Male infertility

Defined as the inability to conceive after 1 year of unprotected sexual intercourse. It affects approximately 15% of couples. Roughly : 30% male factor 30% female factor 30% involve both sexes 10% unknown

Male reproductive physiology The HPG axis. The hypothalamus receives neuronal input from many brain centers, and anatomically linked to the pituitary gland by both portal vascular system & neuronal pathway It secrets GnRH or LHRH to stimulate the secretion of LH and FSH from the anterior pituitary pulsatile in nature (½ life 2-7 min.) vary from once hourly to as seldom as once or twice in 24 h.

Anterior pituitary The site of production and release of FSH & LH under the effect of GnRH Both androgen and estrogen regulate LH secretion through negative feedback

FSH response to GnRH more difficult to measure, and its relatively independent on GnRH. the recently discovered gonadal proteins inhibin and activin may exert significant effect on FSH secretion. Prolactin, can also have effect on HPG axis and fertility.

LH act on leydig cell stimulates the secretion of testosteron. FSH major stimulator of seminiferous tubule growth during development and its essential for the initiation of spermatogenesis at puberity. In adult its major physiologic role is to stimulates quantitatively normal levels of spermatogenesis. Prolactin Also have effect on HPG axis and fertility. The normal role of prolactin in men is less clear, but it may increase the concentration of LH receptors on the leydig cell.

The testis Normal male virility and fertility requires the collaboration of both the exocrine and endocrine testis. The interstitial compartment, (leydig cell)---- Steroidogenesis (endocrine). The seminiferous tubules---- Spermatogenesis (exocrine).

Spermatogenesis Is a complex process by which primitive, totipotent stem cells divide to either renew themselves or produce daughter cell that become spermatozoa. Several cycles of spermatogenesis coexist within the germinal epithelium at any one time. The duration of entire spermatogenesis is 74 days. The transit time of sperm through the fine tubules of the epididymis which is essential for maturation is 10-15 days.

Unlike the somatic cells which replicate by mitoses (identical daughter cells). Germ cells are replicate by meioses in which the genetic material is halved to allow for reproduction.

Management History --is the cornerstone of evaluation. medical history fevers, systemic illness—diabetes, cancer, infection genetic disease--cystic fibroses, klinefelter syndrom. history of post puberital mumps.

surgical history orchiopexy, cryptorchidism herniorrhaphy trauma, torsion pelvic, bladder, or retroperitoneal surgery transurethral resection for prostatism fertility history previous pregnancy (present or other partners) duration of infertility previous infertility treatments female evaluation sexual history---timing & frequency.

family history cryptorchidism, hypospadias midline defect (kartagener syndrom) medication history nitrofurantoin, cimetidin, sulfasalszin, spirinolacton, alpha blockers social history ethanol, smoking, cocaine, anabolic steroids occupational history exposure to ionizing radiation chronic heat exposure (saunas) aniline dyes, pesticides, heavy metals (lead)

Physical examination General examination:hair distribution, gynecomastia. Genital examination size & consistency of the testis induration, tenderness, or cyst of epididymis. presence or absence of vas deferens. varicocele (valsalva maneuver). penile abnormalities, hypospadias, chordee. DRE, to examine the prostate & seminal vesical

Laboratory GUE : infection, glucosuria, hematuria. Semen analysis is the primary source of information on sperm production & reproductive tract patency. sample collection, sexual abstinence duration, liquifaction. should be examine 1 hr. transit at body temp. WHO considered the minimum criteria for normal semen quality. volume : 2—4 ml concen,: 20—40 m/ml motility: 40—60% progression score : 2 (on scale of 0 ,no movement to 4 excellent progression. morphology : >30% (more than 4% kruger normal forms.)

CASA, used to remove the subjective variables in the manual semenalysis. but it can overestimate sperm counts by 30% in the presence of contaminating cells (immature sperm or leukocytes.) then motility underestimated. Seminal fructose and postejaculate urinalysis. both are used to evaluate small ejaculate or unejaculate. Fructose absent in semen-- Seminal vesicle agenesis or obstruction Retrograde ejaculation-- Diabetes, medical therapy, pelvic, bladder,or retroperitoneal surgery

Hormone assessment Evaluation of pit. gonadal axis provide information on the state of sperm production. hyperprolactinemia, gonadotropin deficiency, CAH. FSH & testosterone assay recommended in sever oligospermia sperm densities of <10 million/ml. this combination detect 99% of endocrine abnormalities LH & prolactin levels may be obtained if testosterone & FSH are abnormal

Thyroid hormone, liver function, & other organ specific tests obtained if there is clinical evidence of active disease. High FSH > double value +low testosterone in azospemic patient =testicular failure. Low FSH + low testosterone =hypogonadotropic hypogonadism. High FSH + high testosterone = androgen resistance.

Adjunctive tests indicated if initial evaluation fail to lead to diagnosis & if they change the patient management. Semen leukocyte analysis. pyospermia >1 million leukocyte/ml. should differentiated from immature sperm by special stain like papanicolaou, peroxidase stain, or immunocytology. pyospermia present in infection, immune sensitization, & low grade toxin like cigarette smoke & alcohol.

Antisperm antibody (ASA) test. autoimmune infertility may occur when the blood testis barrier is broken & body is exposed to sperm antigens. ASA indicated in: 1- sperm agglutination or clumping. 2- low motility + history of testis injury. 3- increase leukocyte. 4- unexplained infertility.

