CLINICAL GUIDELINES FOR  EVALUATION AND MANAGEMENT OF AMENORRHEA
<ul><li>Primary Amenorrhea: State in which menarche does not occur </li></ul><ul><li>Secondary Amenorrhea: State in which ...
<ul><li>Primary amenorrhea   </li></ul><ul><li>Failure of menarche to occur  when expected in relation to the onset of pub...
CNS-Hypothalamus-Pituitary Ovary-uterus Interaction Neural control Chemical control Dopamine (-) Norepiniphrine (+) Endorp...
ENDOCRINOLOGY
<ul><li>Inadequate hormonal stimulation of the endomerium   “ Anovulatory amenorrhea ” </li></ul><ul><li>- Euestrogenic  <...
<ul><li>Normal androgens </li></ul><ul><li>Hypothalamic-pituitary dysfunction (stress, weight loss or gain, exercise, pseu...
<ul><li>Normal androgens </li></ul><ul><li>-  Hypothalamic-pituitary failure </li></ul><ul><li>-  Severe dysfunction </li>...
AMENORRHOEA  AN  APPROACH  FOR  DIAGNOSIS <ul><li>HISTORY </li></ul><ul><li>PHYSICAL EXAMINATION </li></ul><ul><li>ULTRASO...
Cryptomenorrhea Outflow obstruction to menstrual blood -  Imperforate hymen - Transverse Vaginal septum with functioning u...
Imperforate hymen
Once Pregnancy and cryptomenorrhea are excluded: The patient is a bioassay for Endocrine abnormalities   Four categories o...
FSH Serum level   Low / normal  High Hypogonadotropic hypogonadim  Gonadal dysgenesis
<ul><li>-  FSH, LH, Prolactin, TSH </li></ul><ul><li>Provera 10 mg  PO daily </li></ul><ul><li>x 5 days </li></ul>+ Bleedi...
FSH  Low / normal High  Hypothalamic-pituitary Failure  Ovarian failure  If < 25 yrs or primary amenorrhea    karyoptype...
Amenorrhea  Utero-vaginal absence Karyotype  46- XX Mullerian  Agenesis (MRKH syndrome) Andogen Insenitivity (TSF syndrome...
<ul><li>Asherman’s  syndrome </li></ul><ul><li>History of  pregnancy associated D&C </li></ul><ul><li>Rarely after CS , my...
 
Amenorrhea Signs of androgen excess Testosterone, DHEAS, FSH, and LH DHEAS 500-700 mug/dL DHEAS >700 mug/dL TEST. >200 ng/...
Amenorrhea PRIMARY AMENORRHEA . Ovarian failure  36% . Hypogonadotrophic  34% Hypogonadism. . PCOS  17% . Congenital lesio...
<ul><li>Chromosomally incompetent </li></ul><ul><li>- Classic turner ’s syndrome (45XO) </li></ul><ul><li>- Turner variant...
Classic  Turner’s Turner Variant  True  gonadal  Dysgenesis  Mixed Dysgenesis  phenotype Female  Female  Female  Ambiguous...
<ul><li>•   Sexual infantilism and short stature. </li></ul><ul><li>•  Associated abnormalities, webbed neck,coarctation o...
Mosaic (46-XX / 45-XO)  ( Classic 45-XO)  Turner ’s syndrome
Ovarian dysgenesis
<ul><li>Steroidogenic enzyme defects (17-hydroxylase) </li></ul><ul><li>Ovarian resistance syndrome </li></ul><ul><li>Auto...
<ul><li>Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions  </li></ul><ul><li>10% of secondary amenorrhea...
<ul><li>The most common cause of chronic anovulation </li></ul><ul><li>Hyperandrogenism ;    LH/FSH ratio </li></ul><ul><...
 
<ul><li>•   Normal height </li></ul><ul><li>•  Normal external and internal genital organs (infantile) </li></ul><ul><li>•...
<ul><li>•   Common cause (20%) </li></ul><ul><li>•  Under stature and  delayed bone age </li></ul><ul><li>( X-ray Wrist  j...
<ul><li>Pituitary inability to secrete gonadotropins </li></ul><ul><li>Pituitary necrosis following massive obstetric hemo...
<ul><li>1 o  or 2 o  Amenorrhea is often first sign </li></ul><ul><li>A body mass index (BMI) <17  kg/m ²   menstrual irr...
<ul><li>Common in women who participate in sports (e.g. competitive athletes,  ballet dancers) </li></ul><ul><li>Eating di...
<ul><li>Post-pill amenorrhea is not an entity </li></ul><ul><li>Depot medroxyprogesterone acetate </li></ul><ul><li>Up to ...
<ul><li>Autosomal recessive trait </li></ul><ul><li>Most common form is due to 21-hydroxylase deficiency </li></ul><ul><li...
<ul><li>Clinical suspicion :  Hirsutism, truncal obesity, purple striae,   BP </li></ul><ul><li>If Suspicion is high :  <...
