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AMENNORHEA SALWA NEYAZI COSULTANT OBSTETRICIAN GYNECOLOGIST
PEDIATRIC & ADOLESCENT GYNECOLOGIST
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Objectives Definition of 1ry & 2ry Amenorrhea
Classssification of 1ry Amenorrhea 1-breast absent uterus present gonadal dysgenesis, hypothalamic causes, hypothyroidism, hyperprolactinemia,17α hydroxylase deficiency 2-breast present , uterus present Hypypothalamic/pituitary failure, ovarian failure, hypothroidism, hyperprolactinemia, outflow tractobstruction, anovulation 3-breast present , uterus absent Androgen insensitivity, 5alpha reductase def., mullarian agenesiss 4-breast absent, uterus absent (XY) Failure of testosterone synthesis due to enzymatic defects, testicular degeneration Investigation & treatment of 1ry Amenorrhea Classification of 2ry AmeHypergonadotropic Hypogonadotrpic, euogonadotrpic, hperprolactinemia, anatomic defects Management of 2ry Amenorrhea
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AMENORRHEA WHAT 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 OR for three previous cycle intervals Primary amenorrhea T 1-
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CLASSIFICATION OF 1RY AMENORRHEA
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A-BREAST ABSENT UTERUS PRESENT GONADAL DYSGENESIS
1-TURNER SYNDROME 45XO Variations of Turner ‘s syndrome 2-Mosaicism 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 Amen, streak gonads
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TURNER SYNDROME FEATURES 1ry amenorrhea No breast development
Normal ♀ genital organs (external /internal) Streak gonads (ovaries are replaced by white 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 4th metacarpal Coarctation of the aorta or VSD Horse shoe kidney or single kidney Lymphedema Amenorrhea A 16 years old girl presented to the clinic with primary amenorrhea, Tanner 1 breast development & normal female external genitalia T 1- The next step in evaluating this patient would be Karyotyping & FSH/LH level T 2-An ultrasound scan is helpful to assess the presence of a uterus F 3-Gonadal dysgenesis & Kalman’s syndrome should not be considered in the deferential diagnosis F 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
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GONADAL DYSGENESIS 4-Pure gonadal dysgenesis 46XX
Mutation in an autosomal gene Accelerated germ cell loss Streak gonads ♀ genetalia , normal Mullerian structures Rarely Turner’s Stigmata 5- Pure gonadal dysgenesis 46 XY ♀ genitalia Streak gonads ↑ risk of malignancy N Mullerian structures
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GONADAL DYSGENESIS 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
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HYPOTHALAMIC FILURE 8-Isolated GnRH deficiency (Kalman’s Syndrome)
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
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HYPOTHALAMIC FILURE 9-Hypogonadotropic Amenorrhea
CNS tumors GnRH pulses LH & FSH estradiol Hypothalamic 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
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HYPOTHALAMIC FILURE 10-Anorexia Nervosa, Malnutrition, Excessive Exercise & Chronic Illness
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
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B-BREAST PRESENT , UTERUS PRESENT
1-HYPOTHALAMIC CAUSES CNS lesions (tumors) Stress, Excessive exercise & low body Wt 2-PITUITARY CAUSES Hyperprolactinemia Hypothyroidism ↑ TRH ↑ prolactin 3-OVARIAN CAUSES PCO 4-OUTFLOW TRACT OBSTRUCTION Imperforate hymen Transverse vaginal septum
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C-BREAST PRESENT , UTERUS ABSENT 1-Testicular feminization/ Androgen insensitivity
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 periferal conversion of androgens to estrogens Sexual hair is absent due to absence of androgen receptors Gonadectomy after puberty ↑ risk of malignancy (gonadoblastoma, dysgerminoma) Androgen insensitivity syndrome T1- The characteristic features of androgen insensitivity syndrome include: absent uterus, breast developed & normal female external genitalia F2- The karyotyping is 46XX T 3-They have a normal male testosterone level T 4-Gonadectomy must be performed after puberty because of the increased risk of malignancy F 5-Estrogen replacement therapy is not indicated because they have enough estrogens to produce breast development
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C-BREAST PRESENT , UTERUS ABSENT 2- 5 α reductase deficiency
Autosomal recessive Formation of the ♂ external genitalia requiers 5α REDUCTASE testosterone dihydrotestosterone Formation of the internal wollfiane structures respond directly to testosterone External genitalia ♀ with mild musculinization Absent uterus At puberty testosterone secretion virilization
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C-BREAST PRESENT , UTERUS ABSENT 3-Mulerian Agenesis/ Mayer –Rokitansky-Kuster-Huser syndrome
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 - vaginoplasty - excision of utrine reminant (if it has fuctioning endometrium) -vaginal dilators
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D-BREAST ABSENT, UTERUS ABSENT
The least common presentation of 1ry Amen All Pt are 46 XY Testosterone or N FSH/LH ↑ A 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 Patients with primary amenorrhea and absent breast & uterus T1- All have 46XY karyotype F 2- FSH/LH level is low T 3-Could be due to deficiency of the enzymes required for androgen synthesis or degenration of the testes in utero F 4-Gonadectomy is not recommended F 5-Hormon replacement therapy with testosterone is indicated
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D-BREAST ABSENT, UTERUS ABSENT
