TREATING ANDROPAUSE: Prohormones and Hormone Metabolic Modifiers
Bruce Biundo, BS Pharm, RPh
Professional Compounding Centers of America, Inc
Andropause, which is also referred to as male menopause, has been the focus of increasing attention during the past few years in the medical and popular press. Researchers and writers have more closely examined the role of sex hormones such as testosterone and estradiol in maintaining the health of middle-aged or elderly men. In this article, we will discuss some of the metabolic changes that occur during andropause and treatment options that address those changes. According to the literature, andropause is a process involving a gradual alteration in sex hormone levels over a period of years that results in physiologic and psychologic changes including depression, impotence, decreased libido, muscular weakness, lethargy, and loss of lean body mass. In many men, the major hormonal change during andropause is either a decrease in the level of testosterone or an increase in the level of estrogen. Others experience both a decline in the level of testosterone and an increase in the level of estrogen. For treatment to be successful, the levels of both testosterone and estrogen must be monitored and managed. Because andropause has only recently been discussed and studied, treatment options have been limited. For many patients, only one treatment has been available: testosterone supplementation (most often by injection). Although this is frequently the appropriate therapeutic choice, clinicians must recognize that other aspects of the patient’s hormonal imbalance must also be addressed. The two major active metabolites of testosterone in men are estradiol and dihydrotestosterone. Because imbalance in the levels of those hormones can be a cause for concern, agents that modify the metabolism of estradiol and dihydrotestosterone are reviewed in this article. The role of prohormones as testosterone boosters is also addressed.
The following substances affect the level of estrogens, testosterone, or dihydrotestosterone:
Zinc – The mineral zinc is important in many ways and plays an important role in andropause. It inhibits aromatase, the enzyme activity that converts testosterone to estradiol. A deficiency of zinc is associated with increased activity of the aromatase system, which results in a higher level of estradiol and a lower level of testosterone. The administration of oral doses of zinc in a range of 50 mg to 100 mg/day can reduce the estradiol level and increase the level of testosterone until physiologic levels of zinc are restored.1
Vitamin C – Deficiencies in vitamin C are also associated with increased aromatase activity; dosing of at least 1 g/day can be helpful in treating an elevated level of estrogen.2
Chrysin – Chrysin is a naturally occurring bioflavinoid that acts as an aromatase inhibitor. The beneficial results of chrysin are similar to those produced by zinc but appear to have more universal application. In controlled studies,3 chrysin was found to be similar in potency and effectiveness to a pharmaceutical aromatase inhibitor used clinically to treat patients with an estrogen-dependent carcinoma. The oral dosage of chrysin, which has relatively poor oral bioavailability, is from 1 to 3 g/day.4 Transdermally administered chrysin is effective at a much lower dose; the recommended dosage is from 100 to 300 mg/day. In addition, chrysin produces anxiolytic effects similar to those of diazepam but without sedation and muscle relaxation.5
Progesterone – In men, progesterone has several important regulatory functions that affect the production of estradiol and dihydrotestosterone from testosterone. Progesterone is an aromatase inhibitor; it curbs the production of excess estradiol.6 It also
serves as a 5?-reductase inhibitor that governs the conversion of testosterone to potent dihydrotestosterone.7According to one article, 7 the development of benign prostatic hypertrophy (BPH) occurs when the progesterone level declines as the patient ages, and this causes the levels of estradiol and dihydrotestosterone to increase. The suggested dosage of transdermally applied progesterone ranges from 2 to 5 mg daily for men.
Saw Palmetto – Saw palmetto, which is considered to be phytotherapy, is a naturally occurring nonprescription plant product that is derived from the berries of Serenoa repens. The use of this agent is increasing. According to a recently published article,8 saw palmetto is safe to use for the treatment of BPH, and it causes no adverse effects. The same article discusses the mechanism of action of saw palmetto, which includes the inhibition of 5?-reductase (the enzyme system that converts testosterone to dihydrotestosterone), adrenergic receptor antagonism, and intraprostatic androgen receptor blockade. A randomized, placebo-controlled trial9 indicated that a saw palmetto herbal blend appears to be a safe, highly desirable option for those with moderately symptomatic BPH. The suggested oral dosage of saw palmetto is 160 mg twice daily.
Nettle Root – In Germany, nettle root has been used to treat BPH for years. Its action is similar to that of saw palmetto because it is believed to be a 5?-reductase inhibitor.9 Nettle root is also considered beneficial because it is believed to displace testosterone from sex hormone binding globulin (SHBG).10 It may therefore be useful for those who have a physiologic level of total testosterone but a low level of active free testosterone. The suggested oral dose is 240 mg/day, and nettle root has been combined with saw palmetto in some formulations.
