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Review Article | Open Access

Volume 2018 |Article ID 4076430 | 17 pages | https://doi.org/10.1155/2018/4076430

Effects of Withania somnifera on Reproductive System: A Systematic Review of the Available Evidence

Academic Editor: Leon Spicer
Received23 Sep 2017
Accepted07 Dec 2017
Published24 Jan 2018

Abstract

Introduction. Withania somnifera (WS) also known as ashwagandha is a well-known medicinal plant used in traditional medicine in many countries for infertility treatment. The present study was aimed at systemically reviewing therapeutic effects of WS on the reproductive system. Methods. This systematic review study was designed in 2016. Required data were obtained from PubMed, Scopus, Google Scholar, Cochrane Library, Science Direct, Web of Knowledge, Web of Science, and manual search of articles, grey literature, reference checking, and expert contact. Results. WS was found to improve reproductive system function by many ways. WS extract decreased infertility among male subjects, due to the enhancement in semen quality which is proposed due to the enhanced enzymatic activity in seminal plasma and decreasing oxidative stress. Also, WS extract improved luteinizing hormone and follicular stimulating hormone balance leading to folliculogenesis and increased gonadal weight, although some animal studies had concluded that WS had reversible spermicidal and infertilizing effects in male subjects. Conclusion. WS was found to enhance spermatogenesis and sperm related indices in male and sexual behaviors in female. But, according to some available evidences for spermicidal features, further studies should focus on the extract preparation method and also dosage used in their study protocols.

1. Introduction

Infertility is a complicated problem with physiologic, psychologic, and economic aspects. Infertility is defined as the inability to conceive after one year of unprotected sexual intercourse [1]. About 15 percent of couples worldwide suffer infertility [2]. One in six couples is involved with infertility during their reproductive age. Based on World Health Organization report, 60–80 million couples suffer from failure of fertility worldwide [3]. It may be difficult to diagnose the reason for infertility but it may include either dysregulation of sex hormonal axis in both men and women or anatomical anomalies [4]. According to different studies, approximately 20%–50% of infertility is due to male, 40% is due to female factors, and 25% of causes are unknown [1, 5].

The causes of male infertility are classified as pretesticular, testicular, posttesticular, and unknown. Sperm abnormality causes 30%–40% of all infertility [6]. Pretesticular causes include disorders in the hypothalamus-pituitary-gonadal axis, systemic diseases, sexual dysfunction, and psychopathy. Testicular dysfunction due to multiple reasons as infection, trauma, varicocele, cryptorchidism, chromosomal anomalies, alcohol, cigarettes, drugs, and radiation is another cause of male infertility. Posttesticular disorders comprise the abnormalities in sperm transfer such as obstruction or dysfunction of epididymis and ductus deferens, immunological defects, and anatomical abnormalities like hypospadias [7, 8].

Different etiologies of female infertility include ovarian diseases, tubal disorders, endometriosis, uterine pathologies, cervical problems, congenital anomalies, and dysfunction of the hypothalamus-pituitary-ovarian axis and systemic diseases [1, 9]. Treatment of infertility may vary due to the different etiologies but it ranges from simple pharmacological treatments to advanced laboratory procedures and surgeries. In developing countries, due to the lack of adequate equipment to diagnosis and treatment for many infertility causes and also probable long-term diagnosis process, many people tend to use alternative and complementary medicine [10]. Herbal medicines are one of the main modalities used in this field.

Withania somnifera, (WS) also known as ashwagandha, Indian ginseng, winter cherry, horse smell, Kaknaje Hindi, is a well-known medicinal plant in Solanaceae family used in traditional medicine in many countries such as Iran and India [11]. This plant is known to cure impotency and increase sex appeal and fertility when used solitarily or in combination with other medications [12, 13]. This wild plant grows in dry and hot-semiarid climate such as southern Mediterranean region, Canary Islands, and northern Africa to northern India (Iran, Jordan, Sudan, Palestine, Afghanistan, and Egypt) [14, 15]. Different parts of this plant such as roots, leaves, flowers, seeds, stems, and fruits are used as remedy in traditional medicine of different countries [1618]. Many phytochemicals have been extracted so far from this plant with possessing different pharmacologic and biological properties [19].

WS has been recommended for management of polyarthritis, lumbago, painful swellings, premature ejaculation, oligospermia, plague, asthma, vitiligo, general debility, impotency, ulcers, uterine infection, leucorrhoea, hemorrhoid, and orchitis in traditional Persian medicine [60, 61]. All these therapeutic uses suggest its anti-inflammatory, aphrodisiac, semenogogue, and deobstruent features [6265]. As far as there are no wide-spectrum and specific studies or systematic reviews about therapeutic effects of WS, on male and female reproductive system, the present study was trying to systemically review therapeutic effects of WS on reproductive system and fertility disorders.

2. Methods

2.1. Study Design and Search Strategy

In this systematic review which was performed in 2016, required data were gathered using databases such as Google Scholar, PubMed, Scopus, Web of Science, and Cochrane Library. The keywords used in present study were “Withania somnifera” (also equivalent terms), “fertility”, “conceive”, “infertility”, “women”, “men”, “female”, “male”, “semen”, “sperm”, “spermicidal”, “Sertoli”, “prolactin”, “follicular stimulating hormone”, “luteinizing hormone”, “testosterone”, “libido”, “aphrodisiac”, “behavior”, “sexual”, “spermatogenesis”, “reproduction”, “semenogogue”, “impotency”, “spermatozoa”, “estrogen”, “pregnancy”, “gonadotropin releasing hormone”, “testis”, “leydig”, and “ovarian”. The time period between 1965 and 2017 was selected. Also, to increase the scope of the study, manual search in some of the valid journal databases was performed. All in vitro or in vivo studies about the effects of WS on reproductive system and fertility among human or animal subjects were included in the study. Review studies, case reports, letter to editors, and short communications were excluded from the study.

To search for unpublished articles (grey literature), European Association for Grey Literature Exploitation (EAGLE) and Health Care Management Information Consortium (HMIC) were searched.

2.2. Articles Evaluation

The selected papers extracted from the databases were assessed by two investigators using Consort 2010 checklist. Discrepancies between the two raters were referred to the third investigator. First, the titles of all articles were reviewed to screen for eligibility and those found to be irrelevant with the objectives of the study were excluded from the study. In the later stages, the abstracts and full-text articles were, respectively, examined to identify and exclude those that did not match the inclusion.

2.3. Data Extraction

One reviewer extracted the data from the included studies while a second author checked the results. Any disagreements were resolved by a discussion of reviewers. Data for the primary objective of the review was collected from the full text of each publication and included the trial name, year of publication, type of study, sample size, results, and other characteristics.

2.4. Statistical Analysis

Statistical analysis was performed by SPSS software package version 16.0 for windows (SPSS Inc., Chicago, USA) [66]. Quantitative data are presented as mean ± standard deviation (SD), while qualitative data are demonstrated as frequency and percent (%).

3. Results

The flowchart of the study is shown in Figure 1. Of 459 recognized studies, 42 studies were included in the present study. These studies were composed of 8 human studies (7 studies on men and one among women), 28 animal studies (20 studies of male animals and 8 studies on female animals), 5 animal-cellular studies, and one cellular study. In these studies, roots (29 studies), leaves (7 studies), fruits (2 studies), unknown extract (2 studies), and stems (1 study) were used. Characteristics and results of human, animal, and animal-cellular studies are shown in Tables 1, 2, and 3, respectively. In all human studies, root extract was used. The duration of human studies ranged from 60 to 90 days. Mostly the WS extract was used orally and once daily in 50 percent of human studies. In the most studies, no side effects were found for WS extract during of studies [17, 20, 21, 30, 36, 40, 45, 46, 58].