<ul><li>15%  of  1ry amenorrhea  </li></ul><ul><li>Normal breasts and Sexual Hair development  & Normal looking external f...
<ul><li>X-linked trait  </li></ul><ul><li>Absent cytosol receptors </li></ul><ul><li>Normal breasts but no sexual hair </l...
<ul><li>.   Attempts to restore ovulatory function  </li></ul><ul><li>.  If this is not possible HRT ( oestrogen and proge...
<ul><li>To achieve pubertal development </li></ul><ul><li>Premarin 5mg D1-D25 + provera 10mg D15-D25  X 3 months;    2.5m...
<ul><li>Although the work-up of amenorrhea may seem to be complex, a carefully conducted physical examination with the his...
<ul><li>Androgen Insensitivity Syndrome </li></ul><ul><li>Hypogonadism </li></ul><ul><li>Klinefelter’s Syndrome (XXY) </li...
<ul><li>–   androgenic insensitivity </li></ul><ul><li>  1. XY: X chromosome is responsible for  the testosterone receptor...
<ul><li>Klinefelter’s syndrome </li></ul><ul><li>Gonadotropin receptor mutations </li></ul><ul><li>Cryptorchidism </li></u...
<ul><li>Isolated hypogonadotropic hypogonadism </li></ul><ul><li>Kallman’s syndrome </li></ul><ul><li>DAX1 mutation </li><...
How would you evaluate this patient? Total testosterone: 134 ng/dL (176-781) Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13...
<ul><li>Klinefelter’s syndrome </li></ul><ul><li>Gonadotropin receptor mutations </li></ul><ul><li>Cryptorchidism </li></u...
Confirmed low testosterone Check LH+FSH (SA if infertility) High gonadotropins – 1 o Low/low nl gonadotropins – 2 o Karyot...
How would you evaluate this patient? Total testosterone: 134 ng/dL (176-781) Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13...
<ul><li>Incidence ~ 1/1,000 live male births </li></ul><ul><li>Extra X chromosome, usually 47 XXY </li></ul><ul><li>Phenot...
Gordon DL et al.  Arch Intern Med (1972) 130:720 Abnormality Frequency (%) Abnormal testicular histology 100 Decreased tes...
<ul><li>Primary goal is to restore testosterone levels to the laboratory reference range </li></ul><ul><li>Prescribe only ...
<ul><li>Signs and symptoms of hypogonadism depend on when the condition occurs in development </li></ul><ul><li>Initial ev...
<ul><li>Idiopathic </li></ul><ul><li>Kallmann’s syndrome  (X-linked):  </li></ul><ul><li>impaired migration of GnRH neuron...
<ul><li>CASES </li></ul>
Case 1   Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function pregnancy test Ultr...
Case 1  Results FSH of 2.2 iu/L LH 15.0 iu/L normal prolactin and thyroid function The ultrasound scan demonstrated the pr...
Case 1   What should the management be?  
Case 1 Endometrial hyperplasia is a risk factor for oligo / amenorrhoeic women with PCOS because of unopposed oestrogen st...
Case 2     An 18 year old woman presents with primary amenorrhoea (she has never had a period).  She has developed small b...
Case 2   Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function ( pregnancy test) U...
Case 2   Results   FSH of 0.5 iu/L LH of 0.5 iu/L normal prolactin and thyroid function  The ovaries appear small on ultra...
Case 2   Hypogonadotrophic hypogonadism Usually of hypothalamic origin and may be congenital, such as Kallmann's Syndrome ...
Case 2   What is the treatment?    
Case 2 If the patient wishes to be pregnant, first line treatment would be pulsatile GnRH or gonadotrophin stimulation of ...
Case 2 Do you need to image the pituitary / hypothalamus?  
Case 2 Do you need to image the pituitary / hypothalamus? Yes in adults with secondary amenorrhoea and hypog/hypog or hype...
Case 2 The patient was administered HMG at increasing high doses, but failed to produce any demonstrable follicular growth...
Case 2 This patient appears to have a second pathology and may well have primary ovarian failure combined with hypothalami...
Case 3     An 18 year old woman presents with primary amenorrhoea (she has never had a period).  She has a normal body mas...
Case 3   Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function (pregnancy test) Ul...
Case 3   Results   FSH of 0.5 iu/L LH of 0.5 iu/L serum prolactin concentration: 5,000 mu/L   What is the diagnosis? What ...
Case 3   Hyperprolactinaemia  A repeat prolactin should be measured.  The diagnosis is likely to be that of a macro-adenom...
Case 3   Dopamine agonists: Bromocriptine or Cabergoline  Check visual fields
Case 4     An 18 year old woman presents with primary amenorrhoea (she has never had a period).  She has a normal body mas...
Case 4   Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function (pregnancy test) Ul...
Case 4   Results   FSH of 40 iu/L LH of 30 iu/L   What is the diagnosis? What further investigations should be done?  
Case 4   Primary ovarian failure / premature ovarian failure   What further investigations should be performed?
