madman
Super Moderator
4.1 Introduction
The appropriate diagnosis and management of male testosterone (T) deficiency requires a thorough understanding of several physiologic processes and may require the integration of subspecialty services. The lack of understanding or appreciation of the complex nuances of low T may lead to missed diagnoses, inappropriate therapy, and potentially significant ramifications to a patient’s overall health and well-being. One of these nuances includes the role and relevance of prolactin (PRL) and, more specifically, hyperprolactinemia as an important clinical condition. However, despite its importance, relatively few clinicians who treat low T have significant experience in managing PRL abnormalities. Given this observation, the objective of this chapter is to provide the practicing clinician a practical guide to evaluating and managing hyperprolactinemia. To accomplish this objective, the chapter is outlined to review the anatomy and physiology of PRL, associated findings and symptoms, its causative role in low T, the appropriate evaluation of hyperprolactinemia, and available management strategies. Although many clinicians may simply choose to refer men with hyperprolactinemia to an endocrinologist, a deeper understanding of these principles remains relevant, given that the initial diagnosis of hyperprolactinemia is most often dependent upon the sexual medicine clinician.
4.2 Prolactin and Hypothalamic-Pituitary-Gonadal Axis
Prolactin is a hormone produced in the anterior pituitary gland that serves predominantly to facilitate milk production in women. Several different actions lead to PRL secretion, including nursing, estrogen therapy/hormones, sexual activity, eating, and ovulation. As with other pituitary hormones, PRL is secreted in a pulsatile fashion and often occurs between stimulating events. It has additionally been suggested to have roles in immunomodulation and cell growth and differentiation and is particularly involved in hematopoiesis and angiogenesis.
Prolactin is most active during periods of pregnancy, where it leads to breast growth and mammary gland milk production. The regulation of PRL secretion is largely controlled via the inhibitory effects of dopamine, although thyrotropin-releasing hormone (TRH) also contributes and is able to directly stimulate release. Central serotonin also shows a stimulatory effect on PRL secretion. Prolactin exhibits mild gonadotropic effects and sensitizes luteinizing hormone (LH) receptors in Leydig cells, thereby increasing T production. Both T and PRL are subsequently able to suppress gonadotropin-releasing hormone (GnRH), thereby helping to maintain appropriate PRL homeostatic levels.
The specific mechanism by which hyperprolactinemia causes low T has not been definitively described, although it likely includes both direct and indirect contributions. The presence of a pituitary adenoma (secreting or non-secreting) may result in suppression of GnRH/LH or destruction of GnRH/LH producing cells with subsequent declines in T production. Additionally, as a mild gonadotroph, PRL may feedback directly to the pituitary, resulting in the suppression of LH and T. Of note, from a purely diagnostic standpoint, true hyperprolactinemia occurs in the absence of macroprolactinomas, which may otherwise result in elevated prolactin levels without associated symptoms. The differentiation between these two conditions and diagnostic testing is beyond the scope of this chapter
4.3 Clinical Symptoms and Prevalence of Hyperprolactinemia in Men
Symptoms related to hyperprolactinemia may be due to the effect of PRL itself, suppression of other hormones (e.g., T), or a mass effect from a PRL-secreting mass. See Table 4.1 for a summary of common presenting symptoms in men with hyperprolactinemia.
4.4 Etiologies for Hyperprolactinemia
Several different conditions and substances have been associated with hyperprolactinemia, including tumors, comorbid conditions, and medications, among others. See Table 4.2 for a more complete list of potential etiologies.
4.5 When to Obtain Prolactin Testing
The appropriate management of men with low T includes obtaining PRL levels in select clinical scenarios. The American Urological Association (AUA) and Endocrine Society guidelines on T deficiency both recommend obtaining PRL in men with low T and low/low-normal LH [15, 16]. From a physiologic standpoint, if LH is in the normal range, then this suggests the ability of the pituitary to release LH to stimulate the testicles and indicates that PRL testing is not required. In contrast, if LH is low or low/normal in the setting of low T, then this represents an inappropriate response and indicates a need to evaluate for potential causes of the hypogonadotropic hypogonadism. In a related manner, men with total T levels <150 ng/dl and low/low-normal LH should undergo a pituitary MRI regardless of PRL levels, given the possibility for non-PRL-secreting adenomas and higher yield at T levels <150 ng/dl [17].