Hypoosmotic swelling (HOST) test differentiate immotile from dead sperm (necrospermia). using hypoosmotic environment 25mM citrate & 75mM fructose viable cells should swell when placed in the solution. Sperm penetration assay (SPA) bioassay of the sperm to penetrate the hamster egg help couple decide to use IUI if good SPA or use IVF and micromanipulation if poor SPA result.

Sperm –cervical mucus interaction interaction between the sperm & cervical mucus if abnormal may suggest the treatment by IUI. (sperm placed beyond the cervix). Chromosomal studies 2—15% of patients with azoospermia or sever oligospermia may have chromosomal abnormalities . klinefelter syndrome (XXY) is the most frequently detected. Cystic fibrosis mutation testing 80% of men with congenital absence of vas will harbor CF gene mutation.

Radiologic testing A- scrotal ultrasound hydrocele, abnormality of peritesticular region color doppler used to investigate varicocele. B- venography expensive, invasive & technician dependent. main indication simultaneous percutaneous treatment of varicocele & diagnosis of recurrence after treatment. C- TRUS : imaging prostate, SV, &ejaculatory duct. Replace vasography in diagnosis of obstruction.

Testicular biopsy and vasography indicated in 1- cases of azoospermia + normal hormone profile 2- sperm retrieval for ICSI in azoospermia. multiple percutaneous fine needle aspiration (mapping) of the testis can detect sperm in 60% of men with unobstructed azoospermia.

Semen culture semen is routinely contaminated with the passage through the urethra.thus used in selected situation like 1- history of genital tract infection 2- abnormal expressed prostatic secretion 3- >1000 bacteria /ml of semen 4- >1 million leukocyte /ml (pyospermia).

Causes of male infertility Pretesticular causes hypothalamic disease gonadotropin deficiency (kallmann syndrome) isolated LH deficiency isolated FSH deficiency congenital hypogonadotropic syndrome

pituitary disease pituitary insufficiency (tumor, infiltrative process, operation, radiation, deposits) Hyperprolactinemia exogenous hormones (estrogen-androgen excess, glucocorticoid excess) Hyper-& hypothyrodism growth hormone deficiency.

Testicular causes chromosomal (klinefelter syndrome [XXY], XXsex reversal,XYYsndrome) noonan syndrome (male turner syndrome) myotonic dystrophy vanishing testis syndrome (bilateral anorchia) sertoli-cell-only syndrome (germ cell aplasia) Y chromosome microdeletions gonadotoxins (radiation, drugs) systemic disease (renal failure, liver failure, sickle cell anemia) defective androgen activity testis injury (orchitis, torsion, trauma) cryptorchidism, varicocele, idiopathic

Posttesticular causes reproductive tract obstruction congenital blockage CAVD young syndrome idiopathic epididymal obstruction polycystic kidney disease ejaculatory duct obstruction acquired blockage Vasectomy, groin surgery, infection, functional blockage sympathetic nerve injury pharmacologic

disorder of sperm function or motility immotile cilia syndrome maturation defect immunologic infertility infection disorder of coitus impotence hypospadias timing & frequency

Treatment Surgical treatment Varicocele, vaso-vasostomy (optical magnification, microsuture & microneedles & smaller surgical instruments ejaculatory duct obstruction (TURED). Orchiopexy, pituitary ablation electroejaculation (spinal cord injuries).

Nonsurgical treatment specific therapy need to reverse known pathohpysiologic effects Pyospermia (20 leukocytes /HPF) sperms posses little cytoplasm so they are highly susceptible to the effects of oxidative agents (infection: STD, penile discharge, prostatitis, epididymitis.) chlmydia, mycoplasma are common Doxycycline & trimethoprim-sulfa + antioxidant like vit. A, E,& C or glutathion. Female partner should be treated

Coital therapy timing & frequency is important. every other day around ovulation is the best to decrease the stress & the sperm reside for 48 h. in the cervical mucus. basal body temp. charting or home kit detect LH surge in urine D. MEDICAL THERAPY Hyperprolactinemia 2. Hypothyroidism 3. Congenital adrenal hyperplasia

4. Testosterone excess/deficiency Infertility associated with (Kallmann syndrome) lack GnRH that stimulates normal pituitary function can be very effectively treated with hCG, 1000–2000 U three times weekly, and recombinant FSH 75 IU twice weekly, to replace LH and FSH One can expect to find sperm in the ejaculate beginning 9–12 months after therapy is started

Individuals with isolated LH deficiency respond well to hCG therapy alone. Anabolic steroids are a common and underdiagnosed reason for testicular failure in which excess exogenous testosterone and metabolites depress the pituitary-gonadal axis and spermatogenesis

Empiric Medical Therapy This form of therapy seeks to overcome pathologic condition that are ill-defined idiopathic infertility or have identifiable but no proven treatment a. Antiestrogen blocks the action of the normally low levels of estrogen on the male hormone axis and results in increased secretion of GnRH, FSH, and LH b. Antioxidant therapy glutathione, 600 mg daily for 3–6 months, or vitamin E, 400–1200 U/ day or glutathione

ASSISTED REPRODUCTIVE TECHNOLOGIES Intrauterine Insemination In Vitro Fertilization ICSI