madman
Super Moderator
Stimulation of Leydig and Sertoli Cellular Secretory Function by Anti-Oestrogens: Tamoxifen (2020)
Anastasia Dimakopoulou, Daniel Foran, Channa N. Jayasena and Suks Minhas
Abstract: Tamoxifen is a selective estrogen receptor modulator (SERM). SERMs act on estrogen receptors to inhibit estradiol mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby upregulating gonadotrophin secretion and release from the pituitary. Hence, Tamoxifen is used to upregulate activation of the HPG axis in the treatment of male-factor infertility. However, due to a lack of robust evidence, Tamoxifen has not been FDA approved for use in male-factor infertility and so its use is currently off-label. In this study, we performed a literature search of the OVID Medline database and identified 37 studies describing the effects of tamoxifen which we then reviewed. Evidence suggests Tamoxifen effectively increases androgen levels and sperm concentrations in males with idiopathic oligozoospermia. Evidence for increased motility and pregnancy rates in these patients is less conclusive. Further randomized control trials are needed to elucidate the safety of Tamoxifen combination therapies and their efficacy in improving pregnancy rates.
1. INTRODUCTION
Tamoxifen is a selective estrogen receptor modulator (SERM) and is an off-label drug widely used in the treatment of idiopathic male factor infertility. Tamoxifen (TAM) originates from triphenylethylene which has anti-estrogenic properties and competes with estrogen at the hypothalamic level to stimulate gonadotropin secretion [1]. A randomized controlled study in 1976, demonstrated that men taking TAM doubled their testosterone and sperm concentration compared to the control group. There was no significant change in sperm motility [2]. Over the last forty years, several studies have been developed to determine the effects of Tamoxifen on testicular steroidogenesis and sperm production.
Spermatogenesis occurs within the testicle whilst the overall control of sperm production is under the control of the Hypothalamic- Pituitary-Gonadal (HPG) axis. The HPG axis relies on the interaction between the hypothalamus that releases a gonadotrophin-releasing hormone (GnRH), the pituitary promoting luteinizing hormone (LH) as well as follicle-stimulating hormone (FSH) secretion, and finally the testicle [3]. LH binds to receptors on the interstitial Leydig cells. Subsequently, LH stimulates testosterone production, whilst FSH stimulates Sertoli cell function for spermatogenesis. In cases of male gonadal dysfunction, positive feedback is generated via the hypothalamus to stimulate the pituitary secretion of gonadotrophins and enhance testicular function (Fig. 1).
Estrogen receptor blockers such as Tamoxifen, mediate the process by counteracting estrogens at hypothalamic receptor sites [5]. Estrogen receptor blockers also deliver positive feedback to raise testosterone and possibly induce spermatogenesis in oligospermic men [6, 7]. Tamoxifen is therefore considered a potential therapy for male infertility and indications for use in this setting, is an area of increasing interest.
Male factor contributes to 50% of all cases of infertility [8] and is defined as the inability to conceive after 1 year of unprotected sexual intercourse [9]. Infertility affects 48.5 million couples globally [10] and other than in vitro fertilization for the female partner there is no effective drug treatment in men with idiopathic infertility. The World Health Organization recommends Tamoxifen as the first choice for the treatment of unexplained oligospermia, which contributes to approximately 30%-40% of cases of infertility [11]. We conducted a review of articles regarding the effects of Tamoxifen on androgens and sperm parameters to explain the action at Leydig and Sertoli cell level, as well as the relevant clinical implications and applications.
3. THE EFFECT OF TAMOXIFEN ON LEYDIG CELL SECRETORY FUNCTION
The testicle has two main physiological compartments. The extratubular compartment (outside the seminiferous tubules) and the intratubular (inside the seminiferous tubules). Leydig cells are interstitial cells located close to the seminiferous tubules, whereas Sertoli cells are part of the seminiferous tubules and assist the production of spermatozoa from pluripotent self-replenishing spermatogonial stem cells [3]. Pituitary LH binds to receptors on the Leydig cells located in the interstitial testicular tissue and stimulates testosterone production. Testosterone diffuses out of the Leydig cells into the systemic circulation. However, substantial testosterone concentrations of more than 100-fold higher compared to the systemic circulation, enter Sertoli cells to enhance spermatogenesis [4]. Spermatogenesis requires effective Testosterone secretion from the Leydig cells, as well as FSH action.