B- 17 α HYDROXYLASE DEFICIENCY Similar to desmolase def Cortisol synthesis also ↑ BP, hypernatraemia & hypokalaemia C-AGONADISM Degeneration of the testes (in utero) after the production of the MIF
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INVESTIGATIONS & TREATRMENT
Hx & Physical examination to place the Pt in one of the four categories
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1-BREAST ABSENT UTERUS PRESENT
↑↑FSH FSH 17α hydroxylase deficiency Kallman’s Syndrome Wt ↑Exercise Stress Wt ↑Exercise Stress Wt ↑Exercise Stress CNS / HP DISORDER Gonadal Dysgenesis ↑Na K ↑Progestrone ↑TSH ProlactinN TSHN PROLACTIN ↑ /N XX Karyotype CT / MRI HEAD Hypothyroidism XY CNS TUMORS Gonadectomy XO
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Breast development / Menses Improve Bone Min Density
TREATMENT 1-BREAST ABSENT UTERUS PRESENT Hypothyroidism Thyroxin Gonadal Dysgenesis Wt ↑Exercise Stress 17αOH-Dif Cortisol XX XO XY CNS Tmr Psychiatric Help Treat thecause Kallman’s Syndrome Gonadectomy Treat accordingly Estrogen Progestrone Replacement Estrogen Progestrone Replacement Breast development / Menses Improve Bone Min Density
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2-BREAST PRESENT UTERUS PRESENT
↑ TSH Hypothyroid ↑ TSH Hypothyroid ↑ TSH Hypothyroid ↑Prolactin TSHN ↑Prolactin TSHN MRI/CT Pituitary Karyotyping Prolactin N TSH N Ovarian Failure ↑FSH -Progestrone chalange +Progestrone chalange Out flow Tract Obstruction Hypoth/ pituit Failure FSH MRI/CT R/O CNS TMR Anovulatory cycle
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2-BREAST PRESENT UTERUS PRESENT
TREATMENT 2-BREAST PRESENT UTERUS PRESENT ↑ TSH Hypothyroid Anovulatory cycle Ovarian Failure Hypoth/ pituit Failure Out flow Tract Obstruction ↑Prolactin TSHN Thyroxin Bromocriptin HRT Surgery Progestin D16-25
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3-BREAST PRESENT UTERUS ABSENT
Testosterone N♀ ↑Testosterone N♂ Karyotyping Karyotyping XX Mullerian Agenesis XY Testicular Feminization Gonadectomy U/S Pelvis U/S MRI Gonads U/S Pelvis U/S KIDNEY IVP
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3-BREAST PRESENT UTERUS ABSENT
XX Mullerian Agenesis XY Testicular Feminization HRT Vaginoplasty Gonadectomy Vaginal dilators
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4-BREAST ABSENT UTERUS ABSENT
All 46 XY Pysical Exam U/S MRI for Gonads HRT Gonadectomy
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2RY AMENORRHEA
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2RY AMENORRHEA 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 CNS / Hypothalamic Pituitary Ovarian Outflow Uterine Cx Vaginal
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HYPOGONADOTROPIC AMENORRHEA “CNS / HYPOTHALAMIC ”
Stress ↑ β-endorphins GnRH FSH LH Estrogens Exercise 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)
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HYPOGONADOTROPIC AMENORRHEA
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 2nd decade of life
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HYPOGONADOTROPIC AMENORRHEA
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 < athletes with regular cycles Anorexia nervosa Pt BMD (0.64) < Normal controls (0.72) Anorexia nervosa Pt may have osteoporotic fractures
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HYPOGONADOTROPIC AMENORRHEA
SHEHAN’S SYNDROME Piuitary failure following sever post partum hemorrhage Deficiency of all pituitary hormones FSH & LH Failure of ovarian follicular development estrogen Amenorrhea Rx HRT hMG for ovulation induction
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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 Wt Functional HypoGt Amen HRT / ovulation induction Secondary amenorrhea T 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
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EUOGONADOTROPIC AMENORRHEA
PCO 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 T 4-Polcystic ovary syndome
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Bind androgen receptors
TREATMENT OF PCO Infertility Amenorrhea Irrigular cycles Hyperinsulinism Obesity Hirsutism Clomid Clomid hMG Gluco phage Wt Ovarian drilling Anti androgens Cyclic progest OCP OCP + Ovulation 70% Pregnancy 40% Ovulation 70% Pregnancy 40% Sprinolactone Cyproterone acetate Flutamide Ovarian Androgen ↑SHBG Ovulation 92% Pregnancy 70% -Protect endometrium -Regulate cycle -menorrhagia Bind androgen receptors Androgens 5αreductase activity
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HYPERGONADOTROPIC AMENORRHEA
WHAT 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 factors Associated autoimmune disease 39% T 4-Polcystic ovary syndome patients may respond to glucophage therapy T 5-Ovarian drilling is an option for patients with PCO not responding to medical treatment
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POF WHAT ARE THE PATHOLOGICAL CHCT OF POF ? TWO TYPES
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 women with POF on HRT 8% hMG/HCG glucocorticoids have been cliamed to give better pregnancy rates
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HYPERPROLACTINEMIA 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
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HYPERPROLACTINEMIA 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
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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
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TREATMENT OF HYPERPROLACTINEMIA
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
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ANATOMICAL CAUSES 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 -ve progestrone chalange test Dx HSG / HYSTROSCOPY Rx Hystroscopic resection of the adhesions followed by estrogen therapy
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