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Hormones, HRT, & LMS
written and compiled by doctordee
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Test Your Tumor

We recommend that all female LMS owners have their tumor tested for estrogen and progestogen receptors. While many of the uterine LMS cells are positive for either estrogen receptors or progestogen receptors or both, sometimes LMS tumors of other sites also have hormone receptors. So maybe ALL LMS owners should have estrogen and progestogen receptor tests done on their tumors? If the tumor is positive for estrogen receptors, or for progestogen receptors, these hormones will stimulate those tumor cells to grow. Even after a hysterectomy, your body produces some estrogen and progestogen in other tissues. If your tumor is estrogen or progestogen receptor positive, or both, you might want to consider hormonal management. The agents for these interventions are MUCH kinder than chemotherapy agents.

[Do NOT use Raloxifene. Do NOT use Tamoxifen. There is a suggestion now that perhaps Raloxifene (Evista) has increased growth of an ovarian cancer. Tamoxifen has been implicated in possibly causing LMS, where it has been used for preventing breast cancer progression.]

Progestogen and estrogen receptor tests are also tests done with 'stains'; they are 'dye' tests. Often tests done on tumors have a 20% cut-off point, so they are read as negative, even if 19% of the cells respond positively. So sometimes even if the test is read as negative you might have benefit from hormone directed therapy. You might ask your friendly pathologist to review the original test slides and see if there is ANY staining? Or if it is possible, have a PCR or probe type test done on the tumor for estrogen and progestogen receptors.

Jim wrote:
"As others have noted, estrogen/progesterone receptor testing is important for uterine LMS, and it can be done on wax embedded tissue sections which will have been saved from the op. If these are positive, then consider anti-oestrogen therapy. Even if negative, stay away from HRT - frankly it is not worth the risk that it may stimulate any remaining cells and make them grow quicker." "If the lady is unlucky and has symptoms (hot flushes etc) then look at other forms of post menopausal relief. The best advice given here is always to make sure that you have a sarcoma specialist on your team even if you only travel for the advice and then have all your treatment done locally. Other than that, make sure of getting scans every 3 months for a couple of years and then drop to 6 months, and let's hope they are always clear."

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.

"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, and we 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. "
Fetch PMID: 11035983

For More Information on Hormone Receptors
For More Information on Testing Your Tumor for Hormones
HRT & LMS

All sex hormones affect the body, including the cardiovascular system, bone metabolism, cognitive function, and the genito-urinary system.

From the endocrine point of view, menopause is considered a deficiency state and estrogen therapy regarded as restoring the pre-menopausal endocrine balance. Estrogen therapy alleviates acute menopausal symptoms and also reduces the risk of cardiovascular disease, osteoporosis and Alzheimer's disease. Cardiovascular protection seems to be the major benefit of oestrogen replacement: it reduces morbidity and mortality from coronary heart disease by approximately 50%. The mechanisms are complex. Estrogen therapy reduces the rate of post-menopausal bone loss, increases bone mineral density (BMD) and decreases fracture rate. Recent evidence suggests that initiation of oestrogen therapy in older women produces larger increases in bone density which might provide a significant protective effect against osteoporosis and fractures.
[HRT is hormone replacement therapy, a choice for women in menopause. HRT can be estrogen, or estrogen and progestogen. Note, we are discussing estrogen replacement alone here [for women who have had a hysterectomy] not combined estrogen/progestogen treatment.]

The results of epidemiological studies of the effects of estrogens 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. Increase in the risk of venous thromboembolism is most significant within the first 12 months of therapy.

HRT or hormone replacement therapy becomes a question for those women who have passed into menopause, whether naturally or surgically.

1. If the woman has had uterine LMS, or has estrogen or progestogen receptors on the cells of her NONgenital LMS primary, HRT could stimulate tumor growth of recurrence or metastases.
2. If the woman has LMS, HRT's stimulation of breast and/or uterine tissue might result in promotion of the SECOND primary cancer that some 7.5% of LMS owners will have. So, even if the LMS is not uterine, HRT might be a bad idea.

