Volume 37 Issue 3

Introduction

By 2030, 1.2 billion of the world’s population will have reached their menopausal life stage; 85–90% of these women will experience symptoms of such severity that they seek medical care.^1,2 Menopause is a normal physiological process in which women cease to menstruate due to ovarian follicle insufficiency; it is clinically diagnosed following twelve consecutive months of amenorrhea.^3,4 The average age of achieving menopause is 52 years in  Australia, but this ranges from 45-to-55.⁵

Perimenopause is the transitional period that leads to menopause; it is characterised by early and late stages, in which hormonal milieus alter dramatically.^3,6 Menstrual-cycle length variations typically signify its onset, but these shifts in oestradiol (E2) and progesterone (P4) concentrations have far-reaching effects on a woman’s physiology, can considerably destabilise regulatory and adaptive systems of the body, impede resilience and leave them vulnerable to dysfunction, disease and reduced quality of life (QoL).^7-9

Commonly cited presentations of perimenopause include heavy menses, vasomotor symptoms, cognitive deficits, altered sensory processing, impaired stress tolerance, anxiety, depression, sleep disturbances, fatigue, central obesity, weight gain, joint pain, decreased libido, urogenital discomfort, hair loss and bone loss^.4,7,9-12 Indeed, in a period that may last 7–14 years, perimenopause presents with extensive symptomatology, to which the approved serotonin-reuptake inhibitors are poorly matched and menopause hormone therapy contraindicated or too infrequently offered – calling for alternative therapies capable of buffering the transitional stressors responsible for symptomatology and poor health outcomes.^8,12-14

Adaptogens are medicinal substances, frequently of plant origin, which favourably modulate the body’s response to stressors by balancing the activity of regulatory neuroendocrine and immunological systems — improving resilience.^15,16 Withania somnifera (L.) Dunal (WS), often referred to by its Sanskrit name Ashwagandha, is considered the superior adaptogen in Ayurvedic medicine, in which it holds a 3000-year-old tradition as a ‘rasayana’ or health-promoting and rejuvenating medicine.^17-19 A member of the Solanaceae plant family, WS is also referred to as Indian ginseng or winter cherry – signifying its vitality properties and morphology.^17,19,20 Commercial cultivation of the drought-resistant, medium-sized shrub occurs principally in India, where the plant is native.^20,21 Further morphological features include a stellate stem and branch structure, oval leaves, small clustered green-yellow flowers, small round red fruits and long tuberous roots.^8,21

In traditional Ayurvedic texts, WS is cited to possess “miraculous potential”, and its leaves, flowers, fruits, seeds and roots are prescribed for all manner of ailments, including cognitive deficits, insomnia, immunomodulation, rheumatism, “chronic stiffness”, cardiac disease, oedema, low libido, aging — and as a resilience tonic; offering cause to consider its efficacy for the perimenopause life-stage.^20-22 In modern botanical medicine, aqueous and hydroalcoholic extracts of the roots and occasionally the leaves are used for their adaptogenic, anxiolytic, anti-depressant, anti-oxidant, anti-inflammatory, anti-arthritic, cardioprotective, anti-diabetic, anti-adipogenic, immune-modulating, nervine, neuroprotective, nootropic and sedative actions.^19,21,23 Such broad herbal actions are credited to WS’s equally extensive bioactive constituents, in which 62 and 48 metabolites have been identified in the leaves and roots, respectively.^19,21 Of these metabolites, the steroidal lactones (withanolides, including withaferin-A), sitoindosides (glycowithanolides), phenolics and alkaloids are most cited for their medicinal potential.^18,21,23

Method

In seeking to answer the question, “Is Ashwagandha (Withania somnifera) a safe and effective treatment for reducing perimenopausal symptoms?” Medline, PubMed, Cochrane and Google Scholar databases were searched using combinations of the keywords and MESH terms detailed in Figure 1. The search limited publications from 2014–2024 to obtain relevant, up-to-date data. Further screening excluded papers that were non-human studies, reviews, used multi-herb compounds, had solely male cohorts, and participants under 35 years old or with severe disease/health conditions.

 

Figure 1. Database search terms.

 

Findings

Gopal et al’s²⁴ randomised, double-blind, placebo-controlled trial (RDBPCT) was the only trial to specifically assess the efficacy and safety of WS for perimenopause symptoms utilising menopause-specific outcome measures. The thirteen other trials included in this review researched perimenopause-related presentations in women-inclusive cohorts.