NumberAuthor/yearDesignParticipantIntervention protocolDuration
of study
Results PlacePart/
compound

(1)Mahdi et al., 2011 [12]Controlled, prospective,
before and after clinical trial
Normozoospermic infertile men (); 3 groups;
heavy smoker ), under psychological stress (), unknown etiology (), control fertile men ()
5 g/d/PO/single dose with milk3 monthsNo marked change in semen volume, liquefaction time (, ), ↑ sperm concentration (, ), ↑ sperm motility in cigarette smokers and psychological stress groups (), ↑ LH, FSH, ↑ T, PRl, cortisol, LPO in seminal plasma and ↑ SOD in 3 groups (), ↑ CAT in psychological stress groups (), ↑ glutathione, ↑ ascorbic acid in psychological stress and unknown etiology groups (), ↑ vitamin E, ↑ vitamin A in 3 groups () after treatment compared to before treatment, ↑ 14% rate of success of pregnancy in the partnersIndiaRoot powder

(2)Ambiye et al., 2013 [20]Double-blind, randomized, placebo-controlled clinical trial (a pilot study)Oligospermic infertile male (); 2 groups: WS () and placebo ()675 mg: 1 capsule of 225 mg/thrice a day/PO90 days ↑ 53% semen volume, ↑ 167% sperm count, ↑ 57% sperm motility (), ↑ 17% serum T (), ↑ 34% LH () after 90 days of therapy compared to the baseline values on Day 0
GASE and GATE in WS-treated compared to placebo were excellent (68.75%)
IndiaFull spectrum
root extract

(3)Dongre et al., 2015 [21]Double-blind, randomized, placebo-controlled clinical trial (a pilot study)Healthy married women (); WS (); placebo ()Capsules of 300 mg/
twice daily/PO after food
8 weeks ↑ total score (FSFI) (), ↑ FSFI domain score for “arousal” (), “lubrication” (), “orgasm” (), “satisfaction” (), ↑ FSDS score (), ↑ number of successful sexual encounters () after treatment compared to placebo
PGART and PGATT in both groups were excellent, no toxic effect during 8 weeks in WS-treated group
IndiaHigh-concentration root water extract

(4)Mamidi et al., 2014 [22]Randomized, single-blind, placebo-controlled, parallel-group studyMen with ED (); 2 groups: WS
() and placebo ()
Four tablets 500 mg thrice a day (6 g)/PO after food60 days ↑ 10.52% on EDSI, ↑ 4.18% on IMHQOL, ↑ 39.22 on QEQ in WS group, ↑ 11.20% on EDSI, ↑ 5.95% on IMHQOL, ↑ 45.74% on QEQ () in control group. No marked difference between two groups on all the scales (). No significant effect in length, circumference, angle of erection of penis after treatment between both groupsIndiaRoot powder

(5)Shukla et al., 2011 [23]Controlled, prospective,
before and after clinical trial
Infertile men (); 3 groups: NZ (), OZ (), AZ () and control, healthy fertile men ()5 g/day/single dose with milk3 months Sperms apoptosis in NZ and OZ men, ROS of spermatozoa in OZ and AZ infertile men (), ↑ metal ions concentration (Cu2+, Zn2+, Fe2+, Au2+) of seminal plasma in 3 groups () after treatment comparison to before treatmentIndiaRoot powder

(6)Gupta et al., 2013 [24]Controlled, prospective, before and after clinical trialInfertile men (); 3 groups:
NZ (), OZ (), AZ () and control, healthy fertile men ()
5 g/day/PO/
single dose with milk
3 months ↑ sperm concentration, ↑ sperm motility, ↓ LPO, ↑ LH, ↑ T (), ↓ FSH, ↓ PRL, ↑ ALT, ↑ AST, ↑ LDH, ↑ IDH, ↑ alanine, ↑ glutamate, ↑ citrate, ↑ GPC, ↑ histidine, ↓ phenylalanine in seminal plasma, after treatment compared to before treatment in NZ, OZ, AZ groups ()IndiaRoot
powder

(7)Ahmad et al., 2010 [25]Controlled, prospective, before and after clinical trialInfertile men (); 3 groups:; NZ (), OZ (), AZ () and control, healthy fertile men ()5 g/day/PO with milk3 months ↑ sperm concentration, ↑ sperm count (), ↑ sperm motility, LPO (), ↑ SOD, ↓ protein carbonyl groups in seminal plasma (), ↑ CAT (), ↑ glutathione (), ↑ vitamins A, E, and C (), ↑ seminal fructose (), ↑ T (), ↑ LH, ↓ FSH, ↓ PRL in all of the groups of infertile men after treatment compared to before treatment, ↑ semen volume in NZ and OZ groups after treatments compared to before treatmentsIndiaRoot
powder

(8)Mamidi and Thakar, 2011 [26]Randomized, single-blind, placebo-controlled, parallel-group studyMen with ED (); 2 groups: WS () and control ()Four tablets 500 mg/PO/thrice a day after food60 days ↑ 12.6% IIEF in WS-treated and ↑ 19.11% in placebo group (), no significant effect in the management of psychogenic erectile dysfunction and IIEF in WS-treated group compared to placebo group ()IndiaRoot powder

ND, not determined; WS, Withania somnifera; FSH, follicular stimulating hormone; LH, luteinizing hormone; ALP, alkaline phosphatase; Cd, cadmium; GSH, glutathione peroxidase; SOD, superoxide dismutase; CAT, catalase; MDA, malondialdehyde; STD, seminiferous tubules diameter; T, testosterone; PRL, prolactin; LPO, lipid peroxidation; GABAAg, amino butyric acid; TG, triglyceride; EDSI, erectile dysfunction severity index; FSFI, female sexual function index; FSDS, female sexual distress scale; IMHQOL, Internet mental health quality of life scale; QEQ, quality of erection questionnaire; NZ, normozoospermic; OZ, oligozoospermic; AZ, asthenozoospermic; IDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GPC, glycerophosphocholine; IIEF, international index of erectile function; PGART, patient’s global assessment of response to therapy; PGATT, patient’s global assessment of tolerability to therapy; GASE, global assessment scale for efficacy; GATE, global assessment scale for tolerability; ↑, increase; ↓, decrease.

NumberAuthor/yearPlant extractParticipantIntervention protocolDuration
of studies
Results Place

(1)AL-Qarawi et al., 2000 [27]Lyophilized aqueous extractImmature female Wistar rats (); 6 groups:
17-day-old rats; G1 (10), G2 (10), control (),
25-day-old rats G1 (), G2 (), control ()
G1 = C. coccineumG2 = W. somnifera
47 mg/100 g body
weight/stomach tube
6 daysIn 25-day-old rats; ↑ FSH levels (), ↑ ovarian weight and deep folliculogenesis and proliferation of granulosa ()
In 17-day-old animals; ↑ body weight () no significant changes in the ovarian weight and folliculogenesis and FSH and LH
Kingdom of Saudi Arabia

(2)Mali et al., 2008 [28]50% ethanolic extract
of fruits
Fertility proven, adult healthy male albino rats50 mg/kg/PO/day60 days ↓ sperm motility, ↓ density of testicular and cauda
epididymal sperms, ↓ weight of testes and seminal vesicle, ↓ ascorbic acid, ↓ sialic acid, ↓ cholesterol, ↓ protein, ↓ fructose, ↓ acid phosphatases, degenerative changes in the seminiferous tubules and germinal epithelium, ↓ spermatogenic elements, in treated rats
India

