Medicinal Plants Used in the Management of Sexual Dysfunction, Infertility and Improving Virility in the East African Community: A Systematic Review.

One of the universal interests enshrined in sustainable development goal (SDG) 3 is good health and well-being. It is linked to and affects other global goals such as SDG 1 (poverty reduction), SDG 2 (end poverty), and SDG 4 (quality and equitable education) [ 1 ]. Critical analysis of the global disease burden shows that one-third of the total world population has more than five ailments [ 2 ]. Accordingly, three in five of the global deaths are ascribed to at least one of the four main noncommunicable diseases (NCDs), namely, cancer, diabetes, cardiovascular, and chronic lung diseases [ 3 – 5 ]. Most global mortalities (up to 71%) are due to NCDs [ 6 ], and 77% of these occur in low- and middle-income countries due to limited access to medical services and poverty [ 7 ]. Whereas the global focus is on the major NCDs, conditions such as sexual dysfunction, infertility, and anaphrodisia (sexual inappetence) represent some of the complex health challenges. Sexual dysfunction refers to the inability to achieve a normal sexual intercourse. It includes orgasmic disorder, retrograded, retarded, premature ejaculation, and erectile dysfunction [ 8 ]. Male erectile dysfunction (ED) or impotence is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance and vaginal intercourse, typically for a period of more than six months [ 9 ]. Though to different degrees, ED affects more than 52% of men in the age bracket of 40 and 70 years. Erectile dysfunction is linked with conditions such as diabetes, sedentary lifestyle, hypertension, obesity, hypercholesterolemia, and smoking [ 10 – 12 ]. On the other hand, infertility is a medical condition characterized by failure to establish a clinical pregnancy after one year of regular and unprotected sex [ 13 ]. Infertility affects more than 48 million couples worldwide. It can be from either one or both partners, but 50% of all cases are due to male infertility [ 14 ]. In women, it may be due to endometriosis (premature ovarian failure) and uterine disorders such as fibroids or thyroid diseases. In males, infertility is associated with defective sperm function, azoospermia, low sperm counts, varicocele, undescended testes, testicular cancer, and low testosterone levels [ 13 , 14 ]. Other risk factors for infertility include diabetes, sexually transmitted diseases, stress, obesity, drug abuse, age, exposure to environmental toxins, radiotherapy, and other cancer treatments [ 15 , 16 ]. Sexual inappetence is a common reproductive challenge that accompanies or is a direct consequence of ED and infertility [ 17 , 18 ]. Sexual inappetence (anaphrodisia or lack of desire/libido) is one of the most common sexual dysfunctions of women. Together, ED, infertility, and sexual inappetence are among the relatively common fecundity challenges that affect couples medically, sexually, and psychologically [ 17 , 18 ]. With medical advancements in assisted reproduction technologies, the use of synthetic agents such as phosphodiesterase type 5 inhibitors (in intracavernosal injection therapy for ED) and stem cell therapy (for infertility) has been encouraged [ 13 ]. However, limited access to medical services, long-term treatment tenure, and side effects of injectable fertility drugs have limited their acceptability among the general population [ 19 – 21 ]. For indigenous communities in developing countries, the use of natural products for prevention and the management of reproductive diseases and conditions are common. The East African Community (EAC) is one of the regions with distinguished ethnomedicinal knowledge and use of natural products [ 22 – 25 ]. The high reliance of these communities on herbal medicine is explained by the exceptionally rich cultural heritage, acceptance, availability, and perceived efficacy [ 26 – 28 ]. In this context, traditional medicine practitioners correlate sicknesses and other medical conditions with their possible causes [ 25 ]. For this reason, herbal medications and posology are prescribed based on the supposed cause of the diseases. Critical cases, or those due to supernatural forces, are managed through diviners' interventions [ 26 , 29 ]. Illnesses are thought to be induced by external polluting influences (e.g., consumption of tabooed foods [ 30 ], breaching of taboos, witchcraft-related rites, fetishes or social rules, and use of objects planted by ill people) that interfere with body physiology [ 26 , 31 – 33 ]. Therefore, traditional management of diseases involves health practices, knowledge, and beliefs that utilize plants and animal- and mineral-based remedies, dispensing of ritually protective herbal medicines or performing rituals for placating spirits [ 26 , 33 ]. These perceptions are similar to traditional medicine concepts in other parts of Africa [ 34 ]. In the EAC, chronic poverty and resource-constrained healthcare systems are common, and the use of herbal remedies for the treatment of sexual dysfunction (ED) and infertility, and enhancing fertility and virility has been sporadically mentioned in ethnobotanical studies. However, no study has systematically collated literature on these medicinal plants with in-depth description and analysis of their claimed efficacy, phytochemistry, and safety. The aim of this paper was, therefore, to systematically synthesize literature on ethnobotany, phytochemistry, bioactivities, and the safety profile of plants used as remedies for managing sexual dysfunction and infertility, and improving fertility and virility in the EAC. As part of an ongoing project, we aimed at identifying highly cited but unstudied species that could be assessed for their aphrodisiac, fertility and phosphodiesterase-5 inhibitory activities, bioactive phytochemicals, and toxicity profiles. This could open lead to the discovery of molecules that can be used in modern medicine.

