1. Male Reproductive Issues
RICHARD E. FREEMAN MD MPH
2013
LOCK HAVEN UNIVERSITY

2. SPERMATOGENESIS

3. SPERMATOGENESIS

4. INFERTILITY DEFINITION: Inability to conceive a child WHO USA
A couple may be considered infertile if, after two years of regular sexual intercourse, without contraception, the woman has not become pregnant (and there is no other reason, such as breastfeeding or postpartum amenorrhea)
USA
a woman under 35 has not conceived after 12 months of contraceptive-free intercourse
a woman over 35 has not conceived after 6 months of contraceptive-free intercourse.
Primary infertility is infertility in a couple who have never had a child.
Secondary infertility is failure to conceive following a previous pregnancy.

5. GENERAL
~ 10% couples are affected by infertility
~40% are from male factors!
~30% of the 40% male factors…cause is unknown

6. History DETAILED SEXUAL HISTORY DETAILED PREGNANCY HISTORY
A detailed history of exposure to occupational and environmental toxins, excessive heat, or radiation should be elicited. Cancer chemotherapy has a dose-dependent and potentially devastating effect on the testicular germinal epithelium.

7. Medical History Childhood illnesses
post pubertal mumps orchitis and testicular trauma or torsion
Cancer chemotherapy/radiation
– destroys germinal epithelium-dose dependent
Diabetic neuropathy
may result in either retrograde ejaculation or impotence
DES exposure
epididymal cysts or cryptochordism
Precocious puberty
adrenal-genital syndrome
Congenital adrenal hyperplasia
Delayed puberty
Klinefelter's syndrome or idiopathic hypogonadism
childhood illnesses should be sought including cryptographies, post pubertal mumps orchitis and testicular trauma or torsion.
Precocious puberty may indicate the presence of an adrenal-genital syndrome, whereas delayed puberty may indicate Klinefelter's syndrome or idiopathic hypogonadism.
Prenatal exposure to diethylstilbesterol should be ascertained because this may cause an increased incidence of epididymal cysts or a slightly increased frequency of cryptorchidism.
CAH: from inborn errors of metabolism resulting in decreased cortisol cause increase ACTH and increase in production of androgens

8. History Hernia repair Cystic fibrosis (CBAVD) Mumps Thyroid disease
Prolactinoma
With cystic fibrosis, the vas deferens or epididymis and seminal vesicles are usually absent. Any generalized fever or illness can impair spermatogenesis. The ejaculate may be affected for three months after the event, as spermatogenesis takes about 74 days from initiation to the appearance of mature sperm.

9. History - Drugs Influence Reproductive cycle and male hormone
anabolic steroids, cimetidine, and spironolactone
Sperm Motility
sulfasalazine and nitrofurantoin
Decrease count and hormone interference
Illicit drugs and alcohol (Liver failure)
Seizure meds… FSH
anabolic steroids, cimetidine, and spironolactone which can effect the reproductive cycle. Medications like sulfasalazine and nitrofurantoin may effect sperm motility.
Illicit drugs and excessive alcohol consumption are associated with a decrease in sperm count and hormonal abnormalities.

10. SOCIAL HISTORY Occupational and environmental toxins,
Excessive heat-iron foundry worker
Radiation- x-ray tech
Illicit drug use

11. Physical Exam Look for HYPOGONADISM!
poorly developed secondary sexual characteristics
eunuchoidal skeletal proportions
Arm span longer than height
Crown to pubis:Pubis to floor ratio <1
sparse male hair distribution
infantile genitalia
muscle mass & development
hypogonadism. Typically this would be viewed as poorly developed secondary sexual characteristics, eunuchoidal skeletal proportions i.e. arm span two inches greater than height, ratio of upper body segment (crown to pubis) to lower body segment (pubis to floor) less than 1, and the lack of normal male hair distribution ie. sparse axillary, pubic, facial, and body hair in conjunction with lack of temporal hair recession. One should be on the lookout also for infantile genitalia ie. small penis, testes, and prostate with under-developed scrotum.

12. Physical Exam Hypogonadism may be associated with:
anosmia- inability to smell
color blindness,
cerebellar ataxia, hair lip, and cleft palate. (Kallmann syndrome-isolated gonadotropin – FSH/LH – deficiency with anosmia)
Thyroid
Liver
Neuro
GU prostate exam
Kallmann's syndrome which is an isolated gonadotropin (LH and FSH) deficiency occurs in both a sporadic and familial form and although uncommon i.e. 1 in 10,000 men

13. LABS FSH, LH DHT TSH ACTH GH Post coital DFI Anti sperm antibodies
SPA (semen penetration assay)
Sperm Penetration Assays (SPA) Penetration of an oocyte requires sperm capacitation, acrosome reaction, fusion and incorporation into the oocyte. Cross-species fertilization is normally prevented by the zona pellucida.

14. Special Tests Vasography Testicular biopsy Ultrasound – color flow
Vasography is indicated in men with at least one palpable vas deferens azoospermia, and a testis biopsy indicating normal spermatogenesis, or in men with low-volume ejaculates with poorly motile sperm in whom ejaculatory duct obstruction is possible.

