In our cohort of men with macroprolactinoma and hypogonadism at presentation that reached normoprolactinemia with cabergoline treatment, 21% showed HH persistence. This is the first study to report hypopituitarism and VFD (reflecting significant tumor mass effect) as independent predictors of HH persistence in men with macroprolactinoma. We found substantial correlations between baseline LH and FSH levels with testosterone levels (reflecting central functional modification) and identified low baseline testosterone as an independent predictor of HH persistence.
In order to correctly select this study’s population, 103 men with macroprolactinoma (with overall baseline HH in 86% of men, Table 1) were screened and divided into 3 groups (Fig. 1). Compared with the patients included in the cohort (group C), patients in group B had a more aggressive disease: they had larger tumors at presentation, with higher serum prolactin levels, lower LH and testosterone levels, and they suffered higher rates of VFDs and hypopituitarism. Eugonadism at presentation, as in group A, was associated with more benign baseline characteristics, compared with groups B and C. Group A had lower rates of sexual dysfunction, and yet, 43% of men in group A suffered sexual dysfunction at presentation, that may be explained by the relatively low mean serum testosterone of 4.4 ng/ml (within the lowest quartile of the normal range, Table 1), which usually increases upon prolactin normalization [19].
Noteworthy, in this study design, there is an inherent selection bias because patients with a more benign presentation must be excluded (group A, with no HH), as well as patients with more aggressive tumors (group B, normoprolactinemia not achieved with cabergoline monotherapy). Additionally, this rigorous selection requires a relatively large sample size, as in our cohort.
Previous studies, with a similar study design, investigated the prevalence of HH persistence, while some performed univariate analysis to reveal clinical factors associated with HH persistence in male macroprolactinoma. In 2000, Pinzone et al. [6] retrospectively evaluated 27 men with macroprolactinoma and found that 93% of men had hypogonadism at presentation, with 48% suffering HH persistence after 4.4 years. They reported no age difference between men with and without HH persistence. Sibal et al. [8] demonstrated gonadal axis dysfunction in 27 out of 35 men (77%) and recovery of function in 16 out of 26 (62%) men under medical treatment with dopamine agonists. In 2006, De rosa et al. [10] prospectively evaluated 50 men with macroprolactinomas (76% had baseline HH) and found that 18 out of 38 (47%) patients that achieved normoprolactinemia had HH persistence after 6 months of cabergoline treatment. The investigators demonstrated that higher basal prolactin levels, larger tumors, and lower testosterone levels were associated with HH persistence after 6 months. Karavitaki et al. (2013) [17] investigated 10 men (9 had gonadal axis dysfunction) treated with cabergoline for 2 years, with HH persistence seen in 5 out 9 men (56%). Men who achieved eugonadism with cabergoline, did so within the first year of treatment.
In 2020, Sehemby et al. [11] studied a cohort of 30 men, and found high rate of baseline central hypogonadism of 100%. All men included achieved normoprolactinemia with cabergoline therapy, and yet 73% of men had HH persistence at the end of the study period (median follow-up of 2 years). In this study of well selected population, higher baseline prolactin levels and larger tumor size were found to be predictors of HH persistence, both factors reflect tumor aggressiveness. The authors provided cutoffs for tumor size smaller than 32 mm (sensitivity and specificity of 75% and 63.6%) and basal prolactin levels below 2098 ng/ml (87.5% and 77.3%) for HH reversal prediction. It should be noted that these cutoffs will probably yield lower specificity in populations of other ethnical origin, with less aggressive prolactinomas and with lower rates of HH persistence: in our cohort, tumor size < 32 mm had 82.6% sensitivity and 50% specificity, and prolactin < 2098 ng/ml had 71.7% sensitivity and 50% specificity for HH reversal prediction.
In their study, Sehemby et al. [11] demonstrated selective suppression of the LH-testosterone axis (without suppression of the FSH-inhibin B axis) and thus they suggest that “chronic functional modification” of the hypothalamus, and not gonadotroph cell damage, is the biological mechanism of persistent HH.
In our cohort, lower baseline testosterone, LH and FSH levels were associated with HH persistence (Table 2). Prolactin levels were lower in men without HH persistence (Table 2). On one hand, these observations suggest that the impairment of the gonadal axis is primarily functional and is derived from the known effect of high prolactin levels over the hypothalamus. On the other hand, we found hypopituitarism and VFD to be strong predictors of HH persistence. These predicting factors reflect tumor mass effect, which may be associated with an irreversible pituitary damage.
Previous studies already demonstrated the relationship between tumor size and permanent gonadal axis suppression. Tirosh et al. [9] illustrated HH persistence in 9 out of 20 men (45%) with giant prolactinoma (i.e., adenoma diameter ≥ 40 mm) and hypogonadism, compared with 14 out of 46 men (32%) with non-giant tumors and HH persistence.
Iglesias et al. [20] found higher HH persistence rates in men with giant prolactinomas, treated with dopamine agonists, compared to men with non-giant prolactinomas (86% vs 20%, respectively) with a similar prolactin normalization rate of approximately 70%.
After normoprolactinemia was achieved (in 46 men), we found that 36 (78%) men in our cohort normalized their testosterone levels within the first 6 months, and 42 (91%) men accomplished eugonadism within the first year. One patient demonstrated recovery of the gonadal axis after as long as 4.5 years. Accordingly, it is possible that a limited number of patients may benefit from gonadal axis function reassessment, even after a long period of axis suppression. In order to aid in the decision of testosterone replacement initiation, our data suggest that men who present with testosterone levels below 1.5 ng/ml along with either VFD or hypopituitarism are more likely to remain hypogonadal despite prolactin normalization (75% sensitivity, 93.5% specificity) and can benefit from testosterone treatment.
Although baseline HH is associated with a more aggressive disease, our data suggest that the long-term outcomes in men with and without HH persistence are comparable, including normal prolactin levels achieved and tumor shrinkage (Table 4). Accordingly, the mean time elapsed from medical treatment initiation to prolactin normalization was identical (5 months) in the two groups. As anticipated, in accordance with the low LH and the pre-specified testosterone levels, men with HH persistence did not demonstrate sexual function improvement (Table 4).
The present study has many strengths including the meticulous data collection of a large cohort at a single tertiary center with a uniform treatment protocol, long-term follow-up, and the ability to ascertain several predictors of HH persistence, two of them (VFD and hypogonadism) have not been previously reported.
This study has a number of limitations. Because of its retrospective nature, outcomes reported by patients were subject to reporting bias. Many patients were not included in the main analysis, due to the severity of their disease (Group B, Table 1). This may be the result of referral bias: as a tertiary referral center, our patients usually present with larger and more aggressive adenomas and require a more aggressive treatment approach. Another limitation is the lack of data regarding free testosterone or sex hormone-binding globulin levels. In addition, our protocol does not specify time intervals for serum testosterone measurements after the patients reached normal prolactin levels. This may have caused overestimation of time elapsed from prolactin normalization to eugonadism restoration.
In conclusion, in this cohort of men with macroprolactinoma that reached prolactin normalization with cabergoline treatment, 21% had HH persistence. We identified low baseline testosterone levels, visual field defect and pituitary hormone deficiency as independent predictors of HH persistence. We found that 91% of men accomplished eugonadism within the first year following prolactin normalization. These findings may support informed clinical decision-making regarding the initiation of testosterone replacement in men with macroprolactinomas.