Aromatase Inhibitors benefit and side effects, toxicity, caution, danger, review of studies by Ray Sahelian, M.D. Alternatives, supplements and herbal extracts

Aromatase, an enzyme of the cytochrome P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer.
   In premenopausal women ovaries are the major sites of estrogen production, while in postmenopausal women estrogen is produced by aromatization of ovarian and adrenal androgens in extragonadal sites, mostly in adipose tissue. Aromatase is a cytochrome P450 hemoprotein-containing enzyme complex that catalyzes the rate-limiting step in the conversion of androstenedione and testosterone to estrone and estradiol (E2). Aromatase inhibitors (AIs) have been developed primarily for use in either natural or surgical postmenopausal patients. In premenopausal women, the ovary can overcome the estrogen blockade by reflex increments of luteinizing hormone (LH) and follicle stimulating hormone (FSH), so AIs must be combined with a gonadotropin releasing hormone (GnRH) agonist to prevent the reflex LH and FSH increments.

Natural aromatase inhibitors, how effective are they?
Natural aromatase inhibitors include flavones, flavanones, resveratrol , oleuropein and others. Some of these can be purchased online such as chrysin, genistein, and quercetin.

Have there been reliable human studies regarding natural aromatase inhibitors? Are there natural alternatives to Tamoxifen and Lupron?
    Plants have substances that have potential aromatase inhibiting activity. Some of these include flavonoids, for instance quercetin, chrysin, naringenin, apigenin, and Genistein. Not enough human research is available to determine which of the flavonoids or other substances found in plants are the most effective aromatase inhibitors. As a general rule, it is preferable to ingest a variety of flavonoids rather than focusing on only one or two although it is possible that in the treatment of a particular medical condition a specific natural aromatase inhibitor may be more effective.

Are natural aromatase inhibitors useful in breast cancer prevention or post breast cancer treatment?
    This is a good question. I suspect that certain natural substances could potentially be helpful in reducing the incidence of breast cancer or as a post breast cancer surgery treatment, but I have not seen specific human studies that have tested natural aromatase inhibiting supplements.

Do you have aromatase inhibitors such as quercetin, chrysin, naringenin, apigenin, and genistein? Also what foods act as aromatase inhibitors to stop estrogen for women?
    See the link above for chrysin. Quercetin and genistein are sold as supplements. As to foods, it is difficult to say since most foods have quite a number of different compounds and substances in them and it would be difficult to pinpoint a particular food as having specific aromatase inhibiting activity.

I have had problems with anastrozole (Arimidex), exemestane (Aromasin) and Femarra which is a newer one. Now the doctors want me to take Tamoxifen which I have not started. I have severe bone and muscle problems in my lower back and hips. Can only sleep on my back because of the pain. I feel this is from the pills. Also, I had chemo, surgery and radiation. This has been 4 years ago. I had stage 3 breast cancer, supposedly inflammatory, a tumor and my lymph nodes all 10 taken out had cancer-no boundaries except for the skin. I have had a hysterectomy 2 years ago. I have read that natural inhibitors include chrysin, genistein and quercetin. Is there something I can take that will help as natural aromatase inhibitors without buying a bottle of each of the above? What would be good to take if taken individually?
   Not enough research is available to know which of these, or in combination, will be of benefit.

Among all natural products manufactured, have you got any "anti aromatase" product. You know better than me that sometimes testosterone or DHEA might be converted into estrogens.

Aromatase inhibitor drugs
The aromatase enzyme catalyses the last step in estrogen biosynthesis. There are two classes of third-generation aromatase inhibitors: irreversible steroidal inhibitors (e.g. exemestane) and reversible non-steroidal inhibitors (e.g. anastrozole, letrozole). All three agents have been found to be equivalent or superior to megestrol acetate as second-line therapy for metastatic breast cancer.
   These types of medications include anastrozole, made by AstraZeneca Plc under the brand name Arimidex, and exemestane, made by Pfizer Inc. under the brand name Aromasin.