15. Sperm Count
Fresh sample (to lab within 30 mins.) –most sperm in initial ejaculate
Male should be abstinent for 48 to 72 hours
sperm concentration > 20 million per ml
total count > 60 million/SAMPLE
ejaculate volume > 1.5 ml
total motile count > 30 million
viable sperm > 50%
normal shapes (morphology) > 60%

16. Sperm Terms Normal ejaculate Normozoospermia
Sperm concentration >20 million/ml
<50% spermatozoa with forward progression
<30% spermatozoa with normal morphology
No spermatozoa in the ejaculate
No ejaculate
Normozoospermia
Normal ejaculate
Asthenozoospermia
Iatrogenic/abstinence
Varioceles, cilia anomalies, Anti-spm Ab
Teratozoospermia
Azoospermia
Aspermia

18. MALE INFERTILITY: CLASSIFICATION
PRE-TESTICULAR
TESTICULAR
POST-TESTICULAR

19. Seminiferous tubules
Rete testes

21. PRE-TESTICULAR CAUSES OF INFERTILITY:secondary testicular failure
Hypothalamic disease
HYPOGONADROTROPIC HYPOGONADISM 
Isolated gonadotropin deficiency (Kallmann's syndrome) 
Isolated LH deficiency
("Fertile eunuch") 
Isolated FSH deficiency 
Congenital hypogonadrotropic syndromes

22. PRE-TESTICULAR CAUSES OF INFERTILITY: secondary testicular failure
Pituitary disease 
Pituitary insufficiency
(tumors, infiltrative processes, operation, radiation) 
Hemochromatosis 
EXOGENOUS HORMONES
Estrogen excess
Androgen excess
Glucocorticoid excess
Hyperprolactinemia 
Hyper and hypothyroidism

23. ENDOCRINE CAUSES Hyper and hypothyroidism EXOGENOUS HORMONES
Estrogen excess:
Inhibits GnRH
also direct effects on spermatogenesis
Low FSH/LH/Testosterone
ETIOLOGY
Hepatic disease
estrogen secreting tumor
OBESITY
Androgen excess:
Direct feedback inhibition on the hypothalmus
Low intratesticular testosterone (necessary for spermatogenesis
Endogenous-congenital adrenal hyperplasia, tumors
Exogenous – anabolic steroids
Glucocorticoid excess
Hyper and hypothyroidism

24. Hyperprolactinemia ETIOLOGY: S/S: Dx: Screening-- low yield TX:
medications, stress, pituitary adenoma
S/S:
erectile dysfunction
low testosterone
decreased libido
Dx: Screening-- low yield
Prolactin level MRI –sella tursica
TX:
Surgical excession of pituitary tumor (adenoma)
Cabergoline(Dostinex)
dopamine 2 receptor agonist

25. TESTICULAR CAUSES: GENETICS Primary Testicular failure
Y Chromosomal abnormalities (Klinefelter's syndrome, XX disorder (sex reversal syndrome), XYY syndrome)
Noonan's syndrome (male Turner's syndrome)
Myotonic dystrophy
Bilateral anorchia (vanishing testes syndrome)
Sertoli-cell-only syndrome (germinal cell aplasia)

26. TESTICULAR CAUSES: Primary Testicular failure
VARICOCELE
Gonadotoxins (drugs, radiation)
Orchitis
Trauma
Systemic disease
(renal failure, hepatic disease, sickle cell disease)
Defective androgen synthesis or action
Cryptorchidism
IDIOPATHIC-Majority

27. VARICOCELE
Most common Attributable cause of Primary and secondary infertility in males- 40%
Left sided
-right angled insertion of L testicular vein into the L renal vein- less valves
Theories
Temperature elevation
Reflux of toxic renal and adrenal metabolites
Gonadotoxin metabolite clearance impairment
Treatment: LIGATION
– improves sperm count and semen quality
INDICATIONS
Palpable varicocele on exam
known infertility
Female partner has normal fertility
Male- abnormal semen parameters
+- discomfort
ADOLESCENT MALE: Testicular hypotrophy (20% discrepancy in size)

28. Disorders of sperm transport
POST-TESTICULAR CAUSES OF INFERTILITY
SPERM TRANSPORT
Disorders of sperm transport 
Congenital disorders-
Congenital Bilateral absence of the Vas deferens (CBAVD)
- Cystic Fibrosis- CF transmembrane conductance regulator test
Acquired disorders 
Functional disorders

29. POST-TESTICULAR CAUSES OF INFERTILITY: SPERM MOTILITY
Disorders of sperm motility or function 
Congenital defects of the sperm tail
Primary Ciliary Dyskinesia (PCD) effects other organs with cilia
Maturation defects
Globozoospermia –
“round-headed sperm syndrome”
No acrosin-no penetration of zona pellucida
Fibrous Sheath Dysplasia-
“stump tail syndrome”
short coiled immotile tails (genetic counseling suggested)
Immunologic disorders- 
Infection

30. SPERM DNA FRAGMENTATION
If greater than 30% have a DNA fragmentation index (DFI):
Reduced fertility potential
Reduction in term pregnancies
Doubling in miscarriages
“Normal” (morphology and motility) sperm may have DNA fragmentation!
Research indicates that sperm with high-levels of DNA fragmentation have a lower probability of producing a successful pregnancy. A review of data on hundreds of semen samples show that patients with a DNA fragmentation level of greater than 30% are likely to have significantly-reduced fertility potential, including a significant reduction in term pregnancies and a doubling of miscarriages. Sperm that appears to be normal by traditional semen analysis parameters (motile, morphologically normal sperm) may even have extensive DNA fragmentation.

