Case
Male Infertility Evaluation and Treatment 2015
32 yo man with primary infertility for over 2 years. Partner is 29 yo and healthy. He says to you that he thinks he’s “shooting blanks.”
Paul J. Turek MD FACS, FRSM Director, The Turek Clinic, Beverly Hills & San Francisco Former Professor and Endowed Chair, UCSF
Male Infertility: Evaluation Male
Female
30%
50%
20%
• 85% of couples conceive @ 1 yr. •Defined as no conception after 1 yr of unprotected sex. • 50% of infertility involves male factor. •Evaluation initiated by couple.
Both
Male Infertility Evaluation
Semen Analysis x 2 Normal
Male Infertility: History • Sexual History:
Prior pregnancies Timing of intercourse (“frontload” before ovulation best) Lubricants. Vegetable oils • PMHx/PSHx: Cancer, fevers, systemic illness, ED Childhood: mumps after puberty; bladder, orchidopexy (for torsion/UDT); hypo- or epispadias; trauma; epididymitis, varicocele Adult surgery: TUIP, TURP, RPLND, spermatocele, hernia Exposures: chemotherapy, XRT, environmental/occupational •Medications Antiandrogens, steroids, estrogens, alpha blockers, beta blockers, Ca+ channel blockers, antipsychotics, cimetidine, sulfasalazine, sulfa antibiotics •Habits EToH (>2 q d); tobacco; cocaine; anabolic steroids
Abnormal
Further Female Evaluation Abnormal
Importantly, medical conditions present as infertility in 1- 5% of cases: Diabetes mellitus Retroperitoneal tumor Prolactinoma Cystic fibrosis Testis cancer Genetic syndromes Neurological disease
Turek. Nat Clin Prac Urol. 2005, 2:1-13
History Physical Exam
Normal
Eliminate Gonadotoxins Not Improved
Treat Female Factor
Improved
Hormone Evaluation Focused Further Evaluation
Treat Female Factor Blood Semen Imaging
Male Infertility: Exposures Ionizing radiation (?pilots, ?cell phones) Chronic heat (cooks, welders, ?laptops; tubs/baths) Aniline dyes Heavy metals (lead, mercury, cadmium) Pesticides 1. DBCP-Dibromochloropropane 2. DDT 3. Kepone
Industrial toxins ( smelly solvents ) 1. Dioxin (paper) 2. PCB, bisphenol A 3. Cl-hydrocarbons 4. N-nitroso (rubber) 5. Paints 6. Benzene
D/C hot tubs 400% Better!
Shefi et al. Braz J Urol. 2007
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Male Infertility: Ejaculation Infertility Associated? No
•Premature Primary or lifelong Secondary or acquired-?ED
•Retrograde or Dry Primary Secondary: diabetes, alpha blockers, MS
•Delayed ejaculation
Yes Yes
Case 32 yo man with primary infertility for over 2 years. Partner is 29 yo and healthy. He says to you that he thinks he’s “shooting blanks.” History: short term anabolic use in college. “Not much comes out with ejaculation.”
SSRIs Masterbatory methods
Yes
•Anejaculation Primary Secondary-antipsychotics, SSRI
Anatomy-The Ejaculate
Anatomy & Physiology-Testis
(caput)
10% Prostate
10 days 4 x 3 cm (20mL)
Rete testis 10% Vas deferens
(corpus)
80% germ cells
64 days 10-15 lobules
(cauda)
600 million sperm
80% Seminal vesicle
Premature ejaculation Retrograde ejaculation Anejaculation
Need 3 months to make and ejaculate sperm. Soft, small testes imply a sperm production problem
Physical Examination
Physical Examination: Varicocele
Inguinal ring
•15% of all men •35% of primarily infertile men •60-80% of secondarily infertile men •Reason for infertility:?hypoxia; hyperthermia?
