Buserelin

The etiology of the dural arteriovenous fistula (AVF) involving the cavernous sinus is still unknown. However, it is of interest that this condition usually occurs in post-menopausal women. The purpose of the present study was therefore to clarify the relationship between sex hormone blood levels and the occurrence of dural AVFs in the cavernous sinus. Serum sex hormone levels and factors associated with atherosclerosis were examined in 26 consecutive patients with dural AVF involving the cavernous sinus presenting at our institute during the last eight years and compared with those of a post-menopause control group. Of the present patient series, 21 (81%) were women. All except five had passed menopause. Five (24%) of the women patients presented with symptoms consistent with cessation of menstruation, namely, a blood level of estradiol significantly lower than the control value. Hypertension was recognized in 10 (71%)of 14 females who had experienced menopause 10 or more years previously and in all male patients. A sudden abnormal decrease of blood estradiol levels in female patients demonstrating symptoms consistent with menopause may thus be an important precipitating factor in the occurrence of dural A VFs involving the cavernous sinus. Hypertension, in older female and male patients, with or without longstanding low blood estradiol levels, may cause atherosclerosis of the feeding vessels in the dura mater, resulting in the opening of a normal AV shunt to provide collateral circulation. [Neurol Res 1999; 21: 631-639]

Keywords: Spontaneous carotid cavernous fistula; estradiol; dural arteriovenous fistula

INTRODUCTION

The majority of spontaneous carotid cavernous fistulas (CCF) are of the dural arteriovenous type.1 It is interesting that this condition usually occurs in postmenopausal women2,3, in older men, or in young women just after childbirth4,5. Several precipitating factors have also been implicated, including pregnancy4,5, abortion5 and arteriosclerosis6. However, the wetiology of fistuals located in cavernous sinus is still a matter of controversy. To our knowledge, blood levels of sex hormones in CCF patients have not been may previously reported. In the present study, therefore, they were assessed in a series of cases in an attempt to cast light on the pathogenesis of the carotid cavernous fistula. The results indicate that a reduction in estrogen may play a contributory role.

MATERIALS AND METHODS

At our institute between 1990 and 1997 we experienced 26 patients with spontaneous carotid cavernous fistulas, all of which were dural AVFs as defined by angiography or magnetic resonance angiography and enhanced computed tomography (Table 1). The age range was 49 to 77 years, and most of the patients (21 of 26) were female. Menopause was defined as complete cessation of menstruation 12 or more consecutive months of amenorrhea as defined by WHO. The women whose amenorrhea had persisted less than one year were defined as pre-menopause.

Female patients

All of the women affected were pre-menopausal (cases 1, 2, 4, 5), drug induced amenorrhea (case 3), or post-menopausal (cases 6-21). The age range was 49 to 77 years, with a mean age of 64 years.

In three (cases 1, 4 and 5) of four pre-menopausal cases (mean age 51, range 49 to 52), symptoms occurred within three months after the cessation of menstruation. In the other (case 2), symptoms developed after 10 months. Case 3 presented with symptoms six months after drug-induced cessation of menstruation.

The remaining patients (cases 6-21) were more than four years after menopause, this occurring at a mean age of 52 years (range from 42 to 57 years).

Male patients

The age range was 49 to 69 years (cases 22-26), but all except one of the men (case 20, 49 years old) were older than 65 years.

Control female group (Table 2)

The control group consisted of 15 volunteers and 16 patients with incidental aneurysms (8), incidental meningiomas (5), an incidental arachnoid cyst (1), a facial spasm (1), and cervical spondylosis (1). Patients with disease affecting the hypothalamus and pituitary gland and individuals receiving hormonal medication or having a past history of ovarian disease were excluded. The control group ranged in age from 47 years to 73 years, with a mean of 57 years. Seven were premenopausal, with a mean age of 51 years, well matching the value for the pre-menopausal CCF patients. Eighteen of the control group were more than four years after menopause, and the mean age was 64 years, somewhat younger than the 69 years for the CCF patients.

In all of the consecutive 26 patients, the blood levels of sex hormones were measured to evaluate the relationship between the post-menopausal period and the development of the symptoms. Past history of treatment for ovarian problems and the possible contribution of atherosclerotic factors (hypertension, diabetes mellitus, hyperlipidemia) were also examined.

The blood levels of estradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined in the morning at our outpatient clinic, and were compared statistically with those of the control group. The measurements were performed by radioimmunoassay using dextrin-coated charcoal.

RESULTS

Relationship between the post-menopausal period and development of the symptoms

Symptoms corresponding to the amenorrhea persisting more than three months developed in five of the eight female patients with dural AVFs who were less than 60 years old (Table 1). In one of them (patient 3), a drug (buserelin acetate) induced amenorrhea. In all except this patient, permanent amenorrhea was recognized retrospectively.

