DR.

SAMEER KUMAR CHAFB BANGALORE

 AMENORRHOEA: is the absence of menses. TYPES : Physiologic- pregnancy, lactation and menopause. Pathologic- lack of regular,spontaneous menses after expected age of menarche. PRIMARY AMEORRHOEA: no menstruation by age of 14 in absence of any secondary sexual developments or no menstruation by 16 yrs regardless of the presence of secondary sexual characteristics. SECONDARY AMENORRHOEA: lack of menses for 6 months or for three menstrual cycles in women who have experienced menarche. ( evaluation need not be deferred to confirm to the definition)

 Spontaneous cyclic menses requires an intact and functional hypothalamic-pituitary-ovarian axis(HPOA), endometrium and outflow tract. Abnormalities in any= amenorrhoea. Inhibin secretion & corpus luteum Nucleus HPOA axis :secretion of progesterone in arcuatus
(medial basal hypothalamus) Pulsatile secretion of GnRH (every 90 min) greater levels than estradiol ( negative feedback on HPOA )

Stimulate ovarian follicle development and estradiol secretion ( negative feedback on HP initially then positive feedback to trigger LH surge)

Stimulates gonadotrophs in ant. Pituitary to synthesize, store & secrete:FSH / LH

 or Breasts / Secondary sexual characteristics

initiated/ not)
Breast Absent
Uterus present Check FSH levels
HIGH (Hypergonadotrophi c hypogonadism) LOW/NORMAL (Hypogondotroph ic hypogonadism)

( implies oestrogen was Breast Present

Absent Uterus

Enzyme deficiencie s
1.5 alpha reductase deficiency 2.17 OH lase 3.17,20 lyase/desmolase 4.Cyt P450 aromatase 5.LH receptor defect(XY) 6.Testicular regression 7.Testosterone biosyntesis disorder

Uterus present

1.CAH ---LOAH/EOAH 2. Hypothyroidism/ Cretinism 3. Polactinoma 4. Cushings syndrome 5. Exercise, Anorexia, Stress

Absen t uterus

(Arrest in pubertal development)

Check karyotype

1.Gonadal dysgenesis(46XO,46XY) 2.Turners (45XO) 3.Fragile X syndrome 4.Mosaicism 5.Pure dysgenesis (46XX/XY) 6.LH/FSH receptor defect 7.17- alpha-OH lase deficiency 8.Galactosemia

Work up for secondary amenorrhoea

1.Physiologic delay 2.Kallmans syndrome 3.Tumours-craniopharyngioma 4.GnRH receptor defect 5.FSH Deficiency 6.Prader willi syndrome 7. Lawrence moon biedl syndrome

Outflow tract abnormalities

1.Mayer Rokitansky Kuster Hauser 2.Mullerian anomalies 3.Androgen insensitivity syndrome 4. True hermaphroditism

Secondary amenorrhoea
Exclude pregnancy( serum b-hcg/card test) r/o menopause , postpartum lactation & post pill amenorrhoea TSH PROLACTI N Medications-SSRIs Prolactinoma( mri/cone down view of sella)

Hypothyroidis m
BLEEDING PRESENT (POSITIVE)

Raise d TSH

Raised prolactin

Progesterone challenge test MPA 5mg bd x 5 days

NO BLEEDING (NEGATIVE TEST)

(SIGNS OF ANOVULATION HYPERANDROGENISMHIRSUTISM,ACNE) 1. PCOS. 2. CAH----17 OHP levels (>500ng/dl) 3. CUSHINGS SYNDROME( late night salivary cortisol / 24 hr free urinary cortisol / 1mg overnight dexamethasone supp test) 4. OVARIAN TUMOURS (USG /testosterone levels <200ng/dl)

TESTOSTERONE >200ng/dl + USG/ MRI/CT >700ng/dl

OVARIAN TUMOUR
Adrenal hyperfunction

DHEAS

500700ng/dl +raised 17 OHP f/by dexa and ACTH testing

Late onset adrenal hyperplasia

BLEEEDING POSITIVE

NO BLEEDING (NEGATIVE)
Combined estrogen+prog challenge

(Hypoestrogenis m) Serum FSH Assay

Low/ normal FSH (CNS Cause)Hypergonadotropic Hypogonadism MRI/CT/GnRH stimulation

No bleeding
OUTFLOW TRACT DYSFUNCTION

High FSH > 40mIU/ml

Abnormal

HYPERGONADOTR OPIC HYPOGONADISM

Normal
Hypothalamic dysfunction Anorexia Exerciseinduced Stress Pseudocyesis Malnutrition Chronic disease pulmonary renal liver diabetes Addisons disease

Pituitaryhypothalamic lesions III tumors infection infarction pituitary failure Sheehans Diabetic vasculitis Toxic-lead

Ovarian failurechromosomal radiaton chemotherapy infection

II

IV

Autoimmune(RF,ANA, Anti thyroid Ab,serum Ca/PO4/electrolytes for parathyroid,anti islet cell Ab) Galactosemia Savage syndrome Idiopathic

 Absence of secondary sexual characteristics (breast development : 1st sign of estrogen exposure in puberty) woman has never been exposed to estrogen stimulation

Absence of a uterus suggests certain enzyme deficiencies and indicate the presence of antimullerian hormone (AMH) in an XY individual .

