5 alpha-furost-20(22)-en-12-one-3 beta

5α-Furost-20(22)-en-12-one-3β: Identity, Phytochemistry, and Scientific Evidence

1. Identity and Chemical Nature

Chemical and Systematic Nomenclature

The compound designated in dietary supplement and phytochemical literature as 5 alpha-furost-20(22)-en-12-one-3 beta refers to the steroidal aglycone core—specifically, the furostane skeleton bearing a 5α (trans A/B ring junction) configuration, an enone double bond between carbons 20 and 22, a ketone function at carbon 12, and a 3β-oriented hydroxyl group. In scientific literature it is written as (5α)-furost-20(22)-en-12-one-3β-ol or, with full stereo-descriptor, as 5α-furostan-20(22)-en-12-one-3β,26-diol when the C-26 hydroxyl is also specified on the aglycone. The compound is properly classified as a furostanol-type steroidal aglycone.

Based on the structure of the aglycones, steroidal saponins generally have three structures: spirostanol, furostanol, and open-chain steroidal saponins. The furostane skeleton consists of a five-ring structure wherein C22–26 is an open chain and C26 possesses a hydroxyl group which is often engaged in a glycosidic linkage. The defining structural difference from the spirostanol series is therefore the open-chain E ring: whereas spirostanols possess a closed six-membered F-ring pyran, furostanols retain the lactol in an open-chain configuration, which is frequently occupied by a glycosidic sugar at C-26. The 12-one (12-oxo) variant further distinguishes this aglycone from simpler furostanols through an additional carbonyl function on ring C, an oxidation state that has structural and possible biochemical implications.

From the viewpoint of biosynthesis, furostan-type saponins are thought to be the precursors of the corresponding spirostan-type saponins in plants. Furostan saponins of natural occurrence are bidesmosides in which a glucose monosaccharide is attached at the 26-OH group of the aglycone, and an oligosaccharide chain is usually connected at 3-OH. The 3β,26-diol aglycone thus represents the free, sugar-stripped sapogenin form; in nature it is rarely found in the free state and almost always exists as the central aglycon of complex, branched oligosaccharide glycosides.

Molecular Formula and Spectroscopic Characterisation

When the 5α-furost-20(22)-en-12-one-3β aglycone is isolated from its full glycoside (e.g., after acid hydrolysis), it retains the steroidal sterane backbone with 27 carbon atoms characteristic of all furostanol sapogenins. Researchers confirm structural identity through high-resolution electrospray ionization mass spectrometry (HRESIMS) and 1D/2D NMR. The molecular formula of the intact glycoside bearing this aglycone was determined as C₅₁H₈₂O₂₃ on the negative ion HRESIMS ([M−H]⁻, m/z 1061.5160). Compound 1, isolated as a white powder, was deduced to possess a furostanol structure by the Ehrlich test.

2. Natural Sources and Botanical Origin

Primary Source: Tribulus terrestris L.

The 5α-furost-20(22)-en-12-one-3β core is most extensively documented as the aglycone of multiple glycosides isolated from Tribulus terrestris L. (family Zygophyllaceae), commonly known as puncture vine, goat's head, or—in Sanskrit-derived Ayurvedic terminology—Gokshura or Gokharu. Tribulus terrestris L. is an annual plant found around the world. Its fruits have been used in traditional Chinese medicine for treatment of eye problems, edema, abdominal distention, emission, morbid leucorrhea, sexual dysfunction, and veiling. It has also been used as a medicine in India, South Africa, and Japan.

Spirostanol and furostanol saponins are considered the most characteristic chemicals in T. terrestris (TT). To date, 108 kinds of steroidal saponins have been isolated from TT. Among them, there are 58 kinds of spirostane saponins and 50 kinds of furostane saponins. Within this library of 50 furostane saponins, multiple compounds share the 5α-furost-20(22)-en-12-one-3β aglycone core, differing only in their oligosaccharide chains and the stereochemistry at C-25.

