Ultrasound in reproductive endocrionology


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my key note address at AICOG 2013.....for all who missed this one and on request of many who were present and wanted a copy...... if you copy these please do but please acknowledge.....

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Ultrasound in reproductive endocrionology

  1. 1. ultrasound in reproductive endocriology in women narendra malhotra jaideep malhotra neharika malhotra bora rishabh bora Inputs from ashok khurana,sonal panchal,asim kurjak,sakshi tomar
  2. 2. Greetings from agra
  3. 3. female reproductive physiology a well orchestrated neuro-endocrinological process Parts of the system Gonads 􀂄 Ovaries Internal genitalia 􀂄 Uterine tubes 􀂄 Uterus 􀂄 Vagina External genitalia
  4. 4. Female endocrinology• 1.Functional anatomy• 2.Overview hormones• 3.gametogenesis and folliculogenesis• 4.puberty and adolescence• 5.regulation of menstrual cycle & problems• 6.infertility• 7.pregnancy• 8.contraception• 9.menopause
  5. 5. advantages of 3D ultrasound1. Surface rendering2. Multi-planar imaging3. Exact volume measurement4. Power Doppler quantification5. Inversion mode6. Automation7. Virtual scanAutomatic Volume ScanMultiplanar Volume Analysis
  6. 6. I. Functional anatomy
  7. 7. characteristics 􀂄 Ovaries function until menopause ↔ testes function until old age (only slight decline) 􀂄 Periodic preparation for fertilization and pregnancy and intermittent release of ova ↔ continuous production of spermatozoaFundamental reproductive unit = single ovarianfollicle, composed of one germ cell (oocyte), surroundedby endocrine cells
  8. 8. OvaryTwo roles 􀂄 gametogenic 􀂄 endocrine 􀂄 The gametogenicpotential is establishedearly in thefetus 􀂄 Endocrine role of theovary is not realized untilpuberty
  9. 9. HORMONE: Estrogen (female)Secretory gland: OvariesSecretory cell: Granulosa (thecal cells as well)Chemical class: Steroid hormoneStimulus for release FSH (granulosa) and LH (thecal)Inhibitors of release None directTransport in blood: Bound to plasma proteinsRemoval from blood: Liver, results excreted by kidneysMechanism of Cytosolic & nuclear receptors;action: alters synth. & activity of enzymesBiological Necessary for ovulation;response(s) produces 2nd sex characteristics 2
  10. 10. HORMONE: ProgesteroneSecretory gland: Adrenal cortex, ovaries, placentaSecretory cell: Granulosa cells of corpus luteumChemical class: Steroid hormoneStimulus for releaseInhibitors of releaseTransport in blood: Bound to plasma proteinsRemoval from blood:Mechanism of Nuclear (& possibly non-action: nuclear) mobile receptorsBiological Alterations to uterus andresponse(s) breasts
  11. 11. HORMONE: Inhibin (male and female)Secretory gland: Testes and ovariesSecretory cell: Sertoli (m) & Granulosa cells (f)Chemical class: GlycoproteinStimulus for release FSHInhibitors of releaseTransport in blood: In solutionRemoval from blood:Mechanism of Fixed receptor systemaction:Biological Inhibits release of FSH from ant.response(s) pituitary
  12. 12. II. Overview Function of the reproductive system • Oogenesis • Puberty and menstruation • Conception - reception of sperm and transport of sperm and ovum • Gestation - maintenance of the fetus • Parturition • Lactation • Contraception • menopauseULTRASOUND HELPS IN ASSESSING ALL THESE ENDOCRINOLOGICALFUNCTIONS
  13. 13. OvaryCortex 􀂄 Contains folliclesin different stages ofdevelopment 􀂄 Medulla 􀂄 Interstitial, steroidproducing cells 􀂄 Stromal cells(connective tissue)
  14. 14. cellular components of the ovaryThe ovary consists of epithelialand mesenchymalcomponents 􀂄 Mesenchymal tissuedifferentiates into interstitial tissue 􀂄 This tissue is the primarysource of hormones 􀂄 Also associated withgerminal elements of the ovary 􀂄 Provides nutritiveenvironment for the oocytes 􀂄 Epithelial tissue differentiatesinto granulosa cells
  15. 15. III. Gameto- & folliculogenesis