Anti-oestrogens, such as TAM, not only have indirect action at the hypothalamic level but also exert a direct effect on Leydig cells [13-15]. Additionally, LH stimulates Leydig cells and seminiferous tubules to increase their sensitivity to gonadotrophins. It is possible that TAM blocks estrogenic receptors on Leydig cells and enhances the conversion of testosterone to potent 5a-dehydrotestosterone (DHT) in the seminiferous tubules and epididymis [16]. Therefore, TAM increases androgens available at the level of the germinal epithelium [17] and optimizes the micro testicular environment for spermatogenesis.
Observational studies in Belgium in the early 1990s demonstrated that men with idiopathic oligospermia (sperm concentration <40mil/ml) and reduced sperm motility (sperm motility <50%) have low levels of seminal testosterone and DHT [18]. Testosterone is converted to DHT in the seminiferous tubules and correlates to higher sperm count or sperm motility. TAM leads to a significant rise in seminal DHT and is therefore recommended for use in oligospermic men with normal gonadotrophins [19]. A TAM dose of 20mg daily can increase significantly both testosterone levels and sperm density within 3 months; however, after 6 months of treatment the hypothalamic-pituitary receptors lose their sensitivity and androgen levels fall [20, 21].
It is difficult to predict response to TAM as a proportion of men may fail to respond. For example, hypergonadotrophic men fail to improve their testosterone levels as high gonadotrophins and low sperm counts are consistent with grossly defective testicular function [20]. TAM is best avoided in men with high baseline oestradiol, as estrogen levels increase significantly on TAM probably due to peripheral conversion of androgens to estrogens [22, 23]. Finally, doses of TAM higher than 20mg daily should be prescribed with caution as high androgen levels could potentially inhibitory pituitary action [23].
4. THE EFFECT OF TAMOXIFEN ON SERTOLI CELL SECRETORY FUNCTION
TAM has additional local effects on Sertoli cell function via stimulating FSH to induce sperm production. The concentration of spermatozoa in human semen is associated with a couple’s ability to achieve pregnancy. TAM may play a substantial role in cases of idiopathic oligospermia. Oligospermia is characterized as idiopathic when no obvious cause is identified for low sperm counts, such as varicocele, genital infection, or chronic disease. Open interventional studies demonstrate a significant increase in sperm concentration of oligospermic men with idiopathic infertility after 3-6 months of treatment [17, 19, 20, 23-31]. Even though T levels decrease after 6 months of treatment, the effect of spermatogenic waves most likely lasts longer and sperm concentration can increase up to 12 months after the introduction of TAM [25]. Sperm motility was also shown to improve significantly with TAM treatment in 5 open studies [16, 19, 24, 27, 29].
It is notable that several randomized controlled studies comparing TAM to placebo failed to reproduce favorable outcomes on Sertoli cell function and sperm concentration [13, 22, 32-34]. Participants were possibly not followed long enough or selected carefully regarding their likelihood to respond to TAM. Careful selection of men likely to benefit from TAM may improve treatment outcomes. It has been suggested that stimulation with TAM 40mg daily for one week increases FSH levels significantly in poor responders [28]. FSH levels increasing above reference range after stimulation with TAM, reveal defective testes unlikely to respond to further stimulation [30, 35]. Genetic studies may also allow for better discrimination between responders and non-responders. Patients receiving tamoxifen are influenced by cytochrome P4502D6 (CYP2D6) genetic variants. For example, Chinese men with homonymous (25% men with idiopathic infertility) or heterozygous (55% men with idiopathic infertility) genotype for the allele CYP2D6*10, have reduced enzyme activity and metabolize TAM at a slow rate. Slow TAM metabolizers are less likely to respond to such treatment. Therefore, these men have low sperm concentration, low motility, low normal morphology, and low spontaneous pregnancy rates on treatment with TAM compared to those with wild genotypes [36]. CYP2D6*10 genotypic analysis may be useful to choose men with idiopathic oligozoospermia more likely to benefit from TAM treatment.
