New consensus statement addresses advances in diagnosing, managing prolactinomas
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The way endocrinologists manage prolactinomas is changing.
Photo by Cara Fleseriu. Printed with permission.
A new international consensus statement from The Pituitary Society incorporates recent evidence on possible newly recognized adverse events associated with dopamine agonists, efficacy of transsphenoidal surgery and treatment of special populations, such as pregnant women and transgender adults.
Published in Nature Reviews Endocrinology in September, the consensus statement on diagnosis and management of prolactin-secreting pituitary adenomas is the first guideline on prolactinomas published since the Endocrine Society guideline in 2011 that was endorsed by The Pituitary Society and the European Society of Endocrinology.
Prolactinomas account for about half of all pituitary adenomas. Stephan Petersenn, MD, professor at the ENDOC Center for Endocrine Tumors in Hamburg, Germany, and lead author on The Pituitary Society’s consensus statement, said these tumors tend to occur at different times for men and women.
“In women, prolactinomas are usually diagnosed between the ages of 25 and 40 years, nearly all are microadenomas,” Petersenn told Healio | Endocrine Today. “In men, prolactinomas are typically identified after the age of 40 and are usually macroadenomas.”
Although prolactinomas are the most common type of pituitary adenoma, endocrinologists tend to be less familiar with treating them compared with other types of endocrine diseases, according to Odelia Cooper, MD, professor of medicine in the division of endocrinology, diabetes and metabolism at the Pituitary Center at Cedars-Sinai Medical Center in Los Angeles.
“Prolactinoma prevalence is estimated at 40 cases per 100,000 adults for microprolactinomas and 10 cases per 100,000 adults for macroprolactinomas,” Cooper told Healio | Endocrine Today. “In comparison, endocrinologists encounter diabetes at a prevalence of 10 cases per 100 adults. Therefore, statistically, general endocrinologists will not often encounter or treat prolactinomas in their daily practice. Further, the training of general endocrinologists is variable across U.S. fellowship programs with many programs not having pituitary centers of excellence to provide sufficient volumes and experience for endocrine fellows. This may impact delivery of expert pituitary care.”
The new consensus statement highlights changes in several aspects of prolactinoma management. One of those changes is that physicians may consider surgery as a first-line therapy in selected patients in lieu of dopamine agonists for microprolactinomas or enclosed prolactinomas.
“The cause for this slight change in perspective for offering surgery much earlier to patients with smaller pituitary adenomas has been multifactorial,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Oregon Health & Science University (OHSU) Pituitary Center in Portland, co-author of The Pituitary Society consensus statement and a Healio | Endocrine Today Co-editor, said in an interview. “Surgery advances with endoscopic technique and performed by more specialized neurosurgeons raised remission rates for prolactinomas, but also decreased chances of pituitary dysfunctions and other complications postoperatively. On the other hand, more adverse effects of dopamine agonists have been recognized, especially impulse control disorders and depression as well as tumor fibrosis, especially with bromocriptine.”
Changes in treatment recommendations have also occurred for special populations. The consensus statement includes specific recommendations for pregnant, perimenopausal and postmenopausal women and transgender adults.
Diagnosing prolactinomas
The consensus statement offers a step-by-step approach for diagnosing prolactinomas. One of the biggest challenges with diagnosis is determining the cause of symptoms, according to Petersenn. A high prolactin level alone does not always indicate a prolactinoma, though a level of 200 ng/mL or higher is usually diagnostic.
“Diagnosis of prolactinomas may be complicated by the fact that hyperprolactinemia is seen in a variety of other conditions,” Petersenn said. “Physicians evaluating those patients should be aware of the effects of stress, various medications, endocrine disorders like hypothyroidism, and assay artifacts like macroprolactinemia.”
Fleseriu said physicians should measure prolactin if adults are exhibiting any features of excess levels, including an absence of menses, low libido, low sexual function or galactorrhea. If a patient has a high prolactin level, some factors that need to be ruled out before conducting an MRI include pregnancy, severe thyroid disorder, renal failure and high prolactin due to medication use.
“Importantly, many medications can increase prolactin, from antiacids and antiemetics to antidepressants,” Fleseriu said. “Furthermore, several older antipsychotics can increase prolactin almost to levels seen with pituitary adenomas.”
Fleseriu added that performing an MRI before eliminating other possible causes for high prolactin level could lead to misdiagnosis, as some adults could have a small pituitary incidentaloma unrelated to the elevated prolactin. However, if prolactin remains high after other causes are ruled out or after medication changes are initiated, a pituitary MRI should be performed.
One point of emphasis in the consensus statement is the impact hyperprolactinemia can have beyond the gonadal axis. Cooper said high prolactin levels can negatively affect bone and cardiometabolic health.
“Vertebral fractures are observed at higher rates in patients with prolactinoma, up to fivefold higher than the general population,” Cooper said. “Prolactin also has a role on glucose and energy homeostasis in rodent models. Similarly in humans, hyperprolactinemia has been associated with increased food intake, weight gain, insulin resistance and visceral adiposity. On initial evaluation, endocrinologists should consider screening patients for osteopenia, osteoporosis and vertebral fractures as well as metabolic syndrome.”
