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Spontaneous regression of pituitary macroadenomas is rare. It is generally thought that absorption of the necrotic tissue after pituitary apoplexy may cause the spontaneous healing of the tumor. However, such cases are often accompanied by hypopituitarism, which sould be treated with hormone replacement therapy. Here we report two cases of spontaneous remission of pituitary macroadenomas in women, who had complete tumor disappearance with preserved pituitary function.

Case 1
A 50-year-old woman complaining occasional headache for years was admitted to our hospital in November 2001. On admission, the patient had normal menstruation without evident changes in either visual acuity or visual fields. MRI examination showed a well-delineated sellar lesion sized 1.3 cm × 1.0 cm × 1.0 cm (Fig. 1A–C), which was partly hyperintense and partly isointense on both T₁- and T₂-weighted images without significant enhancement. Laboratory examinations showed a prolactin (PRL) level of 34.95 ng/ml (reference: PRL<25 ng/ml), and a slightly increased cortisol level. The patient was tentatively diagnosed with non-functioning pituitary adenoma complicated with infarctive apoplexy and cystic change. Afterwards, she was discharged without any treatment, and then was followed up yearly.

In April 2002, laboratory examination showed that her PRL level had decreased to a normal level (13.54 ng/ml). Then, in April 2003 and May 2004, MRI indicated a slightly increased tumor volume (1.5 cm × 1.2 cm × 1.0 cm, Fig. 1D–F), in which the cystic components increased while apoplexic components decreased mildly. The patient's menses became irregular in early 2004 and her last menstruation occurred in July 2004. The reexamination of MRI in December 2004 indicated a complete disappearance of the tumor (Fig. 1G and 1H). The patient had no symptom of hypopituitarism. And the result of the PRL examination after that was 10 ng/ml, and the basal levels of pituitary hormones remained normal.

Case 2
A 28-year-old woman with a two-year history of amenorrhea and galactorrhea was admitted to our hospital in December 2002. She had no apparent headache or visual defect. On admission, her serum PRL level was 141 ng/ml and the basal level of the other hormones were within the normal ranges. MRI scan indicated a sellar tumor sized 1.8 cm × 1.2 cm × 1.0 cm with short T₁ and long T₂ signals, and a leftward moved pituitary stalk (Fig. 2A–C). Thus, the patient was tentatively diagnosed with macroprolactinoma accompanied with hemorrhagic apoplexy.

Since the patient intended to have a child, she was advised to take bromocriptine (2.5 mg/d) for 30 days. Afterwards, she was found pregnant and then stopped taking the medicine. In November 2003, she gave birth to a child successfully. Repeated MRI scan performed one month later showed a complete disappearance of the tumor (Fig. 2D and E). And the levels of PRL (9 ng/ml) and other hormones were within normal ranges. No pituitary insufficiency was detected. The patient was followed up by MRI examination in March 2004 and April 2005, which showed no evidence of tumor recurrence (Fig. 2F and G). A recent examination showed that her PRL level was 20.6 ng/ml, and her menstruation had recovered.

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Fig. 1. MRI images of the case 1. The images obtained in November 2001 showing a well-delineated sellar lesion sized 1.3 cm×1.0 cm×1.0 cm, which was partly hyperintense and partly isointense on T1- and T2-weighted images without enhancement (A-C). The images taken in May 2004 indicating a slightly enlarged tumor mass, in which the cystic cystic components increased while apoplexic components decreased mildly (D-F). The repeated MRI in December 2004 showing that the tumor disappeared completely (G and H). Fig. 2. MRI images of the case 2. The images obtained in December 2002 showing a sellar tumor with short T1 and long T2 signals. The pituitary stalk was pushed leftwards (A-C). The images taken in December 2003 showing a complete disappearance of the tumor (D and E). During the follow-up, no evidence of recurrence was detected in MRI (F and G).

