Polycystic ovarian syndrome-current pharmacotherapy and clinical implications

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<p>lable at ScienceDirect</p><p>Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>Contents lists avai</p><p>Taiwanese Journal of Obstetrics & Gynecology</p><p>journal homepage: www.t jog-onl ine.com</p><p>Review Article</p><p>Polycystic ovarian syndrome-current pharmacotherapy and clinical</p><p>implications</p><p>Rumaisa Rashid a, Suhail Ahmad Mir a, Ozaifa Kareem a, Tabassum Ali a, Rifat Ara b,</p><p>Anjum Malik b, Fiza Amin c, G.N. Bader a, *</p><p>a Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, 190006, India</p><p>b Department of Obstetrics & Gynaecology, Sheri Kashmir Institute of Medical Sciences, Medical College & Hospital, Bemina, Srinagar, 190001, India</p><p>c Department of Gynaecology and Obstetrics, Lala Ded Hospital, Govt Medical College Srinagar, India</p><p>a r t i c l e i n f o</p><p>Article history:</p><p>Accepted 10 September 2021</p><p>Keywords:</p><p>Polycystic ovary syndrome</p><p>Metformin</p><p>GLP-1 agonist</p><p>Laser therapy</p><p>* Corresponding author. Department of Pharmace</p><p>Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.</p><p>E-mail addresses: rumaisa.scholar@kashmiruniver</p><p>scholar@kashmiruniversity.net (S.A. Mir), ozaifa.sc</p><p>(O. Kareem), tabasumali.ku@gmail.com (T. Ali), ri</p><p>amalik5152@gmail.com (A. Malik), Fizamink@gmai</p><p>kashmiruniversity.ac.in (G.N. Bader).</p><p>https://doi.org/10.1016/j.tjog.2021.11.009</p><p>1028-4559/© 2022 Taiwan Association of Obstetrics &</p><p>creativecommons.org/licenses/by-nc-nd/4.0/).</p><p>a b s t r a c t</p><p>Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women is characterized by</p><p>polycystic ovaries, chronic anovulation and hyperandrogenism. The treatment in PCOS is mainly</p><p>symptomatic and involves lifestyle interventions and medications such as Metformin, Oral contracep-</p><p>tives and Antiandrogens. However, the management of PCOS is challenging and current interventions are</p><p>not able to deal with outcomes of this syndrome. This review encompasses latest pharmacotherapeutic</p><p>and non-pharmacotherapeutic interventions currently in use to tackle various symptomatic contentions</p><p>in PCOS. Our focus has been mainly on novel therapeutic modalities for treatment/management of PCOS,</p><p>like use of newer insulin sensitizers viz., Inositols, Glucagon-like peptide-1(GLP-1) agonists, Dipeptidyl</p><p>pepdidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein 2 (SGLT2) inhibitors. Also, evi-</p><p>dence suggesting the use of vitamin D, statins, and Letrozole as emerging therapies in PCOS have been</p><p>summarized in this review. Additionally, novel cosmetic techniques like electrolysis, laser and use of</p><p>topically applied eflornithine to tackle the most distressing feature of facial hirsutism associated with</p><p>PCOS, non-pharmacological therapy like acupuncture and the role of herbal medicine in PCOS man-</p><p>agement have also been discussed.</p><p>© 2022 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an</p><p>open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p><p>Introduction</p><p>Polycystic ovary syndrome (PCOS), is one of the most common</p><p>endocrine disorders, characterized by irregular menstrual cycles,</p><p>hyperandrogenism, and polycystic ovaries (PCO) [1,2]. It is one of</p><p>the most common causes of ovulatory infertility in women of</p><p>reproductive age. The worldwide prevalence of PCOS ranges from 4</p><p>to 21%, while in adolescents this number ranges between 9.1 and</p><p>36% (depending upon the diagnostic criteria used) [3e7]. Various</p><p>features of the metabolic syndrome like insulin resistance and</p><p>hyperinsulinemia are present in the majority of womenwith PCOS.