The interpretation of PRL and what is considered normal are not well established, and significant debate remains on optimal investigational and treatment thresholds. From a practicality standpoint, PRL levels <50 ng/ml are rarely associated with significant pathology, while higher levels (>250 ng/ml) are positively correlated with an increased likelihood for identifiable intracranial pathology, and levels >500 ng/ml are diagnostic of macroprolactinoma [2, 5, 20]. However, in the absence of better data, levels above normal thresholds, but lower than <50, should not prevent an investigation as to underlying causes or preclude treatment in the setting of hypogonadotropic hypogonadism.
Although transient elevations in PRL are not uncommon, the Endocrine Society does not recommend repeat or confirmatory testing in most cases of hyperprolactinemia [21].
4.6 Management of Hyperprolactinemia
As the target audience of this chapter is a non-endocrinologist practicing clinician, a complete and thorough description of the management of hyperprolactinemia is beyond the intended scope. In most cases, practicing clinicians will likely refer patients with elevated PRL to an endocrinology provider, which is consistent with AUA guideline recommendations [15]. However, a brief summary of general treatment strategies will be reviewed to provide a greater level of understanding, given that the initial diagnosis of hyperprolactinemia still relies on the sexual medicine provider. Each of the strategies noted below is based on the Endocrine Society Guideline on hyperprolactinemia [21]. See Fig. 4.1 for a proposed summary algorithm of the evaluation and treatment of hyperprolactinemia.
One of the first steps in managing hyperprolactinemia is to determine who does and does not merit treatment. Men with medication-induced hyperprolactinemia may be considered for medication substitution/trial of discontinuation if clinically viable. If this is not feasible, men with medication-induced hyperprolactinemia and low T (with associated symptoms/findings) are not recommended to undergo dopamine agonist therapies (e.g., cabergoline), but rather be treated with T directly. In cases of symptomatic hyperprolactinemia secondary to medications where the medication cannot be stopped, cautious consideration of a dopamine agonist may be elected.
Similarly, men with asymptomatic microprolactinomas are generally not recommended to be treated with dopamine agonists. In contrast, men with symptomatic microprolactinomas or macroprolactinomas (with or without symptoms) are appropriate for treatment
Once the decision for therapy has been made, dopaminergic agents such as cabergoline are recommended as first-line agents. Initiation of cabergoline leads to normalization of PRL levels in 71–86% and tumor shrinkage in approximately 80% of men [1, 22]. Those with smaller microadenomas may experience even higher success rates (95%) [23]. In men who are resistant to cabergoline (approximately 10%), bromocriptine may be substituted.
Once successful treatment has been achieved for at least 2 years (normalized PRL levels and no visible tumor), therapy may be tapered off with subsequent biochemical follow-up. In men who do not respond, maximally tolerated dosing of dopamine agonists is recommended prior to consideration of surgery.
Surgery is recommended in select cases, including symptomatic patients with prolactinomas who cannot tolerate high-dose cabergoline or are unresponsive to dopamine agonists. Those with aggressive or malignant prolactinomas are recommended for radiation therapy.
4.7 Summary
Hyperprolactinemia is a relatively infrequent, but important, condition that occurs in men with low T. The most common symptoms associated with hyperprolactinemia include sexual symptoms (e.g., low libido and ED), although these are relatively indistinguishable from low T and are likely directly related to T levels. In men with low T, an LH level should be obtained and, if found to be low, PRL levels should subsequently be performed. Current ICSM guidelines also recommend obtaining prolactin in all men presenting with low libido. Men with severely low T (<150 ng/ dl) and those with elevated PRL levels without a clearly defined cause should undergo a pituitary MRI to evaluate for the presence of micro- or macroadenomas. Further evaluations are warranted to identify the cause of hyperprolactinemia, which may include medications, hypothyroidism, and chronic kidney disease, among others. The treatment of hyperprolactinemia is typically best managed by an endocrinologist and consists of medical therapy with cabergoline in the majority of cases. Surgery and radiation are infrequently utilized and are reserved for men who are refractory or intolerant to medications.
