MEDICAL TREATMENT OF MALE INFERTILITY
In the past pharmacological treatment has been used empirically for infertile patients when surgical treatment had failed or was unavailable. Today attempts are made to specifically identify causes of male infertility such as immunological, infectious or hormonal factors in order to prescribe a specific treatment. However, in many cases no specific cause can be found and empirical treatments are still used.
In case of treatment failure, depending on the severity of male infertility, insemination, IVF or microfertilisation (ICSI) can be tried regardless of the etiology.
Methodological problems:
Efficiency of treatment is difficult to evaluate due to lack of randomised studies and to spontaneous improvement of sperm due to regression towards the mean in about 30 % of cases (Baker, Int J Androl,8:421,1985). Pregnancy is the the only valid end point but this depends also on female fertility (cf II), and can be disturbed by the "non paternity" factor in about 5% of cases (Mc Intyre, Lancet 338:870,1991). On the other hand, due to large intra -and inter-individual fluctuations of the sperm it is difficult to demonstrate the superiority of a treatment over placebo due to an insufficient number of patients (type 2 error).
1. Elimination of toxic factors and thermic stress:
- avoid sauna, hot baths, professional exposure to thermic stress or to toxic products (pesticides etc.)
- stop drugs and medications which can decrease fertility or virility, decrease cigarette and alcohol consumption.
2. Systemic disease:
- sperm analysis 3 months after a febrile illness
- try to improve nutritional status in case of malabsorption or malnutrition. Role of zinc could be important for gonadal function in renal insufficiency, sickle cell anaemia and possibly in cirrhosis (Mahajan, Ann Int Med 97:357,1982; Prasad, Am J Hematol 10:119,1981)
3. Treatment of endocrinopathies:
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Hypogonadotrophic hypogonadism
Infertile men with low levels of gonadotrophins can be successfully treated by HCG ( 3 x 2000 U/week i.m. for 2 months) followed by HCG + HMG ( 3x 75 to 3 x 150 U /week ) for 6 -12 months. Recombinant FSH is 3 times more expensive but not more efficient than HMG (F St 70:256,1998). Previous androgen therapy will not affect the responsiveness. Fertility is more difficult to achieve in case of previous cryptorchism (Finkel, NEJM 313:651,1985). Pulsatile GnRH therapy (4-8 ug subcutaneous every 2 hours) using a portable pump, together with i.m. HCG ( 3 x 2500 U/week) is not more efficient than HCG-HMG (Buchter, Eur J Endocr 139:298,1998)
- HMG + HCG is not better than placebo in cases of infertility with normal levels of gonadotrophins (Knuth, JCEM 65:1081,1987).
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Hyperprolactinaemia:
Treatment is useful in case of high levels of prolactin due to pituitary tumours (micro or macro-adenoma). Slight increase of prolactin due to stress or medication probably does not cause infertility. Usually levels of gonadotrophins and T are decreased. Fertility has been restored after long term treatment with bromocriptine, leading to a decrease of the size of the prolactinoma (Cunnah, Clin End 34:231,1991).
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Congenital adrenal hyperplasia:
Although many patients with that condition are fertile, some are not and they can be successfully treated by corticosteroids (0,5 or 0,75 mg of dexamethasone/day) (Bonaccorsi, F St 47:664,1987).
4. Immunologic and infectious diseases:
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antisperm antibodies (e.g. after vasectomy reversal):
In a non-randomised controlled study, Alexander (Int J Fert 28:63,1983) showed a decrease of circulating antisperm antibodies with prednisone (60 mg/d for 1-2 weeks) when compared to placebo. The pregnancy rate was 45 % in the treatment group against 12% in the control group, although there was no change in sperm count and motility. In case of antisperm antibodies in semen, prednisone has been used (usually 40-60 mg on days 1-10 of the female partner's cycle) with different results in 4 controlled studies. The only positive results have been obtained by Hendry with a pregnancy rate of 31% after 9 months of prednisone treatment versus 9% in the placebo group (Hendry, Lancet 335:85,1990). Due to the high rate of side effects with prednisone other ways of treatment are preferred. Washing is inadequate because of the high affinity of antisperm antibodies for sperm surface antigens. Ejaculation into buffer (Tyrode's solution) has been proposed to dilute antibodies secreted by the prostate. IU insemination and IVF have been tried successfully in some cases (Omblet, Hum Rep 12:1165,1997). But there is a decreased fertilisation rate in case of antispermhead antibodies (cf supra) and ICSI is usually more successful (Mazumdar, F St,70:799,1998).