</p><p>Hyperandrogenism, the principle symptom in PCOS, has physical</p><p>utical Sciences, University of</p><p>sity.net (R. Rashid), suhailmir.</p><p>holar@kashmiruniversity.net</p><p>fatara8@gmail.com (R. Ara),</p><p>l.com (F. Amin), gnbader@</p><p>Gynecology. Publishing services b</p><p>and physiological health implications in young and fertile women</p><p>[8]. Obesity, affecting 50% of women, is a common clinical feature of</p><p>PCOS [9]. The women with history of weight gain often proceed</p><p>with the onset of oligomenorrhea and hyperandrogenism, sug-</p><p>gesting that obesity has a pathogenetic role in subsequent devel-</p><p>opment of PCOS [10].</p><p>The clinical presentation of PCOS includes hyperandrogenism</p><p>and/or chronic anovulation. Hyperandrogenism proceeds with</p><p>symptoms like hirsutism, acne, and/or male pattern alopecia.</p><p>Chronic anovulation may be presented as oligomenorrhea, amen-</p><p>orrhea, and/or infertility. However, normalmenstrual cycles may be</p><p>seen in 20% of patients with PCOS [11,12]. PCOS is associated with</p><p>an increased risk of several comorbidities; particularly type 2 dia-</p><p>betes, cardiovascular disease (CVD), obesity, dyslipidemia, hyper-</p><p>tension and glucose intolerance [13].</p><p>PCOS is a heterogeneous syndrome and its exact etiology re-</p><p>mains unknown till date. Being a heterogenic disorder, a large</p><p>number of factors play a contributing role in its development. In-</p><p>sulin resistance and compensatory hyperinsulinemia are proposed</p><p>y Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>to be significant etiological factors involved in PCOS andmanifest in</p><p>higher proportion in both lean and overweight women [14]. A</p><p>number of theories have been put forward to explain the patho-</p><p>genesis of PCOS [15]. For example, hypersecretion of Gonadotropin-</p><p>releasing hormone (GnRH) from hypothalamus. The surge in GnRH</p><p>in turn produces excessive Luteinising hormone (LH) and the</p><p>sequential events hyperstimulate ovaries to produce more testos-</p><p>terone [16]. Another explanation theory of PCOS syndrome is based</p><p>on endocrinological perturbation of insulin axis like hyper-</p><p>insulinemia and insulin resistance. Higher circulating insulin level</p><p>subsides secretion of sex hormone-binding globulin (SHBG) from</p><p>liver. The fall in SHBG increases the level of free circulating</p><p>testosterone in blood and causes hyperandrogenemia [17]. Hyper-</p><p>insulinemia also increases GnRH pulse frequency; however, the LH</p><p>surge predominates over Follicle stimulating hormone (FSH) surge.</p><p>This leads to decreased follicular maturation, increased ovarian</p><p>androgen production, and decreased SHBG; all these steps further</p><p>add to the development of PCOS [18]. `</p><p>Hirsutism, menstrual irregularities and infertility are considered</p><p>the most distressing symptoms experienced by women with PCOS.</p><p>These are accountable for major causes of depression, anxiety and</p><p>low self-esteem in women. Due to complex pathogenesis in PCOS,</p><p>the treatments are individualized depending upon prevailing signs</p><p>and symptoms and very rarely monotherapeutic. Several adjunc-</p><p>tive interventions have been put forward for the management and</p><p>treatment of PCOS. Lifestyle intervention is regarded as the</p><p>cornerstone for the management of PCOS [19]. For infertility</p><p>treatment, lifestyle modifications are combined with ovulation</p><p>induction agents like clomiphene citrate and aromatase inhibitors</p><p>(Letrozole). For Insulin resistance and hyperandrogenic conditions</p><p>insulin sensitizers and antiandrogens are given alone or in com-</p><p>bination. Newer insulin sensitizers have been tried in PCOS which</p><p>include Myoinositols, GLP-1 agonists, DDP-4 inhibitors and SGLT2.