Sperm parameters of oligospermic men demonstrate improvement after treatment with TAM. TAM improves the functional sperm fraction which is defined as the concentration of progressively motile spermatozoa with normal morphology in a semen sample [37-39]. Meta-analysis shows that TAM 20mg daily for 3-6 months improves sperm concentration and motility as well as spontaneous pregnancy rates [7]. In summary, TAM has a good safety profile and is an effective empirical medical therapy (Table 2).
5. TAMOXIFEN IN THE CONTEXT OF COMBINATION THERAPIES
A combination of TAM with other medication is used to increase efficacy and has limited indications. Aromatase inhibitors are occasionally given along with TAM to eliminate increments in estrogen levels, but results are controversial. Combination therapy with Testolactone has no effect on seminal parameters or pregnancy rates [44]. However, the combination of TAM with Anastrozole increases the T/oestradiol ratio in men with high oestrogen levels. As a result, sperm concentration, motility, and pregnancy rates increase significantly [43]. An area of concern is that TAM with Anastrozole requires frequent liver function monitoring, as liver enzymes rise in 10% of men on this combination [43].
It was previously hypothesized that Sertoli cell stimulation with TAM and T undecanoate increases motility in morphological normal spermatozoa. Spermatozoa stimulated with TAM and exogenous testosterone develop in an optimal environment with the best nuclear state, fertilizing capacity, and epididymal function [39]. However, exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis. Low LH reduces testosterone production by Leydig cells and diminishes spermatogenesis by Sertoli cells. Induction of spermatogenesis in men with steroid-induced infertility is achieved after discontinuation of exogenous steroids and prescription of hCG combined with TAM [6, 41].
Finally, the combination of TAM with Kallikrein has positive effects on sperm motility and possibly sperm concentration [45, 46]. Kallikrein in men with sperm concentration above 10mil/ml stimulates sperm metabolism and improves sperm motility [46]. Kallikrein is a proteinase that releases kinins from kininogens present in sperm plasma and stimulates sperm metabolism by activating fructolysis [46].
6. NOVEL CONCEPTS IN THE EFFECT OF TAMOXIFEN ON LEYDIG AND SERTOLI CELLS
Investigation on the anti-oxidant action of TAM is an area of increasing interest. TAM wields antioxidant actions at the testicular level to stimulate spermatogenesis. Reactive oxygen species (ROS) are generated in seminal plasma from endogenous sources such as leucocytes or immature spermatozoa. ROS is physiologically required for sperm movement and fertilization of the oocyte [47]. In cases of excessive oxidative stress, such as genital infections, varicocele, pollutants, and hormonal abnormalities, ROS exceeds the antioxidant capacity of free radical scavengers and the result is lipid peroxidation, apoptosis, and sperm DNA damage [48]. TAM can potentially increase seminal antioxidant capacity and enhance sperm concentration and morphology. The addition of l-carnitine to TAM, a quaternary ammonium compound that is key to spermatozoal metabolism is superior to monotherapy [49]. Seminal ROS measured via fluorescence decreased significantly in oligospermic men with unexplained infertility after treatment with TAM [42]. Recently a small comparative study demonstrated that TAM with folate for 3 months can significantly decrease sperm DNA tail length, which reflects the number of DNA breaks assessed by the Comet assay [31]. It is therefore indicated that TAM with folate could improve sperm quality compared to TAM treatment alone.
