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Estrogen Receptors in NON uterine LMS. Abstracts of Medical Journal Articles 
All Medical Journal Abstracts have been excerpted and edited.
For the complete, unedited Abstract, go to Pubmed. 
For more information, Search Pubmed for estrogen receptors and extratuterine leiomyosarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=estrogen%20extrauterine%20 leiomyosarcoma
1.       Mod Pathol 1999 Nov;12(11):1001-9 Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas. Rao UN, Finkelstein SD, Jones MW. 
This study investigates whether there were differences in ULMS and EULMS with respect to certain molecules associated with tumor aggression. " .... serial sections of each tumor [were tested] for ... Glut1, CD44s, bcl2, cyclin D1, and estrogen receptor, ...k-ras-2 point mutation, p53 gene loss, and mdm2 gene amplification ..." 
" All of the uterine and extrauterine LM were diffusely positive for CD44s, bcl2, and cyclin D1, and uniformly negative for Glut1. In contrast, 50% of the ULMS and 25% of EULMS were Glutl positive. Moreover, Glut1 positivity closely correlated with aggressive biologic behavior reflected by distant metastatic spread. Eighty-percent of LM and 70% of the ULMS were estrogen receptor positive, whereas only one retroperitoneal tumor had focal weak positivity. Over 80% of the extrauterine and 50% of the uterine sarcomas showed absence of CD44s immunoreactivity. Percentage of cyclin D1 immunoreactivity was independent of tumor grade and inversely proportional to the percent of bcl2 positivity. ... P53 allelic imbalance was present in 29% of ULMS and 57% EULMS. Mdm2 amplification was present in three of six EULMS but not in ULMS. In addition to clinical staging, Glut1 positivity together with patterns of immunoreactivity of CD44 and bcl2 may be helpful in identifying aggressive smooth muscle tumors of the uterus and some EULMS. The presence of estrogen receptor staining may be helpful in identifying uterine versus nonuterine LMS. Although sample numbers are too small for definite conclusions, this study suggests that there are differences in glucose transport, expression of adhesion molecules, and estrogen receptors in ULMS and EULMS, which in part may be due to the estrogen dependency of the ULMS. P53 mutations and mdm2 amplifications appear to be more frequent in EULMS."

2. Am J Surg Pathol 1999 Sep;23(9):1082-8 Leiomyosarcoma of the pulmonary veins. Oliai BR, Tazelaar HD, Lloyd RV, Doria MI, Trastek VF. 
PMID: 10478668
FiVF   
 
Properties of Five primary leiomyosarcomas arising from the pulmonary veins were investigated with clinicopathologic correlation and comparison to previously reported cases. Patients were women, mean age 56 years [23-64]. 
"Three cases showed tumor extension along the pulmonary veins into the left atrium. Tumors ranged in size from 2.8 to 7 cm in greatest dimension....... ...Most showed extensive necrosis. All tumors were reactive with antibodies to actin and desmin. Two cases were reactive with antibodies to MIC-2 (dotlike); two cases showed reactivity to keratin antibodies; and two showed reactivity for estrogen, progesterone receptor protein, or both. .... All cases were treated with surgical excision. Follow-up ranged from 2 months to 21 years (mean, 4.8 years). Two patients were alive and well; two were alive with metastases; and one died of disease. Pulmonary vein sarcomas represent intermediate- to high-grade leiomyosarcoma. Although often lethal, complete surgical excision can lead to long-term survival. They occur predominantly in women and may express hormone receptors. Therefore, hormonal manipulation may offer promise as adjuvant therapy." http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10478668&dopt=Abstract
3. Am J Surg Pathol 1996 Jul;20(7):779-93 Smooth-muscle tumors of the vulva. A clinicopathological study of 25 cases and review of the literature. 
Nielsen GP, Rosenberg AE, Koerner FC, Young RH, Scully RE. 
"The clinical and pathological features of 25 smooth-muscle tumors of the vulva were analyzed."... "Thirteen of 17 tumors were positive for estrogen receptors, and 16 of 18 were positive for progesterone receptors. ... We propose ... expanded criteria to distinguish between leiomyomas and leiomyosarcomas of the vulva. Tumors that manifest three or all of the four following features should be considered sarcomas: > or = 5 cm in greatest dimension, infiltrative margins, > or = 5 mitotic figures per 10 hpf, and moderate to severe cytologic atypia. Those that have only one of these characteristics should be diagnosed as leiomyoma, and those that exhibit only two of these features should be considered benign but atypical leiomyomas. " 

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  4. Pathol Res Pract 1996 Mar;192(3):215-23 Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Jautzke G, Muller-Ruchholtz E, Thalmann U. PMID: 8739468 
Fiv "benign metastasizing uterine leiomyomata" result in development of well differentiated, leiomyomatous lung tumors that appear to be benign, usually after a period of several years. "We report on five more such cases in which we investigated the contents of estrogen and progesterone receptors in the pulmonary tumors .... All the lung tumors exhibited a high content of progesterone receptors, and in 4 out of the 5 cases a high estrogen receptor content was also found. ... it is thus recommended ... hormone receptors should be determined in well differentiated, leiomyomatous lung tumors from women. This would both provide information on the pathogenesis of these tumors and establish a basis for possible later institution of hormone treatment. It is likely that the majority of these lung tumors are in fact metastases of extremely well differentiated leiomyosarcomas of the uterus. The possibility that lung tumors of this type may constitute a small group that develop in situ as hormone-sensitive proliferations cannot, however, be fully excluded." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8739468 &dopt=Abstract 

5. Acta Obstet Gynecol Scand 1984;63(6):505-8 Estradiol and progesterone receptors in gynecologic sarcomas. Lantta M, Karkkainen J, Wahlstrom T, Widholm O. PMID: 6507052 "We report the concentrations of estradiol and progesterone receptors found in the tumor tissue of 5 patients with leiomyosarcoma, 4 of uterine and one of ventricular origin, and of 5 patients with uterine or ovarian carcinosarcoma. Steroid receptor positive and negative tumors were present in both groups of sarcoma. ....We suggest that steroid receptors should be analysed in all gynecologic sarcomas." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6507052 &dopt=Abstract 

6. Surgery 1981 Aug;90(2):149-53 
Distribution of steroid hormone receptors in human soft tissue sarcomas. Chaudhuri PK, Walker MJ, Beattie CW, Das Gupta TK. PMID: 6266058 
"Sixty-six human soft-tissue sarcoma specimens were assayed for incidence and distribution of steroid hormone receptors. Liposarcomas (43%) and leiomyosarcomas (60%) had a high incidence of estrogen receptor. .... The incidence of receptors for estrogen and glucocorticoid was higher in female than in male patients (62% and 38%, respectively). .... Data from this study suggest that ... receptors for steroid hormones are present in human soft tissue sarcoma and that their distribution may depend on the histogenetic origin and the sex of patients." 

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7. Arch Surg 1980 Mar;115(3):244-8 
Estrogen receptor proteins in diverse human tumors. Stedman KE, Moore GE, Morgan RT. PMID: 7356378 
"Receptors were detected in many endocrine and nonendocrine tumors. ......... Some tumors also had progesterone, androgen, and/or glucocorticoid receptors. These results suggest the use of hormones and hormone antagonists for therapy of a broad range of human cancer. Clinicians of diverse expertise should be aware of, and responsive to, potential endocrinological involvement in many dissimilar disease states." http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7356378&dopt=Abstract
  
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Cognitive Function and Anti-Estrogen Treatment Medical Journal Article Abstracts

All Medical Journal Abstracts have been excerpted and edited. 
For the complete, unedited Abstract, go to Pubmed. 
1. J Clin Endocrinol Metab 1996 Jul;81(7):2545-9 Comment in: J Clin Endocrinol Metab. 1997 Feb;82(2):702-3
"Add-back" estrogen reverses cognitive deficits induced by a gonadotropin-releasing hormone agonist in women with leiomyomata uteri. Sherwin BB, Tulandi T. Department of Psychology, McGill University, Montreal, Quebec, Canada. PMID: 8675575 
"These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8675575&dopt=Abstract

2. Breast Cancer Res Treat 2001 Nov;64(2):165-76 
Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Paganini-Hill A, Clark LJ. Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, USA. annlia@juno.com 
PMID: 11194452
"""Our study suggests that current use of tamoxifen may adversely effect cognition. Further study of tamoxifen and cognition is needed so that healthy women considering tamoxifen for the primary prevention of breast cancer have comprehensive information about the side effects of the treatment." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11194452&dopt=Abstract

3. J Clin Oncol 2000 Jul;18(14):2695-701 
Cognitive function in breast cancer patients receiving adjuvant chemotherapy. Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF. Department of Medical Oncology and Hematology, Department of Biostatistics, Department of Psychosocial Oncology, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada. PMID: 10894868 
""     
Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls. These differences did not seem to be caused by significant differences in mood disturbance between the two groups. If confirmed, these results have substantial implications for informed consent, counseling, and psychosocial support of patients receiving adjuvant chemotherapy for breast cancer." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10894868&dopt=Abstract
 
4. Pharmacotherapy 1999 Aug;19(8):951-6 
Testosterone and andropause: the feasibility of testosterone replacement therapy in elderly men. Lund BC, Bever-Stille KA, Perry PJ. Clinical and Administrative Pharmacy Division, College of Pharmacy, University of Iowa, Iowa City 52242-1112, USA. PMID: 10453966 
"Andropause, a syndrome in aging men, consists of physical, sexual, and psychologic symptoms that include weakness, fatigue, reduced muscle and bone mass, impaired hematopoiesis, oligospermia, sexual dysfunction, depression, anxiety, irritability, insomnia, memory impairment, and reduced cognitive function. ... It is estimated that 20% of men aged 60-80 years have levels below the lower limit of normal. ... administration of testosterone to this population resulted in improvements in many areas. ... Preliminary data suggest that therapy may benefit elderly men with new-onset depression. ... [There is] potential for increased prostate cancer risk... Currently, insufficient evidence, primarily regarding psychologic safety and efficacy, exists to warrant general administration .... Further clinical investigations of this therapy in men with low testosterone levels and andropause symptoms are justified and necessary." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10453966&dopt=Abstract
5. Cancer 1999 Feb 1;85(3):640-50 
Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF. Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam. PMID: 10091737 
"""A number of patients who have undergone adjuvant (CMF) chemotherapy for operative primary breast carcinoma have reported impaired cognitive function, sometimes even years after completion of therapy. ... Breast carcinoma patients treated with adjuvant CMF chemotherapy have a significantly higher risk of late cognitive impairment than breast carcinoma patients not treated with chemotherapy (OR 6.4). This cognitive impairment is unaffected by anxiety, depression, fatigue, and time since treatment, and not related to the self-reported complaints of cognitive dysfunction." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10091737&dopt=Abstract
6. Dis Mon 1998 Sep;44(9):421-546 
Wellness in women after 40 years of age: the role of sex hormones and pheromones. Cutler WB, Genovese-Stone E. Athena Institute for Women's Wellness Chester Springs, Pennsylvania, USA. PMID: 9803240 
"All sex hormones affect physiologic systems including the cardiovascular system, bone metabolism, cognitive function, sexual response, and sexual attractiveness." "The health and well-being of women who have already had hysterectomies, with or without ovariectomies, can be improved by a recognition of the cascade of difficulties that must addressed" 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9803240&dopt=Abstract


