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Suprefact

Buserelin is a gonadotropin releasing hormone agonist (GnRH agonist). By causing constant stimulation of the pituitary, it decreases pituitary secretion of gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). Like other GnRH agonists, buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction.

It is normally delivered via a nasal spray but is also available as an injection.

Buserelin acetate is marketed by Sanofi-Aventis under the brand name Suprefact.

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Failure of buserelin-induced medical castration to control pulmonary lymphangiomyomatosis in two patients
From CHEST, 6/1/92 by Marc Radermecker

Two women, aged 44 and 29 years, respectively, were admitted to the hospital in early 1987 for recurrent pneumothorax, dyspnea and a diffuse reticulonodular pattern evidenced on the chest x-ray film. Lung biopsy confirmed LAM in both patients. Both were treated sequentially with medroxyprogesterone and a LHRH agonist (buserelin) to achieve reversible medical castration. Neither subjective nor objective improvement was noted after 13 and 5 months, respectively, of buserelin therapy (900 [mu]g/day, nasal spray) despite an effective suppression of the pituitary-gonadal axis. Medroxyprogesterone also was ineffective. Buserelin thus failed to control pulmonary LAM in these two patients, in spite of effective medical castration.

Lymphangiomyomatosis is a rare, progressively worsening disease occurring almost exclusively in women. Histologically, it is characterized by hyperplasia or benign proliferation of atypical smooth muscle cells that affects primarily the lymphatics of the lungs. The etiology of LAM is unknown. It is, however, recognized that proliferation of striated or smooth muscle cells is regulated by steroid hormones (estrogens in particular). Many clinical observations suggest a role for ovarian steroid hormones in the pathogenesis of LAM as well. The disease affects predominantly females of childbearing age. Stabilization and even remission have been observed following menopause or surgical castration.[1,2] Worsening, on the other hand, may occur during pregnancy[3] or estrogen therapy.[4] Relationships between LAM and HCG, HCG antibodies and progesterone or estradiol intracytoplasmic receptors also have been described.[5,6] Attempts to treat LAM with progesterone,[6-10] antiestrogens,[6,11] or by surgical castration[1,2,12] generally have led to variable responses. Best results have been reported following oophorectomy and/or progestogen administration.[1,2,7,8,13,14] It is possible to achieve a reversible medical castration with LHRH-A.[15] The LHRH-As have been successfully applied in estrogen-dependent diseases such as endometriosis, uterine leiomyomas, pulmonary "benign" metastasizing leiomyomas and pulmonary leiomyomatosis.[16-18] Recently, it has been suggested that LHRH-As may also be effective in LAM.[19,20] We here report two cases of pulmonary LAM in which treatment with a LHRH-A (buserelin) failed to control the disease in spite of effective medical castration.

CASE REPORTS

CASE 1

A 44-year-old woman who was a nonsmoker was admitted to the hospital in January 1987 for left pneumothorax. She reported a right pneumothorax five months previously. Crepitations were heard in the right lung base. The rest of the clinical examination was within normal limits except for a grade 2/6 systolic murmur. Her medical history revealed menarche at the age of 12 years and two miscarriages at 24 and 30 years of age. She gave birth at the ages of 27 and 34 years. For seven years, she had been taking oral contraceptives and then changed to an intrauterine device one year prior to her admission. She was receiving no medication. After pneumothorax drainage and lung reexpansion, a chest x-ray film showed a reticulonodular pattern in both basal lungs without evidence of pleural effusion. The ECG was normal. Blood analyses were within normal limits, with the exception of an increased plasma level of ACE (41 nmol/ml/min; NV [+ or -] SD:22 [+ or -] 6). Fiberoptic bronchoscopy was not contributive. The patient refused further pulmonary investigation and was discharged from the hospital without therapy. She was readmitted six months later for a right pneumothorax. Her chest x-ray film was unchanged. Lung function data revealed an obstructive pattern of respiratory insufficiency with a low Dsb (Morgan Instruments), hypoxemia and hypocapnia (Table 1).[21] The abdominal and perineal ultrasound tests as well as the abdominal CT scan were normal. A thoracic CT scan disclosed an accentuation of the pulmonary interstitium with bullous cystic juxtapleural and intraparenchymatous formations. At right pleuroscopy, numerous subpleural blebs were visualized and a lung biopsy confirmed LAM.