7. IMPLICATIONS ON PREGNANCY RATES
Interestingly, pregnancy rates on TAM varied from 21% to 40% for oligospermic men with idiopathic infertility [17, 19, 25]. These percentages were considered high when compared with other therapies for oligospermic men such as clomiphene, hMG, hCG, bromocriptine, mesterolone, kallikrein, or vitamins [26]. Hence data from studies mainly published in the 80s demonstrate that TAM can increase pregnancy rates compared with controls at a statistically significant level (OR 2.42; P=0.0004) [50, 51]. However, data generated before the 90s are considered historical as were mainly based on open studies. Four randomized controlled studies demonstrated that TAM treatment in men with unexplained infertility was associated with increased pregnancy rates compared to placebo [13, 32, 33, 43]. The Peto odds ratio for pregnancy was 2.87 (95% CI 1.44- 5.71). It remains unclear whether TAM was administered to improve assisted reproduction outcomes or natural conception. These data are also considered limited by the low number of positive events [52].
8. SAFETY ASPECTS
SERMs such as TAM are indicted for the treatment and prevention of breast cancer in women and anovulatory infertility. Common side effects include fluid retention, sickness, light-headedness, hot flushes and a two-fold increase in the risk of deep vein thrombosis [40]. Hot flushes can be debilitating in women with breast cancer taking estrogen synthesis inhibitors, such as TAM [53]. Hot flushes can potentially disrupt sleep, cause palpitations, dizziness, and anxiety resulting in low adherence in 38% of women with breast cancer [54]. Interestingly, administration of TAM in pubertal rats causes distortion of the seminiferous tubules, degeneration of Leydig cells, and spermatogenic arrest [55]. However, the use of TAM in hypogonadal men with low sperm count is off-label and side effects are uncommon or possibly underreported (Table 3). In some small studies such as case series, there were no side effects after a 6-month treatment [20, 41]. Other studies state that 3% of men may experience depression [34] and 16% of men experience loss of libido and hair loss [17]. According to a recent meta-analysis side, effects associated with the use of TAM include headache, gynecomastia, nausea, skin rash, testicular enlargement, loss of libido, and visual disturbances. These side effects are transient with low incidence [7]. Notably, 53% of men asked to participate in a TAM study for 3 months dropped out [16]. Men completing the study were found to have significantly high adrenal 11β-hydroxyandrostenedione levels, a potent adrenal androgen that is unclear whether it contributed to the high incidence of dropouts. Future studies are required to establish side effects associated with TAM treatment.
9. LIMITATIONS
Results from randomized placebo-controlled studies were not as impressive as results from open studies investigating the role of TAM in unexplained oligospermia. The cut-off for oligospermia after 2010 changed to less than 15 mil/ml from the original cut-off which was less than 20 mil/ml and in some studies less than 40mil/ml [56]. It is unclear whether men with lower sperm concentrations would have the same response compared to men in the 80s with higher sperm concentrations. Most men taking TAM treatment for oligospermia had no follow-up after the end of the study period and side effects or pregnancy rates remain in most cases difficult to establish.
*Future randomized placebo-control studies are required to investigate the effect of TAM on sperm parameters and pregnancy rates. Evaluation of adverse effects and longer follow-up of participants in future clinical trials would be essential to define the safety profile of TAM. Genetic studies could be the basis to identify poor TAM-responders and develop personalised therapies for men with idiopathic oligospermia.
CONCLUSION
TAM is an off-label treatment approved by WHO in the treatment of idiopathic oligospermia. Doses of TAM at 20mg daily can significantly increase androgen levels, total sperm count, and possibly sperm motility as demonstrated by fewer studies. Cautious selection of men that may benefit from the double action of TAM at central as well testicular level could improve clinical outcomes. A combination of Anastrozole has a role in men with high estrogen levels, however, more studies are required to demonstrate the efficacy and safety of the therapy. In summary, TAM use for 3-6 months is an off-label treatment for men with normal gonadotrophins and low sperm count. TAM can improve Leydig and Sertoli cell function in carefully selected oligospermic men with idiopathic infertility but does not necessarily increase pregnancy rates. Referral for assisted reproduction may still be indicated for the infertile couple.
