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Abstract

Introduction:

Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder that affects millions of women globally. The conventional approach to managing PCOS involves dietary adjustments, lifestyle modifications, pharmacological interventions, and in some cases, surgical procedures. This comprehensive review is dedicated to exploring novel treatment options for PCOS, with a specific focus on physical modalities, herbal approaches, holistic therapies, medical procedures, bacteriotherapeutics, and supplements.

Method:

To conduct this review, a systematic literature search was carried out up to 2023, utilizing reputable databases such as PubMed, Embase, Google Scholar, and the Cochrane Library. The search identified 33 key articles meeting the inclusion criteria, which encompassed both animal and human studies concentrating on PCOS and innovative interventions. The primary emphasis during the evaluation was on efficacy and safety. The articles were organized into six distinct groups: holistic therapies, herbal and natural approaches, physical modalities, medical procedures, bacteriotherapeutics, and supplements. Quality assessment involved the use of the Cochrane risk-of-bias tool and Assessment of Multiple Systematic Reviews (AMSTAR) 2.

Results:

The review unveiled a spectrum of interventions, ranging from acupuncture, yoga, and herbal remedies to high-intensity ultrasound, ultrasound cavitation, probiotics, fecal microbiota transplantation, and supplements. While some interventions exhibited promising results, conflicting reports and uncertainties persisted. Notably, positive effects on insulin resistance and androgen levels were observed with supplements. The intricate nature of PCOS treatments underscores the need for evidence-based strategies.

Conclusion:

While noninvasive and natural treatments show promise in the management of PCOS, rigorous research is indispensable to evaluate their long-term safety and optimal clinical utilization. The integration of lifestyle changes, conventional therapies and novel treatments, presents a potential avenue for a comprehensive and effective approach to treating PCOS, offering hope to millions of affected women worldwide. Caution is advised in the emerging realm of alternative treatments, and consulting health care professionals for informed decision-making in PCOS management continues to be strongly recommended.

Introduction

According to the World Health Organization, polycystic ovary syndrome (PCOS) affects an estimated 8%–13% of reproductive-aged women, with 70% of affected women remaining underdiagnosed worldwide.¹ The prevalence of PCOS has been confirmed through various guidelines^2,3 and has evolved over time with diagnostic criteria proposed since its first description by Stein and Leventhal in 1935.⁴ The standard diagnosis has been refined through international conferences organized by the National Institutes of Health in 1990,⁵ The European Society of Human Reproduction and Embryology (ESHRE)/The American Society for Reproductive Medicine (ASRM)-sponsored PCOS consensus workshop group in Rotterdam in 2003 and 2004,⁶ and the International Evidence-based Guideline for the Assessment and Management of PCOS in 2018, most recently updated in 2023.^7–9

Recommendations for assessing PCOS include evaluating irregular cycles, ovulatory dysfunction, biochemical and clinical hyperandrogenism, ultrasound findings, anti-Müllerian hormone levels, and various other factors such as ethnic variations, cardiovascular disease risk, menopause life stage, impaired glucose tolerance and type 2 diabetes (T2D) risk, glucose testing, obstructive sleep apnea, endometrial hyperplasia and cancer, and risk in first-degree relatives.^7–9 In addition, screening and management of psychological features, lifestyle interventions, and pharmacological treatment principles are essential components of PCOS care.^8,9

The prevalence, screening, and management of psychological features, as well as models of care, encompass diverse aspects such as a patient’s quality of life, depression and anxiety, psychosexual function, body image, eating disorders, information resources and considerations related to culture and language.^8,9 Psychological therapy, antidepressants, and anxiolytic treatment are integral parts of this comprehensive approach.^8,9 Lifestyle management involves effective interventions, behavioral strategies, dietary adjustments, exercise interventions, and considerations of factors affecting weight gain and weight stigma. Intervention studies have demonstrated that controlled diets can improve ovulation,¹⁰ and the addition of exercise to these diets has shown improvement in menstrual cycles, with a decrease in testosterone levels. Weight loss, even as minimal as a 5% reduction in body weight, has proven to be clinically significant.¹¹