  16. 16. follicle 􀂄 Each contains anoocyte 􀂄 Concentric layers ofcells 􀂄 Granulosa cells 􀂄 Thecal cells 􀂄 There is a basalmembrane betweengranulosa and thecalcells 􀂄 Follicle is embeddedin stroma
  17. 17. cellular layers of the follicle
  18. 18. oogenesis – before birth 􀂄 Oogonia (6-7 million) 􀂄 Undifferentiated stemcells in the fetus 􀂄 During the prenatalperiod, oogonia developinto primaryoocytes 􀂄 At birth only primaryoocytes are present
  19. 19. oogenesis - at birth􀂄 Primary oocytes(2 million at birth) 􀂄 Primary oocyte iscovered bysingle-layer offlattenedgranulosa cells =primaryfollicle a.k.aprimordial follicle
  20. 20. primordial folliclesLie in the periphery (cortex) of theovary 􀂄 They are separated from each otherby stromal andinterstitial tissues 􀂄 Majority of primary follicles remainarrested indevelopment state 􀂄 A small population of primaryfollicles starts developingtowards more differentiated form:secondary follicle 􀂄 Still in embryonic ovary, primordialfollicles beginreduction division of meiosis
  21. 21. what happens to the primary folliclesBefore puberty: the developing population ofprimaryfollicles degenerates before reaching the secondaryfollicle stage (atresia) 􀂄 After puberty: one of the simultaneouslydifferentiatingprimary follicles will reach the fully mature form inevery28 days (→ ovulation), the other simultaneouslymaturing primary follicles will degenerateBy menopause: no primary follicle is left(400 havereached the fully mature stage, the resthasdegenerated)
  22. 22. Secondary oocytes(secondary follicles) →mature ovum
  23. 23. secondary follicleAfter puberty, in every ovulatory cycle 6-12 primaryfollicles are selected for development of secondaryfollicles 􀂄 Increase in oocyte size and in granulosa cell layersaround each oocyte 􀂄 Granulosa cells secrete mucoid material that forms thezona pellucida around each oocyteUsually only one will develop into a mature follicle 􀂄 The rest will become atretic and disappear 􀂄 The follicle that is selected for maturation is thought tobe the one whose granulosa cells acquire high levels ofaromatase and LH receptor
  24. 24. purposes of ovarian folliclePreserve resident oocyte 􀂄 Mature oocyte at the righttime 􀂄 Produce best surroundingfor development of healthyoocyte 􀂄 Release oocyte at righttime 􀂄 Produce quality corpusluteum after implantation 􀂄 Preserve hormonalconditions for gestation
  25. 25. ovarian reserve assesment ANTRAL FOLLICLE COUNT• Goal: To determine the functional capacity of the ovary. Specifically the quantity and quality of oocytes remaining.Direct measures AFC/ovarian volume Anti-mullerian Hormone (AMH) Inhibin BIndirect measures FSH
  26. 26. cyclic behavior of female reproductive systemThe cause of cyclicity –hypothalamus Periodicchanges in the frequency ofGnRH bursts 􀂄 Ovarian cycle 􀂄 Uterine (menstrual cycle)
  27. 27. Periodic changes in the frequency of GnRH bursts from the hypothalamus Periodic changes in FSH and LH release from pituitary Periodic changes in ovarian function (ovarian cycle) periodic release of ovum periodic changes in the secretion of estrogens and progesterone - periodic changes in the uterus (uterine cycle, a.k.a. menstrualPeriodicity in the cycle)possibility of - periodic changes in the cervixfertilization and - periodic changes in the vaginaimplantation - periodic changes in the breasts
  28. 28. Uterus:Three-dimensional transvaginal ultrasound can depict a coronal section of the uterus1. Endometrial receptivity2. Cavity problems : Fibroid and polyps3. Congenital uterine abnormalities4. Endometrial assessment in endometrial carcinoma
  29. 29. sagittal section A single coronal section of the uterus cannot demonstrate the whole uterine cavity (endometrium) when the uterine cavity curved too much.coronal section
  30. 30. Three-dimensional images of the endometrial cavity or the endometrium - extraction of theendometrial cavity and volume measurement.
