madman
Super Moderator
Pituitary-testis axis dysfunction following adjuvant androgen deprivation therapy (2022)
Julie Abildgaard, Hein Vincent Stroomberg, A Kirstine Bang, Jakob Albrethsen, Laura Smedegaard Kruuse, Anders Juul, Klaus Brasso, Andreas Røder, and Niels Jørgensen
Abstract
Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary–testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary–testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent an assessment of testosterone deficiency (TD) symptoms, a full biochemical assessment of the pituitary–testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years, and the median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 had secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). Inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary–testis axis function in patients receiving adjuvant ADT.
Introduction
Androgen deprivation therapy (ADT), provided as gonadotropin-releasing hormone (GnRH) agonists or antagonists, remains a backbone in the treatment of patients with high-risk prostate cancer undergoing curatively intended radiation therapy (Kishan et al. 2022). GnRH therapy suppresses the pituitary gonadotropin release (Faure et al. 1982). The lack of testicular stimulation from gonadotropins leads to deficient testosterone production whereby medical castration is obtained. When ADT is discontinued, the pituitary–testis axis is expected to regain its previous function. However, in men treated with ADT for 6 months or shorter, testosterone concentrations normalize in 80–100% of cases within 12–18 months (Murthy et al. 2006, Murthy et al. 2007, Kato et al. 2020, Roy et al. 2020), whereas treatment beyond 2 years may lead to irreversibly low serum testosterone in up to 60% of the patients (Planas et al. 2016, Takei et al. 2018, Spiegel et al. 2019).
Guidelines recommend that testosterone deficiency (TD) is diagnosed based on a combination of the presence of clinical symptoms and low serum testosterone. Furthermore, one should consider measuring serum-free testosterone (FT) instead of total testosterone in conditions that might alter sex hormone-binding globulin (SHBG) or when total testosterone is at the lower end of the normal range (Corona et al. 2020). Thus, the focus of previous studies on serum total testosterone alone is not necessarily translatable to the incidence of TD. Additionally, it remains to be elucidated whether TD following ADT is caused by dysfunction of the pituitary gland, testicles, or a combination of the two.
This study was conducted to investigate how ADT affects the risk of persistent TD in prostate cancer patients treated with radiation therapy and adjuvant ADT. Furthermore, we aimed to understand the pathophysiology of the TD induced by adjuvant ADT through a detailed assessment of the pituitary–testis axis function in all included patients.
Discussion
Castration-based therapy as an adjuvant to curatively intended radiation is the standard of care in high-risk prostate cancer. However, ADT results in a significant decrease in quality of life (Wei et al. 2002, Penson et al. 2003), loss of sexual function (Donovan et al. 2018), and increases in the risk of osteoporosis (Shahinian et al. 2005), anemia (Strum et al. 1997), and metabolic disease (Keating et al. 2006, Wang et al. 2016). A substantial number of prostate cancer patients receiving ADT are willing to trade up to 10% in 5-year survival to maintain sexual function and quality of life (Singer et al. 1991, Wilke et al. 2010). Thus, focus on the long-term consequences and potentially irreparable dysfunction on the pituitary–testis axis due to ADT is of considerable importance to the patients
The study importantly shows that a substantial number of patients receiving adjuvant ADT in combination with radiation therapy experienced lasting pituitary–testis axis dysfunction, several years after cessation of ADT. Testicular dysfunction (pTD), pituitary dysfunction (sTD), and a combination of the two (mTD) were equally frequent causes of TD.
Short-term ADT has been shown to cause Leydig cell atrophy (Giberti et al. 1988, Johansen et al. 1990), but it has not been elucidated if these changes are irreversible. Our data suggest a persistent decline in Leydig cell function (increase in LH, increase in LH to FT ratio, and insufficient response to HCG) even in patients without TD. This was supported by a general decrease in serum INSL3 – a secretory product of the Leydig cells (Ivell et al. 1997, Kawamura et al. 2004). INSL3 has been described to decline with age and around 0.014 ng/mL each year in this age group and could account for up to half of the observed INSL3 decline. The contribution from radiation therapy of the prostate on Leydig cell insufficiency is expected to be sparse (Midzak et al. 2009, Farhood et al. 2019). As to our knowledge, no previous studies have described the long-term consequences of ADT on pituitary function. However, in this study, 35% of all patients showed insufficient gonadotropin secretion following ADT. Thus, ADT also exerts a long-lasting suppression of pituitary gonadotropin secretion.
We found that both testosterone and LH increased with time since ADT cessation, indicating some degree of restoration of pituitary–testis function even several years following treatment. Previous larger studies show that the likelihood of reaching serum testosterone concentrations within the normal range, after both short- and long-term ADT (6–36 months), drastically decreases if testosterone is not normalized within the first 2 years after cessation of ADT (Tsumura et al. 2015, Nam et al. 2018, Roy et al. 2020). The fact that sTD was more common in the first years following cessation of ADT, and pTD later in the follow-up period, suggests that the ADT-induced pituitary dysfunction tends to be reversible, whereas testicular dysfunction is more persistent.