Here are some comments from the ACOR LMS LIST:


Helen: This is my first note to the list. I was diagnosed with LMS this spring - the sarcoma was inside a uterine fibroid. I had surgery in March. Also i got differing advice on the whole question of continuing hormone replacement therapy. The gynecological oncologist said it was OK at very low levels, while the sarcoma expert advised against it. Would appreciate any info from those who have time to respond.

Sarah: Helen, my mom finally stopped taking her Premarin after her (4th) surgery in March 2001. Her first tumor was a uterine fibroid in 1992. She felt all along that the estrogen contributed to her tumor growth, although her OB-GYN doctor insisted that it didn't. When she consulted with Dr. Demetri in June he agreed that she was wise to stop the Premarin since her tumors tested positive for estrogen and progesterone receptors. He recommended taking Evista or Tamoxifen. She is still undecided what to do there...I think she's afraid to take anything at this point for fear it will trigger something else.

doctordee: I would and am avoiding hormone replacement of any kind, including Evista, Tamoxifen, phytoestrogens and soy supplements. The question of safety with LMS and these items has not been answered. Also, I read with interest that 7.5% of LMS patients will have a second primary. I don't have uterine LMS either, but I phased out my premarin because I didn't need any encouragement for a second cancer primary in my breast. I now have these very interesting spells when I don't need clothing.

Penny: A friend of mine who has a very strong cancer family history is reading "Natural Woman, Natural Menopause" I haven't read it, but she says it gives good alternatives to HRT.

doctordee: To manage your menopause nonhormonally:
Have your bone density checked regularly. If bone density becomes a problem, Fosamax works well. Have enough sunlight or Vitamin D. Have enough dairy or calcium & magnesium from other sources. Have enough weight bearing exercise. For the coronary part of the hormone replacement: diet management and exercise are again mainstays. K-Y jelly is very good for the dry vagina problem. I used a beta blocker for the irritability... a beta blocker also helps with those interesting spells. Discuss alternatives for your symptoms with your GP, but check with your sarcoma oncologist before taking any additional medication, or herbal or nutritional supplement. Because of possible help with estrogen deficiency side effects, some LMS patients are considering using Tamoxifen or Raloxifene rather than standard estrogen replacement. Please see section "NOT Tamoxifen" for discussion of both of these agents.

AntiHormone Therapy and Cognition and Other Side Effects
The incidence of Alzheimer's disease is reduced by 50% in post-menopausal women taking oestrogen replacement. Limited clinical trials of estrogen treatment in women with this disease have documented beneficial effects on cognitive function. Estrogen supplementation has been shown to preserve cognitive function in nonAlzheimer's cases, too. Effective anti-estrogen treatment might result in some cognitive diminution [possibly concentration and memory functions decreasing somewhat].

Men also have difficulties with an andropause syndrome.

More Information about Estrogen and Cognitive Defects
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Estrogen Receptor Positive

Estrogen [also sometimes spelled oestrogen] does not CAUSE uterine LMS. But ALL endometrial uterine cancers have a relationship with estrogen levels. Estrogen can stimulate the cells of the endometrium [the lining of the uterus] to grow, so it might increase the chance that cancerous cells develop and grow.

All cancers develop from DNA damage. This might be genetic [for example, faulty repair enzymes that are inherited], or due to viruses, or chemical carcinogens, or radiation. Estrogen does not cause DNA damage.

LMS uterine primary tumors often have estrogen receptors on their cells. Sometimes NONgenital LMS cells will have estrogen receptors on their cell membranes. Estrogen can stimulate cells with estrogen receptors on them to grow and reproduce. You might have your tumor tested for estrogen and progestogen receptors, and if positive, consider ANTI hormone treatment.

Estrogen Levels and Cancer Development
* Oral contraceptives which have a very low level of hormones, might actually lower the level of estrogen in a person's blood. In fact, this might be the reason for the protective effect that oral contraceptives have against some "female" cancers.
* It is also interesting that cigarette smoking, which induces certain liver enzymes that metabolize estrogen, lowers the level of estrogen in the blood. Groups of women who smoke have a lower risk of uterine cancer than women who don't. We are NOT recommending smoking as a preventative for uterine cancer, however, because of the damage it does to the rest of the body.
* There is also some question about groups of people who eat a lot of soy phytoestrogens. These are weaker estrogens than those we produce in our body, and the lower estrogen stimulation they provide in competition with our own estrogen, might protect some vegans and Asian population groups from developing some estrogen dependent cancers.
* There is also some question about hormone levels in meat contributing to the development of some cancers.