The Preferred Reporting Items for the Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [ 35 ] were followed (Supplementary file 1 ). The protocol used was registered with the International Prospective Register of Systematic Reviews (PROSPERO) with registration number CRD42022373152 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022373152 ). Nine multidisciplinary electronic databases (Scopus, Web of Science, PubMed, Science Direct, Google Scholar, Wiley Online Library, Taylor and Francis Online, Springer Link, and Scientific Electronic Library Online) and regional university repositories were searched to gather relevant records on ethnobotany, phytochemistry, biological activities, and toxicity of medicinal plants exploited for the management of sexual dysfunction and infertility, and improving fertility and virility in the EAC. The dates on which we last consulted the databases were 7th January 2023, 31st December 2022, 20th November 2022, 20th January 2023, 4th January 2023, 17th January 2023, 11th November 2022, 10th January 2023, 24th November 2022, 2nd December 2022, and 2nd January 2023, respectively. The EAC was considered as the region encompassing Uganda, Kenya, Tanzania, Rwanda, Burundi, South Sudan, and Democratic Republic of Congo (DRC) from April 2022 [ 36 ]. The searches were performed in parallel using search strings specified for a comprehensive search that covered all fields in records but broadened the scope in PubMed advanced search. Within each axis, keywords were combined with the “OR” operator in the Boolean operator and then linked the two axes' search techniques to the “AND” operator. The keywords used were “plant” “erectile dysfunction” “aphrodisiac” “infertility” OR “fertility” “virility” AND “Uganda” “Kenya” “Tanzania” “Rwanda” “Burundi” “South Sudan” “Democratic Republic of Congo.” For example, in Scopus, the search string used was ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND uganda) AND (LIMIT-TO (AFFILCOUNTRY, “Uganda”)) OR ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND Kenya) AND (LIMIT-TO (AFFILCOUNTRY, “Kenya”)) Kenya OR ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND rwanda) AND (LIMIT-TO (AFFILCOUNTRY, “Rwanda”)) OR ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND burundi) AND (LIMIT-TO (AFFILCOUNTRY, “Burundi”)) OR ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND south Sudan) AND (LIMIT-TO (AFFILCOUNTRY, “South Sudan”)) OR ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND Democratic Republic of Congo) AND (LIMIT-TO (AFFILCOUNTRY, “Democratic Republic of Congo”)) OR ALL (plants, AND erectile AND dysfunction, AND aphrodisiac, AND Tanzania) AND (LIMIT-TO (AFFILCOUNTRY,“Tanzania”)) OR ALL (plant, AND infertility AND fertility AND uganda) AND (LIMIT-TO (AFFILCOUNTRY, “Uganda”)) OR ALL (plant, AND infertility AND fertility AND Kenya) AND (LIMIT-TO (AFFILCOUNTRY, “Kenya”)) OR ALL (plant, AND infertility AND fertility AND tanzania) AND (LIMIT-TO (AFFILCOUNTRY, “Tanzania”)) OR ALL (plant, AND infertility AND fertility AND rwanda) AND (LIMIT-TO (AFFILCOUNTRY, “Rwanda”)) OR ALL (plant, AND infertility AND fertility AND burundi) AND (LIMIT-TO (AFFILCOUNTRY, “Burundi”)) OR ALL (plant, AND infertility AND fertility AND south Sudan) AND (LIMIT-TO (AFFILCOUNTRY, “South Sudan”)) OR ALL (plant, AND infertility AND fertility AND democratic republic of congo) AND (LIMIT-TO (AFFILCOUNTRY, “Democratic Republic of Congo”)). In addition, reference lists of the retrieved studies were also manually searched