Treatment of hypogonadism and infertility
Introduction
Special therapeutic modalities for individual disorders, where these are available, have been mentioned in the preceding chapters. However, the therapeutic principles of hormone substitution described below apply to a number of disorders. Areas of conventional treatment of male infertility that were not described in previous chapters will also be covered here.
When dealing with infertility in men, it is also important to consider the woman. Thorough diagnosis and treatment of conditions affecting female reproductive functions are mandatory, since their optimization constitutes a substantial part of the treatment of male infertility.
Testosterone substitution
All forms of hypogonadism require testosterone substitution. This includes secondary hypogonadism, which may be treated temporarily with gonadotropin-releasing hormone (GnRH) or gonadotropins if fertility is requested. If properly administered, testosterone substitution is a very rewarding therapy for the patient as well as for the physician (1, 2).
Oral, injectable, transdermal, and implantable testosterone preparations are available for clinical use (Fig. 9.4.13.1, Table 9.4.13.1). Other formulations are under development. When evaluating the various preparations, they should be judged according to the general principle that physiologic serum concentrations should be mimicked as closely as possible (3). Accordingly, testosterone treatment of male hypogonadism should avoid both unphysiologically high testosterone serum concentrations (to prevent possible side effects), and abnormally low concentrations (to prevent androgen deficiency). However, most preparations do not fulfil this requirement. Furthermore, in order to cover all biological effects of testosterone, the preparation should be aromatizable to oestrogens and reducible to 5α-dihydrotestosterone (Chapter 9.2.3). Since this requirement is only fulfilled by native testosterone, testosterone as it is produced by the testes should be the active ingredient of preparations used clinically. This excludes synthetic and modified androgen molecules from substitution therapy, at least at the current state of knowledge. Whether specific androgen receptor modulators (SARMs), which are currently under development, will ever be useful in the treatment of hypogonadism remains to be seen (4). Finally, the route of administration of testosterone is of importance as different kinetic and metabolic profiles may result; the patient may also have a personal preference for a particular route.
Table 9.4.13.1 Modalities of current testosterone substitution
Preparation | Application | Dosage |
|---|---|---|
Testosterone undecanoate | Orally, with meals | 2 to 4 capsules of 40 mg per day |
Testosterone enanthate | Intramuscular injection | 200–250 mg every 2–3 weeks |
Testosterone cypionate | Intramuscular injection | 200 mg every 2 weeks |
Testosterone undecanoate | Intramuscular injection | 1000 mg injections, 0, 6, 12 and then every 10–14 weeks |
Transdermal testosterone patch | Skin of abdomen and shoulders | 1 or 2 patches per day |
Testosterone implants | Implantation under abdominal skin | 3–6 implants @ 200 mg per 6 months |
Testosterone gel | Transdermal application | 50, 75, or 100 mg in 5 g gel daily |
Buccal testosterone | Absorption through buccal mucosa | 1 tablet every 12 hours |
Testosterone preparations (Fig. 9.4.13.1, Table 9.4.13.1.)
Intramuscular Testosterone Application
Free testosterone is degraded with a half-life of only 10 min; therefore, esterification of the molecule leads to more suitable forms of injectable preparations. While some substances have been used for many years, others with more favourable absorption profiles are under clinical evaluation. The traditional testosterone esters initially produce supraphysiological testosterone serum levels, slowly declining to possibly pathologically low levels before the next injection. These changes are often noticed by patients in terms of marked swings in vigour, sexual activity and emotional stability.
Testosterone enanthate is one of the most common preparations for testosterone substitution. This substance has a terminal half-life of 4.5 days; maximum concentrations are reached after 10 h following a single injection of 250 mg (1). Multiple-dose pharmacokinetics reveal an optimal injection interval of 2–3 weeks at a dose of 200–250 mg. Individual injection intervals may be extended, once testosterone serum concentrations are in the normal range.
Testosterone cypionate and testosterone cyclohexanecarboxylate resemble the pharmacokinetic properties of testosterone enanthate (1). They do not provide an advantage over the enanthate ester. The recommended dose for testosterone cypionate is 200 mg every two weeks according to trials and clinical experience.