In Summary So Far

* LMS patients with a uterine primary that is estrogen positive run a risk of HRT stimulating any remaining tumor cells.
* 7.5% of LMS patients are at risk for developing a second primary cancer. HRT might promote breast or genital cancers.
* Therefore, HRT might not be a good idea for any female LMS patients whether their primary is estrogen receptor positive or not.


Jim wrote to the ACOR LMS LIST:
OK here is my simple interpretation about receptors and LMS. Please note this is an oversimplification. I'll talk about oestrogen but these general observation apply to progesterone also.

Oestrogen is a hormone produced in large amounts by the ovaries. Hormones are chemical messengers used by the body to control parts that may be widely separated [eg 'Womens bits'].

Some cells have receptors on their surface that bind oestrogen. When the oestrogen binds to the cell surface a change occurs within the cell - even though the oestrogen doesn't enter it - a bit like ringing the doorbell to wake the cell up. This is not the place to go into the details, but whole libraries have been written on what happens when a hormone binds to a cell! For example, the growth/shedding of the lining of the uterus is controlled by the levels of hormones leading to the monthly cycle - this is well understood and in just about any basic textbook.

THIS IS THE IMPORTANT BIT. If a cell which is normally partly controlled by oestrogen becomes cancerous (eg breast cancer or SOME cases of uterine LMS) then the stimulation of these receptors MAY cause the tumour to grow faster - oestrogen may increase the rate of growth of the cancer. So it is a bad idea to give it any more oestrogen (by HRT) if the ovaries have been removed. Small amounts of oestrogen are produced by other tissues (men have low but measurable levels).

It has been established in breast cancer that blocking oestrogen is beneficial if the cancer cells have estrogen receptors. The usual drug for breast cancer is Tamoxifen which stops the oestrogen from binding to the cells. But Dr Judson (Royal Marsden) suggested that Tamoxifen may not be ideal for uterine LMS as there is evidence that Tamoxifen may actually stimulate uterine endometrium and possibly therefore uterine LMS.

Letrozole interferes with Oestrogen production so should be effective in slowing down cells that are stimulated by oestrogen. OK now these anti-oestrogens haven't been around long enough for anyone to know of the effects - Dr Judson said he is just starting to think about putting together a trial to see if they really work. They won't kill LMS but they may slow it down and as they do not appear to have any major side effects (but remember they are new) why not try them?

My personal view is this:
My wife's LMS grew back in a year and the main mass was removed again by surgery - but she was on HRT (a different story) so maybe without HRT it MIGHT take 2 years to grow to the same size and maybe with Letrozole it MIGHT take 4 years. Having had 6 courses of Adriamycin (with horrible side effects) that reduced it by 5%--- then the Letrozole looks like a real bargain.

I would urge everyone with uterine LMS to have the tumor that was removed at operation tested for oest/prog receptors. Testing can be done on the wax embedded tumor that is preserved and stored in the laboratory. I would be very unhappy if my oncologist didn't see the point.

Anti-oestrogen therapy will not cure you and if you have a large mass then surgery (including RFA etc) or possibly chemotherapy is probably the only option. If however you have Uterine LMS and had a recurrence removed then anti-hormone looks a good bet - it is untested but I don't think that there is anything else - I wouldn't go for adjuvant radio/chemotherapy.

If you are clear after initial surgery then I'd probably wait and see. This is based on a 40% chance of a recurrence if there are clear margins; once you have a recurrence however then you are probably 90% certain to get more. Hope that I've pitched this at the right level feel free to e-mail me on or off list with any questions and I'll keep the list updated with my wife's progress. As always the above is not a medical opinion. I post to help everyone with LMS to understand it and to help YOU make a decision in consultation with YOUR medical advisor.

In summary, Jim wrote:
"It is my understanding that oestrogens can stimulate Uterine LMS cells to grow quicker. As hormones closely control many cells of the uterus, this is only to be expected. Remember that LMS cells are not aliens - they are just cells of our own body that don't respond correctly to the signals and so grow out of control. If a tumour arises from uterine tissue it would be expected to still show many of its parent cell's characteristics."