</p><p>Oral Contraceptives are considered as the first line treatment in the</p><p>management of menstrual abnormalities and hyperandrogenic</p><p>symptoms in PCOS [20]. Statins and bromocriptine have also been</p><p>added as a treatment option in PCOS for hyperandrogenic and</p><p>dyslipidemic conditions. 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Iran Red Crescent Med J</p><p>2016;18(12).</p><p>[176] Hamza AH, AlBishri WM, Alfaris MH. Effect of Vitex agnus-castus plant</p><p>extract on polycystic ovary syndrome complications in experimental rat</p><p>model. Asian Pac J Reprod 2019;8(2):63.</p><p>[177] Arentz S, Abbott JA, Smith CA, Bensoussan A. Herbal medicine for the</p><p>management of polycystic ovary syndrome (PCOS) and associated oligo/</p><p>amenorrhoea and hyperandrogenism; a review of the laboratory evidence</p><p>for effects with corroborative clinical findings. BMC Compl Alternative Med</p><p>2014;14(1):511.</p><p>[178] Rondanelli M, Infantino V, Riva A, Petrangolini G, Faliva M, Peroni G, et al.</p><p>Polycystic ovary syndrome management: a review of the possible amazing</p><p>role of berberine. Arch Gynecol Obstet 2020:1e8.</p><p>[179] Li M-F, Zhou X-M, Li X-L. The effect of berberine on polycystic ovary syn-</p><p>drome patients with insulin resistance (PCOS-IR): a meta-analysis and sys-</p><p>tematic review. Evid base Compl Alternative Med 2018;2018.</p><p>[180] Mansour A, Samadi M, Sanginabadi M, Gerami H, Karimi S, Hosseini S, et al.</p><p>Effect of resveratrol on menstrual cyclicity, hyperandrogenism and meta-</p><p>bolic profile in women with PCOS. Clin Nutr ESPEN 2021;40(6):4106e12.</p><p>[181] Hong Y, Yin Y, Tan Y, Hong K, Zhou H. The flavanone, naringenin, modifies</p><p>antioxidant and steroidogenic enzyme activity in a rat model of letrozole-</p><p>induced polycystic ovary syndrome. Med Sci Mon Int Med J Exp Clin Res: J</p><p>Exp Clin Med 2019;25:395.</p><p>[182] Tabrizi FPF, Hajizadeh-Sharafabad F, Vaezi M, Jafari-Vayghan H, Alizadeh M,</p><p>Maleki V. Quercetin and polycystic ovary syndrome, current evidence and</p><p>future directions: a systematic review. J Ovarian Res 2020;13(1):1e10.</p><p>[183] Shim YY, Gui B, Arnison PG, Wang Y, Reaney MJ. Flaxseed (Linum usita-</p><p>tissimum L.) bioactive compounds and peptide nomenclature: a review.</p><p>Trends Food Sci Technol 2014;38(1):5e20.</p><p>[184] Askari K. Effect of hydroalcoholic extract of Vitex agnus-castus fruit on</p><p>fertility and estrous cycle in letrozole-induced polycystic ovary (PCOS) in rat.</p><p>Razi J Med Sci 2017;24(3):42e8.</p><p>[185] Shamsi M, Nejati V, Najafi G, Pour SK. Protective effects of licorice extract on</p><p>ovarian morphology, oocyte maturation, and embryo development in PCOS-</p><p>induced mice: an experimental study. Int J Reprod Biomed 2020;18(10):865.</p><p>[186] Armanini D, Mattarello MJ, Fiore C, Bonanni G, Scaroni C, Sartorato P, et al.</p><p>Licorice reduces serum testosterone in healthy women. Steroids</p><p>2004;69(11e12):763e6.</p><p>[187] Armanini D, Castello R, Scaroni C, Bonanni G, Faccini G, Pellati D, et al.</p><p>Treatment of polycystic ovary syndrome with spironolactone plus licorice.</p><p>Eur J Obstet Gynecol Reprod Biol 2007;131(1):61e7.</p><p>[188] Zhang N, Liu X, Zhuang L, Liu X, Zhao H, Shan Y, et al. Berberine decreases</p><p>insulin resistance in a PCOS rats by improving GLUT4: dual regulation of the</p><p>PI3K/AKT and MAPK pathways. Regul Toxicol Pharmacol 2020;110:104544.</p><p>[189] Xie L, Zhang D, Ma H, He H, Xia Q, Shen W, et al. The effect of berberine on</p><p>reproduction and metabolism in women with polycystic ovary syndrome: a</p><p>systematic review and meta-analysis of randomized control trials. Evid base</p><p>Compl Alternative Med 2019. Dec 13. doi: 10.1155/2019/7918631 2019.</p><p>[190] Meera Murugesan B, Muralidharan P, Hari R. Effect of ethanolic seed extract</p><p>of Caesalpinia bonducella on hormones in mifepristone induced PCOS rats.</p><p>J Appl Pharmaceut Sci 2020;10(2):72e6.