Testosterone propionate has a terminal half-life of only 19 h; after a single injection of 50 mg, the maximum concentration is reached after 14 h. It is obvious that this substance requires frequent injections. Multiple-dose pharmacokinetics reveal optimal intervals of 2–3 days, but fluctuations below normal range values persist (1). Judging by these data the substance is not suitable for long-term treatment of hypogonadism.
An intramuscular preparation widely used in the past contains a mixture of testosterone esters assumed to act synergistically due to different kinetic profiles. However, they may produce even higher initial peaks and perhaps shorter duration of action. This ester mixture does not appear to provide an advantage over single-ester preparations.
In recent years, new testosterone preparations have been introduced. While already in use as oral preparation, an injectable form of testosterone undecanoate in tea seed oil with prolonged duration of action was described in China. If the testosterone was dissolved in castor oil, an even longer half-life of about 34 days was observed (5). Peak values remain within the normal range. In order to achieve a steady state at the beginning of substitution, the second 1000 mg injection is given 6 weeks after the first; further injections follow 10–14 weeks later. Individual intervals are determined according to serum testosterone levels, which are measured immediately before the next injection. These determinations are then repeated in yearly intervals. Values that are too high lead to extension of injection intervals, those that are too low to a shortening in injection intervals. Slow intergluteal injections are recommended. No adverse side effects have been observed, even after many years of use (5).
Subdermal testosterone implants
Testosterone pellet implants were among the first modalities applied for testosterone replacement therapy, reaching back to the late 1930s. Modern pellets are produced by high-temperature moulding and are available in two sizes, containing 100 or 200 mg of crystalline steroid, with a length of 6 or 12 mm and a common diameter of 4.5 mm (1). Implanted with a trocar using a tunnelling technique, they remain under the skin of the lower abdominal wall and are totally biodegradable. If 3–6 implants are inserted, slowly declining serum testosterone levels in the normal range are achieved for 4–6 months (1). There is, however, an initial burst release, so that supraphysiological levels of about 50 nmol/l result. The overall terminal half-life was calculated at 71 days. A review of 973 implantations in 221 men showed that 11% had adverse local effects such as extrusion, bleeding, inflammations, or infections (6). Since surgical removal is inconvenient, pellets should be applied to patients in whom the benefits of testosterone substitution have already been demonstrated by shorter-acting regimens. In cases of foreseeable adverse effects caused by testosterone, implants should not be used. This may apply specifically to older hypogonadal men at risk of prostate disease (7). Despite this, subdermal implants offer a long-acting, cost-effective modality for testosterone substitution, often preferred by patients to other methods. However, pellets are only commercially available in a few countries.
Oral testosterone
If pure testosterone is applied orally, it is readily absorbed by the intestine, but very effectively eliminated by the first-pass effect of the liver. In order to overcome this metabolizing capacity of the liver, more than 1 g of testosterone would have to be administered in one dose. However, if testosterone undecanoate is administered orally, the molecule is absorbed via the lymph, due to the long aliphatic side chain, and reaches the circulation and target organs before the liver. Capsules of 40 mg are commercially available; three to four such capsules have to be taken over the day for full substitution of hypogonadism. Absorption is improved if the capsules are taken with meals (8). Pharmacokinetic analysis shows high intra- and inter-individual variability in serum concentrations (1), and profiles are difficult to predict with precision. This preparation is best suited as a supplement to reduced but still present endogenous testosterone production, since it does not fully suppress pituitary gonadotropin secretion and Leydig cell function. Long-term use is safe, as demonstrated in a 10-year observational study (9).
The incorporation of testosterone into polyethylene matrices with limited water-solubility represents an attempt to develop new formulations for buccal application. The mucoadhesive tablets adhere to the gums above the incisors for many hours, and slowly release testosterone into the circulation. Twice daily application results in even serums levels (10, 11).
Transdermal testosterone
Transdermal testosterone preparations mimic physiological diurnal variations, and their kinetic profile is closest to the ideal substitution. They may be used as first choice and are especially well suited for patients who suffer from fluctuating symptoms caused by other preparations. In addition, upon removal, testosterone is immediately eliminated and they are therefore specifically suited for substitution in advanced age (7).
