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Review |
From the Central Drug Research Institute, Lucknow, India.
| Correspondence to: Dr Singh Rajender, Scientist, Division of Endocrinology, Central Drug Research Institute, Lucknow, UP, India (e-mail: rajender_singh{at}cdri.res.in). |
| Received for publication June 13, 2008; accepted for publication October 9, 2008. |
Approximately 50% of infertility issues are attributable to male factors. A
number of different factors may result in similar reductions of sperm count or
motility and affect sperm morphology. Not only is the etiology of male
infertility difficult to understand, but it is equally challenging to treat
male infertility because of its etiological heterogeneity. Because of complex
and incomplete knowledge of the underlying causes, most infertile men are
described as idiopathically oligozoospermic and/or asthenozoospermic.
Different hormonal treatments have been attempted, aiming to improve mainly
endogenous follicle-stimulating hormone and/or androgen levels and subsequent
spermatogenesis. Various studies have tried to treat infertility through
natural pregnancies or increased sperm retrieval for in vitro fertilization
techniques, or by treating spermatozoa in vitro to improve its fertilizing
potential. The present review focuses on all of the aspects of male
infertility treatment by hormone supplementation.
Key words: Spermatogenesis, oligozoospermia, in vitro fertilization
A multitude of factors, such as physical obstruction of sperm release, reduced sperm count or motility, altered sperm morphology, infections, and hormonal imbalances, have been identified as contributing to male infertility. Anatomic defects, endocrinopathies, immunologic problems, ejaculatory failures, and environmental exposures are significant causes of infertility. Male-factor infertility may arise following the rare deficiencies in gonadotropin induction and maintenance of spermatogenesis, thereby providing a direct basis for hormonal therapy. Extratesticular causes of male infertility are less common. Specific therapies are readily available for extratesticular causes. Direct testicular injury to the male germ cells, Sertoli cells, and Leydig cells is one of the major causes of infertility. Testicular injury leads to a compensatory increase in gonadotropins, which overcomes minor defects in testicular functions. On the contrary, a consequent rise in testosterone may inhibit recovery of spermatogenesis (Shetty et al, 2000). The different causes and treatment modalities of male infertility are listed in Table 1. Despite the identification of the above factors, the etiology of infertility remains unexplained in almost 50% of individuals.
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Because of etiological heterogeneity, the treatment of male infertility is not straightforward. It is assumed that in about 30% of cases male infertility is caused by chromosome aberrations or mutations in genes functioning in the male germ line (Vogt, 2004). Although infertile couples can hope to have children by in vitro fertilization (IVF) techniques, these techniques offer no treatment for male infertility, and involve certain risks. First, the routine techniques of IVF and intracytoplasmic sperm injection (ICSI) are very costly and thus not accessible to all. Second, there is a risk of carrying a genetic defect, if any, forward. A genetically unfit (infertile) man will give rise to a genetically unfit (infertile) child through in vitro methods. Therefore, we may end up increasing the number of infertile individuals in the community. Third, there is always a probability of damaging the male or female reproductive system during sperm extraction from the testis or during hyperstimulation of female reproductive physiology.
Spermatogenesis is initiated and regulated by the hypothalamo-pituitary-gonadal axis (Figure). Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner and acts on the pituitary to stimulate secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH acts on Sertoli cells and LH acts on Leydig cells in the testis. The importance of FSH in spermatogenesis is controversial (Moudgal and Sairam, 1998; Plant and Marshall, 2001), although it is required along with LH for initiation of spermatogenesis. Germ cells do not have androgen receptors, so androgens secreted by Leydig cells act through receptors on the Sertoli cells (Lyon et al, 1975). Testosterone secreted from Leydig cells, inhibin secreted from Sertoli cells, and estradiol formed from aromatization of testosterone act on the hypothalamus and pituitary to regulate gonadotropin secretion by negative inhibition (Figure). Therefore, GnRH, FSH, LH, and testosterone are very instrumental in overall spermatogenesis status in an individual. Of late, estrogens have also been assigned a role in spermatogenesis (Hess et al, 1997).
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The control of gonadotropins over spermatogenesis is complicated and has to be balanced at several stages. Disturbances at the hypothalamo-pituitary axis arise mainly because of gonadotropin deficiency. Various locally secreted peptides and proteins such as cytokines, activin, inhibin, follistatin, and estrogen have autocrine and paracrine control over spermatogenesis. Other hormones, such as growth hormone (GH; Hull and Harvey, 2000a), leptin (Clement et al, 1998), insulin-like growth factor-1 (IGF-1; Gnessi et al, 1997), and thyroid hormone (Beamer et al, 1981), have also been implicated in spermatogenesis. Unlike female infertility, for which most of the causes are hypothalamo-pituitary, male infertility arises mainly because of disturbances at the spermatogenesis level. Extratesticular causes of infertility are less common, but specific treatment is available for these (Mazumdar and Levine, 1998).
