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Male Infertility- Interesting Case Scenarios

If you want to see some interesting cases in Male Infertility, you can see this PPT. Dr Sujoy Dasgupta delivered a GUEST LECTURE on "108 unique cases of male infertility " in a CME organised by Tamralipta Obstetric and Gynaecological Society (TOGS), on 30 January, 2025.

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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- Case Scenarios
Disclaimer • All real cases • Written inform consent from all the patients • Conflict of interest- None • Not received any honorarium for this talk
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)
We cannot treat We bypass
Case 1 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 4% pH 7.6 Vitality 62% Sperm Concentration 12 million/ ml Round cells Nil
Case 1 (Contd) • Married for 5 yr • Just planning for pregnancy • Female 28 • Male 32 Definition of “Infertility”?
Limitations of Semen analysis (WHO) • 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?
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
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
WHO reference ranges
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
Case 3
From which Laboratory?
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
Case 3 (Contd) • Apparently unexplained infertility • Male- 36 years • No apparent risk factors for infertility • Ignore • Antibiotics (empirically) • Culture of semen • Further tests
Disclosed “pain during intercourse” • Diagnosed to be diabetic • Pus cells disappeared after circumcision • Conceived after OI
Male Accessory Gland Infection (MAGI)
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
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
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- Antioxidants?
Sperm DNA Fragmentation
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
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)
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 • Sperm DFI 40% • Next? • Advised TESA-ICSI or donor sperms elsewhere because of high SDF • Conceived spontaneously, live birth 37/40
Case 7 Collection Method Masturbation Total Motility 30% Abstinence 4 days Progressive Motility 15% Collection Complete Non progressive Motility 15% Volume 2 ml Immotile 70% Viscosity Normal Motile Sperm Count 4.2 million Liquefaction Time 45 minutes Normal Morphology 2% pH 7.6 Vitality 62% Sperm Concentration 14 million/ ml Round cells Nil Oligo-Astheno-Terato- (zoo)-spermia (OAT)
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
Mild Male Factor • Investigations- NOT usually recommended • Antioxidants • CC • Other adjuvant Lifestyle changes 1. Heat exposure to scrotum 2. Obesity 3. Food habit 4. Smoking 5. Alcohol 6. Anabolic steroids 7. Chronic scrotal fungal dermatitis (EUA, 2018; ASRM, 2020)
Oxidative Stress in Subfertility I n f e r t i l i t y O X I D A N T P R O D U C T I O N A N T I O X I D A N T D E F E N C E S S Y S T E M 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.
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.
• 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.
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
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 Teratozoospermia
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.
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
Severe male factor- What’s next? • Donor sperm IUI • Antioxidants for 3-6 months, then review • ICSI directly?
When to repeat semen analysis? • Mild problems- After 3 months • Severe problems- ASAP (NICE, 2013; EUA, 2018; ASRM, 2020)
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
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
Severe male factor- What’s next? • Donor sperm IUI • Antioxidants • ICSI directly? • Investigate in details√ • History • Physical Examination • Hormone Assay • Imaging • Genetic Tests
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
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)
Case 10 •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”
Case 11-12 • 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
Case 13 • 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
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
Darren et al. Male infertility – The other side of the equation . 2017 Varicocele Vas derens Testicular location
Case 14 • 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.
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
Surgery for Varicocele (EUA, 2018) • Grade 3 varicocele • Ipsilateral testicular atrophy • Pain • Abnormal semen parameters • No other fertility factors in the couple
In couples seeking fertility with ART, varicocele repair • may offer improvement in semen parameters • may decrease level of ART needed
Case 15 • 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
46,X,Yqh- Case 16 • Female- Grade IV endometriosis • AMH 0.9 ng/ml
Case 17-20
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
Case 21 • 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.