Clinical efficacy

Using KSM-66, a proprietary WS root aqueous extraction standardised to >5% withanolides, twice daily for eight weeks, Gopal et al²⁴ demonstrated the efficacy of WS for perimenopause symptoms in a group of otherwise healthy perimenopausal women (n = 91; WS intervention = 46, placebo = 45). Improvements in the Menopause Rating Scale (MRS) scores from baseline to completion were statistically significant (p<0.00001) in the WS extract group, outperforming the placebo group with a marked 23.5% reduction compared to 10.9% (p<0.0001). This improvement included psychological, somatic-vegetative (such as hot flashes, insomnia, joint pain) and urogenital domains. With respect to menopause-specific quality of life (MENQoL), the impact of vasomotor symptoms, psychological, physical and sexual dysfunction significantly reduced in the WS-group by week-8 (p<0.00001), with vasomotor domains statistically surpassing the placebo (p<0.0001). Self-reported hot flash scores reflected this outcome, with the WS group perceiving significant reductions compared to placebo.²⁴

Sex-hormone profile

Gopal et al²⁴ further demonstrated improvements in the WS participants’ sex hormone profile, with E2 statistically significantly increasing — but remaining within a physiologically safe range, and follicle-stimulating hormone significantly reducing, compared to the placebo (p<0.005) by trial completion. Luteinising hormone and testosterone also decreased, though between-group differences were not statistically significant.²⁴ Smith et al²⁵ also noted statistically significant increases in E2 (59.72%) at completion (week 12), compared to a (non-significant) decrease in placebo E2 — and again, levels remained within range. A further exploratory analysis demonstrated that these increases were most prominent in the perimenopause WS group.²⁵ The WS extract was again root-based but hydroalcoholic, standardised to just 1.5% withanolides (Witholytin^®) and given at 200mg twice daily.²⁵

Perceived stress and fatigue

Potentially associated with the E2 increases, Smith et al²⁵ also cited significant reductions in fatigue scores (45.81%) and, thus, an increase in measurable vitality in the WS group compared to the placebo.⁸ Between-group perceived stress outcomes, however, were non-significant.²⁵ This result is contradictory to Choudhary et al²⁶ and Gopukumar et al²⁷ who reported statistically significant Perceived Stress Scale (PSS) reductions in their WS groups compared to placebo. Both trials, like Smith et al,²⁵ used root WS extract, but aqueous and hydroalcoholic, 600mg and 300mg (sustained release) daily, respectively.^26,27 A finding that may allude to dose or pharmacokinetic-dependent responses of WS extract in reductions of perceived stress. Indeed, Pandit et al²⁸ who also observed PSS improvements of statistical significance compared to placebo, using an aqueous root and leaf WS extract, noted decreasing PSS scores with increasing mg of the WS extract.

Stress-response, sleep, mood and cognition

With respect to measures of hypothalamic-pituitary-adrenal axis activity, all trials noted decreases in serum cortisol measures, indicating decreased stress reactivity.^26-30 Similarly, those that measured happiness, anxiety and depression scores noted statistical improvements in WSE cohorts.^26-32 Cognitive and sleep quality scores also demonstrated statistically significant improvements — particularly in domains relevant to perimenopause disturbances.^9,27,30-32 Table 1 offers a comparative summary of these parameters.

 

Table 1. WS extract efficacy in sleep, mood, cognition, and stress-reactivity: a summary of included article findings

 

Body weight and dietary behaviour

The perimenopause transition negatively impacts aspects of weight management.⁹ Using KSM-66, 300mg twice daily, Choudhary et al²⁶ measured greater improvements in food cravings, uncontrolled and emotional eating in overweight, stressed WS participants than in placebo, with said improvements occurring as early as week 4.²⁶ Significant reductions in body weight and body mass index were apparent by week 8. Notably, food craving domains, including “lack of control”, “emotion”, and “environment”, were prominently decreased, while “physiological” drivers were not — suggesting these behavioural improvements were of neuropsychiatric mechanisms.^26,33 Remenapp et al³⁰ also measured improvements in dietary cravings alongside mood and stress markers, using a root and leaf WS extract (NooGandha^®) in a 30-day trial.

Immune health and resilience

The neuroendocrine shifts of perimenopause potentiate immune dysfunction and disease by amplifying innate inflammatory responses and activating adaptive immune responses.¹³ Using a root and leaf (aqueous) WS extract, Pandit et al²⁸ reduced pro-inflammatory cytokines (Interleukin-1 beta, Interleukin-6 and Tumour Necrosis Factor-alpha) in all WS intervention groups of a chronically stressed cohort. 250mg and 500mg, but not 125mg, demonstrated significant reductions compared to placebo, indicating a dose-dependent response.²⁸ Tharakan et al³⁴ (also using a root and leaf (hydroalcoholic) WS extract standardised to 35% withanolide glycosides), observed significant increases in immunoglobulins, lymphocytes, interferon-gamma and Interlukin-4 in the WS groups of a healthy-adult cohort, at 30-days. Significantly, interferon-gamma plateaued at 30-days, while other innate and adaptive immune parameters continued to improve, indicating an immune-bolstering effect.³⁴

