Indications for Treatment of Microprolactinomas: An Update
by Anne Klibanski, M.D.

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• Tumor Size in Untreated Hyperprolactinemia
• Osteopenia in Hyperprolactinemia
• Conclusions
• References

Although the presence of a macroprolactinomas (> or equal to 1 cm) obligates therapy, treatment of patients with idiopathic hyperprolactinemia or microprolactinomas remains controversial. Infertility or clinically significant galactorrhea have long been recognized as standard indications for treatment of hyperprolactinemia. Infertility may be associated with amenorrhea or anovulatory cycles. However, infertility also may be due to subtle ovulatory disorders including luteal phase dysfunction which may be more difficult to diagnose. Also, hyperprolactinemia may be intermittent in nature, and several prolactin levels may be needed to establish the diagnosis. Intermittent hyperprolactinemia associated with infertility may also occur exclusively in the periovulatory phase of the menstrual cycle. A subset of women are thought to be more sensitive to the rising levels of estrogen associated with the ovulatory phase of this cycle, and hyperprolactinemia occurring during this time period may lead to infertility. Therefore, even mild prolactin elevations in infertile women warrant therapy.

Other indications for treatment include signs and symptoms of androgen excess or headaches. Hyperprolactinemia is known to be associated with androgen excess in a subset of patients, and elevations in serum testosterone, free testosterone and DHEAS have been reported. Prolactin may have a direct stimulatory effect on adrenal androgen production. In women with documented hyperprolactinemia together with mild signs of androgen excess, treatment of hyperprolactinemia with dopamine agonist therapy typically results in normalization of serum androgens. Although headaches do occur in patients with prolactin-secreting macroadenomas, there is, as well, an association between hyperprolactinemia and headaches, even in patients with microadenomas or normal head scans. Therefore, in patients with hyperprolactinemia and headaches, particularly if the onset of headaches coincides with menstrual irregularity or symptoms potentially attributable to hyperprolactinemia, a trial of dopamine agonist therapy may be warranted. A more controversial point is whether women with micropolactinomas or idiopathic hyperprolactinemia without these indications for therapy should be treated, or whether they should be followed with observation alone. The two major points to be considered in this regard are the effects of follow-up without treatment on tumor size, and the metabolic consequences of hypogonadism and estrogen deficiency.

Tumor Size in Untreated Hyperprolactinemia :

In a number of retrospective and prospective studies, patients with idiopathic hyperprolactinemia or microprolactinomas have been found to have a zero to 22% incidence of tumor progression. In a retrospective series of 25 patients reported from the NIH, one patient (4%) had tumor growth. The most comprehensive prospective series was reported by Schlechte et al in which thirty women with hyperprolactinemia who were not treated were evaluated at yearly intervals for three to seven years. Of the 27 women who had serial x-ray evaluations, two had evidence of tumor progression, and four, with initially normal radiographic studies, developed radiographic evidence of a pituitary tumor. None of these patients developed a macroadenoma or pituitary hypofunction associated with these radiographic changes. On the basis of both retrospective and prospective data, it has been documented that the majority of patients with idiopathic hyperprolactinemia or microprolactinomas do not have evidence of tumor progression. Therefore, medical therapy based on tumor size is considered primarily in those women who have clear-cut evidence of tumor enlargement on MRI scan, or who have the new appearance of a microadenoma with previously normal MRI scans. It is critical to emphasize that patients who do not receive therapy must be monitored carefully with serial prolactin levels and MRI scans.

Osteopenia in Hyperprolactinemia:

Hypogonadism frequently accompanies hyperprolactinemia and is often manifested clinically by amenorrhea and/or other ovulatory disorders. Because mean serum estradiol levels in amenorrheic hyperprolactinemic women are typically comparable to the early follicular phase estradiol levels seen in normal women, hyperprolactinemic amenorrheic women have an absolute or relative estrogen deficiency state. Such women lack the rise in serum estradiol levels typically seen in the mid-follicular, ovulatory and luteal phase of the cycle. The long-term metabolic consequences of amenorrhea and its associated estrogen deficiency in young women have been the subject a number of studies. Osteopenia has been found to affect both cortical and trabecular bone compartments and progressive cortical and trabecular bone loss has been demonstrated in untreated patients. In a cross-sectional study of women treated for hyperprolactinemia with transsphenoidal surgery, spinal bone mineral content was 15% higher in women who had post-operative restoration of menses. These data suggested that restoration of normal gonadal function with treatment of hyperprolactinemia might have a beneficial effect on bone loss. In a study conducted at the MGH reported by Biller et al, trabecular bone density by CT was investigated prospectively in 52 hyperprolactinemic women with a mean follow-up interval of 1.8 years. Of the 39 women with a history of amenorrhea, 49% had a spinal bone density of more than 1 SD below normal. Because a decrease of 1 SD of bone mineral density is associated with a 52-100% increase in fracture incidence, these data indicate that hyperprolactinemic women are at increased fracture risk before they enter menopause. Of the group of women who remained amenorrheic during the entire study, there was a significant decrease in mean trabecular bone density. In those patients who were followed after restoration of menses by treatment of hyperprolactinemia, there was an increase in bone density in only a subset of patients. Of note, women with oligoamenorrhea had a trabecular bone density which was midway between the hyperprolactinemic amenorrheic women and the normal controls. Therefore, chronic amenorrhea and its associated estrogen deficiency leads to progressive osteopenia in such women. Data from published studies indicate that, as in other hypogonadal states, the trabecular bone compartment may be first affected by hyperprolactinemic amenorrhea and may be less likely to show improvement following restoration of normal function. These data also indicate that hyperprolactinemic amenorrheic women who have had a sustained period of estrogen deficiency may have a permanent decline in bone density which may persist until the menopause. It is also important to note that hyperprolactinemic women who have regular menstrual periods do not appear to have evidence of osteopenia. Therefore, prolactin does not appear to have an independent, deleterious effect on bone density, and osteopenia is only an important consideration in those women who have associated menstrual disturbances.

Conclusions

In patients who do not desire fertility, who have clinically significant galactorrhea and symptoms and signs of androgen excess or headaches, the two most important indications for medical therapy are tumor size and hypogonadism. Women who have hyperprolactinemia with a normal MRI scan, or a microadenoma, can be followed with serum prolactin levels and head scans. Treatment is required if there is a significant increase in tumor size, development of amenorrhea, or other clinical indications.

References

1. March CM, Kletzky OA, Davajan V, et al. Longitudinal evaluation of patients with untreated prolactin-secreting pituitary adenomas. Am J Obstet Gynecol. 1981; 139:835.
2. Koppelman MCS, Jaffe MJ, Rieth KG, Caruso FC, Loriaux DL. Hyperprolactinemia, amenorrhea, and galactorrhea. A retrospective assessment of twenty-five cases. Ann Intern Med. 1984; 100:115.
3. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab. 1989; 68: 412.
4. Klibanski A, Greenspan SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med. 1986; 315:542.
5. Schlechte JA, El-Khoury G, Kathol M, Walkner L. Forearm and vertebral bone mineral in treated and untreated hyperprolactinemic amenorrhea. J Clin Endocrinol Metab. 1987; 64:1021.
6. Greenspan SL, Oppenheim DS, Klibanski A. Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism. Ann Intern Med. 1989; 110:526.
7. Biller BMK, Baum HBA, Rosenthal DI, Saxe VC, Charpie PM, Klibanski A. Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab. 1992; 75:692.

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