Anastasia Dimakopoulou, Daniel Foran, Channa N. Jayasena and Suks Minhas
Abstract: Tamoxifen is a selective estrogen receptor modulator (SERM). SERMs act on estrogen receptors to inhibit estradiol mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby upregulating gonadotrophin secretion and release from the pituitary. Hence, Tamoxifen is used to upregulate activation of the HPG axis in the treatment of male-factor infertility. However, due to a lack of robust evidence, Tamoxifen has not been FDA approved for use in male-factor infertility and so its use is currently off-label. In this study, we performed a literature search of the OVID Medline database and identified 37 studies describing the effects of tamoxifen which we then reviewed. Evidence suggests Tamoxifen effectively increases androgen levels and sperm concentrations in males with idiopathic oligozoospermia. Evidence for increased motility and pregnancy rates in these patients is less conclusive. Further randomized control trials are needed to elucidate the safety of Tamoxifen combination therapies and their efficacy in improving pregnancy rates.
1. INTRODUCTION
Tamoxifen is a selective estrogen receptor modulator (SERM) and is an off-label drug widely used in the treatment of idiopathic male factor infertility. Tamoxifen (TAM) originates from triphenylethylene which has anti-estrogenic properties and competes with estrogen at the hypothalamic level to stimulate gonadotropin secretion [1]. A randomized controlled study in 1976, demonstrated that men taking TAM doubled their testosterone and sperm concentration compared to the control group. There was no significant change in sperm motility [2]. Over the last forty years, several studies have been developed to determine the effects of Tamoxifen on testicular steroidogenesis and sperm production.
Spermatogenesis occurs within the testicle whilst the overall control of sperm production is under the control of the Hypothalamic- Pituitary-Gonadal (HPG) axis. The HPG axis relies on the interaction between the hypothalamus that releases a gonadotrophin-releasing hormone (GnRH), the pituitary promoting luteinizing hormone (LH) as well as follicle-stimulating hormone (FSH) secretion, and finally the testicle [3]. LH binds to receptors on the interstitial Leydig cells. Subsequently, LH stimulates testosterone production, whilst FSH stimulates Sertoli cell function for spermatogenesis. In cases of male gonadal dysfunction, positive feedback is generated via the hypothalamus to stimulate the pituitary secretion of gonadotrophins and enhance testicular function (Fig. 1).
Estrogen receptor blockers such as Tamoxifen, mediate the process by counteracting estrogens at hypothalamic receptor sites [5]. Estrogen receptor blockers also deliver positive feedback to raise testosterone and possibly induce spermatogenesis in oligospermic men [6, 7]. Tamoxifen is therefore considered a potential therapy for male infertility and indications for use in this setting, is an area of increasing interest.
Male factor contributes to 50% of all cases of infertility [8] and is defined as the inability to conceive after 1 year of unprotected sexual intercourse [9]. Infertility affects 48.5 million couples globally [10] and other than in vitro fertilization for the female partner there is no effective drug treatment in men with idiopathic infertility. The World Health Organization recommends Tamoxifen as the first choice for the treatment of unexplained oligospermia, which contributes to approximately 30%-40% of cases of infertility [11]. We conducted a review of articles regarding the effects of Tamoxifen on androgens and sperm parameters to explain the action at Leydig and Sertoli cell level, as well as the relevant clinical implications and applications.
3. THE EFFECT OF TAMOXIFEN ON LEYDIG CELL SECRETORY FUNCTION
The testicle has two main physiological compartments. The extratubular compartment (outside the seminiferous tubules) and the intratubular (inside the seminiferous tubules). Leydig cells are interstitial cells located close to the seminiferous tubules, whereas Sertoli cells are part of the seminiferous tubules and assist the production of spermatozoa from pluripotent self-replenishing spermatogonial stem cells [3]. Pituitary LH binds to receptors on the Leydig cells located in the interstitial testicular tissue and stimulates testosterone production. Testosterone diffuses out of the Leydig cells into the systemic circulation. However, substantial testosterone concentrations of more than 100-fold higher compared to the systemic circulation, enter Sertoli cells to enhance spermatogenesis [4]. Spermatogenesis requires effective Testosterone secretion from the Leydig cells, as well as FSH action.