(3)Belal et al., 2012 [29]Root powerAdult male albino rats (); alloxan induced diabetes; 4 groups: control (), nondiabetic WS-treated (), diabetic rats (), diabetic group treated with WS ()Mixed with basal diet at ratio of 6.25%/po4 weeksNo significant alteration estrogen and cholesterol in treated with WS both diabetic and nondiabetic rats compared to controls groups (), progesterone in both diabetic and nondiabetic treated with WS (), T (), LH () in nondiabetic treated with WS groups compared to the control group, ↓ TG in diabetic treated with WS compared to diabetic rats (), ↓ FSH in WS-treated groups (), not considered hypoglycemic effectEgypt

(4)Ilayperuma et al., 2002 [30]Methanolic extract of rootsProven fertility, adult male Wistar rats (); 4 groups:
control 1, control 2 () and WS 1, WS 2 ()
3000 mg/kg/PO/day7 daysConsiderable weakness in libido, sexual performance, sexual vigour, and penile erectile dysfunction, no marked change in SGOT, SGPT, urea nitrogen, pH of the seminal vesicular fluid, wet weight of the organs and no deaths in treated periodSri Lanka

(5)Abdel-Magied et al., 2001 [31]Lyophilized aqueous extracts of leavesImmature male Wistar rats (); 3 groups: control (), C. coccineum (), WS ()47 mg/100 g body weight/d/stomach tube6 days ↑ LH, FSH, T, ↑ testicular weight, ↑ STD, ↑ number of seminiferous tubular
cell layers (CL) and diameters, ↑ spermatogenesis in treated groups compared to control group
Saudi Arabia

(6)Dhas et al., 2015 [32]Ethanolic
extracts
Female and male fish (Etroplussuratensis); 4 groups:
control and WS with different ratio + M. pruriens + Moringa oleifera
120-200-300 mg/kg WS
thrice in a day
ND ↑ Gonadosomatic Index (GSI), ↑ fecundity, ↑ striping response, ↑ percentage of fertilization, ↑ percentage of hatching, percentage of deformed, ↑ formed larvae, ↑ volume of milt, ↑ number of sperm cell, ↑ percentage of sperm motility, ↑ sperm survival time, ↑ percentage of active sperm after treatment diets especially the EXD3 contain 300 mg/kg ()India

(7)Shaikh et al., 2015 [33]Glycowithanolides extract of fresh leavesAdult Swiss albino male mice (); 4 groups:
D-galactose treated (), control (), protective (), curative ()
20 mg/kg/injected subcutaneously20 days ↑ epididymal sperm count (), ↑ weight of testes and epididymis and body () and returned to normal histology of testes in protective and curative group compared to D-galactose treated group and no significant increase in weight of testes, epididymis and seminal vesicle in the curative compared to protective groupIndia

(8)Kumar et al., 2015 [15]Ethanolic root extractMales Charles Foster rats (); arsenic induced testicular toxicity; 3 groups: control (), arsenic and WS-treated ()100 mg/Kg/PO/day30 days ↑ sperm count, ↑sperm motility, ↑ T, LH, LPO (), normalization the spermatogenetic stages, after treatment compared to before treatmentIndia

(9)Walvekar et al., 2013 [34]Glycowithanolides extract of fresh leavesAdult Swiss albino male mice (); 4 groups: D-galactose (), control (), protective (),
curative ()
20 mg/kg injected subcutaneously20 days total and mitochondrial LPO, fluorescence product in testes, epididymis and seminal vesicle in protective and curative groups () compared to D-galactoseIndia

(10)Kumar et al., 2015 [35]Alcoholic root extract (5)%Female Swiss albino mice; chlorpyrifos induced toxicity ovaries; 4 groups: control, chlorpyrifos, WS, curcuma50 mg/kg/day8 weeks ↓ estrogen, ↓ cholesterol and restoration in germinal epithelium, graafian follicles and corpus luteum of ovary in WS-treated group compared to chlorpyrifos groupIndia

(11)Patil et al., 2012 [36]Ethanolic extract of fresh leavesHealthy male albino mice (); D-galactose induced stress; 3 groups: D-galactose (), control (), WS + D-galactose ()2% extract15 days ↓ total and mitochondrial LPO, sperm count, recovery of degenerative changes in histological structure both testis and epididymis after the treatment WS compared with D-galactose groupIndia

(12)Rajashree et al., 2011 [37]Alcoholic root extractMale albino rats (); streptozotocin-induced diabetic; 4 groups: STZ (), normal
Control (), WS + STZ (), STZ + insulin ()
500 mg/kg/PO/day30 days weight of testes, caudal sperm count, weight of cauda epididymis in WS-treated diabetics compared to insulin treated groupsIndia

(13)Kiasalari et al. 2009 [38]Root
powder
Wistar male rats (): ZTZ induced diabetic; 4 groups:
ZTZ (), control (), WS + STZ (), sham ()
Plant-mixed pelleted food at ratio of 6.25%/po/day4 weeks ↓ FSH (), LH (), progesterone (), T (), nonsignificant changes on estrogen in somnifera-treated diabetic, nondiabetic group compared to nontreated diabetic and nondiabetic, ns difference glucose, cholesterol after WS treatment, ↓ TG in somnifera-treated diabetic groupIran

(14)Rahmati et al., 2016 [39]Root powderMale rats (); 4 groups: morphine induced addiction: addicted (),
control (),
WS-treated control (),
WS-treated addicted ()
Plant-mixed pelleted food at ratio of 6.25%
( g/kg/day)
21 days estrogen in WS-treated control groups () compared to control group, no marked effect in addict group, T, LH in WS-treated addicted group () compared to control and addicted groups, FSH in WS-treated control group compared to control group ()Iran

(15)Prabu et al., 2014 [40]Hydroalcoholic root extractMale Wistar rats (); 2 groups: control () and WS ()1000 mg/kg/PO (gavage)70 days ↓ WBC, ↓ LYM values (), insignificant neutrophil, RDW, ↓ monocyte, ↓ eosinophil, ↓ RBC counts, ↓ PCT values, no significant difference in body weight, testes and seminal vesicles weight, sperm count, morphology and biochemical parameters between treated group and control group (). No side effects in during treatmentIndia

(16)Bhargavan et al., 2015 [41]Ethanolic root extractHealthy adult male Wistar rats (); 4 groups: ethanol induced oxidative damage in the testes (), control (),
WS + alcohol (), WS ()
200 mg/PO/day28 days testicular weight, body weight and recovered histopathological changes in the seminiferous tubules, sperm count, motility, ↓ sperm abnormality, ↓ MDA (), GSH (), CAT (), T in alcohol + WS cotreatment group compared with alcohol groupIndia

(17)Nirupama and Yajurvedi, 2015 [42]Chloroform and ethanolic extracts of rootsAdult male rats (); 6 groups: chronic stress exposed on testis (), control (), positive control (), stress + ethanolic WS (), stress + mifepristone (), stress + chloroform extract of WS ()10 mg/kg/day/orally (intubation)1 month testicular 3β HSDH activity, ↓ adrenal 3β HSDH activity (), ↓ abnormal sperm count (), ↓ MDA, T (), total epididymal sperm count (), spermatogenesis, (SOD, CAT, GPx, GST, GR), ascorbic acid, tocopherol in WS-treated group compared to stressed ratsIndia

(18)Kumar et al., 2013 [43]Alcoholic extract of rootFemale Swiss albino mice (); chlorpyrifos induced toxicity of ovary; WS + chlorpyrifos (); control ()50 mg/kg/day8 weeks ↓ estrogen and cholesterol (), recovery of ova, granulosa cells, germinal epithelium, mature graafian follicle, mitochondrial cristae of ovary and chromatin material after WS administration compared to before treatmentIndia

