Male Infertility - How Gynaecologists can manage?

Dr Sujoy Dasgupta delivered a talk on "Male Infertility - How Gynaecologists can manage?" in a CME organised by Durgapur Obstetric and Gynaecological Society, supported by Corona Remedies on 28 July 2024

1. Dr Sujoy Dasgupta MBBS (Gold Medalist, Hons ) MS (OBGY- Gold Medalist) DNB (New Delhi) MRCOG (London) Advanced ART Course for Clinicians (NUHS, Singapore) M Sc, Sexual and Reproductive Medicine (South Wales, UK) Clinical Director, Genome Fertility Centre, Kolkata Managing Committee Member, BOGS , 2024-25 Clinical Examiner, MRCOG Part 3 Examination Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London, 2019 Delivered, Dr Kamini Rao Oration, AICOG, 2024 Peer reviewer- Fertility & Sterility, BMJ Case reports, JOGI, Clinical Urology, Journal of Men’s Health Male Infertility- How Gynaecologists Can Manage?

2. Do we understand- “Male Infertility?”

3. Men’s fertility potential depends on female factors Assessment of tests and treatments for the male is challenging due to inconsistent endpoints and the observation that many of these endpoints are dependent upon and measured from the female partner. Ideally, the endpoint for fertility trials should be "live birth or cumulative live birth” (WHO, 2021)

4. Limitations of WHO 2010 Guideline Based on parameters in a large group of fertile men along with defined confidence intervals from recent fathers with known time-to-pregnancy (TTP). The WHO does not consider the values set as true reference values but recommends or suggests acceptable levels. Day to day variation Functional ability of the sperms?

5. We cannot treat We bypass

6. Disclaimer Written inform consent from all the patients Conflict of interest- None

7. Case 1

8. From which Laboratory?

9. Case 2 Collection Method Masturbation Total Motility 41% Abstinence 4 days Progressive Motility 26% Collection Complete Non progressive Motility 15% Volume 2 ml Immotile 59% Viscosity Normal Motile Sperm Count 14.76 million Liquefaction Time 45 minutes Normal Morphology 5% pH 7.6 Abnormal Morphology 95% Sperm Concentration 18 million/ ml Vitality 62% Sperm count 36 million/ ejaculate Round cells Nil

10. Case 2 Collection Method Masturbation Total Motility 41% Abstinence 4 days Progressive Motility 26% Collection Complete Non progressive Motility 15% Volume 2 ml Immotile 59% Viscosity Normal Motile Sperm Count 14.76 million Liquefaction Time 45 minutes Normal Morphology 5% pH 7.6 Abnormal Morphology 95% Sperm Concentration 18 million/ ml Vitality 62% Sperm count 36 million/ ejaculate Round cells Nil Normozoospermia

11. WHO reference ranges

12. Points to note in semen report Volume 1.4 ml Colour Whitish Viscosity Normal Liquefaction Time 45 minutes pH 7.2 Sperm Concentration 16 million/ ml Sperm count 39 million/ ejaculate Total Motility 42% Progressive Motility 30% Non progressive Motility 12% Immotile 58% Normal Morphology 4% Vitality 54% Round cells Nil 1 2 3 4 5 6

13. Case 3 Collection Method Masturbation Total Motility 46% Abstinence 4 days Progressive Motility 33% Collection Complete Non progressive Motility 13% Volume 2 ml Immotile 54% Viscosity Normal Motile Sperm Count 33.12 million Liquefaction Time 45 minutes Normal Morphology 5% pH 7.6 Vitality 32% Sperm Concentration 36 million/ ml Pus cells 10-12/ hpf

14. Case 3 Collection Method Masturbation Total Motility 46% Abstinence 4 days Progressive Motility 33% Collection Complete Non progressive Motility 13% Volume 2 ml Immotile 54% Viscosity Normal Motile Sperm Count 33.12 million Liquefaction Time 45 minutes Normal Morphology 5% pH 7.6 Vitality 32% Sperm Concentration 36 million/ ml Pus cells 10-12/ hpf Leucocytospermia

15. Case 3 ( Contd ) Apparently unexplained infertility Male- 36 years No apparent risk factors for infertility Ignore Antibiotics (empirically) Culture of semen Further tests

16. Disclosed “pain during intercourse” Diagnosed to be diabetic Pus cells disappeared after circumcision Conceived after OI