Of the total of 21 female patients, 16 presented with symptoms of CCF more than four years after experiencing menopause.

Blood levels of sex hormones

All the female patients had blood levels of estradiol of

The blood levels of progesterone in the control group displayed a relatively rapid drop during the initial three years after menopause and then a slower gradual decrease (Figure 2). In all but one of the five premenopausal patients, the progesterone levels were over 0.32 SI units, in spite of the significantly low estradiol value, without any statistically significant difference from the control group (p

The blood levels of FSH (p

Past history of oophorectomy

The past obstetric and gynecological history could be evaluated for all the female patients. In four of the 21, hemi-oophorectomies had been performed because of ovarian cysts (two cases) or leiomyoma development (two cases). In one patient (a 70-year-old woman), total salpingo-oophorectomy had been carried out for uterine cancer. The period until development of symptoms after oophorectomies ranged from 23 to 41 years (average 31 years).

Atherosclerotic factors

Hypertension is defined as a systolic blood pressure of more than 160 mmHg and/or a diastolic blood pressure > 95 mmHg, requiring medication during hospitalization and in the follow-up period. In 14 (54%) of the 26 patients, hypertension was present. All except one of the male patients were hypertensive. Nine (69%) of the 13 female patients for whom more than 10 years had passed after menopause were hypertensive.

Diabetes mellitus was not diagnosed for any of the patients but hyperlipidemia was present in five of the 26.

CASE REPORTS

Case 3

A 50-year-old woman with a leiomyoma had been treated with buserelin acetate (900 (mu)g day^sup -1^) by a local doctor for six months. After administration of this drug (a down-regulator of gonadotropin releasing hormone), menstruation had ceased completely. This patient developed a swelling of the left palpebra followed by double vision 10 days later, and was admitted to our hospital one month after the onset of the initial symptoms.

Neurological and physiological examinations showed left abducent and oculomotor nerve palsies, exophthalmos and conjunctival chemosis.

Enhanced computed tomography demonstrated marked dilatation of the left superior ophthalmic vein (Figure 5A). Magnetic resonance angiography (MRA) revealed an arteriovenous fistula in the left cavernous sinus (Figure 5B). The blood level of estradiol was low (Table 1). Buserelin acetate treatment was terminated because of the possibility of its aggravating the symptoms, all of which improved significantly within three days of withdrawal of the drug. An angiogram made five days after the withdrawal yielded no abnormal findings (Figure 5C). Enhanced computed tomography and MRI also showed no abnormalities (Figure 5D) and the blood level of estradiol had returned to within the normal range.

Case 8

A 58-year-old woman experienced sudden onset of double vision followed by left tinnitus two weeks later, and was admitted to our hospital one month after the onset of the initial symptoms.

Neurological and physiological examinations showed left oculomotor nerve palsy. MRA revealed an AVF in the left cavernous sinus. An angiogram showed this to be fed by the left external and internal carotid meningeal branches with drainage into the cortical veins, superior ophthalmic vein and superior petrosal sinus. External carotid meningeal branches were successfully embolized, and thereafter the left oculomotor nerve palsy was improved over two weeks. This patient was neurologically symptom free except for left mild tinnitus, but the arteriovenous fistula remained on MRA over two years and four months (Figure 6A). Estrogen (premarine 1.25 mg day^sup -1^) combined with progesteron (duphaston 5 mg day^sup -1^) therapy was started after acceptance of sufficient informed consent, and was continued for three months. At the end of this period, left tinnitus was remarkably improved. it completley disappeared over three months. MRA showed remarkable decrease of CCF in the left cavernous sinus (Figure 6B), and five months later complete disappearance was achieved (Figure 60.

DISCUSSION

Dural arteriovenous fistulas (AVFs) most frequently occur in the transverse-sigmoid sinus with no clear sex difference7. In the past, the main cause was believed to be congenital anomalies8, but it has recently been found to be primarily an acquired lesion developing secondary to a theombosis or thrombophlebitis in the sinus9,10.

The etiology of dural AVF located in the caverouns sinus is, in contrast, uncertain and controversial. Furthermore, unlike those involving the transverse sigmoid sinjus, they show a distribution bias with a pronounced female predominance2,3. It is certainly interesting that this condition almost always occurs in post-menopausal women, older men, or in younger women just after delivery or abortion4,5. In fact, in the present series, the majority of the patients with dural AVFs (21 of 26) were pre-menopausal or post-menopausal women, while all but one of the affected men were more than 65 years old. Furthermore, five of the women developed symptoms consistent with the cessation of menstruation, and in one of them, the cessation was induced by the drug buserelin acetate. These findings suggest that a sudden decrease of sex hormones may be an important precipitating factor in the occurrence of dural AVFs involving the cavernous sinus. It is reported that the blood estradiol usually remains between 73 and 147 SI units for 10 years after menopause11. While the control cases in the present investigation demonstrated a gradual decrease in the blood estradiol level after menopause to less than 37 SI units after more than five years, all the female patients had values below 37 SI units even though less than one year had passed since the cessation of menstruation in five of them, the difference from the control group being statistically significant (p

That the proposed influence might be specific to estrogens is evidenced by the lack of any corresponding change in progesterone. Despite significantly low blood level of estradiol in pre-menopausal patients, FSH and LH level did not present significant differences from controls and were maintained at relatively high levels, indicating that the decrease of estradiol was not a secondary result of the dural AVF in the cavernous sinus but rather a primary change.