</p><p>[191] Ramadurai S, Balasundaram U. Rhizomicrobiomics of Caesalpinia bonducella,</p><p>a wonder plant for PCOS treatment. Physiol Mol Biol Plants 2020;26(12):</p><p>2453e63.</p><p>the permanent</p><p>destruction of hair follicles, various techniques like electrolysis and</p><p>laser hair removal methods have been adopted. Another technique</p><p>called acupuncture, has also gained popularity in terms of man-</p><p>aging PCOS. The use of Traditional/Folk medicine has become a</p><p>trending option nowadays, as patients believe that homemade</p><p>remedies can cure the disease with fewer side effects.</p><p>Methodology</p><p>A comprehensive literature search was carried out via elec-</p><p>tronic searches of PubMed, MEDLINE, Google Scholar and</p><p>Cochrane Library databases using multiple search terms related to</p><p>“PCOS”, “management”, “newer treatment options”, “recent ad-</p><p>vances”, “cosmetic interventions” and “herbal treatment” in the</p><p>title and keywords. Both pre-clinical and clinical studies were</p><p>included in the review, and the articles that reported different</p><p>treatment options were used as the main source of study, with</p><p>41</p><p>exclusion of papers where treatment and management strategies</p><p>were not involved.</p><p>Pharmacological interventions</p><p>Treatment of women with PCOS depends on the identification</p><p>and management of symptoms. These could be menstrual disor-</p><p>ders, androgen-related symptoms and anovulation leading to</p><p>infertility. Table 1, describes all the pharmacological and non-</p><p>pharmacological interventions in PCOS. Apart from targeting</p><p>these phenotypes, newer studies have shown that treatment</p><p>should also address new parameters such as higher anti-Müllerian</p><p>hormone levels, plasma metabolomics and gut microbiome</p><p>composition which are among severe phenotypes in PCOS [22].</p><p>Oral contraceptives</p><p>Hormonal contraceptives (oral contraceptives, patch, or vaginal</p><p>ring) are the first-line management protocol for the menstrual</p><p>abnormalities and hirsutism/acne in women with PCOS [20]. Oral</p><p>contraceptives (OCPs) are a good treatment option for those</p><p>women who do not desire to conceive. These act by promoting</p><p>direct negative feedback on LH secretion, which results in</p><p>decreased ovarian synthesis of androgens, thereby reducing</p><p>hyperandrogenism. They increase sex hormone-binding globulin</p><p>from liver and decrease circulating free androgen. Other mecha-</p><p>nisms by which OCPs act include, inhibition of peripheral conver-</p><p>sion of testosterone to dihydrotestosterone, binding of</p><p>dihydrotestosterone to androgen receptors and reduction in adre-</p><p>nal androgen secretion [23].</p><p>The combined oral contraceptive pill does not improve the in-</p><p>sulin resistance that usually underlies the hyperandrogenism. It has</p><p>been reported that OCPs aggravate insulin resistance and also in-</p><p>crease the risk of inflammatory and coagulatory disorders in</p><p>women with polycystic ovary syndrome as well as those without</p><p>this phenotype [24]. OCPs have to be used with caution in women</p><p>with dyslipidemias, as they can worsen triglyceride levels. PCOS</p><p>womenwho are obese should lose weight, as this can help regulate</p><p>menses [25,26].</p><p>The choice of oral contraceptive used in PCOS is very important,</p><p>as most of progestins also possess androgenic effects. An important</p><p>consideration for the progestin component is the degree of</p><p>androgenicity of the progestin [27]. However, newer OCPs contain</p><p>progestins with less androgenicity (norethindrone, desogestrel,</p><p>and norgestimate) and two progestins [cyproterone acetate (CPA</p><p>used in low doses in OCPs) and drospirenone] function as androgen</p><p>receptor antagonists. One of the newest OCPs that contains a</p><p>combination of nonandrogenic progestin i.e. drospirenone, and</p><p>ethinylestradiol is potentially ideal for the treatment of women</p><p>with PCOS. Drospirenone, a spironolactone analog acts as a diuretic,</p><p>whereas CPA is a progestational antiandrogen. CPA competitively</p><p>inhibits the binding of testosterone to the androgen receptor.