How/where to get - I3C and DIM

I3C Background Information

Indole-3-Carbinol / Crucif. Vegetable Study [ Exerpted from RRP Newsletter Spring 1994]

In 1993 Long Island Jewish (LIJ) Medical Center, Department of Otolaryngology, began a human clinical trial to determine whether dietary indole-3-carbinol (I3C) (found in cruciferous vegetables) could alter metabolism of estrogens in RRP patients and as a result reduce the regrowth of respiratory papillomas after surgical removal. The theory runs as follows (as described in Newfield et al, 1993): Estrogens are known to exacerbate laryngeal HPV-induced lesions. There are two pathways for the metabolism of estrogen (16 alpha-hydroxylation versus 2-hydroxylation). There is a possibility that there is a concordance between 16-alpha-hydroxylation and RRP. Cruciferous vegetables contain a compound (indole-3-carbinol) that induces 2-hydroxylation (the "benign" pathway) and "shunts" it away from the 16-alpha pathway. Preliminary results were presented at the HPV meeting September 1993. The most definitive result was finding a nearly linear relationship between the ratio of estrogen metabolism pathways and the severity of RRP disease. For more background information on I3C, estrogen metabolism and respiratory papillomas, see RRP Newsletter, Fall, 1993, Newfield et al., Anticanc Res 13:337-342 (1993); Auborn et al., Anticancer Research 18: 4569-4574 (1998).
There were approximately twelve patients formally enrolled in the LIJ study. Based on this sample, the principal investigator, Dr. Karen Auborn, suggested that approximately half have had some positive response, as evidenced by a change in the estrogen metabolic ratio, as well as a reduction in severity of their RRP.
As this study has evolved, several issues have surfaced which deserve some further attention.
Although cruciferous vegetables are quite natural and have probably been consumed by humans for our entire existence on this planet to date, one cannot unconditionally rule out the possibility of "side effects" from diets that involve very large quantities. Through various sources, one of which is Dr. Jane Guiltinian at the Bastyr College, the RRPF has learned that cabbage family vegetables contain varying amounts of a substance called goitrin, which might exacerbate an innate tendency toward goiters (i.e., for those people who have a tendency toward hypothyroidism). Goitrin presumably acts to block absorption of iodine. It should be noted, however, that neither Dr. Guiltinian nor Dr.Auborn (after doing an extensive literature search dating back to 1966) could find any clearly documented evidence of a human developing a goiter solely due to a diet high in cruciferous vegetables. Furthermore, although Dr. Guiltinian is concerned about the theoretical possibility of goiters being induced by high cabbage diets, she did note in a personal communication (March 1994) that she has prescribed up to a quart of cabbage juice a day for treating some ulcer patients for periods of a month and has not seen this treatment induce a goiter.
This clinical trial was motivated by an earlier study involving mice (Newfield et al., 1993). In this study, human laryngeal tissue was infected with papillomavirus and then implanted in immunocompromised mice. They were divided into two groups, one group received I3C while the other did not. In the I3C group 75% of mice did not show papilloma growth , while all of the mice in the untreated group did develop papilloma tumors. Why has this degree of success not been seen in humans consuming large amounts of cabbage family vegetables? There are many possibilities. To name a few: There is no guarantee that humans will respond in an identical fashion as do the mice; sample sizes are probably not statistically significant; there are differences in the way the mice and humans acquired RRP; and the mice were given pure I3C while the humans are consuming cruciferous vegetables. It is of particular interest to pursue that last factor in more detail. LIJ did not propose the use of I3C to treat RRP patients because of their concern that the FDA has not formally approved I3C for therapeutic purposes in humans. (Ironically, however, the FDA has no problem with I3C being used for metabolism studies.) But the reliance on human consumption of large quantities of cruciferous vegetables as a source of I3C, appears to introduce a variable that is at best difficult to quantify. Even if those patients enrolled in the study religiously comply with the consumption requirements as outlined in the LIJ protocol, there appears to be a great variability of the amount of I3C contained in the vegetables themselves. Not only is there significant variation of I3C from one cruciferous species to another (with savoy cabbage and purple broccoli having higher amounts of I3C), but more importantly there is great variability of I3C from plant to plant within a species. For example I3C typically ranges from 4.5 mg / 100 g to 97 mg / 100 g for green cabbage ( Dr. Leon Bradlow, personal communication ). Therefore it is possible for an adult who is following the LIJ protocol, by consuming approx. 1 pound of cabbage (or the juice therefrom) a day, to be getting anywhere from 20 mg to 440 mg of I3C per day! Estrogen metabolism studies conducted by Bradlow and others (personal communication) indicate that in adults 200 mg is likely sufficient and 400 mg is clearly sufficient to induce the desired shift in metabolic pathways (from 16a-hydroxylation to 2 hydroxylation) in most people. ( For children under 50 lbs. Bradlow suggests that 100 mg would induce the desired effect. ) Based on this information it follows that one needs to be consuming cruciferous vegetables that contain at least an average amount of I3C to have some assurance of getting enough. Unfortunately, there is no easy method for most people to directly determine how much I3C is in a particular head of cabbage. However, indirectly, one could be reasonably assured that they are getting enough I3C if their urine samples indicate that their ratio of estrogen metabolism pathways has improved. Before leaving this issue, it should be noted that the role of stomach acids is quite important to further the breakdown of I3C into dimers and trimers that are the real "players" responsible for the shift in estrogen metabolism ( Preobrazhenskaya et al, Food Chemistry, 48:57-62, 1993 ). In this regard it makes sense to avoid neutralizing agents such as antacids while following this protocol.
I3C is a rather benign substance compared to powerful ( and sometimes toxic ) drugs such as interferon and 13-cis-retinoic acid. The RRPF is hopeful that this clinical study will continue to evolve so as to be able to accurately determine just how effective I3C is for RRP.
 

DIM Background Information

Indole-3-Carbinol to Diindolylmethane: The Next Generation [From RRP Newsletter Fall 97]

by Micheal Zeligs, MD

You might wonder how something named Diindolylmethane (DIM which is the same as B3IM) could be related in any way to Indole-3-Carbinol (I3C). Apart fromtheir disparate chemical names, the relationship is exceedingly close. Each DIM molecule is formed from the combining of two I3C molecules. With two identical, mirror-image rings connected by a carbon bridge, one DIM molecule is like Siamese twins of two I3C molecules. DIM is naturally formed from Indole-3-Carbinol (I3C) during the fermentation or acid digestion of cruciferous vegetables. DIM like I3C is present in broccoli, cabbage, cauliflower, Brussels sprouts , and Chinese cabbage. In some studies in which synthetic I3C was fed to animals, about 4% of what left the stomach turned into DIM. Most interesting was the fact that when I3C was injected into animals, bypassing the stomach and acid digestions, it had no effect whatsoever in changing estrogen metabolism. DIM, however, was equally as potent in changing estrogen metabolism whether injected or given by mouth. Most convincing in establishing the importance of DIM were animal experiments that compared the beneficial enzyme inducing effects of I3C versus DIM. Dietary DIM was a much more powerful inducer than I3C. Could DIM be the major active byproduct of I3C? Our development group certainly thinks so.

