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Human chorionic gonadotropin treatment: a viable option for management of secondary hypogonadism and male infertility (2020)
Julius Fink, Brad J. Schoenfeld, Anthony C. Hackney, Takahiro Maekawa & Shigeo Horie
Abstract
Introduction: Low testosterone and its symptoms is a condition affecting many males with severe repercussions on health. Testosterone affects metabolism, bones, joints and ligaments, the cardiovascular system, liver, sexual functions, muscle mass, and the nervous system. Nowadays, due to recent research showing the benefits of testosterone replacement therapy, this treatment is gaining in popularity among aging men. However, testosterone replacement can increase the risk of infertility.
Areas covered: Human Chorionic Gonadotropin (HCG) is used in the treatment of male infertility due to its Luteinizing Hormone (LH) -like action triggering testosterone and sperm production. Due to these positive effects on testosterone production, HCG has also been used to treat secondary hypogonadism. In this review, based on a literature review for the years 1977–2020 via Google Scholar, we summarize the current research on HCG as a treatment for patients suffering from low testosterone and provide an overview of the pros and contras of HCG therapy as compared to testosterone replacement therapy for the treatment of secondary hypogonadism.
Expert opinion: The testosterone and sperm production triggering effects of HCG without the side effects on fertility seen in testosterone replacement therapy make HCG therapy a prime candidate for patients suffering from secondary hypogonadism.
1. Introduction
The traditional treatment method for patients suffering from low testosterone symptoms is testosterone replacement therapy (TRT). However, TRT is associated with several side effects, especially the risk of infertility. As an alternative treatment, HCG has been introduced to treat low testosterone symptoms without the side effects of exogenous testosterone administration. We reviewed the current body of research in order to assess the pros and contras of both TRT and HCG treatment for the treatment of low testosterone symptoms. TRT has been gaining in popularity after numerous recent studies advocating its many health-related benefits in male patients; i.e., positive effects on glucose metabolism, muscle mass, bone mass density, anti-inflammation, depression, and erectile dysfunction have been reported [1-7]. However, TRT is also associated with several potential side effects such as a decrease in sperm count and motility leading to infertility, an increase of estradiol leading to water retention, an increase of red blood cells and high blood pressure, gynecomastia, an increase in dihydrotestosterone (DHT) leading to skin problems and hair loss [8,9]. Furthermore, even though the correlation between prostate cancer and testosterone levels has been widely refuted during the last decade [10,11] TRT seems to increase prostate-specific antigen (PSA) [12]. In light of these side effects, many patients and physicians tend to be reluctant to use this treatment. This seems especially true for young patients planning to have children in the future. For this reason, this latter group may benefit from a different method to increase testosterone due to the decrease in sperm and the ensuing risk of infertility of TRT.
Human chorionic gonadotropin (HCG) is originally released by the placenta after implantation. However, HCG is also the analog of luteinizing hormone (LH) produced in the pituitary gland. LH activates the testosterone and sperm production mechanism within the testes and HCG is therefore used to treat infertility in males [13,14]. As compared to TRT, HCG treatment has been shown to minimize side effects, especially those in hematocrit, estradiol, prostate volume, and PSA increases [15]. In fact, the European Academy of Andrology guidelines on the investigation, treatment, and monitoring of functional hypogonadism recommend gonadotropin therapy when fertility is desired in patients suffering from secondary hypogonadism [16]. This manuscript will review potential applications of HCG treatment as a method to restore healthy testosterone levels in men suffering from secondary hypogonadism while comparing the benefits and disadvantages of HCG treatment on the one side and TRT on the other.
3. Function of HCG
HCG is a member of the glycoprotein hormone family which includes LH, thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH). HCG is a hormone involved in embryonic signaling and is a key element of gestations development during pregnancy. HCG is produced mainly by differentiated syncytiotrophoblasts and activates multiple pathways via binding to the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) among others. HCG regulates angiogenesis in the uterine endothelium, myometrial quiescence, and immunomodulation at the maternal-fetal interface [18]. Within the HCG molecule, the αsubunit (comprised of 93-amino acid, 14.5 kD) of HCG has some homologies with TSH, LH, and FSH, and the βsubunit (comprised of 145-amino acid, 22.2kD) homology to LH is over 80% [18]. The βsubunit of LH comprises 121 amino acids. The difference of amino acids 121-145 is called the C-terminal peptide (CTP) and makes HCG antibodies also react to LH as well as the other way round [18]. Due to their homogeneity, HCG binds to the LHCGR and mimics the effects of LH, making it a powerful actor in improving sperm and testosterone production. In fact, a recent animal study discovered that HCG is about 10 times more potent than LH in cAMP activation and slightly more potent on cAMP-dependent Erk1/2 phosphorylation [19]. Interestingly though, they could not observe any significant differences between LH and HCG treatments when comparing the activation of downstream signals involving Creb phosphorylation, Stard1 gene expression, and testosterone synthesis [19]. The testosterone-stimulating properties of HCG make it a prime candidate for men suffering from chronically low testosterone levels.