The communication between the central nervous system and the testis balances hormone levels to favor spermatogenesis. Hormone imbalance has been shown to correlate with male infertility (Sieber, 1992; Jarow, 2003). Therefore, a properly planned hormonal treatment of male infertility is one of several possible options. Various studies have tried to treat infertility at the level of hypothalamus, pituitary, or postpituitary. Hormonal treatment involves in vivo treatment to achieve natural pregnancy or to increase the chances of sperm retrieval for IVF techniques, or in vitro treatment of the spermatozoa to strengthen its fertilizing capability. The present review will focus on all the hormonal therapies, with special emphasis on the end results in the form of conception rather than an increase in sperm number/motility without conception. Most of the studies referenced in this review were searched through PubMed and ScienceDirect, using the key words infertility, infertility treatment, steroid hormones, testosterone, FSH, LH, estrogens, spermatogenesis, and fertility.
Hormonal Treatments Aimed at Natural Pregnancies
The best choice to treat an infertile male would be to initiate/enhance
spermatogenesis for natural pregnancies. Therefore, maximum numbers of studies
have tested the efficacy of the hormones in treating infertile individuals and
achieving a natural pregnancy. Because most infertility cases are idiopathic,
various studies have used different hormones with an aim of
initiating/enhancing spermatogenesis.
GnRH— GnRH (termed GnRH-I) is produced by hypothalamic neurosecretory cells and released in a pulsatile manner into the hypothalamo-hypophyseal portal circulation, through which the hormone is transported to the anterior pituitary gland (Figure). In response, the anterior pituitary produces LH and FSH, which in turn regulate gonadal steroidogenesis and gametogenesis in both sexes (Fink, 1988). GnRH is also a paracrine/autocrine regulator in extrapituitary compartments such as the ovary, placenta, uterus, and immune system (Emons et al, 1998). Since its discovery some 30 years ago, many GnRH-I analogues with enhanced biological potency have been developed and studied extensively (Conn and Crowley, 1994). These synthetic analogues have been used as effective treatments for a variety of reproductive endocrinopathies (Kiesel, 2002).
A single randomized study examined sustained GnRH treatment in idiopathic oligoasthenoteratozoospermia, but no effect on either circulating gonadotropins or semen parameters was observed (Badenoch et al, 1988; Table 2). Because GnRH is produced in a pulsatile manner in the body, pulsatile GnRH therapy has also been tried. In pulsatile therapy, GnRH is administered using a portable pump and a butterfly needle placed in the abdominal wall that is changed every 2 days. The dose ranges from 5 to 20 µg/120 min, or from 100 to 400 ng/kg/120 min. Intranasal GnRH administration is done to maintain already-induced spermatogenesis (Klingmuller and Schweikert, 1985). Intravenous GnRH can also maintain already-induced spermatogenesis and induce pregnancies (Blumenfeld et al, 1988) because of its superior pharmacokinetics (Handelsman et al, 1984). Therapy lasts on average 4 months (Buchter et al, 1998).
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Pulsatile GnRH therapy was effective in gonadotropin deficiency caused by hypothalamic or pituitary diseases for inducing androgenization and spermatogenesis (Mortimer et al, 1974; Crowley et al, 1985), but not in men with loss of pituitary gonadotropin function (Wang et al, 1989). Studies have indicated that men with hypogonadotropic hypogonadism respond better to GnRH than to gonadotropins, with improved spermatogenesis (Schopohl et al, 1991; Delemarre-van de Waal, 1993; Buchter et al, 1998); however, another study denied that GnRH has higher efficacy than a human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) combination (Liu et al, 1988). Further studies are needed to conclude whether GnRH is better than gonadotropins in improving spermatogenesis.
GnRH therapy seems to be very effective in recovering fertilization ability in men undergoing treatment for testicular tumor. Cisplatin and radiation therapy used in the treatment of testicular cancer lead to depletion of all of the germ cell population except stem spermatogonia (Kangasniemi et al, 1996; Meistrich et al, 1999). In 2 different studies, 18 men undergoing radiation and cisplatin therapy recovered completely from germ cell damage after treatment with GnRH (Kreuser et al, 1990; Brennemann et al, 1994). But only 1 of the 5 men undergoing Mustargen, Oncovin, procarbazine, and prednisone (MOPP) therapy for Hodgkin lymphoma responded to GnRH (Johnson et al, 1985). Such a treatment may be the last ray of hope to cancer patients who have lost all their germ cells during cancer treatment.
As anticipated, the above studies indicate that pulsatile GnRH therapy offers hope to patients with gonadotropic deficiency caused by loss of hypothalamic function. Since the hypothalamus acts through the pituitary gland, patients with pituitary malfunction and gonadotropin deficiency may not respond to GnRH therapy. Because some controversies are evident as discussed above, more studies comparing the outcome of GnRH therapy in the 2 categories of patients should lend support to the above conclusions. GnRH therapy seems to work well in a selected group of patients, but formation of anti-GnRH antibodies in certain cases raise further issues about the use of this therapy in the treatment of male infertility (Lindner et al, 1981). Another drawback of this therapy is the cumbersome wearing of the pulsatile pump.
Gonadotropins— LH and FSH are 2 major gonadotropins produced by the anterior pituitary under the influence of GnRH. A third gonadotropin is hCG, secreted by the chorionic cells of the placenta. Pituitary insufficiency is conventionally substituted using hCG and hMG, or using purified urinary FSH, or, more recently, by recombinant human FSH (r-hFSH). Because of their prime role in initiating spermatogenesis, various gonadotropins have been tried in different combinations to treat male infertility.
