Tribulus Research

Tribulus for sexual dysfunction in men and women

Kerry Bone
Introduction

Tribulus terrestris (puncture vine) is a prostrate, spreading herb particularly adapted to dry regions which produces a fruit with sharp, rigid spines (hence the common name). It is regarded as a problematic weed in some parts of the world and excessive consumption by livestock can lead to disruption of normal bile excretion (see later under Toxicology).

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The entire plant, but particularly the fruit is used in traditional medicine. In Ayurveda, Tribulus fruit or root, known as Gokshura, is used mainly for diseases of the urinary system (cystitis, painful urination, kidney stones, edema) and of the reproductive system (spermatorrhea, gonorrhea, impotence and uterine disorders after parturition). It is also used to treat gout, coughs and heart disease and is regarded as a diuretic with antiseptic and soothing activity on the mucous membranes of the urinary tract. The entire plant, including the root is also used. (1-3)

In Traditional Chinese Medicine the fruit of Tribulus is used for skin lesions with itching, for pain and distension in the chest, insufficient lactation due to constrained liver Qi and for swollen, painful eyes. (4)

In recent years, much attention has focused on the Bulgarian research on a Tribulus herb product used as a male tonic and for the treatment of infertility and menopausal symptoms. The information in this monograph is mainly centered on this recent research.

Key Constituents

The key constituents of Tribulus leaf include the steroidal saponins, mainly furostanol glycosides (including protodioscin and protogracillin) and small quantities of spirostanol glycosides. (5-7) Other constituents include phytosterols (e.g. [beta]-sitosterol), (8) and perhaps very small quantities of harmala alkaloids (tryptophanderived [beta]-carbolines) which may only occur in some varieties (9) and have not been found in some investigations. (10) Tribulus leaf contains higher concentrations of steroidal saponins than the fruit.

The furostanol glycosides are a subclass of steroidal saponins. They have a sugar group at the carbon-3 (C-3) position and a second sugar group at position C-26. Furostanol glycosides readily convert into spirostanol saponins (with one sugar group at C-3) in the presence of plant enzymes. (11) Such degradation, resulting in loss of sugars, may occur postharvest, in manufacturing or during experimental analysis.

Tribulus leaf standardized extract (TLSE) is a product obtained from the aerial parts of Tribulus terrestris, which contains mainly saponins of the furostanol type (not less than 45%, calculated as protodioscin) which was developed in Bulgaria from Mediterranean varieties of Tribulus.

Pharmacodynamics

Hormonal and Sexual Activity

Oral doses of TLSE have demonstrated the following effects in vivo:

** Marked stimulation of spermatogenesis, increased density of Sertoli cells, increased tenacity and viability of spermatozoa, and accelerated and emphasized sexual activity in rats (70 mg/kg/day). (12) Female rats treated with the saponin fraction produced more offspring. (6)

** Increased plasma Testosterone concentrations compared to controls in male lambs and rams (250 mg/day); acceleration of sexual development, activation of spermatogenesis and stimulation of seminiferous tubule growth in immature sheep. (13)

** Increased testosterone levels, improved semen production and normalized sexual activity in rams with sexual impotence; no morphologic changes in the structure of either testes or epididymides were observed during the treatment period. (14)

** Restored libido and sexual reflexes in 71% of boars suffering absence of libido. Five animals with prolonged poor libido also improved (70 mg/kg/day). (15)

** Aphrodisiac activity in a rat model, which was attributed to an androgenic effect (5 mg/kg/day orally). (16)

** A dose-dependent increase in body weight, penile intracavernous pressure (related to improved erectile function) and sexual activity in rats given oral doses ranging from 2.5 to 10 mg/kg/day. (17)

Tonic and Adaptogenic Activity

TLSE increased the nonspecific resistance in mice with experimental lung infection. The protective effect was based on the activation of alveolar macrophages. (18) Studies indicate that TLSE intensifies protein synthesis and enhances the activity of some enzymes connected with energy metabolism. (19)

TLSE (oral; 100 mg/kg/day for 5 days) increased static physical endurance in rats. Treatment with a related formulation (oral; 300 mg/kg/day for 1 month) markedly increased endurance and (by injection) accelerated the restoration process after heavy exercise. (20) The mechanism of improved endurance was probably not directly connected with the adrenergic system. The preparation did not stimulate the CNS and its mechanism of action was different from that of psychostimulants. (19,20) The same formulation improved resistance to stress and endurance in vivo compared to controls. It increased the concentration of dopamine and serotonin metabolites and the levels of noradrenaline in the hypothalamus. (21)

Pharmacokinetics

Pharmacokinetic studies of TLSE in rats indicated that 12 to 14% of administered protodioscin is excreted in the bile and 6 to 7% in the urine (at 24 hours) when delivered intravenously (50 and 200 mg/kg). After oral administration of the same individual doses, 2 to 4% of protodioscin was apparently excreted in the bile, but protodioscin was not detected in the urine. (22) However, the researchers may have mistaken glucuronide conjugates of furostanol aglycones for protodioscin (see Toxicology below).