The management of nonfertility features includes pharmacological treatment principles in PCOS, such as combined oral contraceptive pills, metformin, a combination of metformin and oral contraceptive pills, anti-obesity pharmacological agents, anti-androgen pharmacological agents, inositol, mechanical laser and light therapies for hair reduction, bariatric/metabolic surgery, and considerations related to pregnancy outcomes, including the use of metformin during pregnancy.^8,9,12

PCOS is known to be a common endocrine disorder and is considered the most frequent cause of infertility in young women of childbearing age.^2,13 Early miscarriage, failure to ovulate, and multiple miscarriages are also prevalent. Therefore, it is important to consider the assessment and treatment of infertility. Considerations and treatment options include preconception risk factors, tubal patency testing, letrozole, clomiphene citrate, metformin, gonadotropins, laparoscopic ovarian surgery, in vitro fertilization and in vitro maturation, inositol, and anti-obesity pharmacological agents.^8,9,14–21

PCOS is still without a definitive etiology, and so despite the availability of various management and treatment options, it is not surprising that many undesirable side effects are common. The drawbacks of various medications include vomiting, diarrhea, loss of appetite, and abdominal discomfort. In the case of oral contraceptives, women may experience headaches, breast tenderness, and mood changes. Bariatric surgery is advocated as a strategy for weight loss in morbidly obese women, however, it comes with an increased risk of nutritional deficiencies. It is important to note that these options are intended for women with less severe symptoms and complications. Laparoscopic ovarian drilling (LOD) and diathermy are effective methods for inducing ovulation; however, there is a risk of infection, internal bleeding, problems associated with anesthesia, and adhesions during and after this minor invasive surgical procedure, leading to difficulties in pregnancy. There may also be excessive damage to the ovaries, particularly in younger women, which can lead to early-onset menopause.^20,21

The International Evidence-based Guideline for the Assessment and Management of PCOS^8,9 offers a comprehensive overview that will continuously undergo updates in response to successful outcomes derived from clinical trials. It is imperative to begin the process of scrutinizing and highlighting treatments currently under investigation, elucidating their respective advantages and disadvantages. This proactive approach allows researchers to optimize their navigation, allocate resources judiciously, and streamline their efforts toward identifying management and treatment options that demonstrate efficacy.

While many reviews focus on assessing the efficacy of specific treatments, there is a growing number of novel and contemporary interventions that, if given greater consideration, have the potential to yield superior outcomes and mitigate the side effects associated with established treatments. This review article succinctly outlines the ongoing investigation of various options, presenting the information in a brief, reader-friendly manner.

Method

This systematic review closely followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement and Checklist. Due to the utilization of only deidentified pooled data, ethical approval was deemed unnecessary for this study. A thorough literature search, encompassing articles published up to 2023, was carried out through electronic databases, including PubMed, Embase, Google Scholar, and the Cochrane Library, to identify pertinent studies.

Exclusion criteria involved eliminating unrelated articles, unsuccessful treatment options for PCOS, and those lacking complete texts. Conversely, inclusion criteria encompassed both animal and human studies focusing on PCOS and novel intervention treatment options. Consideration was given to studies presenting comparisons between these interventions and exploring their outcomes. The review specifically included randomized controlled trials (RCTs), meta-analyses, and systematic reviews, with a primary focus on evaluating the efficacy and safety of novel treatments proposed for PCOS.

To assess the quality of RCTs, the Cochrane risk-of-bias tool was employed, while the AMSTAR 2 tool was utilized for evaluating the quality of systematic reviews. The primary outcomes of interest in the selected studies were improvements in menstrual regularity, ovulation, hirsutism, and insulin resistance. These outcome measures were chosen to comprehensively evaluate the impact of novel interventions on key aspects of PCOS.

Results

The literature search for novel PCOS treatment options retrieved over 20,000 articles. After rigorous selection based on primary outcomes, 33 key articles were identified. These articles were categorized into four universally approved forms of treatment: diet, exercise, pharmacological agents, and invasive surgical procedures, as outlined in the updated guidelines.^8,9 The treatments were further grouped into six main categories, as shown in Figure 1: holistic therapies (reflexology, acupuncture), physical modalities (kinesiology, acupressure, and massage therapy), herbal and natural approaches (herbology, homeopathy), medical surgical procedures (high-intensity ultrasound, ultrasound cavitation, electromagnetic radiation), bacteriotherapeutics (probiotics, symbiotics, fecal microbiota), and supplement and nutraceuticals (N-acetylcysteine [NAC], omega supplements).