4. Different forms of secondary hypogonadism
5. HCG treatment as testosterone replacements therapy
HCG can raise endogenous testosterone while maintaining or even increasing several fertility parameters such as sperm volume and motility, especially when used in combination with clomiphene citrate, tamoxifen, anastrozole, or recombinant follicle‐stimulating hormone (rFSH) [13], [20]. If fertility is the main purpose of the treatment, sequential administration of HCG and rFSH seems to lead to promising outcomes [21]. It is important, however, to assess the symptomatic improvements of HCG as compared to TRT and not focus solely on the serum testosterone response achieved with the treatment. For example, one recent study investigated the effects of HCG (1500 IU/ 3 times per week) in idiopathic hypogonadotropic hypogonadism [22]. It is known that TRT improves symptoms of metabolic syndrome, diabetes, and cardiovascular diseases in those patients. Six months of HCG treatment led to improvements in homeostasis model assessment of insulin resistance (HOMA-IR), basal insulin levels, triglyceride level, body fat, and waist-to-hip ratio. These results indicate similar results as those observed with TRT [22]. Another study showed that HCG treatment (5000 IU, twice per week) in patients with nonorganic erectile failure or lack of sexual desire does improve several sexual parameters as compared with placebo [23]. Interestingly, these effects on sexual behavior did not correlate with serum testosterone levels [23]. Further research with regard to the symptomatic effects of HCG on patients suffering from symptoms due to hypogonadism is important in order to assess the potential of HCG as a cure for secondary hypogonadism.
5.1 Effects on intratesticular testosterone
Exogenous testosterone administration suppresses intratesticular testosterone (ITT), which is crucial for the production of sperm [24]. In such patients, ITT has been shown to be suppressed by 94%. However, with every other day injections of HCG at dosages of 125IU, ITT was only 25% less than baseline, with 250IU 7% less and with 500IU 26% greater than the baseline [25]. In another study, 37 normal men were treated with GnRH antagonist acyline and attributed to one of the following low dose HCG groups: 0, 15, 60, or 125 IU sc every other day or 7.5 g daily testosterone gel for 10 days. In order to measure ITT, testicular fluid was retrieved via percutaneous aspiration at baseline and after 10 days of treatment. The median baseline ITT was 2508 nmol/liter. ITT improved in a dose-dependent manner: 15 IU HCG group reached an ITT of 136 nmol, 60 IU HCG group reached an ITT of 319 nmol, and 125 IU HCG group reached an ITT of 987 nmol/liter. Serum HCG was significantly correlated with both ITT and serum testosterone [24,26]. These studies indicate that HCG can significantly increase ITT in a dose-dependent manner and that dosages between 250 and 500 IU might be optimal to restore physiological ITT levels.
5.2 Effects on serum testosterone
A weekly dosage of 4500IU spread over 3 weekly injections has shown to lead to normal testosterone levels in isolated HH men [27]. Another study showed that single injections of 400IU, 2000IU, and 4000IU of HCG led to significant serum testosterone concentrations in hypogonadal as well as eugonadal males without differences among the groups after administration [28]. In hypogonadal men, 400IU, 2000IU, and 4000IU of HCG increased testosterone from about 200 to 400 ng/dl. In eugonadal men, 400IU, 2000IU, and 4000IU of HCG led to an increase from about 450 to 700 ng/dl in testosterone [28]. Interestingly, higher doses of HCG did not lead to greater testosterone level increases [28]. Another study showed similar results, with no differences in serum testosterone after single injections of 1500, 3000, or 4500IU of HCG, with testosterone increasing 24 hours post-injection and peaking 3-4 days later [29]. Serum testosterone peaked 3 days after injection [28].
From the above information, it can be suggested that low dose HCG (~500IU) injected 3 times per week can restore healthy serum and intratesticular testosterone levels in HH patients. The higher dosages used in infertility treatment to trigger sperm production might not be necessary if the goal is to increase serum testosterone levels. That is, combined treatment with HCG followed by rFSH might also be potent in order to induce fertility [21].