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7. J Nurse Midwifery 1998 Jul-Aug;43(4):262-72 
Primary and secondary prevention strategies among older postmenopausal women. Keller C, Fullerton J, Fleury J. School of Nursing, University of Texas Health Science Center at San Antonio 78284, USA. PMID 9718881 
"HRT, exercise, and nutrition are reviewed in terms of their potential benefits as primary and secondary preventive therapies against coronary heart disease, osteoporosis, breast and genital cancers, and the maintenance of cognitive function among older postmenopausal women. Lifestyle alternatives involving nutrition and exercise that offer many of the same benefits as HRT are discussed. Since both pharmacologic and lifestyle interventions offer significant benefit for primary and secondary prevention of disease and disability, each should be offered ... [and] should be sustained over the long term." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9718881&dopt=Abstract
8. Baillieres Clin Endocrinol Metab 1997 Jul;11(2):311-40 
Menopause and post-menopause. Prelevic GM, Jacobs HS. Department of Medicine, University College London Medical School, UK. PMID: 9403125 
"Oestrogen therapy alleviates acute climacteric symptoms and also reduces the risk of cardiovascular disease, osteoporosis and Alzheimer's disease. ... it reduces morbidity and mortality from coronary heart disease by approximately 50%. ...Oestrogen therapy reduces the rate of post-menopausal bone loss, increases bone mineral density (BMD) and decreases fracture rate. ... The incidence of Alzheimer's disease is reduced by 50% in post-menopausal women taking oestrogen replacement. Limited clinical trials of oestrogen treatment in women with this disease have documented beneficial effects on cognitive function. The results of epidemiological studies of the effects of oestrogens on breast cancer risk are conflicting but recent evidence suggests that the risk is increased in current users after 5 years of use and among older women. In contrast, increase in the risk of venous thromboembolism is most significant within the first 12 months of therapy, strongly suggesting the importance of individual susceptibility. " 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=403125&dopt=Abstract
 
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Information about Letrozole (LET-tro-zole) 
Sold as : Femara, film-coated 2.5 mg tablet. Manufactured by Novartis. It is essential that the package insert be consulted for detailed information on the usual cautions, precautions, and contraindications. 
This drug is approved by the FDA for treatment of cancer in postmenopausal women. It is currently being used for second-line treatment of postmenopausal women with advanced breast cancer who failed Tamoxifen. 
Dosage and Route of Administration
Femara is taken orally with or without food, and is rapidly and completely absorbed, with uptake in peripheral tissues and minimal binding to plasma proteins. It is metabolized to inactive products in the liver by the cytochrome P450 system. The drug and its metabolites are excreted by the kidneys. The usual dose is 2.5 mg PO q day until disease progression. No dosage adjustment is required for geriatric patients, for patients with creatinine clearances of at least 10mL/minute, or patients with moderate hepatic impairment. No studies have been done on use of Femara in patients with severe liver impairment: caution is advised. When liver function is impaired, monitor liver function at baseline and periodically during therapy. Mild elevation in serum transaminases and serum bilirubin are seen most often in patients with established metastatic disease in the liver. 
Indicatons for Use 
Letrozole is indicated only for post-menopausal women. Letrozole use in pre-menopausal women has not been studied, and might increase the risk of benign ovarian tumors and cystic ovarian disease in that population. Letrozole selectively inhibits the conversion of androgens to estrogens, and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone. 
How it works:
It is a hormonal agent, a non-steroidal aromatase inhibitor, preventing the production of estrogen. It inhibits synthesis of estrogens by inhibiting the conversion of adrenal androgens (androstenedione and testosterone) to estrogens (estrone, estrone sulfate, and estradiol). Within 2 weeks, serum estradiol levels are suppressed by 90%, by 6 weeks of therapy; estradiol levels are suppressed by 97%. 
Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, reduction of estrogen levels inhibits tumor growth as well as delaying progression of disease. In post-menopausal women, ovarian secretion of estrogen declines and conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme, is the principal source of estrogens. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P-450 unit of the enzyme. Inhibition of estrogen synthesis reduces concentrations of circulating estrogens, including estrone, estradiol, and estrone sulfate.
SIDE EFFECTS: This drug is generally well tolerated. Fatigue, nausea, constipation, diarrhea, headache, drowsiness or dizziness may occur. If these persist or worsen, notify your doctor promptly. Report promptly any chest pain, stomach pain, trouble breathing, hot flushes, rash or itching. Report promptly any swelling, redness, weakness or pain in legs or arms, vision problems or unusual vaginal bleeding. If you notice other effects not listed above, contact your doctor or pharmacist. Mild bone, muscle and joint pains are the most common side effects. Headache and fatigue can occur as can mild nausea with less frequent vomiting and anorexia. Hot flashes occur in about 6% of patients. Thromboembolic events are rare, and less common than with megestrol acetate. Limit alcohol intake as it may increase the side effects of this drug. Caution performing tasks requiring mental alertness (e.g., driving), since it is possible this drug may cause drowsiness. This drug is not recommended for use during pregnancy. It is not known if this drug is excreted into breast milk. Consult your doctor before breast-feeding. 
Before taking this drug, notify your doctor of any of the following: If you are pregnant, breast-feeding or planning children in the future, inform your doctor. This drug may cause birth defects if either the male or female is taking it at the time of conception or during pregnancy. Men and women who are taking this drug need to use some kind of birth control. However, do not use oral contraceptives ("the pill") without checking with your doctor. Tell your doctor of all nonprescription and prescription medication you may use, especially drugs that may cause drowsiness such as sedatives, tranquilizers, psychiatric medications, certain cough-and-cold products containing antihistamines (e.g., diphenhydramine), anti-seizure drugs, muscle relaxants and narcotic pain relievers (e.g., codeine). Do not start or stop any medicine without doctor or pharmacist approval, including vitamins and herbals. If you have any of the following medical problems:chickenpox or exposure to chickenpox, gout, heart disease, congestive heart failure, shingles, kidney stones, liver disease. If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not "double-up" the dose to catch up. Store at room temperature, away from light and moisture. 
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Information about Anastrozole (ann-uh-STROW-zole) [Arimidex]
Sold as: Arimidex, film-coated tablets, 1 mg, manufactured by AstraZeneca It is essential that the package insert be consulted for detailed information on the usual cautions, precautions, and contraindications. 
 
Indications for use:
Anastrozole is used for the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women. Data from 2 double-blind, randomized clinical trials in such patients indicate that anastrozole is at least as effective as tamoxifen for producing objective tumor response and delaying tumor progression. Anastrozole is also used for the second-line treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Anastrozole therapy generally is continued until tumor progression is evident. 
How it works:
It is a hormonal agent, a potent and selective non-steroidal aromatase inhibitor, preventing the production of estrogen. It inhibits synthesis of estrogens by inhibiting the conversion of adrenal androgens (androstenedione and testosterone) to estrogens (estrone, estrone sulfate, and estradiol). Within 2 weeks, serum estradiol levels are suppressed by 90%, by 6 weeks of therapy, estradiol levels are suppressed by 97%. Anastrozole selectively inhibits the conversion of androgens to estrogens, and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone. 
Estrogen acts as a growth factor for hormone-dependent breast cancer cells, reduction of estrogen levels inhibits tumor growth as well as delaying progression of disease. In post-menopausal women. ovarian secretion of estrogen declines and conversion of adrenal androgens to estrogens in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme, is the principal source of estrogens. Anastrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P-450 unit of the enzyme. Inhibition of estrogen synthesis reduces concentrations of circulating estrogens. Anastrozole does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone. 
Dose and Route of Administration
The usual dosage of anastrozole is 1 mg daily, and it is taken orally with or without food, and is rapidly and completely absorbed, with wide distribution. About 40% of drug binds to plasma proteins. It is extensively metabolized in the liver to inactive forms. Half-life of the drug is approximately 50 hours and steady-state levels are achieved after 7 days. The major route of elimination is fecal with renal clearance accounting for only 10% of excretion. No dose adjustments are required for geriatric patients or patients with either hepatic or renal dysfunction. No studies have been done on use of anastrozole in patients with severe liver impairment: caution is advised, when liver function is impaired, monitor liver function at baseline and periodically during therapy. 
Warning: Do not use if you are pregnant, plan to become pregnant or while breastfeeding. This drug may cause birth defects if either the male or female is taking it at the time of conception or during pregnancy. Men and women who are taking this drug need to use some kind of birth control during therapy and for one month following. However, do not use oral contraceptives ("the pill") without checking with your doctor. 
SIDE EFFECTS: Diarrhea, constipation, nausea, vomiting, loss of appetite (16 to 20%), headache, hot flashes, dizziness, dry mouth, back pain, vaginal dryness and cough may occur. Changes in diet such as eating several small meals or limited activity may help lessen nausea and vomiting. In some cases, therapy with another drug may be necessary to prevent or relieve nausea. Hot flashes occur in 10% of patients. A flu-like syndrome of fever, malaise, muscle and joint pains may occur, as may a dry, scaling skin rash. Blood pressure and white cell count should be monitored. There might occur thrombophlebitis and/or thromboembolism. Hair loss, breast pain, vaginal dryness, weight gain, and rhinitis/sinusitis can occur. 
Notify your doctor if you experience: breathing trouble, rash, vaginal bleeding, shortness of breath, chest pain, pain or swelling in the legs, swelling of the feet or ankles (peripheral edema occurs in 7% of patients), weight gain, tingling of the hands or feet, depression. If you notice other effects not listed above, contact your doctor or pharmacist. 
Before taking this drug, notify your doctor of any of the following: If you have any of the following medical problems:chickenpox or exposure to chickenpox, gout, heart disease, congestive heart failure, shingles, kidney stones, liver disease. Tell your doctor of any nonprescription or prescription medication, or herbal or other supplement you may take. Do not start or stop any medicine without doctor or pharmacist approval. Never begin taking a new medication, prescription or nonprescription, without asking your doctor or nurse if it will interact with alcohol, foods or other medications. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not "double-up" the dose to catch up. Store at room temperature, andaway from heat and moisture. Keep this and all medications out of the reach of children. 