<ul><li>Case 4 </li></ul><ul><li>  </li></ul><ul><li>repeat FSH & LH </li></ul><ul><li>karyotype  </li></ul><ul><li>bone m...
THANK YOU FOR  YOUR  ATTENTION
 
 
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Endo Reproduction

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  • Endo Reproduction

    1. 1. CLINICAL GUIDELINES FOR EVALUATION AND MANAGEMENT OF AMENORRHEA
    2. 2. <ul><li>Primary Amenorrhea: State in which menarche does not occur </li></ul><ul><li>Secondary Amenorrhea: State in which cessation of menstrual periods occurs after menarche </li></ul>ENDOCRINOLOGY
    3. 3. <ul><li>Primary amenorrhea </li></ul><ul><li>Failure of menarche to occur when expected in relation to the onset of pubertal development. </li></ul><ul><li> No menarche by age 16 years with signs of pubertal development. </li></ul><ul><li> No onset of pubertal development by age 14 years. </li></ul><ul><li>Secondary amenorrhea </li></ul><ul><li> Absence of menstruation for 3 or more months in a </li></ul><ul><ul><li>previously menstruating women of reproductive </li></ul></ul><ul><ul><li>age. </li></ul></ul>
    4. 4. CNS-Hypothalamus-Pituitary Ovary-uterus Interaction Neural control Chemical control Dopamine (-) Norepiniphrine (+) Endorphines (-) Hypothalamus Gn-RH Ant. pituitary FSH, LH Ovaries Uterus Progesterone Estrogen Menses – ± ?
    5. 5. ENDOCRINOLOGY
    6. 6. <ul><li>Inadequate hormonal stimulation of the endomerium “ Anovulatory amenorrhea ” </li></ul><ul><li>- Euestrogenic </li></ul><ul><li>- Hypoestrogenic </li></ul><ul><li>Inability of endometrium to respond to hormones “ Ovulatory amenorrhea ” </li></ul><ul><li>- Uterine absence - Utero-vaginal agenesis </li></ul><ul><li>- XY-Females ( e.g T.F.S) </li></ul><ul><li>- Damaged endometrium ( e.g Asherman ’ s syndrome) </li></ul>
    7. 7. <ul><li>Normal androgens </li></ul><ul><li>Hypothalamic-pituitary dysfunction (stress, weight loss or gain, exercise, pseudocyesis) </li></ul><ul><li>Hyperprolactinemia </li></ul><ul><li>Feminizing ovarian tumour </li></ul><ul><li>Non-gonadal endocrine disease (thyroid, adrenal) </li></ul><ul><li>Systemic illness </li></ul><ul><li>High androgens </li></ul><ul><li>PCOS </li></ul><ul><li>Musculinizing ovarian tumour </li></ul><ul><li>Cushing ’ s syndrome </li></ul><ul><li>Congenital adrenal hyperplasia (late onset) </li></ul>
    8. 8. <ul><li>Normal androgens </li></ul><ul><li>- Hypothalamic-pituitary failure </li></ul><ul><li>- Severe dysfunction </li></ul><ul><li>- Neoplastic,destructive, </li></ul><ul><li>infiltrative, infectious & </li></ul><ul><li>trumatic conditions </li></ul><ul><li>involving hypothalamus or pituitary </li></ul><ul><li>- Ovarian failure </li></ul><ul><li>- Gonadal dysgenesis </li></ul><ul><li>- Premature ovarian failure </li></ul><ul><li>- Enzyme defect </li></ul><ul><li>- Resistant ovaries </li></ul><ul><li>- Radiotherapy, chemotherapy </li></ul><ul><li>High androgens </li></ul><ul><li>- Musculinizing ovarian tumour </li></ul><ul><li>- Cushing’s syndrome </li></ul><ul><li>- Congenital adrenal hyperplasia (late onset) </li></ul>
    9. 9. AMENORRHOEA AN APPROACH FOR DIAGNOSIS <ul><li>HISTORY </li></ul><ul><li>PHYSICAL EXAMINATION </li></ul><ul><li>ULTRASOUND EXAMINATION </li></ul>Exclude Pregnancy Exclude Cryptomenorrhea
    10. 10. Cryptomenorrhea Outflow obstruction to menstrual blood - Imperforate hymen - Transverse Vaginal septum with functioning uterus - Isolated Vaginal agenesis with functioning uterus - Isolated Cervical agenesis with functioning uterus <ul><li>- Intermittent abdominal pain </li></ul><ul><li>- Possible difficulty with micturition </li></ul><ul><li>- Possible lower abdominal swelling </li></ul><ul><li>Bulging bluish membrane at the introitus or absent </li></ul><ul><li>vagina (only dimple) </li></ul>
    11. 11. Imperforate hymen
    12. 12. Once Pregnancy and cryptomenorrhea are excluded: The patient is a bioassay for Endocrine abnormalities Four categories of patients are identified 1. Amenorrhea with absent or poor secondary sex Characters 2. Amenorrhea with normal 2ry sex characters 3. Amenorrhea with signs of androgen excess 4. Amenorrhea with absent uterus and vagina
    13. 13. FSH Serum level Low / normal High Hypogonadotropic hypogonadim Gonadal dysgenesis