Case 22-33
Case 34-35 Post-orchidopexy Almost normal count Post-orchidopexy Azoospermia
Case 36 Transverse testicular ectopia (TTE) or crossed testicular ectopia (CTE) 46,X,Yqh-
Case 37-42
Testicular Dysgenesis Syndrome (TDS) • Sharpe et al;, Fertil Steril, 2008
Case 43-45
Case 46
Imaging Scrotal ultrasound 1. Clinically abnormal findings- mass/ atrophy 2. Tight scrotum (Cremasteric reflex) 3. Obese patient • NOT for Varicocele detection • NOT the replacement for clinical examination (EUA, 2018; ASRM, 2020) Transrectal ultrasound (TRUS) 1. Low volume and pH of semen 2. Ejaculatory disorders (EUA, 2018; ASRM, 2020)
Case 47-48
Case 49 • Mumps orchitis 20 years age • Biopsied during TESA • No sperms obtained • Conceived with IVF with sperm donation
Case 50 • Left cryptorchidism (abdominal testis) • Lt orchidectomy at 12 yr • Testicular prosthesis • Azoospermia • Opted for AID
68 Hormone Evaluation FSH, LH, testosterone, HbA1C FSH, LH low Testosterone low Hypogonadotropic hypodonadism Pituitary MRI Testosterone normal/ high Androgen excess Exogenous testosterone Congenital adrenal hyperplasia (CAH) Testicular adrenal rest tumors (TARTs) History, Endocrinology referral 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
Hormonal Investigations • FSH 25.21 IU/L (normal 1-10) • LH 16.8 IU/L (normal 1-10) • Testosterone 159 ng/dl (normal 200-800) Testosterone supplementation? Any other medical therapy?
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
Genetic defect ≠ Donor sperm • Genetic counseling • PGT-SR- preimplantation genetic testing for structural rearrangements (previously- called PGD) • Prenatal invasive testing (EUA, 2021; ASRM/AUA, 2024)
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?
TMSC <5 mil/ml and IUI • Counsel before IUI 1. Double Ejaculate Kucuc et al., 2004; Oritz et al., 2016 2. “Trial IUI”- Post wash- IMSC Ombelet et al., 2014 3. IMSC >1 mil/ml → Further IUI 4. IMSC <1 mil/ml → ICSI Donor sperm is NOT the only solution
Case 51 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)
Azoospermia- What’s next? • Donor sperm IUI? • Testicular FNAC/ Biopsy? • ICSI directly?
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
Measuring testicular volume
Problems with indiscriminate FNAC • Repeat test showed SC 3-4 sperms/ hpf • Repeat semen analysis- 58 mil/ml, TM 48%
Case 51 (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
Case 52 • 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
Case 53 • 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
Case 54 • 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
How to manage- Hypo-Hypo? • hCG 2000-5000 IU 3 times a week • Serum testosterone should be checked every 1–2 months • The sperm count should be monitored monthly • Sperm parameters become normal within 6 months but sometimes it can take 24 months of time • If hCG alone cannot restore spermatogenesis, FSH is added in the dose of 75-150 IU 3 times a week • Often can father the baby at much lower sperm concentration EUA, 2021; ASRM/AUA, 2024
Case 55 • FNAC- B/L maturation arrest • FSH 37.2, LH 24.4, Testo 245.53, E2 37, ratio <10 • Not keen for IVF- ICSI-PGT
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
Case 56
Case 57 • 37 yr • FSH 35.42, LH 10.13, testo 93, E2 14.45 • Undiagnosed Diabetes • Prev FNAC- Lt side- Sertoli Only Syndrome • TESE – Rt side- No sperms, Lt side- Motile Sperms • Chance of sperm retrieval in KS 20- 70% (Kang et al., 2024)
