madman
Super Moderator
Abstract
Purpose
In men with prolactinoma treated with dopamine agonists (DA), the extent, timeline, and predictive factors of gonadotropic axis recovery are still unclear.
Methods
We analyzed data of 97 men with a prolactinoma treated with DA (77/97 macroprolactinomas). We excluded patients with primary hypogonadism, surgery <12 months after DA initiation, and patients with tumors <5 mm or prolactin <45 µg/l at diagnosis.
Results
Among the 97 patients, 12 had normal total testosterone (NT group) and 85 had low testosterone at diagnosis (LTgroup). In the NT group, testosterone rose from a mean of 13.5 nmol/l to 17.1nmol/l at 6 months (n=11; p<0.05) then remained stable at 12 months (n=8). In the LT group, testosterone rose from a mean of 5.2 nmol/l to 9.6 nmol/l at 6 months (n=66; p<0.001) and further to 13.1 nmol/l at 12 months (n=40; p<0.001) then remained stable. Recovery from hypogonadism occurred in 43%, 50%, and 54% of patients at 6, 12 and 24 months, respectively (61%, 69 and 69% if prolactin was normal). Factors independently associated with persistent hypogonadism at 12 months were at baseline the presence of visual field deficit and lower testosterone levels, while the most significant independent predictor of persistent hypogonadism at one year was a testosterone level <7.4 nmol/l at 6 months, with 91% sensitivity and 94% specificity.
Conclusion
Testosterone levels recover in a small majority of men with prolactinoma mostly during the first year of DA treatment. However, testosterone replacement could be considered earlier in patients with large and compressive tumors, and in whom testosterone remains below 7.4 nmol/l after 6 months of DA treatment.
Introduction
Men with prolactinoma frequently suffer from hypogonadotropic hypogonadism, manifesting as decreased libido, erectile dysfunction, gynecomastia, weight gain, anemia and bone loss [1]. The symptoms may occur long before the diagnosis of prolactinoma is recognized [2]. Hypogonadism in prolactinoma may be the result of a mechanical compression of the normal pituitary gland or stalk by a macroadenoma and/or the inhibitory effect of excess prolactin on kisspeptin neurons in the hypothalamus [3]. Recovery from hypogonadism is an important objective of any treatment of prolactinoma. The 2023 guidelines from the Pituitary Society recommend reassessing testosterone levels 6 months after treatment initiation and starting exogenous testosterone therapy if frank hypogonadism persists at that time [4]. Because of the lack of enough evidence-based data, both recommendations are however graded as « weak » [4] and do not define at which level of testosterone the start of hormonal substitution is warranted.
The extent and timeline of gonadotropic axis recovery have been studied mostly in small series of less than 50 medically-treated men and showed variable rates of recovery ranging from 27 to 53% [5–9]. In 2022, two reports described hypogonadism recovery in slightly larger cohorts of men with macroprolactinoma treated with dopamine agonists (DA) [10, 11]. In 63 patients with a median tumor size of 2.9 cm, Al Dahmani et al. reported a recovery rate of hypogonadism of 65% mostly within the first 24 months of cabergoline therapy [11]. They observed that patients who recovered had smaller adenoma size, lower prolactin level and higher testosterone at diagnosis, less secondary hypothyroidism and they achieved earlier prolactin normalization. The series reported by Rudman et al [10] was restricted to 58 male patients who had achieved normal prolactin levels on medical therapy. In this setting, predictors of hypogonadism persistence were initial visual field defects, the presence of TSH and ACTH deficiency, and low baseline testosterone (mean: 2.4 nmol/l compared to 5.5 nmol/l in patients with eugonadism recovery). In both series, patients who had surgery were excluded (even if surgery might have occurred after more than 12 months of medical treatment), as well as those with normal testosterone or microadenoma at baseline, thus resulting in the exclusion of a significant subset of patients encountered in real life practice. Two other studies reported the evolution of testosterone levels in prolactinoma patients with normal initial testosterone,which interestingly showed a significant hormone increase of more than 50% with DA therapy [12, 13].
The purpose of our study was to assess the evolution of central hypogonadism during the first two years of treatment with dopamine agonists in a larger and more representative cohort of 97 men, with either micro- or macroprolactinoma, independently of baseline testosterone levels and normalization of prolactin concentrations.
The strengths of our study include the large and representative cohort of patients (the largest published to date on this subject), the inclusion of microprolactinoma (5–9 mm), the evaluation of cystic components and analysis of the tumor response in parallel to biological response. Limitations include the retrospective design of the study, with missing data for some patients during follow-up, the lack of objective data on sexual function parameters, the lack of free testosterone (index) measurements and the small number of patients who achieved normal prolactin (n=32) at one year, which however reflects real-life practice in our tertiary referral center for resistant or complex cases.
In conclusion, a large majority of men with prolactinoma suffer from hypogonadotropic hypogonadism at diagnosis. Dopamine agonist treatment will lead to a significant increase in testosterone levels, even among those with normal initial testosterone, revealing some degree of initial hypogonadism. Among patients with hypogonadism, recovery of gonadal function was finally observed in 54% of patients, raising to 69% in those who achieved normal prolactin, and this occurs mostly within the first year of medical treatment. We confirm that indicators of mass effect such as tumor size, the presence of a large cystic component, visual field deficit and/or ACTH deficit and low initial testosterone are predictors of persistent hypogonadism, We suggest to consider starting testosterone therapy after 6 months in such patients, especially if total morning testosterone at this time point remains below the cut-off of 7.4 nmol/l. Future studies should strive to prospectively assess both SHBG and free testosterone to better refine our decision making process.