 Hypergonadotropic Hypogonadism
Genetic Disorders Enzyme Deficiencies Gonadotropin Receptor Mutation

Other causes of Primary Ovarian Failure Hypogonadotropic Hypogonadism Genetic Disorders Other Hypothalamic / Pituitary Dysfunctions

Cause of Primary Amenorrhea

Abnormal physical examination 5-reductase deficiency in XY individual 17, 20-desmolase deficiency in XY individual 17-hydroxylase deficiency in XY individual

Hypergonadotropic hypogonadism
Gonadal dysgenesis Pure gonadal dysgenesis Partial deletion of X chromosome

Sex chromosome mosaicism

Environmental and therapeutic ovarian toxins 17-hydroxylase deficiency in XX individual Galactosemia Other Hypogonadotropic hypogonadism Physiologic delay Kallmanns syndrome Central nervous system tumors

Hypothalamic/pituitary dysfunction

Cause of Primary Amenorrhea

LH, FSH : d/t decreased negative estrogen feedback.

Associated with genetic abnormalities (Approximately 30% of patients with primary amenorrhea)
Syndrome of gonadal dysgenesis or Turner syndrome Other disorder :
structurally abnormal X chromosomes, mosaicism, pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks), enzyme deficiencies that prevent normal estrogen production, Gonadotropin-receptor inactivating mutations

Cause of Primary Amenorrhea

Gonadal Dysgenesis Turner syndrome(45,X) :m/c chromosomal abnormality causing gonadal failure and primary amenorrhea P.Ex short stature, webbed neck shield chest, cubitus valgus short metacarpals, low hair line, high arched palate, multiple pigmented nevi, short fourth metacarpals Study cardiac (30%: coarctaion of the aorta) renal (horseshoe kidney), autoimmune(thyroiditis)

Cause of Primary Amenorrhea

Abnormal X Chromosome
46, XX individuals with partial deletions of the X chromosome

: variable phenotypes depending on the amount and location of the missing genetic material
Deletion of the long arm of the X chromosome(Xq-) Xq13~Xq26

- sexual infantilism - normal stature - no somatic abnormalities, no streak gonads - eunuchoid in appearance, delayed epiphyseal closure (some)
Deletion of the short arm of the X chromosome (Xp)

: phenotypically similar to individual with Turner syndrome

Cause of Primary Amenorrhea

Mosaicism
45,X/46XX (m/c) Clinical finding :taller and fewer abnormalities than pure 45,X 20% : spontaneous menstruation (+)

Cause of Primary Amenorrhea

Pure Gonadal Dysgenesis

Phenotypically female with sexual infantilism, primary amenorrhea, normal stature, no chromosomal abnormalities (46, XX or 46, XY) Gonads : usually streaks, some development of 2nd sexual characteristics

< Swyer syndrome >

mutations in the SRY (sex-determining region gene on the Y

chromosome) located at Yp11 result in XY females with gonadal dysgenesis

15~20% of women (46,XY)

Cause of Primary Amenorrhea

Mixed gonadal dysgenesis

XY
Ambiguous genitalia with a streak gonad on one side and a malformed testis on the opposite SRY gene mutation (small proportion )

Cause of Primary Amenorrhea

Congenital Lipoid Adrenal Hyperplasia Autosomal recessive disorder Cholesterol Pregnenolone Not defect of the P450scc gene 15 different mutations in the steroidogenic acute regulatory protein(StAR) : facilitates the transport of cholesterol from the outer to the inner mitochondrial membrane. hypoNa, HyperK, acidosis in infancy XX, XY(m/c) no uterus phenotype : female Genetic cluster : Japanes/Korean and Palestinian Arab population Tx :mineralocorticoid and glucocorticoid replacement