17. Male Accessory Gland Infection (MAGI)

18. Leucocytospermia EUA, 2018; ASRM, 2020; Vignera et al., J Med Microbiology, 2014 The clinical significance is controversial. Special Tests- Round cells vs Pus cells Method of collection Hand washing before collection Culture of semen Antibiotics- only when documented infections Routine antibiotics- can harm Consider prostatic fluid culture

19. Case 4 26 yr, smoker Concentration 14 million/ml, motility 35%, pus cells 8-10/ hpf Acute Rt scrotal pain After antibiotics- symptoms subsided, semen became normal Conceived after IUI+

20. “Pus Cells” and ART outcome

21. Case 5 Trying for pregnancy for 3 years Woman- regular cycle, no dysmenorrhoea AMH 2.8 ng /ml; tubes patent in HSG Semen- “ normozoospermia ” as per WHO Do further tests in male partner Give some medicines

22. Sperm DNA Fragmentation

23. Treatment options for high DFI ( Agarwal et al., World J Mens Health. 2020) ICSI with TESA MACS, IMSI Varicocelectomy Treat infection Control weight, diabetes Quit smoking Antioxidants Frequent ejaculation

24. SDF Testing Indications Infertile men with: Repeated IUI or IVF failure Recurrent spontaneous miscarriages (ESHRE, 2018) Previous low fertilization, cleavage or blastulation rate Varicocele with normozoospermia Advanced male age (>40 y) Significance of SDF Live birth after IUI/ IVF/ ICSI- ? Oocytes can repair the damaged DNA Lack of standardization Lack of definitive treatment Should not be routine (ASRM, 2020; ESHRE, 2023)

25. Don’t advise any test if you do not know what to do with the result !!!

26. Oxidative Stress in Subfertility Infertility OXIDANT PRODUCTION ANTIOXIDANT DEFENCES SYSTEM Oxidative stress (OS) is an imbalance in a cell’s production of Free radicals( oxidants) of intrinsic or extrinsic origin, and its ability to reduce them with scavengers.

27. Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility .  Cochrane Database Syst Rev . 2019;3(3):CD007411. May improve live birth rates Clinical pregnancy rates may also increase Overall, there is no evidence of increased risk of miscarriage , however antioxidants may give more mild gastrointestinal upsets Subfertilte couples should be advised that overall, the current evidence is inconclusive.

28. In some studies, AS was found to be beneficial in reversing OS-related sperm dysfunction and improving pregnancy rates. The most commonly used preparations, either as monotherapy or in combination as multi-AS, were: vitamin E (400 mg), carnitines (500–1000 mg), vitamin C (500–1000 mg), CoQ10 (100–300 mg), NAC (600 mg), zinc (25–400 mg), folic acid (0.5 mg), selenium (200 mg), and lycopene (6–8 mg). Still debatable due to the heterogeneity in study designs and the multifactorial genesis of infertility. 

29. Case 6 P0+2, all early miscarriage, no H/O subfertility Female-28, Male- 34 Karyotypes of both normal Female- 3-D USS, APLA, TSH, sugar- normal DFI 40% Advised TESA-ICSI or donor sperms elsewhere because of high SDF Subclinical varicocele Conceived spontaneously, delivered

30. Case 7 Collection Method Masturbation Total Motility 35% Abstinence 4 days Progressive Motility 17% Collection Complete Non progressive Motility 18% Volume 2 ml Immotile 65% Viscosity Normal Motile Sperm Count 8.4 million Liquefaction Time 45 minutes Normal Morphology 3% pH 7.6 Vitality 62% Sperm Concentration 12 million/ ml Round cells Nil

31. Case 7 Collection Method Masturbation Total Motility 35% Abstinence 4 days Progressive Motility 17% Collection Complete Non progressive Motility 18% Volume 2 ml Immotile 65% Viscosity Normal Motile Sperm Count 8.4 million Liquefaction Time 45 minutes Normal Morphology 3% pH 7.6 Vitality 62% Sperm Concentration 12 million/ ml Round cells Nil Oligo - Astheno-Terato - (zoo)- spermia (OAT)

32. What’s next? Detailed evaluation? How severe? Repeat semen analysis? Some “medicines”? Lifestyle changes?

33. Male Infertility- Mild or Severe? TMSC= Total Motile sperm count = Sperm concentration x total volume x total motility (16 mil/ml x 1.4 ml x 42%) TMSC >5/ 10/ 20 million

34. Mild Male Factor Investigations- NOT usually recommended Antioxidants CC Other adjuvant Lifestyle changes Heat exposure to scrotum Obesity Food habit Smoking Alcohol Anabolic steroids Chronic scrotal fungal dermatitis (EUA, 2018; ASRM, 2020)