Case 58-61
Case 62-65
Case 66-69
Case 70 Mosaic Klinefelter 47,XXY del(9)(q12.q34), del(x)(q27,q28)/ 47XXY/47XY
Case 71-72 45,XY,rob (13;14)(q10;q10) Robertsonian Translocation Azoospermia 46,XY,t(15;17)(q10;q10) Reciprocal balanced Translocation Severe OAT Autosome abnormalities
Testing the “embryos” PGT-SR report Amniocentesis
Case 73-77 46,XY,t(11;21)(p22;p11.2) 46,XY,t(13;18)(p11.2;p11.2) 46.XY,t(2;22)(q37;q11.21) 45, XY,rob(14;21)(q10;q10) 45,XY,rob (13;14)(q10;q10) 46,XY,t(3;6)(p21;p23)
Case 78-79 46,XY,del(Y)(q11.23) Deletion 46,XY,dup(9)(q11-q12) Duplication (Partial trisomy) Family History of Azoospermia in a) Own brother b) 2 maternal uncles c) 2 Cousin brothers (of same maternal aunt) Unbalanced rearrangements
Case 80-81 46,X,inv(Y)(q11q11) 46,XY,inv(3)(p25q21) Inversion
Case 82-86 46,XY,inv(9)(p13,q13) 46,X,inv(Y)(p11.2q11.2) 46,X,inv(Y)(p11q13) 46,X,inv(Y)(p11q11) 46,XY,inv(9)(p12q13) Some inversions may be “polymorphism”
Case 87-92 46,XYqh- 46,XY,16qh+ 46,XY,22ps+ 46,XY,15ps+ 46,XYq+ 46,XY,9qh+ Genetic “aberration” ≠ Advanced interventions Keep geneticist on board
Case 93 • 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
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
Positive YCM report
Case 94-95 AZF a/b Poor prognosis TESA should NOT be attempted AZF c/d Good prognosis Some may have sperms in semen
Our experience with YCM Total Azoospermia N= 1221 NOA (Testicular) N = 1071 YCM present N= 30 YCM negative N = 209 YCM Not tested N= 832 AZF a/b/c/d all deleted 3 AZF a/b/c deleted 3 AZFa only deleted 2 AZFb only deleted 2 AZFc only deleted 5 AZF b+c deleted 7 AZF c+d deleted 4 AZF b+c+d deleted 4
Case 96-97 46,X+mar
Case 98 Mos45,X[12]/46,XY[28] Mosaic- 45,X/46,XY (XY Turner’s or X0/XY)
Case 99 46,XX SRY+ sex reversal (De La Chapelle syndrome)
Case 100 46,X,del(Y)(q11.22q11.23) Don’t advise Karyo alone Don’t interpret karyo alone
Case 101 • LH 30.10, FSH 43.70, E2 38.48, Testo 432 Karyo- 46,XX
Genetic testing • Sperm concentration <5 million/ml • Azoospermia • Testicular atrophy • Elevated FSH • Karyotyping • Y chromosome Microdeletion (YCM)
Surgical Sperm Retrieval (SSR) in Azoospermia (OA>NOA)
Case 102-103 • 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
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.
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%
Case 104 • 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
Case 105 • Azoospermia initially • On the day of IVF- few sperms in the ejaculate • ICSI done • Conceived after 1st cycle • Twin- sIUFD, one live birth
Case 106 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
Assess • Abstinence period • Completeness of collection • Usual amount of ejaculate • Exclude retrograde ejaculation • Suspect obstructive pathology- TRUS • Clinical assessment???
Azoospermia- Low volume and/ or Fructose negative Vasa palpable • Ejaculatory duct obstruction • TRUS
Surgical Management in OA: When to refer? • Vasovasostomy • Vasoepididymostomy • Transurethral resection of ejaculatory ducts in EDO • Patent tract ≠ Conception Baker and Sabanegh, 2013
Azoospermia- Low volume and/ or Fructose negative Vasa palpable • Ejaculatory duct obstruction • TRUS Vasa NOT palpable • CBAVD • Why important?