Cause of Primary Amenorrhea

17-Hydroxylase & 17, 20-Desmolase Deficiency mutation in the CYP 17 gene abnormalities in both the 17 hydroxylase and 17, 20-desmolase functions of the protein Karyotype : 46, XX 46,XY (no uterus) primary amenorrhea, no 2nd sexual characteristic, female phenotype, HTN, hypoK, ACTH Meneralocorticoid production Na retention, K loss, HTN Primordial follicle Gonadotropin

Cause of Primary Amenorrhea

Aromatase Deficiency Autosomal recessive abnormality Aromatizing Androgen estrogen Most mother of affected children : become virilized during pregnancy. suspected before birth. At birth : female child-clitoromegaly and posterior labioscrotal fusion At puberty : no breast development, primary amenorrhea, worsening virilization . absent growth spurt, delayed bone age, multicystic ovaries Tx : estrogen supply

Cause of Primary Amenorrhea

Luteinizing Hormone Receptor Mutation

Inactivation of LH receptors has been identified in XY pseudohermaphrodites with primary amenorrhea in the absence of secondary sexual characteristics caused by homozygous premature stop codon, deletions, and missense mutations in the LHR gene located on chromosome 2.

Follicle-stimulating Hormone receptor Mutation

Autosomal recessive single amino acid substitution in the extracellular domain of the FSH receptor Primary or early secondary amenorrhea, variable development of secondary sexual characteristics high levels of FSH and LH

Diagnosis Treatment

Amenorrhea without Secondary Sexual Characteristics

History
short stature but consistent growth rate, a family history of delayed puberty, normal physical findings (including assessment of smell, optic disks, and visual fields)
Physical delay

Headache, visual disturbance, short stature, symptoms of diabetes insipidus, weakness of limbs Galactorrhea

CNS lesion

Physical Examination

Secondary Sexual Characteristics

History& P.Ex (-)

Coarctation of the aorta (30%) FSH Thyroid dysfunction Echocardiography : every 3~5yrs (Hypergonadotropic TFT : yearly hyporogonadism) Evaluation for hearing loss and hypertension
Karyotype

(hypogonadotropic hypogonadism)

Serum Progesterone(>3.0)
Abnormal Turner syndrome Partial deletion of the X chromosome, mosaicision, Pure gonadal dysgenesis, Mixed gonadal dysgenesis Normal 17- hydroxylase deficiency

17-hydroxyprogesterone (0.2ng/mL) Deoxycorticosterone (DOS) ACTH stimulation test : ACTH bolus administration S-progesterone 17-hydroxyprogesterone ( - )

Secondary Sexual Characteristics

if galactorrhea, headaches, visual field defect (+) CT, MRI Physiologic delay
distinguish from insufficient GnRH secretion history absence of a CNS lesion on CT or MRI X-ray : delayed bone age

Gonadotropin-deficiency
distinguished from physiologic delay : response to GnRH stimulation
Physiologic delay LH : normal LH and FSH Gonadotropin-deficiency

Secondary Sexual Characteristics

All forms of gonadal failure Hypergonadotropic hypogonadism cyclic estrogen and progestin therapy : to initiate, mature, and maintain 2nd sexual characteristics prevention of osteoporosis (additional benefit of estrogen)

Amenorrhea without Secondary Sexual Characteristics

Initiation conjugated estrogen 0.625mg/day (Premarin R ) or estradiol 1mg/day (ProgynovaR ) estrogen +progestin (medroxyprogesterone acetate) (Provera R) daily or progesterone
to prevent unopposed estrogen stimulation of the endometrium in patients with uterus

short

stature : higher estrogen doses (x) normal stature : higher estrogen, after then reduced to the maintenance doses after several months

Medrosyprogesterone acetate 2.5mg daily or 5~10mg for 12~14days every 1~2months Oral micronized progesterone R) (utrogestan 100mg daily or 200mg for 12~14days every 1~2months Progesterone suppositories (progest R) 50mg daily or 100mg 12~14days every 1~2 months

Secondary Sexual Characteristics

Mosaicism and gonadal streak : ovulation (+), able to conceive either spontaneously or after the institution of estrogen replacement therapy 17 hydroxylase deficiency
corticosteroid and estrogen replacement If uterus(+) : progestin supply

Amenorrhea without Secondary Sexual Characteristics

Karyotypes contain a Y cell line (45,X/46, XY mosaicism, or pure gonadal dysgenesis 46, XY)
Predisposed to gonadal ridge tumor, such as gonadoblastomas, dysgerminomas, yolk sac tumors

remove gonads to prevent malignant transformation

Diagnosis
Treatment

Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities

Physical Examination Imperforate hymen presence of a bulging membrane that distend during Valsalva maneuver Others USG or MRI : useful skeletal malformation exam IVP for renal abnormalities karyotype determination (Y chromosome)