Mixed gonadotropin therapy. hCG acts on the corpus luteum to maintain progesterone production during pregnancy. The subunits of hCG and LH are structurally similar, and they act on the same receptor on Leydig cells. hCG obtained from the urine of women is used to substitute for LH deficiency. hMG obtained from the urine of postmenopausal women contains both LH and FSH activity. The dosage of hMG that gives adequate FSH activity fails to provide LH activity; thus, it is used in combination with hCG. Initially, hCG is given alone at a dosage of 1000–2500 IU, intramuscularly or subcutaneously, twice weekly. Testosterone is monitored during therapy. Within this induction phase lasting 8–12 weeks, sperm can be found in some ejaculates (Finkel et al, 1985; Burris et al, 1988; Vicari et al, 1992). Thereafter, hMG is administered at a dosage of 75–150 IU 3 times weekly.
A review of 9 patients with idiopathic hypogonadotropic hypogonadism, 9
patients with Kallmann syndrome (group A), and 21 patients with
hypopituitarism (group B) treated with this regimen showed appearance of first
sperm in the ejaculate with sperm concentration up to 1.2 x
106/mL (0.1–9.0 x 106/mL) in group A and 8.1
x 106/mL (0.1–18 x 106/mL) in group B.
Pregnancies were induced in 5 out of 10 patients belonging to group A and in
17 out of 21 patients in group B. Testicular size increased from 4.4 ±
2.86 to 15.3 ± 7.4 mL (group A) and from 14.0 ± 8.7 to 28.3
± 10.9 mL (group B) (Buchter et al,
1998). Previous studies comparing the effectiveness of GnRH or
hCG/hMG in hypogonadotropic hypogonadism have reported similar results
(Liu et al, 1988;
Schopohl, 1993). Other
studies have reported sperm appearance in ejaculate within 6 months in men
with an average testicular volume 
4 mL and over 9 months in men with
smaller testicular volumes (Table
3). A study treating a 47-year-old azoospermic man (diagnosed with
congenital idiopathic hypogonadotropic hypogonadism) with a recombinant
FSH/hCG combination reported mobile spermatozoa after 6 months, but no
clinical pregnancy was produced (Nilsson
and Hellberg, 2006).
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We know that FSH and LH are both required to initiate and maintain spermatogenesis, and that gonadotropin deficiency arising at the hypothalamus or pituitary level should affect physiological levels of both FSH and LH. Therefore, it is combined gonadotropin therapy that should be most effective. The studies discussed above have proven the efficacy of this therapy very well. As noted in these studies, gonadotropins may help in the patients with infertility caused by gonadotropin deficiency only. Further, because the hypothalamus is upstream from the pituitary, such a regimen should in principle have the capability to treat hypogonadotropic infertility arising at either the hypothalamus or the pituitary level. The latter has been demonstrated to a greater extent by the above studies. In the 14 studies, sperm were recovered in hypogonadotropic hypogonadic men in significant numbers, and pregnancy rates of a maximum 83% were reported. Overall, mixed gonadotropin seems to be promising in the treatment of hypogonadism.
FSH therapy. FSH enhances the production of androgen-binding protein (ABP) by Sertoli cells of the testes, and is critical for regulating and maintaining spermatogenesis in mammals (Matsumoto, 1989; Sharpe, 1989). ABP is required to maintain high local concentration of androgens in the seminiferous tubules (Dohle et al, 2003). FSH deprivation (blockade of FSH receptor or immunization with heterologous purified hormone) in adult male rhesus monkeys leads to infertility and testicular function impairment (Aravidan et al, 1993; Moudgal et al, 1997). Bioneutralization of circulating human FSH reduced quality and quantity of sperm production (Moudgal et al, 1997). Mutations of FSH receptor and FSH-β subunit produce variable degrees of spermatogenetic damage and reduction in sperm production (Tapanainen et al, 1997; Philip et al, 1998). FSH also reverses apoptotic changes in sperm structure occurring because of microbial infections and increases fertilizing potential (Baccetti et al, 1997). Because of its well-established role in spermatogenesis, FSH has been tested in various studies to promote spermatogenesis, with varying degree of success and controversial results.
Two randomized controlled studies have examined the effect of FSH stimulation at the dosage of 150 IU administered 3 times weekly for 3 months in 148 subfertile men (asthenoteratozoospermic, oligoasthenozoospermic, and teratozoospermic) (Matorras et al, 1997), and 1 severely oligoasthenoteratozoospermic subject (Giltay et al, 2004) (Table 4). Two other studies have analyzed the effects of r-hFSH at the dosage of 100 or 150 IU administered 3 times weekly over a period of 3 months in 34 idiopathic oligozoospermic men (Kamischke et al, 1998) and 62 cases of idiopathic oligozoospermia (Foresta et al, 2005). Three of these studies reported no improvements in pregnancy rates with FSH, although 1 claimed benefit from a post hoc analysis for a selected subpopulation (Matorras et al, 1997). Severe oligoteratozoospermia is a rare form of infertility and responds well to FSH treatment (Giltay et al, 2004) compared with other conditions.
