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

Sexual disorders such as erectile dysfunction (ED), sterility, and sexual inappetence represent some of the complex reproductive challenges that require addressing the underlying causes. The aim of this paper was to systematically synthesize literature on the ethnobotany, phytochemistry, bioactivities, and safety of plants used as remedies for managing sexual dysfunction and infertility, and improving fertility and virility in the EAC. Through an extensive review conducted in multidisciplinary electronic databases, 171 plant species were identified to 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%). The most used plants are Mondia whitei, Acalypha villicaulis, Combretum illairii, Erythrina abyssinica, Pappea capensis, Rhus vulgaris, and Warburgia ugandensis while roots (44.9%), leaves (21.8%), stem and root barks (16.7%) of shrubs (35%), trees (31%), herbs (26%), and climbers (8%) are the preferred organs for making decoctions (69%). The research strides to date indicate that Citropsis articulata, Cola acuminata, Ekebergia capensis, Plumbago zeylanica, Tarenna graveolens, Urtica massaica, and Zingiber officinale have been assessed for their bioactivity. The majority (71.4%) of the plants either increased testosterone levels and mounting frequency or elicited prosexual stimulatory effects in male rats. More studies investigating the relevant pharmacological activities (aphrodisiac, fertility, and phosphodiesterase-5 inhibitory activities), safety aspects, responsible compounds, and clinical studies are warranted to establish the pharmacological potential of the unstudied species and elucidate the mechanism of action of the bioactive compounds.


Introduction
One of the universal interests enshrined in sustainable development goal (SDG) 3 is good health and well-being. It is linked to and afects 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 fve ailments [2]. Accordingly, three in fve 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][4][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 sufcient for satisfactory sexual performance and vaginal intercourse, typically for a period of more than six months [9]. Tough to diferent degrees, ED afects 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][11][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 afects 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 fbroids 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 afect 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 efects of injectable fertility drugs have limited their acceptability among the general population [19][20][21].
For indigenous communities in developing countries, the use of natural products for prevention and the management of reproductive diseases and conditions are common. Te East African Community (EAC) is one of the regions with distinguished ethnomedicinal knowledge and use of natural products [22][23][24][25]. Te high reliance of these communities on herbal medicine is explained by the exceptionally rich cultural heritage, acceptance, availability, and perceived efcacy [26][27][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 infuences (e.g., consumption of tabooed foods [30], breaching of taboos, witchcraftrelated rites, fetishes or social rules, and use of objects planted by ill people) that interfere with body physiology [26,[31][32][33]. Terefore, 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]. Tese 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 efcacy, phytochemistry, and safety. Te aim of this paper was, therefore, to systematically synthesize literature on ethnobotany, phytochemistry, bioactivities, and the safety profle 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 profles. Tis could open lead to the discovery of molecules that can be used in modern medicine.

Study Design, Literature Sources, and Systematic Search
Procedures. Te Preferred Reporting Items for the Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [35] were followed (Supplementary fle 1). Te 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=CRD4202237 3152). Nine multidisciplinary electronic databases (Scopus, Web of Science, PubMed, Science Direct, Google Scholar, Wiley Online Library, Taylor and Francis Online, Springer Link, and Scientifc 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. Te 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. ® X9 (Tomson Reuters, Philadelphia, PA, USA), and duplicate reports were removed. Te screening was done according to the title and abstract of the articles. Tis 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.

Inclusion and Exclusion Criteria.
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).

Risk of Bias Assessment.
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 fnal risk of bias assessment among them were declared by discussing the prespecifed criteria. Te 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 identifcation 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. Te risks for biases were classifed as either low (total score, 0-1), moderate (total score, 2), or high (total score, 3-4) [38].

Data
Extraction. 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 efcacy reports were extracted. For each dataset, the frst 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).

Data Analysis.
Descriptive statistical methods were used to analyze the collected data. Results were expressed as ranges, percentages, and frequencies and presented as tables and charts. Tese analyses were performed in Microsoft Excel 2019 for Windows (Microsoft Corporation, Washington, DC, USA).

Results and Discussion
3.1. Description of Included Studies. 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. Te 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. Terefore, 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. Tus, 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 fle 2).

Inventory of Medicinal Plants Reported.
Tis review identifed 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). Te 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 diversifed fora with over 7,000 plant species [23,40]. Tis 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]. Te 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 specifc cultural beliefs and traditions or centred around human relationships [42][43][44].
At the genus level, the most represented genera were Acacia (6 species), Combretum ( [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). Te 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.

Growth Habit, Organs
Used, Dosage Forms, and Posology of the Herbal Remedies. Te 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%). Te 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].
Tis 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]. Te 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]. Te 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].

Records removed before screening
Duplicate records removed (n = 47) Records excluded based on titles and abstracts (n = 235) Studies not from EAC (n = 47) Records sought for retrieval (n = 7)

Full-text articles excluded with reasons
Articles not in English or French (n = 11) Review articles (n = 9) Did not provide any data (n = 8) Total studies included in the review (n = 46) Records not retrieved (n = 0) Eligibility

Identification of new studies from databases, registers and other websites Previous studies
Records assessed for eligibility (n = 67) Studies included in a previous version of review (n = 0) Figure 1: PRISMA fow diagram showing the retrieval and exclusion steps of the systematic review adapted from Page et al. [35]. Evidence-Based Complementary and Alternative Medicine 7   [27] Evidence-Based Complementary and Alternative Medicine 9 10 Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 11   [27] Evidence-Based Complementary and Alternative Medicine 13  Kenya [58,59] Evidence-Based Complementary and Alternative Medicine 15 may also be used directly, i.e., chewed raw (16%) or prepared as an infusion (5%) and taken ( Figure 5). Te 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 efects 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 identifed did not have specifcations of the method of preparation and administration of the herbal remedies.

