Efficacy of Shankhapushpi (Convolvulus pluricaulis) in Posthysterectomy Menopausal Syndrome - A Randomized Controlled Pilot Clinical Trial.

Menopause is a gradual and natural process occurring between the fourth and fifth decade of woman’s life that brings an imbalance in the hypothalamic–pituitary–ovarian (HPO) axis leading to various psycho-somatic disturbances such as hot flushes, heart discomfort, sleep problems, depressive mood, physical exhaustion, and urogenital problems.[ 1 ] In recent times, women tend to attain early menopause through hysterectomy for various pathological conditions such as uterine fibroids, uterine prolapse, abnormal uterine bleeding, pelvic inflammatory disease, adenomyosis, and genital cancer.[ 2 ] In India, the incidence of hysterectomy in women aged between 15 and 44 years is reported to be 11.5%.[ 3 ] Early deficiency of estrogen followed by hysterectomy disturbs the regular functioning of the HPO axis leading to menopausal syndrome and, in due course, these women end up in other complications such as hyperlipidemia, hypertension, heart ailments, and obesity which most of the time may turn out to be irreversible. In contemporary medical science, hormonal replacement therapy (HRT) is the only choice to treat this condition, which again leads to a broad spectrum adverse reactions varying from simple to life-threatening complications such as vaginal bleeding, migraine, anxiety, depression, and breast and ovarian cancer.[ 4 ] Estrogen deficiency, led by hysterectomy, affects multiple systems in the female body, so any medicine administered for the management of such a syndrome should aim at correcting all the involved pathologies. These issues can be addressed by supplementation of rejuvenative herbs that are rich in phytoestrogens, which will help in balancing both physical and mental health by effectively managing the targeted hormonal pathologies. Convolvulus pluricaulis is a herbal source for the regulation of estrogenic activity, and its antioxidant, anti-inflammatory, nootropic, etc properties[ 5 ] can help to ease the menopausal transition. Herbs like Asparagus racemosus ,[ 6 ] commonly known as Shatavari , Withania somnifera ,[ 7 ] Saraca asoca ,[ 8 ] etc., are proved to be effective in the management of naturally attained menopausal syndrome. Till date, no studies have been reported to claim the efficacy of any of these herbs in hysterectomy-induced menopausal syndrome, so through this pilot study, an attempt was made to evaluate the possible effects of C. pluricaulis in managing the posthysterectomy menopausal syndrome.

Thirty women suffering from posthysterectomy menopausal syndrome participated in the study. Neither any patient reported adverse effects nor any discontinued the study. The features at baseline such as mean age ( P = 0.69), socioeconomic status ( P = 0.33), educational status ( P = 0.29), past illness ( P = 0.33), age of menarche ( P = 0.76), bowels ( P = 0.91), chief complaints ( P = 0.81), reason for hysterectomy ( P = 0.44), type of hysterectomy ( P = 0.21), posthysterectomy period ( P = 0.13), sexual history ( P = 0.57), sleep ( P = 0.67), and mental stress ( P = 0.10) were comparable amongst both the groups [ Table 1 ]. Baseline characteristics of subjects in group A and group B DUB: Dysfunctional uterine bleeding Serum estrogen levels assessed from pre (baseline) to post (45 th day) test within A. racemosus group showed difference in terms of increase of 2.54 pg/ml ( P < 0.001), whereas within the C. pluricaulis group, there is no significant difference noted with an increase of 0.38 pg/ml ( P = 0.334) [ Table 2 ]. Statistical analysis of between-group comparisons of interventions on primary and secondary outcomes *P <0.05. MRS: Menopausal Rating Scale, HARS: Hamilton Anxiety Rating Scale, MS-QoL: Menopause Specific Quality of Life, MKI: Modified Kupperman Index Both interventions were comparable in reducing the total score of MRS from pre (baseline) to post (45 th day) assessment with P = 0.872. Both groups revealed comparable improvement on MRS at all three time points [ Table 2 ]. Both the medications have shown comparable results in bringing down the severity of the menopausal symptoms assessed through the MKI score, from pre (baseline) to post (45 th day) assessment with P = 0.265. Comparable improvement was shown by each group on MKI at all three time points [ Table 2 ]. The MS-QoL assessed from pre (baseline) to post (45 th day) test has brought in comparable results by both the interventions with P = 0.258. Each group has shown comparable improvement on MS-QoL at all three time points [ Table 2 ]. Both interventions produced a significant reduction ( P < 0.001) in the total score of MRS, MKI, and MS-QoL from baseline to 15 th day, 30 th day, and 45 th day of intervention [ Table 3 ]. Statistical analysis showing within-group comparison of interventions at different time points *: Statistically significant. MS-QoL: Menopause specific quality of life, MKI: Modified Kupperman Index, MRS: Menopausal Rating Scale Both the interventions were comparable in reducing the total score of HARS assessed from pre (baseline) to post (45 th day) test with P = 0.719. Statistical estimation of within-group comparison in both the groups has shown significant improvement with P < 0.001 [ Table 2 ].