to access additional articles which were screened for their eligibility for inclusion in the study. The literature search was performed between 1st June 2022 and 20th January 2023. All search results were imported into EndNote® X9 (Thomson Reuters, Philadelphia, PA, USA), and duplicate reports were removed. The screening was done according to the title and abstract of the articles. This was conducted independently by 4 authors (CK, CBN, TO, and SO). Two independent reviewers (TO and SO) screened the articles against inclusion criteria, and possible contradictions during article selection and/or extraction were obviated through discussions and consensus. To refrain the authors from bias, (1) only full-text articles or reports published in or translated into English and French; (2) cross-sectional original papers or reports on the ethnobotany, phytochemistry, bioactivities, and clinical trials of plants used in the management of sexual dysfunction and infertility, and improving fertility and virility in EAC; and (3) reports published online until 20th January 2023 were included. Excluded studies were those that (1) provided no data; (2) were neither from EAC nor full-text articles; (3) reported on the use of plants for managing conditions such as menorrhagia, blocked fallopian tubes, inducing twin birth or birth to a particular sex of children; (4) narrative and systematic reviews, or reports not based on original data (expert opinions, editorials, and perspective papers). Quality of the considered reports (risk of bias) was established following the Joanna Briggs Institute quality assessment tool [ 37 ]. Two authors (TO and SO) independently assessed the quality of the included studies. Variations in the final risk of bias assessment among them were declared by discussing the prespecified criteria. The evaluation tool consisted of seven parameters: (1) appropriate sampling design; (2) correct sampling technique; (3) acceptable sample size; (4) adequate study subject and location explanation; (5) appropriate data investigation; (6) use of valid methods for identification of plants and the conditions that they treat; and (7) use of appropriate statistical/ethnobotanical analysis indices. Because most studies met parameters 5 to 7 that were similar across them, we relied on parameters 1 to 4 to ascertain the risk of bias status. A study that did not meet each parameter was scored as 1 if not 0. The risks for biases were classified as either low (total score, 0-1), moderate (total score, 2), or high (total score, 3-4) [ 38 ]. Data were collated in a predesigned Microsoft Excel 2019 standardized sheet. Information on the reported medicinal plants, such as botanical names (and synonyms), plant family, traditional name(s), growth habit, part(s), and their uses (conditions treated), mode of preparation and administration, isolated pure compounds, and relevant efficacy reports were extracted. For each dataset, the first author's last name, year of publication, and country were also extracted. Missing information in some reports such as local names, growth forms, and misspelled botanical names was checked from Google and botanical databases (WFO Plant List, International Plant Names Index, and Tropicos). Descriptive statistical methods were used to analyze the collected data. Results were expressed as ranges, percentages, and frequencies and presented as tables and charts. These analyses were performed in Microsoft Excel 2019 for Windows (Microsoft Corporation, Washington, DC, USA).

