The hormonal effects of Tribulus terrestris and its role in the management of male erectile dysfunction – an evaluation using primates, rabbit and rat (original) (raw)

Elsevier

Phytomedicine

Abstract

Hormonal effects of Tribulus terrestris (TT) were evaluated in primates, rabbit and rat to identify its usefulness in the management of erectile dysfunction (ED). TT extract was administered intravenously, as a bolus dose of 7.5, 15 and 30

mg/kg, in primates for acute study. Rabbits and normal rats were treated with 2.5, 5 and 10

mg/kg of TT extract orally for 8 weeks, for chronic study. In addition, castrated rats were treated either with testosterone cypionate (10

mg/kg, subcutaneously; biweekly for 8 weeks) or TT orally (5

mg/kg daily for 8 weeks). Blood samples were analyzed for testosterone (T), dihydrotestosterone (DHT) and dehydroepiandrosterone sulphate (DHEAS) levels using radioimmunoassay. In primates, the increases in T (52%), DHT (31%) and DHEAS (29%) at 7.5

mg/kg were statistically significant. In rabbits, both T and DHT were increased compared to control, however, only the increases in DHT (by 30% and 32% at 5 and 10

mg/kg) were statistically significant. In castrated rats, increases in T levels by 51% and 25% were observed with T and TT extract respectively that were statistically significant. TT increases some of the sex hormones, possibly due to the presence of protodioscin in the extract. TT may be useful in mild to moderate cases of ED.

Introduction

Hormones are essential chemical mediators that are involved in the various physiological functions, including the sexual function of a living organism. Until the 8th week of gestation, the external genitalia are represented identically in both sexes (Conte and Grumbach, 1995). After this period, the development of the genital structures towards a particular identity depends mainly on the hormonal milieu that prevails. Furthermore, the mammalian reproductive axis is coordinated by the hypothalamic secretion and trophic effects of gonadotrophin releasing hormone, which is in turn controlled by negative feedback from the gonadal steroids.

Testosterone is the most important androgen secreted by the testis in humans. Approximately 8

mg of testosterone is produced daily, the major source (95%) being the interstitial cells of Leydig (Howell and Shalet, 2001). The adrenals contribute to the rest (5%) of testosterone. After puberty, the plasma level of this hormone in males is about 0.6

μg/dl of which, 97–99% is bound to sex hormone binding globulin, and approximately 1–3% remains free and readily available for physiological needs.

Dihydrotestosterone is the other potent androgen secreted by the testes. Testosterone is converted in many target tissues to the much active DHT by the enzyme 5_α_-reductase. The masculinization of the fetus occurs under the influence of DHT. It is noted that during 8–12 weeks of gestation, DHT stimulates the growth of genital tubercle, leading to fusion of the urethral folds and descent of the labioscrotal swelling which later forms the penis and scrotum respectively (Hinman, 1993). There is also a simultaneous inhibition of the descent and growth of the vesicovaginal septum and the vaginal differentiation in the male foetus.

The testes in addition to producing the above mentioned androgens also produce androstenedione and dehydroepiandrosterone that are considered to be weak androgens. DHEA, regarded as the ‘fountain of youth’, was isolated in 1934 and is the major secretory product of adrenal gland, although the testes produce a small quantity. After production and secretion from these glands, the potentiality of this hormone to enter the androgenic pathway depends on the individual's medical condition, age and sex, for every individual has a unique biochemical composition. DHEA is metabolized to form DHEAS, and both hormones are metabolically interconvertible by the action of the enzymes sulphotransferase for conjugation and sulphatase for hydrolysis, present in many tissues (Baulieu, 1996).

In general, androgens are essential for the development of the male external genitalia, the male secondary sexual characters and also in the regulation of erectile response. Sexual desire and activity as well as the nocturnal penile erections are dependent on the circulating androgen levels (Mills et al., 1996). Abnormalities in the synthesis and expression of androgens or its depletion by medical or surgical castration may cause a general decline in libido and sometimes in erectile and ejaculatory functions (Baskin et al., 1997). The incidence of sexual dysfunction resulting from hormonal imbalance is estimated to be 20–25% with hypogonadism (primary and secondary) being the most frequent cause (Manieri et al., 1997). In ageing, there seems to be a continuous decline in the levels of androgen leading to andropause a term akin to menopause in females (Burns-Cox and Gingell, 1997).