To back up a bit in this story, let me explain my introduction to DIM and I3C. About two years ago, I was writing on the subject of cancer prevention. In doing so I reviewed the work of H. Leon Bradlow, Ph.D. in the area of breast cancer prevention. Surprisingly, with regard to I3C, the most compelling evidence for effectiveness resided not with cancer but with Recurrent Respiratory Papilloma (RRP). The evidence for successful suppression of RRP with I3C impressed me deeply, since, as a pediatrcian-anesthesiologist, I knew firsthand of the frustration and seriousness of this condition. I was surprised that no one had worked on improving the formulation of I3C. My resolve to develop I3C into a more widely available dietary supplement led me to intense study of the chemistry of this group of food chemicals. I3C turned out to be quite unstable, with no shelf life, and productive of many breakdown products of questionable benefit. DIM, on the other hand, had none of these problems but presented its own unique challenge. It was completely insoluble in watre and only marginally soluble in oil. This required some real work in nutrient delivery. Our research and development group, BioResponse, created D-MAXTM a delivery system to make DIM more absorbable. When taken as a supplement, D-MAXTM , is DIM packaged in microscopic bubbles of Vitamin E and coated with starch. When examined, D-MAXTM has the consistency of flour. But when added to the diet it provides for the smooth absorption of DIM. We next turned the powder into granules through a food process. By adding flavor during this step, we have been able to produce D-MAXTM Sprinkles. This form of DIM is designed to be added to food, especially to encourage DIM use by children. What became clear inour research was that D-MAXTM was stable on the shelf, tasted better than I3C, and remained stable through the digestive process.

I3C trials (as of Fall 98)

1) Trial at University of Pittsburgh, Children's Hospital and University of Tennessee (see Rosen et al.,, Otolaryngol Head Neck Surg: 1998 June; 118 (6):810-815) :

This clinical trial has been written about extensively in RRP Newsletter issues from 1995 to present. It is generally required that a patient make at least one visit to either the University of Pittsburgh or the University of Tennessee. For more information contact principal investigators:

Clark A. Rosen, MD. - (412) 647-2112 (Univ. of Pittsburgh)

Gayle E. Woodson, MD. - (901) 448-7677 (Univ. of Tennessee)
Jerome Thompson, MD. - (901) 572-4400 (Univ. of Tennessee)

2) Trial at Vancouver Gen. Hospital, Vancouver, BC CANADA:

Principal Investigator: Murray Morrison, MD

Double blinded randomized prospective study of I3C in adults with RRP. The study will continue for approximately the next 12 months. This study is limited to adults, with the maximum number of participants being limited to 30. They are using an I3C product made by Enrich. Participants will have to agree to have a video laryngoscopy every three months performed at the voice clinic in Vancouver, since they use a specific computer program that analyzes the images and any change in instrumentation will have an effect on the their analysis. Patients interested in joining the study or seeking more information should contact:

Murray Morrison, MD - (604) 875-4640; e-mail : emami@intechange.ubc.ca.
 
 

I3C/DIM Update -

Research on using DIM as a cancer preventative(December 2000)

(April 2000; RRP Newsletter Summer 2000)

BioResponse renames Indolplex^TM as "Phytosorb- DIM" with a new suggested dose for RRP.
by Michael Zeligs, M.D.

BioResponse Nutrients is pleased to announce to members of the RRP community using Indolplex that this successful product is being renamed and released as Phytosorb-DIM. DIM is short for diindolylmethane which is a phytonutrient found in cruciferous vegetables of benefit as a dietary supplement for RRP.

The patented formulation of DIM, to be sold as Phytosorb-DIM, is unchanged from that found in Indolplex. However, after two years of monitoring the use of this supplement by individuals with RRP, reports indicate more success at a higher dose of 5-8 mg/kg/day of the formulation, without any side effects (see dosing info below).
 
 

(late November 1999):

Update on I3C from Pittsburgh
by Clark A. Rosen MD.
University of Pittsburgh Voice Center Pittsburgh, PA

The I3C study that was started over 5 years ago at the University of Tennessee is still ongoing (at both the Univ. of Pittsburgh and Tennessee). Theranaturals has offered continued free I3C for study participants and the RRP community should be appreciative for their support of this study. We would not know as much about I3C nor would their be such widespread I3C understanding (outside the RRP community) if we had not had the early and continued support of Theranaturals.

(from RRP Newsletter Fall 1999):

Progress with Absorbable DIM ( Indolplex TM) in the RRP Community
by Michael Zeligs, M.D., BioResponse

An important step forward in understanding dietary indoles and the importance of DIM was made recently by researchers at the Midwest Research Institute in Kansas City. They reported that in human subjects given 400 mg of I3C as an oral supplement, only DIM and no I3C was subsequently identified in their blood using a highly sensitive detection method (1). This important finding focuses new attention on the importance of DIM as an active principle in the benefits so far attributed to I3C. In a second, more recent report using human liver slices in organ culture, no change in enzyme activity was noted when I3C was added directly to the liver slices. However, a powerful up-regulation of enzymes was seen after addition of DIM (2). These are some of the same enzymes responsible for the beneficial shifts in estrogen metabolism seen with I3C and with DIM from Indolplex.

As you may know, we have managed a development effort that has resulted in production of a proprietary formulation of DIM, which we call Indolplex. Indolplex provides dependable and uniform absorption of pure DIM from capsules and from "Chocolate Sprinkles". Pure DIM in crystalline form is not absorbed based on direct sampling of human blood even after large oral doses. The absorption enhancing processing and formulation developed from Indolplex overcomes the barrier to absorbing DIM and allows for the sustained release of active DIM over a period of 3-4 hours after each dose. This has been consistently seen in all individuals tested, using the same technology employed in the report mentioned above. Testing of human subject's urine, before and after daily supplementation with Indolplex, has shown a beneficial shift in estrogen metabolites favoring 2-hydroxy estrone at a dose of DIM from Indolplex that is one tenth of the lowest active dose of I3C in the same test.

Most encouraging, however, are the number of individuals with RRP who have responded to Indolplex with improvement in symptoms. Over 50 individuals taking Indolplex have now completed a questionnaire after using Indolplex for at least 4 months. The vast majority of respondees reported a beneficial impact with symptom reduction and increasing interval between surgery. 15 individuals who completed the questionnaire had previously tried I3C but did not respond. 10 of these 15 did respond to Indolplex with either symptom reduction or increasing intervals between surgery. Notable among adults completing the questionnaires were two individuals who lengthened surgical intervals from every six months to over a year.

Most encouraging among the responses from parents and children was a report concerning Ashley Lawton, a 4 year old girl, whose history is summarized below with her parent's permission.