Anti-oestrogens, such as TAM, not only have indirect action at the hypothalamic level but also exert a direct effect on Leydig cells [13-15]. Additionally, LH stimulates Leydig cells and seminiferous tubules to increase their sensitivity to gonadotrophins. It is possible that TAM blocks estrogenic receptors on Leydig cells and enhances the conversion of testosterone to potent 5a-dehydrotestosterone (DHT) in the seminiferous tubules and epididymis [16]. Therefore, TAM increases androgens available at the level of the germinal epithelium [17] and optimizes the micro testicular environment for spermatogenesis.
Observational studies in Belgium in the early 1990s demonstrated that men with idiopathic oligospermia (sperm concentration <40mil/ml) and reduced sperm motility (sperm motility <50%) have low levels of seminal testosterone and DHT [18]. Testosterone is converted to DHT in the seminiferous tubules and correlates to higher sperm count or sperm motility. TAM leads to a significant rise in seminal DHT and is therefore recommended for use in oligospermic men with normal gonadotrophins [19]. A TAM dose of 20mg daily can increase significantly both testosterone levels and sperm density within 3 months; however, after 6 months of treatment the hypothalamic-pituitary receptors lose their sensitivity and androgen levels fall [20, 21].
It is difficult to predict response to TAM as a proportion of men may fail to respond. For example, hypergonadotrophic men fail to improve their testosterone levels as high gonadotrophins and low sperm counts are consistent with grossly defective testicular function [20]. TAM is best avoided in men with high baseline oestradiol, as estrogen levels increase significantly on TAM probably due to peripheral conversion of androgens to estrogens [22, 23]. Finally, doses of TAM higher than 20mg daily should be prescribed with caution as high androgen levels could potentially inhibitory pituitary action [23].
4. THE EFFECT OF TAMOXIFEN ON SERTOLI CELL SECRETORY FUNCTION
TAM has additional local effects on Sertoli cell function via stimulating FSH to induce sperm production. The concentration of spermatozoa in human semen is associated with a couple’s ability to achieve pregnancy. TAM may play a substantial role in cases of idiopathic oligospermia. Oligospermia is characterized as idiopathic when no obvious cause is identified for low sperm counts, such as varicocele, genital infection, or chronic disease. Open interventional studies demonstrate a significant increase in sperm concentration of oligospermic men with idiopathic infertility after 3-6 months of treatment [17, 19, 20, 23-31]. Even though T levels decrease after 6 months of treatment, the effect of spermatogenic waves most likely lasts longer and sperm concentration can increase up to 12 months after the introduction of TAM [25]. Sperm motility was also shown to improve significantly with TAM treatment in 5 open studies [16, 19, 24, 27, 29].
It is notable that several randomized controlled studies comparing TAM to placebo failed to reproduce favorable outcomes on Sertoli cell function and sperm concentration [13, 22, 32-34]. Participants were possibly not followed long enough or selected carefully regarding their likelihood to respond to TAM. Careful selection of men likely to benefit from TAM may improve treatment outcomes. It has been suggested that stimulation with TAM 40mg daily for one week increases FSH levels significantly in poor responders [28]. FSH levels increasing above reference range after stimulation with TAM, reveal defective testes unlikely to respond to further stimulation [30, 35]. Genetic studies may also allow for better discrimination between responders and non-responders. Patients receiving tamoxifen are influenced by cytochrome P4502D6 (CYP2D6) genetic variants. For example, Chinese men with homonymous (25% men with idiopathic infertility) or heterozygous (55% men with idiopathic infertility) genotype for the allele CYP2D6*10, have reduced enzyme activity and metabolize TAM at a slow rate. Slow TAM metabolizers are less likely to respond to such treatment. Therefore, these men have low sperm concentration, low motility, low normal morphology, and low spontaneous pregnancy rates on treatment with TAM compared to those with wild genotypes [36]. CYP2D6*10 genotypic analysis may be useful to choose men with idiopathic oligozoospermia more likely to benefit from TAM treatment.