Libido, sexual satisfaction and function

In an 8-week randomised, double-blind, placebo-controlled trial (RDBPCT), fifty healthy females (21–50 years old) with sexual dysfunction (impeded arousal, orgasm or desire) were given 300mg of KSM-66 twice daily (with food) or placebo, alongside conservative counselling.³⁵ Steady and significant improvements in sexual function scores were observed in the WS group compared to the placebo, with the domains of arousal, lubrication, satisfaction (p<0.001), orgasm (p=0.004) and successful sexual encounters proving statistically significant, compared to placebo, at week 8.³⁵ The absence of stress, metabolic and sex-hormone outcome measures in this study limited understanding of the WS extract mechanism of action.³⁵

Joint pain and discomfort

Using a WS extract (root and leaf, aqueous) standardised to 10% withanolide glycosides, 32% oligosaccharides and no-more-than 0.5 withaferin-A (Sensoril^®), Ramakanth et al³⁶ gave participants with knee-joint pain, one 250mg WS extract, 125mg WS extract or placebo capsule, twice daily (following food) for 12-weeks. Significant reductions in pain, stiffness, disability and swelling were observed at 12-weeks in the WS extract group, compared to the placebo.³⁶ The 250mg group outperformed (p<0.001) the 125mg group at weeks 4 and 12, achieving statistically significant improvements across efficacy measures as early as week 4 (p<0.01) and requiring the least rescue medication of all cohorts, demonstrating efficacy and a dose-dependent therapeutic response.³⁶ Unfortunately, female (17) and male (43) participant outcomes were not detailed separately.³⁶

Hair thinning and androgenic alopecia

Hair thinning and androgenic alopecia can be a worrisome symptom of perimenopause, with loss of progesterone, lowering oestradiol and relative androgen excess being implicated.¹⁰ In a 75-day RDBPCT of healthy participants (n=61) aged 18–45 years, a topical serum formulated from KSM-66 containing 5% withanolides (withastramonolide A, withanoside IV,  withanolide A, withanone and <0.1% of withaferin A), demonstrated significant reductions in hair shedding (-6.90 versus -3.12; p<0.001) and significant improvements in hair growth, density, thickness and hair follicle cycle markers in the WS group, compared to placebo.³⁷ Outcomes were not detailed by sex; only nine participants were female, and steroid hormone biomarkers were not assessed, making it difficult to determine the mechanism of action or perimenopause population specificity.³⁷

Subclinical Hypothyroid

The onset of subclinical hypothyroidism increases in perimenopause, complicating the symptomatology of this life stage.³⁸ In Sharma et al’s³⁹ 8-week RDBPCT, 300mg twice daily of KSM-66 significantly increased Triiodothyronine (41.5%) and Thyroxine (19.6%) and significantly decreased thyroid-stimulating hormone elevations compared to placebo by trial-completion; effectively normalising thyroid indices in 8-weeks in an otherwise healthy, mixed-gender, 18 to 50-year-old cohort.³⁹ WS extract regulatory effects on the hypothalamic-pituitary-thyroid axis are a proposed mechanism of action, but unfortunately, no biochemical measures, other than thyroid indices, were reported.^19,39

Safety

WS extract was well tolerated across all trials; no serious adverse events were reported, and biochemical, haematological, and vital signs remained stable where measured.^{24-32,34-37,39} Mild presentations, ranging from headache, dizziness, hyperacidity, abdominal discomfort and nausea, were noted in four studies; these resolved with conservative treatment and were not dissimilar to placebo cohorts.^24,26,36,39 Post-intervention assessment of withdrawal outcomes suggests that ceasing WS extract (root and leaf) at 125mg, 250mg, and 500mg does not result in withdrawal symptoms.²⁸

Discussion

Perimenopause is a transitionary state that compromises regulatory neuroendocrine and immune functions, resulting in various symptoms that can reduce QoL and health resiliency.^3,8 WS is an adaptogenic herb that promotes homeostatic health by balancing these complex, multi-directional regulatory pathways.^19,33 However, when reviewing the efficacy and safety of WS for perimenopause symptoms, only one English-language trial was found to specifically assess a perimenopausal cohort utilising menopause-specific outcome measures.²⁴ Using an aqueous root extract (KSM-66), its reductions in MRS scores (a validated tool for assessing psychological, somatic and urogenital perimenopause symptoms) were so marked that the WS extract was deemed clinically efficacious for perimenopausal presentations.²⁴