    14. 14. <ul><li>- FSH, LH, Prolactin, TSH </li></ul><ul><li>Provera 10 mg PO daily </li></ul><ul><li>x 5 days </li></ul>+ Bleeding No bleeing  Prolactin  TSH Further Work-up (Endocrinologist) - Mild hypothalamic dysfunction - PCO (  LH/FSH) Review FSH result And history (next slide)
    15. 15. FSH Low / normal High Hypothalamic-pituitary Failure Ovarian failure  If < 25 yrs or primary amenorrhea  karyoptype  If < 35 yrs  R/O autoimmune disease ?? Ovarian biopsy head CT- scan or MRI - Severe hypothalamic dysfunction - Intracranial pathology
    16. 16. Amenorrhea Utero-vaginal absence Karyotype 46- XX Mullerian Agenesis (MRKH syndrome) Andogen Insenitivity (TSF syndrome) . Gonadal regressioon . Testocular enzyme defenciecy . Leydig cell agenisis 46- XY Normal breasts & sexual hair Normal breasts & absent sexual hair Absent breasts & sexual hair
    17. 17. <ul><li>Asherman’s syndrome </li></ul><ul><li>History of pregnancy associated D&C </li></ul><ul><li>Rarely after CS , myomectomy T.B endometritis, bilharzia </li></ul><ul><li>Diagnosis : HSG or hysterescopy </li></ul><ul><li>Treatment : lysis of adhesions; D&C or hysterescopy + estrogen therapy ( ? IUCD or catheter) </li></ul>Some will prescribe a cycle of Estrogen and Progesterone challenge Before HSG or Hysterescopy
    18. 19. Amenorrhea Signs of androgen excess Testosterone, DHEAS, FSH, and LH DHEAS 500-700 mug/dL DHEAS >700 mug/dL TEST. >200 ng/dL  Serum 17-OH Progesterone level Late CAH Adrenal hyperfunction U/S ? MRI or CT Ovarian Or adrenal tumor Lower elevations  PCOS (High LH / FSH)
    19. 20. Amenorrhea PRIMARY AMENORRHEA . Ovarian failure 36% . Hypogonadotrophic 34% Hypogonadism. . PCOS 17% . Congenital lesions (other than dysgenesis) 4% . Hypopituitarism 3% . Hyperprolactinaemia 3% . Weight related 3% SECONDARY AMENORRHEA . Polycystic ovary syndrome 30% . Premature ovarian failure 29% . Weight related amenorrhoea 19% . Hyperprolactinaemia 14% . Exercise related amenorrhoea 2% . Hypopituitarism 2%
    20. 21. <ul><li>Chromosomally incompetent </li></ul><ul><li>- Classic turner ’s syndrome (45XO) </li></ul><ul><li>- Turner variants (45XO/46XX),(46X- abnormal X) </li></ul><ul><li>- Mixed gonadal dygenesis (45XO/46XY) </li></ul><ul><li>Chromosomally competent </li></ul><ul><li>- 46XX (Pure gonadal dysgeneis) </li></ul><ul><li>- 46XY (Swyer’s syndrome) </li></ul>
    21. 22. Classic Turner’s Turner Variant True gonadal Dysgenesis Mixed Dysgenesis phenotype Female Female Female Ambiguous Gonad Streak Streak Streak - Streak - Testes Height Short - Short - Normal Tall Short Somatic stigmata Classical ± Nil ± karyotype XO XX/XO or abnormal X 46- XX(Pure) 46-XY (Swyer) XO/XY
    22. 23. <ul><li>• Sexual infantilism and short stature. </li></ul><ul><li>• Associated abnormalities, webbed neck,coarctation of the aorta,high-arched pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low hairline on the neck, short metacarpal bones and renal anomalies. </li></ul><ul><li>• High FSH and LH levels. </li></ul><ul><li>• Bilateral streaked gonads. </li></ul><ul><li>• Karyotype - 80 % 45, X0 </li></ul><ul><li>- 20% mosaic forms (46XX/45X0) </li></ul><ul><li>• Treatment: HRT </li></ul>
    23. 24. Mosaic (46-XX / 45-XO) ( Classic 45-XO) Turner ’s syndrome
    24. 25. Ovarian dysgenesis
    25. 26. <ul><li>Steroidogenic enzyme defects (17-hydroxylase) </li></ul><ul><li>Ovarian resistance syndrome </li></ul><ul><li>Autoimmune oophoritis </li></ul><ul><li>Postinfection (eg. Mumps) </li></ul><ul><li>Postoopherectomy </li></ul><ul><li>Postradiation </li></ul><ul><li>Postchemotherapy </li></ul>
    26. 27. <ul><li>Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions </li></ul><ul><li>10% of secondary amenorrhea </li></ul><ul><li>Few cases reported, where high dose estrogen or HMG therapy resulted in ovulation </li></ul><ul><li>Sometimes immuno therapy may reverse autoimmue ovarian failure </li></ul><ul><li>Rarely  spont. ovulation (resistant ovaries) </li></ul><ul><li>Treatment: HRT ( osteoporosis, atherogenesis ) </li></ul>