</p><p>Antiandrogens</p><p>Anti-androgens (spironolactone, flutamide and finasteride) are</p><p>used in the medical management of hyperandrogenism by sys-</p><p>temically reducing the amount of androgen. Antiandrogens are</p><p>mostly used in the treatment of PCOS as these reduce hirsutism and</p><p>other androgen related problems. The anti-androgens work slightly</p><p>in different ways, but they all block the action of testosterone.</p><p>Spironolactone, an antiandrogen, primarily acts by binding to the</p><p>androgen receptor as an antagonist, can cause menstrual irregu-</p><p>larity, and can feminize a male foetus, if the patient becomes</p><p>pregnant. Thus Spironolactone is mostly used in combination with</p><p>Table 1</p><p>Summary of different treatment options in management of PCOS.</p><p>Drug Place in Therapy Adverse Effects</p><p>Synthetic drugs</p><p>Metformin Hyperinsulinemia, Androgen excess, anovulation Nausea and Vomiting (common), Diarrhoea,</p><p>Metallic taste, Lactic acidosis</p><p>Spironolactone Hirsutism, acne Irregular Menstrual cycles, Hyperkalemia, Hypotension</p><p>Oral Contraceptives Regulation of menstrual Cycles, Hirsutism, prevention of</p><p>endrometrial cancers</p><p>Weight gain, fluid retention, breast tenderness</p><p>Clomiphene Citrate Ovulation induction Mood swings, blurred vision, multiple gestations</p><p>Gonadotropins Ovulation induction Ovarian hyperstimulation, multiple pregnancies, abdominal</p><p>pain, breast tenderness</p><p>Pioglitazone, Rosiglitazone Hyperinsulinemia, androgen excess, anovulation Weight gain, oedema, cardiovascular diseases</p><p>Myo-inositol and d-chiro-inositol Androgen excess, anovulation Nausea, difficulty sleeping, headache, tiredness</p><p>Liraglutide, Exenatide Weight loss, anovulation, Hyperandronenism,</p><p>Hyperinsulinemia</p><p>Nausea, Abdominal discomfort</p><p>Sitagliptin, Alogliptin and Linagliptin Hyperinsulinemia, obesity Headache, upper respiratory tract infections</p><p>Empagliflozin Obesity, androgen excess, Hyperinsulinemia Dizziness, Headache</p><p>Statins Hyperandrogenism, Dyslipidemia Worse IR</p><p>Bromocriptine Anovulation e</p><p>Vitamin D Regular of menstrual cycles, hyperandrogenism Weight loss or poor appetite</p><p>Calcium Menstrual regulation, anovulation Dry mouth, headache</p><p>Eflornithine Hirsutism Acne, swollen patches, dry or tingling skin</p><p>Traditional Medicine</p><p>Cinnamon Hyperinsulinemia, regulation of menstrual cycles Nausea, hives, itchy eyes</p><p>Flax seeds Hyperandrogenism, regulation of menstrual cycles Loose stools, delayed clotting time</p><p>Chasteberry Regulation of menstrual cycles, anovulation Nausea, stomach upset, weight gain</p><p>Licorice Hyperandrogenism Mineralocorticoid excess, high blood pressure</p><p>Evening Primrose Hormonal imbalance, dyslipidemia Nausea, diarrhoea (mild)</p><p>Holy basil Hyperandrogenism, Hyperinsulinemia Diarrhoea, hypoglycaemia (large doses),nausea</p><p>Aloe Vera Hyperinsulinemia, androgen excess Abdominal cramps, miscarriage</p><p>Berberine Hyperinsulinemia, dyslipidemia Flatulence, constipation and stomach pain</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>OCPs for treatment of PCOS related symptoms [28,29]. CPA (a</p><p>progestional antiandrogen) competitively inhibits the binding of</p><p>testosterone and its conversion product 5a-dihydrotestosterone to</p><p>the androgen receptor. It is generally well tolerated.