Scrotal patches consisting of a thin film containing 15 mg native testosterone were the first on the market. Applied daily in the evening, they led to sufficient serum testosterone levels for 22–24 h. Under regular use, adequate long-term substitution effects were achieved without serious side effects, as was observed in patients treated for up to 10 years with these patches (12). Later developments superseded this initially useful preparation.
Several non-scrotal transdermal systems also result in physiological serum levels; all of them have to be applied in the evening (1). As resorption of testosterone depends on the use of enhancers, in some cases considerable skin reactions limit the use of these systems.
The patches mentioned above are hardly used today, but recently a new testosterone patch was developed that does not cause as much skin irritation. This patch also need only be changed every other day; however, two systems with either 1.8 or 2.4 mg resorbed per day must be used (13).
A further transdermal application is the use of testosterone gels, which are applied to large skin areas in order to allow sufficient amounts of the hormone to be resorbed. These gels are applied in the morning to the upper arm, shoulders and abdomen and are left to dry for five minutes. During this time contact with women or children must be avoided, because of the danger of contamination. Thereafter the danger is negligible especially if the skin is washed after evaporation of the alcohol. Physiological levels result when the gel is applied in the morning. Long-term use over several years showed good results (14–16).
Obsolete and discontinued testosterone preparations
In order to avoid the hepatic first-pass effect, testosterone suppositories were developed for rectal application. This form of application leads to an immediate and steep increase of testosterone serum levels, with elevated levels lasting for about 4 h. To obtain effective substitution therapy, administration of three suppositories per day was required. This modality did not gain much popularity.
To render the testosterone molecule resistant to the first-pass effect in the liver, a methyl group was introduced into position 17α. The resulting substances, 17α-methyltestosterone and fluoxymesterone, were shown to be toxic to the liver—inducing cholestasis, peliosis, and hepatomas. The use of these substances has therefore been terminated in Europe, but they are still available in some countries.
Mesterolone, resembling 5α-dihydrotestosterone, is protected from fast metabolism in the liver and can be administered orally. It cannot be metabolized to oestrogens, thus lacking some of native testosterone’s activities. Its ability to suppress gonadotropin production is also limited. Considered only a weak androgen, it is not suitable for therapy in hypogonadism.
Monitoring testosterone therapy
Monitoring a patient during testosterone therapy encompasses behavioural aspects, somatic effects, and laboratory parameters. Overall, testosterone replacement therapy should lead to a high quality of life. Individual parameters for assessment of this quality of life under routine clinical conditions are discussed below (Box 9.4.13.1).
Mood and sexual/nonsexual behaviour
Physical and mental activity, alertness and vigour characterize sufficient replacement therapy. Low levels can be accompanied by lethargy, inactivity, and depressed mood. Restitution of libido, increased sexual fantasies, and frequency of erections are markers of adequate therapy (1, 17, 18). Patients under testosterone substitution can have a normal and satisfying sex life. If the sex drive becomes too demanding, the man’s partner may complain and the dose should be reduced.
Somatic parameters
Muscle mass and strength increase in hypogonadal men under testosterone treatment, and patients develop a more masculine phenotype. The anabolic effect of testosterone causes bodyweight to increase by about 5%, but this is mainly due to increased muscle and bone mass. The distribution of fat over the hips, lower abdomen, and buttocks assumes a more masculine type under testosterone treatment (19, 20). In patients in whom epiphyses were not closed, testosterone substitution may cause a brief growth spurt before epiphyses fuse. Hair growth will appear in the upper pubic triangle, temporal recession of hair will form and, depending on the genetic disposition of the patient, balding may occur (21).
Testosterone substitution induces sebum production, and patients may complain about oily skin hair to which they were not accustomed before substitution. Acne may also appear. Gynaecomastia may occur, especially during high-dose testosterone enanthate treatment, since peak levels also cause high oestradiol levels. Lowering of the testosterone enanthate dose or changing the testosterone preparation will cause gynaecomastia to disappear.
Patients who have not gone through puberty will experience mutation of the voice. This occurs after a few weeks or months of testosterone therapy, and is especially rewarding for the patient (22).