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Anastrozole [Arimidex]Q   
Quotes from Medical Journal Article Abstracts 
PubMed/Medline Search on Anastrozole and cancer.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=anastrozole%20cancer 
 
 
 
1. Br J Clin Pharmacol 2001 May;51(5):429-35 
The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant activity of warfarin in healthy volunteers. Yates RA, Wong J, Seiberling M, Merz M, Marz W, Nauck M. AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK. PMID: 11422000 
"Anastrozole had no effect on clotting mechanisms or on the pharmacodynamic activity of warfarin, as assessed by prothrombin time, thrombin time, activated partial thromboplastin time, and factor VII." 
2. Vopr Onkol 2001;47(2):195-9 
[Modern approaches to hormone therapy of breast cancer as a reflection of pathogenesis of the disease]. [Article in Russian] Semiglazov VP. N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St. Petersburg. PMID: 11383456 
" New aromatase inhibitors are more efficient than progestins and much safer than aminoglutethimide. It has been shown recently that these inhibitors keep metastatic breast cancer at bay longer, and with longer survival. .... New methods of endocrine therapy have resulted in less toxic and more convenient procedures. Also, longer therapeutic effects and survival are becoming more apparent." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11383456&dopt=Abstract

3. Gan To Kagaku Ryoho 2001 Apr;28(4):549-60 
[Development of a novel aromatase inhibitor, anastrozole (Arimidex)--its basic and clinical studies]. [Article in Japanese] Tsukagoshi S. Cancer Institute, Japanese Foundation for Cancer Research. PMID: 11329794 " 
"Therefore, anastrozole was found to be at least as effective as tamoxifen (in the response rate and TTP). In US study compared anastrozole with tamoxifen, TTP with anastrozole is a significantly longer than that of tamoxifen (p = 0.005, two-sides). Anastrozole has shown to be at least as effective as tamoxifen, standard endocrine therapy for breast cancer, with good safety profiles." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11329794&dopt=Abstract

4. Curr Med Res Opin 2001;16(4):276-84 
The Twenty-third Annual San Antonio Breast Cancer Symposium. Mokbel K. St George's Hospital, Blackshaw Road, London SW17 0QT, UK. kefahmokbel@hotmail.com PMID: 11268712 
"This paper reviews the recent Twenty-third Annual San Antonio Breast Cancer Symposium. ... fulvestrant (Falsodex), given as a once-monthly intramuscular injection (250 mg), was well-tolerated and at least as good as anastrozole (1 mg) in postmenopausal women with advanced breast cancer that had progressed or recurred on prior endocrine therapy. "
"Another phase III randomised trial found that letrozole (2.5 mg daily) was superior to tamoxifen as a neoadjuvant therapy in postmenopausal women with ER- and/or PgR-positive breast cancer unsuitable for breast-conserving surgery." 

5. Bull Cancer 2000 Dec;87 Spec No:31-39 
[Aromatase inhibitors: a review of clinical trials]. [Article in French] Kerbrat P, Lefeuvre C. Departement d'oncologie medicale, Centre Eugene-Marquis, rue de la Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France. 
PMID: 11250606
""new aromatase inhibitors have been synthetized; they belong to two groups: type I (formestane and exemestane) are steroidal irreversible and specific inhibitors, type II (anastrozole, letrozole and vorozole) are non steroidal reversible inhibitors, interfering with the aromatase heme. Several phase II and III trials demonstrated that these drugs are, at least, as active as aminoglutethimid or progestins in second line treatment, and are less toxic. Recently, an identical activity have been observed for anastrozole and tamoxifen in first line". 
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6. Anticancer Drugs 2000 Oct;11(9):701-6 
Survival in patients with metastatic breast cancer: analysis of randomized studies comparing oral aromatase inhibitors versus megestrol. Messori A, Cattel F, Trippoli S, Vaiani M. Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Azienda Ospedaliera Careggi, Florence, Italy. md3439@mclink.it PMID: 11129731 "We conducted a meta-analysis to assess the effectiveness of aromatase inhibitors versus megestrol. ... A lifetime analysis of the pooled survival curves of aromatase inhibitors versus megestrol found a mean survival gain of 4.1 months per patient. Aromatase inhibitors confer a significant survival benefit to patients with metastatic breast cancer as compared with megestrol. 
7. Oncology 2000;59 Suppl 1:19-23 Gonadotropins stimulate growth of MCF-7 human breast cancer cells by promoting intracellular conversion of adrenal androgens to estrogens. Tanaka Y, Kuwabara K, Okazaki T, Fujita T, Oizumi I, Kaiho S, Ogata E. Third Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. yjtanaka@jb3.so-net.ne.jp Copyright 2000 S. Karger AG, Basel PMID: 11096352 Resistance to estrogen ablation treatment can develop. See this abstract: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11096352&dopt=Abstract 

8. J Clin Oncol 2000 Nov 15;18(22):3758-67 
Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Cancer-Cross Institute, Edmonton, Alberta, Canada. jean-marc.nabholtz@bcom PMID: 11078488 "'""Both treatments were well tolerated. However, thromboembolic events and vaginal bleeding were reported in fewer patients who received anastrozole compared with those who received tamoxifen ... Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Furthermore, we observed both a significant increase in TTP and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11078488&dopt=Abstract
  9. Eur J Cancer 2000 Sep;36 Suppl 4:S84-5  Randomised study of anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women. Vergote I, Bonneterre J, Thurlimann B, Robertson J, Krzakowski M, Mauriac L, Koralewski L, Webster A, Steinberg M, von Euler M. Department Gynaecological Oncology, University Hospitals Leuven, Herestraat 49, B3000, Leuven, Belgium. ignance.vergote@uz.kuleuven.ac.be PMID: 11056332 "Anastrozole was also as effective as tamoxifen in terms of objective response-rate ... Both treatments were well tolerated. However, incidences of thromboembolic events and vaginal bleeding were reported in fewer patients treated with anastrozole than with tamoxifen. In conclusion, these findings indicate that anastrozole can be considered as first-line therapy for postmenopausal women with advanced breast cancer. " 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11056332&dopt=Abstract


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10. Anticancer Drugs 2000 Aug;11(7):591-601 
Cost-utility analysis of second-line hormonal therapy in advanced breast cancer: a comparison of two aromatase inhibitors to megestrol acetate. Dranitsaris G, Leung P, Mather J, Oza A. Department of Pharmacy, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Canada. gdranit@istar.ca PMID: 11036964 "Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole, to megestrol acetate (MA) in postmenopausal women with advanced breast cancer demonstrated that both agents are better tolerated than MA with comparable efficacy. In addition, one trial revealed that tumor response and time to treatment failure were significantly better with letrozole. " 

11. Gynecol Oncol 2000 Aug;78(2):212-6 A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB. Department of Obstetrics and Gynecology, University Hospital of Cleveland, Ohio, 44106, USA. 
PMID: 10926805
.... "Two partial responses were noted (9%; 90% confidence interval 3 to 23%). Two additional patients had short-term stable disease. With the exception of 1 case of venous thrombosis, the toxicity profile was mild. Median durations of progression-free survival and overall survival are 1 and 6 months, respectively" "Anastrozole has minimal activity in an unselected population of patients with recurrent endometrial cancer." Copyright 2000 Academic Press. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10926805</SPAN>&dopt=Abstract 

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  12. Recent Results Cancer Res 1998;152:227-44 The primary use of endocrine therapies. Howell A, Anderson E, Blamey R, Clarke RB, Dixon JM, Dowsett M, Johnston SR, Miller WR, Nicholson R, Robertson JF. CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. PMID: 9928561 "Primary endocrine therapy is potentially superior to primary chemotherapy in patients with ER-positive tumors. ... The fact that in ER-positive [BREAST] tumors primary endocrine therapy is associated with similar response rates to chemotherapy make it an attractive therapy for older women. ... This clinical scenario allows us to use other potentially useful assessments such as the non-invasive estimation of angiogenesis using quantitative imaging techniques of blood flow. The newer anti-estrogens and aromatase inhibitors appear ideally suited to primary therapy since they have rapid and profound inhibitory activities, few or no agonist effects, and low side effect profiles." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9928561&dopt=Abstract

13. J Steroid Biochem Mol Biol 1998 Nov;67(4):293-304 
The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase activity. Long BJ, Tilghman SL, Yue W, Thiantanawat A, Grigoryev DN, Brodie AM. Department of Pharmacology and Experimental Therapeutics, The University of Maryland School of Medicine, Baltimore 21201, USA. PMID: 9883986 Two types of endocrine therapy that have been successfully applied to patients with hormone-dependent breast cancer are the non-steroidal antiestrogen tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens. The major drawback with tamoxifen is that it acts as a partial estrogen-agonist and this is believed to mediate, at least in part, acquired tumor resistance to the drug as well as endometrial hyperplasia and carcinoma in some patients. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9883986&dopt=Abstract 
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14. Drugs Aging 1998 Oct;13(4):321-32 
Anastrozole. A review of its use in the management of postmenopausal women with advanced breast cancer. Wiseman LR, Adkins JC. Adis International Limited, Auckland, New Zealand. demail@adis.co.nz 
PMID: 9805213
"...Anastrozole is generally well tolerated in the majority of patients, the most common adverse events being gastrointestinal (GI) disturbances (incidence 29 to 33%). These events are generally mild or moderate and transient. Other adverse events reported with anastrozole include headache (< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral oedema (< or = 9%). GI disturbance tended to be more common with anastrozole than megestrol, particularly at the 10 mg/day dosage; however, compared with megestrol, anastrozole is less frequently associated with weight gain..."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9805213&dopt=Abstract
  
15. Breast Cancer Res Treat 1998;49 Suppl 1:S53-7; discussion S73-7 
Pharmacological and clinical profile of anastrozole. Lonning PE, Geisler J, Dowsett M. Department of Oncology, Haukeland University Hospital Bergen, Norway. PMID: 9797018
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9797018&dopt=Abstract 

