primary amenorrhea case discussion with syndrome, approach to infertility by Dr Bade Prasanna.pptx

Primary amenorrhea syndromes
#infertility #casehistory #AIS #MRKH #Swyers syndrome #CAH #speroffs #obstetrics #gynaecology # DNB OBGY PG #DGO #MS #NEETPG #DNBPDECT #NEETSS #Discussion #tanners staging
By Dr Bade Prasanna

1. Primary amenorrhea -By Dr Bade Prasanna

2. Physiology of development 2 X chromosomes are required for healthy ovaries which produces harmones at puberty leads to secondary sexual characters and menses Y chromosomes in genotypically male baby has SRY gene : sex determining region of Y chromosomes This has power to develop undifferentiated gonads : testes at 4-5weeks of intrauterine life, so testes develops at 6 to 7weeks

3. Testes has 2 cells : Leydig cells, sertoli cells Leydig cells: produces testosterone at 8weeks , this becomes DHT dihydrotestosterone by 5 alpha reductase Those 2 are androgens These help in 1) fusion of labio scortal swellings( scortum formed), 2) genital tubercle : phallus- penis, 3) genital folds : incorporated into penis as penile urethra,4) descent of testes from inguinal region to scortal region by androgens,5) development of wolffian ducts ( mesonephric duct )

4. Epididymis, vas deferens, ejaculatory ducts, seminal vesicles, appendix of epididymis these are exclusively from mesonephric ducts due to testosterone Mullerian and wolffian ducts: both ducts appear at 6weeks, one of them disappears at 9weeks Fusion of mullerian duct: 10weeks

5. Wolffian ducts remanants : epo ophoron , para ophoron , gartner’s duct (lateral to uterus), gartner’s cyst( 1o cloak and 11 o cloak position of vestibule. Mullerian remnant in males: 1) appendix of testes 2) prostatic utricle (uterus masculinus ) Puberty: transistion from childhood to aduldhood Secondary sexual characteristics appear

6. Normal age : 10years 6months for breast budding Mean age for menarche is 12years 9 months HPO axis activation for development is necessary these are factors affecting the timing of onset : genetics, environmental, nutritional state (obese>thin) ,exposure to light : blind patient attain puberty early, psychological state(pulsation of  Gnrh effected) Neuropeptide Y inhibits Gnrh pulse, leptin inhibits neuropeptide Y , leptin is high in obese

7. Sequence of puberty Begining of growth spurt,earliest sign of puberty Height increases due to growth harmone,IGF-1 , Gn , estrogen Girls adjusted mid parental height [ Father’sHt -13+ mothers’s Ht ]÷2 +/-8.5cm Boys: [Father’s Ht + mother’s Ht+13]÷2 +/-8.5cm

8. Tanner’s staging Telarche : 1) Prepubertal 2)Breast budding: visible, palpable breast tissue 3)Nipple is at or above breast tissue plane 4)Projection of areola and papilla above breast contour 5)Mature breast in contour and proportion, montgomery glands+

9. Adrenache Pubarche (development of pubic hair) is part of adrenarche 1) no sexually stimulated pubic hair 2)coarse cozy pubic hair along labia majora 3)coarse curly hair onto mons pubis 4)adult hair in thickness and texture but less in density 5) same as above with hair on inner aspect of thigh

10. Menarche Compartment1: uterus +outflow tract Compartment 2: ovary Compartment 3: pituitary gland Compartment 4: arcuate nucleus of hypothalamus Low amplitude high frequency favor LH : leutinization of granulosa cells High amplitude low frequency favors FSH

11. Pulsatile GNRH helps in formation Continous GNRH stops LH and FSH formation 2 cell 2 gonadotrophin theory Cholesterol acts on theca cells and produce Androstenodione ASD acts on granulosa cells and converts into estradiol by aromatase under influence of FSH FSH prepares estradiol by aromatase , FSH brings LH receptors out in granulosa cells and helps LH to bind to receptor on granulosa cells and produce progesterone

12. Primary amenorrhea No menses till 15years , Secondary sexual characters + No SCC till 13years of age ASRM : if patient doesn't get menses within 5years of breast development Incidence of pathological amenorrhea: 3to4% (PCOS, Hypothalamic hyperprolactinemia, ovarian failure most common

13. WHO classification Group1: Hypogonadotropic hypogondasim estrogen ⬇️⬇️ FSH ⬇️ or normal, defect in compartment 3, 4 hypothalamus, pituitary Group2: normogonadotropic normogonadism estrogen , FSH normal, compartment 1 uterus + outflow defect Group3 : hypergonadotrophic hypogonadism FSH⬆️⬆️ , estrogen ⬇️ defect in compartment 2