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Five randomized studies designed to cover at least 1 full spermatogenic cycle have treated infertile men with FSH (Table 4). Quantitative pooling of all available data, however, showed no significant effect (odds ratio = 1.29; 95% confidence interval [CI], 0.79–2.11) of FSH therapy on pregnancy rates in 390 couples who were followed for spontaneous pregnancy. R-hFSH treatment in 45 oligozoospermic men at a low dosage of 100 IU (Foresta et al, 2002) and in 30 normogonadotropic oligozoospermic men at a high dosage of 300 IU (Paradisi et al, 2006) for a minimum period of 3 months markedly increased sperm count without significant effects on motility or morphology compared to natural FSH (Foresta et al, 2002). These studies also did not follow up for spontaneous pregnancy outcomes.
Most of the studies using FSH reported no improvement in spermatogenesis or overall semen parameters. However, a few studies using r-hFSH/FSH claimed improvement in sperm counts/seminal parameters (Foresta et al, 2002, 2005; Paradisi et al, 2006), but the authors did not follow up for pregnancy outcomes. As stated above, another study on oligoteratozoospermia (Matorras et al, 1997) reported natural pregnancies in 4 patients treated with FSH. However, 2 out of 4 pregnancies resulted in abortions. Another factor to consider in most of these studies is that the patients were not well characterized in terms of hypothalamus and pituitary function and gonadotropin levels. It can be concluded that FSH alone has no efficacy or has very little efficacy in treating infertility. As discussed earlier, the above observation may not be difficult to explain, because LH in addition to FSH is required to initiate and maintain spermatogenesis, and FSH alone is not likely to improve spermatogenesis in infertile patients. Further studies using well-defined patient groups (in terms of gonadotropin deficiency) will help in understanding the efficacy of FSH alone, if any. However, pituitary extracts are no longer recommended, because of risk of transmitting Creutzfeldt-Jakob disease (Cochius et al, 1992).
Androgen Therapy— Testosterone and its metabolite, dihydrotestosterone, are the principle male sex hormones. Testosterone regulates differentiation of the Wolffian duct during embryonic life, secretion of LH by the hypothalamic-pituitary axis, and spermatogenesis. Dihydrotestosterone promotes the development of the external genitalia and prostate during embryogenesis, and is also responsible for changes that occur at puberty in males (Rajender et al, 2007). Testosterone replacement therapy is necessary for the normalization of androgenic actions in hypogonadal men. The primary goals of treatment include restoration of normal sexual function, prevention of bone loss and muscle wasting, and increased ratio of lean body mass to body fat. Additional actions of androgens on cognitive and nonsexual but male-related function and behavior may also be important. However, it is surprising to observe that individuals who received testosterone replacement therapy for a long time reported decreased sperm count (Anderson et al, 2002). This can be explained on the basis of negative feedback testosterone exerts on the hypothalamus and pituitary, resulting in lesser production of natural testosterone. This is one of the observations that make testosterone a potential agent for male contraception. Therefore, testosterone replacement therapy seems to offer no hope for male infertility treatment.
Despite its contraceptive properties, testosterone therapies have been carried out in infertile men with 2 rationales: 1) low dosage of testosterone improves epididymal maturation of spermatozoa, and, 2) rebound testosterone therapy—high dosage of testosterone is given to suppress spermatogenesis and therapy is stopped abruptly with a logic that it will lead to improved spermatogenesis because of higher release of gonadotropins. Although many preparations for testosterone therapy are available (Table 5), testosterone undecanoate and mesterolone were the most commonly used androgens in male infertility treatment trials. Testosterone undecanoate has been used in dosages between 120 and 240 mg/d and mesterolone in dosages between 75 and 150 mg/d in most of the studies. No single study in either the testosterone undecanoate group or the mesterolone group reported significant improvement in the pregnancy rate (Tables 6 and 7). Pooling of data from all the studies (testosterone + mesterolone) gives an odds ratio of 1.045 (95% CI, 0.74–1.48) for the pregnancy outcomes. Meta-analysis previously showed similar results (Kamischke and Nieschlag, 1999; Liu and Handelsman, 2003). However, studies using testosterone undecanoate in combination with tamoxifen citrate showed improvements in sperm count, motility, and pregnancy rates (Adamopoulos et al, 1997, 2003; Adamopoulos, 2000), which are discussed in a later part of this review. As anticipated, testosterone therapy alone does not offer any hope for the treatment of male infertility. Although good pregnancy rates of up to 41% were obtained in partners of patients treated with androgens, the therapy is not recommended, because many subjects suffer from azoospermia at the end of the treatment.
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GH— GH is secreted by pituitary and is obligatory for growth and development. It is also required for sexual differentiation and pubertal maturation, and regulates gonadal steroidogenesis and gametogenesis (Hull and Harvey, 2000b). GH acts directly at gonadal sites and indirectly via hepatic IGF-1 (Hull and Harvey, 2000). GH is also produced locally in gonadal tissues, and it may act in paracrine or autocrine fashion to regulate local processes that are strategically regulated by pituitary GH (Hull and Harvey, 2000).