    27. 28. <ul><li>The most common cause of chronic anovulation </li></ul><ul><li>Hyperandrogenism ;  LH/FSH ratio </li></ul><ul><li>Insulin resitance is a major biochemical feature (  blood insulin level  hyperandrogenism ) </li></ul><ul><li>Long term risks: Obesity, hirsutism, infertility, type 2 diabetes, dyslipidemia, cardiovasular risks, endometrial hyperplassia and cancer </li></ul><ul><li>• Treatment depends on the needs of the patient and preventing long term health problems </li></ul>
    28. 30. <ul><li>• Normal height </li></ul><ul><li>• Normal external and internal genital organs (infantile) </li></ul><ul><li>• Low FSH and LH </li></ul><ul><li>• MRI to R/O intra-cranial pathology. </li></ul><ul><li>• 30-40% anosmia (kallmann ’s syndrome) </li></ul><ul><li>• Sometimes  constitutional delay </li></ul><ul><li>• Treat according to the cause (HRT), potentially fertile. </li></ul>
    29. 31. <ul><li>• Common cause (20%) </li></ul><ul><li>• Under stature and delayed bone age </li></ul><ul><li>( X-ray Wrist joint) </li></ul><ul><li>• Positive family history </li></ul><ul><li>• Diagnosis by exclusion and follow up </li></ul><ul><li>• Prognosis is good </li></ul><ul><li>(late developer) </li></ul><ul><li>• No drug therapy is required – Reassurance (? Hormone replacement therapy [ HRT] ) </li></ul>
    30. 32. <ul><li>Pituitary inability to secrete gonadotropins </li></ul><ul><li>Pituitary necrosis following massive obstetric hemorrhage is most common cause in women </li></ul><ul><li>Diagnosis : History and  E2,FSH,LH </li></ul><ul><li>+ other pituitary deficiencies (MPS test) </li></ul><ul><li>Treatment : </li></ul><ul><li>Replacement of deficient hormones </li></ul>
    31. 33. <ul><li>1 o or 2 o Amenorrhea is often first sign </li></ul><ul><li>A body mass index (BMI) <17 kg/m ²  menstrual irregularity and amenorrhea </li></ul><ul><li>Hypothalamic suppression </li></ul><ul><li>Abnormal body image, intense fear of weight gain, often strenuous exercise </li></ul><ul><li>Mean age onset 13-14 yrs (range 10-21 yrs) </li></ul><ul><li>Low estradiol  risk of osteoporosis </li></ul><ul><li>Bulemics less commonly have amenorrhea due to fluctuations in body wt, but any disordered eating pattern (crash diets) can cause menstrual irregularity. </li></ul><ul><li>Treatment :  body wt. (Psychiatrist referral) </li></ul>
    32. 34. <ul><li>Common in women who participate in sports (e.g. competitive athletes, ballet dancers) </li></ul><ul><li>Eating disorders have a higher prevalence in female athletes than non-athletes </li></ul><ul><li>Hypothalamic disorder caused by abnormal gonadotrophin-releasing hormone pulsatility, resulting in impaired gonadotrophin levels, particularly LH, and subsequently low oestrogen levels </li></ul>
    33. 35. <ul><li>Post-pill amenorrhea is not an entity </li></ul><ul><li>Depot medroxyprogesterone acetate </li></ul><ul><li>Up to 80 % of women will have amenorrhea after 1 year of use. It is reversible (estrogen deficiency) </li></ul><ul><li>A minority of women taking the progestogen-only pill may have reversible long term amenorrhoea due to complete suppression of ovulation </li></ul>
    34. 36. <ul><li>Autosomal recessive trait </li></ul><ul><li>Most common form is due to 21-hydroxylase deficiency </li></ul><ul><li>Mild forms Closely resemble PCO </li></ul><ul><li>Severe forms show Signs of severe androgen excess </li></ul><ul><li>High 17-OH-progesterone blood level </li></ul><ul><li>Treatment : cortisol replacement and ? Corrective surgery </li></ul>
    35. 37. <ul><li>Clinical suspicion : Hirsutism, truncal obesity, purple striae,  BP </li></ul><ul><li>If Suspicion is high : </li></ul><ul><li>dexamethasone suppression test (1 mg PO 11 pm ) and obtaine serum cortisol level at 8 am : </li></ul><ul><li>< 5 µg/ dl excludes cushing’s </li></ul><ul><li>24 hours total urine free cortisol level to confirm diagnosis </li></ul><ul><li>2 forms ; adrenal tumour or ACTH hypersecretion (pituitary or ectopic site) </li></ul>
    36. 38. <ul><li>15% of 1ry amenorrhea </li></ul><ul><li>Normal breasts and Sexual Hair development & Normal looking external female genitalia </li></ul><ul><li>Normal female range testosterone level </li></ul><ul><li>Absent uterus and upper vagina & Normal ovaries </li></ul><ul><li>Karyotype 46-XX </li></ul><ul><li>15-30% renal, skeletal and middle ear anomalies </li></ul><ul><li>Treatment : STERILE ? Vaginal creation ( Dilatation VS Vaginoplasty) </li></ul>