Sperm parameters of oligospermic men demonstrate improvement after treatment with TAM. TAM improves the functional sperm fraction which is defined as the concentration of progressively motile spermatozoa with normal morphology in a semen sample [37-39]. Meta-analysis shows that TAM 20mg daily for 3-6 months improves sperm concentration and motility as well as spontaneous pregnancy rates [7]. In summary, TAM has a good safety profile and is an effective empirical medical therapy (Table 2).
5. TAMOXIFEN IN THE CONTEXT OF COMBINATION THERAPIES
A combination of TAM with other medication is used to increase efficacy and has limited indications. Aromatase inhibitors are occasionally given along with TAM to eliminate increments in estrogen levels, but results are controversial. Combination therapy with Testolactone has no effect on seminal parameters or pregnancy rates [44]. However, the combination of TAM with Anastrozole increases the T/oestradiol ratio in men with high oestrogen levels. As a result, sperm concentration, motility, and pregnancy rates increase significantly [43]. An area of concern is that TAM with Anastrozole requires frequent liver function monitoring, as liver enzymes rise in 10% of men on this combination [43].
It was previously hypothesized that Sertoli cell stimulation with TAM and T undecanoate increases motility in morphological normal spermatozoa. Spermatozoa stimulated with TAM and exogenous testosterone develop in an optimal environment with the best nuclear state, fertilizing capacity, and epididymal function [39]. However, exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis. Low LH reduces testosterone production by Leydig cells and diminishes spermatogenesis by Sertoli cells. Induction of spermatogenesis in men with steroid-induced infertility is achieved after discontinuation of exogenous steroids and prescription of hCG combined with TAM [6, 41].
Finally, the combination of TAM with Kallikrein has positive effects on sperm motility and possibly sperm concentration [45, 46]. Kallikrein in men with sperm concentration above 10mil/ml stimulates sperm metabolism and improves sperm motility [46]. Kallikrein is a proteinase that releases kinins from kininogens present in sperm plasma and stimulates sperm metabolism by activating fructolysis [46].
6. NOVEL CONCEPTS IN THE EFFECT OF TAMOXIFEN ON LEYDIG AND SERTOLI CELLS
Investigation on the anti-oxidant action of TAM is an area of increasing interest. TAM wields antioxidant actions at the testicular level to stimulate spermatogenesis. Reactive oxygen species (ROS) are generated in seminal plasma from endogenous sources such as leucocytes or immature spermatozoa. ROS is physiologically required for sperm movement and fertilization of the oocyte [47]. In cases of excessive oxidative stress, such as genital infections, varicocele, pollutants, and hormonal abnormalities, ROS exceeds the antioxidant capacity of free radical scavengers and the result is lipid peroxidation, apoptosis, and sperm DNA damage [48]. TAM can potentially increase seminal antioxidant capacity and enhance sperm concentration and morphology. The addition of l-carnitine to TAM, a quaternary ammonium compound that is key to spermatozoal metabolism is superior to monotherapy [49]. Seminal ROS measured via fluorescence decreased significantly in oligospermic men with unexplained infertility after treatment with TAM [42]. Recently a small comparative study demonstrated that TAM with folate for 3 months can significantly decrease sperm DNA tail length, which reflects the number of DNA breaks assessed by the Comet assay [31]. It is therefore indicated that TAM with folate could improve sperm quality compared to TAM treatment alone.