Aromatase inhibitor drugs and bone loss
Breast and prostate cancer treatment can lead to bone loss and increase the risk for osteoporosis and fractures. Fred Saad, M.D., Université de Montréal's Faculty of Medicine and the Centre Hospitalier de l'Université de Montréal, and colleagues evaluated data from more than 3,500 breast and prostate cancer studies. They found that breast cancer patients treated with aromatase inhibitors were more likely to have bone loss and fractures compared with patients who didn't receive the drug therapy. Similarly, men who received androgen deprivation therapy to treat their prostate cancer had an increased risk of bone disorders. Although the numbers vary from one study to the next, an elevated risk is consistently observed. Ways to combat the bone loss, such as exercise, and vitamin D intake may be beneficial.

Aromatase Inhibitors and Breast Cancer
The widespread use of tamoxifen has led to improvements in survival for postmenopausal women with early-stage hormone receptor-positive breast cancer; however, approximately 30% of patients die despite receiving tamoxifen as adjuvant treatment. In addition, concerns exist regarding tamoxifen -associated side effects, including endometrial cancer and thromboembolic disease. The development of the third-generation aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) therefore represents a potential alternative to tamoxifen.

Women with breast cancer who switch from tamoxifen to a newer class of drugs called aromatase inhibitors live longer. Dr. Lauren Cassell of Lenox Hill Hospital in New York said the research is changing how doctors treat breast cancer patients after their tumors are surgically removed. "If they have been on tamoxifen we are switching them to an aromatase inhibitor. If they are newly diagnosed we are using an aromatase inhibitor instead of tamoxifen," she said in a statement. But tamoxifen remains the main option for younger women with breast cancer. "Aromatase inhibitors are only for women who are post-menopausal," Dr. Lauren Cassell said. Dr. Francesco Boccardo of the National Cancer Research Institute and the University of Genoa in Italy and colleagues looked at two studies of 828 women. About half the women got tamoxifen for five years, as was once recommended, and half got tamoxifen at first and then switched to an aromatase inhibitor after two or three years. The women who switched were much less likely to die of breast cancer or of anything else, Dr. Francesco Boccardo reported.

Endometriosis
Aromatase inhibitors may be helpful in treating endometriosis.

Estrogen cream
By increasing levels of estrogen in the body, use of vaginal estrogen products may counter the effects of aromatase inhibitors and thereby raise the risk of breast cancer recurrence. Roughly a fifth of women who use aromatase inhibitors have vaginitis resulting from a lack of estrogen. While estrogen replacement therapy could, in theory, help aromatase inhibitor users with this condition, it is not recommended due to its ability to raise levels of estrogen in the body. Therefore, vaginal estradiol products are often used. However, there is a potential of significant increase in serum estradiol levels after starting vaginal estradiol therapy.

Heart disease risk
Postmenopausal women with early breast cancer who take aromatase inhibitors are more likely to develop heart disease than those who take the old standby tamoxifen, San Antonio Breast Cancer Symposium, San Antonio, Dec. 8-12, 2010.Eitan Amir, MD, senior fellow, oncology and hematology, Princess Margaret Hospital, Toronto.Aman Buzdar, MD, department of breast medical oncology, University of Texas M.D. Anderson Cancer Center, Houston.

Precocious puberty
Aromatase inhibitors have been used in the treatment of selective forms of precocious puberty since the mid-1980s. The primary aim of therapy is attenuation of the effects of estrogen on growth, skeletal maturation, and secondary sexual development. The first-generation agent, testolactone, has been demonstrated to be tolerable and effective in the treatment of familial male precocious puberty, while mixed results with testolactone have been achieved in girls with McCune-Albright syndrome.

Aromatase inhibitor side effect of thinning bones
The bones of breast cancer patients age prematurely as a result of chemotherapy and aromatase inhibitor therapy. Tamoxifen drug is bone-sparing while aromatase inhibitors cause bone loss." Examples of aromatase inhibitors include anastrozole, sold as Arimidex, and exemestane sold as Aromasin.

Toxicity, caution, danger, adverse events
The aromatase inhibitors are increasingly used as adjuvant therapy in postmenopausal women with hormone receptor positive breast cancer. The symptomatic side effects of aromatase inhibitors include: hot flashes, arthralgias, vaginal dryness, mood changes and dyspareunia. The mechanism of arthralgias is uncertain and anti-inflammatory agents are seldom effective. Patients who experience severe musculoskeletal discomfort may necessitate switching to another endocrine agent such as tamoxifen. Physicians should be aware of 'silent' side effects. Screening for bone loss and hypercholesterolemia is critical and patients should be treated accordingly.