Ashley was diagnosed with RRP at 15 months of age. Before starting Indolplex, she had undergone 21 laryngoscopic surgical procedures for recurrent papillomas compromising her airway. Surgical frequency had shortened to every 2 weeks in 1997. During this time, a 6 month trial of I3C failed to produce clinical improvement or a lengthening of the intervals between surgical procedures. Tracheostomy was performed in 1998 to provide a more secure airway. Indolplex (DIM) was begun in June, 1998. Surgical frequency lengthened immediately to 2 months. After 5 months of supplementation, no new papillomas were noted. 14 months past the start of Indolplex, the patient underwent a trachael stenting, tracheostomy removal and was found to be free of papillomas. While under anesthesia for adenoid surgery last month, her larynx and trachea were examined and found to still be completely free of any papillomas.

(from RRP Newsletter Fall 98):

RRPF I3C Research Coordination Efforts

The RRPF continues to encourage research studies involving I3C as an RRP adjunct therapy. In this regard we suggest that those patients who are interested in I3C as an adjunct treatment for RRP become part of a clinical trial. For those who are unable to participate in an I3C trial, but who would like to pursue this therapy on their own, we have been providing information regarding how and where to get I3C and how much to take. In addition, we continue to supply urine analysis testing information and supplies to RRP patients upon request. Thus far we have had requests for and have mailed out approximately 95 test kits. Along with the kits detailed instructions are included for collecting urine samples and sending them to Strang Cancer Prevention Center for analysis. In this regard we ask for your patience. These analyses are being performed as part of a research program by a limited number of scientists who depend on various funding sources to cover laboratory expenses. The RRPF will continue to assist their efforts.
 
 

How to get I3C or DIM and how much to take
Phytosorb-DIM^TM(previously called Indolplex ^TM) products containing DIM are available from:

BioResponse
L.L.C. at P.O. Box 288
Boulder, CO 80306
Email at etzeligs@bio-response.com
303-447-3841 - Telephone; 303-938-8003 - Fax
Credit card orders (Visa and Mastercard) are being accepted - [call for current pricing]

Indolplex is available in two forms:

1. Phytosorb-DIM Capsules; 150 mg; 60 capsules per bottle or 75 mg; 90 capsules per bottle.
2. Phytosorb-DIM Flavored* Sprinkles; 9.0 grams per bottle with directions indicating dosage per teaspoon. 
At the suggested dosing below, 1 bottle should provide a two-to-four month supply for a child about 50 lbs.
* Now available in orange as well as chocolate flavors. 
   
   Shipping : US priority mail  or global priority mail

Special Note: Unlike I3C, Indolplex does not require activation by stomach acid. Indolplex can be taken by individuals who use antacids or H2 blockers like Zantac.

Estimated dosages; BioResponse now recommends that individuals with RRP choose a daily dose which is close to 5-8 mg/kg/day. A typical man weighing 70-85 kg (where kg. = 2.2 lbs.) would take approximately 350 to 600 mg per day. A typical woman weighing 60-70 kg would take from 300 to 500 mg per day.
BioResponse has reformulated its "Sprinkles". These new formulations require lesser amounts of the powder to deliver the increased suggested dose. Detailed dosing instructions are included on the bottle label.
(Please consult your doctor, especially for young children.)

I3C may be purchased from:

Theranaturals Inc.
PO. Box 344
Orem UT 84059-0344
e-mail: theranat@itsnet.com
(801)224-8893 - Telephone; (801) 226-6064 - Fax
http://www.theranaturals.com
[Credit card orders may be placed by phone, fax, web or e-mail]

Theranaturals I3C product pricing as of 9-1-99 (includes shipping via USPS priority mail):
1 bottle - 100 capsules @ 100 mg -$20
3 bottles - 100 capsules @ 100 mg - $55
add $16.00 to above prices for Fed X shipping.

Kronos Pharmacy
3675 S. Rainbow Blvd, #103
Las Vegas NV 89103
Tel: 1-800-723-7455
Local: 702-873-8455
Fax: 702-873-6845
http://www.kronospharmacy.com/
[Credit card orders may be placed by phone (toll free), fax, or web ]
For more detailed information ask to speak with Richard Fura.

Medical Center Compounding Pharmacy I3C product pricing as of 9-1-99 :
1 bottle - 100 capsules @ 400 mg - $59.50 + shipping
1 bottle - 100 capsules @ 200 mg - estimated ~ $33.95 + shipping
SHIPPING: UPS 3rd Day Service ($5.00) or Airborne Overnight ($8.00)

Approximate dosing information is based on preliminary results of Dr. Leon Bradlow's estrogen metabolism studies, as follows:
Estimated dosages - Adults approx. 400 mg, Children (under 50 lbs.) 100 - 200 mg (Please consult your doctor)

Additional I3C Notes

The digestive process is important to properly break down I3C (see RRP Newsletter - Spring 94 ). In this regard, try to avoid taking antacids and it is probably best to take I3C at meal time. It has also been suggested that taking ascorbic acid (vitamin C) along with I3C will produce ascorbigen, which some investigators (Preobrazhenskaya, et al., 1993, Food Chemistry, 48,48-52) speculate may be an even more important anti-carcinogen than I3C.

If you do not appear to be responding to I3C, you might want to give DIM or bis(3-indolyl)methane (B3IM) a try. DIM or B3IM is one of the key reactive by-products of I3C. It can be ordered as Indolplex (from BioResponse) or in pure crystal form through Theranaturals by asking specifically for the B3IM CAPS.

Finally, no matter what product one is using the best way to extend the shelf life is to keep them in a cool dark location such as the refrigerator.
 
 

I3C and Bone Density [ Fall 1998]
By Bill Stern

It has recently been brought to the attention of the RRPF, that taking I3C ( or DIM) could possibly have an effect on bone density. An infectious disease specialist, Dr. Juan Dumois, has noted that a ten year old girl with RRP who has been treated with a fairly high dose of I3C since late 1996, has shown unusually low bone density for a girl her age. There is evidence that a shift in estrogen metabolism might impact bone density. In this regard, almost all published literature involves post menopausal women and osteoporosis (e.g. , see Lim et al., 1997).

Please do NOT interpret this communication as a recommendation by the RRPF to discontinue use of I3C or DIM, we are merely sharing information with the rest of the RRP community. I personally have no intention of stopping I3C/DIM for my daughter Lindsay. It is my strong opinion, that if I3C/DIM is helping control RRP, it would be a mistake to stop taking it. No one taking I3C has reported to the RRPF that they seem to fracture bones more easily, and the case of the 10 year old girl above is just that &emdash; a single case study. Further research studies into better understanding the relationship between estrogen metabolites and bone density are needed to help clarify just how much impact I3C may have on bone density.

What should people do at this time? Do not exceed recommended dosing. It also makes sense to include in your diet sources of vitamin D and calcium. Discuss this information with your doctor.

A simple bone density test is widely available called DEXA (for Dual X-Ray Absorptiometry machine that is used). It does involve a very low dose of radiation. Whether to have this test done or not, should be the topic of discussion with your doctor.