16. Br J Cancer 1998 Sep;78 Suppl 4:12-5 
Aromatase inhibitors and their future role in post-menopausal women with early breast cancer. Lonning PE. Department of Therapeutic Oncology and Radiophysics, Haukeland University Hospital, Bergen, Norway. PMID: 9741783 'In terms of benefits over other endocrine agents, anastrozole causes significantly less weight gain than megestrol acetate; it does not have the partial agonist activity of tamoxifen, and is unlikely to lead to tumour stimulation in patients resistant to tamoxifen or to exert proliferative effects on the endometrium. The lack of oestrogen agonist activity, however, may possibly have detrimental effects on bone mineral density and blood lipid profile. 
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  17. Cancer Epidemiol Biomarkers Prev 1998 Jan;7(1):65-78 Aromatase inhibitors as potential cancer chemopreventives. Kelloff GJ, Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET, Boone CW, Sigman CC. Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland 20852, USA. 
PMID: 9456245
""one chemopreventive strategy for breast and prostate cancers is to decrease estrogen production. This can be accomplished by inhibiting aromatase, the enzyme that catalyzes the final, rate-limiting step in estrogen biosynthesis. .... The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve as potential chemopreventive agents are the subjects of this review. .... The discussion focuses on those inhibitors that are clinically available or in clinical trials, including: aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane, exemestane, and atamestane. On the basis of results from preclinical studies, aromatase inhibitors may be promising agents for clinical trials in populations at high risk for developing estrogen-dependent cancers.Total suppression of aromatase may have adverse effects, as is evident in postmenopausal women (increased osteoporosis, cardiovascular disease, and urogenital atrophy). ...it may be possible to obtain chemopreventive effects without total suppression of aromatase and circulating estrogen levels. Suppressing local estrogen production may be an alternative strategy ...The development of drugs that target this promoter region may be possible. " 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9456245&dopt=Abstract 
  
  
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18. Cancer 1997 Feb 15;79(4):730-9 A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A.Department of Medical Oncology, M.D. Anderson Cancer Center, University of Texas Medical Center, Houston 77030, USA. PMID: 9024711 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9024711&dopt=Abstract 

19. J Clin Oncol 1996 Jul;14(7):2000-11 Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV. M.D. Anderson Cancer Center, University of Texas, Houston, Department of Breast Medical Oncology 77030, USA. Aman__Buzdar@isqm.mda.uth.tmc.edu PMID: 8683230 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8683230&dopt=Abstract

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&&&&&&&&&&&&&&&&&&&&&&&&   Letrozole Medical Journal Article Annotated References note: these are all with respect to breast cancer treatment. 
You can do a pubmed search on letrozole and cancer:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=letrozole%20cancer

1. J Clin Oncol 2001 May 15;19(10):2596-606 
Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M. Rigshospitalet, Copenhagen, Denmark. PMID: 11352951 "Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11352951&dopt=Abstract
2. J Exp Clin Cancer Res 2000 Mar;19(1):17-9 
Letrozole for the treatment of pretreated advanced breast cancer patients: preliminary report. Casali A, Sega FM, Casali M, Giuntini T, Cappellini GC, Terzoli E. Service of Complementary Medical Oncology, Regina Elena Cancer Institute, Rome, Italy. PMID: 10840931 
3. Crit Rev Oncol Hematol 2000 Feb;33(2):137-42 
Steroidal aromatase inhibitors in elderly patients. Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L . Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. 
PMID: 10737375 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10737375&dopt=Abstract 

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4. Endocr Relat Cancer 1999 Mar;6(1):75-92 
Use of aromatase inhibitors in breast carcinoma. Santen RJ, Harvey HA. Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA. Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. .... Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. ... Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. PMID: 10732791 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10732791&dopt=Abstract
5. Ann Oncol 1999 Apr;10(4):377-84 
The third-generation non-steroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer. Hamilton A, Piccart M. Institut Jules Bordet, Brussels, Belgium. " In 1999, tamoxifen remains the first choice in the hormonal therapy of breast cancer. Following tamoxifen failure, the optimal second-line hormonal therapy remains undefined, but aminoglutethimide and megestrol acetate are no longer optimal therapy in this setting. " PMID: 10370778 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10370778&dopt=Abstract 


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6. Ann Oncol 1998 Jun;9(6):639-45 
Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi F, Bodrogi I, Ludwig H, Reichardt P, O'Higgins N, Romieu G, Friederich P, Lassus M. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia. PMID: 9681078 
7. Oncology (Huntingt) 1998 Mar;12(3 Suppl 5):32-5 
Emerging role of aromatase inhibitors in the treatment of breast cancer. Harvey HA. Section of Hematology-Oncology, Hershey Medical Center, Penn State Geissinger Health Systems, Hershey, Pennsylvania, USA. tutorial PMID: 9556789 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9556789&dopt=Abstract

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&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&     NOT Tamoxifen

Annotated Medical Journal Article Citations
Pubmed Searches on Tamoxifen Problems:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=tamoxifen%20leiomyosarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=tamoxifen%20endometrium 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=tamoxifen%20contraindications 
1. Br Med Bull 2000;56(3):773-86 
Novel agents to modulate oestrogen action. Dardes RC, Jordan VC. Department of Gynaecology, Federal University of Sao Paulo, Brazil (UNIFESP). PMID: 11255561 "" " 
"...Tamoxifen is the endocrine treatment of choice for breast cancer, but it also has beneficial effects on bone density and serum lipids in postmenopausal women. Recently, tamoxifen was shown to decrease the risk of invasive breast cancer in women at high risk. [While tamoxifen lowers the overall risk of tumors recurring in breast cancer patients, a new study suggests that if a new cancer does develop it is five times as likely to be of an aggressive type. Read more here: http://www.msnbc.com/news/595888.asp Ed. ] However, tamoxifen has some stimulatory effects on the endometrium. [What this means is that the endometrium...the lining of the womb...is stimulated to grow by tamoxifen. So Tamoxifen is probably not a good medicine to use for uterine cancers. Ed.] Raloxifene is used to prevent osteoporosis and fractures. Raloxifene also lowers circulating cholesterol and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium.[There was a recent case report about raloxifene possibly stimulating an ovarian cancer. Ed.] The SERMs have evolved from mere laboratory curiosities into drugs that hold promise for preventing several major diseases associated with ageing in women." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11255561&dopt=Abstract
 

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2. Eur J Gynaecol Oncol 1999;20(4):327-8 
Uterine leiomyosarcoma in a postmenopausal woman treated with tamoxifen: case report. Sabatini R, Di Fazio F, Loizzi P. III Clinic of Obstetrics and Gynecology, University of Bari, Italy. PMID: 10475136 

3. Int J Gynecol Pathol 1999 Apr;18(2):130-7 
Tamoxifen and the endometrium: review of 102 cases and comparison with HRT-related and non-HRT-related endometrial pathology. Kennedy MM, Baigrie CF, Manek S. Nuffield Department of Pathology, John Radcliffe Hospital, Oxford, United Kingdom. PMID:10202670 
"Tamoxifen, a synthetic anti-estrogen that paradoxically acts as a partial estrogen agonist on the endometrium, is associated with an increased frequency of proliferative endometrial lesions, including hyperplasias, neoplasms, and polyps." http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10202670&dopt=Abstract

4. Cancer Treat Res 1998;94:195-207 
Tamoxifen and the endometrium. Barakat RR. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. PMID: 9587689 
5. Carcinogenesis 1997 Oct;18(10):2009-14 
Proliferative lesions of oviduct and uterus in CD-1 mice exposed prenatally to tamoxifen. Diwan BA, Anderson LM, Ward JM. Intramural Research Support Program, SAIC Frederick, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201, USA. PMID: 9364013 
"Tamoxifen (TAM) is widely used as adjuvant breast cancer therapy after surgery and as a chemopreventive agent in women of child-bearing age. However, TAM therapy has been shown to result in an increased incidence of endometrial carcinoma in women. ... Progressive proliferative hyperplasia of the oviduct was frequently seen in TAM-exposed [MICE] offspring, reaching 100% incidence by 52 weeks in both treatment groups. These females also developed progressive proliferative uterine lesions, including moderate/severe cystic endometrial hyperplasia (34-50%) and polypoid adenomas (27-30%) .... Deciduomas (15%) occurred at young ages (12 and 24 weeks) while leiomyomas (14%), a malignant leiomyosarcoma, and ovarian granulosa cell tumors (14%), were found between 72 and 78 weeks. Our findings thus suggest a strong association between transplacental TAM and reproductive tract abnormalities in female CD-1 mice. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9364013&dopt=Abstract

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6. Acta Obstet Gynecol Scand 1996 Jul;75(6):593-5 
Uterine leiomyosarcoma in patient receiving tamoxifen therapy. McCluggage WG, Varma M, Weir P, Bharucha H. Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland. PMID: 8693940 
7. Med J Aust 1995 Aug 7;163(3):160-1 
Leiomyosarcoma of the uterus in a woman taking adjuvant tamoxifen therapy. Gillett D. Publication Types: Letter PMID: 7643773 [PubMed - indexed for MEDLINE] 
8. Int J Gynecol Pathol 1994 Jul;13(3):248-58 
Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: the effects of tamoxifen. Silva EG, Tornos CS, Follen-Mitchell M. Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030. PMID: 7928058 
"We reviewed the clinical history and pathology material of 72 patients seen at the M. D. Anderson Cancer Center who developed malignant neoplasms of the uterine corpus after being treated for breast carcinoma with either tamoxifen or other therapeutic regimens. The purpose of this study was to investigate the type of malignant tumors seen in the uterus, their association with endometrial polyps or hyperplasia, and their possible relationship to tamoxifen treatment. This study shows that in patients treated for breast carcinoma, the uterine malignancies are characterized by several features: (a) a previously unreported high incidence of clear cell carcinoma (14 cases) and leiomyosarcoma (12 cases); (b) seven of 12 leiomyosarcomas with unusual features, such as epithelioid (5), tubular (1), and myxoid features (2); (c) a higher incidence of serous carcinoma (45% in patients treated for > or = 12 months); (d) endometrial polyps associated with carcinoma more often than endometrial hyperplasia. " 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7928058&dopt=Abstract

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~~~~~~~~~~~~~~~~~~~~~~
Progestogen Therapy

Megestrol Acetate  (meh-JESS-troll) [Megace]

Available as: 
Suspension  
200 mg/5 mL  
with alcohol 0.06% v/v 
Bristol-Myers Squibb  
Tablets  
20 mg*  
scored  
Bristol-Myers Squibb  
  
40 mg*  
scored  
Bristol-Myers Squibb 
It is essential that the package insert be consulted for detailed information on the usual cautions, precautions, contraindications, and exhaustive list of side effects.