The patient was treated with medroxyprogesterone acetate (Farlutal, Depot), 1 g, intramuscularly every third week for five months. She was hospitalized three times for recurrent right pneumothorax during this treatment period. Since there was an obvious worsening of her condition, medroxyprogesterone was discontinued in November 1987 and no other medication was administered for three months. Treatment using buserelin (Suprefact, Hoechst), 900 [mu]g daily by the nasal route, in association with tamoxifen (10 mg twice a day) was started in March 1988. The patient quickly became amenorrheic. She did not complain of decreased libido, weight gain, mucosal dryness or hot flashes. Blood level decreases in estradiol, progesterone, FSH and LH indicated a suppression of the pituitary-gonadal axis and presented a picture of a hypogonadal hypogonadotrophic state (Table 1). This treatment was continued for 13 months during which no improvement was observed in the patient. In March 1989, a definite aggravation occurred in her state and she became dyspneic and severely hypoxic (Table 1). On May 3, 1989, she underwent a left lung transplantation but died two weeks later due to refractory hypoxemia.

CASE 2

A 29-year-old women who was a nonsmoker was admitted to the hospital in February 1987 with a complete left pneumothorax. Drainage was instituted and the patient promptly recovered. Her medical history revealed no respiratory or systemic symptoms and her physical examination was normal. She took oral hormonal contraceptives. A chest x-ray film revealed a diffuse reticulonodular pattern. Lung function tests showed a low [FEV.sub.1] and Dsb with a modest increase of RV. Results of blood gas analyses were normal. Fiberoptic bronchoscopy and a bronchoalveolar lavage were normal. Serology tests showed normal findings except for an increased blood level of ACE (37 nmol/ml/min). The ECG was normal. The patient denied a pleuroscopy and an open-lung biopsy and was discharged from the hospital without therapy. The patient had a complete right

[TABULAR DATA OMITTED]

pneumothorax in September 1987 and progressively became dyspneic when walking uphill. In early 1988, she had two episodes of left pneumothorax and in March she experienced a suffocating pneumothorax. She accepted an open-lung biopsy which confirmed the diagnosis of LAM. Her sexual hormonal status and lung function measured after recuperation are shown in Table 1. Buserelin therapy, 900 [mu]g daily, administered by the nasal route, was started at the end of March 1988. She became amenorrheic and complained of mucosal dryness, weight, gain, gastrointestinal problems and depression. She received this regimen for five months without any subjective or objective improvement in spite of effective medical castration (Table 1). In late August 1988, buserelin therapy was replaced by medroxyprogesterone acetate in high dosage (100 mg daily) in the hope of achieving a potent antigonadotrophic effect and a possible glucocorticoid action. The patient gained weight and a five-month subjective stabilization of her disease was observed without improvement of functional tests. In March 1989, she noted a worsening of her dyspnea and developed bronchospastic attacks. She died suddenly at home in October 1989.

DISCUSSION

We report two typical cases of biopsy-proven pulmonary LAM in which a LHRH-A, buserelin, failed to stabilize the disease in spite of effective medical castration. In 1988, two main reasons prompted us to try LHRH-As to treat LAM. First, menopause or surgical castration has sometimes been found to favorably influence LAM, and second, LHRH-As successfully have been used in the treatment of some estrogen-dependent diseases and in particular in the treatment of pulmonary "benign" metastasizing leiomyoma.[17] They also produced favorable effects in a case of pulmonary leiomyomatosis.[18] Buserelin was chosen from among other synthetic LHRH-As because of its potent and specific LHRH activity and its strong ability to cause a reversible medical castration.[15]