Indeed, HCG dosages used in the treatment of infertility can range from 3,000 to 10,000 IU 2-3 times per week [30]. One study showed that 3-6 months (1000 IU 3 times/week or 2000IU 2 times/week) of HCG treatment in 100 males with hypogonadotropic hypogonadism leads to normal serum testosterone concentrations despite the fact that 81 patients remained azoospermic [31]. These data show that low dose HCG treatment is very effective in restoring normal serum testosterone levels, however, spermatogenesis might require higher dosages of HCG. The exact mechanism by which HCG affects sperm production besides testosterone increase is not completely understood yet and needs further investigation. We summarized studies involving HCG treatment on testosterone and/or fertility parameters in Table 1.
6. Benefits of HCG vs. TRT
7. Intramuscular vs. Subcutaneous injections
The bioavailability (plasma concentration area under the curve and maximum concentration) of HCG has been shown to be higher after intramuscular injection as compared to subcutaneous injection in women [35]. On the other hand, another study showed higher serum HCG concentrations after subcutaneous injection as compared to intramuscular injection in women [36]. In male patients, one study compared the steroidogenesis in response to either intramuscular or subcutaneous HCG administration up to 144 hours post-injection [37]. As compared to intramuscular injection, subcutaneous injection led to a delayed peak in serum HCG levels, however, interestingly testosterone, LH and FSH did not show any significant differences in either form of administration [37]. Evidence would suggest that in order to maintain steady testosterone levels, frequent subcutaneous HCG might be easier and minimize scar tissue at the injection sites.
8. Side effects of HCG treatment
Since HCG treatment raises serum testosterone levels, it can lead to similar side effects as seen in direct TRT, including gynecomastia, high blood pressure, acne, hair loss and raises in estrogen potentially leading to gynecomastia. However, unlike supplementation with supraphysiological doses of testosterone as seen in doping, physiological serum testosterone increases triggered by HCG supplementation only rarely result in side effects (Table 2). Moreover, as compared to TRT, HCG treatment seems to have fewer side effects with regard to affecting hematocrit, estradiol, prostate volume, and PSA increases [15]. Interestingly, serum testosterone seems to peak at 72 hours post HCG injection and significantly correlates with estradiol peaks observed 24 hours after injection [38]. Therefore similar to TRT, even though not in line with guidelines, ancillary drugs such as aromatase inhibitors, selective estrogen receptor modulators, or 5α-reductase inhibitors are used off-label in some rare cases of severe side effects due to increased serum estradiol or DHT levels. However, as opposed to TRT, HCG does not increase the risk of infertility but rather improves fertility. It is currently unknown if long-term administration of HCG can lead to side effects such as gonadotropin resistance. (Table 2)
9. Choosing the right treatment (HCG vs. TRT)
10. Conclusion
HCG therapy is an effective treatment for patients suffering from infertility, often restoring healthy sperm production. However, HCG also increases serum and intratesticular testosterone levels, making it a prime candidate to treat patients with secondary hypogonadism. Even though the cost and injection frequency might be slightly higher as compared to TRT, HCG alone or used with TRT might be the best option for patients who desire to have children in the future. Depending on the response to HCG alone, concomitant TRT might be necessary to bring serum testosterone levels to the desired levels. Responses of serum testosterone levels seem to be independent of the dose of HCG and to peak 3 days post-injection. Therefore, low doses of ~400 IU HCG injected every 3 days intramuscularly or subcutaneously might lead to a significant increase of serum and intratesticular testosterone with few daily fluctuations in levels. Indeed, high dosages commonly seen in the treatment of male infertility going as high as 5000 IU several times per week might be unnecessary if the goal is not to increase sperm production but rather to increase testosterone only. In summary, HCG might be a safe, affordable, and effective method to restore healthy testosterone levels in males suffering from secondary hypogonadism. Nonetheless, further clinical trials should be carried out to demonstrate and elucidate the benefits of HCG therapy.
11. Expert opinion
*The HPG axis seems responsive to HCG in a similar fashion as LH and self-regulates the testosterone production within the testes in an amount of independent manner. Doses of HCG as low as 400 IU seem to significantly increase serum testosterone levels and even with dosages, 10 times that amount (4000 IU), the serum testosterone elevations seem similar to that of a 400 IU dosage (i.e., remaining within the physiological range). Rather than sensing the amount of HCG and accordingly producing testosterone, even small amounts of HCG seem to maximize the response for testosterone production within the testes probably due to receptor sensitivity.