Megestrol acetate is a synthetic progesterone (female hormone) and one of its uses is the palliative management of recurrent, inoperable, or metastatic endometrial carcinoma or breast cancer. The drug is also used as an adjunct to surgery or radiation. It possesses anti-estrogenic effects, inducing the activities of hormones that convert estrogen to less active metabolites.  It also inhibits the release of luteinizing hormone receptors resulting in a decrease in estrogen levels, and  inhibits stability, availability, and turnover of estrogen receptors.   Megestrol acetate shares the actions of the progestins: induction of secretory changes in the endometrium, increase in basal body temperature, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen. It has slight glucocorticoid activity and a very slight degree of mineralocorticoid activity. Megestrol acetate has no estrogenic, androgenic, or anabolic activity. The exact mechanism of the antineoplastic action of megestrol acetate has not been determined, but might result from suppression of luteinizing hormone by inhibition of pituitary function. Results of one study suggested that megestrol acetate produced a local effect on the cancerous cell by converting the actively growing stroma into decidua [sloughed off tissue that forms some of the menstrual discharge].Megestrol acetate has shown a marked suppressive effect on the colony formation of endometrial cancer cells. It is absorbed rapidly and completely from an oral dose, with peak plasma concentrations within 1 to 3 hours. A large percentage of megestrol is stored in body fat. About 70% of drug is metabolized in the liver to inactive steroid metabolites. Sixty to 80% of the parent drug and metabolites is excreted by the kidneys within 10 days after administration. Elimination half-life varies from 15-105 hours with an average of 34 hours.  The usual dosage of megestrol acetate in the palliative treatment of advanced endometrial carcinoma is between 40 and 320 mg daily, depending on body weight and the type of cancer being treated, administered in divided doses.
Megestrol acetate tablets should be stored in well-closed containers at room temperature and megestrol acetate oral suspension should be stored in tight containers at a temperature of 25°C or less. An adequate trial period for determining the effectiveness of megestrol acetate is 2 months. Megestrol acetate is also used in the management of significant weight loss in cancer and AIDS patients. The exact mechanism by which megestrol acetate works to stimulate appetite and weight gain is unknown at this time. Weight gain seems to be from increased fat storage. Megestrol acetate is not intended for prophylactic use to avoid weight loss.

Use with caution in patients with either a history of thromboembolic or hypercoagulable disorders as megestrol acetate has been associated with an increased incidence of thromboembolic events. 
Use with caution in patients with diabetes, cardiac failure, epilepsy, migraines, asthma, hyperlipidemia, mental depression, or renal dysfunction.
Use with caution in patients with abnormal liver function. Dose reduction is recommended in this setting. 
Caution patients on the risk of weight gain and fluid retention. Patients should be advised to go on a low-salt diet. 
Do not use if you are pregnant, plan to become pregnant or while breastfeeding. Do not use if there is abnormal, undiagnosed vaginal bleeding or incomplete abortion. Caution with history of ectopic pregnancy. Because of increased genital abnormalities caused by progestins in both male and female fetuses, the manufacturer states that megestrol acetate is not recommended during pregnancy. If a woman becomes pregnant while receiving megestrol acetate or is inadvertently exposed to the drug during pregnancy, she should notify her physician and should be advised of the potential risks to the fetus. Women of childbearing potential should be advised not to become pregnant while receiving megestrol acetate therapy, and they should be advisedto use an effective form of contraception while receiving the drug. Because of the potential for serious adverse reactions to megestrol acetate in nursing infants, women receiving the drug should discontinue nursing.

Side Effects:

GI effects: occur in at least 5% of patients and include diarrhea, flatulence, nausea, and vomiting. Constipation, dyspepsia, dry mouth, increased salivation, and oral candidiasis have been reported in about 1--4% of patients. Weight gain results from a combination of fluid retention and increased appetite.  GU effects:   Impotence and decreased libido have been reported. Frequency, incontinence, and infection of the urine have been reported. Vaginal bleeding & irregular periods have occurred in patients receiving the drug for breast cancer management. Cardiovascular effects: Increases in blood pressure have been reported in patients receiving high doses (480 to 1600 mg daily) of megestrol acetate. Cardiomyopathy, palpitations, chest pain, chest pressure, edema, peripheral edema, and congestive heart failure have been reported. These side effects were generally mild, and resolved following initiation of treatment for them. Respiratory effects: Dyspnea, cough, pharyngitis, and lung disorder occurred in about 1 to 3% of patients receiving megestrol.  Megestrol, like other progestins, may stimulate respiration in patients receiving high doses. Nervous System effects: reported in patients with AIDS-related cachexia include insomnia, headache, asthenia, paresthesia, confusion, seizures, depression, neuropathy, hypesthesia, and abnormal thinking. Endocrine effects: Tumor flare (with or without hypercalcemia). Development or worsening of diabetes mellitus, hyperglycemia or glucose intolerance, hot flashes, sweating, mood changes. Adrenal suppression might possibly occur.

Other Side Effects:

Carpal tunnel syndrome, clotting problems (e.g., deep-vein thrombophlebitis, pulmonary embolism), gynecomastia, rash, feeling of coldness, and hair loss also have been reported in patients receiving megestrol therapy. Weight gain and increased appetite have been reported in some patients; some evidence suggests that such effects may be dose-related. Also unusual tiredness, weakness, weight loss, galactorrhea, gallbladder obstruction, hepatitis, breast tenderness, chloasma, fever,
hirsutism, and trouble sleeping have been reported.   Mutagenicity studies of megestrol acetate have not been performed. The drug should be used only when the potential benefits justify the possible risks to the patient.
Notify your Doctor: This medication can cause changes in appetite, thirst or weight, diarrhea, constipation, frequent urination, swelling of ankles or feet, increased rate or difficulty breathing. If any of these effects persist or worsen, inform your doctor promptly. Notify your doctor if you experience: changes in vaginal bleeding or discharge, severe or sudden vision changes, headache, loss of coordination, slurred speech, trouble breathing, weakness or numbness in arms or legs, skin rash or itching, pain (in the stomach, side, chest, groin, arm, leg, or especially calf pain). If you notice other effects not listed above, contact your doctor or pharmacist.  

Drug Interactions:
Aminoglutethimide - Aminoglutethimide enhances the hepatic metabolism of megestrol resulting in decreased serum levels.  
dofetilide-contraindicated.


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Consult your doctor before taking this drug. Tell your doctor your medical history, especially: liver disease, congestive heart failure, depression, incomplete abortion,ectopic pregnancy, unusual vaginal bleeding, suspected pregnancy, blood clotting problems, diabetes, any allergies. This drug may decrease adrenal gland activity. Therefore, tell your doctors and dentists of your megestrol use and when you stopped using it. After stopping this drug, additional corticosteroids (e.g., hydrocortisone) may be necessary in stress situations such as trauma, major surgery or serious infection. Consult your doctor or pharmacist for details. Symptoms of adrenal problems include unusual weakness, fever, dizziness, nausea and rapid weight loss. Contraceptive (birth control) measures are recommended for use while using this medication. Megestrol is not recommended for use during pregnancy. . Megestrol may be excreted into breast milk. Because of the potential of harm to the infant, nursing should be stopped while using this drug. Tell your doctor of any nonprescription or prescription medication, or herbal or other supplement you may take. Do not start or stop any medicine without doctor or pharmacist approval. Never begin taking a new medication, prescription or nonprescription, without asking your doctor or nurse if it will interact with alcohol, foods or other medications. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not "double-up" the dose to catch up. Store at room temperature, andaway from heat and moisture. Keep this and all medications out of the reach of children. 

Your condition can cause complications in a medical emergency. For information on enrollment call Medic Alert(TM) at 1-800-854- 1166. In Canada call 1-800-668-1507. 
  &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 

Megestrol Acetate Some Annotated Medical Journal Citations

Pubmed Searches 
megestrol acetate and leiomyosarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=megestrol%20leiomyosarcoma
megestrol acetate and sarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=megestrol%20sarcoma

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1. Gynecol Oncol 1998 Dec;71(3):458-60 
Low-grade endometrial stromal sarcoma preoperative treatment with Depo-Lupron and Megace. Scribner DR Jr, Walker JL. Department of Gynecologic Oncology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, 73190, USA. Two doses of depot Lupron 7.5mg, and Megace 160mg/day, were given to control bleeding and shrink the low grade, inoperable ESS tumor mass in a 46 year old woman. This neoadjuvant therapy allowed for shrinkage of tumor mass, and surgical resection with a TAH with BSO. Additional research is necessary to define the exact role of chemo, radiation, and hormal therapy. [Abstract rewritten because of copyright. Ed.]. Copyright 1998 Academic Press. PMID: 9887250
2. Surg Today 1996;26(2):138-41 
The effectiveness of medroxyprogesterone in the treatment of multiple metastasizing leiomyosarcomas: report of a case. Uchida T, Nakakawaji K, Sakamoto J, Kojima H, Murakami H, Kato J, Yasue M Department of Surgery, Aichi Prefectural Hospital, Kakemachi, Okazaki, Japan. 
PMID: 8919287 
"A 51-year-old woman was admitted to our hospital for further investigation of chest X-ray films which showed multiple shadows that had been growing slowly over 2 years. ... The resected specimens were pathologically diagnosed as metastasizing leimyosarcoma which was positive for the progesterone and estrogen receptors. Thus, 1 month postoperatively, a course of medroxyprogesterone (MPA), 600 mg daily, was commenced. The residual lesions in her chest started to diminish, shortly afterward. She has remained well on this MPA regimen for 45 months. The prognosis of patients with metastasizing leiomyosarcoma is poor because of its low sensitivity to chemotherapy; however, some types of leiomyosarcoma are hormone-sensitive. It is therefore important to examine the hormone receptors of excised tumors from patients suspected of having metastasizing leiomyoma or leimyosarcoma." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8919287&dopt=Abstract

3. Formulary 1995 Sep;30(9):532-4, 542 
Potential cost savings using GnRH agonists as preoperative therapy for uterine leiomyomas. Saltiel E. Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. PMID: 10161243 "Women with large uterine leiomyomas traditionally have had just one choice for therapy--abdominal hysterectomy. Recently, gonadotropin-releasing hormone (GnRH) agonist therapy has been introduced as an option to shrink tumors before surgery. When administered preoperatively, usually for 2 months, GnRH therapy has been shown to reduce tumor size enough to permit an endoscopic myomectomy or a vaginal hysterectomy. It has also been shown to reduce blood loss associated with the tumors and increase hemoglobin levels. When assessed for its economic impact, preoperative GnRH therapy reduces both direct and indirect costs associated with a hysterectomy." [But there are complications if the fibroid is leiomyosarcoma. Ed.] 

