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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)
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
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
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
(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)
OVARIAN TUMOUR
Adrenal hyperfunction
DHEAS
BLEEEDING POSITIVE
NO BLEEDING (NEGATIVE)
Combined estrogen+prog challenge
No bleeding
OUTFLOW TRACT DYSFUNCTION
Abnormal
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
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
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
Hypothalamic/pituitary dysfunction
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
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)
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)
Mosaicism
45,X/46XX (m/c) Clinical finding :taller and fewer abnormalities than pure 45,X 20% : spontaneous menstruation (+)
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
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
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
Diagnosis Treatment
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
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 ( - )
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
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)
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
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
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
Diagnosis
Treatment
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
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
Irradiation Chemotherapy with alkylating agents (e.g. cyclophosphamide) Combination of radiation and other chemothrapeutic agents Galactosemia
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
Cigarette smoking
Alters both gametogenesis and hormonogensis Inverse dose-response relationship with age of menopause
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 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
Thyroid disease
Withdrawal bleeding(-)
Normogonadotropic hypogonadism
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
Outflow obstruction
Asherman syndrome confirmed by showing filling defects on HSG or by visualizing adhesions with hysteroscopy
FSH&LH<5 IU/L
Hypergonadotropic hypergonadism
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
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
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.
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