Transverse septum or blind vaginal pouch in a male complete absence of pseudohermaphrodite : difficult the cervix and uterus to differentiate in a female Absent endometrium not diagnosed by P.Ex

Evaluation of endocrine abnormalities (estrogen & progesterone challenge test) HSG, saline infusion USG Hysteroscopy

Asherman syndrome

not diagnosed by P.Ex

Cause

Cause

Ovarian failure
Pituitary / Hypothalamic Lesions Altered Hypothalamic Gonadotropin releasing Hormone secretion Weight Loss and Dieting

Anorexia Nervosa
Exercise Stress-induced Disorder Obesity Other Hormonal Factors

Cause of Primary Amenorrhea

Irradiation Chemotherapy with alkylating agents (e.g. cyclophosphamide) Combination of radiation and other chemothrapeutic agents Galactosemia

Amenorrhea with 2nd sexual characteristics and Nonanatomic causess

Causes of Ovarian failure after Development of Secondary Sexual Chracteristics Chromosomal etiology Iatrogenic Causes Radiation Chemotherapy Surgical alteration of on blood supply Infections Autoimmune disorders Galactosemia (mild form or heterozygote) Savage syndrome Cigarette smoking Idiopathic

 Normal : menopause
Age of menopause : determined by genetic inheritance

Premature ovarian failure

Premature ovarian failure <35years (1~5% of women) Between 35- 40 yrs = premature menopause cause : decreased follicular endowment or accelerated follicular atresia Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions 10% of secondary amenorrhea Few cases reported, where high dose estrogen or HMG therapy resulted in ovulation. (turners and fragile x syndrome) Sometimes immuno therapy may reverse autoimmue ovarian failure. Problem can present at varying ages 1. if loss of follicles have been rapid, then primary amenorrhoea and lack of sexual development present. 2. If loss of follicles takes place during or after puberty,the extent of phenotypic adult development and the time of onset of secondary amenorrhoea will vary accordingly. Rarely spont. ovulation (resistant ovaries) Treatment: HRT (osteoporosis, atherogenesis)

 Cigarette smoking
Alters both gametogenesis and hormonogensis Inverse dose-response relationship with age of menopause

Sex chromosome disorders

Deletion of the X chromosome (Turner syndrome) : associated with premature ovarian failure despite normal development of the ovaries d/t accelerated atresia of the follicles

 Fragile X carriers
Cause of inherited (X-linked) mental retardation 4-5% of premature ovarian failure
If premature ovarian failure is present in another family member, the chance of finding a premutation increases to 15%

Iatrogenic causes
radiation, sterility dose : 800cGy, ovarian failure :150cGy in some pts. esp. >40yrs chemotherapy (esp. alkylating agents : cyclophosphamide,methotrexate) surgical interference with ovarian blood supply, infection

 Infections
Mumps oophoritis-destruction of follicles. Tubo-ovarian abscess : follicular destruction and premautre ovarian failure

Autoimmune Disorders
Part of a polyglandular autoimmune syndrome Myasthenia gravis, Idiopathic thrombocytopenia purpura (ITP) Rheumatoid arthritis, Vitiligo, Autoimmune hemolytic anemia Diabetes mellitus Other autoimmune disorder

Galactosemia

Lack of functional galactose-1-phosphate uridyl transferase (GALT) Galactose metabolites : toxic effects on ovarian follicles causing premature destruction associated cataracts, MR

 Savage syndrome Gonadotropin resistance, Likely d/t FSH receptor dysfunction High level of FSH and LH levels FSH receptors partially functional They have ovarian follicles, as opposed to those with ovarian failure and no follicles. Biopsy : not advised Autosomal gene mutations An autosomal recessive form of premature ovarian failure is Associated with hearing loss in Perrault syndrome

 Rare disorder Ammenorrhoea and normal growth and development who has elevated gonadotropins despite the presence of unstimulated ovarian follicles. No evidence of autoimmune disease. Laprotomy necessary---to demonstrate not only the presence of follicles but also absence of any lymphocytic infiltration seen with an autoimmune disease. Patients are excellent candidates for oocyte donation.

