Medicinal Plants Used for the Treatment of Erectile Dysfunction in Ethiopia: A Systematic Review

Background Erectile dysfunction has remained as one of the major global health issues. Since the discovery of phosphodiesterase type 5 inhibitors, a significant portion of the patients has solved the issue of erectile dysfunction. However, the wide distribution of phosphodiesterase type 5 enzymes at various sites of the body led phosphodiesterase type 5 inhibitors to cause various unnecessary outcomes. Hence, it is vital to look for and find optional agents that could solve these limitations. The people of Ethiopia depend heavily on medicinal plants to ease their ailments, including erectile dysfunction. Aim of the study. The current study was carried out to systematically review the traditional medicinal plants used for the management of erectile dysfunction in Ethiopia. Method A systematic and manual search was conducted to retrieve relevant articles published from 2000 to August 2020. Electronic databases of PubMed (Medline), Google Scholar, and grey literature were employed to access the studies. Accordingly, fifty-four published articles and thesis papers were finally included in this study. Result Seventy plant species have been reported for the management of erectile dysfunction in Ethiopia. The commonly recorded family was Fabaceae, followed by Asteraceae, Malvaceae, Convolvulaceae, and Solanaceae. The plant species that represented the highest number of citations were Asparagus africanus, succeeded by Ricinus communis and Carissa spinarum. The commonest plant part used was roots. Majority of the medicinal plants were administered orally. The growth forms of the reported species were primarily herbs followed by shrubs. Conclusion The present review compiled medicinal plants utilized by the Ethiopian community to manage erectile dysfunction. The findings will serve as a reference for the selection of plants for further pharmacological, toxicological, and phytochemical investigations in developing new plant-based drugs used for the treatment of erectile dysfunction.


Introduction
Erectile dysfunction (ED) (also called impotence) is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance [1]. It has remained one of the major global health issues which is usually attributed to age, diabetes mellitus, smoking, cardiovascular diseases, kidney disease, previous operations, psychological factors, and drugs [2,3]. Previously, about 52% of ED in men was seen in the age range of 40 to 70 years [3]. However, recent studies reported that ED is becoming highly prevalent even under the age of 40 [4]. In Africa, around 71.45% of people with diabetes developed ED [5]. In Ethiopia, about 60.4% of diabetic patients were reported with varying degrees of ED and the majority of the patients did not receive any medications [6]. More terribly, if this is not halted as early as possible, the number of ED cases globally is predicted to be 322 million by 2025 [7].
Erectile dysfunction can be managed nonpharmacologically via controlling plasma glucose levels and lipid profiles, avoiding smoking and alcohol drinking, psychological therapy, physical exercising, and external devices [8,9]. Pharmacologically, it can be treated with different drugs including phosphodiesterase type 5 inhibitors (PDE5-Is), such as sildenafil, vardenafil, and tadalafil; apomorphine; and synthetic prostaglandin E1 (alprostadil), phentolamine, and papaverine [8,10]. Of those, PDE5-Is are the most commonly suggested and used first-line treatment options in the world. However, the wide distribution of phosphodiesterase type 5 gene at various sites of the body led PDE5-Is to cause various adverse effects such as headache, myalgia, facial flushing, heartburn, nasal congestion, and vision-related problems. Moreover, disease conditions affecting the upstream nitric oxide pathways have been found with loss of efficacy [10]. Hence, it is vital to look for and find optional agents that could solve these limitations.
Since immemorial times, plants have been used as medicines to treat a myriad of human afflictions. This is because plants are a bank of bioactive compounds responsible for mitigating various disease conditions [11]. The people of Ethiopia depend heavily on medicinal plants to ease their ailments [12]. In Ethiopia, there are also more traditional healers than modern physicians [13]. Furthermore, traditional medicinal plants are considered as accessible, affordable, and acceptable in the community [14]. Around 6500 plant species are reported in the Ethiopian flora; of those, approximately 12% are endemic. In those Ethiopian floras, about 1000 plant species are identified as medicinal plants. However, the majority of the plant species are not yet identified [15]. This highlights that screening of the Ethiopian plants might grant various novel structures that might be unlikely to be discovered from other sources; ultimately, they may serve as lead compounds to fight various ailments including ED. Hence, documenting, compiling, and then assessing the effect of traditionally claimed plant species are worthwhile to come up with novel plant-based therapies.

Aim of the Study
The current study was carried out to systematically compile and document the traditional medicinal plants used for the management of ED or impotence in Ethiopia. The central thesis of this paper is therefore to encourage researchers to scientifically confirm the effect of medicinal plants against the global issue of ED.

Methods
This review was carried out following the recommendations stated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [16]. The search strategy flow chart is presented in Figure 1.

Distribution of Medicinal Plants.
The regions of Ethiopia that showed the highest ethnobotanical records were Oromia (35%) and Amhara (27%) that constituted about two-thirds (62%) of the total ethnobotanical records against ED ( Figure 2). Several medicinal plants have been found in the Oromia region, according to most studies. This may be because, in addition to having a large number of traditional healers, those regions are also Ethiopia's most populous [18]. However, studies on the prevalence of ED in different regions of Ethiopia are limited. Table 1, the current review reported 70 Ethiopian plant species that have traditionally been used to treat ED. The top recorded families were Fabaceae (6 species), Asteraceae (5 species), Malvaceae (5 species), Convolvulaceae (4 species), Solanaceae (4 species), and Euphorbiaceae (3 species) ( Figure 3). Alike this study, Semenya and Potgieter [19] reported that Fabaceae and Asteraceae were among the commonly used families for ED. Ajao et al. [20] also stated that medicinal plants under Fabaceae were the top species used for the management of ED in Sub-Saharan Africa. Moreover, the root of Eriosema kraussianum N. E. Br., Fabaceae, displayed a promising effect for ED in experimental rat models [21]. According to a recent study in Ethiopia, plants in the Fabaceae family are the most commonly used traditional medicinal plants [18]. As a result, these studies highlight the screening of plant species belonging to the Fabaceae family that could be important candidates to bring lead compounds to be used for future optional agents.