    37. 39. <ul><li>X-linked trait </li></ul><ul><li>Absent cytosol receptors </li></ul><ul><li>Normal breasts but no sexual hair </li></ul><ul><li>Normal looking female external genitalia </li></ul><ul><li>Absent uterus and upper vagina </li></ul><ul><li>Karyotype 46, XY </li></ul><ul><li>Male range testosterone level </li></ul><ul><li>Treatment : gonadectomy after puberty + HRT </li></ul><ul><li>? Vaginal creation (dilatation VS Vaginoplasty ) </li></ul>
    38. 40. <ul><li>. Attempts to restore ovulatory function </li></ul><ul><li>. If this is not possible HRT ( oestrogen and progesterone ) is given to hypo-estrogenic amenorrheic women ( to prevent osteoporosis; atherogenesis ) </li></ul><ul><li>. Periodic progestogen should be taken by euestrogenic amenorrheic women ( to avoid endometrial cancer ) </li></ul><ul><li>. If Y chromosome is present gonadectomy is indicated </li></ul><ul><li>. Many cases require frequent re-evaluation </li></ul>
    39. 41. <ul><li>To achieve pubertal development </li></ul><ul><li>Premarin 5mg D1-D25 + provera 10mg D15-D25 X 3 months;  2.5mg premarin X 3 months and </li></ul><ul><li> 1.25mg premarin X 3 months </li></ul><ul><li>Maintenance therapy </li></ul><ul><li>0.625mg premarin + provera OR ready HRT preparation OR 30 µ g oral contraceptive pill </li></ul>
    40. 42. <ul><li>Although the work-up of amenorrhea may seem to be complex, a carefully conducted physical examination with the history, and Looking to the patient as a bioassay for endocrine abnormalities, should permit the clinician to narrow the diagnostic possibilities and an accurate diagnosis can be obtained quickly. </li></ul><ul><li>Management aims at restoring ovulatory cycles if possible, replacing estrogen when deficient and Progestogegen to protect endometrium from unopposed estrogen. </li></ul><ul><li>• Frequent re-evaluation and reassurance of the patient. </li></ul>
    41. 43. <ul><li>Androgen Insensitivity Syndrome </li></ul><ul><li>Hypogonadism </li></ul><ul><li>Klinefelter’s Syndrome (XXY) </li></ul><ul><li>Swyer syndrome (XY but no gonads, treated as a girl e.g. </li></ul><ul><li>with estrogen etc.) </li></ul><ul><li>5 alpha-reductase deficiency (5-ARD) – (XY) vagina and labia, as well as penis that can ejaculate </li></ul>
    42. 44. <ul><li>– androgenic insensitivity </li></ul><ul><li> 1. XY: X chromosome is responsible for the testosterone receptors </li></ul><ul><li>i. These receptors become insensitive to testosterone </li></ul><ul><li>ii. Child is born with appearance of female genitalia </li></ul><ul><li>**Mullerian inhibiting system is okay; so internal organs are not female** </li></ul>
    43. 45. <ul><li>Klinefelter’s syndrome </li></ul><ul><li>Gonadotropin receptor mutations </li></ul><ul><li>Cryptorchidism </li></ul><ul><li>Androgen biosynthesis disorders </li></ul><ul><li>Varicocele </li></ul><ul><li>Congenital anorchia </li></ul><ul><li>Mumps orchitis </li></ul><ul><li>Radiation </li></ul><ul><li>Antineoplastic drugs </li></ul><ul><li>Ketoconazole </li></ul><ul><li>Glucocorticoid excess </li></ul><ul><li>Trauma </li></ul><ul><li>Testicular torsion </li></ul><ul><li>Autoimmune orchitis </li></ul><ul><li>Cirrhosis </li></ul><ul><li>Chronic renal failure </li></ul><ul><li>HIV infection </li></ul><ul><li>Idiopathic </li></ul>Congenital Acquired
    44. 46. <ul><li>Isolated hypogonadotropic hypogonadism </li></ul><ul><li>Kallman’s syndrome </li></ul><ul><li>DAX1 mutation </li></ul><ul><li>GPR 54 mutation </li></ul><ul><li>Leptin or leptin receptor mutations </li></ul><ul><li>Gonadotrope receptor mutations </li></ul><ul><li>Hypopituitarism </li></ul><ul><li>Hyperprolactinemia </li></ul><ul><li>Androgen therapy </li></ul><ul><li>GnRH analog therapy </li></ul><ul><li>Glucocorticoid therapy </li></ul><ul><li>Critical illness </li></ul><ul><li>Chronic illness </li></ul><ul><li>Diabetes mellitus </li></ul><ul><li>Opiates </li></ul><ul><li>Pituitary mass lesions </li></ul><ul><li>Infiltrative diseases </li></ul><ul><li>Sellar surgery </li></ul><ul><li>Sellar radiation </li></ul>Congenital Acquired
    45. 47. How would you evaluate this patient? Total testosterone: 134 ng/dL (176-781) Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0) What is the initial diagnosis? Primary hypogonadism What is the next step in work up?