35. When to repeat semen analysis? Mild problems- After 3 months Severe problems- ASAP (NICE, 2013; EUA, 2018; ASRM, 2020)

36. Case 7 details Persistent mild male factor Stopped smoking Not willing for IUI H/O repeated attacks of Tinea crusis Dermatology referral Topical and systemic antifungal Sperm parameters normalized Conceived spontaneously, miscarried 12/40

37. Case 8 Collection Method Masturbation Total Motility 46% Abstinence 4 days Progressive Motility 33% Collection Complete Non progressive Motility 13% Volume 2 ml Immotile 54% Viscosity Normal Motile Sperm Count 33.12 million Liquefaction Time 45 minutes Normal Morphology 3% pH 7.6 Vitality 32% Sperm Concentration 36 million/ ml Round cells Nil

38. Case 8 Collection Method Masturbation Total Motility 46% Abstinence 4 days Progressive Motility 33% Collection Complete Non progressive Motility 13% Volume 2 ml Immotile 54% Viscosity Normal Motile Sperm Count 33.12 million Liquefaction Time 45 minutes Normal Morphology 2% pH 7.6 Vitality 32% Sperm Concentration 36 million/ ml Round cells Nil Teratozoospermia

39. Isolated teratozoospermia Isolated abnormal morphology is not the indication for ART Penn HA, Windsperger A, Smith Z, et al. Fertil Steril . 2011; 95(7):2320–3.

40. Case 9 Collection Method Masturbation Total Motility 30% Abstinence 4 days Progressive Motility 16% Collection Complete Non progressive Motility 14% Volume 1.5 ml Immotile 70% Viscosity Normal Motile Sperm Count 0.54 million Liquefaction Time 45 minutes Normal Morphology 1% pH 7.6 Vitality 34% Sperm Concentration 1.2 million/ ml Round cells Nil

41. Case 9 Collection Method Masturbation Total Motility 30% Abstinence 4 days Progressive Motility 16% Collection Complete Non progressive Motility 14% Volume 1.5 ml Immotile 70% Viscosity Normal Motile Sperm Count 0.54 million Liquefaction Time 45 minutes Normal Morphology 1% pH 7.6 Vitality 34% Sperm Concentration 1.2 million/ ml Round cells Nil Severe OAT

42. Severe male factor- What’s next? Donor sperm IUI Antioxidants for 3-6 months, then review ICSI directly?

43. Case 9 details 2012- Initially 1.2 mil/ml, then 4 million/ ml 2013- 0.5 mil/ml Years after years- different brands of antioxidants, CC 2016- Azospermia (repeatedly) 2016- FNAC- hypospermatogenesis 2018- FSH 5.36, LH 4.6, Testo 537, E2 26 Testicular size normal Karyo 46,XY; Y chromosome- no microdeletion 2019- TESE- No sperms obtained, ICSI done with donor sperms- conceived, delivered

44. Severe Male Factor- if not left untreated ??? Overall, 16 (24.6%) of 65 patients with severe oligozoospermia developed azoospermia . Two (3.1%)patients with moderate oligozoospermia developed azoospermia None of the patients with mild oligozoospermia developed azoospermia . Consider freezing the sperms

45. Severe male factor- What’s next? Donor sperm IUI Antioxidants ICSI directly? Investigate in details √ History Physical Examination Hormone Assay Imaging Genetic Tests

46. Severe Male Factor is NOT ONLY a fertility problem Diabetes Cardiovascular diseases Lymphoma, extragonadal germ cell tumours , peritoneal cancers Repeated hospitalization Increased mortality Testicular Cancer Choy and Eisenberg, 2020; Bungum et al., 2018; Eisenberg et al., 2013; Jungwirth et al., 2018; Hotaling and Walsh, 2009 Self-Testicular Examination Atrophic Testes H/O undescended testicles Testicular microcalcification (post-mumps or others)

47. Case 10 31 yrs Came for IUI (D) Too reluctant for physical examination Malignant teratoma - treated by orchidectomy and chemotherapy Later- adopted a baby Sperm abnormality may be the first symptom of testicular cancer

48. Revisiting History Age Duration of subfertility Previous pregnancy- can have secondary male subfertility Lifestyle Occupation- Driving, IT, chemical industry (heavy metal, pesticides) Medical history- Diabetes, Mumps , Cancer Surgical history- Hernia, Orchidopexy , Pituitary Surgery, Bladder neck surgery Drug history- Sulphasalazine , Finesteride , cytotoxic drugs, steroids Sexual history- Low libido, ED