</p><p>Flutamide (a nonsteroidal antiandrogen without progestogenic</p><p>effect) is very effective in treating hirsutism [30]. However, it is</p><p>rarely used alone due to its high cost and the risk of hepatocellular</p><p>toxicity. Finasteride is a type 2 (5-a-reductase) inhibitor that in-</p><p>hibits the production of dihydrotestosterone. Treatment with fi-</p><p>nasteride has shown decrease in hirsutism scores [31].</p><p>Insulin sensitizers</p><p>Metformin and other insulin sensitizers, like thiazolidinediones</p><p>(TZD) have also been proven to induce ovulation by improving</p><p>insulin resistance [32]. The use of metformin is associated with</p><p>increased menstrual cyclicity, reduction in circulating androgen</p><p>levels and improved ovulation [33]. Metformin (a biguanide) acts</p><p>by inhibiting hepatic glucose production, decreasing intestinal</p><p>glucose uptake and increasing insulin sensitivity in peripheral tis-</p><p>sues [34]. Thiazolidinediones (rosiglitazone) also show insulin-</p><p>lowering effects by improving insulin sensitivity, and in turn</p><p>decrease circulating androgen levels [28]. Metformin is preferred as</p><p>it can cause weight loss, while thiazolidinediones can</p><p>increase</p><p>weight as a result of fluid retention [29].</p><p>Metformin</p><p>Metformin has been used as a first-line treatment for infertility,</p><p>with supportive evidence including data from a Cochrane review</p><p>[35]. A recent RCTs comparing metformin with placebo in PCOS</p><p>women, has showed, that metformin improves live births, clinical</p><p>pregnancy and ovulation rates per woman but, with an increased</p><p>risk of adverse effects (gastrointestinal side-effects) [36].</p><p>According to European Society for Human Reproduction and</p><p>Embryology (EHSRE) and the American Society for Reproductive</p><p>42</p><p>Medicine (ASRM) consensus statement [37], Metformin in PCOS</p><p>should be restricted to women with glucose intolerance only, with</p><p>the findings that metformin treatment does not increase ovulation</p><p>and live-birth rates, when compared with clomiphene citrate alone</p><p>[38]. But the findings of the study by Nestler recommendsMetformin</p><p>in infertility treatment of PCOS, suggesting that its use should not be</p><p>restricted to glucose intolerance and should be used in combination</p><p>with clomiphene citrate to increase ovulation rate [39].</p><p>One of the most important complications of assisted repro-</p><p>ductive technology (ART) in PCOS is an increased risk of ovarian</p><p>hyperstimulation syndrome (OHSS), due to overstimulation of</p><p>follicle-stimulating hormone (FSH). Higher doses of FSH lead to</p><p>increase in number of follicles and oocytes, high serum estradiol</p><p>levels, increased risk of OHSS, increased cancellation rates and</p><p>lower conception rates [40,41]. Studies have shown that Metfor-</p><p>min increases the clinical pregnancy rate and decreases the risk of</p><p>ovarian hyperstimulation syndrome (OHSS) in women with PCOS</p><p>undergoing IVF [42]. In a similar study, short-term use of met-</p><p>formin (4 weeks only) in IVF has shown significant improvement</p><p>in ongoing pregnancy rate with a concomitant fall in the risk of</p><p>OHSS [43].</p><p>Newer insulin sensitizers</p><p>Inositols: Among newer insulin-sensitizing agents, the introduc-</p><p>tion of inositols in the treatment plan of PCOS has proved to be very</p><p>useful in dealing with the related endocrine/metabolic disorders.