(19)Kumar et al., 2012 [44]Aqueous extract of rootsMale mice (); endosulfan exposed spermatozoa; 2 groups: control () and endosulfan + WS ()1000 mg/kg/day8 weeks ↓ MDA, T, ↓ calcium, restoration of spermatozoa structure such as normal plasma and nuclear membrane, Golgi complex, chromatin material and mitochondrial cristae after WS treatment compared to before treatmentIndia

(20)Kaspate et al., 2015 [45]Hydroalcoholic extract of rootsHealthy female Wistar rats with tubal ligated (): 4 groups with various doses of WS100, 200 and
300 mg/kg/PO/day
21 days sexual behavior, ↓ run time, proximity time, ↓ retreats (, ), serum estradiol with doses 200 and 300 mg/kg (, ), normalization in histology of genital organs like vagina, uterine horn and ovary in estrous female rats compared to estrous control female ratsIndia

(21)De and Chakraborty, 2016 [46]Root powderMixed-sex juveniles of Niletilapia (Oreochromisniloticus) (); 9 groups: control () and WS with various concentration ()0.0, 2.0, 3.0, 3.5, 5.0, 6.5, 7.0, 8.0, 9.5 g/kg mixed food30 daysConcentrations up to 7.0 g/kg have no side effect (), percentage of male and ↓ percentage of female with any concentration of WS (), high percentage of survival and male were at the concentration of 6.5 g/kg compared to control groupIndia

(22)Jasuja et al., 2013 [47]Methanolic extract of leaves and rootsMale albino rats (); 6 groups: control (), acephate for 15 days (), acephate for 30 days (), acephate for 15 days + WS for 15 days (), acephate + WS for 30 days (), acephate for 15 days and no treatment for next 15 days ()100 mg/kg/PO/day15–30 days ↓ testicular LPO, GSH, SOD, CAT, T, FSH, LH (, ), recovery of sperm count, motility, morphology, testis histology after WS treatment compared with acephate groupsIndia

(23)Saritha et al., 2011 [48]Leaf powder-mixed pelleted foodFemale rats (); 5 groups: control (), 0.05% Pb + normal pellet diet (), 0.05% Pb + WS diet (), 0.15% Pb + normal pellet diet (), 0.15% Pb + WS diet ()500 mg/kg/PO/day45 days ↓ length of the diestrus phase (), the number of implantations (), the number of live foetuses (), ↓ pre- and postimplantation losses after treatment with WS compared with the rats exposed and no toxicity in all of animals during treatmentIndia

(24)Garg and Parasar, 1965 [49]Root powerAlbino mice of either sex (); 2 groups: control () and WS group ()25 mg/PO/day10 days ↓ fertility rate by 25%, ↓ mating behavior, ↓ number of pups per litter from 5.25 to 3.0 in WS treatment group compared to control groupIndia

(25)Sahin et al., 2016 [50]Hydroalcoholic extract of rootsMale rats (); 5 groups: control (), sildenafil-treated (), Mucuna (), Tribulus (), WS ()300 mg/kg/PO/day8 weeks No significant changes in body weight and reproductive organ weights, abnormal sperms, serum biochemical and hematology parameters (), ↓ mounting latency and intromission latency (), mounting frequency and intromission frequency values (), sperm counts, sperm motility, ↓ MDA, T () in WS groups compared to control groupTurkey

(26)Shaikh et al., 2014 [51]Glycowithanolides extract of fresh leavesAdult Swiss albino male mice (); 4 groups:
D-galactose treated (), control (), protective (),
curative ()
20 mg/kg/injected subcutaneously20 days SOD, GPx, CAT in testes and accessory reproductive organs () in protective and curative group compare to D-galactose groupIndia

(27)Saiyed et al., 2016 [52]Hydroalcoholic extract of rootsFemale Wistar rats (); letrozole induced PCOS: 4 groups: negative control (), positive control (), WS and TT (), standard group with clomiphene citrate ()198 mg/kg28 days number of days in estrus phase (), ↓ duration of diestrus phase in test group () returned to normalcy on FSH, ↓ LH, ↓ T, ↓ estradiol and recovery of ovary and uterine weight but no significant, ↓ cholesterol () compared to positive control groupIndia

(28)Mali, 2013 [53]Hydroalcoholic extract
of fruits
Healthy, male albino rats (); 2 groups: control () and WS ()200 mg/kg/day/po60 days ↓ primary and secondary spermatocytes, mature sperms, ↓ weight of testis and other accessory reproductive organs, abnormal seminiferous tubules, ↓ protein, ↓ sialic acid, ↓ fructose, ↓ ascorbic acid (, ) in WS groups compared to control groupIndia

ND, not determined; WS, Withania somnifera; FSH, follicular stimulating hormone; LH, luteinizing hormone; ALP, alkaline phosphatase; Cd, cadmium; GSH, glutathione peroxidase; SOD, superoxide dismutase; CAT, catalase; MDA, malondialdehyde; STD, seminiferous tubules diameter; T, testosterone; PRL, prolactin; LPO, lipid peroxidation; g, amino butyric acid; TG, triglyceride; EDSI, erectile dysfunction severity index; FSFI, female sexual function index; FSDS, female sexual distress scale; IMHQOL, Internet mental health quality of life scale; QEQ, quality of erection questionnaire; NZ, normozoospermic; OZ, oligozoospermic; AZ, asthenozoospermic; IDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GPC, glycerophosphocholine; TT, Tribulus terrestris; WBC, white blood cell; LYM,lymphocytes.; , increase; ↓, decrease.

NumberAuthor/yearType of studyParticipantIntervention protocolPlant/extractDuration of studiesResultsPlace

(1)Bhattarai et al., 2010 [54]In vitroGnRH neurons of male and female juvenile mice brain () under patch clamp techniqueBath application of the 400 ng/μl under condition of high clMethanolic extract of root powderND Production of potent membrane depolarization of the GnRH neurons, ↑ spontaneous action potentials, ↑   memetic activityRepublic of Korea

(2)Kataria et al., 2015 [55]In vitro & in vivo
(animal)
Rat hypothalamic GnV-3 cells & Wistar adult male rats (); 2 groups: control () and WS ()In vitro: 0.05–1.5% ASH-WEX
In vivo: 4 ml/kg ASH-WEX/oral route
Aqueous extract of leaves24 h & 21 daysIn vitro: significant changes in morphology and physiological in GnV-3 as cell body size and neurite process, ↓ LDH levels at higher concentrations of WS, ↑ release of GnRH extra cellularly in the GnV-3 cells after treatment with WS, no elevated cytotoxicity, viable of 61.2% of cell after WS
In vivo: no marked difference in GnRH level in WS-treated as compared to control group but upregulation of GnRH expression after treatment with WS
India

(3)Singh et al., 2013 [56]In vitro & in vivo (animal)Rat semen & proven fertility, male albino rat (); 3 groups: control (), WS 25 mg (), WS 50 mg ()2, 4, 6, 8, 10, 25 & 50 mg/kg/day/orallyEthanolic extract of stems20 s & 60 daysIn vitro: minimum effective concentration of WS to kill 1 million sperm in 20 s was around 10 ± 0.066
In vivo: ↓ sperm density of cauda epididymal sperms, ↓ weight of testes, ↓ epididymis and seminal vesicle, ↓ spermatogenesis, ↓ sperm motility of cauda epididymal sperms, ↓ seminiferous tubules size, ↓ leydig cell nuclei diameter, ↓ seminiferous tubular diameter, ↓ rate of fertility in high dose WS and no considerable changes in T, FSH, sperms morphology, serum biochemistry, hematological parameters, body weight compared to control group
India