Representative glycosides bearing this exact aglycone scaffold that have been formally characterised from T. terrestris include:

• 26-O-β-d-glucopyranosyl-(25S)-5α-furostane-20(22)-en-12-one-3β,26-diol-3-O-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-β-d-galactopyranoside, isolated from the fruits of Tribulus terrestris L.
• 26-O-β-d-glucopyranosyl-(25S)-5α-furost-20(22)-en-12-one-3β,26-diol-3-O-β-d-galactopyranosyl-(1→2)-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside, isolated from the fruits of Tribulus terrestris L.
• 26-O-β-d-glucopyranosyl-(25R)-5α-furost-20(22)-en-12-one-2α,3β,26-triol-3-O-β-d-glucopyranosyl(1→4)-β-d-galactopyranoside, named tribufuroside J.
• 26-O-β-d-glucopyranosyl-(25R)-5α-furostane-12-one-3β,22α,26-triol-3-O-β-d-glucopyranosyl(1→4)-β-d-galactopyranoside and 26-O-β-d-glucopyranosyl-25(R)-5α-furostan-12-one-3β,22α,26-triol-3-O-α-l-rhamnopyranosyl-(1→2)-O-[β-d-glucopyranosyl-(1→4)]-β-d-galactopyranoside, also isolated from the fruits of Tribulus terrestris.

Other Plant Sources

Although Tribulus terrestris is the most extensively studied source, furostanol saponins bearing the 5α-furost-20(22)-en-12-one core are not exclusive to this plant. Three new furostanol saponins—tuberoside A, B, and C—have been isolated from the seeds of Allium tuberosum. A new furostanol saponin, (25S)-26-O-β-d-glucopyranosyl-5β-furost-20(22)-en-3β,15β,26-triol-3-O-[α-l-rhamnopyranosyl-(1→4)]-β-d-glucopyranoside, was isolated from Asparagus cochinchinensis. Eight steroidal saponins have been isolated from Yucca schidigera Roezl. trunk; these included three novel furostanol glycosides including a 5β(25R)-furost-20(22)-en-3β,26-diol-12-one 26-O-β-d-glucopyranoside.

Additional genera yielding closely related furostanol structures include Smilax scobinicaulis, from whose rhizomes and roots four new furostanol saponins were isolated, with aglycones including 5α-furostan-20(22)-en-6-one variants. The furostanol scaffold has also been characterised in Tupistra chinensis, Ophiopogon japonicus, Capsicum annuum, and various Dioscorea species, underlining its widespread occurrence across monocot and dicot plant families.

Geographic Variation in Content

The survey of the literature data revealed differences in the saponin content and composition of TT growing in different geographic regions of the world. Kostova and Dinchev (2005) reported that the high content of furostanol saponins of the diosgenin type is a characteristic feature of TT from Bulgaria. The saponin composition and the saponin content of TT from different geographic regions is different. This geographic variability is important for interpreting research findings and product quality.

3. Traditional and Historical Use

Traditional Chinese Medicine

The dried fruit of T. terrestris, named "Jili" in Chinese, has been used as a traditional Chinese medicine (TCM) for the treatment of edema, abdominal distention, emission, morbid leucorrhea, and vitiligo. Additionally, T. terrestris (the fruit or the whole plant) has been used not only as an aphrodisiac tonic and an antibacterial agent, but also for the treatment of cardiovascular diseases. Within TCM, the plant is considered to act on the liver and kidney meridians and has historically been deployed in the treatment of visual disturbances (particularly conditions attributed to liver deficiency), male reproductive dysfunction, and urinary complaints.

