Effect of Ferula hermonis Boiss. on fertility potential in vitro and in vivo human and animal studies- an update review

2.1 Effect on testis

Normal testis functions are vital to health. Testicular dysfunction may lead to infertility, poor muscle strength, hypogonadism, low libido and erectile dysfunction, which affect the quality of males' life (Karagiannis and Harsoulis 2005). Osman and his group investigated the protective effect of F. hermonis, bee honey or their mixture on induced testicular toxicity in rats using gamma irradiation. Ionizing radiation is one of the environmental factors that may contribute to reproductive dysfunction by oxidative stress. The orally pretreated rats with F. hermonis (3 mg/kg), bee honey (1.5 ml/ Kg) and their combination for ten consecutive days prior to and twenty days after exposure to gamma irradiation revealed that all the extracts and their combination possess a significant protective potential against irradiation-induced testicular damage. They normalized the weight reduction in testis, restored the antioxidant testicular activities, antagonized the significant changes in alkaline phosphatase, lactate dehydrogenase, acid phosphatase and restored the serum level of testosterone, follicle-stimulating and luteinizing hormones (Osman 2011).

In most mammalian species, the temperature is tightly regulated to maintain optimal reproductive activity. In a study conducted by Hanafi and his group to assess the role of F. hermonis herb in relieving heat stress drawbacks on reproductive performance. Albino rats were exposed to different treatments, and after 8 weeks of treatment, The heat-stressed animals' control group showed oligozoospermia, teratozoospermia and chromosomal aberrations. Analysis of serum chemistry showed elevation in glutamyl transferase, cholesterol, low-density lipoprotein, total lipids, malondialdehyde, uric acid, creatinine, and blood glucose. However, the total antioxidant, protein, testosterone, cholinesterase, DNA, and RNA were markedly decreased in the testis, liver, kidney and brain tissue. The administration of the plant extract has no side effects and showed a protective effect from heat stress (Hanafi et al., 2010).

Following oral administration of 200 and 100 mg for 42 days, local drakes displayed increased weight, volume, width, and length as well as luteinizing hormone (LH), testosterone, and follicle-stimulating hormone (FSH) levels. They also have larger seminal tube diameter and thicker seminiferous epithelium (Al-Salhie and Al-Hummod 2019).

According to research, plant extract enhances animal testicular development and raises FSH, testosterone, and LH levels. The plant also has a protective effect against gamma irradiation-induced testicular dysfunction and health hazards resulting from heat stress in tropical and subtropical regions.

2.2 Effect on libido

Substances that increase performance sexual desire and enjoyment are called aphrodisiacs. They exert their sexual enhancing potentials by promoting erection, causing relaxation of corpus cavernosal smooth muscle and increasing blood flow (Thakur et al., 2009). Botanical extracts have continued to gain consideration as a substitute for improving sexual life due to their affordability, approachability no side effects belief.

The oral administration of ethyl acetate and petroleum ether extracts F. hermonis root extract (600 mg/kg) exhibited a decrease in the intromission rate and prolongation of intromission latency compared with control and sildenafil groups. However, the methanolic extract caused a significant rise in mount rate and an insignificant effect on intromission rate or intromission latency compared with the control (Hadidi et al., 2003).

In another report, the influence of oral administration of ferutinin, teferin and teferdin for Fig. 2 10 days at the dose of 2.5 (acute) and 0.25 mg/kg/day (subchronical) using sexually impotent and potent male rats was studied. Ferutinin administered (2.5 mg/kg) in potent rats reduced intromission latency and mount rate. However, it shortened the ejaculation latency in impotent rats and increased testosterone levels, as teferdin did. However, ferutinin administered (0.25 mg/kg/day) to potent rats negatively affected appetitive and consummatory behaviour), as well as testosterone serum levels. In summary, ferutinin stimulated sexual behaviour after acute ingestion but negatively impacted the potent animals' sexual capacity. The only compound that improves the efficacy of copulation in impotent male rats is ferdin (Zanoli et al., 2005).

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Fig. 2

Major bioactive compounds reported from F. hermonis and play an important role in fertility.

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The chronic administration of different doses (0.5 and 0.2 mg/kg daily for 28 days) of ferutinin using ovariectomized non-estrogen primed rats increased the receptive behaviour in rats. In ferutinin-treated animals, the proceptive behaviours increased the preference for a sexually active male over a sexually receptive female compared with the control. In addition, the suppressed normal mating behaviour due to ovariectomy was restored by ferutinin treatment. These results revealed that the administration of ferutinin caused an estrogenic effect in ovariectomized, non-estrogen-primed rats (Zavatti et al., 2009).

2.3 Effect on erection/ejaculation function

Erectile dysfunction is a male health issue affecting the relationship between husbands and wives. In addition to various commercially available medications, many researchers are working to provide herbal remedies (Baum et al., 2000). The sexual potential of oil extracted from the seeds of F. harmonis enhanced erectile function dose-dependently. But, it turns out to be toxic if used for an extended period (El-Thaher et al., 2001). Similarly, Ayoub et al. recommended using F. hermonis root extract for erection and fertility problems. However, he recommended that it be consumed for a short time and with caution (Ayuob et al., 2014).