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, 2021; ASRM/AUA, 2024) • Partner testing • 25% chance of inheritance • Indian prevalence- 1:10,000- 1:40,000 (Kapoor et al., 2006; Prasad et al., 2010)
Case 107 • TRUS- B/L agenesis of seminal vesicles • Male partner- CFTR carrier • Female partner- CFTR carrier PGT (M)- preimplantation genetic testing for Mendelian disorders (previously called PGD)
Our experience with CBAVD Total Azoospermia N= 1221 CBAVD N = 115 (9.42%) CFTR mutation present (Heterozygous) N= 10 F508de l N= 7 Partn er norm al N= 6 Partn er heter ozygo us N= 1 Compo und heteroz ygous N= 3 Partn er norm al N= 2 Partn er heter ozygo us N= 1 CFTR mutation absent N = 49 CFTR Not tested N= 56
Unilateral vas absent • Usually fertile • CFTR testing if no renal agenesis
Genetic testing • CFTR testing in CBAVD • Karyotyping • Y chromosome Microdeletion (YCM)
Medical Therapy in Idiopathic Severe OAT/ NOA • To improve the chance of sperm retrieval • Sometimes, can lead to appearance of sperms in the ejaculate 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) Anti-estrogens (CC, Tamoxifen) •Block pituitary E2 receptors→ stimulate secretion of FSH, LH •Men with normal FSH, low testosterone but normal T:E ratio Gonadotrophins •“resetting” of the Gn receptors in testicles → improve the sensitivity of testicles to gonadotrophins •may be increase intratesticular testosterone •work better in case of eugonadism rather than high FSH •If successful in raising FSH level 1.5 times baseline and testosterone 600-800 ng/dl, high success rate of microTESA (Alkandari and Zini, 2021; Kumar, 2021; Holtermann et al., 2022; Dabaja and Schlegel, 2014; Holtermann et al., 2022; Anawalt, 2013; Flannigan and Schlegel, 2019; Ring et al., 2016; Chehab et al, 2015; Foran et al, 2023). Shiraishi et al., 2012)
APHRODITE Criteria, RBMO, 2024 Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function 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
Dasgupta et al., Asian J Androl. 2024
Hormone treatment vs ART • Priority for natural conception • Other indications of ART- female partners • Time to pregnancy • Age of female partners, ovarian reserve • Cost
Case 108 • 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
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
Don’t advise any test if you do not know what to do with the result !!!
 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
Semen analysis Mild problem Severe problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
Semen analysis Mild problem Severe problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
Semen analysis Mild problem Severe problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
Semen analysis Mild problem Severe problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
Semen analysis Mild problem Severe problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
Semen analysis Mild problem Severe problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
Treatment burden for MALE infertility falls on FEMALE
Thank you TOGS Lupin

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Male Infertility- Interesting Case Scenarios

  • 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- Case Scenarios
  • 2.
    Disclaimer • All realcases • Written inform consent from all the patients • Conflict of interest- None • Not received any honorarium for this talk
  • 3.
    Men’s fertility potentialdepends 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.
  • 5.
    Case 1 Collection Method Masturbation TotalMotility 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 4% pH 7.6 Vitality 62% Sperm Concentration 12 million/ ml Round cells Nil
  • 6.
    Case 1 (Contd) •Married for 5 yr • Just planning for pregnancy • Female 28 • Male 32 Definition of “Infertility”?
  • 7.
    Limitations of Semenanalysis (WHO) • 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?
  • 8.
    Case 2 Collection MethodMasturbation 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
  • 9.
    Case 2 Collection MethodMasturbation 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
  • 10.
  • 11.
    Points to notein 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
  • 12.
  • 13.
  • 14.
    Case 3 Collection Method Masturbation TotalMotility 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 duringintercourse” • Diagnosed to be diabetic • Pus cells disappeared after circumcision • Conceived after OI
  • 17.
    Male Accessory GlandInfection (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 • 26yr, 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.
    Case 5 • Tryingfor 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- Antioxidants?
  • 21.
  • 22.
    Treatment options forhigh 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
  • 23.
    SDF Testing Indications Infertile menwith: • 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)
  • 24.