Androgen replacement helps to overcome the symptoms associated with andropause such as fatigue, nervousness, hot flushes, insomnia and also helps in restoration of bone density/turnover, muscle mass as well as the sexual function and libido (Vermeulen, 1991; Tenover, 1997). However, the hormonal preparations currently used as a replacement therapy can lead to hypofunction of the hypothalamo-hypophyseal-gonadal axis and also produce adverse effect on prostate gland and liver function, when used indiscriminately. A phytochemical with similar properties to that of the steroids that can bring about the changes necessary for restoration of general well being, sexual interest and activity without producing the undesirous side effects associated with the current hormone replacement therapy will contribute significantly to the management of erectile dysfunction (ED).

The plant Tribulus terrestris (TT) popularly known as puncture vine is a perennial creeping herb with a worldwide distribution. Since ancient times it is regarded as an aphrodisiac in addition to its beneficial claims on various ailments such as urinary infections, inflammations, leucorrhoea, oedema and ascites (Chopra et al., 1958; CHEMEXCIL 1992). The extract (TT) (obtained from Sopharma, Bulgaria & Tegushindo, Indonesia) from the air-dried aerial parts of the plant contains steroidal glycosides (saponins) of furostanol type, the predominant furostanol being protodioscin (PTN) (Fig. 1), which constitutes about 5% of the extract (Dikova and Ognyanova, 1993). The levels of testosterone and lutinizing hormone are increased following treatment with PTN for a period of 30–90 days in patients with hypogonadism (Koumanov et al., 1982). Improvement in sperm count and motility has been reported in patients with low seminological indices following treatment with TT for 3 months (Balanathan et al., 2001). It also increases the sexual behaviour parameters in castrated rats treated with TT extract for 8 weeks compared to the normal rats (Gauthaman et al., 2002). It is also claimed to dilate coronary arteries and improve the coronary perfusion with no adverse effect on long-term use (Wang et al., 1990). In general, the plant TT or its products are consumed by people in different parts of the world for its effect of general well being and muscle building properties in addition to its popular claims as an aphrodisiac. In the present study, the effect of TT extract on some of the sex hormones namely, testosterone (T), dihydrotestosterone (DHT) and dehydroepiandrosterone sulphate (DHEAS) using three different animal models such as primates, rabbit and rat was evaluated to understand whether TT extract would be useful as an adjunct in the management ED.

Section snippets

Materials and methods

The animal models used in this study were the sub-human primates, rabbit and rat. All laboratory and experimental procedures were conducted in accordance with institutional guidelines for animal ethics.

Drugs

The following drugs were used: Tribulus terrestris extract (Sopharma, Bulgaria & Tegushindo, Indonesia), ketamine, halothane (Sigma), standards for T, DHT and DHEAS (Sigma), Tracer 3H (NEN Dupont), SPA reagent (Amersham).

Statistical methods

The variables from the different experimental groups were analyzed and compared by one-way ANOVA with Bonferroni's multiple comparisons. The differences in treatment within each group at different periods were analyzed and compared using Student's paired _t_-test. All the results were expressed as mean±SEM and the level of significance for comparisons set at p<0.05.

Blood pressure in primates

Blood pressure was recorded from the primates throughout the experimental procedure. The systemic blood pressure recorded in the supine posture, from the lower limbs ranged from 70 to 140

mmHg. TT had only very minimal changes in the cardiovascular status. There was an initial, insignificant drop in blood pressure by 2–5

mmHg that returned to normal within few minutes (Fig. 3 – upper panel). The mean values of the blood pressure recordings from all the animals in the experiment for different

Discussion

Testosterone is secreted in the testes and is the main androgen in the plasma of man. The normal daily production of T is 2.5–11

mg/day. It is reduced at the 5_α_ positions to DHT, which serves as the intracellular mediator of most actions of T. The pattern of T levels in male shows peak at about 8 weeks of gestation, the neonatal and at puberty, which continues through adult life and later declines. The influence of androgens on androgen receptors and penile growth (Baskin et al., 1997), the

Acknowledgement

We thank Sopharma Joint Stock Co., Bulgaria and P.T. Tegushindo, Indonesia for providing the Tribulus terrestris extract that was used in this study. The staff of the endocrinology unit in the department is thanked for their assistance in radioimmunoassay.

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