Body habitus 20 sex characteristics
Varicocele
Breast exam Vas deferens
Subclinical Grade I
Penis Epididymis
80%
Grade III Testis
prostate
Grade II
Not detected on physical exam; found by radiologic or other imaging study. Only palpable during or after Valsalva maneuver on physical exam Palpable on routine physical exam without Valsalva maneuver. Visible to the eye and palpable on physical exam.
Repair Clinical Varicocele Only
2
Indications for Varicocele Repair 1. Adolescent-large lesion and hypotrophy (>4 ml difference) 2. Any varicocele and pain 3. Male factor infertility with adequate maternal potential (>1 year) Takes a mean of 8 months to conceive after repair
50
# of couples
40
30
20
How to Approach
Varicocele Repair?
Palomo (retrop., take artery) Modified Palomo (spare artery) Ivanessivitch (inguinal) Subinguinal Laparoscopic Percutaneous (embolizat.)
X
X
10
X
0 2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
Time to pregnancy (Months)
4. Male factor infertility with azoospermia. “Meet Mr Varicocele”
Congenital Absence of the Vas Deferens (CAVD) •Unilateral: most azoospermic •Bilateral: all azoospermic •Any segment of Wolffian duct •If ipsilateral kidney also absent: No CFTR mutations •If ipsilateral kidney is present: 80% have CFTR mutations
Case 32 yo man with primary infertility for over 2 years. Partner is 29 yo and healthy. He says to you that he is “shooting blanks.” History: short term use of anabolics in college. “Not much comes out with ejaculation.” Exam: Bilateral testis volume 20 mL Vas palpable bilaterally Left grade II varicocele
CFTR= Can’t Father Try Retrieval Chromosome7q31.2 1800 mutations described
Male Infertility Evaluation
Turek. Nat Clin Prac Urol. 2005, 2:1-13
History Physical Exam
Semen Analysis x 2 Normal
Abnormal
Further Female Evaluation Abnormal
Normal
Eliminate Gonadotoxins Not Improved
Treat Female Factor
Hormone Evaluation Focused Further Evaluation
Semen Analysis-WHO 2010 Reference Ejaculate volume Sperm concentration Motility Forward progression Morphology
1.5--5.5ml >15 x 106 sperm/ml >40% 2 (scale 1-4) >4% Kruger
Improved Treat Female Factor Blood Semen Imaging
Also: No agglutination (clumping), white cells, or increased viscosity 2-3 days sexual abstinence reduces variability. Problem: Based on 5th centile range for fertile men. “Reading Your Cards”
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Semen Analysis Findings from Infertile Men All normal
What is Sperm Morphology?
24%
Isolated abnormal
52%
Low motility
% Egg Fertil.
36%
Low count
@IVF
2%
Volume
3%
Morphology
11%
Multiple defects
19%
No sperm
5%
% Normal Kruger Morphology
100% “Genetics of Headless Sperm”
Sigman, Lipshultz, Howards. Infertility in the Male. 3rd Ed. 1997
What are White Blood Cells in Ejaculate?
Case
Are round cells and not WBC s In asymptomatic men, WBC s are usually (70%) immature sperm and should not be treated. Treat if >1 million/mL
Peroxidase stain
What are Antisperm Antibodies? Generally cause sperm to clump or agglutinate. Demonstrated by anti-human antibody + beads.
32 yo man with primary infertility for over 2 years. Partner is 29 yo and healthy. He says to you that he is “shooting blanks.” History: short term use of anabolics in college. “Not much comes out with ejaculation.” Exam: Bilateral testis volume 20 mL Vas palpable bilaterally Left grade II varicocele Semen: 1.0mL/no sperm. Confirmed with pellet x 2
Immunobead stain
The H-P-G Axis
G R H
Higher Centers Opioids
Catecholamines
Hormone Evaluation
PRL
GnRH
Anterior Pituitary
-
+
PRL T
T
FSH
T
+
+ Activin
FSH Sertoli Cells
-
Anterior Pituitary
Hypothalamus
Inhibin
T
Testosterone
Testicle
Sertoli Cells
LH Leydig Cells
+
LH Leydig Cells
T
4
Case
Male Infertility: When to Order Hormones?