Toxicology

LD50 values for acute oral administration of TLSE in both mice and rats were greater than 10 g/kg, indicating very low toxicity. No lethality, change in behavior or changes in biochemical indices were observed in rats orally administered doses ranging from 75 mg/kg to 300 mg/kg for 30 and 90 days, or dogs receiving 75 mg/kg for 180 days. (23) Oral administration of TLSE at 50 mg/kg/day or 150 mg/kg/day for 93 weeks did not induce evidence of carcinogenicity. (24)

Consumption of Tribulus by livestock, especially sheep, has lead to the photosensitization syndrome known as geeldikkop (yellow thick head) in South Africa, Australia and Argentina. (25-27) The ingested saponins are rapidly hydrolyzed in the rumen, releasing free sapogenins. Most of the sapogenins (especially diosgenin and yamogenin) are rapidly converted by ruminal microflora to epismilagenin and episarsapogenin which are absorbed. These are conjugated with glucuronic acid in the liver and excreted in the bile as calcium salts of the sapogenin glucuronides. These salts are insoluble in high amounts and precipitate in the bile ducts as crystals. The resultant disruption of bile excretion results in retention of phylloerythrin (a photodynamic chlorophyll metabolite) and induction of photosensitization. (27) This reaction has not been observed in humans and is unlikely, given the large quantities needed to trigger this process and the unique link with ruminant digestive flora.

Ingestion of Tribulus can also cause a unique neuromuscular disorder in sheep, known as tribulus staggers which has been attributed to the accumulation of the harmala alkaloids in the blood over a period of time. (9) This has not been observed in humans and is highly unlikely at the recommended dosage. Also the presence of harmala alkaloids in Tribulus is disputed. (10)

Clinical Studies

Male Infertility and Impotence

The results of open clinical trials conducted by four Bulgarian research teams, including a total of 363 men, indicated that TLSE had a stimulating effect on sexual function. (28-32)

** Treatment with 750 mg for 60 days significantly increased motility and rate of movement of spermatozoa from 38 men with idiopathic oligospermia. In some cases, after repeated treatment at a dosage of 1500 mg/day, a normalization of the sperm profile was observed, accompanied by an increased serum level of LH and testosterone and decreased estradiol.

** Two groups of men with oligospermia after varicocele operation were treated with either 750 mg for 60 days or 1500 mg for 90 days. Significant improvement in sperm motility was observed in both groups. Treatment with 1500 mg also resulted in an increase in ejaculate quantity in all patients.

** Patients with unilateral or bilateral hypotrophy of the testes and oligospermia demonstrated improvement in ejaculate volume, spermatozoal concentration and motility after treatment (1500 mg/day, 60 days). Testosterone levels were also increased. A light palpable pain in the testicular region with slight edema was reported by patients during the treatment, which abated 2 to 3 months after treatment.

** Treatment of 51 infertile males with 750 mg/day TLSE for 3 months significantly increased ejaculate volume, spermatozoa concentration, motility and velocity. Spermatozoa morphology normalized and ejaculate liquefaction time decreased. Semen immune parameters decreased: leukocyte counts, [alpha]-amylase values (an enzyme involved in ejaculate liquefaction), and secretion of local immunoglobulins. Cholesterol, LDL, triglycerides and VLDL decreased and HDL increased. Libido was normalized or enhanced in those reporting poor libido.

** Thirty-one pregnancies were recorded for 100 couples with infertility involving an immunological cause within 12 months of initiating TLSE treatment. The average time taken to conceive was 5.2 months. Prior to treatment spermatozoa number and quality varied between males, but all males and 74% of females had abnormal results for sperm-agglutinating antibody tests. The dosage used was 750 mg/day for males and 750 mg/day from days 21 to 27 of the menstrual cycle for females until conception.