    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 • Sperm DFI 40% • Next? • Advised TESA-ICSI or donor sperms elsewhere because of high SDF • Conceived spontaneously, live birth 37/40
  • 25.
    Case 7 Collection Method Masturbation TotalMotility 30% Abstinence 4 days Progressive Motility 15% Collection Complete Non progressive Motility 15% Volume 2 ml Immotile 70% Viscosity Normal Motile Sperm Count 4.2 million Liquefaction Time 45 minutes Normal Morphology 2% pH 7.6 Vitality 62% Sperm Concentration 14 million/ ml Round cells Nil Oligo-Astheno-Terato- (zoo)-spermia (OAT)
  • 26.
    Male Infertility- Mildor 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
  • 27.
    Mild Male Factor •Investigations- NOT usually recommended • Antioxidants • CC • Other adjuvant Lifestyle changes 1. Heat exposure to scrotum 2. Obesity 3. Food habit 4. Smoking 5. Alcohol 6. Anabolic steroids 7. Chronic scrotal fungal dermatitis (EUA, 2018; ASRM, 2020)
  • 28.
    Oxidative Stress in Subfertility In f e r t i l i t y O X I D A N T P R O D U C T I O N A N T I O X I D A N T D E F E N C E S S Y S T E M 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.
  • 30.
    Smits RM, Mackenzie-ProctorR, 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.
  • 31.
    • In somestudies, 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.
  • 32.
    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
  • 33.
    Case 8 Collection Method Masturbation TotalMotility 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 Teratozoospermia
  • 34.
    Isolated teratozoospermia • Isolatedabnormal morphology is not the indication for ART Penn HA, Windsperger A, Smith Z, et al. Fertil Steril. 2011; 95(7):2320–3.
  • 35.
    Case 9 Collection MethodMasturbation 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
  • 36.
    Severe male factor-What’s next? • Donor sperm IUI • Antioxidants for 3-6 months, then review • ICSI directly?
  • 37.
    When to repeatsemen analysis? • Mild problems- After 3 months • Severe problems- ASAP (NICE, 2013; EUA, 2018; ASRM, 2020)
  • 38.
    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
  • 39.
    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
  • 40.
    Severe male factor-What’s next? • Donor sperm IUI • Antioxidants • ICSI directly? • Investigate in details√ • History • Physical Examination • Hormone Assay • Imaging • Genetic Tests
  • 41.
    Case 10 • 31yrs • 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
  • 42.
    Severe Male Factoris 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)
  • 43.
    Case 10 •Referred forTESA 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”
  • 44.
    Case 11-12 • Secondarysubfertility 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
  • 45.
    Case 13 • Secondarysubfertility • 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
  • 46.
    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
  • 47.
    Darren et al.Male infertility – The other side of the equation . 2017 Varicocele Vas derens Testicular location
  • 48.
    Case 14 • 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.
  • 49.
    Varicocele- always CLINICALDiagnosis (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
  • 50.
    Surgery for Varicocele (EUA,2018) • Grade 3 varicocele • Ipsilateral testicular atrophy • Pain • Abnormal semen parameters • No other fertility factors in the couple
  • 51.
    In couples seekingfertility with ART, varicocele repair • may offer improvement in semen parameters • may decrease level of ART needed
  • 52.
    Case 15 • 35yr- 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
  • 53.
    46,X,Yqh- Case 16 • Female-Grade IV endometriosis • AMH 0.9 ng/ml
  • 54.
  • 55.
    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
  • 56.
    Case 21 • 31yr • Azoospermia • USG- Rt testis in lower abdomen, Lt testis in inguinal canal • FSH 13.40. LH 6.87. Testo 6.89. E2 <10.
  • 57.
  • 58.
    Case 34-35 Post-orchidopexy Almost normalcount Post-orchidopexy Azoospermia
  • 59.
    Case 36 Transverse testicularectopia (TTE) or crossed testicular ectopia (CTE) 46,X,Yqh-
  • 60.
  • 61.
