Surgical Management of Male Infertility

Home , Fertility preservation, Spermarche

10/2/2020

KATHLEEN HWANG, MD ASSOCIATE PROFESSOR OF UROLOGY DIRECTOR OF MALE REPRODUCTIVE HEALTH UNIVERSITY OF PITTSBURGH MEDICAL SCHOOL MAY 22, 2020

Disclosures

 None

Reproductive health

 Fertility Preservation  Adult Male Reproductive Urologist Referrals from Pediatric Urologists Pediatric Endocrinology Pediatric and Adolescent Gynecologist

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Partnership with REI

 We work together in the same space as the REI clinic  New Endeavor Started in 2019  Couples are seen together  ARTs  Cryopreserved Sperm Intrauterine Insemination (IUI) In vitro Fertilization with Intracytoplasmic sperm injection (IVF/ICSI)

Fertility Preservation Strategies for the Male Reproductive System

Preservation Strategies

 Minimizing Testicular Damage  Sperm Cryopreservation  Masturbation  Penile Vibratory Stimulation (PVS)  Electroejaculation (EEJ)  Post-Ejaculate Urinalysis  Testicular Sperm Extraction  Aspiration  Extraction (open biopsy)  Office vs. Operating Room  Random vs. Microdissection

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Relevant Patient Populations: Gonadotoxic

 Cancer Patients: Adult vs. Pediatric  Chemotherapy  Radiation  Surgical  Transgender  Anabolic steroid usage  Post-mortem  Medical disease  Klinefelter’s  Autoimmune disease 7

Martinez et al. Fertility and Sterility 2017 September

Alternate Methods of Inducing Ejaculation

 Various scenarios where masturbation is not possible  Penile Vibratory Stimulation  Electroejaculation

Diabetic neuropathy Multiple sclerosis Spinal Cord Injury Post-RPLND Post-rectal cancer surgery

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Diagnostic and Therapeutic Testis Biopsy Techniques

Open biopsy Fine needle aspiration Microscopic testicular sperm extraction (TESE)

Sperm Collection

Masturbation Penile Vibratory Stimulation  Advantages  Advantages  Simple  Non-invasive  Inexpensive  Rare complications

 Disadv antages  Disadv antages  Requires sperm bank  Specialized equipment and training  Difficulties due to age, culture, physical limitations  Requires intact reflex arc

Sperm Collection

Electroejaculation Testicular sperm extraction  Advantages  Advantages  High Retrieval Rates  Modest retrieval rates

 Disadvantages  Disadvantages  Invasive  Invasive  Anesthesia  Anesthesia  Specialized equipment and training  Specialized training for micro-TESE  Minimal data in teenagers  Usually small numbers of sperm found  Minimal data in pre-therapy population  Rare complications  Rare complications

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Rates of Sperm Cryopreservation

 National vs. Regional

 Implementation of a nurse counseling session that included fertility preservation at Hospital System1 2.9 times likely to bank sperm 6.4% men vs. 17.6% men utilized cryopreservation before vs. after implementation of education session

1Rotker et al. Efficacy of Standardized Nursing Fertility Counseling on Sperm Banking 13 Rates in Cancer Patients. Urology 2017 13

Utilization of Cryopreserved Sperm

 Cohort of 272 men with cancer  Live birth rate of 62.1% with ICSI  Cohort of 898 men with cancer in the Netherlands2  Live Birth rates IUI: 13% IVF: 29% ICSI: 33%

1Garcia et al. Assisted reproductive outcomes of male cancer survivors. J Cancer Surviv 2015 14 2Muller et al. Semen cryopreservation and usage rate for ART in 898 men with cancer. Reprod Biomed. 2016 14

Preserving Fertility in Patients: • Importance the Discussion at the Earliest Possible Time • Sperm cryopreservation BEFORE any Gonadotoxic Therapy • Referral to Specialist if Patient is Interested

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Fertility Preservation

 Prior to initiation of Hormonal Replacement Therapy

 Need to ask the question

 Perhaps 10% or so

 Estrogen suppresses pituitary output of LH and FSH

 Cessation of intratesticular testosterone synthesis

Disruption of spermatogenesis

 Prior to orchiectomy

 Need to ask the question

Fertility Preservation

 Not easy or desirable to ejaculate

 May be sexually immature

 Counts may be lower  Prior to HRT  Certainly on hormonal therapy

 Financial considerations

Sperm Cryopreservation: Covered or not ?