Ayurvedic and South Asian Medicine

In India, the fruits have been used in the treatment of infertility, impotence, erectile dysfunction, and low libido in Ayurveda. The fruits and roots of TT have been used as folk medicine for thousands of years in China, India, Sudan, and Pakistan. T. terrestris is of significant value in many traditional systems of medicine—Ayurveda, Traditional Chinese Medicine, Siddha, and Unani—where it is used as a diuretic, aphrodisiac, antiurolithic, immunomodulatory, antihypertensive, antihyperlipidemic, antidiabetic, hepatoprotective, anticancer, anthelmintic, antibacterial, analgesic, and anti-inflammatory agent. In Ayurveda, the plant carries the Sanskrit name Gokshura and is listed as a rasayana (rejuvenating) herb, emphasising its use for sustaining vitality and reproductive health over the long term.

Iranian Traditional Medicine

According to the Canon of Medicine and Aghili Khorasani's Makhzan al-Advia (The Treasury of Spices) (18th century AD), Bindii or Tribulus terrestris influences libido and is able to boost sex drive in human beings. The plant was thus recognised within the humorist-school framework of Iranian traditional medicine as an empirical aphrodisiac remedy.

Traditional Preparations

Historically, the fruits, roots, and aerial parts of T. terrestris were prepared and consumed in a variety of forms. In ancient medicine, extracts of the aerial parts and fruits have been used for their diuretic, tonic, and aphrodisiac properties. Traditional preparations ranged from decoctions of dried fruits and powder preparations mixed with warm milk (a common Ayurvedic delivery vehicle) to pastes applied topically in regional folk traditions. Some steroidal saponins had previously been isolated from this plant. Many pharmaceutical preparations and food supplements with these saponins as the active compound have been commercially available.

4. Phytochemistry: Key Constituents and Active Compounds

The Furostanol Class and the 12-one Aglycone

The steroidal saponins in T. terrestris are mainly furostanol and spirostanol type. The furostanol saponins are believed to be biogenetic precursors of the spiro analogs. Within the furostanol class, the 12-one variant—the 5α-furost-20(22)-en-12-one-3β series—is distinguished by an additional oxidation at C-12, creating an enone system in conjunction with the C-20(22) double bond. This C-12 ketone function is a recurring motif across multiple isolated compounds from T. terrestris and has been noted in saponins from Yucca, Allium, and other genera.

Furostanol and spirostanol saponins of tigogenin, neotigogenin, gitogenin, neogitogenin, hecogenin, neohecogenin, diosgenin, chlorogenin, ruscogenin, and sarsasapogenin types are frequently found in T. terrestris. Majorly present are furostanol glycosides including protodioscin and protogracillin, of which protodioscin is the most dominant saponin; spirostanol glycosides are present in small quantities.

Broader Phytochemical Profile of the Source Plant

Key bioactive constituents identified in T. terrestris include flavonol glycosides, steroidal saponins, flavonoids, alkaloids, protodioscin, terrestrosins A and E, gitonin, β-sitosterol, tigogenin, spirosta-3,5-diene, diosgenin, stigmasterol, hecogenin, and kaempferol. The steroidal saponins—including the 5α-furost-20(22)-en-12-one-3β series—are considered to be the pharmacologically dominant fraction. TT fruits contain important secondary metabolites such as saponins, polyphenolic compounds, and alkaloids.

Sugar Moieties in the Intact Glycosides

The sugar moieties of steroidal saponins are oligosaccharides which consist of 2–4 kinds of sugar units, e.g., d-glucose, d-galactose, d-xylose, and l-rhamnose. In the isolated 12-one furostanol glycosides from T. terrestris, sugar chains at C-3 typically consist of combinations of galactose, glucose, and rhamnose units, while the C-26 position invariably carries a terminal β-d-glucopyranosyl unit.

5. Mechanisms of Action

Androgen Axis and Reproductive Function

The most widely studied proposed mechanism underlying the biological activities of the furostanol saponin fraction of T. terrestris involves modulation of the androgen axis. Protodioscin, a saponin-like compound found in TT, may trigger testosterone synthesis by the Leydig cells. An intravenous administration of TT extract increased plasma testosterone, dihydrotestosterone, and dehydroepiandrosterone sulfate in primates. An oral administration of TT extract in rabbits and rats also increased dihydrotestosterone levels.