    Testicular Dysgenesis Syndrome(TDS) • Sharpe et al;, Fertil Steril, 2008
  • 62.
  • 63.
  • 64.
    Imaging Scrotal ultrasound 1. Clinicallyabnormal findings- mass/ atrophy 2. Tight scrotum (Cremasteric reflex) 3. Obese patient • NOT for Varicocele detection • NOT the replacement for clinical examination (EUA, 2018; ASRM, 2020) Transrectal ultrasound (TRUS) 1. Low volume and pH of semen 2. Ejaculatory disorders (EUA, 2018; ASRM, 2020)
  • 65.
  • 66.
    Case 49 • Mumpsorchitis 20 years age • Biopsied during TESA • No sperms obtained • Conceived with IVF with sperm donation
  • 67.
    Case 50 • Leftcryptorchidism (abdominal testis) • Lt orchidectomy at 12 yr • Testicular prosthesis • Azoospermia • Opted for AID
  • 68.
    68 Hormone Evaluation FSH, LH,testosterone, HbA1C FSH, LH low Testosterone low Hypogonadotropic hypodonadism Pituitary MRI Testosterone normal/ high Androgen excess Exogenous testosterone Congenital adrenal hyperplasia (CAH) Testicular adrenal rest tumors (TARTs) History, Endocrinology referral 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
  • 69.
    Hormonal Investigations • FSH25.21 IU/L (normal 1-10) • LH 16.8 IU/L (normal 1-10) • Testosterone 159 ng/dl (normal 200-800) Testosterone supplementation? Any other medical therapy?
  • 70.
    Genetic tests intesticular 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
  • 71.
    Genetic defect ≠Donor sperm • Genetic counseling • PGT-SR- preimplantation genetic testing for structural rearrangements (previously- called PGD) • Prenatal invasive testing (EUA, 2021; ASRM/AUA, 2024)
  • 72.
    TMSC PR/CYCLE  10–20million 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?
  • 73.
    TMSC <5 mil/mland IUI • Counsel before IUI 1. Double Ejaculate Kucuc et al., 2004; Oritz et al., 2016 2. “Trial IUI”- Post wash- IMSC Ombelet et al., 2014 3. IMSC >1 mil/ml → Further IUI 4. IMSC <1 mil/ml → ICSI Donor sperm is NOT the only solution
  • 74.
    Case 51 Collection MethodMasturbation 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)
  • 75.
    Azoospermia- What’s next? •Donor sperm IUI? • Testicular FNAC/ Biopsy? • ICSI directly?
  • 76.
    FNAC- role? • Isolatedfoci 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
  • 77.
  • 78.
    Problems with indiscriminateFNAC • Repeat test showed SC 3-4 sperms/ hpf • Repeat semen analysis- 58 mil/ml, TM 48%
  • 79.
    Case 51 (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
  • 80.
    Case 52 • 32year • 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
  • 81.
    Case 53 • 30yr, 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
  • 82.
    Case 54 • 35yr • 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
  • 83.
    How to manage-Hypo-Hypo? • hCG 2000-5000 IU 3 times a week • Serum testosterone should be checked every 1–2 months • The sperm count should be monitored monthly • Sperm parameters become normal within 6 months but sometimes it can take 24 months of time • If hCG alone cannot restore spermatogenesis, FSH is added in the dose of 75-150 IU 3 times a week • Often can father the baby at much lower sperm concentration EUA, 2021; ASRM/AUA, 2024
  • 84.
    Case 55 • FNAC-B/L maturation arrest • FSH 37.2, LH 24.4, Testo 245.53, E2 37, ratio <10 • Not keen for IVF- ICSI-PGT
  • 85.
    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
  • 86.
  • 87.
    Case 57 • 37yr • FSH 35.42, LH 10.13, testo 93, E2 14.45 • Undiagnosed Diabetes • Prev FNAC- Lt side- Sertoli Only Syndrome • TESE – Rt side- No sperms, Lt side- Motile Sperms • Chance of sperm retrieval in KS 20- 70% (Kang et al., 2024)
  • 88.