Indole-3-carbinol – Cruciferous vegetables such as cabbage and broccoli, when eaten in quantities of up to 2 pounds per day, may be prophylactic against some forms of cancer. Indole-3-carbinol (I3C), a phytochemical found in those vegetables, can provide those anticancer benefits in a more concentrated form. I3C has been researched for its ability to alter estrogen metabolism so that metabolites that are considered more protective against cancer are formed instead of metabolites believed to be more carcinogenic. Some studies11 indicate that adding I3C to the diet may protect against breast cancer in women, and it is now thought to offer prophylaxis against prostate cancer in a dosage of 6 to 7 mg/kg/day by
altering estrogen metabolism.11-13 Thus the dosage for a man weighing 180 pounds would be 490 to 572 mg/day of I3C.11-13
Di-indolyl Methane – Di-indolyl methane (DIM) is a metabolite of I3C. DIM and I3C have the same pharmacologic properties, but DIM is effective at a lower dose. Both are effective in redirecting estrogen metabolism. When given orally in the suggested dosage range of 100 to 300 mg/day, DIM and I3C can cause flatulence and bloating; as a result, therapy should be initiated at a low dose and gradually increased.13 The suggested topical application of DIM is 50 to 100 mg/day for men when it is combined with testosterone boosting prohormones.
The following prohormones can be used to increase testosterone levels.
Androstenedione – Androstenedione became a part of our national vocabulary because of its reported value in the muscular development of baseball slugger Mark McGwire. Although androstenedione exerts anabolic and androgenic effects, the primary role of this prohormone is in the formation of testosterone. Androstenedione is a direct precursor to testosterone, and it converts naturally to testosterone through a wellrecognized
pathway. In several published studies, the efficacy of androstenedione as a prohormone is examined; one trial14indicated that it was effective in increasing the level of testosterone, and another15 demonstrated that androstenedione increased the level of estrogen and slightly increased the level of testosterone. Androstenedione has two pathways to active metabolites; this may be the reason for the discrepancy in the results of the studies described. Androstenedione converts to estrone as well as testosterone. Therefore, the effect of androstenedione in increasing the level of testosterone is somewhat compromised by having two pathways to estrogen (one is testosterone-estradiol; the other is a pathway directly to estrone). Androstenedione has been administered orally in a dosage of up to 500 mg/day. Like other hormones, it would probably be effective if it were applied topically at a lower dose (range, 25 to 100 mg).
Androstenediol – This prohormone is not as well known as androstenedione, but it may be more effective in increasing the level of testosterone. Androstenediol is a naturally occurring hormone derived from dehydroepiandrosterone (DHEA). Like androstenedione, it is a direct precursor to testosterone, but unlike androstenedione, androstenediol appears to have only one metabolic pathway to testosterone and does not have the direct estrone pathway. In one study,16 androstenediol was found to be a more effective testosterone booster than androstenedione because of
that metabolic difference. The oral bioavailability of androstenediol, which was questioned in that study, is a focus of current attention because of the reputed efficacy of transdermal forms of that prohormone. Several studies17-19 have indicated that androstenediol augments viral and antibacterial immune responses. In a topical cream formulation of a combination of several prohormones, androstenediol has been formulated in a dose of 20 to 30 mg/day. Androstenediol, if used alone in a topical cream, would probably be prescribed in a dosage of 60 to 100 mg/day.
Norandrostenediol – This prohormone is often sold in over-the-counter supplements and is believed to have several unique qualities. It does not convert to testosterone but to nortestosterone (nandrolone), which enhances muscle mass and strength and improves athletic performance.20 Norandrostenediol is not believed to convert to either dihydrotestosterone or to estrogen to the same degree, as does testosterone.
How do you treat a man in andropause? Therapies other than testosterone supplements alone are now widely available. The best therapy begins with a thorough evaluation of the patient. Follow the adage “first diagnose, then treat.” It is now evident that some men can benefit from a combination of agents, such as a formulation of chrysin with testosterone, or a mixture of androstenedione and androstenediol. Others may prefer to apply DIM topically in combination with prohormones. For some men, a combination that includes androstenediol, norandrostenediol, chrysin, and progesterone is the best treatment option. Our ability to deliver effective doses of hormone replacement has been enhanced by our increased knowledge of transdermal systems. A variety of hormones, prohormones, and metabolic modifiers are available for the treatment of male hormone imbalance. As interest in this medical specialty increases, pharmacists and physicians who work together will provide a major health benefit for their patients.
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20. [No author listed.] Prohormones: Primer – The building blocks to testosterone. 1998. Available at: http://
www.MedLean.com/ML_prohormonesprimer.html Accessed June 8, 2001.
Address correspondence to: Bruce Biundo, BS Pharm, RPh, Professional Compounding
Centers of America, Inc, 9901 S. Wilcrest, Houston, TX 77099.
International Journal of Pharmaceutical Compounding
Vol. 5 No. 5 September/October 2001 351-3