The following websites provide more information on bone density and testing:
 
 

http://www.bone-density.com

http://www.osteorec.com/testing.htm
 
 
 
 

Questions and Guidance regarding I3C and DIM supplementation and Bone Mineral Densisty
[June 2000]

A recent anectdotal report of reduced bone mineral density (BMD) in anadult male individual with RRP needs to be kept in perspective. BMD is a complex issue reflecting many known and unknown factors.

Even with baseline BMD determination before supplementation with dietary indoles (I3C and DIM) there are many overlapping influences on BMD that must be taken into account in interpreting results of BMD testing.

The many factors which determine BMD in a given individual include age,family history, diet, hormonal status, and lifestyle, especially exercise, alcohol intake, calcium intake, vitamin D intake, and exposure to sunlight.

Some of the confounding questions which must be considered include:

1. Do RRP individuals have a lower baseline BMD because of their condition including chronic immune response to HPV virus? Chronic infection and hypermetabolism contribute to BMD loss.

2. Have family history and genetics been considered. Lack of family history of fractures does not mean an individual is not predisposed to low BMD by genetic factors

3. Body Fat. Being Thin is a basic risk to low BMD

4. Vitamin D status: Normal circulating levels of active Vit D requires both adequate intake and exposure to adequate sunlight. Vitamin D intakes often are needed above the RDA up to 400 IU's/day or more in certain individuals, depending on age, genetics and co-existing conditions. Adequate daily calcium/magnesium of 1 gram/700 mg and up from good sources is also needed. Does RRP infection alter Vit D metabolism?

5. Good Digestion: Inflammation of the gastro intestinal tract is associated with lower BMD. Does RRP effect digestion? I3C but not DIM has been shown in animals and some people to be an irritant to the GI tract.Vitamin D may not be efficiently absorbed in some people.

6. Hormonal status: Both adequate estrogen and androgen status are important in maintaining BMD. Declines with aging vary from individual to individual, involve both women and men, and include estrogens (estradiol, estrone, androstenedione) and androgens (DHEA, testosterone)

7. Lifestyle: Diet and weight-bearing exercise are important to maintain BMD. Alcohol consumption, coffee consumption, and smoking are risk factors for lower BMD. Interestingly tea consumption helps support increased BMD.

Regarding the specific action of I3C, a recent study at high dose in mice indicated no effect of I3C on bone density.

Regarding daily intakes of calcium and vitamin D, the conservative Recommended Daily Allowance for calcium is 1000 mg and for Vitamin D is 400IU. This amount of Vitamin D is found in 4-5 servings (1 cup each) of Vitamin D fortified milk. For growing children and older adults the needs for vitamin D and calcium are at least at the RDA levels and increased intake of both nutrients is often suggested. Suggestions to increase calcium to 1200 to 1400 mg per day and Vitamin D above 400 IU are under study in individuals at increased risk for osteoporosis.

The BMD related information above was obtained from the following
References:

1.
Author: Bjarnason, N. H.; Christiansen, C.
Year: 2000
Title: The influence of thinness and smoking on bone loss and response to hormone replacement therapy in early postmenopausal women
Journal: J Clin Endocrinol Metab,Volume: 85, Issue: 2, Pages: 590-6

2.
Author: Brot, C.; Jorgensen, N. R.; Sorensen, O. H.
Year: 1999
Title: The influence of smoking on vitamin D status and calcium metabolism
Journal: Eur J Clin Nutr, Volume: 53, Issue: 12, Pages: 920-6

3.
Author: Cohen-Solal, M. E.; Baudoin, C.; Omouri, M.; Kuntz, D.; DeVernejoul, M. C.
Year: 1998
Title: Bone mass in middle-aged osteoporotic men and their relatives: familial effect
Journal: J Bone Miner Res, Volume: 13, Issue: 12, Pages: 1909-14

4.
Author: De Lorenzo, A.; Lello, S.; Andreoli, A.; Guardianelli, F.; Romanini,C.
Year: 1998
Title: Body composition and androgen pattern in the early period of postmenopause
Journal: Gynecol Endocrinol, Volume: 12, Issue: 3, Pages: 171-7

5.
Author: Hermann, A. P.; Brot, C.; Gram, J.; Kolthoff, N.; Mosekilde, L.
Year: 2000
Title: Premenopausal smoking and bone density in 2015 perimenopausal women
[In Process Citation]
Journal: J Bone Miner Res, Volume: 15, Issue: 4, Pages: 780-7

6.
Author: Hoidrup, S.; Gronbaek, M.; Pedersen, A. T.; Lauritzen, J. B.; Gottschau, A.; Schroll, M.
Year: 1999
Title: Hormone replacement therapy and hip fracture risk: effect modification by tobacco smoking, alcohol intake, physical activity, and body mass index
Journal: Am J Epidemiol, Volume: 150, Issue: 10, Pages: 1085-93

7.
Author: Melhus, H.; Michaelsson, K.; Holmberg, L.; Wolk, A.; Ljunghall, S.
Year: 1999
Title: Smoking, antioxidant vitamins, and the risk of hip fracture
Journal: J Bone Miner Res, Volume: 14, Issue: 1, Pages: 129-35

8.
Author: Schulte, C.; Dignass, A. U.; Mann, K.; Goebell, H.
Year: 1998
Title: Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease
Journal: Inflamm Bowel Dis, Volume: 4, Issue: 4, Pages: 268-75

9.
Author: Sambrook PN, and Eisman JA
Year: 2000
Title: Osteoporosis prevention and treatment
Journal: Medical J Australia, Volume: 172, Issue: 5, Pages: 226-9
 

Indolplex (DIM) News

By Michael Zeligs, MD

[Ed. Note: Dr. Zeligs of BioResponse, developer of Indolplex, containing bioavailable diindolymethane (DIM), is seeking individuals to complete a confidential questionnaire. Any individual who has purchased and used Indolplex for four consecutive months will be given a free bottle of Indolplex 150 mg capsules or Chocolate Sprinkles upon completion of the questionnaire. For more information, contact BioResponse at zeligsmd@sni.net or by phone at 303-447-3841 or fax at 303-938-8003.]

Some individuals have been using Indolplex for approximately seven months with reports of good control (according to BioResponse) of RRP. The following are updates for the optimal use of Indolplex.
 

1. Take Indolplex with food. This improves absorption and should provide for the best response. As a rule, all gel cap type vitamins and supplements should be taken with food. Combining Indolplex and all such supplements at the same meal improves absorption of all these ingredients. Fat contents of the food and supplements combine to increase absorption of all fat soluble components like DIM, Vitamin E, Vitamin A, Vitamin D and essential fatty acids.

2. Drink adequate water with Indolplex. Drinking about 8 glasses of water a day is recommended for general good health. Restricting fluids while taking Indolplex is associated with a darkening of the urine to a light brownish color. This is not a problem and is analogous to the change of urine color seen after eating asparagus. Maintaining healthy water intake will minimize this transient color change.