FIG. 1.

Search strategy for retrieving literature on novel PCOS treatment options. PCOS, polycystic ovary syndrome.

Holistic Therapies and Physical Modalities

Holistic therapies, also known as alternative or holistic medicine, embrace a comprehensive approach to health, addressing physical, mental, emotional, and spiritual dimensions. Various practices under this umbrella, including acupuncture, yoga, meditation, herbal medicine, and dietary changes, have gained popularity in managing PCOS.²² Physical modalities, on the other hand, primarily involve therapeutic approaches employing physical techniques and interventions aimed at enhancing health, which also includes acupuncture.

Acupuncture, a traditional Chinese medicine technique, involves inserting needles into specific points on the body to stimulate healing. This widely used method inserts needles 0.5 cm–0.8 cm deep into the skin and simulates at a low frequency of 2 Hz. Acupuncture²³ has demonstrated effectiveness in regulating menstruation, reducing weight, alleviating headaches, improving mood, and normalizing hormone levels to enhance reproductive function.^22,24 However, conflicting reports exist regarding its efficacy compared with conventional treatments.

In a randomized controlled trial, the combination of acupuncture with clomiphene citrate was compared with clomiphene citrate alone in women with PCOS, revealing a higher ovulation rate in the acupuncture group.²⁵ Another trial assessing the impact of acupuncture on insulin sensitivity found that acupuncture is not as effective as metformin in improving insulin sensitivity in women with PCOS with insulin resistance. Still, it outperformed treatment with metformin alone in enhancing glucose metabolism.²⁶ A systematic review and meta-analysis evaluated the effectiveness of acupuncture in treating oligo-/anovulatory women with PCOS for fertility and symptom control. The review, encompassing eight RCTs with 1546 women, concluded that acupuncture does not rule out a clinically relevant difference in live birth rate, multiple pregnancy rate, ovulation rate, clinical pregnancy rate, or miscarriages. It suggested potential improvements in intermenstrual days, while raising concerns like dizziness, nausea, and subcutaneous hematoma.²⁷

Yoga, highlighted in a meta-analysis, is another holistic approach with reported successes. As a mind body therapy, it aims to reduce menstrual irregularity, clinical hyperandrogenism, impaired fasting blood glucose (IFG), and fasting hyperinsulinemia.²⁸ In addition, a systematic review identifying 16 studies suggested positive outcomes for yoga on stress, anxiety, fatigue, lipids, and testosterone.²⁹

Mindfulness-based interventions were also reported to help reduce stress, anxiety, depression, and body weight in individuals with PCOS.^30,31

Herbal and Natural Approaches

Traditional herbal medicines are naturally occurring substances with minimal or no industrial processing, utilized to treat various illnesses. The advantage of herbal therapy over conventional methods lies in its perceived safety, minimal side effects, and the overall potentiating effect attributed to the presence of multiple active compounds in medicinal herbs.^32,33 Numerous natural and commercial products are advertised and utilized to address the hormonal imbalance associated with PCOS. These include licorice, spearmint tea, ginseng saponin, flaxseed, aloe vera, chasteberry, cinnamon, white peony, milk thistle, chamomile, kasip fatimah, and astragalus polysaccharide. It is important to note that herbal supplements may require time to show efficacy in treating PCOS. Despite their demonstrated effectiveness, numerous questions remain unanswered regarding their applicability across different stages of PCOS.^34–38

Medical Surgical Procedures

Surgical procedures play a significant role in managing PCOS, especially when other treatment modalities have proven ineffective. Although surgery is not the first-line approach, ovarian drilling aids in inducing ovulation, and bariatric surgery improves insulin sensitivity, hormonal balance, and reproductive outcomes in women with PCOS.^8,9 Invitro fertilization can also benefit women with PCOS experiencing infertility. However, there is a need for less invasive procedures, as these interventions can lead to damaged ovaries and nutritional deficiencies.^20,21

High-intensity ultrasound (HIU)³⁹ is a noninvasive, cost-effective procedure that utilizes high-frequency sound waves to heat and destroy targeted tissue, presenting itself as a potential treatment for PCOS. This procedure induces localized thermal damage within the ovaries, preserving the surface and minimizing trauma.⁴⁰ The bioeffects of HIU are classified into the following two main groups: thermal and nonthermal. As ultrasound travels through the tissue, it absorbs energy, converting it into heat and generating biological effects in the targeted areas. The typical frequency range for thermal ablation with HIU is between 600 kHz and 7 MHz.⁴¹ Nonthermal effects arise from cavitation, where microbubbles in the tissue oscillate upon HIU application, leading to their collapse and the occurrence of cavitation.

