Medical Conditions Associated With Male Infertility
I. Diabetes mellitus
Diabetes mellitus is the most common endocrine disease. The incidence of diabetes among men attending infertility clinics was estimated to be 0.3%, and about 1% of subfertile male patients may have diabetes. Diabetes, therefore, has a significant effect on male reproductive function. There is little evidence to suggest that endocrinopathy or spermatogenic disorders are the primary cause of infertility in diabetic men. The most semen abnormalities encountered in infertile diabetic patients are due to overt ejaculatory dysfunction. Diabetes is a well-known cause of autonomic neuropathy. Damage of sympathetic innervation of the bladder neck leads to retrograde ejaculation when the sperm enter the bladder rather than exiting the urethra. This condition is very amenable to medical treatment.
Diabetic patients may also develop failure of emission, where no sperm reach the posterior urethra due to aperistalsis of the vas deferens. If diagnosed, this condition may require electroejaculation to harvest sperm for assisted reproduction.
Calcification of the vas deferens occurs 6 times as frequent in diabetics as in normal men.
Gonadal dysfunction in patients with chronic renal failure has been recognized for a long time. End-stage renal failure results in significant deterioration of both spermatogenesis and steroidogenesis. Semen analysis usually shows low sperm count, low motility. The damage to the spermatogenesis is usually manifested histologically in the form of late maturation arrest with relative preservation of the earlier stages (spermatogonia and spermatocyte)
Yamamoto et al.(1997) in animal study found that chronic renal failure has resulted in overall low sperm fertilizing capacity.
The hormonal profile is characterized by low level of total and free testosterone, modestly elevated LH. FSH is usually normal and elevated only in patients with azoospermia. Serum Prolactin is frequently high. Pituitary function appears to be normal and central defect involving the regulation of LHRH is probably located in the hypothalamus.
The dysfunction of steroidogenesis and spermatogenesis induced by renal failure is not corrected by maintenance hemodialysis and the abnormal testicular histology usually persists. Paternity among these patients is usually rare.
Improvement of the reproductive function after renal transplantation is a realistic expectation. Transplantation may significantly improve spermatogenesis although severe germ cell damage caused by renal failure may be irreversible. Numerous reports have documented successful paternity in men with renal failure after kidney transplantation. Immunosuppressive treatment potentially can cause chromosomal aberration but cumulative data indicate a low incidence (3.4%) of fetal anomalies.
III. Cancer and male infertility
Several forms of cancer and their treatment may have an adverse effect on male fertility. In many cases, infertility may be the first symptom of these types of cancers.
Cancer patients demonstrate hypothalamic and pituitary dysfunction. Severe liver and renal function impairment result in changing of a hormonal metabolism, excretion and binding globulin synthesis, which, in turn, affect testicular function.
Testicular cancer is a common malignancy of men in reproductive age. Semen abnormalities (usually severe oligospermia in 17-77% of the patients) are present even before initiation of treatment. The potential causes for this alteration has been described as:
- Local pathological changes in the contralateral testis after orchiectomy
- Antisperm antibodies ( 21-77% of patients)
- Endocrine factors( elevation of beta GCG and alpha fetoprotein, Estradiol, LH and low serum testosterone).
- Increase intrascrotal temperature and functional/structural changes in the epididymis secondary to a change in
(Sertoli cell only syndrome, fibrosis, carcinoma in situ)
Lymphomas (Hodgkin's disease and non-Hodgkin's lymphoma) are a group of malignant diseases of lymphoreticular origin. The survival period of patients has increased significantly and cure has become a realistic goal. The pretreatment sperm production is usually impaired. Testicular biopsy frequently reveals tubular hyalinization and focal maturation arrest. The reasons of testicular dysfunction are not clear. Possible causes may include fever, general stressful effect of malignant disease, and decrease nutritional status. Patients were found to have azoospermia, oligospermia with low motility and poor normal morphology. Concentrations of testosterone, Prolactin, FSH and LH are within normal limits. Recovery of spermatogenesis was documented in about 20-40% of patients dependent, probably, on dose, duration and type of treatment. Sperm quality (motility and morphology) is higher in patients with non-Hodgkin lymphoma.
Endocrine tumors (thyroid cancer, brain tumors, acromegaly, Cushing's disease, and virilizing adrenal tumors) rarely may cause infertility
IV. Cancer treatment and male infertility
Infertility is the major consequence of cancer treatment (chemotherapy, radiation, and surgery). The type of treatment, dose received (drugs or radiation), pretreatment semen analysis and age of the patients are important predictive factors for posttreatment fertility potential.
Temporary oligospermia occurs after ionizing radiation of testis at small dose of 10-30cGy and irreversible azoospermia at exposure of 200cGy. Radiation may also cause Leydig cell dysfunction and testicular atrophy.