    46. 48. <ul><li>Klinefelter’s syndrome </li></ul><ul><li>Gonadotropin receptor mutations </li></ul><ul><li>Cryptorchidism </li></ul><ul><li>Androgen biosynthesis disorders </li></ul><ul><li>Varicocele </li></ul><ul><li>Congenital anorchia </li></ul><ul><li>Mumps orchitis </li></ul><ul><li>Radiation </li></ul><ul><li>Antineoplastic drugs </li></ul><ul><li>Ketoconazole </li></ul><ul><li>Glucocorticoid excess </li></ul><ul><li>Trauma </li></ul><ul><li>Testicular torsion </li></ul><ul><li>Autoimmune orchitis </li></ul><ul><li>Cirrhosis </li></ul><ul><li>Chronic renal failure </li></ul><ul><li>HIV infection </li></ul><ul><li>Idiopathic </li></ul>Congenital Acquired
    47. 49. Confirmed low testosterone Check LH+FSH (SA if infertility) High gonadotropins – 1 o Low/low nl gonadotropins – 2 o Karyotype Prolactin, other pituitary hormones, iron studies, sella MRI
    48. 50. How would you evaluate this patient? Total testosterone: 134 ng/dL (176-781) Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0) What is the initial diagnosis? Primary hypogonadism What is the next step in work up? Karyotype: 47 XXY
    49. 51. <ul><li>Incidence ~ 1/1,000 live male births </li></ul><ul><li>Extra X chromosome, usually 47 XXY </li></ul><ul><li>Phenotype strongly influenced by CAG n repeat in the androgen receptor gene </li></ul><ul><li>Manifestations </li></ul><ul><ul><li>Hypogonadism </li></ul></ul><ul><ul><li>Gynecomastia </li></ul></ul><ul><ul><li>Behavioral disorders </li></ul></ul><ul><ul><li>Bronchiectasis/emphysema/bronchitis </li></ul></ul><ul><ul><li>Mediastinal germ cell tumors </li></ul></ul><ul><ul><li>Non-Hodgkin’s lymphoma </li></ul></ul><ul><ul><li>Diabetes mellitus </li></ul></ul><ul><ul><li>Lower extremity varicosities </li></ul></ul>
    50. 52. Gordon DL et al. Arch Intern Med (1972) 130:720 Abnormality Frequency (%) Abnormal testicular histology 100 Decreased testicular length 99 Azoospermia 93 Low testosterone 79 Decreased facial hair 77 Increased gonadotropins 75 Decreased sexual function 68 Gynecomastia 55 Decreased axillary hair 49 Decreased penis length 41
    51. 53. <ul><li>Primary goal is to restore testosterone levels to the laboratory reference range </li></ul><ul><li>Prescribe only for patients with confirmed hypogonadism </li></ul><ul><li>Role in “treating” decline in testosterone levels with aging uncertain </li></ul><ul><li>Multiple preparations </li></ul><ul><ul><li>Oral </li></ul></ul><ul><ul><li>Intramuscular </li></ul></ul><ul><ul><li>Transdermal </li></ul></ul><ul><ul><li>Buccal </li></ul></ul>
    52. 54. <ul><li>Signs and symptoms of hypogonadism depend on when the condition occurs in development </li></ul><ul><li>Initial evaluation focuses on distinguishing between primary and secondary hypogonadism </li></ul><ul><ul><li>Primary: LH elevated, testosterone low </li></ul></ul><ul><ul><li>Secondary: LH low, testosterone low </li></ul></ul><ul><li>Goal of testosterone replacement is physiological testosterone levels and preservation of testosterone-dependent physiological functions </li></ul>
    53. 55. <ul><li>Idiopathic </li></ul><ul><li>Kallmann’s syndrome (X-linked): </li></ul><ul><li>impaired migration of GnRH neurones </li></ul><ul><li>anosmia, disturbance colour vision, dyskinesis </li></ul><ul><li>Prader-Willi syndrome (aut. dom., chromosome 15): </li></ul><ul><li>obesity, muscle hypotonia, mental retardation, short stature, small hands/feet, cryptorchidism, HH </li></ul><ul><li>Mutations in pathway for GnRH secretion and action (KAL, DAX1, GnRH receptor, etc….) </li></ul><ul><li>May be difficult to distinguish from constitutional delay </li></ul><ul><li>GnRH tests can sometimes help but results may be unreliable </li></ul>
    54. 56. <ul><li>CASES </li></ul>
    55. 57. Case 1 Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function pregnancy test Ultrasound scan of the pelvis (uterus and ovaries)  
    56. 58. Case 1 Results FSH of 2.2 iu/L LH 15.0 iu/L normal prolactin and thyroid function The ultrasound scan demonstrated the presence of polycystic ovaries and an endometrial thickness of 15 mm.