Lasjaunias and Berenstein12 earlier reported successful treatment with oral dihydrostilbestrol of a 48-year-old woman with a spontaneous CCF whose symptoms developed and worsened in pre-menstrual periods. They also stressed a causal relationship with hormonal changes and suggested that many patients might benefit from a trial of estrogen therapy prior to more aggressive treatment. This is very interesting because the premenstrual period is characterized by a substantial decrease of estradiol. In one patient (case 8) with persistence of CCF more than two years after endovascular surgery, estrogen replacement was effective, which induced complete remission of CCF. In comparative young CCF patients with dural AVF resisting endovascular and the treatments, small dose estrogen therapy for the short term may be an effective non-invasive treatment.

In one other patient (case 3) of the present series, symptoms developed five months after buserelin acetate administration had induced cessation of menstruation and improved after the drug treatment was stopped. indeed, the dural AVF disappeared after seven days. At the time of the worst symptoms, measurements of sex hormone levels in the blood revealed a very low value for estradiol (

Thus, in the patients who present with symptoms consistent with pre-menopause, a sudden decrease in blood estradiol with a comparatively well maintained blood progesterone level may be an important precipitating factor in the occurrence of spontaneous carotid cavernous fistulas.

The effects of progesterone on blood coagulation and fibrinolysis reportedly include increases in endogenous coagulation factors, especially factor VIII 13 on which estradiol exerts no marked effects14 . However, it has been reported that endogenous estrogen stimulates protein synthesis in the vascular system, particularly that of prostaglandin, an inhibitor of platelet aggregation 15 . Estrogen also reduces the numbers of smooth muscle cells and collagen fibers in the arterial wall, resulting in decrease of stiffness16.

Recently, decrease of estradiol was concluded to be an important risk factor for arteriosclerosis because of the apparent similarity of the degree of risk between men and post-menopausal women concerning disease of the coronary arteries19.

Thrombosis in the cavernous sinus might be one cause of dural AVFs since it is frequently recognized as an accompanying change18,19. The envisaged mechanism of development is as follows: A physiologic A-V shunt normally present in the dura mater20 opens and becomes symptomatic when a thrombus develops or during a change of pressure in the dural sinus (pressure dilatation mechanism)21. In the present series, thromboses in the cavernous sinus were not delineated neuroradiologically, so that this possibility could not be evaluated.

In the patients presenting with symptoms consistent with cessation of menstruation, however, reduction in prostaglandin production due to a sudden decrease in endogenous estrogen may have raised the vascular resistance and therefore the formation of feeding vessel microthromboses in the dura mater of the cavernous sinus. The resulting disturbance of the blood circulation of the dura mater would be expected to cause opening of the normal AV shunts to provide a collateral circulation. The fact that hypertension was frequent in the female patients who presented with symptoms seven years after menopause and also in male patients, is also of interest in this respect.

In five (24%) of 21 female patients with dural AVF, hemi-oophorectomies or total oophorectomy had been performed. Furuhashi11 reported that serum estrogen and progesterone levels in such castrated women are significantly lowered as compared with values for postmenopausal women. Remarkable and persistent decrease of serum estrogen may thus have accelerated arteriosclerosis, affecting the feeding vessels in the dura mater of the cavernous sinus.

Specific estrogen receptors are known to be present in normal human leptomeningeS22 23 , and the possibility that they may abound in the cavernous sinus clearly deserves consideration, given the marked female predominance in the distribution both of dural AVFs of the cavernous sinus, and of aneurysms (cavernous aneurysms, ophthalmic aneurysms, etc.), which are frequently recognized bilaterally.

ACKNOWLEDGEMENTS

This work was supported in part by an Academic Frontier Project by Monbushou (The Ministry of Education, Culture and Science).

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Akira Kurata, Yoshio Miyasaka, Hidehiro Oka, Katsumi Irikura, Ryusui Tanaka, Taketomo Ohmomo, Shigeki Nagai and Kiyotaka Fujii

Department of Neurosurgery, Kitasato University School of Medicine, Kanagawa, Japan

Correspondence and reprint requests to: A. Kurata, Department of Neurosurgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, Japan 228. Accepted for publication April 1999.

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