</p><p>Treatment with two inositol isomers, Myo-inositol (MI) and D-</p><p>chiro-inositol(DCI), could be proposed as a favorable therapeutic</p><p>approaches for the treatment of patients with PCOS [44]. Inositols</p><p>improve insulin resistance, serum androgen levels and other fea-</p><p>tures of metabolic syndrome [45]. They act as insulin's secondary</p><p>messengers and mediate different functions of insulin. Despite</p><p>their similarities, MI and DCI play different roles in etiology and</p><p>treatment of PCOS. MI is transformed into an inositol phospho-</p><p>glycan (IPG) insulin second messenger (MI-IPG) that is involved in</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>cellular glucose uptake, whereas DCI is used to make an IPG insulin</p><p>second messenger (DCI-IPG), which plays an important role in</p><p>glycogen synthesis [46]. At a lower dose, DCI restores normal in-</p><p>sulin sensitivity by reducing the circulating androgens. On the</p><p>contrary, MI exerts its beneficial effects mainly at the ovary level,</p><p>where it is highly concentrated, and is crucial for follicle stimu-</p><p>lating hormone (FSH) signalling [47]. Both MI and DCI reduce the</p><p>levels of luteinizing hormone (LH), LH/FSH ratio and testosterone</p><p>levels in PCOS [46,48,49].</p><p>MI and DCI can be synergistically integrated by combining them</p><p>in a ratio of 40:1. Both preclinical and the clinical studies support</p><p>the MI/DCI ratio of 40:1, as the best one for restoring ovulation in</p><p>PCOS [50]. A recent study by Nordio et al., using different ratios of</p><p>MI/DCI suggested that the 40:1 MI/DCI ratio was the best for PCOS</p><p>treatment aimed at restoring ovulation and normalizing other pa-</p><p>rameters of PCOS. Further, a decreased activity was observed when</p><p>the 40:1 ratio was modified in favour of DCI [51]. Study by Arturo</p><p>bevilecqua et al., supported the same ratio of 40:1 of MI/DCI for</p><p>PCOS. The study reported that, the mice treated with this ratio</p><p>recovered normal histological features, proper ratio of theca/</p><p>granulosa cell layer thickness and faster recovery of their fertility.</p><p>The higher DCI treatment formula with a ratio of 5:1 was found to</p><p>be ineffective with negative pathological outcomes [52]. Thus MI/</p><p>DCI (40:1) represents a promising alternative by counteracting</p><p>PCOS at both systemic and ovary level [53].</p><p>MI also plays a critical role in in-vitro fertilization (IVF) in PCOS.</p><p>Study has shown that follicles with matured and fertilized oocyte,</p><p>have higher follicular fluid (FF) volume and content of MI,</p><p>compared to follicles with immature and unfertilized oocytes [54].</p><p>Moreover the positive correlation was found between the levels of</p><p>MI in FF with embryo quality [55]. RCT has reported that MI</p><p>administration improved oocyte quality in IVF/ICSI (intra-</p><p>cytoplasmic sperm injection) cycles in women with PCOS. Study</p><p>further reported that MI administration was associated with a</p><p>reduction in the quantity of recombinant FSH (rFSH) administered</p><p>and the number of days of stimulation [56], suggesting that MI</p><p>improves FSH sensitivity, ovarian function and oocyte development.</p><p>GLP-1 agonists: GLP-1 receptor agonists are the class of antidiabetic</p><p>drugs which mimic the incretin actions. Incretins are gut hor-</p><p>mones, that increase insulin secretion from pancreas in response to</p><p>ingested food [57]. GLP-1 agonists provide a dual control by</p><p>reducing body fat and hyperglycaemia in diabetic and non-diabetic</p><p>patients [58]. The promising effects of these drugs have provided a</p><p>platform for their use in PCOS. Two GLP-1receptor agonists viz.,</p><p>Exenatide and Liraglutide have been studied in PCOS so far.