Most of the patients undergoing chemotherapy for testicular malignancies become azoospermic 7-8 weeks after starting treatment. The recovery of spermatogenic failure after chemotherapy occurs in approximately 50-64% of the patient with testicular cancer after 1-3 years. Chemotherapy with cisplatin at dose <400mg/m2 were shown to be unlikely cause of permanent infertility. The reported data suggests that 30% of patients seek paternity after treatment and half of them apparently achieve it.
Since it is difficult to predict temporary or permanent sterility after treatment, sperm cryopreservation has been recommended before treatment for cancer patients who desires to have children. Although sperm quality is often poor even before treatment and further decreases with the cryopreservation, recent application of ICSI enables cancer patients to achieve pregnancy with poor quality cryopreserved spermatozoa.
In rare cases of cancer in solitary testis, successful testicular sperm extraction and cryopreservation were reported at the time of radical orchiectomy.
Presently there is no substantial evidence of an increased risk of malignancies or malformations in children of men with testicular cancer conceived either naturally or with assisted reproduction. Limited data suggest that BEP (bleomycin, etoposide, and cisplatin) chemotherapy may not increase the risk of numerical chromosomal abnormalities. Robbins et al (1995) did report on elevation of aneuploidy during treatment (BOVP, Novanthrone, oncovin, Vinblastine, Prednisone) of patients with Hodgkin's disease which did not return to normal reference level.
Preservation of fertilty is important during the cancer treatment.
- Sperm cryopreservation.
- Gonadal shielding
- Suppression of hypothalamo-pituitary-gonadal axis to slow spermatogenesis. It was hypothesized that suspended spermatogenesis may be less vulnerable to the devastating effect of chemotherapy or radiation ( Glode, 1981) and spermatogonial population of the testis may be protected. While still experimental, this approach may be improve and protect fertility in patients receiving chemotherapy of radiation therapy
- Germ cell transplantation.Not clinically available. Animal experiments revealed the possibility of transplantation of the spermatogonial stem cells with subsequemt proliferation , active spermatoigenesis and sperm production. It is conceivable that frozen testicular tissue obtained before chemo/radiation therapy may be transplanted into the testis after treatment to reinitiate the spermatogenesis.
V. Treatment of male infertility in cancer patients
- Sperm retrieval for assisted reproduction
- Rectal probe electroejaculation ( for patients with testicular cancer after retroperitoneal lymph nodes dissection )
- Dinulovic D., Radonic G. Diabetes mellitus and male infertility. Arch Androl 1990;25:277-93
- Gerig NE, Meacham RB, Ohl DA. Use of electroejaculation in the treatment of ejaculatory failure secondary to diabetes mellitus. Urology, 1997;49(2):239-42
- Dunsmuir WD, Holmes SA. The aetiology and management of erectile, ejaculatory and fertility problems in men with diabetes mellitus. Diabet Med 1996;13(8):700-708
- Yamamoto Y., Sofikitis N., Miyagawa I. Effects of chronic renal failure on sperm fertilizing capacity. Urol Int, 1997;58(2):105-107
- Meistrich ML. Hormonal Stimulation of the recobery of spermatogenesis following chemo-or radiotherapy: Review article. APMIS 1998; 106(1): 37-46
- Martin RH., Ernst S., Rademaker A., Barclay L., Ko E., Summers N. Chromosomal abnormalities in sperm from testicular cancer patients before and after chemotherapy. Hum Genet 1997;99:214-218
- Baumgarten SR., Lindsay GK., Wise GJ. Fertility problems in the renal transplant patient. J Urol 1977;118:991-993
- Lim VS. Reproductive function in patients with renal insufficiency. Am J Kidney Dis 1987;IX:363-367
- Handelsman DJ. Hypothalamic-Pituitary Gonadal dysfunction in renal failure, dialysis and renal transplantation.Endocr Rev 1985;6:151-169
- Prem AR, Punekar SV., Kalpana M., Kelkar AR., Acharya VN. Male reproductive function in uraemia: efficacy of hemodialysis and renal transplantation. Br J Urol 1996;78:635-638
- Botchan A., Hauser R., Gamzu R., Yogev L., Lessing JB., Paz G., Yavetz H. Sperm quality in Hodkin's disease versus non-Hodkin's lymphoma.Hum Reprod 1997;12:73-76
- Meirow D., Schenker JG. Cancer and Male Infertility. Hum Reprod 1995;10:2017-2022
- Ali ST., Shaikh RN et al. Semen analysis in insulin-dependent/non-insulin dependent diabetic men with/without neuropathy.Archives of andrology 1993;30:.47-54
- Wilson JL, Markus JH. Calcification of the vas deferens. Its relation to diabetes mellitus and arteriosclerosis. New engl J med 1951;245:321-325