PrL-Secreting Pituitary Adenomas - Holland-Frei Cancer Medicine - NCBI Bookshelf

Clinical Presentation

With very few exceptions, prolactinomas are slow growing, and the clinical presentation differs in men and women. In women of reproductive age, the symptoms are typically oligomenorrhea or secondary amenorrhea, galactorrhea, and sterility, followed by decreased libido, dry vaginal mucosa due to a deficiency in estrogen, weight gain, and psychological symptoms such as depression and anxiety. In men and postmenopausal women, the tumors grow to much larger sizes and are detected only once they begin to produce mass effect, resulting in headaches, visual disturbances (most commonly a bitemporal hemianopsia from chiasmal compression), hypopituitarism, ophthalmoplegia, and, rarely, hydrocephalus from obstruction of the foramen of Monro. Men may also experience a diminished libido, impotence, and infertility from decreased androgen production.

There still exists significant debate on the exact mechanism of hypogonadism caused by hyperprolactinemia. The most likely theory is that prolactin, through dopamine inhibition, alters the hypothalamic release of gonadotropin-releasing hormone (GnRH), causing disruptions in the normal pulsatile secretion of LH.¹⁸ Prolonged periods of hyperprolactinemia have also been linked to bone demineralization, which is the result of hypogonadism and not of the elevated prolactin levels per se, as previously believed, since bone density is normal in eumenorrheic hyperprolactinemic women.¹⁹

Diagnosis

Besides prolactinomas, hyperprolactinemia can be associated with a variety of causes, such as pregnancy, hypothyroidism, prolactin-stimulating drugs, and renal failure, which need to be considered in the differential diagnosis. A definitive diagnosis of prolactinoma is difficult and in most cases requires radiographic evidence in addition to elevated PRL levels. In men, a basal PRL value greater than 100 ng/mL is almost always indicative of a prolactinoma. In women, levels over 200 ng/mL are also highly suggestive of prolactinomas, and values of 100 to 200 ng/mL are also likely to be associated with a prolactin-secreting adenoma.²⁰ The greatest diagnostic uncertainty lies in women with PRL values between 50 and 100 ng/mL, also termed moderate hyperprolactinemia. In these cases, the elevated prolactin could be from a prolactin-secreting tumor but could also be from “stalk effect” caused by a nonsecreting adenoma that interferes with the flow of prolactin-inhibitory factor (PRIF) from the hypothalamus. Although various endocrine stimulation tests to differentiate these two possibilities have been suggested, they have not proven to be reliable.²¹

Serum PRL levels are an index of secretory activity and have been found to be associated with the size of the prolactinoma, excluding any associated cystic or necrotic component. If the PRL is less than 200 ng/mL, 80% of tumors are microadenomas, and if PRL is greater than 200 ng/mL, only 20% are microadenomas. This relationship, however, does not hold true for giant prolactinomas (> 4 cm and PRL > 1000 ng/mL).²²

Treatment

The treatment options available to a patient with a prolactinoma include observation, medical therapy, surgical therapy, and radiotherapy. The best treatment depends on tumor size, prolactin level, clinical manifestations, tolerance of medical therapy, and the desire for fertility. Studies have demonstrated that the vast majority of microprolactinomas (< 10 mm) do not increase in size.²³ In addition, autopsy series have found the frequent occurrence of incidental microprolactinomas. Based on this, in patients with only mildly elevated prolactin, normal pituitary function, no clinical symptoms, and no desire for pregnancy, observation with serial radiographic and endocrine evaluation is reasonable.

Lactotrophs are controlled by a negative dopaminergic effect from the hypothalamus, and based upon this, dopamine agonists have become the standard medical therapy. Unlike long-term medical treatment for other endocrine-active pituitary disorders, dopamine agonists have been remarkably effective in both reducing the size of the tumor and normalizing serum prolactin levels below the accepted remission level of 25 ng/mL. Bromocriptine was the first of these medications, but more recently, others such as carbergoline, quinagolide, lisuride, pergolide mesylate, and terguride are also being used. Biomolecular studies have shown that dopamine agonists selectively activate type D2 dopamine receptors blocking the transcription of the prolactin gene.²⁴ The shrinkage of prolactin cells results in amyloid deposition and fibrosis of the tumor.²⁵ Dopamine agonists have been shown to have a high response rate, with reports of normalization of prolactin in 70% to 80%, tumor shrinkage in 80% to 90%, and restoration of ovulation in 80% to 90%.²⁶ Based upon these results, some would argue that medical treatment should be used in all patients except the 30% that have significant side effects.²⁷

Dopamine agonists do have some significant disadvantages that may temper their use in all patients. The effects are irreversible, making the therapy lifelong in most cases and thus requiring significant compliance. Additionally, there can be significant side effects, including nausea, vomiting, postural hypotension, and headaches, as well as depression and anxiety, which can make long-term compliance even more difficult in some patients. In cases of pituitary apoplexy and in tumors with large cystic components, dopamine agonists are not effective.

The role of surgery in the treatment of prolactinomas has been under discussion. Some argue that surgery should be the initial treatment, with medical therapy as an adjunct only in cases without remission.²⁸ The rate of long-term remission varies significantly, however, depending on the size of the tumor and preoperative prolactin levels. The most favorable results have been demonstrated in microadenomas with levels below 200 ng/mL, with remission rates ranging from 50% to 84% in long-term follow-up.^26,28,29 The remission rate drops with macroadenomas and with prolactin levels between 200 and 500 ng/mL, but these tumors are amenable to surgical resection. Surgery has not been shown to be useful in giant adenomas and in tumors with prolactin levels greater than 500 ng/mL, with the remission rate decreasing to 0%. These lesions are better treated with medical therapy, possibly in conjunction with surgery and radiation. Overall, the lower the prolactin level, the greater the chance of long-term cure.

Because of the successful long-term control of prolactinomas with medical and surgical options, conventional radiotherapy is generally not considered a primary mode of treatment. It is utilized in certain invasive tumors, but even that utilization is under debate.³⁰ The use of gamma knife radiosurgery as either a primary treatment modality or an adjuvant therapy are also being discussed in the literature.^31,32

Recommendation

Based upon the results discussed above, the recommendation is that optimum treatment of prolactinomas needs to be tailored to the tumor size, the prolactin level, and the patient's own wishes. Medical therapy is the first option for almost all prolactinomas. Treatment with a dopamine agonist can be considered as the primary treatment with almost all microadenomas, including patients desiring pregnancy or those with primary amenorrhea.

Based upon the most current literature, surgical removal with a high remission can be recommended for most macroadenomas with prolactin less than 200 ng/mL. For tumors larger than 2 cm and prolactin less than 500 ng/mL, patients should first be treated with a dopamine agonist to reduce the tumor volume and then undergo surgical resection. Any residual tumor can then be treated medically. For very large or invasive tumors or for tumors with prolactin greater than 500 ng/mL, medical therapy should be the primary treatment modality.

The subgroup that needs specific discussion is those patients who are pregnant and harbor prolactinomas. There is a small but serious risk related to the possible rapid expansion of the tumor. Complications occur primarily with macroprolactinomas that have suprasellar extension and are much less frequent in cases of microprolactinomas.³³ If the patient becomes symptomatic, a dopamine agonist can be administered. However, the data regarding the effects of continuous dopamine agonist therapy on the fetus are limited, but they suggest no ill effect. Surgery should be undertaken during pregnancy only if the tumor does not respond to medical treatment and if there are progressive neurological symptoms. Patients with macroadenomas who desire pregnancy should undergo a transsphenoidal resection prior to conception.