GH deficiency is associated with abnormally small testis (Spiteri-Grech and Nieschlag, 1992). GH resistance is associated with reduced fertility in men (Laron and Klinger, 1998). GH deficiency has been correlated with high incidences of azoospermia (91%) and oligozoospermia (18%) (Shimonovitz et al, 1993). GH when used as an adjunct along with conventional therapy has been reported to induce spermatogenesis in patients with hypogonadotropic hypogonadism who are not responding to gonadotropin or pulsatile LH therapy (Shoham et al, 1992). GH administration has been reported to restore sperm motility, concentration, and normal morphology in GH-deficient dwarf rats (Gravance et al, 1997) and oligozoospermic men (Breier et al, 1998). A study on 9 oligozoospermic and 9 asthenozoospermic men treated with GH for 12 weeks reported increased sperm motility in both groups, and 3 pregnancies were reported in asthenozoospermia but not in oligozoospermia (Ovesen et al, 1998). Another study on oligozoospermic men also reported no improvement upon GH therapy (Lee et al, 1995). A study using recombinant GH (rbGH) in 10 severely oligozoospermic men reported significant improvement in sperm concentration in 5 out of 10 patients (Radicioni et al, 1994), but no improvement in seminal parameters was observed in men with normal GH levels. Taking into consideration the natural functions of GH and the results from the above studies, it seems that GH may be used as a supplement along with other therapies. So, studies using a combination of GH and gonadotropins may be worth trying.
Antiestrogens—
Estrogen is also known as a "female hormone" because it plays a
central role in female reproduction. However, many studies in the last decade
have defined roles for estrogens in male reproduction as well
(Hess et al, 1997). Its role
is well established in negative regulation of gonadotropin secretion
(Finkelstein et al, 1991),
masculinization of the brain during development, and maintenance of sexual
behavior in adult males (Lauber et al,
1997). Estradiol and environmental estrogens have been shown to
stimulate sperm capacitation, acrosome reaction, and fertilizing ability in
mammals (O'Donnell et al,
2001; Adeoya-Osiguwa et al,
2003). Estrogen receptor 
has been localized in the nuclei
of Leydig cells, round spermatocytes, spermatids, and sperm
(Pelletier and El-Alfy, 2000;
Pelletier et al, 2000).
Estrogen receptor β has been detected in the nuclei of spermatogonia,
spermatocytes, developing spermatids, sperm, and Sertoli cells
(Pelletier and El-Alfy,
2000). Estrogen has been shown to regulate reabsorption of luminal
fluid in the head of the epididymis, and disruption of this function leads to
entry of sperm diluted in epididymis, rather than concentrated, resulting in
infertility (Hess et al,
1997). Because estrogens exert a negative feedback on gonadotropin
secretion, various antiestrogens have been tried for infertility treatment,
with the rationale that absence of feedback inhibition will lead to increased
secretion of gonadotropins.
Tamoxifen. Tamoxifen is presently the most commonly used drug for breast cancer treatment (Furr and Jordan, 1984). Tamoxifen is a synthetic nonsteroidal estrogen antagonist that competitively binds to estrogen receptors in the hypothalamus, leading to increased GnRH secretion (Vermeulen and Comhaire, 1978). Because of its own agonistic property, tamoxifen also induces some estrogenic responses. The effects depend on subtype of receptor involved and cell types (Hoffmann and Schuler, 2000). Tamoxifen has also been recommended in the treatment of gynecomastia and oligozoospermia (Noci et al, 1985; Parker et al, 1986). Various studies have reported beneficial effects of tamoxifen therapy in male infertility.
Twenty-two studies have analyzed the possible use of tamoxifen in the treatment of male infertility (Table 8). Overall, more than 690 men who presented with oligozoospermia and/or asthenozoospermia were administered tamoxifen at a dosage of 10–20 mg daily over a period of 1–6 months. Among all the reported studies, only 2 studies have included placebo controls (AinMelk et al, 1987; Adamopoulos et al, 1997). Highly varying results were obtained in these studies. Sperm count was observed in 8 studies, of which only 3 reported improvement in sperm count (Höbarth et al, 1990; Kotoulas et al, 1994; Kadioglu et al, 1999), whereas 5 did not (Maier and Hienert, 1990; Sterzik et al, 1991, 1993; Krause et al, 1992; Caroppo et al, 2003a). Morphological features of spermatozoa were analyzed in 5 studies, of which 1 reported improvement in some teratozoospermic men (Caroppo et al, 2003) and all others reported no improvement (Maier and Hienert, 1990; Sterzik et al, 1991, 1993; Krause et al, 1992).
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Sperm motility was analyzed in 5 studies, of which none reported improvement (Maier and Hienert, 1990; Sterzik et al, 1991, 1993; Krause et al, 1992; Breznik and Borko, 1993). Among all 6 studies following up for pregnancy rates (Bartsch and Scheiber, 1981; Traub and Thompson, 1981; Buvat et al, 1983; Török, 1985; AinMelk et al, 1987; Breznik and Borko, 1993), values ranging from 12% to 40% pregnancy rates were reported. However, another study involving 89 subjects has reported higher pregnancy rates in the control group, along with an interesting observation of increase in seminal zinc and decrease in serum prolactin (PRL) levels (Breznik and Borko, 1993). The increase in seminal zinc concentrations should rather improve pregnancy rates, because seminal zinc concentration is linearly correlated with sperm motility (Skandhan et al, 1978).
Several studies have explored hormone levels in the treated groups to further understand the possible mechanism of action of these treatments. Most of the studies have reported improvement in serum FSH and testosterone levels (Török, 1985; Lewis-Jones, 1987; Hampl et al, 1988; Sterzik et al, 1991, 1993; Krause et al, 1992; Kadioglu et al, 1999). One study reported improvement only in testosterone (Krause et al, 1992), whereas another study reported no improvement in either testosterone or FSH levels (Sterzik et al, 1991). Improvements in FSH and testosterone levels in most of the studies reporting positive outcomes in terms of sperm count, motility, or pregnancy may indicate that FSH and testosterone levels can be used as markers to assess the treatment progress during tamoxifen therapy.