The BioResponse staff thanks all those individuals who have added Indolplex to their routine of dietary supplementation. It was our hope that Indolplex would offer an alternative to those with RRP who have failed to respond to I3C. This has proved true in several cases. One example is a special little girl named Ashlyn who showed no response to I3C. After enduring a tracheostomy and frequent surgeries, improvement was noted following use of Indolplex. We look forward to your comments to help continue our efforts to improve dietary indole supplementation in RRP.
 

Frequently Asked Questions:

Q: I take 400mg I3C daily...should the 400mg be taken all at once or spread out during the course of the day?

A: "Regarding the question of relative benefits of a single large or smaller divied doses of DIM/I3C and clininical response in RRP, I am not aware of a study that does this comparison. The Rosen study used a twice a day dosing regimen. Theoretically, if the objective in supplementing is to convert the metabolism of vocal cord epithelium then it is necessary to either deliver 2OH estrone to this tissue via the blood or to have DIM arrive at the tissue in sufficient concentration to shift the estrogen metabolism of the vocal cord tissue itself. The latter is probably most important. Both of these objectives would seem to be served best by a single high dose of indole. This would yield higher blood levels of 20H estrone from the liver and higher blood levels of DIM. Keep in mind that a larger single dose may also provoke more of short term side effects like transient dizziness." (Michael Zeligs, MD, BioResponse)

A: There is no need to spread a daily dosing of I3C throughout the day. There really shouldn't be any difference whether the dosage is taken all at once or twice a day.(Dr. Leon Bradlow, Strang Cornell Cancer Prevention Center)
 

Q: In lieu of taking the Indole-3-Carbinol/I3C capsules, how much cabbage, broccoli or cauliflower can be eaten daily or how much juice from these vegatable should one drink?

A: My answer to your question regarding cruciferous vegetables as sources for I3C is based on some articles which are included in past RRP Newslletter issues. The bottom line is that one can get an estimate of an average amount of I3C per unit mass of cruciferous vegetable, however, the variability is quite large and unpredictable. So if an RRP patient chooses to use cruciferous vegetables as their sole source of I3C, it is clearly on a user beware basis. Given these caveats suggested amounts are as follows: In order for adult subjects to obtain a clinically effective dose of indole-3-carbinol, they need to consume about a pound of cabbage a day (yields 8 ounces of juices). Children need about half a pound (yields about 4 ounces of juice). These amounts are for green cabbage, which appears to be the best source of indole-3-carbinol (It is claimed that green Savoy cabbage may contain more indole-3-carbinol than other cabbages - Bradlow, 1993, private communication)

For more information see: background section above; 94 Spring RRP Newsletter - (http://www.rrpf.org/rrpf/news/RRP_Newsletter_Spring94.html) "Indole-3-Carbinol / Crucif. Vegetable Study" and
93 Fall RRP Newsletter - (http://www.rrpf.org/rrpf/news/RRP_Newsletter_Fall93.html) "Treatment Protocols and Cabbage Juice Recipes"(Bill Stern, RRP Foundation)

Q: I am taking other medications will they have an adverse interaction with I3C/DIM and will I3C/DIM have an adverse effect on these other medications?

A: Any medication which decreases stomach acidity would certainly decrease the conversion of I3C to the active DIM and ICZ. Stomach acid is required for this conversion and prevacid decreases this activity. If a patient must take these compounds he/she should switch to DIM which does not require stomach acid to be active. (Dr. Leon Bradlow, Strang Cornell Cancer Prevention Center)

A: I3C induces certain p450 enzymes-cyp1A1, cyp1A2 (the reason it modulates estrogen metabolism and detoxifies many carcinogens). However, it can therefore modify and inactivate certain medications. Pharmaceutical companies do test for this and the information should be available. For example, if your medications indicates you should not drink grapefruit juice, this is one of those. A person should check with their doctor, their pharmacist and possibly the PDR and inserts in their medication. Most medications are not affected but there are medications that could be inactivated. (Dr. Karen Auborn, Dept. of Otolaryngology, Long Island Jewish Medical Center)

Indolplex^TM from DIM: Frequently asked questions and research update (June 1998)
By Michael Zeligs, MD

1. What is DIM
DIM stands for Diindolylmethane: a dietary indole found in
cruciferous vegetables and formed spontaneously from the combination (or
"condensation") of Indole-3-carbinol (I3C), a closely related indole, also
present in these vegetables. DIM occurs naturally within the cruciferous
vegetable plant after crushing or chewing from the action of plant enzymes
from precursors called glucosinolates. DIM is also formed directly from
I3C, without enzymes, in an acidic environment such as in our stomachs,
when I3C powder is taken as a food supplement. Based on this, DIM is
described as a direct and active metabolite of I3C. This is true since in
various tests of estrogen metabolism it is DIM, and not I3C, which promotes
a shift in the balance of estrogen metabolites.

2. What is the DIM containing product Indolplex^TM ?.

Indolplex^TM is a fine-powder formulation which contains pure DIM
for use as a dietary supplement. As described above the DIM in Indolplex^TM
is a component of the human diet and is found in all cruciferous
vegetables. Indolplex^TM acts to promote and support a favorable metabolism
of estrogen and related hormones. The main function of Indolplex^TM is to
overcome the extreme insolubility of DIM and make it absorbable from the
human intestine. Indolplex^TM provides consistent levels and absorption of
highly insoluble DIM. The formulation and composition of Indolplex^TM
constitute a patent-pending, nutrient delivery system developed by
BioResponse.

In its production process, BioResponse includes testing of each
batch of Indolplex^TM by an independent analytic laboratory. This quality
control assures the consistent level and purity of DIM in the product. In
addition, BioResponse has established the shelf life stability of
Indolplex^TM through testing levels of DIM during exposure to elevated
temperature and humidity. This independent laboratory testing has
documented at least a 1 year shelf-life during which levels of DIM do not
significantly change.

Indolplex^TM can therefore be included in dietary supplements for human
consumption to augment the dietary intake of cruciferous vegetable related
ingredients. A daily intake of 3-5 servings of vegetables, especially
cruciferous vegetables, is recommended by the USDA "Dietary Guidelines for
Americans". Since Indolplex^TM contains the predominant dietary indole
which results from the digestion of cruciferous vegetables, its use as a
supplement relates to normal dietary intake from crucifers. Unlike I3C,
Indolplex^TM provides a source of dietary indole which is shelf-stable
following mixture and encapsulation or tableting with other dietary
supplement ingredients. Indolplex^TM can augment or replace deficient daily
intake of dietary indoles and contribute to health promotion.

3. How is Indolplex^TM unique ?

Indolplex^TM is differentiated from all other dietary supplements and I3C
by the following key points:

Indolplex^TM with DIM is the only pure dietary indole which is new to the
marketplace and introduced in conjunction with a patent-pending nutrient
delivery system. Indoles have been proven in a variety of research to be of
benefit in estrogen related disorders.