Laboratory parameters
Testosterone serum levels are useful in assessing the efficacy of substitution therapy. The individual pharmacokinetic profiles of different preparations must be considered. The best point of time to obtain a blood sample for assessing the adequacy of substitution is the time of administration of the next dose (whether by injection, implant, or oral preparation). Therapy can be regulated more easily by adjusting the interval of doses than the dose itself. Once the optimal regimen for an individual patient has been found, serum testosterone determinations are necessary at annual check-ups, or if substitution becomes less effective.
Serum oestradiol should be measured if high serum levels of testosterone occur, especially under treatment with testosterone enanthate, and intervals should be extended if oestradiol is too high. Dihydrotestosterone (DHT) measurements are usually neither informative nor necessary.
Gonadotropins are of limited value as indicators for testosterone action, since they are decreased in hypogonadotropic hypogonadism and in patients with primary hypogonadism, especially Klinefelter’s syndrome patients, they often do not show significant reduction, although substitution may be clinically sufficient. Oral and transdermal testosterone substitution have little effect on gonadotropins.
Parameters of erythropoiesis will increase since testosterone is a stimulator of this system. Therefore, haemoglobin, erythrocyte, and haematocrit tests are part of routine surveillance of the hypogonadal patients under testosterone treatment. If too much testosterone is administered, or supraphysiological levels are induced, polycythemia may be encountered (23). The older the patient or the higher his BMI, the more susceptible he becomes to polycythemia (5, 24, 25). In such cases, the dose and the interval of application must be reduced in order to prevent embolic or thrombotic events.
Lipid profiles may change under testosterone substitution (1). Presumed adverse effects such as decreasing high-density lipoprotein (HDL) levels and increasing low-density lipoprotein (LDL) levels have been reported when comparing different treatment modalities (26). However, beneficial effects were also seen, especially in older hypogonadal men, where LDL levels decreased under testosterone substitution. Elevated serum leptin levels, a possible link between energy metabolism and the gonadal axis, are reduced by testosterone substitution in hypogonadal men (27). Leptin may therefore be a useful parameter with which to monitor long-term testosterone substitution.
Liver function parameters should not alter under the testosterone preparations recommended here, since the toxic substances with 17α-alkyl substitution should no longer be used.
Prostate
Testosterone substitution therapy increases prostate volume in hypogonadal men, but only to the extent seen in age-matched controls (28). Prostate volume, as determined by transrectal ultrasonography, is a sensitive end organ parameter for surveillance. Prostate specific antigen (PSA) increases slightly during therapy, but remains within the normal range.(5, 12) Since testosterone therapy must be terminated if a prostate carcinoma occurs, and prostate carcinoma is a disease of advanced age, patients above 45 years of age under testosterone treatment should be regularly investigated, first at bimonthly and later at half-yearly intervals (24). PSA testing and palpation of the prostate should be performed, if possible supported by transrectal ultrasonography. Uroflow measurements also contribute to a complete picture of prostate function under testosterone substitution. As a sign of adequate prostate and seminal vesicle stimulation, ejaculate volume will increase into the normal range.
Bones
Testosterone replacement therapy in hypogonadal men will increase the low bone mineralization, preventing or reversing osteoporosis and (ultimately) bone fractures (1, 29). With respect to bones in particular, it is important to use testosterone preparations that can be converted into oestrogens, since these hormones play a significant role in bone metabolism (20) Bone density should be measured prior to treatment in patients receiving testosterone substitution, and then regularly every two years as long as treatment continues. Quantitative computed tomography (QCT) of the lumbar spine provides accurate information; other effective methods are dual photon absorptiometry and dual energy X-ray absorptiometry. Sonographic measurement of bone density (e.g. of the phalangi) provides a useful parameter.
GnRH and gonadotropins
Well-administered and monitored testosterone substitution therapy leads to high quality of life. However, it will not induce fertility; in fact, if residual spermatogenesis is present, it will be suppressed by testosterone therapy. In eugonadal men, this phenomenon is exploited for hormonal male contraception. While in primary hypogonadism no effective treatment to improve fertility is available, spermatogenesis can be induced and maintained in cases with secondary hypogonadism by GnRH and/or gonadotropins (30). Patients with hypothalamic disturbances (idiopathic hypogonadotropic hypogonadism, Kallman’s syndrome) can be treated with pulsatile GnRH or with gonadotropins, while patients with pituitary insufficiency must receive gonadotropins in order to achieve fertility. During this stimulatory therapy, testosterone treatment is interrupted, since the endogenous testosterone production by Leydig cells is also stimulated. Once paternity has been achieved, the treatment scheme is switched back to testosterone substitution.