A study reported the potential of HIU for causing local damage within the ovaries. Notably, this procedure, applied ex vivo to canine and bovine ovaries immersed in melted gelatin and guided by ultrasound imaging, demonstrated the potential risk of causing internal damage without affecting the ovarian surface. It is crucial to highlight that this study did not involve human subjects, emphasizing the need for further research to assess safety and efficacy before clinical application.⁴⁰ Limitations of this procedure include the requirement for regional or general anesthesia to ensure patient comfort and immobility.⁴² Another limitation involves the effectiveness of therapeutic ultrasound in penetrating specific barriers, such as bone, and considerations related to treatment time.⁴³

Ultrasound cavitation also known as ultrasonic liposuction, is a nonsurgical fat removal procedure that uses noninvasive technology to break down unwanted fat. This medical procedure uses low-frequency sound waves to destroy and break down fat cells. It is mainly used as a weight loss method and to treat insulin resistance in women with PCOS.

One study found that 20 obese women with PCOS who received twice-weekly abdominal treatment for 3 months had a highly significant (p < 0.001) decrease in body mass index, WHR, luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, and progesterone levels. This outcome was similar to that of another group of women with obese and PCOS who received biweekly electroacupuncture for 3 months.⁴⁴ In another study, 20 obese women with inclusion criteria of amenorrhea, LH/FSH ratio >1.5, and confirmation of PCOS underwent abdominal ultrasound cavitation for 4 months. This was coupled with an exercise training program and hypocaloric diet, leading to a reduction in body weight and visceral fat. It was associated with significant correction of hormonal and menstrual abnormalities, resulting in a statistically significant (p < 0.001) increase in the number of women with normal ovulation and follicular growth compared with 20 obese women who received exercise training and a hypocaloric diet only.⁴⁵

Ultrasound cavitation is considered an effective and safe method for weight loss in women with PCOS and abdominal obesity, demonstrating higher ovulation rates, a greater incidence of regular menstrual cycles, and lower testosterone and fasting insulin levels. However, the nature of cavitation and the limited number of subjects used in the experiments are major limitations that make further investigation necessary.⁴⁶

Intermediate frequency (IF) electric field exposure is another novel noninvasive method being explored in a PCOS animal model.^47,48 In Sprague–Dawley (SD) rats induced with polycystic ovaries (PCO), an electromagnetic radiation (EMR) field of 150 kHz was applied to the whole body for 8 weeks. The study results demonstrated a reduction in cystic follicles and their size after 8 weeks of noninvasive EMR exposure. While the IF had no significant effect on body weight (p > 0.05), histological degeneration was observed in the preantral and antral follicles of the exposure group. It is crucial to note that this study was limited to only one PCO-induced model, and validation with other models is imperative. Moreover, intensive experimentation is needed before human trials can be recommended. This research is based on the application of an alternating electric field known as tumor treating fields (TTFs) (100 kHz–300 kHz) to cancer cells.⁴⁹

Studies utilizing TTFs have demonstrated that programmed cell death is induced during the mitosis of ovarian cancer cells without affecting healthy cells.²¹ In vitro application of this field (100 kHz–400 kHz) to selective human ovarian cancer cells resulted in a significant reduction in cell numbers compared with untreated cells. The frequency curves revealed that the inhibitory effect was maximal at 200 kHz for the cancer cell lines. Application of this frequency for 72 h resulted in 77%, 70%, and 50% reductions in cell numbers of A2780 (p < 0.001), OVCAR3 (p < 0.001), and Caov-3 (p < 0.001) cells, respectively. The effect was found to be frequency- and intensity-dependent, and additional treatment in combination with the chemotherapy drug paclitaxel demonstrated improved feasibility.⁵⁰

Bacteriotherapeutics

Bacteriotherapeutics, including probiotics, synbiotics, and even fecal microbiota transplantation (FMT), have demonstrated significant efficacy in treating PCOS. This is attributed to the recognized role of dysbiosis as one of the primary causes of PCOS.

