Medical treatment of male infertility
R.C. Martin-Du Pan
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:
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).
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).
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:
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).
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).
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
- 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)
The percentage of ovulatory dysfunction is higher in female partners of male patients with slight oligospermia than in wives of patients with severe oligospermia (78 % vs 33 %). It means that in case of slight oligospermia the cause for infertility infertility might be with the female partner (Silber, F St 40:503,1983).1. Insemination:
In case of male infertility, intrauterine insemination (IUI) of sperms selected and activated by swim-up or percoll gradient procedure gives better results than intracervical insemination. Percoll gradient and swim up preparations of semen seem better than wash, swim-down or heparin techniques (F St 69:122,1998). The main indication of IUI is hostile cervical mucus with 60 % pregnancy rate (Allen, F St 44:569,1985). Results are poor in women 40 years of age or older (Hum Rep 11:1109,1996). Results are bad in case of unexplained or immunologic infertility and in case of severe OAT and according to some authors IUI is not better than intercourse in case of male infertility ! ( Ho 1989,Velde, 1989). Others have found that IUI is slightly better than intercourse with 5,6% vs 1,3% pregnancy/cycle (Kirby, F St 56:102, 1991). Pregnancy rate is 8%/cycle when the sperm concentration and the total motile sperm count are 5 million. The minimum sperm values that resulted in pregnancy were a concentration of 2 million/ml and a total motile sperm count of 1,6 million (Dickey, F St 71:684,1999). Results can be improved by IUI with controlled ovarian hyperstimulation . In case of male infertility the monthly probability of pregnancy was increased 2-3fold with combined IUI and superovulation, compared to IUI alone (Hughes, 12:1865,1997; Guzik, NEJM 340:177,1999). In case of unexplained infertility, IUI with ovulation induction is more cost effective than IVF (Zayed, Hum Rep 12:2408,1997).
It has been found, that it results in better outcome if the sperms are collected during intercourse in a condom compared to masturbation (Sofitikis, J Androl 14:366, 1993). In case of oligoasthenospermia, sperm can be improved by repeating the collection 2 or 24 h later (contrary to normospermia) (Tur-Kaspa, F St 62:371,1994; Barash, F St 64:1008,1995; Ron-El, Hum Rep 13:630,1998).2. IVF
Whereas a minimum of 2 to 5 million mobile spermatozoa are required for IUI (F St 71:684,1999), IVF requires 0,5 to 1 million mobile sperms.
Fertilisation rate is decreased in OAT compared to euspermia (50% vs 80%). But if fertilisation occurs then the pregnancy rate is the same regardless of the initial sperm quality (Acosta 1988). Failure to fertilise can be due to immunologic factors (antibodies against acrosine), to lack of sperm binding to zona pellucida, to extreme oligo-, astheno- or teratospermia or to immature or defective oocytes. Fertilisation can be improved by percoll sperm preparation and sperm pre-treatment with pentoxiphylline and 2 deoxyadenosine.3. GIFT:
GIFT has the disadvantage over IVF that a laparoscopic surgery under general anaesthesia is needed. Whether fertilisation took place or not remains unknown therefore a crucial diagnostic information is lost. However, if one of the tubes is patent this technique can be used after a previous IVF attempt with ovocyte fertilisation (Mastroyannis 1993).4. Microfertilisation (ICSI)
-Intracytoplasmic sperm injection (ICSI) consists in the direct injection of a single spermatozoon into the ooplasm of a metaphase II oocyte. It allows a high rate of fertilisation (51-57%), which compensates for a higher rate of damage to the oocyte (van Steirteghem, Hum Rep 8:1055,1993). Pregnancy rate by cycle varies between 28-35 % for ICSI. Pregnancies have been achieved in case of extreme oligospermia or asthenospermia, in case of immunological infertility as well as with spermatozoa obtained from testicular biopsies in case of obstructive or non-obstructive azoospermia (Nagy, F St 63:808,1995; Silber, Hum Rep 10:2031,1995 ). When ICSI is performed with ejaculated, epididymal or testicular sperm, similar fertilisation and pregnancy rates have been achieved (Cha, F St 67:985,1997; Aytoz F St 70:500,1998). Pregnancies have also been obtained from elongated spermatids but not from round spermatids (Sousa Hum Rep 14:1279,1999).
In case of obstructive azoospermia (normal testes and FSH levels) sperm can be retrieved using percutaneous epididymal aspiration or fine needle aspiration in case of failure of vaso-vasostomy or epididymo-vasostomy (Safran, Hum Rep suppl 13, 4:47,1998). In non-obstructive azoospermia (small testes and increased FSH serum levels) and in case of spermatogenic arrest, focal spermatogenesis can be observed in 40-50% of cases using repeated testicular biopsies or testicular sperm extraction (Silber, Hum Rep 10:2031,1995; Su, J Urol 161:112,1999). Vascular injuries can occur following testicular biopsies (Hum Rep 13:3390,1998).
The indications for ICSI are a sperm concentration less than 500.000 motile sperm, less than 4% normal sperm forms (strict criteria), failure of fertilisation in a previous IVF cycle or azoospermia (cf supra).