Pulsatile GnRH
GnRH must be applied in pulsatile fashion to induce pituitary gonadotropin secretion. This can be achieved using a portable mini-pump, which discharges gonadotropin-releasing hormone at regular intervals through a butterfly needle placed subcutaneously in the abdominal wall. The needle position is changed every two days. The reservoir of the pump is refilled as required. The doses used range from 5 to 20 μg/120 min or, in younger patients, from 100 to 400 ng/kg/120 min. The pumps are worn in a belt around the waist day and night. During the first weeks of treatment serum luteinizing hormone, follicle-stimulating hormone (FSH) and testosterone values are checked at shorter intervals to find the appropriate dose. Testicular size will increase; the increase precedes the appearance of sperm and is therefore an important predictive parameter. In order to discover subtle increases, monitoring testicular volumes by ultrasonography is worthwhile. After 3 months, ejaculates can be investigated for the appearance of sperm. Pregnancies can occur with sperm counts well below the lower limit of normal, provided that female reproductive functions are optimal. On an average, pregnancies can be achieved after 6–7 months of treatment (30, 31).
Maldescended testes should not prevent the initiation of pulsatile GnRH therapy, as spermatogenesis and pregnancies can be achieved despite this additional defect (32). When GnRH treatment fails, a mutation of the GnRH receptor gene may be the cause (33). Another reason for therapeutic failure may be the development of gonadotropin-releasing hormone antibodies. This has, however, only been observed in one patient in whom gonadotropin-releasing hormone was administered intravenously (34), and has not been observed in patients receiving gonadotropin-releasing hormone subcutaneously.
However, it is advisable to inform the patient that therapy may have to last for at least a year, or perhaps even longer, before pregnancy may occur.
Gonadotropin therapy
In cases of pituitary insufficiency or GnRH receptor gene defects, gonadotropins must be applied to achieve fertility; gonadotropins can also be applied in hypothalamic disorders instead of pulsatile GnRH. Until recently, human chorionic gonadotropin (hCG) in combination with human menopausal gonadotropin (hMG) were used for this treatment. As the α-subunits of hCG and luteinizing hormone are structurally very similar, they act on the same receptor on Leydig cells. hMG has both FSH and luteinizing hormone activity and is mainly used to stimulate the FSH receptor. In recent years, highly purified urinary hMG preparations became available, and most recently recombinant human FSH was introduced into clinical practice. Long-acting gonadotropin preparations would be highly desirable, but their development is slow.
Since hMG does not contain enough luteinizing hormone activity in addition to FSH activity to stimulate Leydig cells, the combination of hMG with hCG is required to induce spermatogenesis and achieve fertility. Stimulation therapy is initiated by administration of hCG alone. Originally, hCG was administered intramuscularly, but it is now also given subcutaneously. The usual dose is 1000–2500 IU twice per week (for example, Monday and Friday) for a period of 4–12 weeks. Dose adjustments are made to achieve testosterone (and oestradiol) levels within the normal range. Testosterone treatment is stopped since endogenous testosterone production under hCG should be sufficient to maintain androgenicity. Following this induction phase, hMG is administered (intramuscularly or subcutaneously) at a dose of 75–225 IU three times a week (Monday, Wednesday, Friday). The first sperm appear on average after a period of four months in hypopituitary patients, and after six months in hypothalamic patients. Pregnancies are achieved on an average after 10 months of treatment. The duration of therapy until sperm appear and pregnancies are induced is predicted to some extent by initial testicular size and the presence of unilateral or bilateral maldescent. Small and/or maldescended testes require longer periods of treatment. Testicular growth can be monitored exactly by ultrasonography, and this is a good parameter to predict therapeutic development (30, 31, 35).
Highly purified urinary human FSH (urinary hFSH) can also be used in combination with hCG for inducing spermatogenesis in hypogonadotropic disorders. In a multicentre trial, the median time to initiation of spermatogenesis as judged by the appearance of sperm in ejaculates was nine months. In all patients who had not gone through puberty, complete virilization could be achieved and the rate of appearance of sperm in the ejaculate was high (36). The use of recombinant human FSH (r-hFSH) with hCG has also been tested, and treatment with r-hFSH is comparable to the use of urinary preparations (37–39).