Dopamine agonists and adverse events
The most common first-line treatment for prolactinomas is dopamine agonist therapy. According to the consensus statement, cabergoline is the preferred choice of therapy due to its long half-life, high efficacy and good tolerability. Medications that are less commonly used include bromocriptine and quinagolide, though quinagolide is not approved for use in the U.S. If adults are receiving one of the less commonly used drugs and are not responding or not tolerating them, they should be switched to cabergoline, according to the consensus statement.
Cabergoline can result in frequent, mild adverse events, including gastrointestinal symptoms, dizziness and fatigue. Additionally, new research has focused on the potential for impulse control disorder. According to a study published in The Journal of Clinical Endocrinology & Metabolism in 2019, 61.1% of adults receiving dopamine agonist therapy for prolactinomas reported some sort of impulse control disorder compared with 42.4% of a community control group not taking dopamine agonists. Cooper said impulse control disorders have been reported with both cabergoline and bromocriptine.
“Men seem to be at higher risk for impulse control disorders,” Cooper said. “It is critical to counsel patients and their families on these potential behaviors and to consider baseline questionnaires for impulse control behaviors. Endocrinologists should ask about these behaviors at each subsequent visit in dopamine agonist-treated patients.”
Medication vs. surgery
One of the biggest changes with prolactinoma treatment in recent years is a choice of medication or surgery as first-line therapy. Cooper said dopamine agonist therapy was considered the primary therapy for most adults in the past because surgery was not considered optimal for biochemical control. However, the consensus statement recommends surgery for selected patients with microprolactinomas or well-circumscribed macroprolactinomas. The statement said surgery “by an experienced neurosurgeon offers a high chance of cure, is cost-effective and avoids long-term dopamine agonist treatment.”
In a meta-analysis published in The Journal of Clinical Endocrinology & Metabolism in 2019, adults with macroprolactinomas had a 67% long-term disease remission rate after surgery compared with a 34% remission rate for adults who withdrew from dopamine agonists. For adults with microprolactinomas, remission rates were 83% with transsphenoidal surgery vs. 36% with dopamine agonist therapy.
“The efficacy of surgery correlates with degree of cavernous sinus invasion,” Cooper said. “Enclosed macroadenomas, with Knosp grade 0 or 1, can potentially achieve remission rates of up to 95%. This now presents an intriguing option for patients to minimize long-term dopamine agonist treatment, especially in younger patients, and to consider treating these adenomas as we do other pituitary adenomas.”
Physicians must weigh several factors when deciding whether medication or surgery is the best course of treatment for a patient, according to Olabisi Sanusi, MD, assistant professor of neurosurgery and otolaryngology, skull base and neurosurgical oncology at OHSU in Portland.
“There are many factors to consider when deciding whether to proceed with surgery on microprolactinomas or well-defined enclosed macroadenomas, such as the extent of tumor; has there been prior treatment with dopamine agonists, prior surgery, radiation or a combination of the above; the patient’s age and the chances of achieving remission relative to risk of surgery,” Sanusi told Healio | Endocrine Today. “On the other hand, if the decision for medication is made, what are the chances the patient will need surgery? This decision will look different for every patient.”
With the new recommendations, the decision to proceed with surgery or dopamine agonist therapy is now a more patient-centered one, according to Cooper.
“I first ask my patients what are their short-term and long-term goals,” Cooper said. “If patients are seeking more immediate fertility, then dopamine agonists will be optimal, assisting that goal more quickly and bypassing the recovery time from surgery. However, for the other patients who are facing years of dopamine agonists with potential side effects and the necessity for long-term monitoring, the script is different. While there is the option of drug holiday to consider after at least 2 years on dopamine agonists, only 34% may sustain normoprolactinemia off dopamine agonists. These remission rates are actually now closer to those who undergo initial surgery.”
In addition to taking a patient-centered approach, endocrinologists should involve a neurosurgeon in the decision-making process.
“Shared decision-making is key,” Sanusi said. “An open dialogue between endocrinologists and neurosurgeons is crucial to the treatment plan for the patient. Of particular importance is discussing and understanding what surgery can or cannot provide and anticipating potential need for adjuvant treatment.”
Treatment during pregnancy, menopause
Even when endocrinologists are generally knowledgeable about treating prolactinoma, they may need guidance when treating people in specific situations, Petersenn said. The consensus statement offers guidance on treating specific populations, including pregnant and perimenopausal women.
According to the statement, pregnancy is considered a risk factor for prolactinoma enlargement, and the risk is higher for women who have not had prior surgery. Petersenn said pregnant women with prolactinomas, especially those with macroprolactinomas, should be seen regularly by an endocrinologist.
“In patients with symptoms of local mass effects, MRI without gadolinium should be performed and treatment reinitiated once adenoma progress is confirmed,” Petersenn said. “In patients with large macroprolactinomas, debulking surgery may be considered prior to conception, or dopamine agonist treatment continued without interruption after conception.”