Luteinizing hormone releasing hormone is a hypothalamic decapeptide which is carried through the pituitary portal system from the eminentia mediana to the anterior pituitary gland. It binds specifically to high affinity receptors on the pituitary gonadotrophic cells and stimulates the synthesis and release of gonadotrophins (LH and FSH). Gonadotrophin secretion is characterized by its periodicity, largely dependent on the normal pulsatility (every 90 min) of the hypothalamic LHRH release.[22-24] Continuous perfusion of natural LHRH leads, after a short period of increased gonadotrophin release, to a turnoff of the gonadotrophic cell function and inhibition of gonadotrophin secretion (down regulation or desensitization by receptor loss).[25] Natural LHRH is quickly degradated (half life to 3 to 4 min) by pituitary and hypothalamic peptidases.

During the last decade, many LHRH-As with activity 10 to 300 times higher than natural LHRH have been synthesized. The increased biologic activity of these agonists mainly resides in their prolonged half-life and in their high affinity for specific receptors on pituitary gonadotrophic cells. Chronic administration of LHRH-As by intravenous, intramuscular or subcutaneous routes or nasal sprays (500 to 1,200 [mu]g/day) causes, after a 10- to 15-day period of increased gonadotrophin release, a marked decrease in LH and FSH secretion. Simultaneously, blood levels of estradiol, estrone and androstenedione drop to values encountered after surgical castration.[25] This LHRH-A-induced castration is quickly and perfectly reversible.

In our two patients who had normal utero-ovarian cyclic function before buserelin administration, we obtained a hypogonadal hypogonadotrophic state which was poorly tolerated by patient 2. Several possibilities could account for the failure of buserelin to control LAM in these patients. First, LHRH-A-induced hormonal castration is probably not as effective a castration as a surgical one. Second, surgical castration is not systematically effective in LAM. Finally, estrogen, glucocorticoid and progesterone receptors were not measured on the lung biopsy specimens of our patients. The lack of these receptors could have explained the poor response to hormonal therapy, even though rigorous correlation between hormonal therapy and steroid receptor level is lacking.[7]

Recently, the successful application of LHRH-As has been reported in two patients with advanced biopsy-proven LAM.[19,20] Both patients were treated intramuscularly for, respectively, 19 and 21 months with two different LHRS-As (triptorelin, 4 mg/month; goserelin, 3.6 mg/month). A marked improvement of their clinical status and blood gas values followed rapid chemical castration resulting from treatment with LHRH-As. However, no significant change was noticed in lung function and chest x-ray film findings. Differences in the type of LHRH-A or the way of administration (intramuscular vs nasal spray) are unlikely to explain the different therapeutic responses observed since a hypogonadotrophic hypogonadism was obtained in every patient. Furthermore, severity of the disease was comparable in the four patients when treatment with LHRH-As was started. These apparently divergent results may again illustrate the variable responsiveness as reported after any treatment in LAM and probably underline our lack of knowledge concerning the pathogenesis of the disease.

We do not conclude from this negative report that LHRH-As have no place in the treatment of pulmonary LAM. They may be effective in some cases and prove to be predictive of the therapeutic benefit which may follow surgical castration.

REFERENCES

[1] Banner AS, Carrington CB, Emory WB, Kittle F, Leonard G, Ringus J. Efficacy of oophorectomy in lymphangiomyomatosis and metastasizing benign leiomyoma. N Engl J Med 1981; 305:204-09

[2] Kitzsteiner KA, Mallen RG. Pulmonary lymphangiomyomatosis treatment with castration. Cancer 1980; 46:2248-49

[3] Hughes E, Hodder RV. Pulmonary lymphangiomyomatosis complicating pregnancy: a case report. J Reprod Med 1987; 32:553-57

[4] Shen A, Iseman MO, Waldron JA, King TE. Exacerbation of pulmonary lymphangiomyomatosis by exogenous oestrogens. Chest 1987; 91:782-85

[5] Brentani MM, Carvalho CR, Saldiva PH, Pacheco MM, Oshima TF. Steroid receptors in pulmonary lymphangiomyomatosis. Chest 1984; 85:96-99