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Aromatase Inhibitors: Letrozole & Anastrazole

Non Steroidal Reversible Aromatase Inhibitors.
letrozole (Femara) anastrozole (Arimidex) vorozole (Rizivor) and others


Simplified Mechanism of Action
Ovaries make the estrogen for women's bodies until menopause.
After menopause, the only source of estrogen in the body is that made by aromatase enzymes.
Aromatase Inhibitors prevent the aromatase from making estrogen.

Mechanism of Action
The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme aromatase act by decreasing estrogen production throughout the body in postmenopausal women. 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 last step in estrogen synthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use. The newly developed, orally administered, nonsteroidal competitive inhibitors, such as anastrozole (Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times more potent inhibitors of aromatase than is aminoglutethimide. Besides the competitive aromatase inhibitors anastrozole, letrozole and vorozole there are the irreversible inhibitors 4-OH androstenedione and exemestane.

Either anastrozole (1.0 mg/d) or letrozole (2.5 mg/d) are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and are now recommended following Tamoxifen failure. In this setting they showed a trend toward improved response duration and survival. They also produced less weight gain and fewer cardiovascular and thromboembolic side effects, replacing the routine use of megestrol acetate in this setting. Letrozole [Femara] and anastrozole (Arimidex) are NOW sometimes being prescribed for hormone receptor positive LMS by doctors at sarcoma centers.

Anti-Hormone Medication and Estrogen Receptor Positive [ER+] LMS
These agents will not shrink LMS tumors, but either might slow tumor growth or at least prevent growth stimulation of the ER+ tumor by estrogen.

AntiHormone Therapy and Cognition
The incidence of Alzheimer's disease is reduced by 50% in post-menopausal women taking oestrogen replacement. Limited clinical trials of estrogen treatment in women with this disease have documented beneficial effects on cognitive function. Estrogen supplementation has been shown to preserve cognitive function in nonAlzheimer's cases, too. Effective anti-estrogen treatment might result in some cognitive diminution [possibly concentration and memory functions decreasing somewhat].

More Information on Cognitive Function and Estrogen and Androgens
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Search Pubmed for Information on Cognitive Function and Andropause

More Information on Aromatase Inhibitors
Search Pubmed for Aromatase Inhibitors and uterine cancer
Search Pubmed for Aromatase Inhibitors and cancer
Letrozole [Femara]

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.

More Information About Letrozole
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.

More Information About Anastrozole
NOT Tamoxifen

Estrogen look-alikes [agonists] like tamoxifen compete with estrogen for binding to estrogen receptors. They can block tumor growth stimulated by estrogen. This seems to work very well with breast cancer cells that are ER+.

However, with uterine tissue, the tamoxifen-receptor complex can stimulate the uterine endometrium and promote uterine endometrial tumor growth. Tamoxifen therapy has been shown to result in an increased incidence of endometrial cancers and other endometrial growths in women. It acts as a stimulator of the uterus. It has been implicated in the appearance of leiomyosarcomas in women being treated with it. It is not recommended for use of people with endometrial tumors, because it can stimulate uterine endometrial growth. It can stimulate growth of uterine LMS tumors and their metastases.