14. Causes of amenorrhea A) anatomical: MRKH, AIS, Asherman (intrauterine adhesions due to infections like TB Imperforate hymen, transverse vaginal septum, cervical agenesis, stenosis, vaginal agenesis B) Primary hypogondism (POI) 1)Gonadal dysgenesis: 45XO mosiac 46XX/46XO most common turner syndrome, 46XX, 46XY swyers’s syndrome pure gonadal dysgenesis

15. 2) enzyme deficiency: 17alpha hydroxylase deficiency Aromatase deficiency no estrogen formation, sex steroids are deficient 3) premature ovarian failure : radiation, chemotherpay , mumps, idiopathic C) hypothalamic causes: dysfunctional stress, exercise, eating disorder Isolated Gn deficiency idiopathic hypogonadotropic hypogonadism

16. Kallmann syndrome: KAL1 mutation anosmia, Gn cell deficiency, color blindness, height normal, no puberty D) pituitary causes: sheehans syndrome due to PPH (2° amenorrhea) Prolactinoma Fragile X syndrome FMR gene mutation Autoimmune, cocaine, empty sella syndrome, antidepressant opiates

17. E) Endocrine: CAH (adrenal) Tumors , cushing syndrome, thyroid causes, ovarian tumors producing harmones , PCOS multifactoral cause Incidence: turners 1:2500 , mullerian agenesis 1: 4500, imperforate hymen 1:1000 cryptomenorrhea

18. History Age , growth chart if available Age of thelarche Cyclic abdomen pelvic pain Smell perception Maternal age at menarche Neonatal infection of CNS Surgery done in abdomen, inguinal region Chemo,raditherapy CNS symptoms, ⬆️ICT , hirsutism, acne

19. Physical examination Height, weight, BMI, acanthosis nigricans Thyroid, breast for galactorrhea Tanner breast, estrogen Pubic hair (androgenic ) Features of turner’s syndrome: short height, webbing of neck, low hair line, cubitus vulgus , CVS, renal anamolies , pigment nevi

20. Per abdomen : abdominal striae, centripetal fat distribution, any palpable masses Check external genitalia Inguinal masses/ hernia Cliteromegaly >1cm Patency of vagina Rectal examination: bulge from [proximal vagina, retained menstrual fluid Hirsutism, ask about hair removal practices

21. Investigation 1 st investigation: ultrasound uterus, gonads, beta hcg : UPT HSG, SIS ( ashermann ) CT, MRI hypothalamus pituitary causes Harmonal evaluation: must LH, FSH, prolactin, TSH Karyotype: 45XO turners, 46XY AIS, 46XX MRKH (serum terosterone ) 46XY swyers

22. Disorders of sexual development SRY gene: most important gene SOX 9 gene: sertoli cell development SF1 gene: steroidogenesis to happen in normal way DAX 1 gene: X chromosome: duplication: supression of SRY gene WT1 gene mutation: gondal + renal abnormalities seen

23. Chicago consensus classification DSD disorders of sexual development 46XX DSD,46XY DSD, OTHERS 46XX DSD: androgen excess CAH, Maternal androgen intake Ovarian disorders ovotesticular DSD, SOX 9 duplication, SRY translocation Mullerian disorders MRKH

24. 45XO : turners syndrome 46XY/45XO: mixed gonadal dysgenesis (testes on one side, streak ovary on other side) Ovo testicular condition: 46XX/46XY mosaic 47XXY klinfelters syndrome ( semniferous tubules, dysgenetic )

25. 46XY male DSD A) testicular development disorder : swyer syndrome, ovotesticular formation, vanishing testes syndrome B) disorder of androgen synthesis : leydig agenesis, 5alpha reductase deficiency C) andorgenic receptors are faulty : AIS Androgen insensitivity syndrome, partial AIS D) persistent mullerian duct syndrome

26. Others: Severe hypospadiasis Cryptorchidism Penile agenesis Cloacal exostrophy Ambigous genitalia : prader classification

27. AIS Androgen insensitivity syndrome X linked recessive condition Androgenic receptor are faulty/ absent Genotypically male 46XY Gonads undescended testes because for testes to descent , testosterone is required Mullerian structures absent Baby born as female raised as female

28. Tall height Axillar, pubic hair negative androgens not acting on receptors Breast development seen Androgens: testosterone in periphery  estrogen Treatment: gonadectomy but after pubertyage then estrogen replacement, vaginoplasty for sexually active female Partial AIS: Same receptors are positive, REIFENSTEIN’S SYNDROME, raised as males and gynecomastia is seen at puberty