49. Case 10-11 Secondary subfertility of 6 yrs Previous- one male baby, 10 yrs, natural conception Only female was evaluated initially (including Lap dye test) Male- azoospermia on repeated occasions Diabetic for 7 yrs, uncontrolled Endocrine, imaging all normal Lost to F/U Secondary subfertility of 10 yrs Previous- one male baby, 12 yrs, natural conception; followed by 2 TOP Only female was evaluated initially- multiple cycles of OI with CC, letrozole , hMG Varicocele surgery 10 yr ago Male- Severe OAT on several occasions Endocrine, imaging all normal Planning for ICSI

50. Case 12 Secondary subfertility Koch’s abscess in Right testicle Repeated I/D Finally right orchidectomy Azoospermia TRUS- Right ejaculatory duct cystic and widely dilated Waiting for TESA ICSI

51. Case 12 Referred for TESA after investigations Rt sided orchidopexy during appendicectomy at 18 yr Subsequently Rt testis atrophied Lt side operated after 6 months, could not be brought to scrotum, biopsied, seen by USG at lower abd “Reflective practice”

52. Darren et al. Male infertility – The other side of the equation . 2017 Varicocele Vas derens Testicular location

53. Case 13 34-yrs-old, Army-man, past smoker Repeated analysis- 100% immotile sperms Advised varicocelectomy outside No palpable varicocele Went for ICSI Ejaculated sperms- poor morphology TESA- ICSI done, Conceived but miscarried 14/40.

54. Varicocele - always CLINICAL Diagnosis (EUA, 2018) Subclinical: not palpable or visible, but can be shown by special tests (Doppler ultrasound). Grade 1: palpable during Valsava manoeuvre , but not otherwise. Grade 2: palpable at rest, but not visible. Grade 3: visible at rest

55. Surgery for Varicocele (EUA, 2018) Grade 3 varicocele Ipsilateral testicular atrophy Pain Abnormal semen parameters No other fertility factors in the couple

56. In couples seeking fertility with ART, varicocele repair may offer improvement in semen parameters may decrease level of ART needed

57. Case 14 35 yr- Azoospermia Lt undescended testis 19 yr age- Lt orchidopexy 21 yr age- left testicular cancer (mixed germ cell Tx )→ orchidectomy , f/b 3 cycles of chemotherapy (BPC) 33 yr age-Papillary Ca Thyroid→ Total thyroidectomy and neck LN dissection f/b Radio-iodine. Now on Eltroxin 150 FSH 27.14, LH 6.69, Testosterone 336 ng/dl, E2 26.0 pg/ml. Female age 35

58. 46,X,Yqh- Case 15 Female- Grade IV endometriosis AMH 0.9 ng /ml

59. Case 16 42-yr male, office worker Severe OAT Hypergonadotrophic hypogonadism Twin brother having same problem Can’t afford ICSI Opted for IUI (D) Lost to follow up

60. Case 17 28 years Nonobstructive azoospermia Testo 74.47, LH 17.25, FSH 29.91 H/O Laparotomy for GI perforation , 17 yr age 3 cycles IUI (D) failed Conceived after first cycle of IVF with donor sperms- now 24/40, twin pregnancy

61. Case 18 31 yr Azoospermia USG- Rt testis in lower abdomen, Lt testis in inguinal canal FSH 13.40. LH 6.87. Testo 6.89. E2 <10.

62. Case 19-24

63. Case 25-30

64. Case 31-32 Post- orchidopexy Almost normal count Post- orchidopexy Azoospermia

65. Cryptorchidism in adults (EUA, 2018) In adulthood, a palpable undescended testis should NOT be removed because it still produces testosterone. Correction of B/L cryptorchidism , even in adulthood, can lead to sperm production in previously azoospermic men Perform testicular biopsy at the time of orchidopexy in adult- to detect germ cell neoplasia in situ

66. Case 33 Transverse testicular ectopia  (TTE) or crossed testicular ectopia (CTE) 46,X,Yqh-

67. Case 34 Subcoronal Hypospadias

68. Case 35 36 yr Apparently unexplained infertility Multiple cycles of OI C/O inability to deposit sperms in the vagina Multiple operations for hypospadias Conceived after 1 st cycle of IUI (H), delivered