Probiotics, live microorganisms known for providing health benefits, have been suggested as a potential therapeutic option for PCOS owing to their capacity to modulate the gut microbiota and reduce inflammation. These beneficial microorganisms can be sourced from dietary items such as yogurt or dietary supplements. Several studies have explored the use of probiotics in PCOS treatment, yielding varied results.

A systematic review and meta-analysis of 13 studies, involving 855 participants with PCOS, revealed significant increases in sex hormone binding globulin (SHBG) concentrations in the probiotic group compared with the placebo group. Moreover, the probiotic group exhibited a notable decrease in free androgen index (FAI) concentrations. However, no significant differences were observed in other hormonal and inflammatory indices, such as testosterone, dehydroepiandrosterone (DHEA), glutathione (GSH), high-sensitivity C-reactive protein (hsCRP), total antioxidant capacity (TAC), and hirsutism score.⁵¹

In a separate study, a systematic review and meta-analysis of RCTs involving seven studies with 236 women with PCOS and 235 control subjects, found that symbiotic dietary supplementation (a combination of probiotics and prebiotics) improved the quantitative insulin sensitivity check index, lowered triglyceride levels (TG), and increased high-density lipoprotein (HDL) levels. Nevertheless, no significant effects of probiotics were noted on homeostatic model assessment of insulin resistance, fasting plasma glucose (FPG), low-density lipoprotein (LDL), total cholesterol (TC), and anthropometric indices.⁵²

Conversely, another review of seven RCTs indicated that probiotic supplementation in patients with PCOS led to reductions in weight, body mass index, fasting blood glucose (FPG), insulin, TG, hirsutism, total testosterone, and CRP. However, it had no impact on total LDL and HDL cholesterol levels.⁵³ The heterogeneity among these studies, including variations in probiotic strains, dosages, and treatment durations, may account for the mixed results. In addition, the underlying mechanisms through which probiotics improves features of PCOS remain incompletely understood, necessitating further research for clarity. It is crucial to recognize that probiotics should not be considered a replacement for standard PCOS treatments but rather a complementary therapy.

FMT is regarded as a comprehensive approach encompassing the bacteriome, virome, fungiome, archaeome, and parasitome, whereas probiotics predominantly consist of bacteria.⁵⁴ FMT involves the transfer of feces from a healthy donor into the patient’s gut to rebalance the gut microbiome, offering a holistic strategy for alleviating PCOS with minimal side effects. In an animal study, PCOS rats treated with 2 × 10⁹ FMT for 14 consecutive days exhibited improvements in their estrous cycle and normalized ovarian morphology.⁴⁸ However, the feasibility of repeated FMT administrations may pose practical challenges.⁵⁴

Supplement and Nutraceuticals

Supplements may improve health outcomes in women with PCOS by influencing key pathways thought to induce PCOS.⁵⁵

Omega-3 fatty acids, essential fatty acids studied for their potential in PCOS treatment, have been shown to have anti-inflammatory properties and regulatory effects on insulin and androgen levels. Used as supplements or when present in appropriate concentrations in the diet, these fatty acids have demonstrated effectiveness in improving insulin sensitivity, lowering androgen levels, and enhancing menstrual regularity in women with PCOS. Accessible through dietary sources like fish or supplements, a meta-analysis of nine studies involving 591 patients revealed that compared with the control group, omega-3 fatty acids improved the homeostasis model assessment (HOMA) index, reduced TC and TG levels, and increased adiponectin levels in women with PCOS with insulin resistance.⁵⁶ Another meta-analysis, incorporating 10 articles with 778 participants, indicated that omega-3 fatty acid supplementation in women with PCOS statistically improved insulin sensitivity, HOMA for insulin resistance (HOMA-IR), TG, low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, though it had no impact on serum glucose levels.⁵⁷ This positive effect on insulin resistance in women with PCOS was further supported by another meta-analysis.⁵⁸ While these findings are promising, additional research is necessary to fully comprehend the potential benefits of omega-3 fatty acids.