29. History 31year old female Born as female baby She has operated for inguinal hernia at 14years of age At 16 years she had primary amenorrhea [Incidence of inguinal hernia in AIS is 1 to 4%, female children with inguinal hernia consider karyotype]

30. Work up No swelling of lymph nodes No axillary hair Female vulva, no perineal hair, blind end vagina Pelvic MRI shows abnormal signal shadows in bilateral groins Breasts fully developed, vulva completely formed. Chromosome : 46XY

31. Treatment Abdominal bilateral inguinal testicle resection Preop and post op harmone levels Estrogen 63 to 5 pg /ml Testosterone 5.34 to 0.152 ng/ml Progesterone: 0.267 to 0.05 ng/ml LH: 29.3 to 75.8 mIU /ml FSH:16.1 to 114mIU/ml Prolactin: 252 to 207 IU/ml HPE: left side testis shows leydig cell tumor Lesson: tesicle resection once attained puberty age to avoid gonadoblastomas

32. SWYER’S SYNDROME Born as female, raised as female SRY gene defect 46XY testes are not formed Pure gonadal dysgenesis , bilateral streak gonads Mullerian ✅️ uterus ✅️ infantile Puberty: absent Treatment: gonadectomy , EPHY because uterus present, ovum donation + IVF

33. History 14years old female presented with primary amneorrhea with no secondary sexual characteristics No history of cyclical abdominal pain,   harmonal imbalance, radiation exposure,  chemotherapy,  no headache, visual disturbances

34. No breast development No axillary hair pubic hair (sparse sometimes) External genitalia developed vulva seen Usg : hypoplastic uterus with fallopian tubes and absent ovaries Both kidneys normal Karytope : 46XY Note: gonadectomy to be done after attaining puberty age to prevent gonadal tumor gonadoblastoma 20 to 30%

35. Diagnostic laparoscopy: infantile uterus, fibrous bands on either sides , streak gonads Removal of bilateral white structures done HPE: streak gonads with ovarian differentiation Treatment: HRT with conjugated estrogen for 3months followed conjugated estrogen and medroxyprogesterone cyclically Breast developed,uterine growth increased, attained menarche Pregnancy : donor oocyte, ART DD: mixed gonadal dysgenesis HPE: ovary+testicular differentiation

36. Early diagnosis of swyers syndrome is essential Risk of gonadal malignacies Need for removal of gonads Early HRT for induction of puberty Improving bone mineral density Counselling regarding dertility options

37. CAH/ Adrenogenital syndrome 46XX Cortisol pathway defect Most common: 21 hydroxylase deficiency Cortisol is less ACTH ⬆️⬆️ Adrenal hyperplasia as cortisol not there adrenal hyperplasia ⬆️

38. 17OH progesterone ⬆️⬆️ screening test, testosterone Ambiquos genitalia external Heterosexual precious puberty Primary amenorrhea Confirmatory test: ACTH stimulation test  very high 17OH progesterone >10ng/ml confirms diagnosis Treatment: hydroxycortisone 10to20mg/m2 BSA Target of 17OH progesterone 300 -900 ng/dl Plastic surgery for gender alignment

39. History 16years 8 months old female came c/o primary amenorrhea with hirustisim

40. Examination Male morphotype Lack of breast development Clitoromegaly Severe hirsutism score 29 Usg : hypoplastic uterus, macropolycystic ovaries Abdominal scan adrenal glands normal 17OHP : 354 ng/ml (high) Cortisol 62g/ml (low) Testosterone: 3.69 ng/dl

41. Treatment Hydrocortisone 20mg/day Spironolactone dose 100mg/day Continous follow up Stimulate menstruation by progestin 17OHP decreased to 163.9ng/dl Testosterone decreased to 1.64ng/ml

42. MRKH syndrome 46XX, no uterus no vagina Skeletal + renal anamolies Secondary sexual characters normal HPO axis : normal Problem is NO UTERUS 1 st line investigation: USG , inv of choice: karyotyping Treatment: vaginoplasty , surrogacy for infertility, no HRT

43. History 25year old female c/o primary amenorrhea, painful sexual intercourse Mother confirms No exposure of medications or illness during pregnancy

44. Examination Breast well developed Normal labia majora, minora, normal pubic hair development Harmonal tests all normal MRI : agenesis of uterus cervix, proximal 2/3rd of vagina along with agenesis of kidneys Karyotype: 46XX

45. Treatment Counselled for vaginoplasty Split thickness skin graft was taken from anterior medial aspect of right thigh Blunt dissection as done and space was created on either side of vestibule Intervening tissue resected and neovagina created Mold wraped with skin graft and inserted in neovagina Per rectum exmination done normal Dilator inserted for 3months to prevent neo vaginal stenosis

46. Thankyou Happy learning