AMENNORHEA

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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,17a 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

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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

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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 Turners Stigmata
• 5- Pure gonadal dysgenesis 46 XY
• ? genitalia
• Streak gonads ? ? risk of malignancy
• N Mullerian structures

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GONADAL DYSGENESIS

• 6- 17-a 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 FILURE8-Isolated GnRH deficiency
(Kalmans Syndrome)

• Anosmia Hypogonadotropic Hypogonadism
• X linked ----Mutation in the KAL gene
• More common in ? gt ?
• 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 FILURE9-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 FILURE10-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 ABSENT1-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)

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C-BREAST PRESENT , UTERUS ABSENT2- 5 a reductase
deficiency

• Autosomal recessive
• Formation of the ? external genitalia requiers
• 5a 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 ABSENT3-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- 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

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D-BREAST ABSENT, UTERUS ABSENT

• B- 17 a HYDROXYLASE DEFICIENCY
• Similar to 17-20 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
17a hydroxylase deficiency
Kallmans Syndrome
?Wt ?Exercise Stress
?Wt ?Exercise Stress
?Wt ?Exercise Stress
CNS / HP DISORDER
Gonadal Dysgenesis
?Na ?K ?Progestrone
?TSH Prolactin?N
TSH?N PROLACTIN? ? /N
XX
Karyotype
CT / MRI HEAD
XY
Hypothyroidism
CNS TUMORS
Gonadectomy
XO
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TREATMENT 1-BREAST ABSENT UTERUS PRESENT
Hypothyroidism ? Thyroxin
Gonadal Dysgenesis
?Wt ?Exercise Stress
17aOH-Dif Cortisol
XX
XO
XY
CNS Tmr
Kallmans Syndrome
Psychiatric Help Treat thecause
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
?Prolactin TSH?N
?Prolactin TSH?N
? TSH Hypothyroid
MRI/CT Pituitary
Karyotyping
Prolactin ? N TSH ? N
Ovarian Failure
?FSH
Progestrone chalange
-Progestrone chalange
Out flow Tract Obstruction
Hypoth/ pituit Failure
?FSH
Anovulatory cycle
MRI/CT R/O CNS TMR
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TREATMENT 2-BREAST PRESENT UTERUS PRESENT
? TSH Hypothyroid
Hypoth/ pituit Failure
Ovarian Failure
Anovulatory cycle
Out flow Tract Obstruction
?Prolactin TSH?N
Thyroxin
Bromocriptin
HRT
Progestin D16-25
Surgery
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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 ? ? ß-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 lt 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 lt
• athletes with regular cycles
• Anorexia nervosa Pt ?? BMD (0.64) lt Normal
  controls (0.72)
• Anorexia nervosa Pt may have osteoporotic
  fractures

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HYPOGONADOTROPIC AMENORRHEA

• SHEHANS 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

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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

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TREATMENT OF PCO
Infertility
Amenorrhea Irrigular cycles
Hyperinsulinism Obesity
Hirsutism
Clomid
Clomid
hMG
Gluco phage
Wt ??
Ovarian drilling
Anti androgens
OCP
OCP
Cyclic progest

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 ?5areductase
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

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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 ? gt 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 ?lt 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
• Ashermans 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