madman
Super Moderator
The deleterious effects of anabolic androgenic steroid abuse on sexual and reproductive health and comparison of recovery between treated and untreated patients: Single-center prospective randomized study (2022)
Manaf Al Hashim
Abstract
Anabolic androgenic steroids (AAS) abuse is a global health-related concern, as most of the related studies showed increasing trends and deleterious effects, mostly on sexual and fertility health. Unfortunately, there are no consensuses about the management pathways due to the lack of specific guidelines. We aimed to confirm the deleterious effects of AAS abuse, monitor spontaneous recovery, and demonstrate the effects of treatment regimens on recovery. We enrolled 520 patients with a confirmed history of AAS intake within 1 year of presentation and evaluated their symptoms, hormone levels, and semen every 3 months until 12 months. All patients were monitored for spontaneous recovery in the first 3 months; if they showed no recovery, they were randomized to undergo either continued observation or commence medications. The most common presentation (84%) was a combination of sexual symptoms while some patients (18%) were infertile. Most patients (90%) reported low levels of luteinizing hormone, follicle-stimulating hormone, and total testosterone. After the 3-month observation, most patients (89%) started treatment, but some (11%) continued observation only. Treated patients showed faster improvement in the International Index of Erectile Function (IIEF) values, hormone levels, testicular size, and semen parameters compared to non-treated patients (p < 0.005). Among the 94 patients who presented with infertility (18%), 61 had oligospermia and 33 had azoospermia. All received treatment, but only 14 (15%) achieved successful pregnancy at 12 months while all azoospermic's patients continued to have infertility at the end of the follow-up period. These findings demonstrated the significant negative impact of AAS abuse on sexual health and fertility, and the need for medical treatment to have faster recovery from their adverse effect.
| INTRODUCTION
The use of performance-enhancing drugs (PEDs) to enhance sports, performance, and /or physical appearance has progressively increased among young and middle-aged men. One of the most abused PEDs is anabolic androgenic steroids (AAS) (Pope, 2014). AAS abuse results in supraphysiological testosterone levels with eventual negative effects on the hypothalamic-pituitary Adrenal (HPA) axis, leading to a unique condition known as anabolic steroid-induced hypogonadism (ASIH) and manifestations of hormonal disturbances, gynecomastia, testicular dysfunction, and infertility, all of which are well-described but poorly understood (Boregowda et al., 2011; Coward et al., 2013; Cyrus et al., 2014; Liu et al., 2006). The lifetime prevalence of AAS abuse is estimated to be 6% in men; therefore, the resultant adverse effects constitute a public health concern since these medications can result in deleterious health effects (Sagoe & molde, 2014; Fronczak, 2012).
Even though AAS abuse is underreported in many communities, and up to 50% of AAS users do not disclose their use to their physician, it is becoming an alarming global phenomenon and well noticed in many regional and global communities (Cohen et al., 2007; Graham et al., 2008; Maha et al., 2019; Pany & Panigraphy, 2019).
Spontaneous recovery of the negative effects caused by AAS abuse can be achieved after discontinuing their usage, but this requires several months to years; however, in many patients, the effects may be permanent (Kanayama et al., 2015; Rasmussen et al., 2016; Shankara-Narayana et al., 2020). Presently, the peer-reviewed literature contains limited information in describing the demographics, characteristics, and psychological profiles of AAS users. Furthermore, no comprehensive management recommendations or guidelines have been proposed for the treatment of AAS induced adverse effects, such as infertility and ASIH, and all available medication regimens are off-label (Menon, 2003; Tan & Vasudevan, 2003; De Luis et al., 2001; Wenker et al., 2015; Ramasamy et al., 2015; Abram McBride & Coward, 2016; Tatem et al., 2020). Particularly in our region (the Middle East), studies on the prevalence and significant negative effects of AAS abuse, as well as management strategies are unavailable, therefore, we aimed to provide objective evidence of the deleterious effects of this condition on sexual health and fertility and possible effects of treatment medications on early recovery from their adverse effects.