** Improvement in sperm profile was not observed in patients with chronic prostatitis (750 to 1500 mg/day).

** Of 14 patients suffering reduced libido, 12 showed considerable improvement after 30 days (1500 mg/day) and one patient was slightly improved after 60 days' treatment. Libido was improved in 27 of 36 patients with chronic prostatitis. The other nine patients, with chronic prostatitis for over 5 years, demonstrated no improvement. Libido was incidentally improved in patients with hypotrophy of the testes and idiopathic oligospermia.

** Libido and sexual activity were improved in some patients with Klinefelter's syndrome (genetic hypogonadism), Noonan syndrome (a multifaceted disorder which includes cryptorchidism) and simple cryptorchidism.

** TLSE was well-tolerated in all of the above studies.

Tribulus has been part of a number of herbal formulations successfully used in uncontrolled clinical trials in India and Russia to treat sexual dysfunction or sexual inadequacy in men. The main formulations contained 7 to 12.5% of Tribulus by weight. Improvement in sexual function was observed in convalescing postmyocardial infarction male patients, (33) and in leprosy patients experiencing testicular and epididymal changes. Patients with oligospermia showed objective improvement. (34) Impotence and loss of libido improved in male diabetics. (35) Improvement was observed in men with impotence. (36,37) Sperm count and motility improved in approximately 60 to 70% of subfertile and oligospermic men. (38,39)

Female Infertility

In an open study involving infertile women, TLSE (750 to 1500 mg) was administered every day for 2 to 3 months (Group 1), only on days 5 to 14 of the menstrual cycle for 2 to 3 months (Group 2), or used in the preovulatory phase in combination with an ovulation stimulant for 3 months (Group 3). (15) Group 1 did not show improvement in the ovulation parameters measured and side effects were observed, especially when the treatment was abruptly terminated. Of the 36 women in Group 2, 6% of women experienced normalized ovulation with resultant pregnancy, 61% demonstrated normalized ovulation without pregnancy and 33% demonstrated no effect from treatment. Parallel control studies on a comparable cohort were carried out utilizing three conventional ovulation stimulants. The best results were obtained with 62 women treated using epimestrol: 39% had normalized ovulation with pregnancy, 35% had normalized ovulation without pregnancy and 26% demonstrated no effect from treatment. No side effects were recorded for the TLSE group, compared with an incident rate of 6.5%, 10.6% and 38% in women treated with the ovulation stimulants. For the 20 women treated with TLSE and an ovulation stimulant (Group 3), the effect from their combined use was better than treatment with either single agent.

Menopause

In an open study, 98% of 50 menopausal women experienced some symptom improvement after TLSE treatment, but not after placebo. Fifty-two percent of patients were experiencing natural menopause and 48% had postoperative symptoms after removal of their ovaries. Predominant symptoms included hot flashes, sweating, insomnia and depression. The dosage prescribed varied, but generally a maintenance dose of 500 to 750 mg/day of TLSE was reached after higher initial doses. Treatment did not result in significant changes in FSH, LH, prolactin, estradiol, progesterone and testosterone, although FSH tended to be lower. (15)

Body Composition and Exercise Performance

TLSE given for 8 weeks at a daily dose of 3.21 mg/kg did not enhance body composition or exercise performance in eight resistance-trained males when coupled with a resistance-training program in a randomized, double-blind, placebo-controlled trial. The authors concede that the lack of improvement in body composition in both groups may be attributed to the fact that these subjects were already lean and may not have consumed enough protein or calories to gain lean body mass. In addition, the method chosen to assess exercise performance was not the most objective measure available. (40) The dose of TLSE used was low (240 to 260 mg/day).

Other Conditions

In an open trial of 406 patients with coronary artery disease treated with saponins isolated from Tribulus, improvement was observed for angina pectoris and for ECG readings of myocardial ischemia. The saponin fraction was said to dilate the coronary arteries and improve coronary circulation. No side effects or adverse reactions on blood, hepatic or renal functions were observed. (41)

Mechanism of Action

TLSE (750 mg/day for 5 days) increased serum FSH and estradiol compared to baseline values in human female volunteers and increased the level of LH and testosterone in male volunteers, (42) thus demonstrating increased sex hormone production in both men and women. In other words, the sexual and tonic activities of Tribulus may not result from a direct hormonal activity of the saponins or direct effects on the gonadal tissue. Instead, they could be mediated at the level of the hypothalamus or pituitary.

It has been suggested in one article that protodioscin is converted in the human body into DHEA. (43) There is no sound evidence to support such a speculation.