NAC, an antioxidant and mucolytic agent, offers various health benefits, including the reduction of oxidative stress and inflammation. As these factors are implicated in the pathogenesis of PCOS, NAC emerges as a potential therapeutic agent for the condition. Studies investigating NAC’s role in PCOS treatment have revealed significant positive outcomes.

In a RCT, patients with hyperinsulinemia with PCOS experienced reduced circulating insulin levels and improved insulin sensitivity after oral administration of NAC at a dose of 1.8 g/day for 5–6 weeks.⁵⁹ Another review demonstrated the success of using NAC in treating infertility and inducing ovulation in patients with clomiphene citrate–resistant PCOS. However, the review highlighted mixed results regarding the impact of supplementation with NAC on ovulation induction, emphasizing the need for further RCTs to determine its definitive role in patients with clomiphene citrate–resistant PCOS.⁶⁰ In addition, NAC has shown efficacy in improving lipid profiles, hormone levels, and long-term health in women with PCOS.⁶¹

Despite the promising aspects of using NAC in PCOS treatment, there are limitations to the available evidence. Most studies have been small and conducted over a relatively short period, necessitating larger, longer-term investigations to confirm the effectiveness of NAC supplementation and possible long-term side effects. While generally well-tolerated, NAC may induce gastrointestinal symptoms such as nausea, vomiting, and diarrhea.

Various supplements have been explored for their potential benefits in managing PCOS. Vitamin D has been associated with improved HOMA-IR values,⁶² reflecting enhanced insulin sensitivity. Folic acid (Vitamin B-9) has shown effectiveness in normalizing homocysteine levels, a benefit also observed with Vitamins B-1, B-6, and B-12.^63,64 Vitamin K supplementation has been shown to reduce waist circumference, fat mass, fasting insulin, and HOMA-IR in women with PCOS.⁶⁵ Furthermore, Vitamin E has been linked to improvements in endometrial thickness.⁶⁶ Among mineral supplements, chromium picolinate, calcium, magnesium, selenium, and zinc have shown promise in the effective management of PCOS.⁵⁵ These diverse supplements collectively offer potential advantages, addressing different aspects of PCOS and contributing to overall health and well-being.

Conclusion

PCOS necessitates a comprehensive treatment strategy given its intricate endocrine nature. These current management practice involves a blend of dietary and lifestyle modifications, pharmacological interventions, and surgical measures. However, there is a rising demand for noninvasive treatments with minimal side effects. This review underscores the broad spectrum of PCOS treatments, spanning physical modalities, herbal approaches, holistic therapies, medical procedures, bacteriotherapeutics, and supplements. While holistic and herbal methods show promise, uncertainties persist, necessitating further research. Surgical interventions and bacteriotherapeutics hold potential but require additional investigation for safety and efficacy. The complexity of PCOS underscores the importance of evidence-based strategies, and consulting a physician is crucial for informed decision-making. The emergence of potentially effective noninvasive and natural treatments offer comfort to patients and reliable outcomes to physicians, potentially minimizing side effects associated with conventional therapies. Although these options show promise, rigorous research is essential to assess their long-term safety, efficacy, and optimal clinical use. Integrating lifestyle changes, conventional therapies, and tailored novel treatments holds the potential for a comprehensive and effective approach to treating PCOS, providing hope to millions of affected women worldwide.

Footnotes

Acknowledgment

The authors wish to thank all published authors highlighted in this article for their dedicated work in the treatment of PCOS.

Consent for Publication

All authors have granted their consent for the publication of this article.

Author’s Contributions

S.M. wrote the original article. V.S. and B.N.C. provided guidance, edited, and approved the article.

Author Disclosure Statement

The author confirms that this article content has no conflict of interest.

Funding Information

No financial support was received for this article.

Abbreviations Used

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Exploring the Novel Alternative and Modern Treatment Options for Polycystic Ovary Syndrome-A Review

Abstract

Introduction:

Method:

Results:

Conclusion:

Introduction

Method

Results

Holistic Therapies and Physical Modalities

Herbal and Natural Approaches

Medical Surgical Procedures

Bacteriotherapeutics

Supplement and Nutraceuticals

Conclusion

Footnotes

Acknowledgment

Consent for Publication

Author’s Contributions

Author Disclosure Statement

Funding Information

Abbreviations Used

References