The appropriate diagnosis and management of male testosterone (T) deficiency requires a thorough understanding of several physiologic processes and may require the integration of subspecialty services. The lack of understanding or appreciation of the complex nuances of low T may lead to missed diagnoses, inappropriate therapy, and potentially significant ramifications to a patient’s overall health and well-being. One of these nuances includes the role and relevance of prolactin (PRL) and, more specifically, hyperprolactinemia as an important clinical condition. However, despite its importance, relatively few clinicians who treat low T have significant experience in managing PRL abnormalities. Given this observation, the objective of this chapter is to provide the practicing clinician a practical guide to evaluating and managing hyperprolactinemia. To accomplish this objective, the chapter is outlined to review the anatomy and physiology of PRL, associated findings and symptoms, its causative role in low T, the appropriate evaluation of hyperprolactinemia, and available management strategies. Although many clinicians may simply choose to refer men with hyperprolactinemia to an endocrinologist, a deeper understanding of these principles remains relevant, given that the initial diagnosis of hyperprolactinemia is most often dependent upon the sexual medicine clinician.
4.2 Prolactin and Hypothalamic-Pituitary-Gonadal Axis
Prolactin is a hormone produced in the anterior pituitary gland that serves predominantly to facilitate milk production in women. Several different actions lead to PRL secretion, including nursing, estrogen therapy/hormones, sexual activity, eating, and ovulation. As with other pituitary hormones, PRL is secreted in a pulsatile fashion and often occurs between stimulating events. It has additionally been suggested to have roles in immunomodulation and cell growth and differentiation and is particularly involved in hematopoiesis and angiogenesis.
Prolactin is most active during periods of pregnancy, where it leads to breast growth and mammary gland milk production. The regulation of PRL secretion is largely controlled via the inhibitory effects of dopamine, although thyrotropin-releasing hormone (TRH) also contributes and is able to directly stimulate release. Central serotonin also shows a stimulatory effect on PRL secretion. Prolactin exhibits mild gonadotropic effects and sensitizes luteinizing hormone (LH) receptors in Leydig cells, thereby increasing T production. Both T and PRL are subsequently able to suppress gonadotropin-releasing hormone (GnRH), thereby helping to maintain appropriate PRL homeostatic levels.
The specific mechanism by which hyperprolactinemia causes low T has not been definitively described, although it likely includes both direct and indirect contributions. The presence of a pituitary adenoma (secreting or non-secreting) may result in suppression of GnRH/LH or destruction of GnRH/LH producing cells with subsequent declines in T production. Additionally, as a mild gonadotroph, PRL may feedback directly to the pituitary, resulting in the suppression of LH and T. Of note, from a purely diagnostic standpoint, true hyperprolactinemia occurs in the absence of macroprolactinomas, which may otherwise result in elevated prolactin levels without associated symptoms. The differentiation between these two conditions and diagnostic testing is beyond the scope of this chapter
4.3 Clinical Symptoms and Prevalence of Hyperprolactinemia in Men
Symptoms related to hyperprolactinemia may be due to the effect of PRL itself, suppression of other hormones (e.g., T), or a mass effect from a PRL-secreting mass. See Table 4.1 for a summary of common presenting symptoms in men with hyperprolactinemia.
4.4 Etiologies for Hyperprolactinemia
Several different conditions and substances have been associated with hyperprolactinemia, including tumors, comorbid conditions, and medications, among others. See Table 4.2 for a more complete list of potential etiologies.
4.5 When to Obtain Prolactin Testing
The appropriate management of men with low T includes obtaining PRL levels in select clinical scenarios. The American Urological Association (AUA) and Endocrine Society guidelines on T deficiency both recommend obtaining PRL in men with low T and low/low-normal LH [15, 16]. From a physiologic standpoint, if LH is in the normal range, then this suggests the ability of the pituitary to release LH to stimulate the testicles and indicates that PRL testing is not required. In contrast, if LH is low or low/normal in the setting of low T, then this represents an inappropriate response and indicates a need to evaluate for potential causes of the hypogonadotropic hypogonadism. In a related manner, men with total T levels <150 ng/dl and low/low-normal LH should undergo a pituitary MRI regardless of PRL levels, given the possibility for non-PRL-secreting adenomas and higher yield at T levels <150 ng/dl [17].