The proposed pathway is indirect: furostanol saponins, and particularly protodioscin (itself a 5α-furost-5-en-type glycoside), are hypothesised to stimulate luteinising hormone (LH) secretion from the pituitary, which in turn drives testicular steroidogenesis. The steroidal saponins, such as protodioscin and protogracillin, are thought to confer TT unique biological activities. However, whether the 5α-furost-20(22)-en-12-one-3β glycosides specifically contribute to this mechanism—as opposed to protodioscin—has not been separately demonstrated in controlled human studies.

Nitric Oxide / Erectile Function Pathway

Administering TT to rabbits results in a rise in cAMP and a relaxing effect on the corpus cavernosum, suggesting that TT affects the erectile process through the NOS pathway. This nitric oxide synthase (NOS) mechanism is consistent with the observed pro-erectile effects reported in some clinical studies.

Cytotoxic Activity

Multiple in vitro studies have evaluated furostanol saponins with the 5α-furost-20(22)-en-12-one-3β scaffold for antiproliferative properties. The inhibitory effects of compounds isolated from Tribulus terrestris, including furostanol saponins with the 12-one core, were evaluated against tumour cells, and compounds showed potential anti-tumour activity. Isolated saponins were evaluated for cytotoxic activity against two human cancer cell lines including HeLa (cervical carcinoma) and SMMC-7221 (hepatocellular carcinoma). Compounds 1 and 7 demonstrated cytotoxicity against the tested cell lines. These findings are preliminary and from in vitro systems only; no clinical evidence exists for antitumour activity.

Antifungal Activity

T. terrestris (the fruit or the whole plant) acts as an antibacterial agent and is used for the treatment of cardiovascular diseases. Preclinical studies have also demonstrated antifungal effects of steroidal saponin fractions. It is still unclear which components are responsible for the antibacterial activity, but alkaloids contribute to the general antibacterial effect of the total extracts.

Cardiovascular Mechanisms

Many pharmaceutical preparations with these saponins as the active compound have been commercially available. Examples of these are "tribusaponins" and "Xin-nao-shu-tong," which have been used for the treatment of cardiovascular disease. Mechanistic research suggests that saponin fractions from TT may exert anti-atherosclerotic and platelet-modulating effects, though the specific contribution of the 12-one furostanol series has not been delineated in published studies.

Antiurolithiatic and Diuretic Effects

Tribulus terrestris (puncture vine) possesses various pharmacological properties including antiurolithic, diuretic, anti-inflammatory, and immunomodulatory in vitro and in vivo effects. One of the prominent medicinal effects of Tribulus terrestris is its diuretic capacity, which is attributed to its high content of nitrates and essential oils found in its seeds. Research indicates that the alkaloidal fraction of the herb contributes to its ability to enhance urine production, with studies demonstrating its comparative efficacy to established diuretics like urea.

Furostanol-to-Spirostanol Biotransformation

Saponins undergo the transformation of spirostanol glycosides to furostanol glycosides in stored rhizomes. The reverse transformation—furostanol to spirostanol—also occurs enzymatically. This metabolic interconversion means that after ingestion, furostanol saponins may partially convert to their spirostanol counterparts in the gut environment, complicating the attribution of specific biological effects to any single glycoside type.

6. Scientific Evidence by Area of Use

6.1 Sexual Dysfunction and Libido — Male

The most clinically substantiated area of research for TT extracts standardised to furostanol saponin content is male sexual dysfunction. A Phase IV, prospective, randomised, double-blind, placebo-controlled clinical trial included 180 males aged between 18 and 65 years with mild or moderate erectile dysfunction (ED), with or without hypoactive sexual desire disorder (HSDD); patients with ED and hypertension, diabetes mellitus, and metabolic syndrome were included in the study. Each Tribestan film-coated tablet contained the active substance Tribulus terrestris extractum siccum (35–45:1) 250 mg, standardised to furostanol saponins (not less than 112.5 mg). Each patient received orally 3×2 film-coated tablets daily after meals, during the 12-week treatment period. At the end of each month, participants' sexual function, including ED, was assessed by International Index of Erectile Function (IIEF) Questionnaire and Global Efficacy Question (GEQ).