For patients with a hypothalamic disorder, the use of pulsatile GnRH appears to be the more physiologic modality, but no clear advantage of this treatment over gonadotropin treatment has been established (30, 31). Since intramuscular injections of gonadotropins are no longer necessary, and the patient can self-administer the preparation subcutaneously, most patients if given the choice prefer gonadotropins over GnRH, and only the more technically minded prefer the portable mini-pump.
Treatment with hCG may induce antibody formation (40), but neutralizing hCG antibodies that interfere with therapy have only been encountered in rare instances (41). Due to the high percentage of contaminating proteins, antibodies were often encountered with the original urinary hMG preparation, but are no longer seen with the highly purified or recombinant preparations. Therefore, the risk of antibody formation is negligible and does not provide a real criterion for the choice of therapy.
Some clinicians believe that testicular maldescent should preclude stimulatory therapy in hypogonadotropic patients. However, as analysis of treated cases shows, bilateral maldescent may extend the necessary treatment period (until sperm first appear) to an average of 13 months, compared to 4–5 months (32). Patients with maldescended testes should not be deterred from treatment, but should be instructed that treatment may take much longer.
In general, the second course of treatment to induce spermatogenesis usually takes less time than the first (30). Therefore, an initial course of treatment should be recommended even if paternity at this stage may not be requested. A first course of treatment will provide patients with a degree of certainty concerning their fertility chances, and will shorten the time required to induce a pregnancy in a later course of treatment.
After initiation of spermatogenesis with gonadotropins it may be maintained for some time with hCG alone (42), but eventually azoospermia will recur. If sperm counts are maintained for longer periods by hCG alone, residual FSH production has to be assumed, since in the long run hCG alone is not able to maintain spermatogenesis (43). The option of cryopreservation of a semen sample for later use should also be discussed with the patient, as it may eliminate the necessity and the costs of another treatment cycle (Chapter 9.4.15).
In hypopituitary patients, human growth hormone (hGH) treatment concomitant to gonadotropin application does not improve sperm quality, but may increase the seminal plasma volume as it induces growth of the prostate and seminal vesicles (44).
Treatment of infertility
The therapy of endocrine hypogonadism and the special therapeutic modalities for single infertility disorders described in the preceding chapters demonstrate that there are a number of male fertility disturbances which can be treated rationally and effectively. However, for other disorders there are no rational treatment modalities available. The group of patients with idiopathic infertility is large and for their condition neither the cause is known nor does a rational therapy exist (Chapter 9.4.12). Finally, symptomatic treatment as provided by methods of assisted reproduction—insemination, in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI)—open the possibilities for paternity even if rational therapies are not available (Chapter 9.4.14). Often, early preventive treatment, long before paternity may be considered, is the most effective way to preserve fertility (Table 9.4.13.2).
Table 9.4.13.2 Therapeutic possibilities in male infertility
Disorder | Therapy | Chapter where described |
|---|---|---|
Rational treatment | ||
IHH and Kallman’s syndrome | GnRH or gonadotropins | 9.4.14 |
Pituitary insufficiency | Gonadotropins | 9.4.14 |
Prolactinomas | Dopamine agonists | 2.3.10 |
Infections | Antibiotics | 9.4.9 |
Chronic general diseases (for example, renal insufficiency, diabetes mellitus) | Treatment of the basic disease | 9.4.7 |
Drugs/toxins | Elimination | 9.5.1 |
Obstructive azoospermia | Epididymovasostomy | 9.4.11 |
Retrograde ejaculation | Imipramin | 9.4.16 |
Preventive treatment | ||
Testicular maldescent | GnRH/hCG/orchidopexy | 9.4.1 |
Delayed puberty | Testosterone/GnRH/hCG | 7.2.9 |
Infections | Early antibiotics | 9.4.9 |
Exogenous factors (irradiation, drugs, toxins) | Elimination | 9.5.1 |
Malignancies | Gonadal protection | 9.4.8 |
Cryopreservation of sperm | 9.4.15 | |
No (for infertility) therapy | ||
Bilateral anorchia | Testosterone substitution | 9.4.1 |
Complete SCO | – | 9.4.2 |
Gonadal dysgenesis | Testosterone substitution | 7.2.9 |
Empirical treatment | ||
Varicocele | 9.4.1 | |
Immunological infertility | 9.4.11 | |
Idiopathic infertility | 9.4.12 and 9.4.13 | |
Symptomatic treatment | ||
Hypospadias | IUI | |
OAT | IUI, ICSI | 9.4.14 |
Globozoospermia | ICSI | 9.4.2 |
Immotile cilia | ICSI | 9.4.2 |
Congenital bilateral absence of the vas deferens (CBAVD) | TESE | 9.4.10 |
Other obstructive azoospermias | MESA/TESE | 9.4.10 |
Non-obstructive azoospermia with incomplete spermatogenetic failure | TESE | 9.4.2 |
Klinefelter’s syndrome | TESE may be possible | 9.4.3 |
IUI, intra-uterine insemination; ICSI, intracytoplasmic sperm injection; TESE, testicular sperm extraction; MESA, microsurgical epididymal sperm aspiration; GnRH, gonadotropin-releasing hormone.