Individuals with partial androgen insensitivity syndrome exhibit phenotype between almost normal male and complete female, depending upon loss of androgen function (Rajender et al, 2007). These individuals are invariably infertile, and to date no treatment is effective in androgen insensitivity syndrome patients. A 32-year-old male with incomplete androgen insensitivity was able to induce 3 pregnancies in a period of 5 years after tamoxifen treatment, and during the period of treatment his seminal parameters and serum levels of FSH reverted to normal levels (Gooren, 1989). This treatment may offer hope to a subcategory of partial androgen insensitivity patients who have small but descended testicles and infertility. Because most of the above studies have shown improvement only in sperm count, without improvement in motility or morphology, tamoxifen seems very promising in treating oligozoospermia, and it is the most commonly recommended drug for idiopathic oligozoospermia in United States.
Tamoxifen With Kallikrein. Combination therapy of tamoxifen citrate and kallikrein was designed in men with oligoasthenozoospermia based on the previous results, which suggested that tamoxifen is effective in oligozoospermia and kallikrein is effective in asthenozoospermia; hence, a combination should be useful in oligoasthenozoospermia. Not many studies have tested this combination. Three studies involving more than 84 oligoasthenozoospermic men using this combination have reported improvements in sperm count (Höbarth et al, 1990; Maier and Hienert, 1990) and motility (Maier, 1989; Höbarth et al, 1990; Maier and Hienert, 1990); however, another study reported no significant improvements in seminal parameters (Höbarth et al, 1990). None of these studies followed up for pregnancy outcomes in the patients. All the above studies taken together emphasize the role of this combination in improving both sperm count and motility; however, further studies on this therapy are warranted for better conclusions.
Tamoxifen With Testosterone. Studies using tamoxifen citrate in combination with testosterone undecanoate in men with idiopathic OAT reported improvement in total sperm count, motility, and functional sperm fraction after 3 and 6 months (Adamopoulos, 2000). Pregnancy rates per couple per month of 33.9% in the treatment group and 10.3% in the placebo group were recorded (Adamopoulos et al, 1997). Recent studies conducted with similar designs demonstrated similar results in idiopathic oligozoospermia using testosterone undecanoate and tamoxifen citrate (Adamopoulos et al, 2003). The above combination has reported improvement in sperm count and motility with good pregnancy rates; however, all the studies are limited to 1 geographical region. Therefore, studies from other regions may unveil further information on the effectiveness of this combination.
Clomiphene Citrate. Clomiphene citrate is an orally active nonsteroidal agent distantly related to diethylstilbestrol. Its use has been shown to enhance secretion of LH-releasing hormone and FSH-releasing hormone, and hence of gonadotropins (Patankar et al, 2007). Nineteen studies were conducted (18 in human males and 1 in mink males), in various conditions of male infertility ranging from oligozoospermia intractable to hormonal treatment to azoospermia, using clomiphene citrate. Dosages of 10–25 mg/kg were administered ranging over periods of 10 days to 9 months. Sperm motility, concentration, and morphology improved significantly in oligozoospermic patients (Micic and Dotlic, 1985; Hayashi et al, 1988; Homonnai et al, 1988; Breznik and Borko, 1993) (Table 9). More than 50% pregnancy rates were obtained in oligozoospermic patients and patients recovered from varicocelectomy not responding to hCG (Epstein, 1977). Interestingly, 3 out of 6 azoospermic mink males induced pregnancy (Lukola and Sundqvist, 1986). One study reported contrasting results in which clomiphene citrate administration was not found to improve sperm motility and concentration significantly (Charny, 1979). Clomiphene citrate improved blood levels of LH, T, FSH, and PRL (Hayashi et al, 1988), but 1 study reported a significant decrease in serum PRL levels (Breznik and Borko, 1993). Clomiphene citrate has improved sperm count in the maximum number of studies and motility and morphology in approximately 20%–30% of the studies, and pregnancy rates of up to 50% are evident. Therefore, clomiphene is as promising as tamoxifen, when the latter is used in combination with either kallikrein or testosterone.
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Thyroid Hormone— The thyroid gland produces thyroxine (T4) and triiodothyronine, with T4 being the major form of thyroid hormone. Thyronines act on the body to increase the basal metabolic rate, affect protein synthesis, and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness. The thyroid hormones are essential for proper development and differentiation of every organ in the human body. These hormones also regulate protein, fat, and carbohydrate metabolism.
Although thyroid hormones may affect testicular development, their role in spermatogenesis is still controversial. Thyroidectomy in immature male rats caused severe inhibition of gametogenesis and Leydig cell development (Chowdury and Arora, 1984; Chowdury et al, 1984). Hypothyroid male mice were infertile in 1 study (Beamer et al, 1981) but fertile in others (Chubb and Nolan, 1985; Chubb and Henry, 1988). Hypothyroidism had a depressive effect on libido in stallions (Lowe et al, 1975), but no such effect was observed in hypothyroid male rats (Cooke et al, 1991). There is some evidence that sperm motility is reduced in thyroid dysfunction (Corrales-Hernandez et al, 1990). Infertile buck rabbits that showed poor sexual desire, deterioration in semen qualities, and arrested spermatogenesis showed great improvement in sexual desire and semen qualities after a moderate amount of thyroxin administration, and the libido could be seen even in the nonbreeding season (Maqsood, 1950). Mild hyperthyroidism achieved using injection of thyroxin stimulated spermatogenesis and increased secretory activities of the testis and sexual behavior in male mice, buck rabbits, and rams (Maqsood, 1951).