4. Fertil Steril 1995 Jul;64(1):191-2 
Fibroid growth in response to high-dose progestogen. Harrison-Woolrych M, Robinson R. Department of Obstetrics and Gynaecology, University of Cambridge, Rosie Maternity Hospital, United Kingdom. PMID: 7789558 
"To challenge the conventional belief that leiomyomata are estrogen-dependent tumors by presentation of a case report suggesting high-dose progestogen therapy is associated with a dramatic increase in size of a fibroid uterus. ...One white woman treated with tamoxifen and high-dose megestrol acetate for breast carcinoma... While taking tamoxifen and high-dose megestrol acetate, the patient suffered a dramatic increase in size of her fibroid uterus, which reversed when the progestogen was withdrawn. " [NB both megestrol acetate and tamoxifen have been associated with a tumor flare phenomenon.]


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5. Clin Endocrinol (Oxf) 1995 Jan;42(1):91-3 
Megestrol-induced Cushing's syndrome. Steer KA, Kurtz AB, Honour JW. Bloomsbury Department of Chemical Pathology, Middlesex Hospital, London, UK. . PMID: 7889638 
6. J Dermatol Surg Oncol 1994 Aug;20(8):544-7 
Uterine adenocarcinoma metastatic to the skin responsive to megestrol acetate. Spencer DM, Bigler LR, Wilkin JK, Gams RA. Division of Dermatology, Ohio State University, Columbus. " "Megestrol acetate can be successfully utilized in the treatment of endometrial adenocarcinoma metastatic to the skin as well as ostensibly in the treatment of other progesterone-sensitive metastatic cutaneous carcinomas." PMID: 8056889



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7. Eur J Gynaecol Oncol 1993;14(1):44-5 
Response of "benign" metastasizing leiomyoma to progestin withdrawal. Case report. Cohen JD, Robins HI. Division of Hematology/Oncology Denver Veterans Administration Medical Center. PMID: 8472731 
"We report a rare case of a benign metastasizing leiomyoma in which progestin therapy permitted or promoted pulmonary metastases, but progestin withdrawal induced a marked tumor regression. The significance of these observations is discussed relative to the estrogen and progesterone receptor positivity of this patient's tumor."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8472731&dopt=Abstract
8. Gynecol Oncol 1989 Nov;35(2):275-8 
Low-grade endometrial stromal sarcoma recurring over three decades. Styron SL, Burke TW, Linville WK. Department of Obstetrics and Gynecology, Brooke Army Medical Center, Fort Sam Houston, Texas 78234-6200. PMID: 2807024 
"Endometrial stromal sarcoma (ESS) is an uncommon uterine malignancy with a variety of histologic characteristics and clinical courses. We describe a patient who recently underwent her third resection of a locally recurring low-grade ESS 29 years after original diagnosis. Tissue from her recurrent tumor contained high levels of estrogen and progesterone receptors and had a diploid DNA content. In addition to multiple resections, she has previously been treated with vincristine chemotherapy and is now receiving megestrol acetate therapy. Mitotic activity is the most important prognostic feature distinguishing high- and low-grade ESS. The mainstay of therapy for both high- and low-grade tumors is surgical excision. A beneficial adjuvant role for cytotoxic chemotherapy or radiotherapy is yet to be clearly established for low-grade ESS; however, recent reports suggest that progestational agents may produce significant responses in recurrent or persistent disease patients whose tumors produce steroid hormone receptors. Indolent tumors may require years of close observation and multiple treatment approaches to maintain a patient in a functional capacity." 
9. Gan To Kagaku Ryoho 1988 Apr;15(4 Pt 2-1):924-8 
[Progestogen therapy in the treatment of endometrial cancer--clinical results and mechanism of steroid action].[Article in Japanese] Okada H. Dept. of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine. PMID: 2968780 
"It became clear that progestational activity was not always associated with anticancer activity, and norethindrone had no influence on the inhibitory effect of MPA, although norethindrone has a strong affinity for progesterone receptor. Similarly, RU 486, which is known as a potent antiprogestogen agent and has a high affinity to progesterone receptor, did not influence the effect of MPA. These results clearly indicated that the anticancer activity of MPA was not mediated by high affinity low capacity progesterone receptor, and a pharmacological effect must be considered for understanding the effect of MPA on endometrial cancer. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2968780&dopt=Abstract

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10. Gan To Kagaku Ryoho 1987 Oct;14(10):2837-44 
[Hormone dependency and progestogen therapy in the treatment of endometrial cancer]. [Article in Japanese] Okada H, Nakata Y, Fujimoto J, Fujita H. Dept. of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine. PMID: 2959204 
"The anti-tumor activities of steroid compounds on endometrical cancer (Ishikawa cell line) were examined in vitro by human tumor clonogenic assay (HT CA). Clinically effective progestational compounds including medroxyprogesterone acetate (MAP), and 17 alpha hydroxy-progesterone caproate were effective. Norethindrone (ENT), which is also a potent progestational compound, and RU486, which is known to be a progesterone antagonist were ineffective in this in vitro system, neither having any influence on the effect of MAP. These results indicated that the anti-tumor activity of MAP did not proceed via the so-called progesterone receptor system. Morphological changes induced by MAP in undifferentiated endometrial cancer, the effectiveness of tamoxifen, hormonochemotherapy, and the use of MAP for adjuvant therapy and prophylaxis were also discussed." 
11. Gynecol Oncol 1987 Jan;26(1):87-97 
Endometrial stromal sarcoma: a clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors. Katz L, Merino MJ, Sakamoto H, Schwartz PE. PMID: 3792939 " 
"All four of the patients who were treated with hormonal therapy [megestrol acetate] are alive, free of disease, or with stable tumor from 2 to 6 years after diagnosis. The presence of estrogen receptors (ER) and progestin receptors (PR) was demonstrated in the tumor in some of the cases; this may explain the sensitivity of this neoplasm to hormonal therapy."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3792939&dopt=Abstract 
12. Semin Oncol 1985 Mar;12(1 Suppl 1):23-7 
Progestin therapy in lesions of the endometrium. Wentz WB. PMID: 3975648 
"This paper details several studies of the effect of a single progestin, megestrol acetate, in patients with persistent endometrial hyperplasia and recurrent or persistent endometrial adenocarcinoma. Results of these studies indicate that megestrol acetate inhibits recurrence of adenomatous and atypical hyperplasia as well as adenocarcinoma in situ. These diseases when left untreated often progress to invasive adenocarcinoma. Additional studies presented here show that megestrol acetate is effective in the treatment of endometrial adenocarcinoma in inoperable patients and increases survival in patients with recurrent endometrial cancer." 

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13. Am J Obstet Gynecol 1983 Jun 1;146(3):316-22 
Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia. Gal D, Edman CD, Vellios F, Forney JP. PMID: 6859142 
"Fifty-two postmenopausal women who were poor surgical risks and had histologically proved adenomatous hyperplasia, atypical hyperplasia, or adenocarcinoma in situ of the endometrium were treated with megestrol acetate, 40 mg per day, continuously for 9 to 104 months (mean, 42 months). More than 90% of these women had complete remissions of the hyperplasia. Three women with carcinoma in situ were followed up for 57, 65, and 104 months, without recurrence of the disease. Four women required hysterectomy; none had invasive adenocarcinoma. No adverse side effects of the drug were observed. Thus, we conclude that the continuous use of megestrol acetate is an effective, safe, alternative form of therapy for endometrial hyperplasia in postmenopausal women. "
 
14. Cancer 1979 Apr;43(4):1189-94 
Complete remission of widely metastatic endometrial stromal sarcoma following combination chemotherapy. Lehrner LM, Miles PA, Enck RE. PMID: 445321 
A 21-year-old female underwent a hysterectomy with the finding of an endometrial stromal sarcoma (7-9 mitoses/10 HPF) confined to the uterus. However, within 30 months of hysterectomy, metastases occurred in the spinal cord, femur and lungs. Treatment consisted of surgery and irradiation for the spinal cord metastases and ten courses of combination chemotherapy, Adriamycin, vincristine, cyclophosphamide (6 courses) and megestrol acetate (continuous since course 7). This therapy resulted in a complete clinical remission which has been maintained for eight months since completion of chemotherapy. It is suggested that this regimen be employed in patients with this rare and lethal tumor. 

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Lupron Depot Abstracts from Medical Journal Articles.
*** Treatment of Uterine Fibroids with Lupron Depot---and Unsuspected LMS 
PubMed Search:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=lupron%20leiomyosarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=lupron%20leiomyoma%20leiomyosarcoma 
***
Obstet Gynecol 1998 Oct;92(4 Pt 2):664-6 Aborted leiomyosarcoma after treatment with leuprolide acetate. Mesia AF, Williams FS, Yan Z, Mittal K. Department of Pathology, Kaplan Comprehensive Cancer Center, New York University Medical Center, New York 10016, USA. 
PMID: 9764655
" "     
Leuprolide acetate has been used to decrease uterine size and shrink leiomyomata. In carefully selected patients, its treatment benefits are well recognized. However, if leuprolide acetate is inadvertently given to a patient with an unsuspected leiomyosarcoma, complications may occur... A patient presumed to have leiomyomata was treated with monthly injections of leuprolide acetate... In the third month of treatment, unusual manifestations, including increased bleeding, aborting mass, urinary retention, and severe pain, occurred suggesting a possible malignancy and requiring immediate operation... The use of leuprolide acetate can delay the diagnosis and treatment of leiomyosarcoma and thus may increase the risk of morbidity and affect the treatment outcome of patients with leiomyosarcoma. The histologic changes ascribed to leuprolide acetate treatment in leiomyomata also were seen in this leiomyosarcoma. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9764655&dopt=Abstract
>
Gynecol Oncol 1993 May;49(2):266-7 Gonadotropin releasing hormone (GnRH) agonist therapy for reduction of leiomyoma volume. Murphy NJ, Wallace DL. Department of Obstetrics and Gynecology, St. Luke's Hospital, Kansas City, Missouri 64111. PMID: 8504999 
"A patient with menorrhagia, dysmenorrhea, and an enlarged uterus was treated with a GnRH agonist for leiomyoma volume reduction. A laser-assisted myomectomy yielded five tumors that did not appear to be well demarcated and had a combined weight of only 30 g. Postoperative pathologic evaluation revealed leiomyosarcoma with 22 mitoses per 10 high-power fields. The 8-month delay in therapy was associated with Stage IV, grade 3 disease at diagnosis. In rare cases GnRH agonist therapy may palliate symptoms and delay definitive surgical therapy of leiomyosarcoma, resulting in more advanced disease at diagnosis." 