69. Case 36

70. Imaging Scrotal ultrasound Clinically abnormal findings- mass/ atrophy Tight scrotum ( Cremasteric reflex) Obese patient NOT for Varicocele detection NOT the replacement for clinical examination (EUA, 2018; ASRM, 2020) Transrectal ultrasound ( TRUS ) Low volume and pH of semen Ejaculatory disorders (EUA, 2018; ASRM, 2020)

71. Case 37 Azoospermia initially On the day of IVF- few sperms in the ejaculate ICSI done Conceived after 1 st cycle Twin- sIUFD , one live birth

72. Case 38-39

73. Epididymal cysts NOT associated with infertility Surgery may cause obstruction Weatherly D, et al. Epididymal Cysts: Are They Associated With Infertility? Am J Mens Health. 2018

74. Case 40 Mumps orchitis 20 years age Biopsied during TESA No sperms obtained Conceived with IVF with sperm donation

75. Case 41 Left cryptorchidism (abdominal testis) Lt orchidectomy at 12 yr Testicular prosthesis Azoospermia Opted for AID

76. Hormone Evaluation Sperm concentration <10 million/ml Sexual dysfunction Clinically suspected endocrinopathy FSH, LH, testosterone, HbA1C FSH, LH low Testosterone low Hypogonadotropic hypodonadism Pituitary imaging FSH high LH high Testosterone low Global testicular failure LH normal Testosterone normal Spermatogenesis defect LH high Testosterone normal Sublinical hypogonadism PRL, TSH If clinically suspected

77. Role Of Medical Therapy (EUA, 2018, ASRM, 2020) Hypogonadotropic hypodonadism hCG 2000-5000 IU 3 times a week If hCG alone cannot restore spermatogenesis, FSH is added 75-150 IU 3 times a week Serum testosterone and semen analysis every 1–2 months Usual time to recover 6 – 12 months (may take 24 months) Often conceives at lower sperm concentration Idiopathic Male infertility CC Tamoxifen Letrozole hCG All empirical Evidences? Testosterone supplementation Strongly CONTRAINDICATED Feedback inhibition on FSH, LH→ secondary hypogonadism Aromatase inhibitors ( Letrozole , Anastrozole ) If T:E2 ratio <10 (T- ng /dl, E2- pg/ml)

78. FSH Testosterone Semen Diagnosis Treatment APHRODITE Group 1 Low Low Abnormal including Azoos Hypogonadotropic hypogonadism hCG (+ FSH if needed) APHRODITE Group 2 Normal Normal (≥350 ng /dl) Abnormal including Azoos Reduced Gonadotropin action, functional hypogonadism FSH only APHRODITE Group 3 Normal Low Abnormal including Azoos Reduced Gonadotropin action, biochemical hypogonadism FSH (+ hCG ) APHRODITE Group 4 High Normal/ Low Abnormal including Azoos Functional hypogonadism hCG (+ FSH if needed) APHRODITE Group 5 Normal Normal (≥350 ng /dl) Normal Unexplained couple infertility ?FSH only APHRODITE Criteria, RBMO, 2024 A ddressing male P atients with H ypogonadism and/or infe R tility O wing to altere D , I diopathic TE sticular function

79. Genetic tests in testicular failure The spermatozoa of infertile men show an increased rate of aneuploidy , structural chromosomal abnormalities, and DNA damage Carrying the risk of passing genetic abnormalities to the next generation (AUA, 2018) Karyotype Y chromosome microdeletion

80. TMSC PR/CYCLE 10–20 million 18.29% 5–10 million 5.63% <5million 2.7% Guven et al, 2008;Abdelkader & Yeh , 2009 Hamilton etral ., 2015 Criteria TMSC Treatment Pre wash TMSC > 5 million IUI Pre wash TMSC 1 - 5 million IVF Pre wash TMSC <1 million ICSI Male factor- IUI, IVF or ICSI?

81. TMSC <5 mil/ml and IUI Counsel before IUI Double Ejaculate Kucuc et al., 2004; Oritz et al., 2016 “Trial IUI”- Post wash- IMSC Ombelet et al., 2014 IMSC >1 mil/ml → Further IUI IMSC <1 mil/ml → ICSI Donor sperm is NOT the only solution

82. ICSI with Ejaculate vs Testicular sperms

83. Case 42 Collection Method Masturbation Abstinence 5 days Collection Complete Volume 3.0 ml Colour Whitish Viscosity Normal Liquefaction Time 45 minutes pH 7.8 Sperm Concentration Nil (even after centrifugation) Round cells Nil