Jim wrote:
"My wife was diagnosed with LMS after hysterectomy for a fibroid 2 years ago, common story on the list, so I thought I'd share what we learnt from Dr Judson at the Royal Marsden (London)." He continued: "First a bit more history. Local mets were detected 1 year ago; she had 6 courses of Adriamycin that resulted in some shrinkage. 5 weeks ago she had abdominal surgery--several tumours were removed. Unfortunately the surgeon saw a lot more small suspicious patches which he couldn't remove." " Dr Judson suggested anti-hormone therapy - even though the receptor assays were not back yet. He suggested letrozole, which is an aromatase inhibitor [i.e. it effectively blocks oestrogen production], rather than Tamoxifen, which interferes with the binding of oestrogen on the cells. The reason he gave was that while Tamoxifen has anti-oestrogen activity in Breast cancer it has been shown to act as an oestrogen in some cases including Uterine Endometrium. It is therefore possible (? probable?) that Tamoxifen might actually stimulate Uterine LMS." "I've thought about this since - it seems strange that the same drug can have two opposite effects - it appears that it is down to the cell receptors. It may bind but not be a good enough fit to trigger the action (i.e. Breast cancer cells) while slightly different receptors will be triggered. Anyway Maureen is trying Letrozole for 3 months and then having a scan and review. Hope this might help in that it may give you another option to discuss."
The best information available about the serious side effects of tamoxifen comes from 30 years of clinical trials, including the BCPT. In the BCPT, women taking tamoxifen had more than twice the chance of developing endometrial cancer (cancer of the lining of the uterus or womb) compared with women who took the placebo (36 of the 6,600 women taking tamoxifen versus 15 of the 6,600 women taking placebo). The risk was higher in women over the age of 50. The increased risk is in the same range as the risk for postmenopausal women taking single-agent estrogen replacement therapy. Like all cancers, endometrial cancer is potentially life threatening. Women who have had a hysterectomy (surgery to remove the uterus) are not at risk for endometrial cancer. BUT if they have had uterine cancer removed, tamoxifen could stimulate metastases or recurrences.
Women taking tamoxifen in the BCPT had three times the chance of developing a pulmonary embolism (blood clot in the lung) as women who took the placebo (18 women taking tamoxifen versus 6 on placebo). Three women taking tamoxifen died from these embolisms. Women in the tamoxifen group were also more likely to have a deep vein thrombosis (a blood clot in a major vein) than women on placebo (35 women on tamoxifen versus 22 on placebo). Women taking tamoxifen also appeared to have an increased chance of stroke (38 women on tamoxifen versus 24 on placebo). [PDQ document.]

Information about raloxifene [Evista] is limited compared with the data available on tamoxifen because of the shorter time it has been studied (about 5 years) and the smaller number of women who have been studied. Studies of raloxifene have generally involved women who received the drug to determine its effect on osteoporosis, and the duration of both therapy and followup have been short.

Women taking raloxifene in clinical trials have about three times the chance of developing a deep vein thrombosis or pulmonary embolism as women on a placebo. In osteoporosis studies of raloxifene, the drug did not increase the risk of endometrial cancer. An important part of STAR will be to assess the long-term safety of raloxifene versus tamoxifen in women at increased risk of breast cancer. [PDQ document]. [There has been a report that raloxifene has encouraged the growth of an ovarian cancer. It is not known whether raloxifene would stimulate LMS metastases that are estrogen sensitive.]

More Information About NOT Tamoxifen

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Megace Therapy
Megestrol acetate [Megace]

Megestrol acetate, a synthetic progesterone, has a normalizing effect upon the uterine endometrium. It inhibits recurrence of atypical hyperplasia as well as adenocarcinoma in situ. These conditions, when left untreated, often progress to invasive adenocarcinoma. Additional studies have shown that megestrol acetate is effective in the treatment of endometrial adenocarcinoma in inoperable patients and increases survival in patients with recurrent endometrial cancer.

Estrogen and progesterone receptor studies are recommended in all cases of cancers of endometrial origin. Hormonal therapy can be given either alone or with chemotherapy agents, to enable resection of previously inoperable uterine endometrial tumors as neoadjuvant treatment. Hormonal therapy can be used as adjuvant treatment, when the cancer is in remission. Hormonal therapy can also be used palliatively to diminish symptomatology and increase survival. Sometimes progesterone might promote growth in a tumor [tumor flare], in which case removal of the progestogen might result in diminution of the tumor.

More Information About Megestrol Acetate
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General Information about Megestrol Acetate (meh-JESS-troll AH-set-tate)

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 25C 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 Promptly IF:
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.

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, and away 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.
Gonadotrophin Releasing Hormone [GnRH]Agonists
leuprolide acetate [Lupron Depot]

Gonadotropin-releasing hormone agonist [GnRHa] therapy essentially shuts down ovarian production of hormones. In the premenopausal woman with a hormone sensitive tumor, GnRHa therapy could prevent hormonal stimulation of the tumor.

