOAmenorrheaIrrigular cyclesHirsutismInfertilityOCPOCPAntiandrogensCyclic progest-Protectendometrium-Regulate cycle-menorrhagiaOvarianAndrogenSHBGSprinolactoneCyproterone acetateFlutamideBind androgen receptorsAndrogens5reductase activity+ClomidhMGOvariandrillingOvulation 70%Pregnancy 40%Ovulation 92% Pregnancy 70%HyperinsulinismObesityGlucophageWt ClomidOvulation 70%Pregnancy 40%

HYPERGONADOTROPIC AMENORRHEAWHAT IS PREMATURE OVARIAN FAILURE (POF) ?2ry Amenorrhea FSH & LH estrogen Before the age of 40 Y

WHAT IS THE INCIDENCE OF POF ?1%WHAT IS THE CAUSE?Unknown / autoimmune / genetic factorsAssociated autoimmune disease 39%

POF

WHAT ARE THE PATHOLOGICAL CHCT OF POF ?TWO TYPESOvarian sclerosis & lack of folliclesResistant ovary syndromeHOW TO MANAGE POF?R/O other autoimmune diseases RH factor ANA, Antithyroid Antibodies, Antichromosomal Antibodies, glucose, cortisol, Ca , Ph, TSHHRT to prevent osteoprosisSpontaneous pregnancy can occur in women with POF on HRT 8%hMG/HCG glucocorticoids have been cliamed to give better pregnancy rates

HYPERPROLACTINEMIA

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

HYPERPROLACTINEMIA

Galactorrhea 1/3 of Pt Amenorrhea/ Hyperprolactinemia Pt at risk of osteoporosis due to estrogenTREATMENT - 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

TREATMENT OF HYPERPROLACTINEMIA

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 Normalize the menstrual cycle

TREATMENT OF HYPERPROLACTINEMIAIDIOPATHIC HYPERPROLACTINEMIA Rx Dopamine agonist Bromocriptin or PergolideSide effects of dopamine agonists -Postural hypotension -Nausea -Headache -Nasal stuffinessStarting with a low dose & gradually it helps to avoid The side effects

ANATOMICAL CAUSES

Uncommon cause of 2ry AmenorrheaAshermans Syndrome Hx of D/C for RPOC after abortion / puerperium or previous uterine infectionIntrauterine AdhesionsNormal hormones-ve progestrone chalange testDx HSG / HYSTROSCOPYRx Hystroscopic resection of the adhesions followed by estrogen therapy

Primary amenorrheaT 1-Amenorrhea A 16 years old girl presented to the clinic with primary amenorrhea, Tanner 1 breast development & normal female external genitaliaT 1- The next step in evaluating this patient would be Karyotyping & FSH/LH levelT 2-An ultrasound scan is helpful to assess the presence of a uterusF 3-Gonadal dysgenesis & Kalmans syndrome should not be considered in the deferential diagnosisF 4-Short stature & webbed neck will make the clinical diagnosis of Mullerian agenesis almost certain T 5-If the karyotyping is 46XX & FSH level is low then the problem is due to hypothalamic or CNS disorder

Androgen insensitivity syndromeT1- The characteristic features of androgen insensitivity syndrome include: absent uterus, breast developed & normal female external genitaliaF2- The karyotyping is 46XXT 3-They have a normal male testosterone levelT 4-Gonadectomy must be performed after puberty because of the increased risk of malignancyF 5-Estrogen replacement therapy is not indicated because they have enough estrogens to produce breast developmentPatients with primary amenorrhea and absent breast & uterusT1- All have 46XY karyotypeF 2- FSH/LH level is lowT 3-Could be due to deficiency of the enzymes required for androgen synthesis or degenration of the testes in uteroF 4-Gonadectomy is not recommended F 5-Hormon replacement therapy with testosterone is indicated

Secondary amenorrheaT 1-Excessive exercise & anorexia nervosa may result in hypogonadotropic amenorrhea F 2-Athletes who develop amenorrhea must be reassured that it is more convenient not to have menses with their heavy training schedule F 3-Anorexia nervosa patients will require Hormone replacement therapy as it will improve their disease

T 4-Polcystic ovary syndome T 4-Polcystic ovary syndome patients may respond to glucophage therapyT 5-Ovarian drilling is an option for patients with PCO not responding to medical treatment