GnRH analogs are used to treat a variety of conditions including endometriosis, central precocious puberty, and gender dysphoria (Kennedy et al. 2005, Carel & Leger 2008, Hembree et al. 2017). Whether the persisting dysfunction of the pituitary–testis axis observed in this study is transferrable to other patient groups is unknown but should be a subject of future studies.
ADT is associated with an increased risk of metabolic diseases, including diabetes and cardiovascular disease (Keating et al. 2006, Wang et al. 2016). It remains to be elucidated if the patients with persisting TD are at higher risk of metabolic disease compared with the patients with a fully recovered pituitary–testis axis. In this study, we found no substantial differences in metabolic profile, including body composition and blood lipids, between patients with and without TD. Patients with mTD generally had a poorer metabolic profile compared to the other groups but also tended to have a higher BMI before ADT initiation, which could explain the differences.
The use of testosterone treatment in patients with previous prostate cancer is highly debated as testosterone has been suggested to increase prostate cancer risk and disease progression (Morgentaler & Traish 2009). In contrast, a short time to recovery of endogenous serum testosterone is not considered a risk factor for relapse (Roy et al. 2020, Zapatero et al. 2021). Randomized controlled trials of testosterone treatment for the recovery of serum testosterone levels are missing. Since trends in survival rates are improving over time in this group of patients, potential treatment options should be considered for future research to reduce the long-term consequences of persistent TD in men otherwise cured (Orrason et al. 2020).
In this study, 55% of patients were diagnosed with TD. A precise estimate of the prevalence of TD in this group could not be made due to the limited sample size as well as the fact that 12 of 51 patients were included with known symptoms of TD. Furthermore, 15 of the 66 invited patients declined their initial invitation introducing some degree of selection bias in the study, which is a limitation. Due to the observational nature of the study, causal conclusions could not be drawn. We did not have a clinical andrological assessment of patients prior to ADT. Thus, we cannot rule out that patients with preceding TD were included. The risk of late-onset TD increases with age (Wu et al. 2010). We based comparisons in the cross-sectional data on a laboratory-specific age-matched control cohort but were unable to draw comparisons on our longitudinal data. Our study is limited by the inclusion of a restricted number of patients. We did not have significant power to evaluate changes in pituitary–testis hormones over time, based on the type of TD. Consequently, all TDs were pooled in these analyses.
Conclusions
In conclusion, persistent TD is a very common long-term consequence of adjuvant ADT in prostate cancer survivors. Causes of TD are equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of pituitary–testis function following adjuvant ADT as well as the need for randomized controlled trials investigating the safety and feasibility of testosterone treatment in prostate cancer survivors following adjuvant ADT.
Julie Abildgaard, Hein Vincent Stroomberg, A Kirstine Bang, Jakob Albrethsen, Laura Smedegaard Kruuse, Anders Juul, Klaus Brasso, Andreas Røder, and Niels Jørgensen
Abstract
Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary–testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary–testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent an assessment of testosterone deficiency (TD) symptoms, a full biochemical assessment of the pituitary–testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years, and the median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 had secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). Inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary–testis axis function in patients receiving adjuvant ADT.
Introduction
Androgen deprivation therapy (ADT), provided as gonadotropin-releasing hormone (GnRH) agonists or antagonists, remains a backbone in the treatment of patients with high-risk prostate cancer undergoing curatively intended radiation therapy (Kishan et al. 2022). GnRH therapy suppresses the pituitary gonadotropin release (Faure et al. 1982). The lack of testicular stimulation from gonadotropins leads to deficient testosterone production whereby medical castration is obtained. When ADT is discontinued, the pituitary–testis axis is expected to regain its previous function. However, in men treated with ADT for 6 months or shorter, testosterone concentrations normalize in 80–100% of cases within 12–18 months (Murthy et al. 2006, Murthy et al. 2007, Kato et al. 2020, Roy et al. 2020), whereas treatment beyond 2 years may lead to irreversibly low serum testosterone in up to 60% of the patients (Planas et al. 2016, Takei et al. 2018, Spiegel et al. 2019).
Guidelines recommend that testosterone deficiency (TD) is diagnosed based on a combination of the presence of clinical symptoms and low serum testosterone. Furthermore, one should consider measuring serum-free testosterone (FT) instead of total testosterone in conditions that might alter sex hormone-binding globulin (SHBG) or when total testosterone is at the lower end of the normal range (Corona et al. 2020). Thus, the focus of previous studies on serum total testosterone alone is not necessarily translatable to the incidence of TD. Additionally, it remains to be elucidated whether TD following ADT is caused by dysfunction of the pituitary gland, testicles, or a combination of the two.
This study was conducted to investigate how ADT affects the risk of persistent TD in prostate cancer patients treated with radiation therapy and adjuvant ADT. Furthermore, we aimed to understand the pathophysiology of the TD induced by adjuvant ADT through a detailed assessment of the pituitary–testis axis function in all included patients.