Our systematic search ( Figure 1 ) retrieved no previous review on the subject in East Africa. From databases, registers, and other websites, the search returned 396 unique reports published between 1962 and 2022. The highest number of reports were from Scopus ( n  = 172) and Google Scholar ( n  = 108), followed by Web of Science ( n  = 44), Science Direct ( n  = 42), Wiley Online Library ( n  = 11), Taylor & Francis Online ( n  = 7), Springer Link ( n  = 4), PubMed ( n  = 3), regional university repositories ( n  = 3), and SciELO ( n  = 2). Of these, duplicates ( n  = 47) were removed, and 349 unique articles were screened. A total of 235 articles were excluded after reading their titles and abstracts, while 47 others were excluded because they were not from any country within the EAC. Therefore, 67 records were assessed for their eligibility and inclusion in the study. Based on the inclusion and exclusion criteria, some full-text articles were excluded with reasons, namely, (i) articles not in English or French ( n  = 11), (ii) review articles ( n  = 9), and (iii) those that did not provide any data ( n  = 8). A manual search resulted in 7 eligible articles. Thus, data were extracted from a total of 46 articles in this systematic review. Regarding the assessment of the risk of bias among studies, most reports were judged as having a low (47.8%) or moderate risk of bias (34.8%) (Supplementary file 2 ). This review identified 46 reports on plants used in the management and treatment of ED and infertility, and increasing fertility and sexual appetence (virility) in the EAC. Some of the sexual dysfunctions captured from herbalists include erectile disorders, pain during penetration, premature ejaculation, lack of sexual arousal, and short-lasting erections (among men) and lack of orgasm, dyspareunia, lack of sexual arousal, atrophic vaginitis, and short orgasms among women [ 39 ]. In total, 171 plant species from 59 botanical families have been reported for the management of sexual inappetence, i.e., used as aphrodisiacs (39.4%), ED (35.9%), infertility (18.7%), and increasing fertility (6.0%) ( Table 1 ). The highest number of plants cited was from Kenya (96), followed by Uganda (66), Tanzania (24), Rwanda (1), and DRC (1). Burundi and South Sudan had no reports on plants in the category under scrutiny. It is not surprising that Kenya ranked the highest, as it is known to have diversified flora with over 7,000 plant species [ 23 , 40 ]. This is also supported by the fact that most of the ethnobotanical reports reviewed ( n  = 25) were from Kenya as compared to Uganda ( n  = 18), Tanzania ( n  = 7), Rwanda ( n  = 1), and DRC ( n  = 1). Analysis of transregional distribution of the plants revealed that Uganda and Kenya shared 8 species and Tanzania and Kenya shared 6 species while Kenya and Rwanda shared one species ( Tagetes minuta L.). Only one plant ( Pachycarpus robusta ) was cited to be used in Uganda, Kenya, and Tanzania [ 41 ]. The rest of the countries did not share any plant. Such marked divergence in the use of plants across the region could be due to their preference which is related to specific cultural beliefs and traditions or centred around human relationships [ 42 – 44 ]. The majority of the plants retrieved in this study were from families: Fabaceae (16.9%, 29 species), Euphorbiaceae (7.0%, 12 species), Asteraceae (5.8%, 10 species), Apocynaceae, Rubiaceae (5.3%, 9 species each), and Capparaceae (4.7%, 8 species) ( Figure 2 ). Species from these botanical families have been reported to have aphrodisiac and fertility potential in ethnobotanical surveys from Ethiopia [ 45 ], Southern Africa [ 46 ], Iran [ 47 ], and India [ 48 ]. The dominance of families, especially Fabaceae and Asteraceae, is due to the extensive range of their distribution across global biomes [ 49 ]. Moreover, they contain phytochemicals such as phenolics, tannins, and alkaloids which are known to have therapeutic effects [ 50 , 51 ]. At the genus level, the most represented genera were Acacia (6 species), Combretum (5 species), Cassia and Tragia (3 species each), Abrus , Allium , Boscia , Cadaba , Cleome , Croton , Impatiens , Maytenus , Sonchus , Uvaria , Vachellia , and Vernonia (2 species each). The commonly mentioned plants were Mondia whitei (12 times), Warburgia ugandensis (4 times), Acalypha villicaulis , Combretum illairii , Erythrina abyssinica , Pappea capensis , and Rhus vulgaris (3 times each). Some of the plants listed such as Abrus