In this preliminary study explored for effects of single herbal medicines in hysterectomy-induced menopausal syndrome, it was found that both A. racemosus and C. pluricaulis were equally potent in managing posthysterectomy menopausal symptoms assessed through MRS, MKI, and also in enhancing MS-QoL. It was also observed that both medications were equally helpful in reducing the anxiety levels assessed through HARS. Although the study proved A. racemosus was better than C. pluricaulis in improving the serum estrogen levels, SPP helped in maintaining the stable estrogen levels. The majority of the subjects (70%) in this study were aged between 41 and 50 years, which is in support of the prevalence of various gynecological disorders at this age, resulting for the indication of hysterectomy.[ 3 ] About 46.66% patients underwent hysterectomy to get relieved from uterine fibroids and or associated dysfunctional uterine bleeding, followed by ovarian cysts, etc., supporting that women undergo hysterectomy to get alleviated from such gynecological conditions.[ 14 ] Ninety percent subjects were experiencing hot flushes, followed by irritability (50%), anxiety, night sweats, palpitations, and general weakness. Hot flushes are noticed because of the narrowing of the thermoneutral zone due to changes in the levels of reproductive hormones at menopause.[ 15 ] Seventy percent women underwent hysterectomy without salpingo-oophorectomy, in whom the intensity of disturbance caused by menopausal syndrome was less compared to women who underwent hysterectomy with salpingo-oophorectomy. The average posthysterectomy period in these women was 7.76 ± 4.92 years, and their average duration of illness was 4.80 ± 2.80 years. Women who undergo hysterectomy without salpingo-oophorectomy typically experience menopausal symptoms gradually with less severity as ovarian hormone production declines progressively rather than dropping suddenly. Thirty percent women in this study underwent hysterectomy with bilateral salpingo-oophorectomy. The average posthysterectomy period in them was 6.78 ± 5.05 years, while the mean duration of illness was 2.67 ± 2.16 years. Although hysterectomy associated with salpingo-oophorectomy causes an abrupt decline in the ovarian hormones triggering earlier menopausal symptoms,[ 16 ] this study found that the duration taken for the development of menopausal symptoms after surgery was similar in both the groups of patients, with and without salpingo-oophorectomy. This unexpected finding may be due to the small sample size. Seventy percent subjects experienced unsatisfactory sexual life in this study. Low estrogen during menopause thins out the epithelium, causing disorganization of vaginal connective tissue and reduction in the vulvovaginal vascularity, which together lead to reduced lubrication during penovaginal intercourse, causing dyspareunia and reduced libido.[ 17 ] About 76.67% subjects reported sleep disturbances, which may be attributed to the influence of estrogen deficiency on the hypothalamus that indirectly affects sleep-regulating neurotransmitters such as serotonin and dopamine.[ 18 ] Seventy percent subjects experienced moderate mental stress, followed by severe type (16.66%) of mental stress, which plays a crucial role in aggravating vasomotor symptoms in menopausal women. Stressful environments disrupt the hypothalamus, thermoregulatory center, and emotional instability during menopause by altering thermal sensitivity in key brain regions such as the preoptic nuclei, limbic system, and hippocampus.[ 19 ] This study suggests that both A. racemosus and C. pluricaulis were equally beneficial in relieving the menopausal symptoms of three major domains, namely vasomotor, psychological, and urogenital domains, assessed through MRS and MKI. This could be because of the bitter taste (tikta rasa) and cold potency ( sheeta veerya ) of C. pluricaulis that helps in combating the symptoms such as increased perspiration, burning sensation.[ 20 ] and hot flushes. Similarly, with its memory enhancer, psychostimulant, and tranquilizer effect,[ 21 ] it will help in alleviating the psychosomatic symptoms of postmenopausal syndrome. Chemical constituents present in C. pluricaulis , such as kaempferol,[ 22 ] sitosterols,[ 23 ] and ascorbic acid[ 24 ], demonstrated estrogenic activity through phytoestrogens present in them. These phytoestrogens can bind to estrogen receptors in the brain, potentially influencing various neurotransmitters like serotonin and dopamine, as well as enzymatic functions, which can help regulate the hypothalamic activity,[ 25 ] thereby easing both vasomotor and psychological symptoms experienced by the ladies as a result of menopause[ 26 ] after hysterectomy. C. pluricaulis with its antioxidant, anti-inflammatory, and immune-modulating properties[ 21 ] will help in reducing physical exertion, muscular pain, and infections of the genitourinary system. These effects are possibly attributed to phytochemicals present in the C. pluricaulis such as ayapanin, covolamine, scopoletin, and shankhpuspine[ 5 ] which may further contribute to the reduction of menopausal symptoms. The immunomodulatory effect of convolamine[ 5 ] present in C. pluricaulis can help in preventing repeated infections of the urogenital tract,[ 27 ] for which postmenopausal women are the culprits. All these activities of C. pluricaulis will not only help in the effective management of posthysterectomy menopausal symptoms, but also the quercetin, beta-sitosterol, delphinidine, kaempferol, taraxerol, etc., present in C. pluricaulis would help in the prevention of estrogen-dependent diseases like breast cancer in posthysterectomy menopausal women in their future life with antiproliferative and anti-cancerous effects.