[6] Graham HL, Spelsberg TC, Dines DE, Payne WS, Bjornsson J, Lie JT. Pulmonary lymphangiomyomatosis: with particular reference to steroid receptor assay studies and pathologic correlation. Mayo Clin Proc 1984; 59:3-11

[7] Dishner W, Cordasco EM, Blackburn J, Demeter S, Levin H, Carey WD. Pulmonary lymphangiomyomatosis. Chest 1984; 85:796-99

[8] McCarty KS Jr, Moosler JA, McLellan R, Sieker HO. Pulmonary lymphangiomyomatosis responsive to progesterone. N Engl J Med 1980; 303:1461-65

[9] Sawicka EH, Morris AJ. A report of two lung surviving cases of pulmonary lymphangioleiomyomatosis and the response to progesterone therapy. Br J Dis Chest 1985; 79:400-06

[10] Svendsen TL, Viskum K, Hansbourg N, Thorpe SM, Nielsen NC. Pulmonary lymphangioleiomyomatosis: a case of progesterone receptor positive LAM treated with medroxyprogesterone, oophorectomy and tamoxifen. Br J Dis Chest 1984; 78:264-71

[11] Clemm C, Jehn U, Wolf-Hornung B, Siemon G, Walter G.

Lymphangiomyomatosis: a report of three cases treated with tamoxifen. Klin Wochenschr 1987; 65:391-93

[12] Logan RF, Fawcette IW. Oophorectomy for pulmonary lymphangioleiomyomatosis: a case report. Br J Dis Chest 1985; 79:98-100

[13] Adamson D, Heinrichs WL, Raybin DM, Raffin TA. Successful treatment of pulmonary lymphangiomyomatosis with oophorectomy and progesterone. Am Rev Respir Dis 1985; 132:916-21

[14] Eliasson AH, Philips YY, Tenholder MF. Treatment of lymphangioleiomyomatosis: a Meta-analysis. Chest 1989; 196:1352-55

[15] Hardt W, Schmidt Gollwitzer M. Sustained gonadal suppression in fertile women with the LHRH agonist buserelin. Clin Endocrino 1983; 19:613-17

[16] Meldrum DR, Chang RJ, Lu J, Vale W, Rivier J, Judd HL. Medical oophorectomy using a long acting GNRH agonist: a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab 1982; 54:1081-83

[17] Hague WM, Abdulwahid NA, Jacobs HS. Use of LHRH analogue to obtain reversible castration in a patient with benign metastasizing leiomyoma. Br J Obstet Gynaecol 1986; 93:455-60

[18] Maheux R, Samson Y, Farid NR, Parent JG, Jean C. Utilization of luteinizing hormone releasing hormone agonist in pulmonary leiomyomatosis. Fertil Steril 1987; 48:315-17

[19] Eysvogel M, Page P. Lymphangiomyomatosis. Chest 1990; 98:1045-46

[20] Rossi GA, Balbi B, Oddera S, Lantero S, Ravazzoni C. Response to treatment with an analog of the luteinizing-hormone-releasing hormone in a patient with pulmonary lymphangioleiomyomatosis. Am Rev Respir Dis 1991; 143:174-76

[21] Quanjer PH, ed. Standardized lung function testing: report of working party. ECSC Bull Eur Physiopathol Respir 1983; 19:195

[22] Knobil E. The neuroendocrine control of the menstrual cycle. Rec Prog Hor Dis 1980; 36:53-88

[23] Leyendecker G, Wildt L, Hansmann M. Pregnancies following chronic intermittent (pulsatile) administration of GN-RH by means of a portable pump (Zyklomat): a new approach to the treatment of infertility in hypothalamic amenorrhea. J Clin Endocrinol Metab 1980; 51:1214-16

[24] Schally AV, Kastin AG, Arimura A. FSH releasing hormone and LH releasing hormone. Vitam Horm 1972; 30:83-164

[25] Rabin D, MacNeill LW. Pituitary and gonadal desensitization after continuous luteinising hormone releasing hormone infusion in normal females. J Clin Endocrinol Metab 1980; 51:873-76

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