Kamenov et al. (2017) reported that TT at a standardised dose, with 250 mg of the saponin furostanol, taken for 12 weeks, improved sexual function in men with mild to moderate ED. Importantly, TT was well tolerated by patients with ED. Patients affected by mild to moderate ED and/or low libido may significantly benefit from oral therapy with TT, without any significant changes in biochemistry laboratory test results. Based on the origin of the herbal medicine used and the fact that this TT preparation is standardised with respect to furostanol saponins (calculated against protodioscin), the results of this trial should not be extrapolated directly to other TT preparations obtained from other regions.

6.2 Sexual Dysfunction and Libido — Female

A randomised double-blind placebo-controlled trial was designed to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty-seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks using the Female Sexual Function Index (FSFI). At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI, desire, and arousal scores.

An additional uncontrolled clinical assessment evaluated TT extract in female sexual dysfunction: this qualitative-quantitative study based on hospital records of female patients of reproductive age presenting sexual dysfunction used 250 mg Tribulus terrestris extract (1 tablet thrice daily for 90 days). Safety monitoring included vital signs, physical examination, and laboratory tests. Efficacy analysis included results of the FSFI, DHEA levels, total and free testosterone. There was a statistically significant improvement in total FSFI scores (P < 0.0001) post-treatment, with improvement among 106 (88.33%) of subjects. These findings are limited by the uncontrolled design. The active components of T. terrestris include the steroidal glycoside saponins furostanol and spirostanol, which are found in the leaves of the plant.

6.3 Testosterone Levels and Androgen Profile

The proposition that TT extracts act as testosterone boosters in healthy subjects is not well supported. Despite the proposed effects of TT supplementation as a testosterone booster through different mechanisms, 80% of the studies analysed in a systematic review did not report significant changes in the androgen profile following TT supplementation (400–750 mg/d for 2–3 months). However, only two studies exclusively enrolled subjects with low testosterone levels (<350 ng/mL) and observed effects of TT supplementation as a testosterone booster. In both studies, subjects received 3 capsules daily (750 mg) of TT (Trib Gold, origin Bulgaria, 250 mg of TT and a minimum of 45% of saponins per capsule) over the course of 3 months. Through a randomised, single-blind, placebo-controlled trial, 70 patients with late-onset hypogonadism reported a ~58 ng/mL (27%) increase in mean total testosterone levels (from ~215 to ~273 ng/dL, p < 0.001) in the group receiving TT.

The overall evidence thus suggests that TT extracts standardised to furostanol saponins may produce modest testosterone increases in men with clinically low testosterone levels but show no significant androgenic effect in eugonadal healthy males. Touted benefits of tribulus for men and women include improved testosterone levels, sexual dysfunction, and bodybuilding. No strong evidence supports this.

6.4 Athletic Performance and Body Composition

T. terrestris is also used among athletes to increase muscle resistance and improve performance in sports, although scientific evidence to support this effect is lacking. Based on PRISMA guidelines, a systematic review assessed the effects of TT on immunological, hematological, biochemical, renal, lipidic, hormonal behaviour, and anti-inflammatory response in physically active adult males, reviewing 340 identified records of which a total of 7 studies met the inclusion and exclusion criteria. Overall, participants supplemented with TT displayed significant improvements in lipid profile. Inflammatory and hematological biomarkers showed moderate beneficial effects with no significant changes on renal biomarkers. No positive effects were observed on the immune system response. No TT-induced toxicity was reported. In conclusion, there was no clear evidence of the beneficial effects of TT supplementation on muscle damage markers and hormonal behaviour.