Furthermore, Gopal et al’s²⁴ findings of improved anxiety, depression, irritability, fatigue, joint pain, sleep quality, mental acuity and sexual well-being extracted from the MRS and MRQoL are supported by ten other papers in this review, which, despite heterogeneity in extraction methods, parts of the plant used, dosing, study lengths and cohort characteristics, all demonstrated efficacy in their researched, perimenopause-relevant domains.^25-32,35,36 For example, stress reactivity (serum cortisol) improved in root, root and leaf, aqueous and alcoholic extracts trials, despite differing withanolide and other bioactive constituent concentrations.^21,26-32 This suggests that WS contains multiple metabolites and, thereby, diverse mechanisms through which it can catalyse positive adaptive responses and, in turn, favourably influence health outcomes. More precisely, WS can attenuate the hypothalamic-pituitary-adrenal axis and, or potentiate gamma-aminobutyric acid-A, serotonergic and anti-oxidative mechanisms, in turn stabilising neuropsychiatric, gonadal, cognitive, immune and cardiometabolic functions via a multitude of avenues and constituent concentrations.^19,23,33 This is a conclusion shared by Mikulska et al,¹⁷ Speers et al,³³ Wiciński et al¹⁹ and Wiciński et al²³ and supported by the findings of Candelario et al⁴⁰ and Nasimi Doost Azgomi et al.⁴¹

Similarly in Gopal et al²⁴ improvements in vasomotor symptoms, follicle-stimulating hormone or E2 were unlikely the result of a singular pathway or simply direct steroidal stimulation —  but instead, a combined hypothalamic-pituitary regulative, GABAmemetic, anti-inflammatory and anti-oxidative effect, engagement and mechanisms of which might vary depending on the person’s physiological need and the WS extract given.^{19,20,25,33,41,42} Smith et al’s²⁵ mirrored increases in E2 offer some evidence of this. The WS extract used in their trial was of lower dose and steroidal (withanolide) standardisation than Gopal et al,²⁴ and due to hydroalcoholic extraction, contained an altered constituent profile.^20,21,25 However, the outcome (higher E2) was the same and, notably, marked in the perimenopause but not post-menopause participants.²⁵ Furthermore, as in Gopal et al,²⁴ E2 levels remained within “safe” ranges.²⁵ This suggests a physiologically selective and constituent-synergistic effect rather than just a steroidal hormone-stimulatory one.^21,25 This distinction in WS mechanism of action is important when assessing efficacy and clinical suitability for the perimenopause transition. Gopal et al²⁴ studied women in later-stage perimenopause (evidenced by two absent periods) when E2 is lower, but in early perimenopause, E2 fluctuates and at times is high or mismatched with P4, requiring modulation rather than stimulation.^4,11 Further studies are needed to evaluate the effects of WS across all stages of perimenopause, and should include P4, other ovulatory measures and a more culturally diverse cohort than Gopal et al.^24,2,43

With clinical application and patient-centred care further in mind, the within and between study differences in outcome measures of PSS and Hamilton Anxiety Scale (HAM-A) scores suggest a dose-dependent and pharmacokinetic effect variance of WS extract upon perceived stress and anxiety.^25-29 Should perceived stress and anxiety be a perimenopausal client’s prominent symptom, a mid-range dose or sustained-release capsule once daily may be as effective and easier to adhere to than Gopal et al²⁴ and Choudhary et al’s²⁶ 300mg twice daily.^27,28 Similarly, in a perimenopause client with prominent immune, arthralgia or arthritic presentations, a root and leaf WS extract, with a higher percentage of withanolide glycosides, may be more efficacious than a WS extract root alone.^21,34,36 Of course, these posology estimations are extrapolated and not specific to the complex multi-system interactions of perimenopause, to which this author proposes a combined preparation of standardised preparations may better permit a synergistic, whole-plant like adaptogenic effect.^7,8,21 It is also important to acknowledge that an integrative health management approach, including supportive dietary and lifestyle behaviours, would enhance WS’s positive effects in perimenopause.^1,9

Conclusion

WS is a plant with multiple bioactive constituents and modulatory effects capable of reducing the symptoms of perimenopause.^21,24,33 This literature review has highlighted that a WS aqueous root extract (KSM-66) can offer profound, clinically relevant QoL-enhancing effects in late perimenopausal women. It has further highlighted that in cohorts inclusive of perimenopause women, variations of WSE can improve androgenic alopecia, joint pain, subclinical hypothyroid, immune and stress resilience, cognition, sleep, mood, fatigue, weight and dietary, behavioural concerns, with no risk to safety, up-to-12 weeks. Further research, with longer trial periods, culturally diverse, early and late perimenopause cohorts, comparisons of root, root and leaf and combined commercial preparations to determine the full potential of WS in perimenopause symptom and disease risk alleviation is indicated.

Conflict of interest

The authors declare no conflicts of interest.

Funding

The authors received no funding for this study.

Author(s)

Cheryl Bryson BHSc (NutDMed), MIntegrativeMed (candidate)
Southern Cross University

Contact information
Cheryl Bryson
Email hello@naturallynourishednomad.com

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