31. Causes of DFI Age…>46 Pollution Smoking Febrile illness Drugs
Radiation
Chemicals
Testicular cancer
Varicocele
Prolonged heat:
Hot tubs
Truck drivers
Cyclists
Heat/fever inhibits spermatogenesis

32. AZOOSPERMIA
Obstructive – 40%
TRUS=Transrectal ultrasound

33. INFERTILITY Treatment
Find the cause!!!!
PESA/MESA
microsurgical epididymal sperm aspiration
TESE
testicular sperm extraction
IVF-
invitro fertilization
AIDS
–artificial insemination by donor
TUREJD
-Transurethral resection of the ejaculatory ducts
Microsurgical Epididymal Sperm Aspiration (MESA) MESA is an alternative treatment method for obstructive azoospermia in order to obtain sperm from the epididymis with the use of an operating microscope. It is not a surgical technique to be used for 1) the non-obstructed system if ejaculation is normal; 2) the severely oligospermic patient with primary testicular dysfunction, or 3) the vasectomy patient who incorrectly views MESA as an easy alternative to a first-time vasectomy reversal
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34. INFERTILITY MEDICATIONS
Gonadotropin-Releasing hormone agonists
Gonadotropins- LH FSH
Anti-estrogens:
- Clomiphene, Tamoxifen
Aromatase inhibitors:
– Testolactone /Anastrozole
aromatase converts testosterone to estradiol
Antioxidants
-L-carnitine, Kallikrein, Thyroid

36. Male Menopause

38. Male Menopause - Andropause
Occurs between and is a gradual decline over the years
1/10 will experience hot flashes
Also called…
Hypogonadism
Male climacteric
Viropause
ADAM (androgen decline in aging males)

39. Andropause
By age 80, testosterone levels are around pre-pubertal levels!

40. Physical Symptoms Taking longer to recover from injuries and illness.
Less endurance for physical activity.
Feeling fat and gaining weight.
Difficulty reading small print.
Loss or thinning of hair.
Sleep disturbances and fatigue.
"Sore body syndrome" - stiffness.
Excessive sweating.
Cold hands and feet.
Itching.

41. Psychological Symptoms
Irritability.
Indecisiveness.
Anxiety and fear.
Depression.
Loss of self-confidence and joy.
Loss of purpose and direction in life.
Feeling lonely, unattractive and unloved.
Forgetfulness and difficulty concentrating.

42. Sexual Symptoms Reduced interest in sex.
Increased anxiety and fear about losing sexual potency.
Increased fantasies about having sex with a new and younger partner.
More relationship problems and fights over sex, love and intimacy.
Loss of erection during sexual activity (impotence).
Reduced interest in sex. Men may require direct physical stimulation to get an erection; a stimulating sight or fantastic fantasy may not arouse them as it did before.
Loss of erection during sexual activity (impotence). Erections may take longer to occur and the full erection may not get quite as firm as it used to.
There is less of an urge to ejaculate. Sometimes a man might not feel the need to orgasm at all.

43. Sexual Symptoms cont’d
There is less of an urge to ejaculate.
The force of ejaculation is not as strong as it once was. The amount of the ejaculate is less and one may have fewer sperm.
The testicles shrink and the scrotal sack droops. The sack does not bunch up as much during arousal.

44. Low T2 in men may cause… Angina Atherosclerosis High blood cholesterol
High blood triglycerides
High blood pressure.
High body mass index (obesity).
Osteoporosis

45. Labs Thyroid Panel Free T3 Free T4 TSH PSA
DHEA Sulfate Dihydrotesterone(DHT) Estradiol LH IGF-1 Testosterone, Total & Free           Total Testosterone           Free Testosterone           %Free
Thyroid Panel            Free T3           Free T4           TSH
PSA 

46. Treatment Viagra, Levitra, Cialis
Testosterone replacement therapy - TRT
Side Effects:
Increase cholesterol
Increase blood pressure
Growth of body hair
Male-pattern baldness
Acne
Fluid retention
aggression

47. TRT – Cont’d
Monthly injections
Patch - scrotum
Implants q 4 mos

49. QUESTIONS ?????
SOURCE:
Wein: Campbell-Walsh Urology 10th ed
Chapter 21 Male infertility
2011 Saunders
Can be accessed on MD Consult