Purpose
In men with prolactinoma treated with dopamine agonists (DA), the extent, timeline, and predictive factors of gonadotropic axis recovery are still unclear.
Methods
We analyzed data of 97 men with a prolactinoma treated with DA (77/97 macroprolactinomas). We excluded patients with primary hypogonadism, surgery <12 months after DA initiation, and patients with tumors <5 mm or prolactin <45 µg/l at diagnosis.
Results
Among the 97 patients, 12 had normal total testosterone (NT group) and 85 had low testosterone at diagnosis (LTgroup). In the NT group, testosterone rose from a mean of 13.5 nmol/l to 17.1nmol/l at 6 months (n=11; p<0.05) then remained stable at 12 months (n=8). In the LT group, testosterone rose from a mean of 5.2 nmol/l to 9.6 nmol/l at 6 months (n=66; p<0.001) and further to 13.1 nmol/l at 12 months (n=40; p<0.001) then remained stable. Recovery from hypogonadism occurred in 43%, 50%, and 54% of patients at 6, 12 and 24 months, respectively (61%, 69 and 69% if prolactin was normal). Factors independently associated with persistent hypogonadism at 12 months were at baseline the presence of visual field deficit and lower testosterone levels, while the most significant independent predictor of persistent hypogonadism at one year was a testosterone level <7.4 nmol/l at 6 months, with 91% sensitivity and 94% specificity.
Conclusion
Testosterone levels recover in a small majority of men with prolactinoma mostly during the first year of DA treatment. However, testosterone replacement could be considered earlier in patients with large and compressive tumors, and in whom testosterone remains below 7.4 nmol/l after 6 months of DA treatment.
Introduction
Men with prolactinoma frequently suffer from hypogonadotropic hypogonadism, manifesting as decreased libido, erectile dysfunction, gynecomastia, weight gain, anemia and bone loss [1]. The symptoms may occur long before the diagnosis of prolactinoma is recognized [2]. Hypogonadism in prolactinoma may be the result of a mechanical compression of the normal pituitary gland or stalk by a macroadenoma and/or the inhibitory effect of excess prolactin on kisspeptin neurons in the hypothalamus [3]. Recovery from hypogonadism is an important objective of any treatment of prolactinoma. The 2023 guidelines from the Pituitary Society recommend reassessing testosterone levels 6 months after treatment initiation and starting exogenous testosterone therapy if frank hypogonadism persists at that time [4]. Because of the lack of enough evidence-based data, both recommendations are however graded as « weak » [4] and do not define at which level of testosterone the start of hormonal substitution is warranted.
The extent and timeline of gonadotropic axis recovery have been studied mostly in small series of less than 50 medically-treated men and showed variable rates of recovery ranging from 27 to 53% [5–9]. In 2022, two reports described hypogonadism recovery in slightly larger cohorts of men with macroprolactinoma treated with dopamine agonists (DA) [10, 11]. In 63 patients with a median tumor size of 2.9 cm, Al Dahmani et al. reported a recovery rate of hypogonadism of 65% mostly within the first 24 months of cabergoline therapy [11]. They observed that patients who recovered had smaller adenoma size, lower prolactin level and higher testosterone at diagnosis, less secondary hypothyroidism and they achieved earlier prolactin normalization. The series reported by Rudman et al [10] was restricted to 58 male patients who had achieved normal prolactin levels on medical therapy. In this setting, predictors of hypogonadism persistence were initial visual field defects, the presence of TSH and ACTH deficiency, and low baseline testosterone (mean: 2.4 nmol/l compared to 5.5 nmol/l in patients with eugonadism recovery). In both series, patients who had surgery were excluded (even if surgery might have occurred after more than 12 months of medical treatment), as well as those with normal testosterone or microadenoma at baseline, thus resulting in the exclusion of a significant subset of patients encountered in real life practice. Two other studies reported the evolution of testosterone levels in prolactinoma patients with normal initial testosterone,which interestingly showed a significant hormone increase of more than 50% with DA therapy [12, 13].
The purpose of our study was to assess the evolution of central hypogonadism during the first two years of treatment with dopamine agonists in a larger and more representative cohort of 97 men, with either micro- or macroprolactinoma, independently of baseline testosterone levels and normalization of prolactin concentrations.
The strengths of our study include the large and representative cohort of patients (the largest published to date on this subject), the inclusion of microprolactinoma (5–9 mm), the evaluation of cystic components and analysis of the tumor response in parallel to biological response. Limitations include the retrospective design of the study, with missing data for some patients during follow-up, the lack of objective data on sexual function parameters, the lack of free testosterone (index) measurements and the small number of patients who achieved normal prolactin (n=32) at one year, which however reflects real-life practice in our tertiary referral center for resistant or complex cases.
In conclusion, a large majority of men with prolactinoma suffer from hypogonadotropic hypogonadism at diagnosis. Dopamine agonist treatment will lead to a significant increase in testosterone levels, even among those with normal initial testosterone, revealing some degree of initial hypogonadism. Among patients with hypogonadism, recovery of gonadal function was finally observed in 54% of patients, raising to 69% in those who achieved normal prolactin, and this occurs mostly within the first year of medical treatment. We confirm that indicators of mass effect such as tumor size, the presence of a large cystic component, visual field deficit and/or ACTH deficit and low initial testosterone are predictors of persistent hypogonadism, We suggest to consider starting testosterone therapy after 6 months in such patients, especially if total morning testosterone at this time point remains below the cut-off of 7.4 nmol/l. Future studies should strive to prospectively assess both SHBG and free testosterone to better refine our decision making process.