Andrologists commonly examine the thyroid function during the assessment of infertile men. Studies done in patients with clinically manifested thyroid dysfunction suggest beneficial effects of thyroid hormones in improving most semen parameters (Abalovich et al, 1999). Hypothyroidism is associated with decreased libido and impotence (Griboff, 1962) in men. An epidemiological study undertaken in 388 men who were partners in infertile couples clearly suggested a positive correlation between T4 and sperm concentration (Meeker et al, 2007). A single study has reported some improvement in sperm count and motility in hypothyroid men after achieving euthyroidism with T4 (Jaya Kumar et al, 1990). No more studies have been undertaken to explore the role of thyroid hormones in treating male infertility. It is clear from all the above evidence that thyroid hormone treatment has potential to treat infertility only in individuals in whom infertility is traceable to thyroid deficiency.
Hormonal Treatments Aimed at Improving the Chances of Sperm Retrieval for IVF Techniques
IVF is carried out when it is impossible to achieve natural pregnancy
because of either male- or female-factor infertility. ICSI or IVF has also
been recommended when pregnancy has not occurred after 12 months of treatment
with gonadotropins and sperm concentration is <5 x 106/mL
(Burger and Baker, 1984;
Burris et al, 1988;
Vicari et al, 1992;
Kung et al, 1994;
Buchter et al, 1998;
Liu et al, 2002). IVF
requires a good number of sperm with normal motility and morphology, because
the fertilization is natural. When there are abnormalities in number, quality,
or function of sperm, ICSI can be carried out using even a single
spermatozoon. If the cause is male factor with severe oligozoospermia or
azoospermia, retrieval of even a single good sperm may be difficult.
Therefore, hormonal therapies have been undertaken to improve the chances of
retrieving healthy sperm for IVF and ICSI.
Idiopathic OAT has been treated to retrieve healthy spermatozoa using FSH
(Ashkenazi et al, 1999;
Dirnfeld et al, 2000), hCG and
FSH (Bakircioglu et al, 2007),
hMG (Beretta et al, 2005), and
recombinant FSH (Caroppo et al,
2003b) (Table 10).
A pregnancy rate of 33.7% has been obtained in a total of 86 men treated prior
to ICSI using FSH (Baccetti et al,
2004). Successful pregnancy by ICSI in azoospermic men has been
correlated with FSH levels of 20 IU/L
(Zitzmann et al, 2006). Sperm
ultrastructural (Caroppo et al,
2003b) and motility improvements
(Dirnfeld et al, 2000)
observed after FSH therapy in oligoasthenozoospermia have been correlated with
improved embryo implantation, spontaneous pregnancy rates, and higher success
rates in IVF (Ben-Rafael et al,
2000). Another study using testosterone undecanoate in individuals
with IVF failure reported no improvement
(Comhaire et al, 1995). The
studies undertaken to improve sperm retrieval are summarized in
Table 10. The above studies
seem promising because even if the increase in sperm count after the treatment
is minor, this may result in a manifold increase in the success rate of
IVF/ICSI.
|
Hormonal Treatment of Spermatozoa In Vitro to Improve Its Fertilizing Potential
A great proportion of infertile patients opt for in vitro methods. As
discussed in the previous section, the outcome of IVF depends upon the
capability of the sperm to fertilize the ovum. Despite retrieval of a
sufficient number of sperm from the testis, the sperm may not be capable of
fertilizing the egg. Therefore, spermatozoa have been subjected to various in
vitro hormonal treatments to achieve higher IVF fertilization rates.
Relaxin— Relaxin has been reported to improve normal boar spermatozoal motility (Carrell et al, 1995; Han et al, 2006; Miah et al, 2006), accelerate acrosome reaction (Carrell et al, 1995) and rate of glucose utilization (Miah et al, 2006), and improve zona-free hamster egg penetration (Carrell et al, 1995; Han et al, 2006). Endogenous relaxin may play a role in delaying declines of motility and of the grade of forward progress in ejaculated sperm (Essig et al, 1982).
A study designed to investigate the effect of purified porcine relaxin on spermatozoa obtained from oligozoospermic (n = 10), asthenozoospermic (n = 11), and normozoospermic (n = 10) men reported significant enhancement of sperm motility and hamster egg penetration capacity (Park et al, 1988). Contrasting results have been obtained wherein relaxin treatment did not improve the motility of normal spermatozoa at any of the concentrations ranging from 3 to 3000 ng/mL (Harris et al, 1988; Neuwinger et al, 1990). One study analyzed effects of the combined application of porcine relaxin and prostaglandins on human spermatozoa at the concentration of 25 µg/mL (prostaglandin E2 [PGE2]) and 100 ng/mL (relaxin). Both improved motility independently in washed spermatozoa; the 2 combined had no effect on fresh normal semen, and relaxin but not PGE2 enhanced motility in semen incubated at 37°C. This suggests that the concentration of relaxin and prostaglandin that occurs in normal semen is the maximal available that has effects on motility (Colon et al, 1986). The number of studies on relaxin has been too low to draw a conclusion about its efficacy.