DISCUSSION

Tumor apoplexy is one of the main causes of the spontaneous remission of pituitary adenomas. Pituitary apoplexy can be classified into the following forms: hemorrhagic infarction, simple infarction, and frank hemorrhage, of which the first two are the most common forms.¹ The internal pressure in the tumor cavity increases suddenly after the tumor hemorrhage, which causes the blockage of the vessels supplying the tumor and results in tumor necrosis. The necrotic tumor can be liquefied and absorbed, which ultimately results in the tumor's spontaneous remission. In addition, the infarctive apoplexy can directly cause the blockage of the blood vessels and the tumor necrosis. Of the 255 cases with pituitary adenomas reported by Bjerre,² seven cases had the symptoms of sterile meningitis, which was thought to have been caused by the necrotic substance flowing into the suprasellar subarachnoid cavity. In two of the seven cases, the spontaneous remission of the tumor caused a empty sella. Patients with apparent clinical symptoms of apoplexy required emergency surgery; therefore Van- Zandijcke³ thought that non-symptomatic apoplexy could better explain the spontaneous remission. According to neuroimaging analysis, both of our cases had manifestation of apoplexy. For case 2, MRI indicated short T₁ and long T₂ signals, which are typical manifestation of adenoma-hemorrhage apoplexy. For case 1, the manifestation of MRI was more complicated. Compared with her MRI image in November 2001 before the tumor remission, the T₂-weighted image in May 2004 showed that the cystic components of the tumor slightly increased while the components of the apoplexy decreased, and the latter's signals gradually increased, indicating that the cystic component was liquefied and absorbed and the tumor was remitting. Moreover, the pituitary adenoma apoplexy can result in hypopituitarism, and the patients need long-term hormone replacement therapy. Compared with the hemorrhage apoplexy, the infarctive apoplexy is more liable to involve the tumor itself and has less symptoms of hypopituitarism.⁴ Both the cases in our group had normal pituitary functions after the spontaneous remission, and did not need hormone replacement therapy.

As we all know, the level of estrogen increases continuously during pregnancy and drops sharply after childbirth. As early as in 1980, Lamberts⁵ has reported a case of GH-PRL mixed adenoma, whose plasma GH and PRL levels increased significantly at the time of ovulation, while the plasma 17 beta-estradiol concentration decreased. By taking tamoxifen, her symptoms were improved and the GH level decreased. Therefore, tamoxifen is advised for those who have pituitary adenomas that are resistant to bromocriptine. In 1985, Fujimoto⁶ reported a case of PRL macroadenoma without tumor apoplexy, whose symptoms disappeared one month after her delivery and the tumor reduced in size spontaneously. It was believed that the increased PRL level during the pregnancy and the spontaneous reduce of the tumor were related to the changing levels of the body estrogen. In another case,⁷ the PRL level was significantly reduced in a man with invasive prolactinoma after dopamine agonist treatment. Since the patient had hypogonadism, testosterone was used as a replacement therapy. However, the patient's serum PRL increased extraordinarily with the testosterone replacement, and was not brought back to the original level until testosterone replacement was stopped or the aromatase inhibitor was used along with testosterone. Therefore, the authors believe that, under the effect of aromatase, testosterone was changed into estradiol, influenceing the curative effect of the medicine. Estrogen could reduce the sensitiveness of dopamine agonists to prolactinomas. And contrarily, reducing the body's endogenous estrogen level would be a potential and experimental therapy.⁸ Karunakaran,⁹ when studying women with hyperprolactinaemia and microprolactinoma, found that those who were passing through the menopause or pregnancy had a significant chance to achieve normal PRL levels. In our group, one case had the spontaneous tumor remission after her delivery and the other were passing through the menopause. Thus, we infer that the decrease of the endogenous estrogen levels lends itself to the tumor remission.

Close follow-up should be carried out for patients with non-symptomatic pituitary adenoma accompanied by tumor apoplexy. Even in those female patients with small adenoma and moderately increased PRL level, who have no significant symptoms and no requirement of childbirth,¹⁰ a close follow-up is necessary. As to the patients with their pituitary adenomas spontaneously remitted, a long-term and close follow-up is a must, because the tumor may recur after even 7 years.¹¹

In summary, tumor apoplexy and decreased endogenous estrogen level may be the major causes for the spontaneous remission of pituitary macroadenomas in women. It is important to take the spontaneously remitting course of the pituitary macroadenomas into consideration in the assessment of the effect of various treatment protocols.

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