(4)Ganu et al., 2010 [57]In vitro &
in vivo (animal)
Healthy male rats () & adult male mice (); 8 groups: control (), abutilon indicum with various doses (), WS with various doses (), sildenafil () 1 mg/ml & 100, 200, 400 mg/kg/POAqueous extract of roots28 d ↑ sperm count in all groups (), ↑ mounting frequency () with WS 200, 400, ↑ frequency of penile erection episodes (), ↑ number of female licking behaviors with WS 400 (), ↑ mating behavior with WS 400 (), ↑ body weight with WS 400 (), ↑ testes weight, ↑ weight of prostate with WS 400, 200 () compared to controlIndia

(5)Prithiviraj et al., 2013 [58]In vitro & in vivo (animal)Male Wistar albino rats (); 5 groups: cadmium-induced oxidative injury in testis (), control (), cadmium + WS (), cadmium and vitamin E (), control and WS ()300 mg/kg dissolved in 2% gum acacia /gavageRoot power30 days ↑ SOD (), ↑ CAT (), ↑ GPX (), ↑ GSH (), ↑ levels of Vit C (ascorbic acid) (), Vit E (αtocopherol) (), ↓ ROS, ↓ LPO, ↓ caspase-3 in Cd + WS testis compared to Cd testis, ↓ GST () in Cd + WS compared to normal level, ↓ apoptotic cells (), ↑ weight and volume of testes, ↑ leydig cell number (), ↓ necrotic or pathological change of testes in Cd + WS compared to control, no toxic side effect, stress, changes in behaviorIndia

(6)Kyathanahalli et al., 2014 [59]In vitro & in vivo (animal)Prepubertal male rats (); 3 groups: streptozotocin-induced testicular oxidative
impairments (), control (), STZ + WS ()
500 μg & 500 mg/kg/day/oral
gavage
Aqueous root extract15 daysIn vitro: considerable inhibition of deoxyribose and stable free radical DPPH
In vivo: ↓ LPO, ↓ ROS in testis cytosol 38%, mitochondria 24% of STZ + WS groups but no marked change, ↑ total Thiol (TSH, GSH), ↑ nonprotein thiol (NPSH) in testis cytosol and mitochondria, ↑ weights of testis, ↓ blood glucose of STZ + WS group compared to STZ group ()
India

ND, not determined; WS, Withania somnifera; FSH, follicular stimulating hormone; LH, luteinizing hormone; ALP, alkaline phosphatase; Cd, cadmium; GSH, glutathione peroxidase; SOD, superoxide dismutase; CAT, catalase; MDA, malondialdehyde; STD, seminiferous tubules diameter; T, testosterone; PRL, prolactin; LPO, lipid peroxidation; GABAA g-amino butyric acid; TG, triglyceride; EDSI, erectile dysfunction severity index; FSFI, female sexual function index; FSDS, female sexual distress scale; IMHQOL, Internet mental health quality of life scale; QEQ, quality of erection questionnaire; NZ, normozoospermic; OZ, oligozoospermic; AZ, asthenozoospermic; IDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GPC, glycerophosphocholine; ↑, increase; ↓, decrease.

Many phytochemicals have been extracted from WS, which includes alkaloids, flavonoids, steroidal lactones, saponins, neurotransmitters, essential and nonessential fatty acids, ergostane, and gamma amino butyric acid; of all these components, alkaloids, and withanolids such as withaferin A, withanosides, sitoindosides, beta-sitosterol, and various amino acids like alanine have more prominent effect on fertility status [20, 2325, 2830, 34, 38, 51, 55].

In animal studies, WS is known to have gonadotropic function which increases gonadal weight by growthing follicles size in female and also increasing seminiferous tubular cell layers in male animals [27, 28, 31, 33, 35, 37, 41, 5759]. WS is found to improve spermatogenic activity which is proposed to be due to supporting hypothalamic-hypophysial-gonadal hormonal axis and testosterone balance in testes [15, 31, 42]. WS is found to compensate LH and FSH decrease or increase in diabetic Wistar rats [27, 29, 31, 38, 47]. Also, WS increases testosterone [15, 29, 38, 39, 44, 47] and progesterone [29, 38] in male rats and decreases triglyceride and cholesterol in both male and female rats [28, 29, 35, 38, 43, 52].

In a study by Shukla et al. about effects of WS on men, WS root powder was used for 3 months and it was shown that sperm parameters such as count and motility in sperm analysis had improved due to decrease apoptosis and reactive oxidative stress among men with normospermia and oligospermia; also copper, zinc, iron, and gold ions of seminal plasma had increased after the treatment and subsequently semen quality increased. This increase in semen quality is proposed to be due to the increase in essential neurotransmitters, metallothionein which has antioxidative function, and metal ions as cofactors for essential enzymes [23].

In two clinical trials, the effects of 5 grams of WS root for 3 months on semen parameters of infertile men were investigated. Improvement in semen quality, increased vitamins E, C, and A, and increased fertility were reported which is proposed to be due to the high amount of alkaloids, ergostane steroids, and essential amino acids in WS which improved detoxification, decreased oxidative stress, and restorated testosterone secretion [12, 25].

In another human study, treatment by WS aqueous extract in married healthy women increased their sexual function index and diminished sexual distress index statistically significant [21]. In two studies using WS root extract for men with psychologic erectile dysfunction, there was no statistically significant difference between the intervention and control group considering sexual function indices [22, 26]. Also, WS root extract was found to decrease prolactin level after 3 months of administration among infertile men [12, 24, 25].

In a study by Bhattarai et al. about effects of WS root extract, it was found that GABA mimetic features of this extract led to an increased activity of gonadotropin releasing hormone secreting neurons [54]. On the other hand, WS root extract was found to decrease libido and sexual function which led to impotency and erectile dysfunction in animal studies [30]. Ethanolic WS fruit and stem extract were found to induce infertility in male rats due to the decrease in sperm motility, count, and degeneration of seminiferous tubules, although this extract did not have an effect on sperm morphology [28, 53, 56].

Prabu et al. in a study on male rats found that hydroalcoholic WS root extract was found to decrease white blood cell and lymphocyte counts in blood, but no considerable effect on reproductive indices [40]. Alcoholic WS root extract can decrease estrogen and cholesterol level in female Wistar mice and recover corpus luteum, graafian follicles, and germinal epithelium which has been damaged due to the chlorpyrifos exposure [35].

WS leaves and roots have been found to improve oxidative stress indices such as an increase in superoxide dismutase, catalase, glutathione, lactate dehydrogenase, alanine, glutamine, phenylalanine, and decrease in cortisol and fructose [12, 2225, 34, 36, 47, 51, 58].

In a study investigating effects of 6.5 mg of WS root extract on Nile tilapia, it was found that this extract with androgenic effects decreased prolactin level and estrogen level by inhibiting aromatase activity and induced male phenotype formation; this phenomenon was proposed to be due to components such as tannin, saponins, terpenoids, steroids, and flavonoids [46].

4. Discussion

Traditional and complementary medicine have been more popular nowadays to cure health related conditions [67]. This proposes a new strong potential in traditional and complementary medicine to come up with new medical combinations with fewer side effects [6870]. Traditional Persian medicine is one of the most well-known categories of traditional medicine using herbal medicine as one of the main therapeutic modalities [71].

Withania somnifera is one of the herbal medicines widely used for the treatment of infertility and sexual dysfunction. This plant has been known to contain more than 80 types of phytochemicals such as steroidal and nonsteroidal alkaloids, steroidal lactones and saponins like isopelletierine, anaferin, anahygrine, hygrine, cuscohygrine, tropine, pseudotropine, withananine, ashwagandha, withaferins, withananinine, pseudowithanine, somnine, somniferine, somniferinine, 3-tropyltigloate, withanine, withasomine, visamine, mesoanaferine, sitoindoside (7–10), hentriacontane, amino acids such as aspartic acid, glycine, tryptophan, proline, alanine, tyrosine, hydroxyproline valine, cystine, glutamic acid, and cysteine, calcium, phosphorus, iron, flavonoids, starch, reducing sugars, proteolytic enzyme “chamase,” glycosides, dulcitol, and volatile oil. Of all these components, withaferin A and sitoindosides had the key role in WS therapeutic effects [11, 13, 23, 33, 34, 60, 61, 72].