6.5 Antiurolithiatic (Kidney Stone Prevention)

T. terrestris is traditionally used because of its aphrodisiac and antiurolithiatic activities with almost complete inhibition of stone formation. Preclinical data in rat models support the antiurolithic and anticalcifying potential of TT aqueous extracts, attributable in part to the saponin fraction's antioxidant effects on renal cells. However, no robust controlled human clinical trials specifically examining the 5α-furost-20(22)-en-12-one-3β-containing fraction for kidney stone prevention have been published.

6.6 Cytotoxicity and Anticancer Activity

Furostanol saponins from Tupistra chinensis were evaluated for cytotoxic activity against human A549 and H1299 tumour cells. Evidence from T. terrestris is similarly confined to the preclinical domain. Several pharmacological studies have revealed that T. terrestris extracts have different effects, including cardioprotective, hepatoprotective, and antitumoral activities. All anticancer evidence for furostanol saponins of the 12-one type remains in vitro or in animal models; no human clinical trials examining oncological endpoints have been conducted with this specific compound class.

Evidence Strength Summary

• Sexual dysfunction (male and female): Moderate — supported by at least one Phase IV RCT and additional smaller RCTs using extracts standardised to furostanol saponins. Effect sizes are modest and results are not fully consistent across studies.
• Testosterone modulation: Weak — effects appear limited to hypogonadal men; no significant effect in healthy men across most trials.
• Athletic performance/body composition: Weak — systematic review found no clear evidence of benefit on hormonal or muscle-damage markers.
• Antiurolithiatic: Preliminary — preclinical only.
• Anticancer/antimicrobial: Preliminary — in vitro and animal data only.

7. Body Systems and Health Areas of Association

T. terrestris has diuretic, aphrodisiac, antiurolithic, immunomodulatory, antidiabetic, absorption enhancing, hypolipidemic, cardiotonic, central nervous system, hepatoprotective, anti-inflammatory, analgesic, antispasmodic, anticancer, antibacterial, anthelmintic, larvicidal, and anticariogenic activities. Furostanol saponins bearing the 5α-furost-20(22)-en-12-one-3β core are associated with the following body systems through the broader research body on TT:

• Reproductive/endocrine system: Modulation of sex hormone synthesis; aphrodisiac and pro-sexual effects.
• Urinary/renal system: Diuresis, antiurolithiatic (prevention of calcium oxalate crystal deposition).
• Cardiovascular system: Cardioprotective and anti-atherosclerotic effects observed in preclinical studies; use in Chinese pharmaceutical preparations for cardiovascular indications.
• Immune system: Immunomodulatory activity noted in animal studies; not confirmed in humans.
• Gastrointestinal/hepatic system: Hepatoprotective effects in preclinical settings; paradoxically, hepatotoxicity has been reported in case reports (see Safety section).
• Musculoskeletal system: Proposed benefits for muscle performance and recovery in athletes; not confirmed by systematic review evidence.

8. Dosage Forms and Reported Dosages

The dietary supplement ingredient Tribulus is prepared from the leaves, root, and fruit of the Tribulus terrestris L. plant, which contains numerous chemical compounds, including steroidal saponins (plant steroids). Commercial preparations containing the furostanol saponin fraction—including the 5α-furost-20(22)-en-12-one-3β glycosides—are available in the following forms:

• Standardised dry extract tablets/capsules: The most extensively clinically studied formulation. Each Tribestan film-coated tablet contains the active substance Tribulus terrestris, herba extractum siccum (35–45:1) 250 mg, standardised to furostanol saponins (not less than 112.5 mg). Each patient received orally 3×2 film-coated tablets daily after meals during the 12-week treatment period.
• Lower-dose extract (female sexual dysfunction trial): Sixty-seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks.
• Higher-dose regimen (testosterone/hypogonadism studies): Subjects received 3 capsules daily (750 mg) of TT (Trib Gold, origin Bulgaria, 250 mg of TT and a minimum of 45% of saponins per capsule) over the course of 3 months.
• Adverse event dosage reference: Sleep disturbances, exhaustion, fatigue, and elevated heart rate have been reported after consuming more than 1,000 mg per day.