Julius Fink, Brad J. Schoenfeld, Anthony C. Hackney, Takahiro Maekawa & Shigeo Horie
Abstract
Introduction: Low testosterone and its symptoms is a condition affecting many males with severe repercussions on health. Testosterone affects metabolism, bones, joints and ligaments, the cardiovascular system, liver, sexual functions, muscle mass, and the nervous system. Nowadays, due to recent research showing the benefits of testosterone replacement therapy, this treatment is gaining in popularity among aging men. However, testosterone replacement can increase the risk of infertility.
Areas covered: Human Chorionic Gonadotropin (HCG) is used in the treatment of male infertility due to its Luteinizing Hormone (LH) -like action triggering testosterone and sperm production. Due to these positive effects on testosterone production, HCG has also been used to treat secondary hypogonadism. In this review, based on a literature review for the years 1977–2020 via Google Scholar, we summarize the current research on HCG as a treatment for patients suffering from low testosterone and provide an overview of the pros and contras of HCG therapy as compared to testosterone replacement therapy for the treatment of secondary hypogonadism.
Expert opinion: The testosterone and sperm production triggering effects of HCG without the side effects on fertility seen in testosterone replacement therapy make HCG therapy a prime candidate for patients suffering from secondary hypogonadism.
1. Introduction
The traditional treatment method for patients suffering from low testosterone symptoms is testosterone replacement therapy (TRT). However, TRT is associated with several side effects, especially the risk of infertility. As an alternative treatment, HCG has been introduced to treat low testosterone symptoms without the side effects of exogenous testosterone administration. We reviewed the current body of research in order to assess the pros and contras of both TRT and HCG treatment for the treatment of low testosterone symptoms. TRT has been gaining in popularity after numerous recent studies advocating its many health-related benefits in male patients; i.e., positive effects on glucose metabolism, muscle mass, bone mass density, anti-inflammation, depression, and erectile dysfunction have been reported [1-7]. However, TRT is also associated with several potential side effects such as a decrease in sperm count and motility leading to infertility, an increase of estradiol leading to water retention, an increase of red blood cells and high blood pressure, gynecomastia, an increase in dihydrotestosterone (DHT) leading to skin problems and hair loss [8,9]. Furthermore, even though the correlation between prostate cancer and testosterone levels has been widely refuted during the last decade [10,11] TRT seems to increase prostate-specific antigen (PSA) [12]. In light of these side effects, many patients and physicians tend to be reluctant to use this treatment. This seems especially true for young patients planning to have children in the future. For this reason, this latter group may benefit from a different method to increase testosterone due to the decrease in sperm and the ensuing risk of infertility of TRT.
Human chorionic gonadotropin (HCG) is originally released by the placenta after implantation. However, HCG is also the analog of luteinizing hormone (LH) produced in the pituitary gland. LH activates the testosterone and sperm production mechanism within the testes and HCG is therefore used to treat infertility in males [13,14]. As compared to TRT, HCG treatment has been shown to minimize side effects, especially those in hematocrit, estradiol, prostate volume, and PSA increases [15]. In fact, the European Academy of Andrology guidelines on the investigation, treatment, and monitoring of functional hypogonadism recommend gonadotropin therapy when fertility is desired in patients suffering from secondary hypogonadism [16]. This manuscript will review potential applications of HCG treatment as a method to restore healthy testosterone levels in men suffering from secondary hypogonadism while comparing the benefits and disadvantages of HCG treatment on the one side and TRT on the other.
3. Function of HCG
HCG is a member of the glycoprotein hormone family which includes LH, thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH). HCG is a hormone involved in embryonic signaling and is a key element of gestations development during pregnancy. HCG is produced mainly by differentiated syncytiotrophoblasts and activates multiple pathways via binding to the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) among others. HCG regulates angiogenesis in the uterine endothelium, myometrial quiescence, and immunomodulation at the maternal-fetal interface [18]. Within the HCG molecule, the αsubunit (comprised of 93-amino acid, 14.5 kD) of HCG has some homologies with TSH, LH, and FSH, and the βsubunit (comprised of 145-amino acid, 22.2kD) homology to LH is over 80% [18]. The βsubunit of LH comprises 121 amino acids. The difference of amino acids 121-145 is called the C-terminal peptide (CTP) and makes HCG antibodies also react to LH as well as the other way round [18]. Due to their homogeneity, HCG binds to the LHCGR and mimics the effects of LH, making it a powerful actor in improving sperm and testosterone production. In fact, a recent animal study discovered that HCG is about 10 times more potent than LH in cAMP activation and slightly more potent on cAMP-dependent Erk1/2 phosphorylation [19]. Interestingly though, they could not observe any significant differences between LH and HCG treatments when comparing the activation of downstream signals involving Creb phosphorylation, Stard1 gene expression, and testosterone synthesis [19]. The testosterone-stimulating properties of HCG make it a prime candidate for men suffering from chronically low testosterone levels.
