Re: Systematic Review Suggests Ashwagandha May Benefit Male Fertility, but Data Are Limited and Inconsistent

Ashwagandha (Withania somnifera, Solanaceae) Infertility Systematic Review Date: 07-13-2018 HC# 061871-596 Azgomi RND, Zomorrodi A, Nazemyieh H, et al. Effects of Withania somnifera on reproductive system: a systematic review of the available evidence. BioMed Res Int. January 2018;2018:4076430. doi:10.1155/2018/4076430. Infertility – "the inability to conceive after one year of unprotected sexual intercourse" - affects 60-80 million couples worldwide. Infertility has many causes, including systemic diseases, infections, hormonal imbalances, anatomical anomalies, and psychological issues. The man, woman, or both can have fertility challenges. Ashwagandha (Withania somnifera, Solanaceae) has been used in traditional medicine for many purposes, including to treat infertility. All parts of the plant have been used medicinally, though roots are the most commonly used, and many bioactive compounds and bioactivities have been identified. The purpose of this systematic review was to summarize ashwagandha's known effects on the reproductive system. The authors conducted a search of Google Scholar, PubMed, Scopus, Web of Science, and Cochrane Library in 2016. They searched using keywords "Withania somnifera" or the equivalent and a wide variety of other terms relevant to fertility or sexuality. They used a date limit of 1965 to 2017. The authors also manually searched "valid journal databases," and reviewed the European Association for Grey Literature Exploitation and the Health Care Management Information Consortium for unpublished articles. They excluded review studies, case reports, letters to the editor, and short communications. Of 190 studies initially identified, 42 were included in the review. The rest were excluded for being duplicates, irrelevant, conference presentations, or containing duplicate data or "inadequate or inappropriate results." Seven studies were excluded for "poor reporting quality assessment" though the criteria for defining unacceptably poor reporting were not described. Eight of the included studies were in humans (seven in males, one in females), 28 were in animals (20 in males, eight in females), five were "animal-cellular" studies that included in vitro and in vivo studies (all involving male rodents), and one was entirely in vitro. The studies used roots (n=29), leaves (n=7), leaves plus roots (n=1), fruits (n=2), unknown extracts (n=2), and stems (n=1). The human studies all used root extracts, given orally; duration ranged from eight weeks to three months. Most human studies did not observe any adverse effects for ashwagandha. Table 1 summarizes "characteristics and results of human studies." All reviewed trials were conducted in India. Study size ranged from 46 to 180 people. The studied women were healthy and married. The studied men were infertile with normal or low sperm counts or had erectile dysfunction. Dosage ranged from 600 mg to 6 g a day. Studies in men lasted two to three months; the single study in women lasted eight weeks. A wide variety of outcomes were measured including semen and sperm parameters, hormone changes, sexual arousal, erectile dysfunction, and others. Results included improved semen quality, increased fertility (only reported in one study), better oxidative stress indices, and improved sexual function in women. However, there was no significant difference between the intervention and control for treatment of psychological erectile dysfunction. Table 2 summarizes "characteristics and results of animal studies." Study size ranged from 12 to 360 animals (mice, rats, and fish). Dosages in rodents ranged from 10 to 3000 mg/kg/day; one of two fish studies used dosages of up to 9500 mg/kg in food. Routes of administration were variable and included oral, feeding tube, and injection. Studies lasted from six to 70 days. The studies took place in Saudi Arabia (n=2), India (n=21), Egypt (n=1), Sri Lanka (n=1), Iran (n=2), and Turkey (n=1). A wide variety of outcomes were measured. Results included increased gonad (ovary or testis) weight, "compensate[d] LH and FSH decrease or increase" in diabetic rats, increased testosterone and progesterone in male rats, increased sperm count and motility, reduced abnormal sperm count, and decreased cholesterol and triglycerides in female and male rats, as well as decreased estrogen in female rats. Ashwagandha also reportedly decreased white blood cell counts, minimized the effect of chemical toxins on ovaries and testes, and improved hormonal balance. However, in four animal studies, ashwagandha results were not favorable. Negative effects reported included erectile dysfunction, decreased libido, delayed puberty, and decreased sperm count and motility. Two of the studies reporting negative results used fruit extracts, while another used an enormous (3000 mg/kg/day) dose of a methanolic root extract. In one study of female rats a relatively large dose of leaf powder was associated with more implantations, fewer fetal losses, and more live pups, but in a study using female mice, a much smaller dose of root powder was associated with lowered fertility and fewer pups per litter. Table 3 summarizes "animal-plant and cellular studies." Study size ranged from six to 48 mice or rats as well as cell samples. Route of administration included oral, oral gavage, and cell baths. Preparations came from the root, stem, or leaf. Five studies were conducted in India and one in the Republic of Korea. Numerous outcomes were measured. Results included possible GABAA mimetic activity, upregulation of gonadotropin-releasing hormone expression, reduced measures of oxidative stress, increased sperm count, increased mating, and increased testes weight. Contrarily, one study reported decreased fertility, weight of testes, and sperm density. The authors conclude that ashwagandha may have a positive effect on infertility in both sexes, although a few animal studies reported opposite effects. They advocate for larger, better-designed studies to obtain more conclusive data. Variation in the causes of infertility, products used, and dosages may contribute to the inconsistency of results in existing literature, which must, therefore, be interpreted with caution. The authors report having no conflicts of interest. —Heather Anderson, MD