84. Case 42 Collection Method Masturbation Abstinence 5 days Collection Complete Volume 3.0 ml Colour Whitish Viscosity Normal Liquefaction Time 45 minutes pH 7.8 Sperm Concentration Nil (even after centrifugation) Round cells Nil Azoospermia (?Non-Obstructive)

85. Azoospermia - What’s next? Donor sperm IUI? Testicular FNAC/ Biopsy? ICSI directly?

86. FNAC - role? Isolated foci of spermatogenesis ASRM, 2020 Consider TESA in indeterminate cases- NOT NECESSARY FSH >7.6 <7.6 Testicular long axis (cm) <4.6 >4.6 89% chance of NOA 96% chance of OA

87. Measuring testicular volume

88. Problems with indiscriminate FNAC Repeat test showed SC 3-4 sperms/ hpf Repeat semen analysis- 58 mil/ml, TM 48%

89. Case 42 ( Contd ) Azoospermia - one occasion FNAC - B/L maturation arrest FSH 0.22, LH 0.34, Testo 549 Pituitary MRI- normal Started hMG After 6 months- 2 mil/ml

90. Case 43 32 year H/O delayed puberty Was on TRT (17-23 yr age) Gynaecomastia surgery, 22 yr LH 0.06, FSH 0.02, Testo 0.63, PRL 1.18, TSH 2.48 Low libido, ED Anosmia MRI- B/L olfactory bulb absent Genetic tests advised Lost to follow up

91. Case 44 30 yr, azoospermia 17 yr age, sudden testicular atrophy, started testo 250 mg IM monthly injection from 23 yr age B/L testes 6 cc each FSH 1.11, LH 0.26, Testo 194 ACTH, cortisol , PRL- all normal Advised HRT Lost to follow up

92. Case 45 35 yr 2019- sudden loss of body hair, low libido→ nonfunctioning Pituitary macroadenoma → Endoscopic surgery H/P Lymphocytic hypophysitis Sexual function and sec sex characters improved after Sx On cortisol , L- thyroxine supplementation Azoospermia diagnosed Started hCG f/b hMG by endocrinologist Sperm conc 1-2/ hpf after 4 months After 8 months- 8 mil/ml IUI planned

93. Case 46 FNAC- B/L maturation arrest FSH 37.2, LH 24.4, Testo 245.53, E2 37, ratio <10 Not keen for IVF-ICSI-PGT

94. Case 46 ( Contd )

95. Case 47

96. Case 48-51

97. Case 52-54

98. Sex Chromosome abnormalities The most common - the Klinefelter’s syndrome (KS) 47,XXY or 46,XY/47,XXY mosaicism KS mosaic can have variable extent of germ cell production inside the testicles Sperms carrying abnormalities in sex chromosomes (24,XY sperms) and autosomes ( disomy for chromosomes 13, 18 and 21) Needs PGT-A

99. Case 55-56 45, XY rob (14, 21), (q10, q10) Azoospermia Robertsonian Translocation 46,XY;t(2:22)(q37;q11.21) Severe OAT Reciprocal Translocation

100. Case 57 46,XY22ps+ Oligospermia → Azoospermia YCM normal Spermes obtained by TESA Amniocentesis Normal K aryo & CMA Live born by 34/40

101. Case 58 FISH- more accurate risk estimation of affected offspring Limited role clinically Only specific indication- Macrocephalia ( Themset et al., 2009)

102. Case 59-62 46, XY,t (15:17) (q10;q10) 46,XY;t(2:22)(q37;q11.21) 45,XY,der(13;14)(q10;q10) 46,X,del(Y)(q11.23)

103. Case 63 46,XY, dup(9)(q11-q12) Duplication of long arm of chromosome 9- partial trisomy FNAC B/L Late maturation arrest Family History of Azoospermia in Own brother 2 maternal uncles 2 Cousin brothers (of same maternal aunt)

104. Case 64-65 46,XYqh- Severe OAT 46,XY,16qh+ Azoospermia Genetic abnormality ≠ Advanced interventions

105. Case 66-69 46,XY,15ps+ 46,X,Y,q+ 46,X,inv(Y)(p11.q11) 46,X,inv(Y)(p11.2q11.2) Keep Geneticist on board

106. Case 70 37 yr Inguinal hernia operated Rt sided- 2 yr ago and Lt sided15 yr ago B/L testes- 18 cc each FSH 5.96. LH 4.74. Testo 212. Estradiol 14.22. FNAC- Sertoli cell only