The lack of rational therapeutic possibilities led in the past to the use of medications whose efficacy had not been proven. These empirical medications were, or in some instances still are, prescribed in consecutive therapeutic cycles without proven effects. In recent years, the principles of evidence-based medicine have been introduced into andrology, and many of these therapies have been evaluated in controlled clinical trials (33). The results of trials and meta-analyses of some of these therapies are summarized in Fig. 9.4.13.2. This recent knowledge has to be transferred to physicians’ day-to-day practice, and this may take some time. Often, pregnancies occur independently of the prescribed medication, solely due to the placebo effect. The happy couple would not recognize that their pregnancy was a random placebo result. Discipline is required of physicians not to prescribe such medications in order to exploit this placebo effect. They should rather recognize that intensive counselling can in many cases be as effective as, or even more effective than, doubtful medication or other therapeutic modalities (45).
Since empirical treatments continue to be prescribed despite evidence-based studies showing their ineffectiveness, they will be summarized here so that the attending physicians may form their own opinion as to whether or not to use such medication (Table 9.4.13.2). Ultimately, it is the physician’s decision as to whether waiting or counselling should be recommended, and which couples should be advised to seek assisted reproduction, donor insemination, adoption, or remain childless.
Since hormones are necessary for normal spermatogenesis, and since GnRH and gonadotropins work so effectively in hypogonadotropic hypogonadism, hormones and antihormones have been and are extensively used for the treatment of idiopathic infertility (45, 46). However, the efficacy of pulsatile GnRH treatment in idiopathic male infertility could never be demonstrated beyond doubt. Additionally, hCG/hMG treatment had been used for many years before a controlled study demonstrated that pregnancy rates were similar under hCG/hMG and placebo (45), demonstrating the inefficacy of this approach.
More recently, highly purified rFSH has been recommended for the treatment of idiopathic infertility, in particular in the context of assisted reproduction to enhance pregnancy rates. Controlled studies showed no or only slight improvements in conventional semen parameters, and no increase in pregnancy rates (47–49). However, a recent Cochrane review (50) recommends further studies to finally assess the potential of FSH in male infertility.
Androgens have been prescribed for idiopathic infertility for many years, with mesterolone in particular a favourite candidate. However, a meta-analysis of all studies revealed that 359 patients have to be treated to achieve one more pregnancy than in the untreated population (45) Finally, antioestrogens are prescribed under the assumption that the resulting increase in endogenous gonadotropins will improve semen parameters and enhance the chances for pregnancy. However, this could not be confirmed in controlled studies and this treatment remains empirical. In addition, tamoxifen, if taken over longer periods, may have toxic side effects.
Among the nonhormonal therapies, kinins (kallikrein and more recently angiotensin-converting enzyme inhibitors) enjoyed much popularity. An analysis of all controlled studies, however, demonstrated that increased pregnancy rates could not be achieved (45). Antioxidant treatment with vitamin C, vitamin E, or glutathione may be based on a pathophysiological concept; however, methods to identify patients who would benefit from such treatment are not yet available.
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