precatorius , Allium sativum , Cola acuminata , Combretum hereroense , Mondia whitei , Plumbago zeylanica , Ricinus communis , and Syzygium guineense are traditionally used for treating infertility and ED in South Africa [ 52 ], Ghana [ 53 ], Cameroon, Guinea, Gabon [ 54 ], Iran [ 47 ], Benin [ 55 ], and Ethiopia [ 45 ]. It is worth mentioning that organs of some of the highly cited species such as Abrus precatorius and Erythrina abyssinica are used in Uganda for rituals and ceremonies of love, weddings, and childbirth [ 56 ]. In regards to the treatment of infertility, most plan species recorded were indicated to be used for the treatment of female infertility ( Table 2 ). The most cited species were Erythrina abyssinica and Combretum illairii (3 times each). Interestingly, some species ( Cadaba glandulosa , Cadaba farinose , Combretum illairii , Hoslundia opposita , and Allophylus pervilleria ) were shown to be used for the treatment of both female and male infertility, which could make them good candidates for further studies of their biological activities. The plants occurred as shrubs (35%), trees (31%), herbs (26%), and climbers (8%) ( Figure 3 ). Figure 4 illustrates which plant organs are widely used in preparation of the herbal remedies, that is, roots (44.9%), leaves (21.8%), and stem and root barks (16.7%). The frequent use of roots is unsustainable but may be linked to the fact that the conditions treated are internal to the body (are hidden), just as root structures are hidden in the ground. On the other hand, the relatively frequent use of leaves could be related to their availability and the fact that they are the photosynthetic sheet of plants that accumulate therapeutic phytochemicals [ 57 ]. This review noted a tendency of including more than one plant part and adjuvants in herbal remedies. For multiple plant parts, a total of 13 species were encountered to be used in combination with others. For example, in Kenya, decoction of Uvaria leptocladon , Boscia coriaceae , and Combretum hereroense roots is used for treating ED. For infertility in women, the roots are used with Croton dichagamus roots [ 58 , 59 ]. Similarly, the decoction of Markhamia zanzibarica roots mixed with Uvaria acuminata roots is administered as an aphrodisiac. For infertility in women, it is used with Salvadora persica and Uvaria acuminata roots [ 58 , 59 ]. A striking example of using adjuvants is from Tanzania where roots of Polygala aphrodisiaca are cooked with a young cock while Duosperma kilimandscharicum leaf and root decoction are taken with goat blood or goat meat soup as an aphrodisiac [ 41 ]. The use of cow and goat milk for preparation of Morus mesozygia roots as an aphrodisiac was also documented in Kenya [ 60 ]. In Uganda, Acanthus pubescens leaves are taken in tonto , a traditional beer prepared from Musa  ×  paradisiaca L. var. sapientum fruits [ 61 ]. The use of more than one plant organ and adjuvants as witnessed in this review are tailored to various reasons. For instance, it may be an obvious way of masking the toxicity of herbal remedies or hiding the secrecy of the formularies [ 62 , 63 ]. The commonest method of preparing herbal remedies is decoctions (69%). This could be because decoction procedures allow for better extraction of the bioactive phytochemicals in plant matrices [ 64 ]. However, the plant organs may also be used directly, i.e., chewed raw (16%) or prepared as an infusion (5%) and taken ( Figure 5 ). The remedies are administered orally, either by taking decoctions, infusions, and eating or chewing. Only one study reported inhalation of fumes from Cannabis sativa leaves for treatment of ED in Uganda [ 65 ]. Aloe volkensii (leaf decoction) in Kenya when utilized for treating infertility is used as a wash for genitals [ 58 ], hinting that internally mediated fertility effects would be unlikely when such herbal remedies are administered orally. While most of the plants had their method of preparation and routes of administration indicated in the use reports, up to 8% of the species identified did not have specifications of the method of preparation and administration of the herbal remedies. To decipher the therapeutic mechanisms and compounds responsible for the bioactivities of the plants reported in EAC, a holistic review of their bioactivity related to the traditional claims and phytochemistry was undertaken. However, only five reports on bioactivity from EAC were encountered for seven plants reported in