Indolplex^TM provides protection from unwanted estrogen metabolites.
Indolplex^TM promotes the production of 2 hydroxyestrone, a key metabolite
in men and women and is an estrogen blocker. Indolplex^TM provides proven
bioavailability of highly insoluble active DIM through action of its
patent-pending dosage form and delivery system.

4. How is Inolplex^TM used as a dietary supplement?

The dose range for Indolplex^TM on a weight basis is from 3-5 mg/kg/day .
(One kg is equal to 2.2 lbs.) This is the range in which consistent shifts
in estrogen metabolism have been demonstrated. Use by adults at a doses of
up to 5 mg/kg/day has been side effect free. To facilitate flexible and
appropriate dosage in supplement consumers BioResponse is introducing
Indolplex^TMin both 75 and 150 mg strength capsules. This will allow
individuals of different weights to combine capsules of either strength to
achieve an Indolplex^TM dose in the 3-5 mg/kg/day range.

It is recommended that individuals with RRP choose a daily dose which is
close to 4 mg/kg/day. To be close to 4 mg/kg/day a typical man weighing
70-85 kg would take from 300 to 375 mg per day. A typical woman weighing
60-70 kg would take from 225 to 300 mg per day.
.

Indolplex^TM is also available in a "Chocolate Sprinkles" form in which the
Indolplex^TM is contained in chocolate granules for a pleasant tasting
alternative to be given by spoon or on food. The dose of "Sprinkles" can
be individualized with each quarter teaspoon being appropriate for each 16
kg of body weight (approximately 35 pounds). Using a measuring spoon ,this
provides 4-5 mg/per kg of Indolplex. The Sprinkles weigh more than the
milligrams of Indolplex in capsules because of the addition of the
chocolate flavoring and fructose. This formulation is especially
appropriate for young children and individuals who do not wish to take
capsules. Chocolate Sprinkles are great on cereal, applesauce, ice cream
to name a few tasty ideas.

Regarding potential side effects: No reported side effects have occured
using Indolplex^TMin the range of 3-5 mg/kg/day in either adults or
children. Based on the experience of individuals taking I3C at excessive
dosage the most commonly reported side effect has been dizziness, head
ache, or unsteady gait. We reccomend that IndolplexTM consumers look for
this side effect and reduce dosage if it occurs.

5. Availability of Indolplex^TM

The 150 mg strength Indolplex^TM capsules will be available by mid-August
and contain 60 capsules. The 75 mg bottles contain 90 capsules per bottle
and are available now. Both bottles are available for $33.00 per bottle
which includes priority mail shipping.

Chocolate Sprinkles are now available for $44.00 per bottle which includes
shipping. and represents at least a month's supply. As an introductory
offer, for every bottle of Chocolate Sprinkles purchased, a second bottle
will be included for FREE. This 2 for one special is a great way to try the
Sprinkles.

6. Testing of the Indolplex^TM formulation Indolplex^TM products.

Indolplex^TM has been extensively tested in human subjects to establish a
consistent shift in urinary estrogen metabolites at the 3 mg/kg/day dose.
There are a number of individuals with RRP currently using Indolplex^TM
products with good results. Most importantly there are some individuals
with RRP who have failed to have good responses to I3C who subsequently did
respond to high doses of pure DIM.

Whether individuals with RRP will have a more dramatic or consistent
response to Indolplex^TM over I3C is not known at this time. BioResponse
intends to test Indolplex^TM in individuals with RRP in controlled trials as
soon as such research is designed. In the meantime, use of Indolplex^TM by
RRP individuals will provide useful information. The important point to
remember is that the active indole, DIM, is the most potent dietary
substance for achieving the desired shift in estrogen metabolites.

7. Present and Future Research.

New findings from the research community indicate that there are
individuals that possess more or less an inherited or genetically
determined ability to respond to dietary indoles with a shift in estrogen
metabolism. Whether individuals with RRP are special in this regard is not
yet known.

The bigger question is whether RRP individuals are somehow more susceptible
to as yet unidentified environmental influences that shift metabolism of
estrogen or other hormones to make them better "hosts" for the human
papilloma virus. This question relates another distinct estrogen
metabolite identified as 4-hydroxyestrone, present in low amounts in
certain tissues. This metabolite arises from its own class of cytochrome
enzymes and is associated with abnormal growth in other estrogen sensitive
disorders. In preliminary research, both the responsible enzymes and
levels of 4-hydroxyestrone are reduced by DIM and I3C in estrogen sensitive cells in culture.

Future research will determine whether individuals with RRP produce
elevated levels of 4-hydroxyestrones in papilloma tissue. If increased
production of 4-hydroxyestrone is modified due to exposure to environmental
substances, new approaches to reducing susceptibility and treating RRP may
be possible.
 
 
 

References:

Auborn K; Abramson  A; Bradlow HL; Sepkovic D; Mullooly V

Anticancer Research 1998; 18: 4569-4574

Estrogen Metabolism and Laryngeal Papillomatosis: A Pilot Study on Dietary Prevention

Department of Otolaryngology, Long Island Jewish Medical Center,
Albert Einstein College of Medicine, New Hyde Park, NY
Strang-Cornell Cancer Research Laboratory, New York, New York 10021, USA.

Evidence exists that estrogen metabolism has a role in the pathogenesis of recurrent 
respiratory papillomatosis (RRP). This disease has a papillomavirus etiology and is 
characterized by recurrent benign tumors with a significant propensity to become
malignant. We have measured the systemic transformation of estrogen using an 
enzyme-linked-immunoassay to measure estrogen metabolites in the urine of patients
with RRP and compared these ratios to the severity of RRP, a measure of the average
growth rate of papillomas.  Our results show an inverse relationship between the ratio of
C-2 to C-16a hydroxylated estrogens and the severity of RRP.  In a pilot study, patients 
consumed cruciferous vegetables to induce C-2 hydroxylation. In this group of patients,
an increase in the ratio correlated with an improvement in RRP.  The ratio did not change 
in a subset of these patients, and their RRP did not improve.  Regardless, the ratio correlated 
with severity of their RRP.

Bradlow HL; Sepkovic DW; Telang NT; Osborne MP

Ann N Y Acad Sci 1995 Sep 30;768:180-200

Indole-3-carbinol. A novel approach to breast cancer prevention.

Strang-Cornell Cancer Research Laboratory, New York, New York 10021, USA.

The results show that all of the carcinogens, oncogenes, and
tumor-associated viruses that we have studied profoundly affect
the extent of 2- and 16 alpha-hydroxylation in a prorisk
direction. All of the dietary and biological responses associated
with increased cancer risk decrease 2-hydroxylation and increase
16 alpha-hydroxylation. Remarkably, although PAHs are reported to
induce P450-1A1, we have found them to decrease 2-hydroxylation.
Finally, using indole-3-carbinol to induce 2-hydroxylation
results in the chemoprevention of mammary tumors in rodents and
recurrences of laryngeal papillomas in humans. Also correlating
with these studies in HPV is the decrease in the C-2/C-16 alpha
metabolite ratio observed in women with CIN relative to control
subjects. The greatest decrease was observed in women with the
most severe form, CIN3 (Figure 23). These findings are under
further investigation.