[ 5 ] A. racemosus , well known as female rejuvenate, with its rejuvenative property toward psychosomatic health and healthy aging, is beneficial in with standing most of the health disturbances at all stages of women’s life.[ 28 ] A. racemosus helps in managing the menopausal symptoms by providing the phytoestrogens[ 6 ] which mimic estrogen by occupying the estrogen receptors to activate the required estrogenic activity.[ 29 ] Decline in the estrogen levels at menopause will increase the risk of elevation in oxidative stress, further intensifying the threat for various diseases. Herbs rich in antioxidants can help to overcome these ill effects of oxidative stress.[ 30 ] A. racemosus reduces oxidative stress as it triggers both enzymatic and nonenzymatic actions and also acts as a potent antioxidant by increasing glutathione peroxidase activity.[ 6 ] Shatavarin I-VI, flavonoids, especially isoflavones, glycosides, steroidal saponins, asparagine, etc., have shown antioxidant, adaptogenic, and cardio-protective activity, that helps in managing physical (exertion, multiple joint pain) and cardiac (heart racing, heart beat skipping) symptoms in postmenopausal women.[ 28 ] Both the interventions were effective in improving the MS-QoL in subjects of hysterectomy-induced menopausal syndrome. This could be because of the estrogenic activity of C. pluricaulis achieved by sitosterols,[ 23 ] kaempferol,[ 22 ] and other flavonoids. Furthermore, antioxidant, anti-inflammatory, nootropic, etc., properties[ 5 ] of C. pluricaulis can help ease the menopausal transition by enhancing the psychosomatic health. Phytoestrogenic properties of A. racemosus act on stressors by balancing the hormonal fluctuations[ 31 ] and thereby support improving the MS-QoL. This is also attributed to the positive effect of A. racemosus on the symptoms of menopause, which in turn increased the satisfaction level in postmenopausal patients.[ 6 ] In the current study, A. racemosus was significantly effective in improving the serum estrogen levels, whereas C. pluricaulis was able to maintain the stable levels of serum estrogen. This is achieved by estrogenic activity through the phytoestrogens present in the phytochemicals such as kaempferol,[ 22 ] quercetin,[ 32 ] sitosterol,[ 23 ] ascorbic acid[ 24 ] of C. pluricaulis. A. racemosus , being a rich source for phytoestrogen,[ 6 ] shows estrogenic activity by binding to the estrogen receptors.[ 33 ] Both the interventions were effective in managing the anxiety symptoms evaluated through HARS. C. pluricaulis with its rejuvenative property for enhancing the intellect, potentially improves psychological symptoms such as depression, anxiety, and impaired memory.[ 34 ] Neuroprotective[ 5 ] and nootropic[ 35 ] activities are attributed by phytochemicals such as convolvine and convolamine. It also exhibits antidepressant and anxiolytic effects through compounds such as scopoletin and phytosterols through the serotonergic signaling pathway.[ 21 ] All the above said activities of C. pluricaulis might have helped in the reduction of psychological symptoms such as depressive mood, restlessness, and irritability in posthysterectomy menopausal women. A. racemosus with its revitalization and rejuvenative properties[ 28 ] and with the phyto-constituents such as steroidal saponins, exhibits neuroprotective activity by restoring the GABAergic pathway.[ 36 ] Flavonoids present in the A. racemosus have neuroprotective effects.[ 37 ] Phytochemicals like sarasasapogenin[ 38 ] and racemoside improve memory dysfunction.[ 36 ] Vitamin C present in A. racemosus helps in reducing neuronal damage.[ 39 ] Thus, altogether these properties of A. racemosus contribute for its antidepressant, anxiolytic, and nootropic activities in posthysterectomy menopausal women. Limitations of this study are the small sample size, which reduces the generalizability of the findings to a broader population. The hormonal profile assessed was limited to serum estradiol, which may not fully represent the complex hormonal changes occurring during the posthysterectomy menopausal phase. Lack of postintervention follow-up limits the ability to assess the long-term efficacy and safety of the treatment. Future studies can focus on comparative analysis between Shankhapushpi ( C. pluricaulis Choisy) and standard HRT to evaluate their relative efficacy and safety.