this study. In this context, the aqueous extract of Citropsis articulata root bark was reported to increase the in vivo levels of serum testosterone and mounting frequency in male rats [ 66 , 67 ]. Joseph et al. [ 68 ] found that aqueous extract of Cola acuminata (fruits) and Zingiber officinale (rhizome) had no significant effect on mounting frequency and testosterone levels in rats. Aqueous extract of Tarenna graveolens roots increased testosterone levels but had no significant effect on mounting frequency while aqueous extract of Urtica massaica leaves elicited no appreciable increase in mounting frequency and testosterone levels in male rats [ 68 ]. Other reports were for ethanolic stem bark extract of Ekebergia capensis which alleviated sexual dysfunction by increasing the mounting frequency and testosterone levels of male rats to 2.38 ± 0.02 ng/ml, 7.68 ± 0.66, and 14.5 ± 0.777 ng/mL at doses of 300, 400, and 500 mg/kg, respectively [ 69 ]. The latest report is on Plumbago zeylanica , whose aqueous root extract administered at 150, 300, and 450 mg/kg was found to elicit prosexual stimulatory effects in male rats [ 70 ]. Though some of these reports supported the traditional use of the medicinal plants, most studies performed preliminary phytochemical screening only but not isolation and structural elucidation of the responsible bioactive compounds. Ndukui et al. [ 69 ], for example, found saponins and steroid glycosides as the major secondary metabolites in Ekebergia capensis stem bark. Traces of tannins, anthraquinones, alkaloids, carotenoids, flavonoids, and anthracyanosides were also detected. Some of these secondary metabolites (tannins, phlobatannins, glycosides, phenols, saponins, quinones, terpenoids, and steroids) were also detected in Plumbago zeylanica [ 70 ]. It is worth noting that none of these studies probed into the mechanism of action of the extracts. We, therefore, performed further searches and retrieved other 9 species (along with Zingiber officinale ) cited in the EAC that have been explored for their phytochemical profiles as well as aphrodisiac, procopulatory, and fertility effects ( Table 3 ). One of the most studied plants in this context is Allium cepa ( A . cepa ) which is locally used in culinary recipes. It has been reported to improve copulatory behaviour in sexually experienced rats [ 71 ]. Malviya et al. [ 72 ] indicated that ethyl acetate fraction of A . cepa bulb at 200 mg/kg restored the mating behaviour (ejaculatory latency, postejaculatory interval, mount, intromission, and ejaculatory frequencies and mount and intromission latencies) of drug-mediated sexually dysfunctional male rats. Quercetin ( 1 ) ( Figure 6 ), a flavonoid present in extracts of A . cepa , enhanced sperm motility through the regulation of protein kinase C-mediated activation of the human voltage-gated proton channel and could explain its therapeutic effect when used in the treatment of human infertility [ 14 ]. Similarly, S-allyl cysteine ( 2 ) isolated from Allium sativum restored erectile function in diabetic rats through inhibiting reactive oxygen species formation via modulation of nicotinamide adenine dinucleotide phosphate oxidase subunit expression in penile tissues [ 73 ]. The third highly investigated species is Mondia whitei . It has been found to increase sexual arousal and copulatory efficiency and improve sexual sensation in rats [ 74 – 78 ]. A follow-up study with a polyherbal formulation containing Mondia whitei , Dracaena arborea , and Bridelia ferruginea deduced that the administration of the formula enhanced the sexual performances and increased the mounting and intromission frequencies of normal rats and prediabetic rats [ 79 ]. Zingiber officinale (ginger) is the most thoroughly studied plant cited in this report. A bioactive compound from this species (zingerone, 5 ) attenuated zearalenone-induced steroidogenesis impairment in TM3 Leydig cell lines [ 80 ] and elicited dose-dependent enhancement of fertility in male and female rats as witnessed by increments in gonadal weights and sperm counts [ 81 ]. A gingerol ( 6 )-rich fraction of ginger at 50, 100, and 200 mg/kg when administered to male rats with carbendazim‐induced toxicity led to increased sperm motility and count but attenuated sperm abnormality [ 82 ]. Herbal extracts from plants such as Allium cepa , Allium sativum , Mondia whitei , and Zingiber officinale improve semen quality and sperm parameters such as concentration, viability, motility, morphology, and