For women with microprolactinomas and intrasellar macroprolactinomas, dopamine agonist therapy is rarely continued in pregnancy, according to Fleseriu. Dopamine agonists have not been approved for use in pregnancy, and data are limited overall, especially for the second and third trimester.
“Both bromocriptine and cabergoline have shown a good safety profile when administered during early pregnancy, but more data is available for bromocriptine as it has been available longer,” Fleseriu said. “It is important to discuss with patients the more limited data available on the use of cabergoline during pregnancy and associated rare, but potential adverse effects on the fetus. Thus, for small pituitary adenomas, dopamine agonists should be stopped at pregnancy onset.”
Fleseriu said some studies, but not all, have found dopamine agonist use during pregnancy is linked to a higher rate of miscarriage and preterm birth. Studies examining congenital malformations or neonatal abnormalities, as well as follow-up studies of children for up to 12 years, found no differences between women who used a dopamine agonist during pregnancy and the general population, according to Fleseriu.
“For large adenomas, either bromocriptine or cabergoline can be continued to prevent tumor enlargement,” Fleseriu said. “After discussion with patients and reviewing available data as well as all pros and cons of therapy, I prefer using cabergoline due to higher potency, ease of administration at twice per week and better tolerability.”
Dopamine agonist therapy can be restarted soon after delivery if a woman is not lactating, but that decision depends on a number of factors.
“For women with large microadenomas, or small macroadenomas, if they did not need dopamine agonists during pregnancy, we usually perform an MRI to establish a baseline and restart dopamine agonists if there is no desire for lactation,” Fleseriu said. “If there is mild tumor enlargement, but not optic chiasm compression and desire for lactation, we hold off on restarting dopamine agonists for several months. Starting dopamine agonists will stop lactation soon thereafter.”
For women who are entering menopause, the consensus statement recommends those with a well-controlled microprolactinoma enter into a dopamine agonist withdrawal trial as menopause is associated with a physiological decrease in circulating prolactin. For women with a macroprolactinoma, treatment should be focused on controlled adenoma growth rather than prolactin level.
Fleseriu said the question remains whether stopping dopamine agonist therapy for women who have persistent hyperprolactinemia during menopause will worsen bone quality and increase the risk for osteoporosis. She said more research is needed to explore the topic.
More research needed
There have been several advances in prolactinoma management in recent years, but a few areas remain understudied. Future research should examine differences in adenoma aggressiveness and response to dopamine agonist therapy between men and women, Fleseriu said. Studies are also needed to address clinical challenges with treating refractory prolactinomas.
With the changes in recommendations regarding surgery, more research is needed to identify better methods for physicians to determine whether dopamine agonist therapy or surgery is the best first-line treatment for an individual, Petersenn said.
“Further research is required to develop better algorithms to inform the patient about the most effective treatment approach for their specific situation,” Petersenn said. “Similarly, long-term studies are required to better establish the risks of ongoing medical treatment.”
Treating transgender adults with prolactinomas is another area where more research is needed. The consensus statement said transgender women receiving combination estradiol and cyproterone acetate may have mild or asymptomatic hyperprolactinemia. In addition, there is no evidence gender-affirming hormone therapy increases incidence of prolactinomas. However, the authors labeled both recommendations as weak.
“There is no clear evidence yet for increased incidence of prolactinomas in transgender women receiving gender-affirming HT,” Fleseriu said. “However, more studies are needed as estrogen increases prolactin secretion by suppressing hypothalamic-dopamine release and by increasing prolactin-secreting cell size; prolactin can increase in 20% of cases. However, if prolactin significantly increases, an MRI should be performed.”
Another area where more studies are needed is with the treatment of rare, aggressive prolactinomas. The consensus statement defines aggressive prolactinomas as invasive adenomas with an unusually rapid growth rate or adenomas with clinically relevant growth even though the patient is receiving the maximum-tolerated dopamine agonist therapy. The consensus statement recommends temozolomide treatment if the maximum-tolerated dose of dopamine agonist therapy is reached, but Petersenn said, more studies are needed.
“Further research is clearly needed to evaluate the potential of new drugs currently used in other cancers, as well as the potential of new radiation techniques,” Petersenn said.
- References:
- De Sousa SMC, et al. J Clin Endocrinol Metab. 2020;doi:10.1210/clinem/dgz076.
- Petersenn S, et al. Nat Rev Endocrinol. 2023;doi:10.1038/s41574-023-00886-5.
- Zamanipoor Najafabadi AH, et al. J Clin Endocrinol Metab. 2020;doi:10.1210/clinem/dgz144.
- For more information:
- Odelia Cooper, MD, can be reached at odelia.cooper@cshs.org.
- Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu; X (Twitter): @MariaFleseriu
- Stephan Petersenn, MD, can be reached at stephan.petersenn@endoc-med.de.
- Olabisi Sanusi, MD, can be reached at sanusi@ohsu.edu; X (Twitter): @MdOlabisi
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