107. Y chromosome microdeletion (EUA, 2018) Most common genetic defect in male infertility after KS Never found in normozoospermic men Highest frequency in azoospermic men (8-12%), followed by oligozoospermic (3-7%) men. Extremely rare with a sperm concentration > 5 million/ mL (~0.7%). AZFa - Sertoli cell only syndrome AZFb - maturation arrest AZFc - variable phenotype

108. Negative YCM Report

109. Positive YCM report

110. Case 71-72 AZF a/b Poor prognosis TESA should NOT be attempted AZF c/d Good prognosis Some may have sperms in semen

111. Case 73-74

112. Case 75 YCM is a negative predictive marker, not POSITIVE marker

113. Case 76 46,X,del(Y)(q11.22q11.23) Don’t advise Karyo alone Don’t interpret karyo alone

114. Case 77-79 46,X,del(Y)(q11.23) 46,X,del(Y)(q11.2) 46,X,+mar

115. Case 80 Mos45,X[12]/46,XY[28]; AZFa deleted

116. 39 yr FSH 25.4, LH 12.6, Estradiol 14, Testo 61. Case 81

117. Case 81 ( Contd ) 46,XX SRY+ sex reversal

118. Case 83 LH 30.10, FSH 43.70, E2 38.48, Testo 432 Karyo - 46,XX

119. Genetic testing Sperm concentration <5 million/ml Azoospermia Testicular atrophy Elevated FSH Karyotyping Y chromosome Microdeletion (YCM)

120. In presence of genetic defect PGT-SR (previously- PGD) Prenatal invasive testing (EUA, 2018; ASRM, 2020)

121. Case 84 1 mil/ml Diabetic Idiopathic hypo/hypo hCG and FSH started Finally 16 mil/ml 2 times IUI (H) Both early miscarriage APLA negative Couple karyotype done 46,XY,t(3;7)(p25 ;q22)

122. Surgical Sperm Retrieval ( SSR ) in Azoospermia (OA>NOA)

123. Case 85-86 42 yr FSH 43.56 Karyo , YCM normal Trial TESA - Motile sperms obtained ICSI done, conceived, delivered 35/40 26 yr FSH 5.7 Karyo , YCM normal Trial TESE- No sperms obtained Refused donor sperms

124. Predictors of sperm retrieval? FSH Testicular Size LH , Testosterone BMI AMH - semen, serum Inhibin B- semen, serum Age Ultrasound parameters No reliable positive prognostic factors guarantee sperm recovery for patients with NOA The ONLY negative prognostic factor is the presence of AZFa and AZFb microdeletions .

125. Case 87 36 yr FNAC B/L- Maturation arrest Karyo , YCM done Surgical sperm retrieval? 46,X,inv(Y)(p11q13)

126. Testicular sperm extraction

127. If previous FNAC was done ( Schwarzer , 2013) Diagnosis Chance of sperm retrieval (Micro- TESE >> TESE ) Sertoli -cell-only syndrome (Germ cell hypoplasia ) 32% Maturation arrest 66.7% Hypospermatogenesis 100% Tuberous sclerosis 33.3% Mixed atrophy 95.2%

128. Case 88 33 yr Secondary anejaculation and ED B/L abdominal testes 3 yr age- attempted Rt orchidopexy but failed 13 yr age- Left sided orchidopexy attempted but partial success. 32 yr age- B/L orchidectomy after failed orchidopexy attempt

129. Case 89 Collection Method Masturbation Abstinence 2 days Collection Complete Volume 0.5 ml Colour Whitish Viscosity Normal Liquefaction Time 45 minutes pH 6.8 Sperm Concentration Nil (even after centrifugation) Round cells Nil

130. Case 89 ( Contd ) Collection Method Masturbation Abstinence 2 days Collection Complete Volume 0.5 ml Colour Whitish Viscosity Normal Liquefaction Time 45 minutes pH 6.8 Sperm Concentration Nil (even after centrifugation) Round cells Nil

131. Assess Abstinence period Completeness of collection Usual amount of ejaculate Exclude retrograde ejaculation Suspect obstructive pathology- TRUS Clinical assessment???