Based on the present study, it was shown that extracts of WS fruits, leaves, stems, and especially roots enhance sperm quality indices such as motility and count in men [12, 20, 24, 25] and also decrease the effects of chemical toxins on gonads in both men and women [13, 15, 29, 3338, 41, 44, 45, 59]. WS can increase gonadal weight in both sexes, enhance folliculogenesis and spermatogenesis, and improve LH, FSH, and testosterone balances [15, 27, 31, 35, 36, 38, 42, 44, 45]. Sexual behavior indices such as female sexual function index and female sexual distress index improve statistically significant after WS extract administration [21].

The mechanism of WS effect on the reproductive system is not known entirely yet, but this mechanism is proposed to be linked to the antioxidative features and ability to improve the hormonal balance of LH, FSH, and testosterone and improve detoxification process. Also, the GABA mimetic feature of WS extract is thought to play the main role in inducing gonadotropin releasing hormone secretion and improving hormonal balance [23, 27, 31, 3436, 42, 44, 47, 51]. In the male reproductive system, it is assumed that WS by providing metal ions facilitates enzyme activities, modifies oxidative stress, and prevents cell apoptosis [23]. The root extract of WS has been shown to induce alanine transaminase activity which increases alanine in seminal fluid leading to a less oxidative stress index and improved semen quality [24]. Normalizing lactate, phenylalanine, glutamine, citrate, and histidine in seminal fluid are another feature of WS extract which improves enzymatic processes in tricarboxylic acid cycle (TCA) and fatty acid metabolism [12, 59]. On the other hand, some animal studies have suggested that WS extract may cause reversible spermicidal and infertilizing effect in male and delayed puberty in both sexes; this might be due to the dose, preparation method, adjuvant components, and duration of use designated in mentioned studies [28, 30, 49, 53, 56].

5. Conclusion

Based on the results, it deems that Withania somnifera has a positive effect in the treatment of infertility both in male and female. Although some studies proposed that WS extract might have infertilizing and spermicidal effect. Due to the growing interest in using herbal medicine especially those which possess the antioxidative and reproductive system supporting properties, further studies are needed to be designed with higher population and more-structured methodology so a more precise and decisive conclusion can be made.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This research was supported by Tabriz University of Medical Sciences and presented as a Ph.D. thesis (Ramin Nasimi Doost Azgomi, no. 3) at School of Traditional Medicine, Tabriz University of Medical Sciences.