2.5 | Medications and treatment regimens
• The patients were informed that all medications were off-label, and in the absence of specific guidelines, the medications and the duration of treatment were based on data from similar studies on the treatment of adverse effects of AAS abuse.
• The treatment regimen included human chorionic gonadotrophin (HCG) 1500 IU injections /three times weekly and clomiphene citrate (CC) 25 mg tablets once daily, both of which were used for low testosterone and/or oligospermia or azoospermia. HCG is a direct luteinizing hormone (LH) analogue that has been shown to stimulate testosterone production by Leydig cells and CC is a well-known centrally acting selective oestrogen receptor modulator (SERM) that acts by inhibiting oestrogen's negative feedback on the hypothalamus, thereby increasing serum LH, FSH, and endogenous testosterone levels while preserving and even potentially improving sperms parameters (Menon, 2003; Tan & Vasudevan, 2003; Wenker et al., 2015). The duration of treatment was initially 30 days. Subsequent treatment was either continued at the same doses or titrated according to the results of follow-up hormone tests (FSH, LH, testosterone, and estradiol) that were performed monthly during treatment and seminal fluid analysis that was performed every 3 months.
• Patients who showed gynecomastia with ASIH and/or infertility at presentation were administered tamoxifen tablets (10 mg twice daily) instead of CC because it has similar gonadotrophin stimulatory effects, but unlike CC, tamoxifen is quite active in the periphery, making it effective in the treatment of early-onset gynecomastia in men (De Luis et al., 2001; Mannu et al., 2018).
• Patients who experienced gynecomastia with high estradiol levels and/or low testosterone/estradiol (T/E) ratio (N: >1/10) were treated with the aforementioned regimens with the addition of letrozole (2.5 mg) or anastrozole (1 mg) tablets every other day for 30 days. Subsequently, the dose was titrated according to the results of follow-up hormone tests. They are both aromatase inhibitors (AIs) that effectively block the production of oestrogen without any effects on other steroidogenic pathways, thereby reducing oestrogen levels and the associated gynecomastia (Tatem et al., 2020).
• FSH injection (75 IU thrice weekly) was administered to treat infertility that did not respond to LH and CC, in those cases, we discontinued CC and added FSH, as it directly stimulates Sertoli cells to support sperm production. The duration of treatment was initially 3 months, and treatment was subsequently continued or stopped depending on the results of semen analysis (Tatem et al., 2020).
4 | DISCUSSION
Our study confirmed the increasing global trend of AAS abuse in the young population; the largest user population in our study was 20–40 years old, consistent with results from other global and regional studies, such as those conducted in Saudi Arabia (Maha et al., 2019). Surprisingly, despite cultural differences worldwide, the aims of AAS users are almost identical. Most of our patients' decisions to use AAS were driven by their coaches' advice and friends' recommendations. Their primary aim was to improve training fitness and physical appearance as in other studies (Cohen et al., 2007; Graham et al., 2008; Pany & Panigraphy, 2019). They commonly used a combination of oral and injectable AAS, like Nandrolone decanoate, Testosterone enanthate, Metandienone, and Testosterone isocaproate. The most common source of AAS for our patients was their coaches; only some patients received their medicines through online purchases, which may be the main source of AAS in other societies (Pirola et al., 2010). These medicines were usually not registered and were illegally imported from the international market without any consideration for appropriate storage and dispensed without prescription by non-licensed personnel and coaches.
Most patients (83%) complained of moderate to severe sexual symptoms, while a substantial proportion (18%) also complained of infertility; this explains why such a large majority of patients preferred to start early treatment. Additionally, while a small proportion of patients showed spontaneous recovery after 3 months of follow-up, most still complained of severe symptoms and had low hormone levels. This contradicts the findings of the study, which reported a high recovery rate of 79% after 3 months (Lykhonosov et al., 2020). We confirmed the AAS impact is based on many factors, including the basic physiological status of patients, the duration and the doses of the courses, and whether early or late at the time of seeking treatment, all these factors are predictors of treatment responses like what was suggested by other studies (Kohn et al., 2017).