7. IMPLICATIONS ON PREGNANCY RATES
Interestingly, pregnancy rates on TAM varied from 21% to 40% for oligospermic men with idiopathic infertility [17, 19, 25]. These percentages were considered high when compared with other therapies for oligospermic men such as clomiphene, hMG, hCG, bromocriptine, mesterolone, kallikrein, or vitamins [26]. Hence data from studies mainly published in the 80s demonstrate that TAM can increase pregnancy rates compared with controls at a statistically significant level (OR 2.42; P=0.0004) [50, 51]. However, data generated before the 90s are considered historical as were mainly based on open studies. Four randomized controlled studies demonstrated that TAM treatment in men with unexplained infertility was associated with increased pregnancy rates compared to placebo [13, 32, 33, 43]. The Peto odds ratio for pregnancy was 2.87 (95% CI 1.44- 5.71). It remains unclear whether TAM was administered to improve assisted reproduction outcomes or natural conception. These data are also considered limited by the low number of positive events [52].
8. SAFETY ASPECTS
SERMs such as TAM are indicted for the treatment and prevention of breast cancer in women and anovulatory infertility. Common side effects include fluid retention, sickness, light-headedness, hot flushes and a two-fold increase in the risk of deep vein thrombosis [40]. Hot flushes can be debilitating in women with breast cancer taking estrogen synthesis inhibitors, such as TAM [53]. Hot flushes can potentially disrupt sleep, cause palpitations, dizziness, and anxiety resulting in low adherence in 38% of women with breast cancer [54]. Interestingly, administration of TAM in pubertal rats causes distortion of the seminiferous tubules, degeneration of Leydig cells, and spermatogenic arrest [55]. However, the use of TAM in hypogonadal men with low sperm count is off-label and side effects are uncommon or possibly underreported (Table 3). In some small studies such as case series, there were no side effects after a 6-month treatment [20, 41]. Other studies state that 3% of men may experience depression [34] and 16% of men experience loss of libido and hair loss [17]. According to a recent meta-analysis side, effects associated with the use of TAM include headache, gynecomastia, nausea, skin rash, testicular enlargement, loss of libido, and visual disturbances. These side effects are transient with low incidence [7]. Notably, 53% of men asked to participate in a TAM study for 3 months dropped out [16]. Men completing the study were found to have significantly high adrenal 11β-hydroxyandrostenedione levels, a potent adrenal androgen that is unclear whether it contributed to the high incidence of dropouts. Future studies are required to establish side effects associated with TAM treatment.
9. LIMITATIONS
Results from randomized placebo-controlled studies were not as impressive as results from open studies investigating the role of TAM in unexplained oligospermia. The cut-off for oligospermia after 2010 changed to less than 15 mil/ml from the original cut-off which was less than 20 mil/ml and in some studies less than 40mil/ml [56]. It is unclear whether men with lower sperm concentrations would have the same response compared to men in the 80s with higher sperm concentrations. Most men taking TAM treatment for oligospermia had no follow-up after the end of the study period and side effects or pregnancy rates remain in most cases difficult to establish.
*Future randomized placebo-control studies are required to investigate the effect of TAM on sperm parameters and pregnancy rates. Evaluation of adverse effects and longer follow-up of participants in future clinical trials would be essential to define the safety profile of TAM. Genetic studies could be the basis to identify poor TAM-responders and develop personalised therapies for men with idiopathic oligospermia.
CONCLUSION
TAM is an off-label treatment approved by WHO in the treatment of idiopathic oligospermia. Doses of TAM at 20mg daily can significantly increase androgen levels, total sperm count, and possibly sperm motility as demonstrated by fewer studies. Cautious selection of men that may benefit from the double action of TAM at central as well testicular level could improve clinical outcomes. A combination of Anastrozole has a role in men with high estrogen levels, however, more studies are required to demonstrate the efficacy and safety of the therapy. In summary, TAM use for 3-6 months is an off-label treatment for men with normal gonadotrophins and low sperm count. TAM can improve Leydig and Sertoli cell function in carefully selected oligospermic men with idiopathic infertility but does not necessarily increase pregnancy rates. Referral for assisted reproduction may still be indicated for the infertile couple.