  • 89.
  • 90.
  • 91.
    Case 70 Mosaic Klinefelter 47,XXYdel(9)(q12.q34), del(x)(q27,q28)/ 47XXY/47XY
  • 92.
    Case 71-72 45,XY,rob (13;14)(q10;q10) RobertsonianTranslocation Azoospermia 46,XY,t(15;17)(q10;q10) Reciprocal balanced Translocation Severe OAT Autosome abnormalities
  • 93.
  • 94.
    Case 73-77 46,XY,t(11;21)(p22;p11.2) 46,XY,t(13;18)(p11.2;p11.2)46.XY,t(2;22)(q37;q11.21) 45, XY,rob(14;21)(q10;q10) 45,XY,rob (13;14)(q10;q10) 46,XY,t(3;6)(p21;p23)
  • 95.
    Case 78-79 46,XY,del(Y)(q11.23) Deletion 46,XY,dup(9)(q11-q12) Duplication (Partialtrisomy) Family History of Azoospermia in a) Own brother b) 2 maternal uncles c) 2 Cousin brothers (of same maternal aunt) Unbalanced rearrangements
  • 96.
  • 97.
    Case 82-86 46,XY,inv(9)(p13,q13) 46,X,inv(Y)(p11.2q11.2)46,X,inv(Y)(p11q13) 46,X,inv(Y)(p11q11) 46,XY,inv(9)(p12q13) Some inversions may be “polymorphism”
  • 98.
    Case 87-92 46,XYqh- 46,XY,16qh+46,XY,22ps+ 46,XY,15ps+ 46,XYq+ 46,XY,9qh+ Genetic “aberration” ≠ Advanced interventions Keep geneticist on board
  • 99.
    Case 93 • 37yr • 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
  • 100.
    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
  • 101.
  • 102.
    Case 94-95 AZF a/b Poorprognosis TESA should NOT be attempted AZF c/d Good prognosis Some may have sperms in semen
  • 103.
    Our experience withYCM Total Azoospermia N= 1221 NOA (Testicular) N = 1071 YCM present N= 30 YCM negative N = 209 YCM Not tested N= 832 AZF a/b/c/d all deleted 3 AZF a/b/c deleted 3 AZFa only deleted 2 AZFb only deleted 2 AZFc only deleted 5 AZF b+c deleted 7 AZF c+d deleted 4 AZF b+c+d deleted 4
  • 104.
  • 105.
  • 106.
    Case 99 46,XX SRY+sex reversal (De La Chapelle syndrome)
  • 107.
    Case 100 46,X,del(Y)(q11.22q11.23) Don’t adviseKaryo alone Don’t interpret karyo alone
  • 108.
    Case 101 • LH30.10, FSH 43.70, E2 38.48, Testo 432 Karyo- 46,XX
  • 109.
    Genetic testing • Sperm concentration<5 million/ml • Azoospermia • Testicular atrophy • Elevated FSH • Karyotyping • Y chromosome Microdeletion (YCM)
  • 110.
    Surgical Sperm Retrieval(SSR) in Azoospermia (OA>NOA)
  • 111.
    Case 102-103 • 42yr • 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
  • 112.
    Predictors of spermretrieval? • 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.
  • 113.
    If previous FNACwas 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%
  • 114.
    Case 104 • 33yr • 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
  • 115.
    Case 105 • Azoospermiainitially • On the day of IVF- few sperms in the ejaculate • ICSI done • Conceived after 1st cycle • Twin- sIUFD, one live birth
  • 116.
    Case 106 Collection MethodMasturbation 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
  • 117.
    Assess • Abstinence period •Completeness of collection • Usual amount of ejaculate • Exclude retrograde ejaculation • Suspect obstructive pathology- TRUS • Clinical assessment???
  • 118.
    Azoospermia- Low volume and/or Fructose negative Vasa palpable • Ejaculatory duct obstruction • TRUS
  • 119.