Aromatase inhibitors and bipolar mood disorder: a case report.
Bipolar Disord. 2006. Goodwin GM. University Department of Psychiatry, Warneford Hospital, Headington, Oxford, UK.
The aromatase inhibitor letrozole produced irritable mood elevation followed by depression in a woman with a history of postpartum depression. A 60-year-old Caucasian woman who had a severe depressive episode after the birth of her only child, 32 years earlier, was treated successively with anastrozole and letrozole following a mastectomy, radiotherapy and chemotherapy. The patient was prescribed anastrozole for about 6 weeks. During this time she experienced labile mood, increased activity, tremulousness and difficulty sleeping. These symptoms disappeared after stopping the anastrozole. On letrozole, she developed an acute irritable activated mood elevation, which then subsided into a prolonged major depression after withdrawal of letrozole. These effects occurred during co-prescription of amitriptyline at a low dose for urinary frequency. The present case suggests caution may be warranted when employing aromatase inhibitors, especially in women with a past history of postpartum affective disorder or bipolar disorder. As with postpartum mania, the primary mechanism of the effect may be acute reduction in circulating estrogen levels.

The heart disease risk associated with adjuvant aromatase inhibitor treatment is increased compared with tamoxifen therapy in postmenopausal women with early breast cancer. Aromatase inhibitors are superior to tamoxifen in the setting of metastatic breast cancer, but increased cardiac events are associated with their use. Cancer 2008.

Questions
Q. I was looking at purchasing quercetin supplement. I’ve read that quercetin is one of the best flavones and aromatase inhibitors, however you don’t mention that it’s an aromatase inhibitor on your webpage. Is quercetin also an aromatase inhibitor? Is quercetin safe for women? Which supplements can also be considered aromatase inhibitors?
   A. Plants have substances such as flavonoids that influence or inhibit the aromatase enzyme. There are countless substances in plants that inhibit aromatase, not just quercetin. Some of these include chrysin, naringenin, apigenin, and genistein. Not enough research is available to determine which of the flavonoids or other substances found in plants is the most effective aromatase inhibitor. As a general rule, it is preferable to ingest a variety of flavonoids rather than focusing on only one or two. 

Q. I am purchasing chamomile, Olive-Leaf-Extract, and quercetin. I think these are aromatase inhibitors and I do want suppress decrease my estrogen levels because I have endometriosis, however, I’m wondering if taking one of each 5 days a week considered “too much”?
   A. We can't make that decision for you. Please discuss with your personal health care consultant. What may be too little for one person may be too much for another and we have no way of knowing your full medical history, lab studies, and physical exam results.

I would like to thank you for providing such an extremely informative website. It has been very helpful for me in treating health issues naturally. I was diagnosed several months ago with low testosterone and slightly high estrogen. I'm on a quest to increase testosterone and DHT levels in my body, and reduce estrogen levels. Besides my daily liquid basic multivitamin, I am taking 900 mg of gamma oryzanol daily to boost testosterone levels, and this does help. I was wondering if there are any natural supplements that will inhibit aromatase without inhibiting 5 alpha reductase also. I know mushrooms can inhibit aromatase, but i've read that mushrooms also inhibit dht also. Can I inhibit aromatase without lowering DHT? Thank you for your help with this matter.
    There are several herbs that have an influence on these enzymes, but they are not as specific as pharmaceutical medications. Rather than focusing to such detail on which enzymes or chemicals in the body to alter, I prefer to focus on the overall health of the body and treat overt signs and symptoms rather than treat laboratory numbers from blood studies.

Does anyone know of a topical herbal hair product for menopausal female with hair loss and high levels of serum DHT? If not, any leads on what herbs or otherwise one might use to make something topical? Any research or anecdotal evidence to support? Also, do you think long acting T3 vs. T4 supplementation works the same on the conversion of testosterone to DHT?
    I am not aware of a natural herbal product used topically that has been proven to work for hair loss although there are some companies working on such products and there may be one soon. I have not seen any research on the difference between long acting T3 versus T4 in terms of influence on the conversion of testosterone to DHT.

5-alpha reductase Inhibitors
Propecia and Proscar are the brand names for finasteride.