Frequently Used Medicinal Plants.
The plant species that represented the highest number of citations were Asparagus africanus Lam. (8 citations), Ricinus communis L. (6 citations), and Carissa spinarum L. (4 citations), as well as Ferula communis L., Aloe macrocarpa Tod., and Tragia brevipes Pax with three citations each. Congruent to the present study, the people of Nigeria also traditionally use the root of Asparagus africanus Lam. for the management of ED [75]. The usage of this plant for the treatment of ED might be due to the presence of saponins [76], because plant species with saponins as their major constituent displayed significant promotion of erection [77]. The second most cited plant species is Ricinus communis L. (also known as castor bean). Recent in vivo studies of Ricinus communis L. have confirmed that it increases serum testosterone levels and multiple majors of sexual activity, supporting the current conventional claim [78]. The third cited plant, Carissa spinarum L., alike the Ethiopian people, the people of South and Central Benin use its roots for the treatment of sexual weakness. As a result, scientific evaluation of these claimed species is needed in order to uncover important leads in the fight against ED.
Plant species like Syzygium aromaticum L., Zingiber officinale Roscoe, and Gloriosa superba L are traditionally claimed in Ethiopia; they scientifically displayed significant      7 BioMed Research International aphrodisiac effect. That is, 50% ethanolic extract of Syzygium aromaticum L., (oral; 100, 250, and 500 mg/kg to rats) improved libido and erection, intromission frequency, mounting behavior, and mating performance [79,80]. Hexane extract of the flower bud of Syzygium aromaticum (L.) Merr. & Perry. (clove) (oral; 15 mg/kg to mice) raised delta (5) 3-beta and 17-beta-hydroxysteroid dehydrogenase (Δ 5 , 3 β-HSD, and 17 β-HSD) and serum levels of testosterone [81]. Aqueous extract of Zingiber officinale (oral; 600 mg/kg to male Wistar rats) was tested for its possible androgenic activity and increased testis relative weight, serum testosterone, testicular cholesterol, and epididymal α-glucosidase activity [82]. Aqueous, chloroform, and alcohol extracts of Gloriosa superba at the dose of 500 mg/kg body weight showed an aphrodisiac effect with an increase in sexual and orientation behavior. Its aphrodisiac effect could be due to the presence of steroids, saponins, and alkaloids [83]. Hence, these studies support the acclaimed use of these plant species as a treatment for sexual dysfunction in Ethiopia.
These days, in Ethiopia, the continuation of traditional plant remedies is highly threatened due to deforestation, overgrazing, environmental degradation, agricultural expansion, and the rise of the population [15]. This, in turn, jeopardizes the extinction of essential medicinal plants which may have stored indispensable compounds that are responsible for addressing the existing global health issues. Therefore, early detection of the pharmacological activities of the reported species against ED is strongly recommended.

Growth Forms of the Medicinal Plants.
The growth forms of the reported species were herb (37%), shrub (34%), tree (22%), climber (4%), and succulent (3%) (Figure 4). This study is consistent with studies conducted by Worku [12] and Yirgu et al. [18] who reported that herbs were the most dominant plant growth forms as well as used as remedies in the Ethiopian traditional medicine. The highest use of herbaceous plants as compared to other growth forms could be due to their accessibility, the higher possibility of obtaining pharmacologically active compounds, and the sociocultural beliefs and practices of the healers in treating the ailment [84].

Plant Parts
Used. The most common plant part used was root (41 species), followed by leaves (7 species), fruit (3 species), and bark (3 species) ( Figure 5). Similarly, in another study, it was reported that the root was the predominant plant part used for the management of ED [85]. The people of South Africa, Limpopo province, also use roots as the most preferred medicinal plant part [19]. In contrast to this study, the people of Western Uganda use leaves as the commonest plant part for ED [86]. Irrespective of the dominancy, however, confirming the pharmacological activity of the claimed plant part is necessary, because most plant parts reside several bioactive principles. 4.6. Mode of Administration. The most common route of administration of the medicinal plants was oral (86%), followed by topical (10%), oral/topical (3%), and nasal (1%) ( Figure 6). In agreement with this study, Semenya and Potgieter [19] mentioned the oral route as the dominant route for ED. The commonly reported cosolvents were "tella (local drink)" (8 species), butter, honey (5 species), and coffee (4 species).

Conclusion
The present review compiles and documents for the first time seventy (70) medicinal plant species used for the management of ED in Ethiopia. Fabaceae was the dominant plant family used for the management of ED in Ethiopia. Asparagus africanus was the most repeatedly cited plant species against ED. Plant species like Syzygium aromaticum L., Zingiber officinale Roscoe, and Gloriosa superba L. are traditionally claimed in Ethiopia; they scientifically displayed significant aphrodisiac effect. This suggests the reported plant species could be a source of a new class of drugs against ED. Thus, the current findings may serve as references for the selection of plants for further pharmacological, toxicological, and phytochemical investigations in developing new plant-based drugs used for the treatment of ED.

Data Availability
The datasets used to support the findings of this study are available from the corresponding author upon request.