Bradlow HL; Telang NT; Sepkovic DW; Osborne MP

J Endocrinol 1996 Sep;150 Suppl:S259-65

2-hydroxyestrone: the 'good' estrogen.

Strang Cancer Research Laboratory, New York, New York 10021, USA.

The issue of the role of 2-hydroxyestrone (2-OHE1) in breast
cancer has been the subject of considerable controversy as to
whether it is carcinogenic or anticarcinogenic. The expanding
data base outlined below is most consistent with the conclusion
that 2-OHE1 is anticarcinogenic. In every experimental model in
which 2-hydroxylation was increased, protection against tumors
was achieved. Correspondingly, when 2-hydroxylation was
decreased, an increase in cancer risk was observed. Even more
dramatically, in the case of laryngeal papillomas induction of
2-hydroxylation with indole-3-carbinol (I3C) has resulted in
inhibition of tumor growth during the time that the patients
continue to take 13C or vegetables rich in this compound.

Colquhoun-Flannery W; Carruth JA

J Laryngol Otol 1995 Sep;109(9):873-5

Diet-modified sex hormone metabolism: is this the way forward in
recurrent respiratory papillomatosis and squamous carcinoma
prophylaxis?

Department of Otolaryngology, Southampton General Hospital, UK.

We report two cases of recurrent laryngeal papillomatosis in
women who subsequently developed squamous cell carcinoma as they
approached the climacteric. The role of human papilloma virus
(HPV) and oestrogen metabolism is outlined. The use of indoles
from cruciferous vegetables is also discussed.

Lim SK, Won YJ, Lee JH, Kwon SH, Lee EJ, Kim KR, Lee HC, Huh KB, Chung BC

J Clin Endocrinol Metab 1997 Apr; 82(4):1001-1006

Altered hydroxylation of estrogen in patients with postmenopausal osteopenia.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

To study the possible contributions of the differences in estrogen 
metabolism to bone mass in postmenopausal osteopenia, spinal and femoral 
bone mineral densities (BMD) were measured, and 18 urinary metabolites 
of estrogen were analyzed by a gas chromatography-mass spectrometry 
assay system in 59 postmenopausal women (5-10 yr after menopause). The 
BMD of the spine and femoral neck showed positive correlations with body 
weight, height, and body mass index as we expected. Compared to 
nonosteopenic subjects, there were no significant differences in serum 
estrone (E1) and estradiol (E2) levels in patients with osteopenia. 
However, the urinary 16 alpha-hydroxyestrone [16 alpha-(OH)E1] level was 
significantly lower in patients with spinal osteopenia (P < 0.001). 
Among the 18 urinary metabolites of estrogen, the 16 alpha-(OH)E1 and 16 
alpha-(OH)E1/2-hydroxyestrone [2-(OH)E1) ratio showed positive 
correlations with spinal BMD (P < 0.05), whereas 2-(OH)E2 showed a 
negative correlation with femoral neck BMD (P < 0.05). The urinary 16 
alpha-(OH)E1 level also revealed a positive correlation with the 
age-matched z score of BMD in the spine (P < 0.05). In multiple stepwise 
regression analysis, weight, 16 alpha-(OH)E1, interaction between 16 
alpha-(OH)E1 and 2-(OH)E2, 2-(OH)E2, and years after menopause were 
statistically significant for spinal BMD (r2 = 0.4968). For femoral neck 
BMD and weight, 16 alpha-(OH)E1 and 2-(OH)E2 were the independent 
determinants (r2 = 0.3369). In conclusion, the activity of estrogen 16 
alpha-hydroxylase was decreased and/or the activity of estrogen 
2-hydroxylase was enhanced in post-menopausal osteopenia. We speculated 
that these derangements may serve as contributing factors for the 
acceleration of bone loss in post-menopausal osteoporosis.

Michnovicz JJ Bradlow HL

Nutr Cancer 1991;16(1):59-66

Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol.

Institute for Hormone Research New York, NY 10016.

Research studies have demonstrated a strong association between
  estrogen metabolism and the incidence of breast cancer, and we have
  therefore sought pharmacological means of favorably altering both
  metabolism and subsequent risk. Indole-3-carbinol (I3C), obtained
  from cruciferous vegetables (e.g., cabbage, broccoli, etc.), is a
  known inducer of oxidative P-450 metabolism in animals. We
  investigated the effects in humans of short-term oral exposure to
  this compound (6-7 mg/kg/day over 7 days). We used an in vivo
  radiometric test, which provided a highly specific and reproducible
  measure of estradiol 2-hydroxylation before and after exposure to
  I3C. In a group of 12 healthy volunteers, the average extent of
  reaction increased by approximately 50% during this short exposure (p
  less than 0.01), affecting men and women equally. We also measured
  the urinary excretion of two key estrogen metabolites, 2-
  hydroxyestrone (2OHE1) and estriol (E3). We found that the excretion
  of 2OHE1 relative to that of E3 was significantly increased by I3C,
  further confirming the ongoing induction of 2-hydroxylation. These
  results indicate that I3C predictably alters endogenous estrogen
  metabolism toward increased catechol estrogen production and may
  thereby provide a novel "dietary" means for reducing cancer risk.

Michnovicz JJ, Adlercreutz H, Bradlow HL

J Natl Cancer Inst 1997 May 21;89(10):718-723

Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans.

Rockefeller University Hospital and The Institute for Hormone Research, New York, NY 10016, USA.

BACKGROUND: The oxidative metabolism of estrogens in humans is mediated primarily by cytochrome P450, many isoenzymes of which are inducible by dietary and pharmacologic agents. One major pathway, 2-hydroxylation, is induced by dietary indole-3-carbinol (I3C), which is present in cruciferous vegetables (e.g., cabbage and broccoli). PURPOSE: Because the pool of available estrogen substrates for all pathways is limited, we hypothesized that increased 2-hydroxylation of estrogens would lead to decreased activity in competing metabolic pathways. METHODS: Urine samples were collected from subjects before and after oral ingestion of I3C (6-7 mg/kg per day). In the first study, seven men received I3C for 1 week; in the second study, 10 women received I3C for 2 months. A profile of 13 estrogens was measured in each sample by gas chromatography-mass spectrometry. RESULTS: In both men and women, I3C significantly increased the urinary excretion of C-2 estrogens. The urinary concentrations of nearly all other estrogen metabolites, including levels of estradiol, estrone, estriol, and 16alpha-hydroxyestrone, were lower after I3C treatment. CONCLUSIONS: These findings support the hypothesis that I3C-induced estrogen 2-hydroxylation results in decreased concentrations of several metabolites known to activate the estrogen receptor. This effect may lower estrogenic stimulation in women. IMPLICATIONS: I3C may have chemopreventive activity against breast cancer in humans, although the long-term effects of higher catechol estrogen levels in women require further investigation.
 