References

  1. R. S. Gibbs, B. Y. Karlyn, A. F. Haney, and I. Nygaard, “Danforth's obstetrics and gynecology: Wolters Kluwer Health Adis (ESP),” 2012. View at: Google Scholar
  2. J. Boivin, L. Bunting, J. A. Collins, and K. G. Nygren, “International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care,” Human Reproduction, vol. 22, no. 6, pp. 1506–1512, 2007. View at: Publisher Site | Google Scholar
  3. H. J. Tournaye and B. J. Cohlen, “Management of male-factor infertility,” Best Practice & Research Clinical Obstetrics & Gynaecology, vol. 26, no. 6, pp. 769–775, 2012. View at: Publisher Site | Google Scholar
  4. L. Speroff and M. A. Fritz, Clinical gynecologic endocrinology and infertility: lippincott Williams wilkins, Clinical gynecologic endocrinology and infertility, lippincott Williams & wilkins, 2005.
  5. J. H. Jung and J. T. Seo, “Empirical medical therapy in idiopathic male infertility: promise or panacea?” Clinical and Experimental Reproductive Medicine, vol. 41, no. 3, pp. 108–114, 2014. View at: Publisher Site | Google Scholar
  6. M. Godmann, R. Lambrot, and S. Kimmins, “The dynamic epigenetic program in male germ cells: Its role in spermatogenesis, testis cancer, and its response to the environment,” Microscopy Research and Technique, vol. 72, no. 8, pp. 603–619, 2009. View at: Publisher Site | Google Scholar
  7. D. R. Smith, E. A. Tanagho, and J. W. McAninch, Smith's general urology, Lange Medical Books/McGraw-Hill, 2008.
  8. C. Krausz, “Male infertility: Pathogenesis and clinical diagnosis,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 25, no. 2, pp. 271–285, 2011. View at: Publisher Site | Google Scholar
  9. A. Direkvand-Moghadam, Z. Suhrabi, M. Akbari, and A. Direkvand-Moghadam, “Prevalence and predictive factors of sexual dysfunction in Iranian women: Univariate and multivariate logistic regression analyses,” Korean Journal of Family Medicine, vol. 37, no. 5, pp. 293–298, 2016. View at: Publisher Site | Google Scholar
  10. M. Rafieian-Kopaei, “Medicinal plants and the human needs,” Journal of HerbMed Pharmacology, vol. 1, no. 1, pp. 1-2, 2011. View at: Google Scholar
  11. L. Mishra, B. B. Singh, and S. Dagenais, “Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review,” Alternative Medicine Review, vol. 5, no. 4, pp. 334–346, 2000. View at: Google Scholar
  12. A. A. Mahdi, K. K. Shukla, and M. K. Ahmad, “Withania somnifera improves semen quality in stress-related male fertility,” Evidence-Based Complementary and Alternative Medicine, vol. 2011, Article ID 576962, 9 pages, 2011. View at: Publisher Site | Google Scholar
  13. V. Sharma, S. Sharma, Pracheta, and R. Paliwal, “Withania somnifera: A rejuvenating ayurvedic medicinal herb for the treatment of various human ailments,” International Journal of PharmTech Research, vol. 3, no. 1, pp. 187–192, 2011. View at: Google Scholar
  14. T. K. Biswas and S. Pandit, “In Search of Spermatogenetic and Virility Potential Drugs of Ayurvedic Leads: A Review,” Andrology-Open Access, vol. 04, no. 02, 2015. View at: Publisher Site | Google Scholar
  15. A. Kumar, R. Kumar, M. S. Rahman, M. A. Iqubal, G. Anand, P. K. Niraj et al., “Phytoremedial effect of Withania somnifera against arsenic-induced testicular toxicity in Charles Foster rats,” Avicenna Journal of Phytomedicine, vol. 5, no. 4, p. 355, 2015. View at: Google Scholar
  16. N. J. Dar, A. Hamid, and M. Ahmad, “Pharmacologic overview of Withania somnifera, the Indian Ginseng,” Cellular and Molecular Life Sciences, vol. 72, no. 23, pp. 4445–4460, 2015. View at: Publisher Site | Google Scholar
  17. G. Singh, P. Sharma, R. Dudhe, and S. Singh, “Biological activities of Withania somnifera,” Annals of Biological Research, vol. 1, no. 3, pp. 56–63, 2010. View at: Google Scholar
  18. R. Jain, S. Kachhwaha, and S. Kothari, “Phytochemistry, pharmacology, and biotechnology of Withania somnifera and Withania coagulans: A review,” Journal of Medicinal Plants Research, vol. 6, no. 41, pp. 5388–5399, 2012. View at: Publisher Site | Google Scholar
  19. A. Saiyed, N. Jahan, S. F. Majeedi, and M. Roqaiya, “Medicinal properties, phytochemistry and pharmacology of Withania somnifera: an important drug of Unani Medicine,” Journal of Scientific & Innovative Research, vol. 5, no. 4, pp. 156–60, 2016. View at: Google Scholar
  20. V. R. Ambiye, D. Langade, S. Dongre, P. Aptikar, M. Kulkarni, and A. Dongre, “Clinical evaluation of the spermatogenic activity of the root extract of Ashwagandha (Withania somnifera) in oligospermic males: a pilot study,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 571420, 6 pages, 2013. View at: Publisher Site | Google Scholar
  21. S. Dongre, D. Langade, and S. Bhattacharyya, “Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Improving Sexual Function in Women: A Pilot Study,” BioMed Research International, vol. 2015, Article ID 284154, 2015. View at: Publisher Site | Google Scholar
  22. P. Mamidi, K. Gupta, and A. B. Thakar, “Ashwagandha in Psychogenic Erectile dysfunction: Ancillary findings,” International Journal of Research in Ayurveda and Pharmacy, vol. 5, no. 1, pp. 36–40, 2014. View at: Publisher Site | Google Scholar
  23. K. K. Shukla, A. A. Mahdi, V. Mishra et al., “Withania somnifera improves semen quality by combating oxidative stress and cell death and improving essential metal concentrations,” Reproductive BioMedicine Online, vol. 22, no. 5, pp. 421–427, 2011. View at: Publisher Site | Google Scholar
  24. A. Gupta, A. A. Mahdi, K. K. Shukla et al., “Efficacy of Withania somnifera on seminal plasma metabolites of infertile males: A proton NMR study at 800 MHz,” Journal of Ethnopharmacology, vol. 149, no. 1, pp. 208–214, 2013. View at: Publisher Site | Google Scholar
  25. M. K. Ahmad, A. A. Mahdi, K. K. Shukla et al., “Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males,” Fertility and Sterility, vol. 94, no. 3, pp. 989–996, 2010. View at: Publisher Site | Google Scholar
  26. P. Mamidi and A. Thakar, “Efficacy of Ashwagandha (Withania somnifera Dunal. Linn.) in the management of psychogenic erectile dysfunction,” AYU (An International Quarterly Journal of Research in Ayurveda), vol. 32, no. 3, p. 322, 2011. View at: Publisher Site | Google Scholar
  27. A. A. Al-Qarawi, H. A. Abdel-Rahman, A. A. El-Badry, F. Harraz, N. A. Razig, and E. M. Abdel-Magied, “The effect of extracts of Cynomorium coccineum and Withania somnifera on gonadotrophins and ovarian follicles of immature wistar rats,” Phytotherapy Research, vol. 14, no. 4, pp. 288–290, 2000. View at: Publisher Site | Google Scholar
  28. P. Mali, P. Chouhan, and R. Chaudhary, “Evaluation of antifertility activity of Withania somnifera in male albino rats,” Fertility and Sterility, vol. 90, p. S18, 2008. View at: Publisher Site | Google Scholar
  29. N. M. Belal, E. El-Metwally, and I. Salem, “Effect of dietary intake Ashwagandha roots powder on the levels of sex hormones in the diabetic and non-diabetic male rats,” World Journal of Dairy & Food Sciences, vol. 7, no. 2, pp. 160–166, 2012. View at: Google Scholar
  30. I. Ilayperuma, W. D. Ratnasooriya, and T. R. Weerasooriya, “Effect of Withania somnifera root extract on the sexual behaviour of male rats,” Asian Journal of Andrology, vol. 4, no. 4, pp. 295–298, 2002. View at: Google Scholar
  31. E. M. Abdel-Magied, H. A. Abdel-Rahman, and F. M. Harraz, “The effect of aqueous extracts of Cynomorium coccineum and Withania somnifera on testicular development in immature Wistar rats,” Journal of Ethnopharmacology, vol. 75, no. 1, pp. 1–4, 2001. View at: Publisher Site | Google Scholar
  32. S. A. Dhas, T. Selvaraj, T. Citarasu, S. M. J. Punitha, and M. M. Babu, “Effect of supplemented diet with maturation plant extract on reproductive performance of Etroplus suratansis,” Aquaculture Reports, vol. 2, pp. 58–62, 2015. View at: Publisher Site | Google Scholar
  33. N. H. Shaikh, V. M. Deshmukh, and M. V. Walvekar, “Alteration in testicular morphology and sperm count due to Glycowithanolides treatment during aging,” Asian Journal of Pharmaceutical and Clinical Research, vol. 8, no. 3, pp. 72–77, 2015. View at: Google Scholar
  34. M. Walvekar, N. Shaikh, and P. Sarvalkar, “Effects of glycowithanolides on lipid peroxidation and lipofuscinogenesis in male reproductive organs of mice,” Iranian journal of reproductive medicine, vol. 11, no. 9, p. 711, 2013. View at: Google Scholar
  35. R. Kumar, M. Ali, A. Kumar, and V. Gahlot, “Comperative biomedical effect of Withinia Somnifera and Curcuma Longa on ovaries of pesticide induced mice,” European journal of pharmaceutical and medical research, vol. 2, no. 7, pp. 249–53, 2015. View at: Google Scholar
  36. R. B. Patil, S. R. Vora, and M. M. Pillai, “Protective effect of spermatogenic activity of Withania Somnifera (Ashwagandha) in galactose stressed mice,” Annals of Biological Research, vol. 3, no. 8, pp. 4159–4165, 2012. View at: Google Scholar