132. Case 89 ( Contd ) TRUS- B/L agenesis of seminal vesicles Male partner- CFTR carrier Fem ale partner- CFTR carrier

133. Congenital bilateral absence of vas deferens ( CBAVD ) Semen- Volume <1.5 ml, pH <7.0, fructose negative TRUS Renal ultrasound Cystic fibrosis mutation (CFTR) testing (EUA, 2018; ASRM< 2020) Partner testing Indian prevalence- 1:10,000- 1:40,000 ( Kapoor et al., 2006; Prasad et al., 2010)

134. CBAVD is NOT uncommon CFTR negative CFTR carrier; Wife- normal CFTR refused Both partners CFTR carrier CFTR negative CFTR carrier; Wife- normal

135. Genetic testing CFTR testing in CBAVD Karyotyping Y chromosome Microdeletion (YCM)

136. Surgical Management of obstructive azoospermia Vasovasostomy Vasoepididymostomy Transurethral resection of ejaculatory ducts in EDO Patent tract ≠ Conception Baker and Sabanegh , 2013

137. Case 90 Delayed puberty Testo 100.86. FSH 28.33. LH 13.65. E2 27.83 Testosterone injection started at puberty - sec sex charac , voice, genital size improved MRI pitutary microadenoma GH, TSH, Cortisol, PRL, - all normal Karyo - 47,XXY Pituitary Incidentaloma

138. Targeted female investigations If no risk factors for tubal block- 3 cycles of IUI, then tubal patency test If risk factors- tubal patency first Ovaries Tubes- IUI or IVF/ICSI? No ART if female age <21 yr

139. Meticulous semen analysis in a standard laboratory Physical examination and rational investigations Avoid non-evidence based drugs for long time Donor sperm is NOT the only solution IUI or ICSI- depends on the overall assessment Take Home Messages

140. Semen analysis Mild problem Severe problem Lifestyle changes Antioxidants History Physical Exam Repeat semen ASAP Hormonal evaluation Low FSH, LH Pituitary imaging hCG / FSH supplementation High FSH Karyotype YCM ICSI TESA for azoospermia Donor sperms Repeat semen after 3 months Normal hormones Cannot afford ICSI No sperms in TESA S/O obstruction Idiopathic Obstructive Azoo TRUS CFTR test for CBAVD Pituitary failure Testicular failure

141. Semen analysis Mild problem Severe problem Lifestyle changes Antioxidants History Physical Exam Repeat semen ASAP Hormonal evaluation Low FSH, LH Pituitary imaging hCG / FSH supplementation High FSH Karyotype YCM ICSI TESA for azoospermia Donor sperms Repeat semen after 3 months Normal hormones Cannot afford ICSI No sperms in TESA S/O obstruction Idiopathic Obstructive Azoo TRUS CFTR test for CBAVD Pituitary failure Testicular failure

142. Semen analysis Mild problem Severe problem Lifestyle changes Antioxidants History Physical Exam Repeat semen ASAP Hormonal evaluation Low FSH, LH Pituitary imaging hCG / FSH supplementation High FSH Karyotype YCM ICSI TESA for azoospermia Donor sperms Repeat semen after 3 months Normal hormones Cannot afford ICSI No sperms in TESA S/O obstruction Idiopathic Obstructive Azoo TRUS CFTR test for CBAVD Pituitary failure Testicular failure

143. Semen analysis Mild problem Severe problem Lifestyle changes Antioxidants History Physical Exam Repeat semen ASAP Hormonal evaluation Low FSH, LH Pituitary imaging hCG / FSH supplementation High FSH Karyotype YCM ICSI TESA for azoospermia Donor sperms Repeat semen after 3 months Normal hormones Cannot afford ICSI No sperms in TESA S/O obstruction Idiopathic Obstructive Azoo TRUS CFTR test for CBAVD Pituitary failure Testicular failure

144. Semen analysis Mild problem Severe problem Lifestyle changes Antioxidants History Physical Exam Repeat semen ASAP Hormonal evaluation Low FSH, LH Pituitary imaging hCG / FSH supplementation High FSH Karyotype YCM ICSI TESA for azoospermia Donor sperms Repeat semen after 3 months Normal hormones Cannot afford ICSI No sperms in TESA S/O obstruction Idiopathic Obstructive Azoo TRUS CFTR test for CBAVD Pituitary failure Testicular failure

145. Semen analysis Mild problem Severe problem Lifestyle changes Antioxidants History Physical Exam Repeat semen ASAP Hormonal evaluation Low FSH, LH Pituitary imaging hCG / FSH supplementation High FSH Karyotype YCM ICSI TESA for azoospermia Donor sperms Repeat semen after 3 months Normal hormones Cannot afford ICSI No sperms in TESA S/O obstruction Idiopathic Obstructive Azoo TRUS CFTR test for CBAVD Pituitary failure Testicular failure

146. Treatment burden for MALE infertility falls on FEMALE

147. Thank you Durgapur OBGYN Society Corona remedies