  31. 31. uterine vascularity and wall Layers of the uterus wall 􀂄 Endometrium (with uterine glands) 􀂄 Myometrium 􀂄 Perimetrium 􀂄 The thickness of the endometrium changes during the menstrual cycle
  32. 32. Three-dimensional images of the endometrialcavity or the endometrium - 3D images of the endometrial cavity
  33. 33. ovarian cycle or follicular maturationPrimary oocyte (meioticarrest, diploid) 􀂄 During each ovariancycle, primary oocytescompletefirst meiotic division 􀂄 First meiotic division iscompleted shortly beforeovulation 􀂄 Followed by extrusion ofthe first polar body andformation of the secondaryoocyte
  34. 34. SonoAVC Sonography-based Automated Volume CountAutomatically calculates the number and volume ofhypoechoic structures in a volume dataset.Can significantly reduce time for assessment and reporting.From the calculated volume an average diameter can be calculated.It also lists the objects according to their size.
  35. 35. SonoAVC follicle TM New Graph & Graph with 2 lines Exam SummarySelection if >4exams/cycle SonoAVC Index Cut-off value set
  36. 36. Report page of Sono AVC
  37. 37. Other tools for volume calculation .....
  38. 38. Infolding of follicular wall
  39. 39. What is specific in PCO morphology…• Multiple antral follicles• Distribution of antral follicles• Stromal predominance• Stromal vascularity
  40. 40. • Polycystic ovarian morphology has been found to be a better discriminator than ovarian volume between polycystic ovarian syndrome and control women.Legro, et al, JCEM 90(5): 2571-79.
  41. 41. 3D 4 D PCOD
  42. 42. Threshold volume
  43. 43. • PCO shows multiple follicles and therefore is likely to lead to errors when counted manually.• Therefore an automated volume calculator is used : Sono AVC.
  44. 44. Stromal vascularity• Even with same echogenecity, PCOS has more stromal flow.
  45. 45. Volume histogram
  46. 46.  Women with PCOS had  higher AFC(median 16.3 v/s 5.5 per ovary),  ovarian volume ( 12.56 v/s 5.6ml)  stromal volume ( 10.79 v/s 4.69ml)  stromal vascularization (VI 3.85v/s 2.79%, VFI 1.27 v/s 0.85). Though 2Dpower Doppler indices were not higher in PCOS than in controls. Lam PM, et al, Hum Reprod 2007 Dec ; 22(12):3116-23
  47. 47. Deciding the stimulationprotocolASSESSING OVARIAN RESERVEAND RESPONSE
  48. 48. Predictors of ovarian response are enumerated as:• Number of antral follicles• Stromal flow: stromal FI• Total ovarian stromal area• Total ovarian volumeKupesic S et al, Hum Reprod 2002; 17(4):950-55
  49. 49. • AFC is reported the benefit to predict ovarian response and reduce cancellation cycles.Chang MY, et al. Fertil Steril 1998; 69:505-10
  51. 51. In spite of deciding the time of hCG based on 2D and CD assessment of the follicle, there were lots of failures.3D US was therefore tried for follicular assessment with 3D PD.
  52. 52. Follicular Volume Follicular volumes of between 3 – 7 cc are optimum for oocyte retrieval . The limits of agreement between the volume of the follicular aspirate and 3D volume of the follicle were + 0.96 to – 0.43 with 3D and + 3.47 to – 2.42 by 2D volume estimation.
  53. 53. cumulusOn the day of HCG – Ifcumulus like echoes is not seen in allthree planes in the follicle , it is lesslikely to be mature fertilizable oocyte.
  54. 54. Perifollicular 3D PD
  55. 55. • Follicles with more uniform perifollicular vascular network are more likely to produce pregnancy.