Other remarkable findings in our study included the high rate of abnormal semen findings (79%), the significant delay in spontaneous recovery in the untreated group, and the considerable percentage of patients presenting with infertility. Although all patients presenting with infertility were treated, the outcome was disappointing since only 15% of the patients reported a successful pregnancy before the end of the 12-month follow-up period, these findings are highlighting the long-term negative influence of AAS abuse on fertility and the need for longer-than-expected time for recovery (Boregowda et al., 2011; de Oliveira Vilar Neto et al., 2021; Windfeld-Mathiasen et al., 2021)
In our study, the treatment regimens used for ASIH, infertility, and gynecomastia were well tolerated by all patients and were according to the recommendations of many similar studies (Mannu et al., 2018; Tatem et al., 2020; Corona et al., 2022). The regimes and the doses of the medications should be followed closely as there are variant patient responses and should be adjusted individually; the best results were obtained when they followed up monthly for hormones and every 3 months for semen analysis. With this treatment, the recovery of AAS abuse adverse effects was faster and there were good complaince and patient satisfaction. However, in the absence of specific guidelines for treating AAS-induced adverse effects, uncertainty regarding the use of specific medicines and doses for individuals, and used medications are off-label, all factors urge the need for more studies to prove their specific use and doses.
5 | CONCLUSIONS
Our study characterizes the harmful effects of AAS abuse on sexual and reproductive health, especially in patients who use AAS repeatedly and over prolonged periods. These patients show a significantly high rate of sexual symptoms (ED and loss of desire), and untreated patients show a very low recovery rate over 12 months. There is also a high incidence of abnormal semen with a low recovery rate, especially in patients with azoospermia. Infertility may persist even after 1 year of treatment. The use of medications was well tolerated, and patients who received them showed significantly faster recovery of AAS withdrawal symptoms and hormone levels than untreated patients did. However, considering the absence of relevant guidelines and the off-label use of medications, insights for individual-specific usage of these agents are not available. Therefore, highlighting the urgent need for specific treatment guidelines.
6 | LIMITATIONS
Lack of testicular biopsies and DNA fragmentation monitoring, the need for a longer follow-up period, and being a single-centre study were limitations of this study.
Manaf Al Hashim
Abstract
Anabolic androgenic steroids (AAS) abuse is a global health-related concern, as most of the related studies showed increasing trends and deleterious effects, mostly on sexual and fertility health. Unfortunately, there are no consensuses about the management pathways due to the lack of specific guidelines. We aimed to confirm the deleterious effects of AAS abuse, monitor spontaneous recovery, and demonstrate the effects of treatment regimens on recovery. We enrolled 520 patients with a confirmed history of AAS intake within 1 year of presentation and evaluated their symptoms, hormone levels, and semen every 3 months until 12 months. All patients were monitored for spontaneous recovery in the first 3 months; if they showed no recovery, they were randomized to undergo either continued observation or commence medications. The most common presentation (84%) was a combination of sexual symptoms while some patients (18%) were infertile. Most patients (90%) reported low levels of luteinizing hormone, follicle-stimulating hormone, and total testosterone. After the 3-month observation, most patients (89%) started treatment, but some (11%) continued observation only. Treated patients showed faster improvement in the International Index of Erectile Function (IIEF) values, hormone levels, testicular size, and semen parameters compared to non-treated patients (p < 0.005). Among the 94 patients who presented with infertility (18%), 61 had oligospermia and 33 had azoospermia. All received treatment, but only 14 (15%) achieved successful pregnancy at 12 months while all azoospermic's patients continued to have infertility at the end of the follow-up period. These findings demonstrated the significant negative impact of AAS abuse on sexual health and fertility, and the need for medical treatment to have faster recovery from their adverse effect.
| INTRODUCTION
The use of performance-enhancing drugs (PEDs) to enhance sports, performance, and /or physical appearance has progressively increased among young and middle-aged men. One of the most abused PEDs is anabolic androgenic steroids (AAS) (Pope, 2014). AAS abuse results in supraphysiological testosterone levels with eventual negative effects on the hypothalamic-pituitary Adrenal (HPA) axis, leading to a unique condition known as anabolic steroid-induced hypogonadism (ASIH) and manifestations of hormonal disturbances, gynecomastia, testicular dysfunction, and infertility, all of which are well-described but poorly understood (Boregowda et al., 2011; Coward et al., 2013; Cyrus et al., 2014; Liu et al., 2006). The lifetime prevalence of AAS abuse is estimated to be 6% in men; therefore, the resultant adverse effects constitute a public health concern since these medications can result in deleterious health effects (Sagoe & molde, 2014; Fronczak, 2012).