Bioactivity and Phytochemistry of the Reported Plants.
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 fve 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 ofcinale (rhizome) had no signifcant efect on mounting frequency and testosterone levels in rats. Aqueous extract of Tarenna graveolens roots increased testosterone levels but had no signifcant efect 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]. Te latest report is on Plumbago zeylanica, whose aqueous root extract administered at 150, 300, and 450 mg/kg was found to elicit prosexual stimulatory efects in male rats [70]. Tough 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, favonoids, 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 ofcinale) cited in the EAC that have been explored for their phytochemical profles as well as aphrodisiac, procopulatory, and fertility efects ( 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.   (Figure 6), a favonoid present in extracts of A. cepa, enhanced sperm motility through the regulation of protein kinase C-mediated activation of the human voltagegated proton channel and could explain its therapeutic efect 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]. Te third highly investigated species is Mondia whitei. It has been found to increase sexual arousal and copulatory efciency and improve sexual sensation in rats [74][75][76][77][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 ofcinale (ginger) is the most thoroughly studied plant cited in this report. A bioactive compound from this species (zingerone, 5) attenuated zearalenoneinduced 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 ofcinale 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][84][85]. Such studies substantiate that the traditional claims of using the plants in the treatment of sexual dysfunction in EAC may be credible.
Te contraceptive efect 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 efects in fertility studies. Such diferential bioactivities are species-specifc and may depend on the extraction method and solvents employed [87,88].

Clinical Studies.
Clinical evaluation of herbal products is a requirement before they are promoted and used. In this study, we did not fnd 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 ofcinale is the only plant encountered in this study that have been subjected to clinical studies investigating its efect 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.

Adverse Side Efects and Toxicity of Medicinal Plants and
Bioactive Phytochemicals Reported. Further analysis of reports considered in this systematic review showed that no ethnobotanical survey captured the side efects 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 identifed 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 confrmed to be safe. It attenuated reactive oxygen Decoction 69% Infusion 5% Used directly 16% Not specified 8% Roasted and chewed 2% Figure 5: Methods of preparation of herbal remedies used in the treatment of erectile dysfunction and infertility, and enhancing fertility and virility in the EAC. Antifertility efect in rats [101].
Allium cepa L Bulb Aqueous, ethyl acetate Enhanced copulatory behaviour in male rats [71,106]. Ethyl acetate fraction of extract at 200 mg/kg restored the mating behaviour of drug-mediated sexually dysfunction male rats [72].

Fruits
Powder used directly Increase sperm count, motility, and fertilization ability in African catfsh increase in testicular weight, body weight, testosterone levels, and follicle-stimulating hormone [116,117].

Parquetina nigrescens
Leaves Aqueous Te extracts improved sexual activity, behaviour, and competence through improving sexual hormone secretion [102,125].

Sesamum indicum
Seeds Ethanol It promotes body weight gain, seminal parameters, antioxidant action, and testosterone level [126]. Sesamin (4), a compound in this species, resisted cyclophosphamide-induced sperm nuclear maturity and DNA damage by increasing the expression levels of histones H2A and H2B in the testis [127].
(3) Figure 6: Some of the bioactive molecules characterized from extracts of plants reported in EAC for treatment of ED and infertility, and enhancing fertility and virility (based on studies outside the region). Te numbers 1 to 6 refer to the molecules mentioned in Table 3. Table 4: Toxicity profle of plants with reports of efcacy that is used in the treatment of ED and infertility, and enhancing virility and fertility in EAC.

Abrus precatorius
Seeds contain abrin, a toxalbumin with a human lethal dose of 0.1-1 μg/kg [148]. Poisoning is characterized by severe vomiting and abdominal pain, bloody diarrhoea, convulsions, and alteration of sensorium with depression of central nervous system [149].
Allium cepa L Oral administration of extracts to mice at 250 and 500 mg/kg/day for 30-90 days had no visible toxicity symptoms. An oral dose of 30 g/kg/day for 30 days resulted into hypothermia, tachypnea, tachycardia, piloerection, and polyuria in the treated mice [150].
Allium sativum L Its bulb extract induced mild alterations at 300 mg/kg in mice, indicating that it is relatively safe [151].

Cannabis sativa
Cannabidiol (a major nonpsychotropic constituent of this species) in extracts of this species is potentially toxic through the inhibition of hepatic drug metabolism, alterations of in vitro cell viability, reduced fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters [152].

Catha edulis Forsk
Crude khat can damage the liver and kidneys and modulate levels of liver enzymes, urea, creatinine, and electrolytes essential for liver and kidney functions [153].

Mondia whitei
Low toxicity in mice exposed to the extract for 90 days [155].

Parquetina nigrescens
Toxic to rats at 100 and 300 mg/kg of methanol leaf and aerial part extract. Renal haemorrhage, infammation, and hepatic infammation were noted [156].

Conclusion
Te EAC has a rich ethnobotanical knowledge of herbal remedies for the management of sexual dysfunction and infertility, and improving fertility and virility. Tough 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.

Data Availability
Tis is a systematic review article, and no raw experimental data were collected. All data generated or analyzed during this study are included in this article.