GH— rbGH and recombinant human insulin-like growth factor-I (rhIGF-I) were reported to maintain motility longer after 24-hour treatment at room temperature in mature equine spermatozoa without any effects on hyperactivation. This property of rbGH and rhIGF-I can be utilized to store spermatozoa longer at room temperature (Champion et al, 2002).
Müllerian Inhibiting Substance— Müllerian inhibiting substance (MIS) is a hormone present in seminal plasma. MIS inhibits the development of Müllerian ducts in males during prenatal development. But MIS is also present in adult male semen, where its function is unknown. In a study conducted to see the effect of MIS on spermatozoa, MIS was found to improve both sperm viability and motility (Siow et al, 1998). Therefore, MIS may be useful in storing spermatozoa for a longer time.
Conclusion and Future Directions
Maximum numbers of studies have been conducted to enhance spermatogenesis
with the aim of achieving natural pregnancies using various hormones. The
comparison across these hormones shows good efficacy of GnRH in
hypogonadotropic hypogonadism arising at the hypothalamic level. But mixed
gonadotropin promises treatment to a good extent in hypogonadotropic
hypogonadism arising at either hypothalamus or pituitary. Because some
controversial observations are evident, further studies may lend support to
these conclusions. FSH, testosterone, GH, and thyroid hormones all seem to be
ineffective in idiopathic infertility, except that GH and thyroid hormones may
serve as supplements in infertile patients with associated GH deficiency and
hypothyroidism, respectively. Among antiestrogens, tamoxifen in combination
with kallikrein and/or testosterone is highly effective for improving sperm
count and motility, and results in good pregnancy rates. Clomiphene citrate is
equally effective in treating infertility, with highly significant increases
in sperm count, motility, and morphology along with good pregnancy rates.
Because natural estrogens have several beneficial effects, widespread use of
antiestrogens should be discouraged. Therefore, tissue-specific antiestrogens
should be developed especially for young adults.
Comparison between exogenous gonadotropin administration and enhanced in vivo gonadotropin production by using antiestrogens has shown better results in the latter. Looking at the above observations, it seems that stimulation of in vivo hormone production using various exogenous hormonal or nonhormonal agents should produce better results than direct exogenous administration of the target hormones. For example, a study using Panax ginseng reported an increase in testosterone and a subsequent increase in sperm count and motility (Salvati et al, 1996). On the other hand, as discussed above, direct testosterone injection suppresses spermatogenesis rather than treating infertility. Given this, therapies inducing testosterone production in vivo may be effective in treatment, rather than exogenous administration of testosterone, which acts as a contraceptive.
Among other categories of treatment regimens, the rate of sperm retrieval for IVF can be enhanced using various gonadotropins, and in vitro hormonal treatments of spermatozoa may prolong life of stored sperm without significant loss of motility. As is true for every therapy, hormonal treatments should be followed for any detrimental side effects, such as irreversible azoospermia or damage to the germinal epithelium. For example, it has been reported that tamoxifen disrupted the testicular seminiferous epithelium and induced the formation of multinucleated cells in the testis (Damber et al, 1989; Krause et al, 1992; D'Souza, 2004). In some studies, rebound testosterone therapy has been discouraged, because it leads to azoospermia in some subjects (Charny and Gordon, 1978; Comhaire, 1990).
The best parameter to follow in infertility treatment would be the final outcome in the form of conception rather than a simple increase in sperm count/motility. But almost 30% of the studies did not follow the patients for pregnancy outcomes. Further, among the oligozoospermic patients, there is always a probability, albeit low, of natural pregnancy. Out of the total, merely 23% of studies included placebo control. Among certain studies not using the placebo control, there had been marginal positive outcomes, which are difficult to discriminate from chance events. Therefore, a well-designed study must use a placebo control group to estimate the frequency of natural pregnancies.
Most of the studies discussed in this review have included patients with low sperm counts (oligozoospermic) with or without compromised sperm motility and/or morphology. Maximum numbers of studies have not included azoospermic patients. Hormonal disturbances mostly reduce spermatogenesis level (causing oligozoospermia) except when there is complete lack of hormone function because of mutation in its receptor (causing azoospermia). In other cases, azoospermia must be the result of lack of a crucial component of the spermatogenesis process, such as in Sertoli cell–only syndrome. Therefore, in cases of azoospermia, merely fulfilling the hormonal requirements would not help, and it remains a challenge to treat azoospermia.
In brief, hormonal therapies bear good promise, but only in cases with hormonal deficiency. Because the etiology differs a lot in infertility cases, it is difficult to estimate the success rate of hormone therapy. It would be illogical to expect a positive outcome with a hormone already present at a normal level in the patient. Therefore, studies using specific hormones in a highly characterized pool of patients for particular endocrine deficiencies are encouraged. Even if the patients are uncharacterized, they should be identified as responders or nonresponders at the beginning of the study, so that an appropriate therapy can be undertaken. Nevertheless, the dietary habits, lifestyle, and overall health status of the individual should also be monitored before and during the therapy.
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