Even though AAS abuse is underreported in many communities, and up to 50% of AAS users do not disclose their use to their physician, it is becoming an alarming global phenomenon and well noticed in many regional and global communities (Cohen et al., 2007; Graham et al., 2008; Maha et al., 2019; Pany & Panigraphy, 2019).
Spontaneous recovery of the negative effects caused by AAS abuse can be achieved after discontinuing their usage, but this requires several months to years; however, in many patients, the effects may be permanent (Kanayama et al., 2015; Rasmussen et al., 2016; Shankara-Narayana et al., 2020). Presently, the peer-reviewed literature contains limited information in describing the demographics, characteristics, and psychological profiles of AAS users. Furthermore, no comprehensive management recommendations or guidelines have been proposed for the treatment of AAS induced adverse effects, such as infertility and ASIH, and all available medication regimens are off-label (Menon, 2003; Tan & Vasudevan, 2003; De Luis et al., 2001; Wenker et al., 2015; Ramasamy et al., 2015; Abram McBride & Coward, 2016; Tatem et al., 2020). Particularly in our region (the Middle East), studies on the prevalence and significant negative effects of AAS abuse, as well as management strategies are unavailable, therefore, we aimed to provide objective evidence of the deleterious effects of this condition on sexual health and fertility and possible effects of treatment medications on early recovery from their adverse effects.
2.5 | Medications and treatment regimens
• The patients were informed that all medications were off-label, and in the absence of specific guidelines, the medications and the duration of treatment were based on data from similar studies on the treatment of adverse effects of AAS abuse.
• The treatment regimen included human chorionic gonadotrophin (HCG) 1500 IU injections /three times weekly and clomiphene citrate (CC) 25 mg tablets once daily, both of which were used for low testosterone and/or oligospermia or azoospermia. HCG is a direct luteinizing hormone (LH) analogue that has been shown to stimulate testosterone production by Leydig cells and CC is a well-known centrally acting selective oestrogen receptor modulator (SERM) that acts by inhibiting oestrogen's negative feedback on the hypothalamus, thereby increasing serum LH, FSH, and endogenous testosterone levels while preserving and even potentially improving sperms parameters (Menon, 2003; Tan & Vasudevan, 2003; Wenker et al., 2015). The duration of treatment was initially 30 days. Subsequent treatment was either continued at the same doses or titrated according to the results of follow-up hormone tests (FSH, LH, testosterone, and estradiol) that were performed monthly during treatment and seminal fluid analysis that was performed every 3 months.
• Patients who showed gynecomastia with ASIH and/or infertility at presentation were administered tamoxifen tablets (10 mg twice daily) instead of CC because it has similar gonadotrophin stimulatory effects, but unlike CC, tamoxifen is quite active in the periphery, making it effective in the treatment of early-onset gynecomastia in men (De Luis et al., 2001; Mannu et al., 2018).
• Patients who experienced gynecomastia with high estradiol levels and/or low testosterone/estradiol (T/E) ratio (N: >1/10) were treated with the aforementioned regimens with the addition of letrozole (2.5 mg) or anastrozole (1 mg) tablets every other day for 30 days. Subsequently, the dose was titrated according to the results of follow-up hormone tests. They are both aromatase inhibitors (AIs) that effectively block the production of oestrogen without any effects on other steroidogenic pathways, thereby reducing oestrogen levels and the associated gynecomastia (Tatem et al., 2020).