Sexual behaviour and penile erection are androgen-dependent. The testosterone treatment of castrated rats restored penile erection and sexual desire (Heaton and Varrin 1994). The mechanism of action of androgens improves penile erection by controlling corporal nitric- oxide synthase activity (Zvara et al., 1995). It has been reported (Bucci et al., 2009) that testosterone can elicit vasodilatation by modulating hydrogen peroxide levels through the conversion of L-cysteine to hydrogen peroxide. Likewise, Some natural products possess phosphodiesterase type 5 (PDE5) inhibitory activity. PDE5 is highly concentrated in the corpus cavernosum smooth muscle and breaks down cyclic guanosine monophosphate (cGMP).As a result, this leads to the corpus cavernosum smooth muscle relaxation that allows penile erection (Ko et al., 2004). The erectile effect of F. hermonis is not yet known. However, Colman et al. reported the signalling pathway of ferutinin through the rise of nitric oxide (NO) synthase activity in the brain. This signify that ferutinin is linked to the activation of NO production, which is known to be crucial for maintaining homeostasis (Colman-Saizarbitoria et al., 2006).

This plant contains potent antioxidant compounds (daucane sesquiterpenoid and fucose-rich sulfated polysaccharide). Knowing that oxidative stress was associated with erectile dysfunction pathophysiology (Azadzoi et al., 2005), F. hermonis could be an encouraging solution for solving this dysfunction (Abbas 2017).

2.4 Effect on sperm parameters

The botanical extracts positively affect sperm parameters through venotonic, anti-oedematous, anti-inflammatory, and antioxidant activity. Medicinal plants may contain compounds that increase the level of serum testosterone and the generation of sperms (Tahvilzadeh et al., 2016). The ethanolic extracts (seed and root) of F. harmonis increased erection in rats and exhibited a high safety level. Additionally, consuming one tablet of F. harmonis daily for 90 days increased sperm motility and sperm count in men (Kassis et al., 2009). In addition, it was found that F. harmonis improves testosterone serum level and sperm count due to its antioxidant potential against toxicity induced in rat testis (Rajeh and Al-Shehri 2019). Similarly, results revealed a decrease in the number of morphologically abnormal sperms post-treatment with the extract on male albino mice at doses 25, 50, 100, and 500 when compared with controls (Adel Mahdi, 2019). Likewise, the administration of F. hermonis was found to ameliorate the detrimental effect of heat stress on semen picture, and the values returned to normal compared to the control (Hanafi et al., 2010). In another report, supplementing methanol extract of F. hermonis with Cycram (Cycram + F. hermonis 0.025 ml/100 g body weight/day) protects induced alterations in sperm abnormalities of male rats against Cycram toxicities. The protective actions of F. harmonis is attributed to the increasing antioxidant enzyme activities and plasma lipid peroxidation suppressing (Girgis et al., 2021).

2.5 Effect on testosterone level

It is well known that spermatogenesis is stimulated by the rise in testosterone levels. Before concluding the ability of botanical extracts to enhance libido and increase the testosterone level, the treatment period must be specified. There are contradicting results reported in acute and subchronic toxicity studies. Zanoli et al. (Zanoli et al., 2003) reported that the acute and subchronic treatments of F. hermonis on males enhanced testosterone levels, improved copulatory performance and stimulated sexual desire in potent and impotent rats, respectively. However, after receiving the extract for 10 days, there was a notable decline in the proportion of rats who were able to ejaculate, as well as a significant drop in testosterone and deterioration of the copulatory pattern.

In another study, testosterone levels markedly increased 30 min after F. hermonis root extract administration and remained elevated for the following 24 h, whether vitamin C was administered alone or in combination. This significant increase in testosterone stopped after 3 days.

However, the 3 weeks of administration caused a significant decline in testosterone in all groups. Contrarily, after 42 days of treatment, testosterone levels rose more in the group receiving F. hermonis and vitamin C than in the group receiving F. hermonis alone. However, the chronic administration of the extract impaired fertility and significantly reduced the testosterone level (Ayuob et al., 2014).

The impact of F. hermonis was not explored on prolactin (linked to sexual dysfunction), 5- alpha-reductase (necessary for the testosterone conversion to dihydrotestosterone) and on aromatase enzyme (essential for the synthesis of oestrogen from testosterone) that are important for sexual function (Smith 2007) (Creasy 2001) (De Ronde and de Jong 2011). In a recent study, Sesquiterpenes such as Ten-uferidin, Ferutidin, and Ferutinin were reported to increase permeability of lipid bilayer and mitochondria, Suggesting that these compounds may increase hormonal levels (Naguib 2003).

2.6 Effect on fertility

The pregnancy rate of females mated with male mice who received F. hermonis extract (42 days) was markedly reduced. However, A significant reduction in offspring /mother was also seen. Moreover, the weight of litters born to those mothers was lower than the control and the number of pregnant mice after being matted to males (administered with F. hermonis/ vit C) was statistically insignificant (Ayuob et al., 2014).