  56. 56. Perifollicular 3DPD
  57. 57. SonoAVC for IVF pre hCGPre hCG OHSS prediction Even when the age of the patient and total number of follicles are similar, the ovarian volume was significantly higher in the patients who developed OHSS ( 271+/- 87 v/s 157.30 +/- 54.20ml)
  58. 58. corpus luteum 􀂄 After release of ovumit fills up withblood:corpushemorrhagicum 􀂄 Granulosa cellsincrease in number andclotted blood isabsorbed 􀂄 Granulosa cellsaccumulate a lot ofcholesterol 􀂄 Luteinization processforms the corpus luteum
  59. 59. luteal phasefollicular remnant (mainlyouterlayer of granulosa cells)↓corpus hemorrhagicum↓c. luteum: secretes estrogenand progesteronesurvives for 14 days (inpregnancy: for 12 weeks)↓c. albicans
  60. 60. ovarian hormones Steroids 􀂄 Estrogens 􀂄 Androgens 􀂄 Progesterone PeptidesProduced in both interstitial and follicular cellsDerivatives of cholesterol (coming from LDL-lipoproteins and de novo synthesis)
  61. 61. estrogens• Development and maintenance of uterus, uterine tubes,• vagina, external genitalia and breasts• Cyclic changes in the endometrium, cervix, vagina• Growth of the ovarian follicles• Motility of the uterine tubes ↑• > Pregnancy: uterine muscle mass ↑, excitability ↑,• breasts ↑• Female secondary sex characteristics (fat deposits, etc)• Estrous behavior in animals, increased libido in humans
  62. 62. progesterone• 􀂄 The most distinctive hormone between males and• females• 􀂄 Chemical structure: C21• 􀂄 Source:• 􀂄 c. luteum• 􀂄 placenta• 􀂄 follicles (small amount)• 􀂄 adrenal cortex
  63. 63. physiological role of progesterone• 􀂄 Cyclic changes in the endometrium, cervix, and vagina• 􀂄 Myometrium excitability ↓ ↓ (smooth muscle• contractility ↓ in general → constipation, venous• varicosities)• 􀂄 Estrogen receptor number ↓ in endometrium• 􀂄 Breasts: supports the secretory function during lactation• 􀂄 Thermogenesis ↑• Inhibits LH secretion• 􀂄 Sodium excretion↑ (inhibits aldosterone receptors) →• followed by compensatory increases in aldosterone• secretion (→ mild water retention)• 􀂄 Precursor for steroids in all steroid-producing tissues• Progesterone is the ovarian hormone of pregnancy It is responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy
  64. 64. peptide hormones of the ovaryRelaxin• 􀂄 Relaxes pelvic joints• 􀂄 Softens and dilates cervix• 􀂄 Sperm mobility - in males Inhibin• 􀂄 Selective inhibitory control of FSHActivin• 􀂄 Selective stimulaton of FSH• 􀂄 Cell differentiation Follistatins• 􀂄 Inhibit FSH secretionGonadotropin surge attenuating factor• 􀂄 Prevents premature LH surge POMC hormonesVasopressin and oxytocin (in luteal cells)
  65. 65. hormonal control of ovulation
  66. 66. proliferative phase
  67. 67. secretary phase
  68. 68. 6mm HIGH NEGATIVE PREDICTIVE VALUE IN CASES WITH MINIMAL ENDOMETRIAL THICKNESS !!! CUT OFF VALUEGonan et al., Ultrasound Obstet Gynecol 1991 6 mmKhalifa et al., Hum Reprod 1992 7 mm
  69. 69. Relative echogenicity of the endometrium and adjacentmyometrium as demonstrated on a longitudinal US scan
  71. 71. Spiral artery perfusion 4 TYPES OF COLOR MAPSZONE 1 ZONE 3ZONE 2 ZONE 4
  73. 73. SUBENDOMETRIAL ZONE PR = 26.7 % P < 0.05 OUTER HYPERECHOGENIC ZONE PR = 36.4 % INNERHYPOECHOGENIC P > 0.05 ZONE PR = 37.9 % Zaidi et al., Ultrasound Obstet Gynecol 1995
  74. 74. CUT-OFF VALUE OF UTERINE PI & RI PI = 3 - 4 RI = 0.93 - 0.95 • LOW UTERINE RECEPTIVITY • VERY UNLIKELY IMPLANTATION Steer et al., Fertil Steril 1992
  76. 76. VI NEW PARAMETERSFI FOR PREDICTION OFVFI IVF OUTCOME Kupesic et al, J Ultrasound Med 2001
  77. 77. IV. Regulation: the menstrual cycle
  78. 78. Menstrual cycle – controlled by gonadotropins, gonadal hormonesOvarian cycle –follicular phase – avg 15 d (range, 9-23 days)ovulationluteal phase – 13-14 d – less variable than follicularEndometrial cycle – menstruation, proliferative and secretory phases
  79. 79. 28 day cycleCycling begins at puberty Fig. 5
  80. 80. Phases of Endometrial Cycle Figure 81-7; Guyton & Hall
  81. 81. Ovarian Cycle: follicular phase FSH and LH in the ovulation Follicular phase LH surge LH surge lasts 48 h Inc GnRH bursts FSH LH 1 4 14 Endometrial proliferative phase secretory phase (12d) 28 Cycle: menstrual (11 d)Copyright © 2006 by Elsevier, Inc.