Newfield L; Goldsmith A; Bradlow HL; Auborn K

Anticancer Res 1993 Mar-Apr;13(2):337-41

Estrogen metabolism and human papillomavirus-induced tumors of the larynx: chemo-prophylaxis with indole-3-carbinol.

Department of Otolaryngology, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, NY
 

A relationship was established between estradiol 16
alpha-hydroxylation, papillomavirus and its malignant sequelae.
In this study, we determined that 16 alpha-hydroxylation was
substantial in normal larynx and further increased in laryngeal
papillomas. Estradiol or 16 alpha-hydroxyestrone stimulated
proliferation in both kinds of cells while 2-hydroxyestrone was
antiproliferative. Indole-3-carbinol, which induces
2-hydroxylation, abrogated the proliferative effects of
estradiol. In immunocompromised mice, papilloma cysts formed in
HPV-11 infected laryngeal tissue implanted under the renal
capsules in 100% of control mice but only in 25% of mice fed
indole-3-carbinol.

Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow, HL

Otolaryngol Head Neck Surg 1998 Jun;118(6):810-815

Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis.

Department of Otolaryngology--Head and Neck Surgery, University of Pittsburgh Medical Center, Pennsylvania, USA.
 

OBJECTIVE:

We report the preliminary results of a phase I trial using indole-3-carbinol for 
the treatment of recurrent respiratory papillomatosis. Indole-3-carbinol is 
a chemical that is found in high concentrations in cruciferous 
vegetables and has been shown to alter the growth pattern of recurrent 
respiratory papillomatosis cell cultures and to be effective in an in 
vivo animal model of recurrent respiratory papillomatosis. METHODS: 
Eighteen patients were treated with oral indole-3-carbinol and had a 
minimum follow-up of 8 months and a mean follow-up of 14.6 months. All 
patients received indole-3-carbinol, and outcome measures included a 
change in papilloma growth rate and the need for surgery during 
treatment compared with before treatment. All patients had serial 
examinations with videoendoscopy to document papilloma location and 
growth rate. RESULTS: Thirty-three percent (6 of 18) of the study 
patients had a cessation of their papilloma growth and have not required 
surgery since the start of the study. Six patients have had reduced 
papilloma growth rate, and 6 (33%) patients have shown no clinical 
response to indole-3-carbinol. Indole-3-carbinol affects the ratio of 
hydroxylation of estradiol; changes in the ratios of urinary 
2-hydroxylation and 16-hydroxylation of estradiol caused by 
indole-3-carbinol correlated well with clinical response. No major 
complications or changes in the children's growth curve were noted. 
CONCLUSIONS: The preliminary results of treating recurrent respiratory 
papillomatosis with indole-3-carbinol holds promise. Longer follow-up of 
this patient group and a blinded, controlled trial are required. We 
conclude that indole-3-carbinol appears to be safe and well tolerated 
and may be an efficacious treatment for recurrent respiratory 
papillomatosis.

Suto A , Bradlow HL, Wong GY, Osborne MP, Telang NT

Steroids 1992 Jun;57(6):262-8

Persistent estrogen responsiveness of ras oncogene-transformed mouse mammary epithelial cells.

Department of Surgery Memorial Sloan-Kettering Cancer Center New York,NY.

 Ovarian steroids are associated with the proliferation of normal as
  well as tumorigenically transformed mammary epithelial cells. The
  experiments performed in this study were designed to establish that
  (1) tumorigenic transformation induced by the ras oncogene is
  associated with alterations in estradiol biotransformation, (2)
  altered endocrine responsiveness persists in the fully transformed
  tumor cell phenotype and (3) specific perturbations induced by the
  ras oncogene can be experimentally downregulated. The ras
  transfectant pH06T and the tumor-derived T1/Pr1 cells exhibited 3-
  and 43-fold increases, respectively, in C-16 alpha hydroxylation of
  estradiol relative to the parental mouse mammary epithelial cells (P
  less than 0.0001). At the cellular level, this alteration
  corresponded with approximately 90-fold increase in the anchorage-
  independent growth of T1/Pr1 cells (P less than 0.0001). Estrogen
  responsiveness of T1/Pr1 cells was demonstrated by their suppression
  of growth in phenol red-free and/or tamoxifen-supplemented medium and
  by the reversal of antiproliferative effect of tamoxifen by phenol
  red and estradiol. Indole-3-carbinol, a naturally occurring tumor
  suppressive agent, was able to upregulate C-2 hydroxylation at the
  expense of C-16 alpha hydroxylation of estradiol. Treatment of T1/Pr1
  cells with indole-3-carbinol resulted in a substantial decrease in
  anchorage-independent growth.

Wilker C, Johnson L, Safe S

Toxicol Appl Pharmacol 1996 Nov;141(1):68-75

Effects of developmental exposure to indole-3-carbinol or 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproductive potential of male rat offspring.

Department of Veterinary Anatomy and Public Health, Texas A&M University,
College Station 77843-4466, USA.

Treatment of pregnant female Sprague-Dawley rats on Gestational Day 15 with a
single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.5, 1.0, or
2.0 micrograms/kg) or indole-3-carbinol (I3C, 1.0 or 100 mg/kg), an aryl
hydrocarbon (Ah) receptor agonist which is found in cruciferous vegetables,
resulted in reproductive abnormalities in the male offspring (three to five
litters in each treatment group). Anogenital distance and crown to rump length
were altered by both compounds; however, the timing of the effects (Day 1 or 5)
was variable and the responses were not necessarily dose-dependent. In
62-day-old offspring, seminal vesicle (24 to 26%), prostate (32 to 44%),
testicular parenchymal (14%), and epididymal weight (19%) were decreased by one
or more doses of TCDD. In contrast, I3C at one or more doses decreased daily
sperm production/g testicular parenchyma (13 to 20%) and daily sperm
production/testis (22%). Total number of sperum in the epididymis was
significantly decreased (30 to 33%) in rats perinatally exposed to TCDD and
this was due to a decreased (49 to 51%) number of sperm in the tail of the
epididymis. Perinatal exposure to I3C did not affect any of these parameters.
TCDD did not affect epididymal transit time of sperm through the complete
epididymis at any of the doses (0.5 to 2.0 micrograms/kg). However, at the two
highest doses (1.0 and 2.0 micrograms/kg), TCDD increased epididymal transit
rate of sperm through the tail of the epididymis by 33 and 37%, respectively.
In contrast, primarily due to decreased transit rate (39%) of sperm through the
head plus body of the epididymis. I3C (1 mg/kg) significantly increased total
epididymal transit time by 31%. In conclusion, perinatal exposure of pregnant
rats to I3C, an Ah receptor agonist similar to TCDD, causes reproductive
abnormalities in male rat offspring; however, I3C and TCDD elicited both common
and different responses.

last updated on 07-28-2002