4. Different forms of secondary hypogonadism
5. HCG treatment as testosterone replacements therapy
HCG can raise endogenous testosterone while maintaining or even increasing several fertility parameters such as sperm volume and motility, especially when used in combination with clomiphene citrate, tamoxifen, anastrozole, or recombinant follicle‐stimulating hormone (rFSH) [13], [20]. If fertility is the main purpose of the treatment, sequential administration of HCG and rFSH seems to lead to promising outcomes [21]. It is important, however, to assess the symptomatic improvements of HCG as compared to TRT and not focus solely on the serum testosterone response achieved with the treatment. For example, one recent study investigated the effects of HCG (1500 IU/ 3 times per week) in idiopathic hypogonadotropic hypogonadism [22]. It is known that TRT improves symptoms of metabolic syndrome, diabetes, and cardiovascular diseases in those patients. Six months of HCG treatment led to improvements in homeostasis model assessment of insulin resistance (HOMA-IR), basal insulin levels, triglyceride level, body fat, and waist-to-hip ratio. These results indicate similar results as those observed with TRT [22]. Another study showed that HCG treatment (5000 IU, twice per week) in patients with nonorganic erectile failure or lack of sexual desire does improve several sexual parameters as compared with placebo [23]. Interestingly, these effects on sexual behavior did not correlate with serum testosterone levels [23]. Further research with regard to the symptomatic effects of HCG on patients suffering from symptoms due to hypogonadism is important in order to assess the potential of HCG as a cure for secondary hypogonadism.
5.1 Effects on intratesticular testosterone
Exogenous testosterone administration suppresses intratesticular testosterone (ITT), which is crucial for the production of sperm [24]. In such patients, ITT has been shown to be suppressed by 94%. However, with every other day injections of HCG at dosages of 125IU, ITT was only 25% less than baseline, with 250IU 7% less and with 500IU 26% greater than the baseline [25]. In another study, 37 normal men were treated with GnRH antagonist acyline and attributed to one of the following low dose HCG groups: 0, 15, 60, or 125 IU sc every other day or 7.5 g daily testosterone gel for 10 days. In order to measure ITT, testicular fluid was retrieved via percutaneous aspiration at baseline and after 10 days of treatment. The median baseline ITT was 2508 nmol/liter. ITT improved in a dose-dependent manner: 15 IU HCG group reached an ITT of 136 nmol, 60 IU HCG group reached an ITT of 319 nmol, and 125 IU HCG group reached an ITT of 987 nmol/liter. Serum HCG was significantly correlated with both ITT and serum testosterone [24,26]. These studies indicate that HCG can significantly increase ITT in a dose-dependent manner and that dosages between 250 and 500 IU might be optimal to restore physiological ITT levels.
5.2 Effects on serum testosterone
A weekly dosage of 4500IU spread over 3 weekly injections has shown to lead to normal testosterone levels in isolated HH men [27]. Another study showed that single injections of 400IU, 2000IU, and 4000IU of HCG led to significant serum testosterone concentrations in hypogonadal as well as eugonadal males without differences among the groups after administration [28]. In hypogonadal men, 400IU, 2000IU, and 4000IU of HCG increased testosterone from about 200 to 400 ng/dl. In eugonadal men, 400IU, 2000IU, and 4000IU of HCG led to an increase from about 450 to 700 ng/dl in testosterone [28]. Interestingly, higher doses of HCG did not lead to greater testosterone level increases [28]. Another study showed similar results, with no differences in serum testosterone after single injections of 1500, 3000, or 4500IU of HCG, with testosterone increasing 24 hours post-injection and peaking 3-4 days later [29]. Serum testosterone peaked 3 days after injection [28].
From the above information, it can be suggested that low dose HCG (~500IU) injected 3 times per week can restore healthy serum and intratesticular testosterone levels in HH patients. The higher dosages used in infertility treatment to trigger sperm production might not be necessary if the goal is to increase serum testosterone levels. That is, combined treatment with HCG followed by rFSH might also be potent in order to induce fertility [21].
