Ipriflavone Overview

Synonyms: 7-isopropoxyisoflavone, 7-isopropoxy-isoflavone

Possible uses, recommended dosage based on available research, and scientific support for use (scale of 0-10):

Osteoporosis treatment and prevention, 600 mg - 9
Cholesterol reduction, 600 mg - 7
Hyperparathyroidism, 600-1200 mg - 7
Otosclerosis, 600-800 mg - 7
Paget's Disease, 600-1200 mg - 7
Renal osteodystrophy, 400-600 mg - 7
Breast cancer prevention - 5
Athletic performance - 4
Muscle gain - 3
Side effects

Most side effects rarely occur at an incidence higher than placebo.
May decrease lymphocyte count. Regular lymphocyte measurements should be taken while taking this supplement.
May inhibit the metabolization of some drugs, such as theophylline.

5-methyl-7-methoxyisoflavone overview

Synonyms: 5-methyl-7-methoxy-isoflavone, sometimes referred to as "methoxy"

Possible uses, recommended dosage based on available research, and scientific support for use (scale of 0-10):

Cholesterol reduction - 4
Osteoporosis - 4
Muscle gain - 3
Side effects

This substance has not been studied enough to know the risks and side effect profile.

Background

Ipriflavone (7-isopropoxyisoflavone) is a synthetic derivative of the phytoestrogen daidzen [1], and 5-methyl-7-methoxyisoflavone ("methoxy") is a derivative of ipriflavone. The existing research indicates that their pharmacological properties are similar, although methoxy is more potent.

The estrogenic effects of some isoflavones were first discovered in the 30's, when estrogenic effects were observed in animals feeding on plants rich in these substances. However, these compounds often had beneficial properties, or were estrogenic in some tissues but not others. This eventually lead to research of synthetic derivatives of these compounds in an attempt to find compounds that had beneficial effects but without estrogenic properties. One of the compounds that came out on top was ipriflavone, which caused weight gain in experimental animals and had a calcium-retaining effect in in vitro studies, but was devoid of estrogenic activity. Research on ipriflavone since that point has focused on the potential use to prevent bone loss and treat bone diseases [2].

Derivatives of ipriflavone have also been researched. A patent from 1979 describes a set of derivatives that were more potent, including 5-methyl-7-methoxyisoflavone [3]. There is very little information on this compound, so this article will primarily discuss the effects of ipriflavone.


Ipriflavone and bone disease

Ipriflavone has been researched in humans for the treatment of osteoporosis and other bone diseases for over 20 years [2]. In vitro, ipriflavone inhibits bone resporption and stimulates osteoblast activity [4]. In animals, ipriflavone is protective against osteoporosis induced by glucocorticoids, immobolization, experimental diabetes, and hormone deficiency [5]. In humans, over 60 studies have been conducted on the effect ipriflavone has on bone mineral density (primarily in post-menopausal women), many of them double-blind and placebo-controlled [6]. Most of the research has taken place in Italy, Hungary, and Japan [7]. Evidence has been generated supporting a benefit for the treatment of osteoporosis of various origins, and several reviews have concluded that there is significant evidence for a beneficial effect, although there is less evidence for a benefit during the later stages of osteoporosis [1, 6-7]. This is primarily because, although most of the research has been positive, a large-scale, long-term study failed to find an effect, and the authors concluded that this may have been because the study subjects had too low of a bone mineral density to begin with for the drug to be of benefit [4]. Since most of the other studies were shorter in duration, it could also be that the benefit of ipriflavone is only temporary. It has also been pointed out that the results from ipriflavone studies vary depending on the region where the study took place [8].

The mechanisms of action of ipriflavone are not yet well-established, but many possibilities have been identified. Ipriflavone is rapidly metabolized, and most of its effects are assumed to be due to the metabolites. It metabolizes into daidzein, a phytoestrogen, at about a 10% rate, and some of the effects are presumed to be due to this metabolite [8]. Ipriflavone does not interact directly with estrogen receptors, but unique binding sites for ipriflavone have been identified [6], and it is presumable that some of its metabolites may bind to this site. In vitro, ipriflavone increases intestinal calcium transport, and this may contribute to its activity [9]. It is likely that the effects of ipriflavone are due to a combination of factors.