  82. 82. OvarianCycle: follicular phase ovulation LH surge Increase in estradiol to stimulate LH surge. Then estradiol has Negative feedback on GnRH to reduce LH, FSH. FSHestradiol neg LH feedback--GnRH 1 4 14 28Endometrial Proliferative phase Secretory phase (12d)Cycle: menstrual (11 d) Copyright © 2006 by Elsevier, Inc.
  83. 83. reproductive endocrinology of women• Complicated• Delicate interactions of neural-hormonal-peripheral changes
  84. 84. The numbers game• 7 million oogonia (by 20-24 weeks)• 2 million oocytes at birth• 100-400,000 oocytes at start of pubertyPre-puberty, development of the oogoniabegins but can not be completed and thecells die (atresia)
  85. 85. puberty an endocriological event
  86. 86. Puberty and adolescence• Precosious• Delayed• Primary gonadal failure• A.U.B/D.U.B
  87. 87. ultrasound in puberty events• Follicles and ovary• Uterine growth• Endometrium growth All are in response to ovarian steroidogenisis
  88. 88. hypthalamic-pitutary problems• gonadotrophins and releasing hormones• Prolactin• thyroid hormonesPROBLEMS AREAmenorrheaPrecocious puberty/delayed pubertyAnovulatory DUBMenstrual disorders
  89. 89. Primary gonadal failure PituitaryInsult LH, FSH Ovary/testis Estrogen/ Testosterone Clinical hypogonadism
  90. 90. Secondary gonadal failureInsult Pituitary LH, FSH Ovary/testis Estrogen/ Testosterone Clinical hypogonadism
  91. 91. Clinical features: Time of onset• First trimester: female genitalia, ambiguous genitalia, virilisation• Third trimester: micropenis, cryptorchidism• Childhood, adolescence: delayed puberty, eunuchoid proportions ( long bone length)• Adult – Decreased libido, erectile dysfunction – Fatigue – Loss of muscle mass – Reduced facial, body hair – Loss of bone mass – Gynaecomastia (1° > 2°) – sperm count (1° > 2°)
  92. 92. Investigation• LH, FSH – primary vs secondary• Semen analysis• Primary – Karyotype• Secondary – Pituitary function – MRI pituitary – Prolactin – Iron studies
  93. 93. Primary amenorrhoea• Absence of menses by 15y in presence of normal 2° sexual characteristics• Causes – Chromosomal – Hypothalamic – Anatomic – Pituitary
  94. 94. Hypothalamic/pituitary• Functional eg. anorexia nervosa, exercise• GnRH deficiency – eg Kallman syndrome• Constitutional delayed puberty• Hyperprolactinaemia• Pituitary lesions
  95. 95. Ovarian disease• Turner syndrome commonest (45,X) – Normal genital development until puberty – Dysmorphic features• Variants of gonadal dysgenesis: 45,X/46XX mosaic, 46,XY – 46,XY have high risk of gonadoblastoma or dysgerminoma – removal required• Fragile X• Polycystic ovary syndrome
  96. 96. Secondary amenorrhoea• Absence of ≥3 cycles or 6 months, if previous menses• Etiology – Pregnancy – Functional hypothalamic amenorrhoea – Hypothalamic/pituitary disease – Systemic disease – Hyperprolactinaemia (GnRH suppression) – Thyroid dysfunction – Polycystic ovarian syndrome – Premature ovarian failure – Uterine disease
  97. 97. V. Hormones & contraception• Combination contraceptives contain – Estrogen – Progesterone• Inhibit ovulation by negative feedback that reduces FSH and LH (no surge)• Alters the production of cervical mucus• May alter the endometrium
  98. 98. VI. Menopause• Permanent cessation of cycling• Typically between 45-55 (35-65)• Due to “ovarian failure” – Responsiveness to LH/FSH reduced – Therefore, less estrogen and progesterone produced• Adrenal cortex becomes the major producer of sex hormones in post- menopausal women
  99. 99. Newer machines andtechnology has made itpossible to have usg asan accurate tool forcomplete reproductiveassesment…anatomicaland physiologicalBT12 EnhancementsNew clinical value for youand your patients
  100. 100. MANAGINGINFERTILTY (AOFOG BOOK)dr jaideep malhotra
  101. 101. THANKYOU