Quality Issues

Two studies have highlighted that most Tribulus products on the market are quite different from the Bulgarian extract (TLSE). (44,45) The first study, conducted in the US, found that the level of protodioscin varied substantially with the plant part (leaf, stem or fruit) and origin (Bulgaria, India or China) of the Tribulus. (44) Only leaf from Bulgaria was high in protodioscin. Analysis of products selected from the US market found deficiencies of protodioscin in the majority.

The second study from Australia produced similar results. (45) An Eastern European variety of Tribulus (from Slovakia) contained high levels of protodioscin in the leaf but none in the fruit. Leaf from Australia and India did not contain protodioscin.

The principle of phytoequivalence dictates that, if the benefits demonstrated in a clinical trial are claimed for a herbal product, then that product must closely match the one used in the clinical trial. The Bulgarian clinical trials which have shown that Tribulus boosts libido and fertility and alleviates menopausal symptoms, all used Tribulus leaf rich in protodioscin collected from Bulgaria. Therefore only similar products might reasonably be expected to have the same effects. If a Tribulus product is made from the root or fruit of the plant, or is sourced from anywhere else other than Eastern Europe, it will probably contain low levels of protodioscin and so will be quite different from the Bulgarian standardized extract. This is despite what might be claimed on the label for such products, because often inferior methods of analysis have been used to measure the furostanol saponins, such as gravimetric or colorimetric techniques. The quality of Tribulus products is best assessed by high performance liquid chromatography as used in the two studies cited above.

Clinical Summary

Actions

Tonic, aphrodisiac, estrogenic in females (indirectly), androgenic in males (indirectly), fertility agent.

Recommended Therapeutic Uses

** Male erectile dysfunction

** Male and female infertility

** Menopausal symptoms

** Decreased libido in men and women

** To restore or build vitality (especially during convalescence or after surgery) and to assist in responding to stress; to improve physical performance.

Dosage and Administration

The recommended adult dosage for the hormonal effects is one tablet of standardized concentrate, containing 100 mg of furostanol saponins (calculated as protodioscin), three to four times per day. Higher doses may be necessary in some cases, especially for male impotence.

Suggested Combinations

Tribulus combines well with damiana, Korean ginseng, saw palmetto or ashwaganda (Withania somnifera) in male sexual inadequacy and infertility and low libido in women; black cohosh or wild yam in menopause; and ashwaganda, Eleutherococcus or Korean ginseng for tonic use.

Adverse Reactions

As with all saponin-containing herbs, oral intake may cause esophageal reflux and irritation of the gastric mucous membranes.

Contraindications and Cautions

According to Traditional Chinese Medicine, Tribulus should be used with caution in pregnancy. (46) If Tribulus is being used to promote fertility in women, its use is best stopped after pregnancy is established. While it is unlikely that normal human doses of Tribulus leaf would cause cholestasis, this should be considered in unexplained cases of cholestasis in patients taking Tribulus. Steroidal saponin-containing herbs such as Tribulus are best kept to a minimum in patients with pre-existing cholestasis.

Male Infertility: Clinical Anecdotes

These have been provided by Dr. Therese Lovell, MD. (47)

Case 1

A 42-year-old male with very low sperm count, 38% abnormal forms and poor motility. No pregnancy with unprotected sex (same partner) for last 7 years.

Therapy: One tablet* b.i.d. Wife was pregnant before the 3 months when I planned to repeat his semen analysis.

Case 2

A 59-year-old male unable to fertilize his partner's egg outside of the IVF laboratory using ICSI (intracytoplasmic sperm injection). To date only one successful pregnancy resulted from ICSI which miscarried before/at 9 weeks.

Therapy: One tablet* b.i.d. At the 3 month review week we discovered his partner is pregnant ... with no IVF intervention! A natural cycle, spontaneous insemination had occurred.

Acknowledgments

The contribution of Michelle Morgan and Janice McMillan in the preparation of this article in gratefully acknowledged.

*This tablet contained Tribulus terrestris herb, standardized for 100 mg furostanol saponins as protodioscin.

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by Kerry Bone, FNIMH, FNHAA

P.O. Box 713 * Warwick QLD 4370, Australia

+61 7 4661 0700 * Fax +61 7 46610788 * www.mediherb.com

FNIMH = Fellow, National Institute of Medical Herbalists (UK)

FNHAA = Fellow, National Herbalists Association of Australia

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