    Surgical Management inOA: When to refer? • Vasovasostomy • Vasoepididymostomy • Transurethral resection of ejaculatory ducts in EDO • Patent tract ≠ Conception Baker and Sabanegh, 2013
  • 120.
    Azoospermia- Low volume and/or Fructose negative Vasa palpable • Ejaculatory duct obstruction • TRUS Vasa NOT palpable • CBAVD • Why important?
  • 121.
    Congenital bilateral absenceof vas deferens (CBAVD) • Semen- Volume <1.5 ml, pH <7.0, fructose negative • TRUS • Renal ultrasound • Cystic fibrosis mutation (CFTR) testing (EUA, 2021; ASRM/AUA, 2024) • Partner testing • 25% chance of inheritance • Indian prevalence- 1:10,000- 1:40,000 (Kapoor et al., 2006; Prasad et al., 2010)
  • 122.
    Case 107 • TRUS-B/L agenesis of seminal vesicles • Male partner- CFTR carrier • Female partner- CFTR carrier PGT (M)- preimplantation genetic testing for Mendelian disorders (previously called PGD)
  • 123.
    Our experience withCBAVD Total Azoospermia N= 1221 CBAVD N = 115 (9.42%) CFTR mutation present (Heterozygous) N= 10 F508de l N= 7 Partn er norm al N= 6 Partn er heter ozygo us N= 1 Compo und heteroz ygous N= 3 Partn er norm al N= 2 Partn er heter ozygo us N= 1 CFTR mutation absent N = 49 CFTR Not tested N= 56
  • 124.
    Unilateral vas absent •Usually fertile • CFTR testing if no renal agenesis
  • 125.
    Genetic testing • CFTRtesting in CBAVD • Karyotyping • Y chromosome Microdeletion (YCM)
  • 126.
    Medical Therapy inIdiopathic Severe OAT/ NOA • To improve the chance of sperm retrieval • Sometimes, can lead to appearance of sperms in the ejaculate 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) Anti-estrogens (CC, Tamoxifen) •Block pituitary E2 receptors→ stimulate secretion of FSH, LH •Men with normal FSH, low testosterone but normal T:E ratio Gonadotrophins •“resetting” of the Gn receptors in testicles → improve the sensitivity of testicles to gonadotrophins •may be increase intratesticular testosterone •work better in case of eugonadism rather than high FSH •If successful in raising FSH level 1.5 times baseline and testosterone 600-800 ng/dl, high success rate of microTESA (Alkandari and Zini, 2021; Kumar, 2021; Holtermann et al., 2022; Dabaja and Schlegel, 2014; Holtermann et al., 2022; Anawalt, 2013; Flannigan and Schlegel, 2019; Ring et al., 2016; Chehab et al, 2015; Foran et al, 2023). Shiraishi et al., 2012)
  • 127.
    APHRODITE Criteria, RBMO,2024 Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function 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
  • 128.
    Dasgupta et al.,Asian J Androl. 2024
  • 129.
    Hormone treatment vsART • Priority for natural conception • Other indications of ART- female partners • Time to pregnancy • Age of female partners, ovarian reserve • Cost
  • 130.
    Case 108 • Delayedpuberty • 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
  • 131.
    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
  • 132.
    Don’t advise anytest if you do not know what to do with the result !!!
  • 133.
     Meticulous semenanalysis 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
  • 134.
    Semen analysis Mild problemSevere problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
  • 135.
    Semen analysis Mild problemSevere problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
  • 136.
    Semen analysis Mild problemSevere problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
  • 137.
    Semen analysis Mild problemSevere problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
  • 138.
    Semen analysis Mild problemSevere problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
  • 139.
    Semen analysis Mild problemSevere problem 1. Lifestyle changes 2. Antioxidants 1. History 2. Physical Exam 3. Repeat semen ASAP 4. 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
  • 140.
    Treatment burden forMALE infertility falls on FEMALE
  • 142.