Indeed, HCG dosages used in the treatment of infertility can range from 3,000 to 10,000 IU 2-3 times per week [30]. One study showed that 3-6 months (1000 IU 3 times/week or 2000IU 2 times/week) of HCG treatment in 100 males with hypogonadotropic hypogonadism leads to normal serum testosterone concentrations despite the fact that 81 patients remained azoospermic [31]. These data show that low dose HCG treatment is very effective in restoring normal serum testosterone levels, however, spermatogenesis might require higher dosages of HCG. The exact mechanism by which HCG affects sperm production besides testosterone increase is not completely understood yet and needs further investigation. We summarized studies involving HCG treatment on testosterone and/or fertility parameters in Table 1.
6. Benefits of HCG vs. TRT
7. Intramuscular vs. Subcutaneous injections
The bioavailability (plasma concentration area under the curve and maximum concentration) of HCG has been shown to be higher after intramuscular injection as compared to subcutaneous injection in women [35]. On the other hand, another study showed higher serum HCG concentrations after subcutaneous injection as compared to intramuscular injection in women [36]. In male patients, one study compared the steroidogenesis in response to either intramuscular or subcutaneous HCG administration up to 144 hours post-injection [37]. As compared to intramuscular injection, subcutaneous injection led to a delayed peak in serum HCG levels, however, interestingly testosterone, LH and FSH did not show any significant differences in either form of administration [37]. Evidence would suggest that in order to maintain steady testosterone levels, frequent subcutaneous HCG might be easier and minimize scar tissue at the injection sites.
8. Side effects of HCG treatment
Since HCG treatment raises serum testosterone levels, it can lead to similar side effects as seen in direct TRT, including gynecomastia, high blood pressure, acne, hair loss and raises in estrogen potentially leading to gynecomastia. However, unlike supplementation with supraphysiological doses of testosterone as seen in doping, physiological serum testosterone increases triggered by HCG supplementation only rarely result in side effects (Table 2). Moreover, as compared to TRT, HCG treatment seems to have fewer side effects with regard to affecting hematocrit, estradiol, prostate volume, and PSA increases [15]. Interestingly, serum testosterone seems to peak at 72 hours post HCG injection and significantly correlates with estradiol peaks observed 24 hours after injection [38]. Therefore similar to TRT, even though not in line with guidelines, ancillary drugs such as aromatase inhibitors, selective estrogen receptor modulators, or 5α-reductase inhibitors are used off-label in some rare cases of severe side effects due to increased serum estradiol or DHT levels. However, as opposed to TRT, HCG does not increase the risk of infertility but rather improves fertility. It is currently unknown if long-term administration of HCG can lead to side effects such as gonadotropin resistance. (Table 2)
9. Choosing the right treatment (HCG vs. TRT)
10. Conclusion
HCG therapy is an effective treatment for patients suffering from infertility, often restoring healthy sperm production. However, HCG also increases serum and intratesticular testosterone levels, making it a prime candidate to treat patients with secondary hypogonadism. Even though the cost and injection frequency might be slightly higher as compared to TRT, HCG alone or used with TRT might be the best option for patients who desire to have children in the future. Depending on the response to HCG alone, concomitant TRT might be necessary to bring serum testosterone levels to the desired levels. Responses of serum testosterone levels seem to be independent of the dose of HCG and to peak 3 days post-injection. Therefore, low doses of ~400 IU HCG injected every 3 days intramuscularly or subcutaneously might lead to a significant increase of serum and intratesticular testosterone with few daily fluctuations in levels. Indeed, high dosages commonly seen in the treatment of male infertility going as high as 5000 IU several times per week might be unnecessary if the goal is not to increase sperm production but rather to increase testosterone only. In summary, HCG might be a safe, affordable, and effective method to restore healthy testosterone levels in males suffering from secondary hypogonadism. Nonetheless, further clinical trials should be carried out to demonstrate and elucidate the benefits of HCG therapy.
11. Expert opinion
*The HPG axis seems responsive to HCG in a similar fashion as LH and self-regulates the testosterone production within the testes in an amount of independent manner. Doses of HCG as low as 400 IU seem to significantly increase serum testosterone levels and even with dosages, 10 times that amount (4000 IU), the serum testosterone elevations seem similar to that of a 400 IU dosage (i.e., remaining within the physiological range). Rather than sensing the amount of HCG and accordingly producing testosterone, even small amounts of HCG seem to maximize the response for testosterone production within the testes probably due to receptor sensitivity.