Diagnosis
Treatment

Amenorrhea with 2nd sexual characteristics and Nonanatomic causess

Pregnancy test (urine or S-hCG) Pregnancy (-)

Serum TSH Serum prolactin FSH levels Estrogen status Imaging of the pituitary and hypothalamic assessment as necessary

Amenorrhea with 2nd sexual characteristics and Nonanatomic Pregnancy test (-) Progesterone challenge test causess medroxyprogesterone acetate, (MPA)
Check TSH & 5mg or 10mg for 10dsys po prolactin level 100~200 mg progesterone in oil IM withdrawal bleeding within 2~10days Normal PRL after the last dose abnormal TSH Serum estradiol > 40pg/mL

Both normal

Normal TSH Abnormal PRL

Progesterone challenge test

Thyroid disease

Withdrawal bleeding (+)

Withdrawal bleeding(-)

Normogonadotropic hypogonadism

Estrogen /Progesteron challenge test

2.5mg conjugated PRL < 100pg/mL estrogen or 2mg micronized estradiol, for 25days with 5~10mg of MPA for the last Consider others 10days
Withdrawal bleeding(-)

PRL >100pg/mL

Perform MRI to evaluate for prolactinoma

Withdrawal bleeding (+)

MRI (-) Consider others

Check FSH & LH level

Outflow obstruction

FSH>20IU/L LH > 40IU/L

Asherman syndrome confirmed by showing filling defects on HSG or by visualizing adhesions with hysteroscopy

FSH&LH<5 IU/L

Hypergonadotropic hypergonadism

MRI to evaluate for pituitary tumor

Normal MRI Hypogonadotropic hypogonadism

Amenorrhea with 2nd sexual characteristics and Nonanatomic causess

Follicle-stimulating Hormone Levels S-FSH > 25~40mIU/mL (on at least two blood samples) : hypergonadotropic amenorrhea Follicular reserve assessment: 1.clomiphene challenge test:D3 FSH ---- D5-D9=CC------D10 FSH value >10-15mIU/ml indicate poor reserve. 2. E2 & FSH:LH ratio weekly x 4 times E2 > 50pg/ml and FSH <40mIU/ml shows adequate reserve and possibility of ovular induction . Dx for cause of ovarian failure
History : chemotherapy, radiation therapy Galactose 1 phosphate uridyl transferase (GALT) level Fragile X carrier status Karyotype (<30years of ages & < 60 inches tall) : presence of a Y cell line autoimmune disorder( anti ovarian antibody assays) Ovarian biopsy : not advised

Amenorrhea with 2nd sexual characteristics and Nonanatomic causess

Follicle-stimulating Hormone Levels Extent of an autoimmune workup required for a patient with ovarian failure
Screening with nonspecific test (ANA, RA, ESR) Normal PTT : exclude lupus anticoagulant Serum electrolytes, calcium, phosphorus concentrations : evaluate possibility that parathyroid autoantibodies are active TSH, antithyroglobulin antibodies, antimicrosomal antibodies 24hr urinary free cortisol : detect the presence of antiadrenal antibodies Parietal cell antibodies, islets of Langerhans antibodies and antiadrenal antibodies : unclear

repeated yearly d/t transient nature of autoimmune disorders

Amenorrhea with 2nd sexual characteristics and Nonanatomic causess

Thyroid abnormalities : thyroid hormone, radioactive iodine, antithyroid drugs

Hyperprolactinemia : dopamine agonists (bromocriptine or cabergoline)

Surgery for particularly large pituitary tumors Ovarian failure : hormone replacement Conjugated estrogen 0.625-1.25mg/day or Micronized estradiol 1-2 mg/day or Transdermal patch 0.1mg/day. Estrogen + progestin +(medroxyprogesterone acetate 10mg D-11 TO D-25) ( to prevent unopposed estrogen stimulation of the endometrium in patients with uterus) Y cell line(+) : Gonadectomy Surgical removal, radiation therapy, or a combination of both is generally advocated for treatment of central nervous tumors other than prolactinoma

 Hypergonadotropic hypogonadism rarely ovulate and most are insensitive to any modality of ovulation induction . oocyte harvesting after induction of donor followed by IVF+ET may prove successful removal of the gonads if dysgenetic and containing Y material is appropriate. early recognition of galactosemia and institution of appropriate diet may protect ovaries. in case of chemotherapy/ radiation, risk to ovaries present. They may be protected by :1. Elective laproscopic transposition out of pelvis. 2. Harvesting and cryopreservation of oocytes. 3. Maintenance of ovarian dormancy by GnRH agonist treatment. 4. Transplantation to an unaffected peripheral site.

 Mosaics may ovulate spontaneously in 0% cases and spontaneous pregnancies are rare (2%). Turner mosaics and some cases of deletion / mutation /translocation of X chromosome may ovulate with ERT. PCOS:1. Regularisation of of hyperinsulinemia with sensitizers like metformin /thioglitazones restores fertility and ovulation 2. Low dose OCPs with or without antiandrogens reglarize cycles and corect/diminish hirsutism. 3. Ovulation induction with clomiphene,gonadotropins,GnRH analogues, ovarian diathermy.

Thank you