Fertil Steril 1991 Oct;56(4):778-80 Uterine leiomyosarcoma with massive necrosis diagnosed during gonadotropin-releasing hormone analog therapy for presumed uterine fibroid. Hitti IF, Glasberg SS, McKenzie C, Meltzer BA. Department of Pathology, LaGuardia Hospital, Forest Hills, New York 11375. PMID: 1915958 
"Recurrence of heavy vaginal bleeding and massive necrosis of a uterine leiomyosarcoma are reported in a 41-year-old female who was being treated with GnRH-a for a presumed uterine fibroid. The pathogenic mechanisms of such an event are reviewed and discussed in light of the available literature on the subject of GnRH-a and the treatment of uterine smooth muscle neoplasms." 

Obstet Gynecol 1990 Mar;75(3 Pt 2):529-32 Unsuspected leiomyosarcoma: treatment with a gonadotropin-releasing hormone analogue. Meyer WR, Mayer AR, Diamond MP, Carcangiu ML, Schwartz PE, DeCherney AH. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut. PMID: 2106109 
"We present a case of a 46-year-old woman evaluated for abnormal uterine bleeding and an enlarged uterus, with normal endometrial sampling. Three months of leuprolide acetate injections resulted in a nonenlarging uterus and resolution of iron deficiency anemia and menorrhagia. Intraoperative examination suggested leiomyosarcoma, which was confirmed by postoperative permanent histologic sections. Residual uterine sarcomatous disease was confirmed on reexploration. Similar cases will continue to raise arguments against conservative hormonal intervention in the perimenopausal woman with an enlarged uterus. As the gynecologist gains familiarity with the use of gonadotropin-releasing hormone analogue therapy in the treatment of myomatous uteri, the criteria for hysterectomy will become less rigid and the potential for delay in the diagnosis and treatment of sarcomatous disease will become more common. Physicians must be cognizant of this potential complication of conservative therapy of leiomyomata uteri. "
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*** Lupron Depot and Breast & Ovarian Cancer 
Annotated References
Pubmed Searches
Lupron Depot and Breast Cancer
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=lupron%20cancer%20breast
Lupron Depot and Ovarian Cancer
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=lupron%20cancer%20ovary
 
*** 
Cancer Chemother Pharmacol 1999;43(6):461-6 Endocrinological and clinical evaluation of two depot formulations of leuprolide acetate in pre- and perimenopausal breast cancer patients. Boccardo F, Rubagotti A, Amoroso D, Agostara B, Amadori D, et. al. U.O. Universitaria di Oncologia Medica, Istituto Nazionale per la Ricerca sulCancro, Genova, Italy. one 
The present results indicate that the two formulations exert a comparable estrogen-suppressive effect and warrant further study of the 3-monthly formulation of leuprolide acetate in breast cancer patients. PMID: 10321505

Zentralbl Gynakol 1998;120(6):284-92 [Primary endocrine therapy as pre- and perimenopausal metastatic breast carcinoma with leuprorelin acetate depot. German Leuprorelin Study Group]. [Article in German] Untch M. """Leuprorelinacetate-depot is a safe and effective palliative drug for pre- and perimenopausal metastatic breast cancer patients. Like other GnRH-agonists which have been evaluated for this indication, leuprorelinacetate-depot can be used as first-line endocrine treatment in these patients". PMID: 9659699
Eur J Gynaecol Oncol 1996;17(4):286-8 Leuprolide acetate as a salvage-therapy in relapsed epithelial ovarian cancer.
Marinaccio M, D'Addario V, Serrati A, Pinto V, Cagnazzo G. I Department of Obstetrics and Gynecology, University of Bari Medical School, Italy.
""Treatment is well-tolerated and no toxicity has been noted. These data stress the significant activity of Leuprolide acetate as a salvage therapy in patients with relapsed advanced epithelial ovarian cancer after previous platinum-based chemotherapies." PMID: 8856307

Gan To Kagaku Ryoho 1995 Mar;22(4):495-508 [Long-term clinical study on TAP-144-SR, an LH-RH agonist depot formulation, in premenopausal patients with advanced or recurrent breast cancer. TAP-144-SR Breast Cancer Study Group]. [Article in Japanese] Taguchi T, Koyama H, Yayoi K, Wada T, Takatsuka Y, Sonoo H, Morimoto K, Tominaga T, Abe R, Enomoto K, et al. Japan Society for Cancer Chemotherapy, Dept. of Surgery, Center for Adult Diseases, Osaka. PMID: 7887641 

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J Clin Endocrinol Metab 1993 Jun;76(6):1439-45 A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin "add-back" regimens for women with leiomyomata uteri. Friedman AJ, Daly M, Juneau-Norcross M, Rein MS, Fine C, Gleason R, Leboff M. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115. PMID: 8501148 
Treatment of women with myomas with GnRH agonists (GnRH-a) for 3-6 months will result in profound hypoestrogenism, a significant but temporary reduction in uterine volume, and menstrual suppression. Long-term (i.e. > 6 months) treatment with a GnRH-a is not recommended because of accelerated bone resorption and the presence of hypoestrogenic symptoms. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8501148&dopt=Abstract
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***************************
Lupron Depot AND Endometrial Cancer 
 
</*****************
Mol Cell Endocrinol 2001 May 15;176(1-2):121-8 Direct effects of GnRH agonists in human hormone-sensitive endometrial cells. Sica G, Schinzari G, Angelucci C, Lama G, Iacopino F. Istituto di Istologia ed Embriologia, Facolta di Medicina e Chirurgia, Universita Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy. ibiis@rm.unicatt.it "The antiproliferative effect of two GnRH agonists (leuprorelin acetate and triptorelin), alone or combined with tamoxifen (TAM) or medroxyprogesterone acetate (MPA), on human estrogen-sensitive endometrial cancer cells (Ishikawa) was investigated. Although ineffective when tested alone in all the culture conditions used, both analogues counteracted or even suppressed the estrogen-stimulated growth of Ishikawa cells. "PMID: 11369451 

Cancer Lett 2000 Mar 13;150(1):71-8 Inhibitory effect of luteinising hormone-releasing hormone analogues on human endometrial cancer in vitro. Noci I, Coronnello M, Borri P, Borrani E, Giachi M, Chieffi O, Marchionni M, Paglierani M, Buccoliero AM, Cherubini A, Arcangeli A, Mini E, Taddei G. Department of Obstetrics and Gynecology, University of Florence, Italy. PMID: 10755389 


Arch Gynecol Obstet 2000 Feb;263(3):148-9 Uterine adenocarcinoma after GnRH agonist treatment. Dessole S, Ruiu GA, Cherchi PL, Ambrosini G. We report endometrial adenocarcinoma in two patients shortly after suspending GnRH-agonist treatment for menometrorrhagia and uterine fibromata. PMID: 10763848 [PubMed - indexed for MEDLINE] 

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Gynecol Endocrinol 1999 Dec;13(6):382-9 Estriol add-back therapy in the long-acting gonadotropin-releasing hormone agonist treatment of uterine leiomyomata. Nakayama H, Yano T, Sagara Y, Kikuchi A, Ando K, Wang Y, Watanabe M, Matsumi H, Osuga Y, Momoeda M, Taketani Y Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan. PMID: 10685331
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10685331&dopt=Abstract
Gynecol Oncol 1998 Dec;71(3):458-60 Low-grade endometrial stromal sarcoma preoperative treatment with Depo-Lupron and Megace. Scribner DR Jr, Walker JL. Department of Gynecologic Oncology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, 73190, USA. Two doses of depot Lupron 7.5mg, and Megace 160mg/day, were given to control bleeding and shrink the low grade, inoperable ESS tumor mass in a 46 year old woman. This neoadjuvant therapy allowed for shrinkage of tumor mass, and surgical resection with a TAH with BSO. Additional research is necessary to define the exact role of chemo, radiation, and hormal therapy. [abstract rewritten because of copyright. Ed.]. Copyright 1998 Academic Press. PMID: 9887250


Gynecol Oncol 1998 Dec;71(3):396-403 Differential inhibitory effects on human endometrial carcinoma cell growth of luteinizing hormone-releasing hormone analogues. Borri P, Coronnello M, Noci I, Pesciullesi A, Peri A, et. al. Istituto di Clinica Ginecologica ed Ostetrica, Universita degli Studi di Firenze, Viale Morgagni 85, Florence, 50134, Italy. MID: 9887238 Copyright 1998 Academic Press. 

Depress Anxiety 1998;7(4):171-7 Depressive symptoms associated with gonadotropin-releasing hormone agonists. Warnock JK, Bundren JC, Morris DW. Department of Psychiatry, University of Oklahoma Health Sciences Center-Tulsa, Oklahoma 74129, USA. PMID: 9706454 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9706454&dopt=Abstract

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J Reprod Med 1996 Jun;41(6):415-21 Comment in: J Reprod Med. 1997 Apr;42(4):253 GnRH agonists before surgery for uterine leiomyomas. A review. Crosignani PG, Vercellini P, Meschia M, Oldani S, Bramante T. L. Mangiagalli Obstetrics and Gynecologic Clinic, University of Milan, Italy. PMID: 8799917
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8799917&dopt=Abstract
> Minerva Ginecol 1992 Jul-Aug;44(7-8):383-6 [The use of leuprolide in endometrial glandular hyperplasia]. [Article in Italian] Menozzi G, Gozzi M, Greci P, Stratico G, Talarico G. Ospedale Montecchi, Suzzara, Mantova. PMID: 1407643 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1407643&dopt=Abstract 
 

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&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Anti-Progestogen Treatment RU486 [mifeprostine] For information on uses, side-effects, dosage, contraindications, precautions, we refer you to the package insert provided by the manufacturers.