 Variable depending on State

 Viral Testing

 Semen sample processing

 Cryo Storage fees (monthly vs. annually)

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Fertility Options for Transgender Individuals

Data on Fertility Preservation in Transgender Population

20 Adeleye et al, Urology 2018 20

Fertility Preservation Counseling

• 72 subjects with 141 orchiectomy specimens • Histological Assessment for level of spermatogenesis • 81% had germ cells present • 40% had elongated spermatids

• Size Matters • 85% of specimens > or = to 25 mL in testicular size had mature spermatids

• Testicular Sperm Extraction Options • Even ex vivo at time of orchiectomy Jiang et al, Urology 2019 21

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 Retrospective assessment of post thaw quality of frozen vials

 Total 260 TransWomen

 12 had prior hormonal therapy

 All stopped at least 3 months prior to semen cryopreservation

GRS Male to Female Fertility Issues

GRS: Male to Female

 Fertility Issues  Options for Sperm Cryopreservation  Ejaculation prior to starting endocrine therapy  Ejaculation after starting endocrine therapy  Sperm retrieval at time of orchiectomy

 New WPATH guidelines Sept 2011  “All Health Care Professionals should discuss reproductive options prior to initiating MEDICAL and/or SURGICAL treatment”

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Fertility Preservation: M to F

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PATIENT KNOWLEDGE AND INTEREST IN CRYOPRESERVATION OF SPERM IN PATIENTS PRESENTING FOR MALE TO FEMALE GENDER AFFIRMING SURGERY

 Ruth Blum MD1, Rafaela Mangino PA2, James Rosoff MD2, Stanton Honig MD1,2

 Division of Urology, University of Connecticut, Farmington, CT 1 Department of Urology, Yale University, New Haven, CT 2

RESULTS

Patient Patients Interested in PatiCharacteristicsents Not interested in P-Value Cryopreservation (N=9) Cryopres(N=79)ervation (N=70) Average ageAverage(years) age2 6(years) (16-39) 3436 (1(168-68-68)) 0.04 Duration of dressing in 8.4 (1.5-17) 9.8 (1-52) 0.61 female gendeDurationr (years) of dressing in Duration of hormone 9.8 (1-52) female gender6.9 (years)(1-17) 5.4 (1-27) 0.35 therapy (years) Patients witDurationh prior of hormone 0 (0%) 5.67 (10 (1.9%-27)) 0.25 childretherapyn (years) Patients with prior children 9.6% (N=7) Knowledge of 100% (N= 79) cryopreservation Interest in 11.4% (N=9) cryopreservation

Interest in Fertility Preservation (M to F)?

Ejaculate prior to starting EST

Unable to ejaculate or already on EST Sperm present and cryopreserve

Check ejaculate on EST

Sperm present and No sperm cryopreserve

Stop EST and obtain ejaculate

No sperm present, proceed with Sperm present and cryopreserve TESE prior to or at time of GAS/orchiectomy

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Feminizing effect on Testis Histology

 Schneider et al J Sex Med 2015:12:2190-2200.

 108 pts from multiple GAS centers

 3 groups  Discontinued estrogen 6 weeks prior to surgery  Discontinued estrogen 2 weeks prior to surgery  No estrogen discontinuation

Feminizing effect on Testis Histology

 Results  Stopped estrogen  Higher T levels, higher intra-testicular Testsosterone levels  Higher gonadotropins  EXTREMELY variable histology in all the groups  (even in those that did NOT stop estrogen)  Suppression of gonadotropins did NOT necessarily reflect the differentiation status of germ cells (spermatogenesis)  Could reflect compliance of patients taking meds.

Orchiectomy Histology Data in GAS (AUA 2018)

 Lao and Honig (n=21)

 Correlation of histology to sperm retrieval data

 Spermatogenesis in 26% pts (based on histology)

 50% sperm retrieval rate (in those interested)

 Mixed population of estrogen/non estrogen

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The Future

What About Prepubertal Males?

 No effective means of fertility preservation currently available  Numerous investigational approaches being studied  Cryopreservation of testicular tissue  Completed under research study and experimental  Autotransplantation  Xenotransplantation  In vitro sperm maturation

Research: Transgender FP Protocol

Title: Testicular tissue cryopreservation in the setting of feminizing therapy

Specific Aims:

Testicular tissue freezing prior to feminizing therapy study is open to transgender female patients who have not reached spermarche. The study aims to determine the acceptability and provide a new fertility preservation option (testicular tissue freezing) for young transgender patients and provide research tissue to enable researchers to responsibly develop next generation technologies that may allow patients to use their tissues for reproductive purposes in the future.

Research will: 1) Optimize tissue processing and cryopreservation methods 2) Confirm the presence and quantity of germ cells (sperm precursors) in patient tissues (to be reported back to patients) 3) Develop next generation cell- and tissue-based therapies to preserve fertility and treat infertility.

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Research: Transgender FP Protocol

Title: Ovarian tissue cryopreservation in the setting of masculinizing therapy

The study aims to determine the acceptability and provide a new fertility preservation option (ovarian tissue freezing) for young transgender patients and provide research tissue to enable researchers to responsibly develop next generation technologies that may allow patients to use their tissues for reproductive purposes in the future. Ovarian tissue will be used for research to address various research aims, including, but not limited to:

1) To optimize techniques for cryopreservation of ovarian tissues, including determining efficacy of cryopreservation techniques 2) To investigate factors affecting ovarian tissue and follicles, such as previous treatment with leuprolide acetate, or hormone therapy

 Have the conversation about Fertility Preservation Options EARLY Conclusions  Even if your local institution does not have a Fertility Preservation Program

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Thank You