•Sperm density 2-3 x normal) implies only that sperm production will not be normal. Example: hypospermatogenesis Touch imprint
5
Low Volume Ejaculate
Low Volume Azoospermia
10% Prostate
“Houston, we have a problem”
Rule: All azoospermic men need a testis biopsy Exception: Low volume (1.5cm) Dilated ducts Ca++ near ducts Midline/eccentric cysts
Make him a better “LoVER” Midline, Mullerian cyst
Low Volume Azoospermia Proceed to TURED after TRUS Before resection
Much of Male Infertility is Genetic
Varicocele (1/2 respond) 42%
•TRUS to guide resection •70% semen improvement •25% pregnancy rate
Unexplained
23%
Testis Failure
1.5%
unexplained After resection “Clearing the Reproductive Pipes”
Congenital Absence of the Vas Deferens (CAVD)
When to do Genetic Testing?
Situation Sperm 1yr? Yes
Non-Surgical
No
Yes
Hormone based Non-hormone based
Genetic Evaluation Turek. Nat Clin Prac Urol. 2005, 2:1-13
No
Assisted reproduction
Correct Male Factor (Varicocele, blockage)
IUI IVF IVF-ICSI
Clomiphene Citrate (clomid)
Summary Non-Surgical Therapy
Nonsteroidal hormone An anti-estrogen (SERM) Increases GnRH output: Raises T and FSH
E2 GnRH
Rx 12.5-25 mg/day
T
Check FSH, T in 4 weeks Monitor semen q 3 mos Good for 2ndary hypogonadism due to diabetes, prolactinoma
LH FSH
Leydig Cells
Side Effects: gynecomastia, weight gain, visuals, acne
Female Fertility Evaluation What? o o o o
Coital Surgical
History and Physical Exam Blood tests – cycle day 3 FSH, AMH, Estradiol Hysterosalpingogram Endometrial biopsy
T
Specific therapy works: Remove toxins (heat, EtOH, drugs) Treat infections (UTI, prostatitis) Improve coital timing, performance Treat pathology (ED, prolactinoma, retrograde ejaculation) Empirical therapy may not work: Clomid Have a timeline in place. Use 6-9 months for this. ProXeed Then choose other avenues. Vits/herbals
Treatment of Male Infertility Non-Surgical Hormone based Non-hormone based
When?
40 years old yesterday
Coital Surgical Assisted technology
7
Treatment: Assisted Reproduction Sperm Extraction Techniques
Treatment: Assisted Reproduction Intrauterine Insemination (IUI) $200-500
Sex $free
IVF +/- ICSI $10,000
MESA/PESA Epididymal Sperm Aspiration
TESE Testis Sperm Extraction >40 million sperm
40 million sperm
5 million sperm
0 sperm
TESA Testis Sperm Aspiration Micro-TESE
Total Motile Sperm Count
1. All aspirated sperm requires IVF-ICSI. 2. No differences in outcomes based on sperm source.
(vol x concentration x motility)
Nonobstructive Azoospermia: Patchy or Focal Sperm Production Bx-FNA Discrepancy
Bx
Intratestis Variability
Intertestis Variability
-
-
-
25% of testes
And +
+
27% FNA +
Nonobstructive Azoospermia: How to Best Find Sperm?
19% of testes
Turek et al. J. Urol. 163: 1709, 2000
Microdissection TESE
FNA Mapping, Directed TESE
Nonobstructive Azoospermia: FNA Mapping
Male Infertility Evaluation and Treatment Summary • • • • • • “Know Before You Go” “Mapmaker, Mapmaker, Make Me a Map”
Lifestyle and exposures matter! Varicoceles can matter. Semen volume matters. Don’t forget about genetics. Fixing things is cheaper than IVF. Most men with testis failure will have sperm.
Thanks!!
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Figures thanks to Netter s Images, 2nd Edition
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