• FSH injection (75 IU thrice weekly) was administered to treat infertility that did not respond to LH and CC, in those cases, we discontinued CC and added FSH, as it directly stimulates Sertoli cells to support sperm production. The duration of treatment was initially 3 months, and treatment was subsequently continued or stopped depending on the results of semen analysis (Tatem et al., 2020).
4 | DISCUSSION
Our study confirmed the increasing global trend of AAS abuse in the young population; the largest user population in our study was 20–40 years old, consistent with results from other global and regional studies, such as those conducted in Saudi Arabia (Maha et al., 2019). Surprisingly, despite cultural differences worldwide, the aims of AAS users are almost identical. Most of our patients' decisions to use AAS were driven by their coaches' advice and friends' recommendations. Their primary aim was to improve training fitness and physical appearance as in other studies (Cohen et al., 2007; Graham et al., 2008; Pany & Panigraphy, 2019). They commonly used a combination of oral and injectable AAS, like Nandrolone decanoate, Testosterone enanthate, Metandienone, and Testosterone isocaproate. The most common source of AAS for our patients was their coaches; only some patients received their medicines through online purchases, which may be the main source of AAS in other societies (Pirola et al., 2010). These medicines were usually not registered and were illegally imported from the international market without any consideration for appropriate storage and dispensed without prescription by non-licensed personnel and coaches.
Most patients (83%) complained of moderate to severe sexual symptoms, while a substantial proportion (18%) also complained of infertility; this explains why such a large majority of patients preferred to start early treatment. Additionally, while a small proportion of patients showed spontaneous recovery after 3 months of follow-up, most still complained of severe symptoms and had low hormone levels. This contradicts the findings of the study, which reported a high recovery rate of 79% after 3 months (Lykhonosov et al., 2020). We confirmed the AAS impact is based on many factors, including the basic physiological status of patients, the duration and the doses of the courses, and whether early or late at the time of seeking treatment, all these factors are predictors of treatment responses like what was suggested by other studies (Kohn et al., 2017).
Other remarkable findings in our study included the high rate of abnormal semen findings (79%), the significant delay in spontaneous recovery in the untreated group, and the considerable percentage of patients presenting with infertility. Although all patients presenting with infertility were treated, the outcome was disappointing since only 15% of the patients reported a successful pregnancy before the end of the 12-month follow-up period, these findings are highlighting the long-term negative influence of AAS abuse on fertility and the need for longer-than-expected time for recovery (Boregowda et al., 2011; de Oliveira Vilar Neto et al., 2021; Windfeld-Mathiasen et al., 2021)
In our study, the treatment regimens used for ASIH, infertility, and gynecomastia were well tolerated by all patients and were according to the recommendations of many similar studies (Mannu et al., 2018; Tatem et al., 2020; Corona et al., 2022). The regimes and the doses of the medications should be followed closely as there are variant patient responses and should be adjusted individually; the best results were obtained when they followed up monthly for hormones and every 3 months for semen analysis. With this treatment, the recovery of AAS abuse adverse effects was faster and there were good complaince and patient satisfaction. However, in the absence of specific guidelines for treating AAS-induced adverse effects, uncertainty regarding the use of specific medicines and doses for individuals, and used medications are off-label, all factors urge the need for more studies to prove their specific use and doses.
5 | CONCLUSIONS
Our study characterizes the harmful effects of AAS abuse on sexual and reproductive health, especially in patients who use AAS repeatedly and over prolonged periods. These patients show a significantly high rate of sexual symptoms (ED and loss of desire), and untreated patients show a very low recovery rate over 12 months. There is also a high incidence of abnormal semen with a low recovery rate, especially in patients with azoospermia. Infertility may persist even after 1 year of treatment. The use of medications was well tolerated, and patients who received them showed significantly faster recovery of AAS withdrawal symptoms and hormone levels than untreated patients did. However, considering the absence of relevant guidelines and the off-label use of medications, insights for individual-specific usage of these agents are not available. Therefore, highlighting the urgent need for specific treatment guidelines.
6 | LIMITATIONS
Lack of testicular biopsies and DNA fragmentation monitoring, the need for a longer follow-up period, and being a single-centre study were limitations of this study.