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prostatitis
Male accessory gland infection (MAGI) occurs twice as often in the male partner of infertile couples than in fertile men. However, the role of infection and antibiotic treatment in male infertility is still controversial (Keck, Hum Rep Update 4:891,1998). MAGI can be diagnosed if 2 or more criteria are fulfilled: 1) history of recurrent urinary tract infection or prostatitis, 2) expressed prostatic fluid with more than 40 leukocytes or urinary sediment with more than 15 leukocytes after prostatic massage and/or positive bacterial culture, 3) more than 1 million /ml leukocytes in the ejaculate, 4) growth of 1000 or more pathogens (E coli, Streptococcus faecalis, Proteus sp) in seminal fluid or 10000 or more non pathogens (Staphylococcus epidermis, Corynebacterium sp, Acinetobacter) (Comhaire, Int J Androl, 9:91,1986)In asymptomatic men with MAGI, rectal ultrasonography may show asymmetry of the prostate gland, thick walled abscesses, oedema, concrements, thickened capsule or asymmetrical enlargement of seminal vesicles ( Christiansen, Brit J Urol,67:173,1991).MAGI could affect male fertility by decreasing sperm count or motility and accessory gland function (decreased levels of zinc, acid phosphatase, fructose). Leukocytes are the main source of reactive oxygen species (free radicals) which can decrease sperm function (acrosome reaction and zona-binding). MAGI is associated with an increased prevalence of sperm antibodies (Witkin, 1983). Chronic infection could lead to ductal stenosis and subclinical orchitis (Nilsson, F St 19;748,1968). The role of different micro-organisms such as mycoplasma or chlamydia in prostatitis and infertility and the role of leukocytes in seminal fluid are also controversial (Keck, Hum Rep Update 4:891,1998, Wolf, F St 63:1143,1995). The number of leukocytes can decrease spontaneously. However, they tend to recur and only frequent ejaculations together with antibiotic treatment have a long-lasting effect on leukocytospermia (Branigan F St 62:580,1994,Yanushpolsky F St 63:142,1995, F St 66:822,1996).Our attitude is to treat men with prostatitis if it is associated with positive urethral chlamydia , mycoplasma or bacterial culture in semen (cf supra), with positive Mar test or associated genital tract infection in the female partner. Both partners are treated for at least 3 weeks and are advised to use condoms. If no specific germ is isolated we use ciprofloxacin (2 x 500mg) together with metronidazole (2 x 500 mg) and AINS (diclofenac 100 mg) in the male partner in case of severe oligospermia or azoospermia of possible obstructive origin. In case of mycoplasma or chlamydia we use either doxycycline (200 mg/d for 2 weeks) or roxythromycine (2 x 150 mg/d for 2 weeks).
5. Treatment of sexual dysfunction (cf Prof Ruedi)
6. Non-specific drug treatments: (cd O'Donovan 1993)
In case of infertility with oligo-, astheno-, teratospermia (OAT) of unknown origin or when other specific treatments have failed, empirical treatments can be tried to improve sperm count or mobility if FSH levels are normal. Antiestrogens (clomid and tamoxifen) act on estrogen receptors in the hypothalamus preventing feed-back inhibition by estrogens. This results in increased FSH and LH secretion stimulating testosterone (T) and possibly spermatogenesis. Compared to placebo, tamoxifen did not in 4 studies although it increased FSH levels. However, a meta-analysis of 8 studies shows a beneficial effect of antiestrogens (O'Donovan, Hum Rep 8:1209,1993).
Androgens: mesterolone is a synthetic androgen which is not aromatised in estrogens and has no inhibitory effect on gonadotrophins. In a large study of WHO (Int J Andr 12:254,1989), the pregnancy rate was higher with mesterolone than with placebo. However, the sperm parameters were not improved by mesterolone (150 mg) and the results have not been confirmed by a controlled study (Gerris, F St 55:603,1991)
Other products such as arginine, HCG, HMG, pentoxiphylline, growth hormone, testolactone, GnRH, kallikrein, prostaglandin inhibitors and antioxidants have not shown any beneficial effect in controlled studies in normogonadotrophic patients (Rolf, Hum Rep14:1028,1999; Knuth, JCEM 65:1081,1987; MartinDuPan, Hum Rep12:396,1997 and 13:2984,1998)
7. Preventive treatments: (Hum Rep 13:1025,1998)
- cryopreservation: before chemotherapy for cancer or radiotherapy (seminoma). Before vasectomy (controversial). After HCG-HMG treatment for HH. Problem: ability of sperm to resist to decongelation. NB: GnRH agonists are efficient in mice but not in men to protect the gonads from chemotherapy.
- vaccination: Mumps, Tuberculosis
-operation:
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cryptorchism: benefit proved in bilateral but not in unilateral cryptorchism. But the operation is necessary before 10 years of age because of increased risk of cancer (easier to detect in the scrotum) ( Chilvers, J Ped Surg 21:691,1986, UK Testicular Cancer Group, BMJ 308:1393,1994). Surgery has even been recommended in the first year of life (Canavese, Pediatr Surg Int 14:2,1998)
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varicocele: present in 15 % of adolescents and sometimes associated with a decreased testical volume. After spermatic vein ligation an increase of testical volume and sperm output has been observed (Laven, F St, 58:756,1992). Surgical correction is recommended if there is marked varicocele, if the left testis is smaller than the right or if there is scrotal discomfort (Okuyama, J Urol;139:562,1988).
- condoms use : with occasional partners to avoid sexually transmitted diseases
- prenatal diagnosis: amniocentesis or chronic-villus sampling allow to diagnose fetal chromosomal abnormalities (eg.trisomy, XXY) indicating in certain cases (ethical problems) to terminate the pregnancy (D'Alton, NEJM 328:114,1993)
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