Accidental Use in Presence of LMS
Leuprolide acetate [Lupron Depot] has been used to decrease uterine size and shrink leiomyomata [uterine fibroids]. In carefully selected patients, it is very useful.

But what if leuprolide acetate is inadvertently given to a patient with an unsuspected leiomyosarcoma? One patient treated for leiomyomata with monthly injections of leuprolide acetate had increased bleeding, aborting mass, urinary problems and severe pain in the third month, requiring an immediate operation.

Gonadotropin-releasing hormone [GnRH] agonist therapy may palliate symptoms and delay definitive surgical therapy of leiomyosarcoma, resulting in more advanced disease at diagnosis, with resulting effect upon patient survival. Similar cases will continue to raise arguments against conservative hormonal intervention in the perimenopausal woman with an enlarged uterus.

As the use of GnRH agonists in the treatment of fibroid uterus increases, the potential for delay in the diagnosis and treatment of sarcomatous disease will become more common. Physicians must be aware of this potential complication of conservative therapy of uterine fibroids.


Use to Prevent Estrogen Stimulation of Breast Cancer
Gonadotropin-releasing hormone agonist [GnRHa] therapy essentially shuts down ovarian production of hormones. In the premenopausal woman with a hormone sensitive tumor, GnRHa therapy can help prevent hormonal stimulation of the tumor. Premenopausal patients after primary surgery showed the best response during the GnRH agonist treatment.

Treatment is well tolerated. The main side effects (hot flushes, increased sweating, headache etc.) were related to estrogen suppression. Leuprolide acetate-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, leuprolideacetate-depot can be used as first-line endocrine treatment in these patients. [GnRH agonists have lowered serum testosterone, suggesting that androgens in post-menopausal women may be partly produced by the ovaries. This fall in testosterone may explain why some post-menopausal breast cancer patients have been reported to respond to treatment with GnRH agonists, as it would decrease the androgens that are converted into estrogen. However, it would be likely that the aromatase inhibitors would be more potent estrogen inhibitors in the post-menopausal cancer patient.]


Use to Prevent Estrogen Stimulation of Endometrial Cancer
Endometrial cancer patients usually have complete hysterectomies, removing ovaries as well as other bits and pieces. So, most LMS patients with endometrial cancer have gone through a surgically induced menopause, and aromatase inhibitors would be the drug of choice for their estrogen sensitive tumors. GnRH agonists do shut down ovarian production of hormones. For this reason, GnRH agonists would be best used in the PRE menopausal patient, where the major source of estrogen is ovarian.

Or in ovarian cancer patients, to prevent stimulation of the tumor by LH and FSH. There is one clinical trial of Lupron Depot reported in PubMed, published in 1997. Of 25 patients, there were no responders, but 8 patients had stable disease for a median 5 months [range 1 to 8]. They concluded that leuprolide does not appear to be a clinically active agent in the treatment of recurrent or metastatic endometrial cancer. However, the median age at study entry was 62 years. It is unlikely that the majority of patients in this study were peri or pre menopausal. One would rather use as subjects for this experiment pre-menopausal women whose tumors are positive for hormone receptors, and whose ovaries were still present and working.

So Lupron Depot might be useful for cancer treatment in LMS. Its use would probably be limited to two groups of people:
a) people with ovarian LMS, b) those whose ovaries are still present and working, and whose LMS [of whatever primary] is positive for a hormone receptor.


It is noted that there has been a report of endometrial adenocarcinoma in two patients shortly after suspending GnRH-agonist treatment for menometrorrhagia and uterine fibromata. When being treated with Lupron Depot, symptoms of severe hypoestrogenism can surface. Not only bone demineralization, hot flashes, sweating & headache, and sex organ problems, but also problems with cognition and mood. When women are treated with Lupron Depot for uterine fibroids for long periods, sometimes an "add back" regimen of weak estrogens is given.

More Information About Lupron Depot
Search Pubmed for Lupron Depot and cancer
Search Pubmed for Lupron Depot and sarcoma
Anti-Progestogen Therapy
RU486 [mifeprostine]

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. There were two members of the LMS list who took it, but there was no slowing of their tumor growth while on it.

More Information About Mifeprostine
Search Pubmed for mifeprostine and cancer

written August 2001


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