Given the differences observed in the composition, the plant organ used to obtain the extract, the need for selective extraction methods targeted at the class of phytocompounds, and the standardisation of T. terrestris extracts is an absolute necessity. Extraction is most commonly achieved using ethanol or aqueous-ethanol solvent systems; investigation on the constituents in the ethanol extract of the plant led to the isolation of new furostanol glycosides.

9. Safety Considerations and Interactions

Short-Term Safety in Clinical Studies

Research evaluating the safety of Tribulus in humans is limited. More research is needed to determine the safety of Tribulus as a dietary supplement ingredient, especially long term and in varying doses. Short-term studies (up to 3 months) have reported few adverse effects, such as stomach cramps and nausea.

Hepatotoxicity and Nephrotoxicity — Case Reports

Despite a relatively mild adverse event profile in short-term clinical trials, case reports have documented serious toxicity:

• A case of a 46-year-old man who took tribulus supplements daily for 2 months was described. He developed severe jaundice prompting hospital admission. His total bilirubin peaked at 48 mg/dL, with concomitant renal dysfunction (creatinine of 7.1). His liver biopsy showed features consistent with drug-induced liver injury.
• Another reported case describes a 30-year-old man who developed nausea and poor appetite after taking tribulus tablets as part of his muscle-building programme. His total bilirubin peaked at 39 mg/dL, with a creatinine of 3.1 mL/dL. His liver biopsy showed bland cholestasis. After 6 weeks of stopping tribulus, his bilirubin downtrended to 4.4 mg/dL with a creatinine of 1.2 mg/dL.
• A case of T. terrestris-induced hepatotoxicity, nephrotoxicity, and neurotoxicity in an Iranian male patient who used the plant's extract to prevent kidney stone formation was reported. He presented with seizure and very high serum aminotransferases and creatinine after consuming herbal water for 2 days.

Animal Toxicology

Tribulus has been linked to liver injury and death in animals in a phenomenon described as "geeldikkop" or tribulosis. Animals grazing on different tribulus species can develop marked photosensitivity and icterus, followed by severe jaundice and death. The plant itself is known to be toxic to rats and sheep after ingesting large amounts. Effects include damage to the heart, liver, and kidneys.

Drug Interactions and Other Adverse Effects

Studies of experimental pharmacology (in vitro studies and animal models in vivo) and clinical pharmacology (efficacy and safety clinical trials) have sometimes led to divergent results; moreover, the presumed pharmacodynamic mechanisms have yet to be confirmed by molecular biology studies. Given the proposed effects on sex hormone levels, potential interactions with hormone-sensitive medications (e.g., hormonal contraceptives, testosterone replacement therapy, anabolic steroids, anti-oestrogens) are biologically plausible, though not specifically characterised in controlled studies. Data from the literature are somewhat controversial regarding the efficacy of TT extracts in disorders including libido disorders for both males and females, erectile dysfunction, and abnormal sperm motility.

Gynecomastia

A case of gynaecomastia has been reported in association with use of a Tribulus terrestris plant product, documented in the peer-reviewed literature (Jameel et al., 2004, Breast journal), suggesting the possibility of oestrogen-related effects in some users.

Standardisation as a Critical Safety Factor

Phytochemical studies have shown great disparities in the content of active substances, in particular the concentration of furostanol and spirostanol saponins, considered to be the predominant active ingredients related to the therapeutic action. Because the 5α-furost-20(22)-en-12-one-3β glycosides occur alongside many other chemically active saponins, alkaloids, and flavonoids whose ratios vary with geographic origin, plant part, and extraction method, the actual dose of these specific furostanol compounds ingested may differ substantially from what label claims imply.

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