DNA integrity through increment in gonadal hormone levels (testosterone and luteinising hormone), sequestering free radicals and enhanced production of nitric oxide [ 83 – 85 ]. Such studies substantiate that the traditional claims of using the plants in the treatment of sexual dysfunction in EAC may be credible. The contraceptive effect observed in plants such as Catha edulis (cathinone) and Cannabis sativa seed extracts is supported by studies which instead link their use to ED [ 86 ]. Nevertheless, plant extracts from certain families have been shown to elicit contradictory effects in fertility studies. Such differential bioactivities are species-specific and may depend on the extraction method and solvents employed [ 87 , 88 ]. Clinical evaluation of herbal products is a requirement before they are promoted and used. In this study, we did not find any clinical studies in EAC that was performed on the extracts or isolated compounds from the cited plants. Further searches for global reports indicated that Zingiber officinale is the only plant encountered in this study that have been subjected to clinical studies investigating its effect on male ED, female sexual function, and infertility [ 89 ]. For example, its capsules improved the sexual function and quality of life in four weeks of a randomized, double-blind clinical trial involving women of reproductive age ( n  = 190) [ 90 ]. Another randomized double-blind placebo-controlled trial found that 3-month oral treatment using 500 mg/powder/day reduced sperm DNA fragmentation in infertile men [ 91 ]. Such promising clinical results demonstrate the need for more clinical trials on species such as Mondia whitei , Acalypha villicaulis , Combretum illairii , Erythrina abyssinica , Pappea capensis , Rhus vulgaris , and Warburgia ugandensis that are widely used in the region. Further analysis of reports considered in this systematic review showed that no ethnobotanical survey captured the side effects of herbal preparations used in the management of sexual dysfunction, infertility, and improving virility in the EAC. However, some of the plants such as Abrus precatorius (roots, leaves, and seeds) cited in the EAC are known to contain highly poisonous compounds (abrine, precatorine, and hypaphorine) [ 139 ]. It could be positioned that the preparation of remedies with more than one plant and plant part or with the addition of adjuvants may be a way of masking the toxicity of the medicinal plants [ 36 , 93 ]. From available toxicological studies, extracts from six of the investigated bioactive species have been shown to be safe ( Table 4 ). Four species ( Abrus precatorius , Catha edulis , Cannabis sativa , and Parquetina nigrescens ) have been indicated to elicit marked toxicity, indicating that their use may lead to adverse reactions in herbal medicine practice. For bioactive compounds identified in the listed species ( Table 3 ), quercetin ( 1 ) is potentially cytotoxic and hepatotoxic at higher doses (100 to 2,000 mg/kg) [ 94 , 95 ]. Similarly, cathinone ( 3 ) is a psychoactive compound that is toxic to sperm cells [ 96 ], and its abuse has been associated with fatal renal, hepatic, and cardiac injuries [ 97 ]. On the other hand, S-allyl cysteine ( 2 ) is considered to be safe, with very minor acute/subacute toxicity in mice and rats (LD 50  > 54.7 mM/kg) when administered intraperitoneally [ 98 ]. Sesamine ( 4 ) is the major lignan in sesame seeds and has been confirmed to be safe. It attenuated reactive oxygen species and nitric oxide production in zebra fish (LD 50 ) [ 99 ]. Toxicity studies with zingerone ( 5 ) and gingerol ( 6 ) have shown that they are safe [ 100 , 104 ].

The EAC has a rich ethnobotanical knowledge of herbal remedies for the management of sexual dysfunction and infertility, and improving fertility and virility. Though we retrieved 171 medicinal plants being used, most of the species have not been subjected to phytochemical and bioactivity studies that lend credence to traditional claims of using them. We recommend performing toxicity studies and clinical trials using compounds isolated from some of the investigated species. Five highly cited unstudied species from this review ( Acalypha villicaulis , Combretum illairii , Erythrina abyssinica , Pappea capensis , Rhus vulgaris , and Warburgia ugandensis ) have been selected for further investigation of their phytochemistry, aphrodisiac, fertility, and phosphodiesterase-5 inhibitory activities.