The interpretation of PRL and what is considered normal are not well established, and significant debate remains on optimal investigational and treatment thresholds. From a practicality standpoint, PRL levels <50 ng/ml are rarely associated with significant pathology, while higher levels (>250 ng/ml) are positively correlated with an increased likelihood for identifiable intracranial pathology, and levels >500 ng/ml are diagnostic of macroprolactinoma [2, 5, 20]. However, in the absence of better data, levels above normal thresholds, but lower than <50, should not prevent an investigation as to underlying causes or preclude treatment in the setting of hypogonadotropic hypogonadism.
Although transient elevations in PRL are not uncommon, the Endocrine Society does not recommend repeat or confirmatory testing in most cases of hyperprolactinemia [21].
4.6 Management of Hyperprolactinemia
As the target audience of this chapter is a non-endocrinologist practicing clinician, a complete and thorough description of the management of hyperprolactinemia is beyond the intended scope. In most cases, practicing clinicians will likely refer patients with elevated PRL to an endocrinology provider, which is consistent with AUA guideline recommendations [15]. However, a brief summary of general treatment strategies will be reviewed to provide a greater level of understanding, given that the initial diagnosis of hyperprolactinemia still relies on the sexual medicine provider. Each of the strategies noted below is based on the Endocrine Society Guideline on hyperprolactinemia [21]. See Fig. 4.1 for a proposed summary algorithm of the evaluation and treatment of hyperprolactinemia.
One of the first steps in managing hyperprolactinemia is to determine who does and does not merit treatment. Men with medication-induced hyperprolactinemia may be considered for medication substitution/trial of discontinuation if clinically viable. If this is not feasible, men with medication-induced hyperprolactinemia and low T (with associated symptoms/findings) are not recommended to undergo dopamine agonist therapies (e.g., cabergoline), but rather be treated with T directly. In cases of symptomatic hyperprolactinemia secondary to medications where the medication cannot be stopped, cautious consideration of a dopamine agonist may be elected.
Similarly, men with asymptomatic microprolactinomas are generally not recommended to be treated with dopamine agonists. In contrast, men with symptomatic microprolactinomas or macroprolactinomas (with or without symptoms) are appropriate for treatment
Once the decision for therapy has been made, dopaminergic agents such as cabergoline are recommended as first-line agents. Initiation of cabergoline leads to normalization of PRL levels in 71–86% and tumor shrinkage in approximately 80% of men [1, 22]. Those with smaller microadenomas may experience even higher success rates (95%) [23]. In men who are resistant to cabergoline (approximately 10%), bromocriptine may be substituted.
Once successful treatment has been achieved for at least 2 years (normalized PRL levels and no visible tumor), therapy may be tapered off with subsequent biochemical follow-up. In men who do not respond, maximally tolerated dosing of dopamine agonists is recommended prior to consideration of surgery.
Surgery is recommended in select cases, including symptomatic patients with prolactinomas who cannot tolerate high-dose cabergoline or are unresponsive to dopamine agonists. Those with aggressive or malignant prolactinomas are recommended for radiation therapy.
4.7 Summary
Hyperprolactinemia is a relatively infrequent, but important, condition that occurs in men with low T. The most common symptoms associated with hyperprolactinemia include sexual symptoms (e.g., low libido and ED), although these are relatively indistinguishable from low T and are likely directly related to T levels. In men with low T, an LH level should be obtained and, if found to be low, PRL levels should subsequently be performed. Current ICSM guidelines also recommend obtaining prolactin in all men presenting with low libido. Men with severely low T (<150 ng/ dl) and those with elevated PRL levels without a clearly defined cause should undergo a pituitary MRI to evaluate for the presence of micro- or macroadenomas. Further evaluations are warranted to identify the cause of hyperprolactinemia, which may include medications, hypothyroidism, and chronic kidney disease, among others. The treatment of hyperprolactinemia is typically best managed by an endocrinologist and consists of medical therapy with cabergoline in the majority of cases. Surgery and radiation are infrequently utilized and are reserved for men who are refractory or intolerant to medications.
