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

SPERMATOGENESIS

SPERMATOGENESIS

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.

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

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.

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

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.

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.

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

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.

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

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.

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.

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%

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

MALE INFERTILITY: CLASSIFICATION PRE-TESTICULAR TESTICULAR POST-TESTICULAR

Seminiferous tubules Rete testes

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

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

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

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

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)

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

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)

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

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

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.

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

AZOOSPERMIA Obstructive – 40% TRUS=Transrectal ultrasound

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 .shtml

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

Male Menopause

Male Menopause - Andropause Occurs between 45-60 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)

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

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.

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.

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.

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.

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

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 

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

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

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