Study demonstrated that Shankhapushpi ( C. pluricaulis Choisy) was beneficial in managing posthysterectomy menopausal syndrome assessed through MRS, MKI, MS-QoL, and HARS. It was helpful in maintaining stable estrogen levels, suggesting its potential as a nonhormonal herbal medicine. There are no conflicts of interest.

It was a pilot clinical study with a randomized controlled trial design conducted between September 2023 and June 2024. A total of 30 women who underwent hysterectomy were recruited from the Outpatient and Inpatient Department of KLE Ayurveda Hospital and Research Centre, Karnataka, India, after obtaining written informed consent from all of them. The study was reported based on the CONSORT statement guidelines [ Figure 1 ].[ 9 ] Flow chart showing enrolment of subjects Women under the age of 50, with a history of hysterectomy (before attaining natural menopause) at least 3 months prior to enrollment, with or without oophorectomy, with a minimum menopause rating scale (MRS) score of 5 and a Modified Kupperman’s Index (MKI) score of 7, were enrolled. Women on any hormonal therapy, women with a known history of uncontrolled medical conditions such as hypertension, diabetes mellitus, coronary vessel disease, neurological diseases, or psychiatric disorders were excluded. Hamilton Anxiety Rating Scale (HARS) was used for excluding other psychological ailments like anxiety. In total 42 women who underwent hysterectomy (before attaining natural menopause) were screened from Outpatient and Inpatient Department of KLE Ayurveda Hospital and Research Centre, Karnataka, India, and 30 among them were enrolled and randomly assigned into two groups ( n = 15 in each), A. racemosus group (control) and C. pluricaulis group (interventional) through computer-generated random numbers in the ratio of 1:1 by block randomization method. The Institutional Medical Research Centre was responsible for maintaining the process of randomization and allocation. The principal investigator was provided with allocation information only after ensuring the baseline assessment. Considering the nonavailability of published data on clinical interventions in hysterectomy-induced menopausal syndrome, this pilot study was planned and conducted in the form of a RCT with 30 eligible subjects. The study was initiated after obtaining approval from the Institutional Ethics Committee for Human Subjects (BMK/21/PG/RV/01) and CTRI Registration (CTRI/2022/11/047631). Patients of the A. racemosus group ( n = 15) were treated with A. racemosus powder, while patients of the C. pluricaulis group ( n = 15) received C. pluricaulis powder. Both interventions were administered in a dose of 6 g, twice daily after food with lukewarm water for a period of 45 days. A. racemosus tuberous roots were procured from GMP-certified KLE Ayurveda Pharmacy, Karnataka, India, and C. pluricaulis raw drug as a whole plant was procured from GMP-certified Dabur Pharmacy, Uttar Pradesh, India. Both the raw drugs were dried, and then a fine powder of 80 mesh size was prepared. The prepared herbal powders were packed into pouches of 6 g capacity and stored at the Institutional Medical Research Center. Raw materials’ authentication and finished product’s analysis were carried out at a Government of India approved ASU drug testing laboratory, KAHER’s Shri BMK Ayurveda Mahavidyalaya, Belagavi, Karnataka, India. The primary outcomes of the study included change in the serum estrogen levels assessed from baseline to 45 th day and severity of menopausal symptom score assessed through MRS[ 10 ] and MKI,[ 11 ] along with Menopause-Specific Quality of Life (MS-QoL)[ 12 ] from baseline to 15 th , 30 th , and 45 th day. The secondary outcome measure was, change in the level of anxiety evaluated through HARS,[ 13 ] which was assessed from baseline to the 45 th day. The data collected was recorded in MS Excel and analyzed statistically using SPSS Version 25.0 (IBM Corporation, Chicago, Illinois, United States). Chi-square test was applied to estimate the association of the data at baseline. An independent t -test was applied to compare the variables between the two groups, and a Dependent t -test was used to compare the variables within the groups at three different time points. Values are specified in terms of mean ± standard deviation. The level of statistical significance for all the tests was set at P < 0.05.