2.7 Effect on epididymis

Chronic administration of F. hermonis (42 days) caused a reduction in ERβ expression in the epididymis and marked degenerative histopathological changes in epididymis (Ayuob et al., 2014). Interference of phytoestrogens in steroid regulation might drop the quality of sperm, thereby fecundity. However, several parameters can be evaluated on epididymis, such as epididymal sperm counts, reproductive organs' weight, sperm density, sperm parameters, epididymal cell protein secretion and many more. However, non of the above parameters were reported to the best of our knowledge using F. hermonis (Glover and Assinder 2006).

2.8 Effect on implantation

The estrogen and progesterone hormones enable the implantation process and the maintenance of embryo implantation (Al-Dissi et al., 2001). The abortifacient and anti- implantation activities of plant secondary metabolites may be accredited to their effects on blood estrogenic and progesterone levels, interfering with the fertility process. The anti-implantation of F. hormonis extract (3 mg/kg/day) for 42 days has been investigated in female mice and resulted in a few viable fetuses and implantations. These alternations were also associated with degeneration of ova, increased connective tissue and ovarian atrophy, while most ovarian follicles suffered follicular atresia (Homady et al., 2002). However, the exact mechanism of this effect of the extract remains unclear.

2.9 Effect on menstrual regulation

Female reproductive problems are a global health issue. The alcoholic extract of F. hermonis root extract (6 mg/kg) showed a moderate estrogenic effect, potent FSH -like, and LH-like activities. The ferutinin content in F. hermonis methanol extract was 92 ± 1.33 mg/g. Molecular docking of target proteins, FSHR and ERα with ferutinin, showed strong interaction. Based on these data, it can be inferred that this plant is a promising female fertility-improving agent (Elmotayam et al., 2022).

2.10 Effect on aged laying hens

Consuming ferula has been associated with higher animal productivity, quality, and yield of animal products such milk, meat, and eggs. In older laying hens, ferula, a dietary supplement, increased the expression of the reproductive genes ERα and FSHR and promoted the production of reproductive hormones. These effects improved production efficiency throughout the post-peak egg-laying period and were advantageous for ovarian function by encouraging follicle development and ovulation. These findings demonstrate that the Ferula supplement can enhance the hormonal profile, reproductive gene expression, egg quality, and productive performance of aged laying hens (Hao et al., 2021).

2.11 Secondary metabolites of plant

Plant secondary metabolites contain diverse compounds synthesized from different biosynthetic pathways (Piasecka et al., 2015). They are generally classified into phenolics, flavonoids, terpenes, alkaloids, and steroids (Kessler and Kalske 2018). Phytochemical studies of F. hermonis showed the presence of different sesquiterpenes, terpenoid and saponins (Al-Ja’fari et al., 2011). However, the hormonal actions of the F. hermonis are mostly accredited to the primary sesquiterpene ester, ferutinin. Several reports have highlighted the ferutinin estrogenic potential (Sattar and Iranshahi 2017) (Elmotayam et al., 2022). Several reports revealed that ferutinin is an effective substitute hormonal therapy to treat and prevent postmenopausal symptoms since ferutinin can imitate the endocrine function of the ovaries (Tiosano et al., 2014) (Ferretti et al., 2012). Ferutinin is also classified as a phytoestrogen with an affinity for the G protein-coupled estrogen receptor and estrogen receptor subtypes ERβ and ERα (Oseni et al., 2008). Molecular docking of ferutinin with ERα and FSH receptors pinpointed the ferutinin contribution in regulating female reproductive function (Elmotayam et al., 2022). The antioxidants of plant secondary metabolites are promising agents that treat oxidative stress (Sm and Mahaboob Basha 2017), repair damage (Smits et al., 2018) and imitate endogenous estrogen actions, modulate and inhbit hormone productions and actions (Mvondo et al., 2017). Numerous in vivo and in vitro techniques have been used to demonstrate the antioxidant capacity of phytochemicals. There are several report on the antioxidant activities of F. hermonis crude extracts (Dehghan et al., 2007, Kose and Sarikuuml 2010) and isolated compound such as daucane sesquiterpenoid esters (Ibraheim et al., 2012) and fucose-rich sulfated polysaccharide (El Rashed et al., 2021).

2.12 Other biological activity

Different biological activities were reported, including antioxidant (El Rashed et al., 2021), antimicrobial (Kuete et al., 2012) (Boghrati and Iranshahi 2019), antidiabetics (Ghareeb et al., 2014), anti-inflammatory (Geroushi et al., 2010), anticancer (Abutaha et al., 2019) (Kuete et al., 2012), antiviral, Alzheimer's, (Ghareeb et al., 2014), immunomodulatory effects and to treat and ameliorate diabetes neuropathy (Zanoli et al., 2005), antispasmodic, and analgesic. The plant also treats dysentery, stomach disorders, fever and skin infections (Elmotayam et al., 2022). Other traditional uses for F. hermonis are increasing cows' milk production, cauterizing wounds, and curing animal infections (Canogullarİ et al., 2009) (See Table 1).