A 33-year-old man is referred for evaluation of male infertility. He and his 29 years old wife have been trying to conceive for last 2 years. She is gravida (G0), para (P0) with complete medical evaluation revealing regular ovulatory cycles and normal reproductive anatomy with no history of reproductive tract disorders, pelvic infection or surgery. The couple has had unprotected vaginal intercourse at least 2–3 times a week, having undergone a normal puberty and well previously, he complains of poor libido and poor erection with decreased volume of ejaculate for past 1 year. He shaves once a week. There is no past history of any chronic ailments or any reproductive disorders, and has taken no medications or any illicit drugs. He has no family history of hypogonadism, cleft palate or infertility; he has 2 brothers who have fathered children. He works as a software professional with no habitual smoking or drinking. He has never fathered a child. He is well virilized with normal male voice and normal upper/lower segment ratio. His body mass index (BMI) is 33.5 kg/m2 with bilateral nontender gynecomastia; a normal genitourinary examination with normally descended testes that are 12 mL bilaterally and easily palpable vasa deferentia. His laboratory tests (performed at 8.00 am) reveal total testosterone 220 ng/dL (N: 300–1000 ng/dL), luteinizing hormone (LH)-2 mIU/mL, follicle stimulating hormone (FSH)-6 mIU/ mL. Hematogram, urine analysis, hepatic and renal profiles, serum prolactin, thyroid profile and iron studies are normal. Repeat hormonal analysis reveal similar results. The seminal fluid analysis yields no sperms with volume of 2.45 mL, normal pH (≥7.2) and fructose. Repeat semen analysis shows similar results. Sella imaging reveals no hypothalamic/pituitary abnormality.
What are the various forms of treatment for male infertility?
Medicine
• Specific treatment is available only for infertility due to hypogonadotropic hypogonadism
– Hyperprolactinemia: Discontinuation of causal medication, treatment with dopamine agonist, such as cabergoline or bromocriptine. Normal spermatogenesis takes three months. As a result, restoration of a normal sperm count usually does not occur for at least three and sometimes six months or more after the serum prolactin and testosterone concentrations have returned to normal.
– Other causes: Gonadotropin therapy—treatment is initiated with human chorionic gonadotropin (hCG), 1500–2000 IU 2–3 times per week subcutaneously or intramuscularly for at least six months. hCG has the biologic activity of luteinizing hormone. The hCG dose should be adjusted upward according to symptoms of hypogonadism, serum testosterone concentrations, and semen parameters. Some patients with acquired hypogonadotropic states (pretreatment testes ≥ 8 cc) can be stimulated with hCG alone to produce sufficient sperm. If after six to nine months the patient remains azoospermic or severely oligospermic (<10 million/mL), then human menopausal gonadotropin (hMG) or recombinant follicle-stimulating hormone (FSH) at dosage of 150 IU thrice a week should be added. The dosage of FSH may be doubled if conception has not occurred and sperm concentrations remain < 20 million/mL within 6 months of initiation of combination therapy with hCG. On average, conception occurs after 2–3 years of gonadotropin therapy and occurs when sperm concentrations are between 5 and 20 million/mL, men with postpubertal gonadotropin deficiency might respond to hCG monotherapy, but men with prepubertal onset of gonadotropin deficiency virtually always benefit from combination hCG plus FSH therapy. An FSH level greater than 8 IU/L should raise the suspicion of primary spermatogenic failure; gonadotropin therapy is unlikely to improve fertility. In general, gonadotropin therapy is not useful for men with idiopathic infertility.
Pulsatile gonadotropin-releasing hormone (GnRH) therapy—only men who have hypogonadotropic hypogonadism due to hypothalamic disease can be treated with GnRH. GnRH has to be delivered in pulses using a portable pump with an attached catheter and needle for many months or years; most patients find it inconvenient to use GnRH therapy for so long.
• Treatment of uncertain efficacy:
• Empirical therapy: Antiestrogens (Clomiphene citrate), aromatase inhibitors (letrozole, anastrozole), vitamin E, pentoxifylline, kallikrein, zinc, arginine, etc.
• Assisted reproductive techniques: In infertile couples, 40–45% of ART procedures (including ICSI) result in pregnancy.
– Intrauterine insemination: The intrauterine insemination (IUI) proce- dure consists of washing an ejaculated semen specimen to remove prostaglandins, concentrating the sperm in a small volume of culture media, and injecting the sperm suspension directly into the upper uterine cavity using a small catheter threaded through the cervix. The insemination is timed to take place just prior to ovulation, typically using home urine luteinizing hormone (LH) measurement.
– In vitro fertilization (IVF) is employed using the ejaculated sperm from a man with moderate oligospermia.
– Intracytoplasmic sperm injection (ICSI) has revolutionized the treatment and improved the prognosis for fertility of men with very severe oligospermia, asthenospermia (low sperm motility), teratospermia (a higher rate of abnormal sperm morphology), and even azoospermia. This technique involves the direct injection of a single spermatozoon into the cytoplasm of a human oocyte, usually obtained from follicles produced under controlled ovarian hyperstimulation.
Approximately 10–18% of infertile men, previously classified as having idiopathic oligozoospermia, have microdeletions of the Y chromosome. Complete deletions of the AZFa or AFZb regions lead to azoospermia and Sertoli cell only syndrome. A substantial number of men with known causes of infertility also have Y chromosome microdeletions, but such deletions are rare in men with sperm concentrations over 5 million/mL. Yq microdeletions are the most common identifiable genetic cause of spermatogenic failure in around 4% of oligozoospermic men. AZFc deletion accounts for approximately 60% of Y microdeletions. These Y chromosome deletions may be transmitted from father to son by ICSI. In addition, low-level sex chromosome mosaicism has been reported in infertile couples. Therefore, genetic counseling and chromosome and other molecular genetic tests are undertaken before ICSI is undertaken. Routine karyotyping is recommended for infertile men with spermatogenic failure and a sperm concentration less than 10 million/mL and all subfertile men with hypergonadotropic hypogonadism. Testing for Y chromosome microdeletions should also be considered for all men with idiopathic spermatogenic deficiency and pretreatment sperm concentrations < 5 million/mL; some experts use a threshold of < 10 million/mL. All men with congenital bilateral or unilateral absence of a vas deferens should be screened for gene mutations associated with cystic fibrosis.
– Retrieval of sperm from the testis—new surgical techniques have been introduced to retrieve spermatozoa from patients with nonobstructive azoospermia. A technique called microdissection of the testis to extract sperm (TESE) from the seminiferous tubules has been successful in obtaining sperm in over 50% of patients with nonobstructive azoospermia, including patients with Klinefelter syndrome.
• Causes of male factor infertility for which medical treatment is not available
– Klinefelter syndrome or variants
– Y chromosome microdeletions (azoospermia and hyalinized tubules)
– Sertoli cell only syndrome
– Germ cell arrest at primary spermatocyte or earlier stage
– Other: Idiopathic, cryptorchidism, postirradiation or postchemotherapy (azoospermia associated with hyalinized tubules or Sertoli cells only) Possible treatment options include donor sperm, possible germ cell trans-plantation or cultured testicular stem cells.
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