    57. 59. Case 1   What should the management be?  
    58. 60. Case 1 Endometrial hyperplasia is a risk factor for oligo / amenorrhoeic women with PCOS because of unopposed oestrogen stimulating progressive hyperplasia and potentially malignancy / adenocarcinoma. Regular withdrawal bleeds should be induced either with cyclical progestogens or the COC pill. If fertility is required then ovulation induction should be instituted with clomifene citrate followed by gonadotrophin therapy if this is unsuccessful. If the patient is overweight she should be encouraged to lose weight. Women with polycystic ovary syndrome have insulin resistance and at an increased of cardiovascular disease and type II diabetes.  
    59. 61. Case 2     An 18 year old woman presents with primary amenorrhoea (she has never had a period). She has developed small breasts and has some pubic hair. She is very overweight with a body mass index of 39 kg/m 2 . What investigations should be performed in order to make the diagnosis?  
    60. 62. Case 2 Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function ( pregnancy test) Ultrasound scan of the pelvis (uterus and ovaries)  
    61. 63. Case 2 Results   FSH of 0.5 iu/L LH of 0.5 iu/L normal prolactin and thyroid function The ovaries appear small on ultrasound scan, as does the uterus.   What is the diagnosis?
    62. 64. Case 2   Hypogonadotrophic hypogonadism Usually of hypothalamic origin and may be congenital, such as Kallmann's Syndrome (association with lack of smell) The low gonadotrophin concentrations have failed to stimulate ovarian development and adequate puberty. The small amount of breast development and pubic hair can be explained by oestrogen being produced in the peripheral fat and adrenal androgen secretion. Overall this patient will be oestrogen deficient and bone mineral densitometry should be performed to exclude osteoporosis.
    63. 65. Case 2   What is the treatment?    
    64. 66. Case 2 If the patient wishes to be pregnant, first line treatment would be pulsatile GnRH or gonadotrophin stimulation of the ovaries with a preparation that contains both FSH and LH bio-activity (ie, one of the traditional hMG preparations rather than recombinant FSH). Otherwise HRT should be given.  
    65. 67. Case 2 Do you need to image the pituitary / hypothalamus?  
    66. 68. Case 2 Do you need to image the pituitary / hypothalamus? Yes in adults with secondary amenorrhoea and hypog/hypog or hyperPRL, but tumours less common in adolescents if no other symptoms and normal PRL  
    67. 69. Case 2 The patient was administered HMG at increasing high doses, but failed to produce any demonstrable follicular growth as assessed both by ultrasound scan and persistently low serum oestradiol concentrations. Can you explain?  
    68. 70. Case 2 This patient appears to have a second pathology and may well have primary ovarian failure combined with hypothalamic hypogonadotrophic hypogonadism, thus explaining the combination of ovarian failure with low gonadotrophin concentrations.  
    69. 71. Case 3     An 18 year old woman presents with primary amenorrhoea (she has never had a period). She has a normal body mass index and no other obvious problems. What investigations should be performed in order to make the diagnosis?  
    70. 72. Case 3 Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function (pregnancy test) Ultrasound scan of the pelvis (uterus and ovaries)  
    71. 73. Case 3 Results   FSH of 0.5 iu/L LH of 0.5 iu/L serum prolactin concentration: 5,000 mu/L   What is the diagnosis? What further investigations should be done?  
    72. 74. Case 3   Hyperprolactinaemia A repeat prolactin should be measured. The diagnosis is likely to be that of a macro-adenoma of the pituitary gland and therefore either MRI or CT imaging of pituitary should be performed.   What treatment should be provided?
    73. 75. Case 3   Dopamine agonists: Bromocriptine or Cabergoline Check visual fields
    74. 76. Case 4     An 18 year old woman presents with primary amenorrhoea (she has never had a period). She has a normal body mass index and no other obvious problems. What investigations should be performed in order to make the diagnosis?  
    75. 77. Case 4 Answer:   Full physical examination Serum endocrinology: FSH, LH, prolactin, thyroid function (pregnancy test) Ultrasound scan of the pelvis (uterus and ovaries)  
    76. 78. Case 4 Results   FSH of 40 iu/L LH of 30 iu/L   What is the diagnosis? What further investigations should be done?  
    77. 79. Case 4   Primary ovarian failure / premature ovarian failure   What further investigations should be performed?
    78. 80. <ul><li>Case 4 </li></ul><ul><li>  </li></ul><ul><li>repeat FSH & LH </li></ul><ul><li>karyotype </li></ul><ul><li>bone mineral densitometry </li></ul><ul><li>auto-antibody screen </li></ul><ul><li>Treatment should be with hormone replacement therapy combined with egg donation is fertility is required. </li></ul>
    79. 81. THANK YOU FOR YOUR ATTENTION
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