Anti-progestogens block the action of progesterone at the cellular level through binding to the progesterone receptor. Mifepristone [RU486] remains the leading compound of this class and is the only one presently used in clinical practice. Beyond the main action of antiprogestins on human pregnancy, these compounds are useful in the treatment of uterine leiomyomas and endometriosis, and might be useful for contraception. Oncologically, tumors like leiomyoarcomas expressing progesterone receptors might be successfully treated with these antihormones. The initial results in the treatment of both benign (fibroids, endometriosis) and malignant (endometrial and ductus carcinoma) gynaecological conditions are encouraging. Clinically achievable doses of RU 486 inhibit endometrial cancer cell lines. Administration of RU486 results in ovarian inhibition and prevention of menstrual cycles. This ovarian inhibition was achieved without estrogen deprivation, and may provide a useful longterm approach to the treatment of steroid-dependent disease processes. Whether this will allow control of LMS growth and progression is unknown. Both RU486 [25 mg daily] and leuprolide acetate [lupron depot, 3.75 monthly] are effective in decreasing blood flow to the uterus (increasing resistive index) and decreasing uterine volume due to fibroids after 3 months. A significant decrease in uterine artery blood flow may provide a mechanism for the decrease in uterine size and the decrease in uterine blood loss at the time of surgery for uterine fibroids. Whether RU486 will prove helpful in downgrading LMS tumors is unknown. Effective Use of Mifeprostine for control of any aspect of LMS is unproven at this time. August 2001 
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Mifepristone [RU 486] Anti-Progestogen Agent. 
 
 
Pubmed search for RU486 and Leiomyosarcoma:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=mifepristone%20leiomyosarcoma

Pubmed search for RU486 and VEGF
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=mifepristone%20VEGF
Annotated Medical Journal Article Citations

Environ Health Perspect 2000 Oct;108 Suppl 5:785-90 Regulation of vascular endothelial growth factor expression by estrogens and progestins. Hyder SM, Huang JC, Nawaz Z, Boettger-Tong H, Makela S, Chiappetta C, Stancel GM. Department of Integrative Biology and Pharmacology, University of Texas-Houston Medical School, Houston, Texas 77225, USA. salman.hyder@uth.tmc.edu 
"Estrogens increase the expression of vascular endothelial growth factor (VEGF) mRNA in the rodent uterus. This regulatory effect is rapid, beginning within 1 hr after hormone treatment, dose dependent, and blocked by the pure antiestrogen ICI 182,780. The induction of the transcript is blocked by inhibitors of RNA but not of protein synthesis, andwe have recently identified estrogen response elements in the VEGF gene. Collectively, these findings indicate that estrogens regulate uterine VEGF expression at the transcriptional level via the classical nuclear estrogen receptor pathway. Estrogen induction of VEGF occurs in the stromal layer of the rodent uterus, and estradiol induces expression of VEGF transcript levels in cultured human uterine stromal cells. Progestins also induce VEGF expression in the rodent uterus, although the effect is less marked and slower in onset than estrogenic effects. The effect of progestins is blocked by the antiprogestin mifepristone (RU-486), suggesting that it is also mediated by a classical nuclear receptor pathway. In addition, progestins regulate expression of VEGF mRNA and protein in cultured human T47-D breast cancer cells. The development of uterine leiomyomas is associated with exposure to ovarian sex steroids, abnormal uterine bleeding is commonly seen in patients with leiomyomas, and fibroids require an increased vascular supply for their growth. These observations suggest that VEGF and other angiogenic factors may represent potential targets for the treatment and prevention of uterine fibroids. "PMID: 11035983

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Presse Med 1999 Dec 4;28(38):2123-31
[Anti-progesterones] [Article in French]
Sitruk-Ware R. Service d'Endocrinologie, Hopital Saint-Antoine, Paris. PMID: 10613204 
"THERAPEUTIC APPLICATIONS: Antiprogestins are a promising class of therapeutic agents in the field of reproductive health. Mifepristone (exRU486) remains the leading compound of this class and is the only one presently used in clinical practice. Beyond the main action of antiprogestins on human pregnancy, these compounds may prove useful in the treatment of uterine leiomyomas and endometriosis, and for contraception. IN CANCEROLOGY: Rare tumors such as meningiomas or leiomyoarcomas expressing progesterone receptors may [perhaps] be successfully treated with these antihormones. MAIN INDICATIONS: The main characteristics of the different antiprogestins discovered so far are addressed and the key results from the large clinical studies conducted with mifepristone are described here for indications where the product is approved for clinical use: medical termination of pregnancy during the first trimester, cervical dilatation prior to surgical termination of pregnancy, preparation for prostaglandin action in the therapeutic termination of pregnancy beyond the first trimester, labor induction in case of foetal death in utero." 
J Soc Gynecol Investig 1998 Nov-Dec;5(6):334-8 Inhibition of endometrial cancer cell lines by mifepristone (RU 486). Schneider CC, Gibb RK, Taylor DD, Wan T, Gercel-Taylor C. Department of Obstetrics and Gynecology, University of Louisville School of Medicine, Kentucky 40202, USA. PMID: 9824816 


Zhonghua Fu Chan Ke Za Zhi 1998 Aug;33(8):490-2 [A clinical control study on the treatment of uterine leiomyoma with gonadotrophin releasing hormone agonist or mifepristone]. [Article in Chinese] Zeng C, Gu M, Huang H. 4th Municipal Hospital, Wuhan. PMID: 10806751 "...... To compare the results and side effects in treating uterine leiomyoma with gonadotrophin releasing hormone agonist (GnRH-a) or mifepristone. ... 75 patients with uterine leiomyoma who had clinical symptoms ... were divided into two groups. The GnRH-a group (30 patients) was treated by injection of GnRH-a 150 micrograms/day subcutaneously for three months, and the mifepristone group (45 patients) was treated by mifepristone 12.5 mg/day po for three months. ... The clinical symptoms improved obviously in both groups. The volume of leiomyoma reduced 20.0% or more in 90.0% (27/30) of the patients in GnRH-a group, while it was 91.1% (41/45) in mifepristone group. However, the recurrent rates were 40.0% and 17.8% in the 2 groups. ... It suggested that mifepristone is a more practical and hopeful drug in treating uterine leiomyoma." 




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Cancer Res 1998 Feb 1;58(3):392-5 Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Hyder SM, Murthy L, Stancel GM. Department of Integrative Biology, Pharmacology and Physiology, University of Texas Health Sciences Center-Houston, 77225, USA. shyder@farmr1.med.uth.tmc.edu PMID: 9458078 
"Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with the degree of vascularity, progression, and metastasis of breast cancer, and cases of this disease with increased vascular density have a poor prognosis. We show that in T47-D human breast cancer cells, progesterone induces a dose-dependent increase of 3-4-fold in media VEGF levels, with a maximum response occurring at a concentration of 10 nM. This effect is blocked by the antiprogestin RU 486. ..." 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9458078&dopt=Abstract
  Fertil Steril 1997 Dec;68(6):967-76 Mifepristone (RU486): a review. Mahajan DK, London SN. Department of Obstetrics and Gynecology, Louisiana State University School of Medicine, Shreveport 71130, USA. DMAHAJ@LSUMC.EDU 
PMID: 9418681
" 
"Mifepristone effectively blocks P receptors in the placenta, resulting in the termination of pregnancy. In addition, it has been used in the treatment of leiomyomata, endometriosis, advanced breast cancer, and meningioma. It is a powerful tool to study the molecular action of P and in the future may be used as an estrogen-free contraceptive." 


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Hum Reprod Update 1995 Jan;1(1):19-34 Clinical uses of antiprogestogens. Van Look PF, von Hertzen H. Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland. 
"Antiprogestogens, which block the action of progesterone at the cellular level through binding to the progesterone receptor, are proving to be one of the most significant developments in endocrinology in recent years. ... Most of the clinical research to date has focused on the use of mifepristone given in combination with prostaglandin for termination of early pregnancy.... In fertility regulation, the sequential combination regimen of mifepristone plus prostaglandin as used for inducing abortion has proved to be effective also for menses induction and can be expected to be an efficacious once-a-month contraceptive. Mifepristone alone, without adjuvant prostaglandin, has yielded promising results as an anti-implantation agent and in emergency contraception. Other potential uses include once-a-week contraception, ovulation inhibition (in a sequential regimen with a progestogen), and as a daily mini-pill. Mifepristone, and other antiprogestogens for which biological data have been reported also bind to the cellular receptors for glucocorticoid hormones and, consequently, possess antiglucocorticoid in addition to their antiprogestational activity. Because of this antiglucocorticoid effect, mifepristone has been employed successfully in the palliative treatment of hypercortisolism due to Cushing's syndrome, and its use has been proposed for treating certain forms of depression and of glaucoma, and in wound healing. However, for scientific and practical reasons, it would be preferable if molecules were developed that have only the antiprogestational or the antiglucocorticoid activity rather than both."PMID: 9080204 


Am J Obstet Gynecol 1994 Jun;170(6):1623-7; discussion 1627-8 The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study. Reinsch RC, Murphy AA, Morales AJ, Yen SS. Department of Obstetrics and Gynecology, Kaiser Permanente, University of California, San Diego 92103. 
" We noted a significant decrease in uterine volume compared with pretreatment in both groups at 3 months. There was no significant decrease between groups. ...: Both RU 486 (25 mg daily) and leuprolide acetate (3.75 mg monthly) are effective in decreasing blood flow to the uterus (increasing resistive index) and decreasing uterine volume at 3 months. A significant decrease in uterine artery blood flow may provide a mechanism for the decrease in uterine size and the decrease in uterine blood loss at the time of surgery." PMID: 8203418 
Curr Opin Obstet Gynecol 1994 Jun;6(3):269-78 RU486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri. Murphy AA, Castellano PZ. Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia. ""RU486 has been shown to relieve pelvic pain associated with endometriosis and to decrease American Fertility Society endometriosis scores. Uterine leiomyomata show a significant reduction in size after administration of RU486 for 3 months. Although much research remains to be carried out, RU486 appears promising as alternative therapies for these diseases." PMID: 8038415 
 
Hum Reprod 1994 Jun;9 Suppl 1:116-20 
Clinical efficacy of the antiprogesterone RU486 in the treatment of endometriosis and uterine fibroids. Kettel LM, Murphy AA, Morales AJ, Yen SS. Department of Reproductive Medicine, University of California, San Diego, La Jolla 92093. PMID: 7962456


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