Muscle gain

The patent applications for ipriflavone and 5-methyl-7-methoxyisoflavone make them look like promising compounds for increasing muscle mass. The ipriflavone patent describes a number of tests. It indicates that ipriflavone at 30 mg/kg was anabolic to muscle tissue without androgenic effects using the rat levator ani assay, although the degree of the anabolic effect was not given. It also indicates a significant reduction in nitrogen excretion, increased methionine incorporation into muscle tissue, increased swim time in the forced swim test, resistance to the catabolic effect of cortisol (with a greater effect than anabolic steroids), and increased weight gain in animals after ipriflavone administration. Ipriflavone caused weight gain in calves, cattle, hogs, poultry, rabbits, and guinea pigs, all without increased food intake. Finally, it describes a study using 10 treated and 10 control patients where ipriflavone caused 2-3 kilograms of weight gain in "thinned (asthenic), reconvalescent, dystrophic patients suffering from pathological thinness" [10].

The patent for 5-methyl-7-methoxyisoflavone examines its effects and the effects of some other derivatives of ipriflavone and compares them to those of ipriflavone. Of these compounds, methoxy was the most potent. All of the compounds increased the retention of calcium, phosophorus, potassium, and nitrogen. They also report that these compounds lacked androgenic, estrogenic, CNS, and hepatotoxic effects, increased resistance to hypoxia, and reduced cholesterol. Finally, when given to chickens, these substances caused significant weight gain over control and ipriflavone [3].

There are a number of reasons to treat this information with caution. First, the information provided in patent applications is often unreliable and bias. Second, a mechanism of action for how these anabolic effects are achieved is not described. Third, although it would seem that an anabolic effect on muscle tissue is demonstrated, the degree of this effect is not given. It could be that there is only a small effect, and the majority of the weight gain caused by these isoflavones is from bone or another tissue. Also, ipriflavone and its metabolites appear to accumulate primarily in the gastrointestinal tract, liver, kidneys, bones, and adrenal glands [6], although this does not rule out the possibility of an indirect effect.

There are few reports in the scientific literature on ipriflavone that are not primarily concerned with its potential use in the treatment of osteoporosis. However, one study found that ipriflavone administration to rabbits, dogs, and rats had an anti-hypoxic effect, decreased lactic acid concentrations in myocardial tissue, and improved mitochondrial energetics, especially under stressful conditions [6, 11]. This provides further support for the possibility that these compounds could increase athletic performance. At this point, there is not enough evidence to draw conclusions either way.


Dosage and side effects

Ipriflavone is generally well tolerated and free of side effects. As of 1997, 2,769 patients had been treated with ipriflavone in clinical studies with an incidence of adverse reactions of 14.5% vs. 16.1% with placebo. The primary reported side effect was gastrointestinal discomfort, but the fact that reports of side effects were greater in the placebo group indicates that this is probably not due to the ipriflavone. The fact that calcium was usually included in both placebo and treatment groups is a more probable reason for the effect [6]. Animal studies also indicate that ipriflavone is safe with long-term administration [12]. However, there are two potentially serious concerns. First, ipriflavone may inhibit some cytochrome P450 enzymes, and consequently may reduce the metabolization of some drugs, such as theophylline [13]. Secondly, one study found that in a small portion of treated subjects, lymphocyte (a type of immune cell) concentrations decreased, and took a while to recover after discontinuation of therapy. There were no differences in terms of infections and adverse events in this group, but this is still a reason for caution [4].

Since there is little research on 5-methyl-7-methoxyisoflavone, the safety and side effect profile, other than what was previously mentioned from the patent application, is largely unknown.

For ipriflavone, the dose used in most clinical trials has been 600 mg daily (200 mg three times daily), and this dosage should be lowered in those with kidney disorders. It is also normally taken with a calcium supplement. Many users of methoxy and ipriflavone for body composition/aesthetic purposes feel they get the best results with 1-2 grams daily.