  37. R. Rajashree, M. I. Glad Mohesh, M. V. Ravishankar, and P. Sembulingam, “Effect of alcoholic extract of withania somnifera linn roots on reproductive organs in streptozotocin induced diabetic rats,” Indian Journal of Public Health Research & Development, vol. 2, no. 1, pp. 20–23, 2011. View at: Google Scholar
  38. Z. Kiasalari, M. Khalili, and M. Aghaei, “Effect of withania somnifera on levels of sex hormones in the diabetic male rats,” Iranian Journal of Reproductive Medicine, vol. 7, no. 4, pp. 163–168, 2009. View at: Google Scholar
  39. B. Rahmati, M. H. G. Moghaddam, M. Khalili, E. Enayati, M. Maleki, and S. Rezaeei, “Effect of withania somnifera (L.) dunal on sex hormone and gonadotropin levels in addicted male rats,” International Journal of Fertility & Sterility, vol. 10, no. 2, pp. 239–244, 2016. View at: Google Scholar
  40. P. C. Prabu, K. Biravi, S. Jarisa, S. Sreepriya, and S. Panchapakesan, “Biochemical, pathomorphological and semen characteristics analysis in male wistar rats treated with withania somnifera root extract,” Asian Journal of Chemistry, vol. 26, no. 12, pp. 3700–3704, 2014. View at: Publisher Site | Google Scholar
  41. D. Bhargavan, B. Deepa, H. Shetty, and A. Krishna, “The protective effect of Withania somnifera against oxidative damage caused by ethanol in the testes of adult male rats,” International Journal of Basic & Clinical Pharmacology, vol. 4, no. 6, pp. 1104–1108, 2015. View at: Google Scholar
  42. M. Nirupama and H. Yajurvedi, “Efficacy of Ashwagandha (Withania somnifera L.) root extracts in preventing stress induced testicular damage in rat,” European Journal of Biomedical AND Pharmaceutical sciences, vol. 2, no. 7, pp. 413–424, 2015. View at: Google Scholar
  43. R. J. K. Kumar, A. Singh, M. Nath, and A. Kumar, “Effect of Withania somnifera on Estrogen, Cholesterol and Subcellular structure of ovary of chlorpyrifos exposed mice,” Caribbean journal of science and technology, vol. 1, pp. 1061–1069, 2013. View at: Google Scholar
  44. R. Kumar, M. Ali, J. Singh, A. Nath, and A. Kumar, “Bioremedial impact of Withinia Somnifera on endosulfan exposed spermatozoa of mice,” International Journal of Pharmaceutical Sciences and Research, vol. 3, no. 5, p. 1343, 2012. View at: Google Scholar
  45. D. Kaspate, A. Ziyaurrahman, T. Saldanha, P. More, S. Toraskar, and K. Darak, “To study an aphrodisiac activity of hydroalcoholic extract of Withania somnifera dried roots in female Wistar rats,” in Proceedings of the International Journal of Pharmaceutical Sciences and Research, vol. 6, p. 2820, 2015. View at: Google Scholar
  46. M. De and S. B. Chakraborty, “Use of Withania somnifera root powder for production of monosex Nile tilapia, Oreochromis niloticus,” IOSR Journal of Pharmacy and Biological Sciences, vol. 11, no. 05, pp. 28–31, 2016. View at: Publisher Site | Google Scholar
  47. N. D. Jasuja, P. Sharma, and S. C. Joshi, “Ameliorating effect of Withania somnifera on acephate administered male albino rats,” African Journal of Pharmacy and Pharmacology, vol. 7, no. 23, pp. 1554–1559, 2013. View at: Google Scholar
  48. S. Saritha, P. S. Reddy, and G. R. Reddy, “Partial recovery of suppressed reproduction by Withania somnifera Dunal. in female rats following perinatal lead exposure,” International Journal of Green Pharmacy, vol. 5, no. 2, pp. 121–125, 2011. View at: Publisher Site | Google Scholar
  49. L. Garg and G. Parasar, “Effect of Withania somnifera on reproduction in mice,” Planta Medica, vol. 13, no. 1, pp. 46-47, 1965. View at: Publisher Site | Google Scholar
  50. K. Sahin, C. Orhan, F. Akdemir et al., “Comparative evaluation of the sexual functions and NF-ΚB and Nrf2 pathways of some aphrodisiac herbal extracts in male rats,” BMC Complementary and Alternative Medicine, vol. 16, no. 1, article no. 318, 2016. View at: Publisher Site | Google Scholar
  51. N. Shaikh, S. Desai, and M. Walvekar, “Protective effects of glycowithanolides on antioxidative enzymes in testes and accessory reproductive organs of D-galactose induced stressed mice,” International Journal of Current Microbiology and Applied Sciences, vol. 3, no. 4, pp. 458–464, 2014. View at: Google Scholar
  52. A. Saiyed, N. Jahan, S. A. Makbul, M. Ansari, H. Bano, and S. H. Habib, “Effect of combination of Withania somnifera Dunal and Tribulus terrestris Linn on letrozole induced polycystic ovarian syndrome in rats,” Integrative Medicine Research, vol. 5, no. 4, pp. 293–300, 2016. View at: Publisher Site | Google Scholar
  53. P. C. Mali, “Control of fertility in male wistar rats treated with hydroalcholic extract of Withinia somnifera fruits,” International Journal of Pharmacology & Biological Sciences, vol. 7, no. 3, 2013. View at: Google Scholar
  54. J. P. Bhattarai, S. A. Park, and S. K. Han, “The methanolic extract of Withania somnifera acts on GABAA receptors in gonadotropin releasing hormone (GnRH) neurons in mice,” Phytotherapy Research, vol. 24, no. 8, pp. 1147–1150, 2010. View at: Publisher Site | Google Scholar
  55. H. Kataria, M. Gupta, S. Lakhman, and G. Kaur, “Withania somnifera aqueous extract facilitates the expression and release of GnRH: In vitro and in vivo study,” Neurochemistry International, vol. 89, pp. 111–119, 2015. View at: Publisher Site | Google Scholar
  56. A. R. Singh, K. Singh, and P. S. Shekhawat, “Spermicidal activity and antifertility activity of ethanolic extract of Withania somnifera in male albino rats,” International Journal of Pharmaceutical Sciences Review and Research, vol. 21, no. 2, pp. 227–232, 2013. View at: Google Scholar
  57. G. Ganu, D. H. Nagore, M. Rangari, and H. Gupta, “Pharmacological evaluation of ayurvedic plants for aphrodisiac activity in experimental animals,” Journal of Complementary and Integrative Medicine, vol. 7, no. 1, article no. 31, 2010. View at: Publisher Site | Google Scholar
  58. E. Prithiviraj, S. Suresh, N. V. Lakshmi, M. Karthik, L. Ganesh, and S. Prakash, “Protective effect of Withania somnifera (Linn.) on cadmium-induced oxidative injury in rat testis,” in Phytopharmacology, vol. 4, pp. 290–90, 269, 2013. View at: Google Scholar
  59. C. N. Kyathanahalli, M. J. Manjunath, and Muralidhara, “Oral supplementation of standardized extract of Withania somnifera protects against diabetes-induced testicular oxidative impairments in prepubertal rats,” Protoplasma, vol. 251, no. 5, pp. 1021–1029, 2014. View at: Publisher Site | Google Scholar
  60. Q. Uddin, L. Samiulla, V. K. Singh, and S. S. Jamil, “Phytochemical and pharmacological profile of Withania somnifera dunal: A review,” Journal of Applied Pharmaceutical Science, vol. 2, no. 1, pp. 170–175, 2012. View at: Google Scholar
  61. S. Imtiyaz, S. J. Ali, M. Aslam, M. Tariq, and S. S. Chaudhary, “Withania somnifera: a potent unani aphrodisiac drug,” International Research Journal of Pharmaceutical And Applied Sciences, vol. 3, pp. 59–63, 2013. View at: Google Scholar
  62. I. S. Avicenna, Kitāb al-Qānūn fī al-Tibb (Canon of medicine), Senior Press Superintendent, Jamia Hamdard Printing Press, New Delhi, India, 1998.
  63. A. M. Khan, Eksir-e-Azam (The great elixir), Institute of medicine historical studies, Islamic and complementary medicine, Tehran, Iran, 2007.
  64. M. A. Khorasani, Makhzan al Advieh (The storehouse of medicaments). Research institute for Islamic and Complementary Medicine, vol. 351, Bavardaran Press, Tehran, Iran, 2001.
  65. D. T. Tuhfat al-mu’minin, The Present for the Faithful, Research Center of Traditional Medicine: Nashre Shahr Press, Tehran, Iran, 2007.
  66. S. Inc, SPSS (release 16.0) statistical software, Chicago, Ill, USA, 2008.
  67. P. Fisher and A. Ward, “Complementary medicine in Europe,” British Medical Journal, vol. 309, no. 6947, pp. 107–111, 1994. View at: Publisher Site | Google Scholar
  68. V. C. Karande, A. Korn, R. Morris et al., “Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility,” Fertility and Sterility, vol. 71, no. 3, pp. 468–475, 1999. View at: Publisher Site | Google Scholar
  69. M. C. Inhorn, Quest for Conception: Gender, Infertility And Egyptian Medical Traditions, University of Pennsylvania Press, 1994.
  70. M. B. Gewali and S. Awale, Aspects of traditional medicine in Nepal, Institute of Natural Medicine University of Toyama, Japan, 2008.
  71. M. J. Abbasi-Shavazi, M. C. Inhorn, H. B. Razeghi-Nasrabad, and G. Toloo, “The ‘Iranian ART Revolution’: infertility, assisted reproductive technology, and third-party donation in the Islamic Republic of Iran,” Journal of Middle East Women’s Studies, vol. 4, no. 2, pp. 1–28, 2008. View at: Publisher Site | Google Scholar
  72. N. Singh, M. Bhalla, P. de Jager, and M. Gilca, “An overview on Ashwagandha: A Rasayana (Rejuvenator) of Ayurveda,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 8, no. 5, pp. 208–213, 2011. View at: Publisher Site | Google Scholar

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