Of 877 children born after ICSI procedures 2,6% had major congenital malformations compared with 2 to 2,8% in the general population .The same rate has been detected among 578 neonates in USA (Palermo, JAMA 276:1893,1996; ESHRE Hum Rep 13:1737,1998). However, the problem of sperm selection is unresolved. The incidence of structural chromosome aberrations is 4 times higher in spermatozoa with amorphous head compared to normal heads (Lee, Hum Rep 11:1942,1996) In case of abnormal morphology there is a good fertilisation rate but a low implantation rate (Tasdemir, Hum Rep 12:1214,1997). When performing ICSI, genetic risks must not be overlooked (Mak, J Urol 156:1245,1996). 70 to 80% of the patients with agenesis of the vas deferens carry gene alleles for cystic fibrosis (Chillon, NEJM 332:1475,1995). In case of azoospermia due to microdeletions of the Y chromosome (13% of the cases), the genetic defect can be transmitted to the male progeny (Pryor, NEJM 336:534,1997; Jiang F St 71:1029,1999). Infertile male have an increased risk of transmitting numerical anomalies (predominantly sex chromosomes) to their offspring (Pang, Hum Rep 14:1266,1999). There is a higher rate of karyotype abnormalities in azoospermic (13%) and oligospermic men (4,6 %) than in the general population (O,4%)(Johnson, F St 70:397,1998). Therefore, genetic testing and counselling are required when performing ICSI because of male infertility.
Due to the success with ICSI the woman`s age has become the principal cause of the sterility of the couple (Sherins, F St 64:64,369,1995). Older women are also at higher risk to have miscarriages and children with abnormal karyotypes.
Due to the advances in the treatment of male infertility (due to microfertilisation techniques such as ICSI), some gynaecologists tend to treat the semen rather than the man and to abandon the search for an aetiology of male infertility (Cummins, Hum Rep 7:1214,1994). The reasons to examine the male partner and to establish the cause of his infertility are the following:
1.Effective andrological treatment:
- in case of endocrinological or infectious cause of male infertility or in case of sexual dysfunction, a specific treatment can be prescribed. The female partner should also be treated in case of venereal disease or prostatitis.
- in case of obstructive azoospermia, epidimo-vasostomy or vaso-vasostomy, if successful, result in an enduring response (Belker, J Urol 145:505,1991; Kolettis, J Urol 158:467,1997). Subsequent pregnancies do not demand repeated interventions.
- in case of OAT due to drug abuse, thermic stress or exposition to toxic products, the avoidance of these products can lead to improvement of sperm.
Occasionally the medical examination will enable to diagnose a testicular or pituitary tumour.
2. Ethical reasons:
- women who may have no cause of infertility are exposed to aggressive treatments such as superovulation, laparoscopy, anaesthesia, oocyte retrieval, resulting sometimes in multiple pregnancies, which are associated with a wide range of complications that may endanger the patient (Schenker, F St 61:415,1994) and is associated with an excessive morbidity among the survivors of multiple births (Callahan, NEJM 331:244,1994).
-it is important for the male partner to be involved in the treatment not only as a gamete producer but as a future father.
3. Economical reasons:
- in many countries micromanipulations and IVF techniques are not available. Nevertheless, in the absence of tubal blockage and severe male factor, the use of IUI with ovarian stimulation is more cost-effective than IVF (Van Voorhis, F St 70:995,1998). IVF does not represent an appropriate first-line treatment option for couples with infertility (Karande, F St 71:468,1999).
- clinics that have invested in expensive equipment are likely to use this equipment for economical reasons and also to be competitive with other clinics.
- the cost of a successful delivery with IVF has been estimated at 66.000 dollars for the first cycle. This cost rises to 160.000 dollars in case of male infertility or in older women (Neumann, NEJM 331:239,1994).
- in ICSI the natural process of selection of motile sperm is replaced by the choice of a single spermatozoa by the biologist, which raises concern about the genetic quality of the chosen spermatozoa. Male infertility can be associated with other genetic abnormalities.
- 70 to 80 % of patients with congenital absence of the vasa deferentia have mutations in the gene complex controlling cystic fibrosis. Therefore, genetic testing and counselling is mandatory for those patients and prenatal diagnosis should be discussed in couples at high risk (Meschedde, Lancet 343:1366,1994; Johnson, F St 70:397,1998).
- the links between advanced paternal age and several autosomal dominant diseases such as retinoblastoma, polykystic renal disease or Marfan syndrome is well known (Bordson, F St 56:397,1991).
Progress in medicine can only be achieved if efforts are made for a better understanding of the aetiology of male infertility. The possible deleterious effects of new drugs, industrial pollution (lead), aromatic solvents (Tielemans, F St 71:692,1999) or estrogen-like substances in food on sperms (Sharpe, Lancet 341:1392,1993) must be studied. Male oligospermia is comparable to anaemia. We do not treat all the cases of anaemia by transfusions but we try to give a specific treatment (vitamins, iron, erythropoietin etc.) In a similar way, we should not treat all cases of male infertility by assisted procreation.
Edited by Aldo Campana,