Discussion
Castration-based therapy as an adjuvant to curatively intended radiation is the standard of care in high-risk prostate cancer. However, ADT results in a significant decrease in quality of life (Wei et al. 2002, Penson et al. 2003), loss of sexual function (Donovan et al. 2018), and increases in the risk of osteoporosis (Shahinian et al. 2005), anemia (Strum et al. 1997), and metabolic disease (Keating et al. 2006, Wang et al. 2016). A substantial number of prostate cancer patients receiving ADT are willing to trade up to 10% in 5-year survival to maintain sexual function and quality of life (Singer et al. 1991, Wilke et al. 2010). Thus, focus on the long-term consequences and potentially irreparable dysfunction on the pituitary–testis axis due to ADT is of considerable importance to the patients
The study importantly shows that a substantial number of patients receiving adjuvant ADT in combination with radiation therapy experienced lasting pituitary–testis axis dysfunction, several years after cessation of ADT. Testicular dysfunction (pTD), pituitary dysfunction (sTD), and a combination of the two (mTD) were equally frequent causes of TD.
Short-term ADT has been shown to cause Leydig cell atrophy (Giberti et al. 1988, Johansen et al. 1990), but it has not been elucidated if these changes are irreversible. Our data suggest a persistent decline in Leydig cell function (increase in LH, increase in LH to FT ratio, and insufficient response to HCG) even in patients without TD. This was supported by a general decrease in serum INSL3 – a secretory product of the Leydig cells (Ivell et al. 1997, Kawamura et al. 2004). INSL3 has been described to decline with age and around 0.014 ng/mL each year in this age group and could account for up to half of the observed INSL3 decline. The contribution from radiation therapy of the prostate on Leydig cell insufficiency is expected to be sparse (Midzak et al. 2009, Farhood et al. 2019). As to our knowledge, no previous studies have described the long-term consequences of ADT on pituitary function. However, in this study, 35% of all patients showed insufficient gonadotropin secretion following ADT. Thus, ADT also exerts a long-lasting suppression of pituitary gonadotropin secretion.
We found that both testosterone and LH increased with time since ADT cessation, indicating some degree of restoration of pituitary–testis function even several years following treatment. Previous larger studies show that the likelihood of reaching serum testosterone concentrations within the normal range, after both short- and long-term ADT (6–36 months), drastically decreases if testosterone is not normalized within the first 2 years after cessation of ADT (Tsumura et al. 2015, Nam et al. 2018, Roy et al. 2020). The fact that sTD was more common in the first years following cessation of ADT, and pTD later in the follow-up period, suggests that the ADT-induced pituitary dysfunction tends to be reversible, whereas testicular dysfunction is more persistent.
GnRH analogs are used to treat a variety of conditions including endometriosis, central precocious puberty, and gender dysphoria (Kennedy et al. 2005, Carel & Leger 2008, Hembree et al. 2017). Whether the persisting dysfunction of the pituitary–testis axis observed in this study is transferrable to other patient groups is unknown but should be a subject of future studies.
ADT is associated with an increased risk of metabolic diseases, including diabetes and cardiovascular disease (Keating et al. 2006, Wang et al. 2016). It remains to be elucidated if the patients with persisting TD are at higher risk of metabolic disease compared with the patients with a fully recovered pituitary–testis axis. In this study, we found no substantial differences in metabolic profile, including body composition and blood lipids, between patients with and without TD. Patients with mTD generally had a poorer metabolic profile compared to the other groups but also tended to have a higher BMI before ADT initiation, which could explain the differences.
The use of testosterone treatment in patients with previous prostate cancer is highly debated as testosterone has been suggested to increase prostate cancer risk and disease progression (Morgentaler & Traish 2009). In contrast, a short time to recovery of endogenous serum testosterone is not considered a risk factor for relapse (Roy et al. 2020, Zapatero et al. 2021). Randomized controlled trials of testosterone treatment for the recovery of serum testosterone levels are missing. Since trends in survival rates are improving over time in this group of patients, potential treatment options should be considered for future research to reduce the long-term consequences of persistent TD in men otherwise cured (Orrason et al. 2020).
In this study, 55% of patients were diagnosed with TD. A precise estimate of the prevalence of TD in this group could not be made due to the limited sample size as well as the fact that 12 of 51 patients were included with known symptoms of TD. Furthermore, 15 of the 66 invited patients declined their initial invitation introducing some degree of selection bias in the study, which is a limitation. Due to the observational nature of the study, causal conclusions could not be drawn. We did not have a clinical andrological assessment of patients prior to ADT. Thus, we cannot rule out that patients with preceding TD were included. The risk of late-onset TD increases with age (Wu et al. 2010). We based comparisons in the cross-sectional data on a laboratory-specific age-matched control cohort but were unable to draw comparisons on our longitudinal data. Our study is limited by the inclusion of a restricted number of patients. We did not have significant power to evaluate changes in pituitary–testis hormones over time, based on the type of TD. Consequently, all TDs were pooled in these analyses.
Conclusions
In conclusion, persistent TD is a very common long-term consequence of adjuvant ADT in prostate cancer survivors. Causes of TD are equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of pituitary–testis function following adjuvant ADT as well as the need for randomized controlled trials investigating the safety and feasibility of testosterone treatment in prostate cancer survivors following adjuvant ADT.