</p><p>Liraglutide: In a study, treatment with Liraglutide (1.8 mg/kg)</p><p>decreased weight (by 5 kg), testosterone production and improved</p><p>ovulation rate in overweight PCOS women [59]. Moderate weight</p><p>loss was seen when Liraglutide was given alone or in combination</p><p>with Metformin. However, increased weight reduction was re-</p><p>ported with higher dose of Liraglutide alone (3 mg/kg) [60]. Lir-</p><p>aglutide treatment has proven to be more efficient than metformin</p><p>in terms of weight loss and insulin sensitivity with less gastroin-</p><p>testinal side effects [61]. In fact, most of the studies of liraglutide in</p><p>obese PCOS patients have shown encouraging results with respect</p><p>to its causing weight loss [62,63]. However, the reports of weight</p><p>gain (average-5kg) on termination of the therapy have also been</p><p>reported [64]. Although Liraglutide has shown encouraging results</p><p>in PCOS, nonetheless, the number of clinical studies carried so far</p><p>are limited, with smaller sample size and have been mostly</p><p>restricted to obese PCOS patients. So, studies with high quality,</p><p>larger sample size and other pharmacotherapies are extensively</p><p>needed in order to validate the positive effects of Liraglutide.</p><p>43</p><p>Exenatide: Exenatide is the another GLP-1 receptor agonist</p><p>showing properties like weight reduction, direct CNS effects and</p><p>decreased food absorption [65]. The RCT of obese/overweight PCOS</p><p>patients with Exenatide therapy (12 weeks) has shown a significant</p><p>reduction in weight loss and central adiposity [66]. The improve-</p><p>ments in IR, menstrual cycle and inflammatory markers, may</p><p>further increase the chances of pregnancy rates in these patients. In</p><p>another RCT, overweight PCOS women were randomly distributed</p><p>into groups and treated with either Metformin (1 g, two times/day)</p><p>or Exenatide (10ug, two times/day) or metformin þ Exenatide</p><p>(1 g þ 10ug two times/day) for a period of 2 months [67]. The study</p><p>reported the superiority of combined therapy rather than treat-</p><p>ments alone in improving menstrual cycle and ovulation rate.</p><p>However, testosterone levels and IR were significantly decreased in</p><p>all the groups. Recently, an in-vivo study on rat PCOS DHEA model,</p><p>has shown that Metformin and Exenatide improve both endocrine</p><p>and reproductive functions in PCOS rats [68]. The significant</p><p>improvement in the insulin resistance was seen, which is mediated</p><p>via AMP-activated protein kinase (AMPK) and</p><p>the histone/protein</p><p>deacetylase (SIRT1) pathway. This led the researchers to conclude,</p><p>that AMPKa- SIRT1 axis may be the new promising target for PCOS</p><p>treatment.</p><p>Four months of treatment with Exenatide (5ug for 1 month &</p><p>10ug for 3 months twice daily) on thirty overweight/obese PCOS</p><p>patients was associated with a weight loss of at least 3% [69].</p><p>Further reduction in serum markers were also seen (endothelial,</p><p>inflammation and clot function), which gives the additional benefit</p><p>of this therapy in prevention of cardiovascular risk incidences in</p><p>these Patients. In another study of Exenatide treatment in obese</p><p>PCOS women, metabolic changes were detected in sixty-seven</p><p>women using nontargeted gas chromatography-tandem mass</p><p>spectrometry [70]. Total of 62 metabolites were detected between</p><p>healthy and PCOS groups, while 31 metabolites were noted before</p><p>and after Exenatide treatment. The study revealed that Exenatide</p><p>treatment improved insulin sensitivity, glycolipid metabolism and</p><p>reduced body weight in PCOS. The changes in the circulating levels</p><p>of zinc-a2-glycoprotein (ZAG) (protein which plays important role</p><p>in fertilization and lipid metabolism) in PCOS women, was also</p><p>seen after Exenatide and metformin treatment [71]. 182 women</p><p>with PCOS and 150 controls without PCOS were recruited in the</p><p>study. Among PCOS, only eighty two overweight/obese patients</p><p>were included in the study and 12 week treatment of Exenatide</p><p>(10ug, two times/day) and metformin (1000 mg, two times/day)</p><p>was given randomly. The study confirmed that circulating ZAG</p><p>(levels decreased in PCOS patients) levels were up-regulated in</p><p>both the treatments in PCOS, reporting ZAG as a new therapeutic</p><p>indicator in PCOS. The above studies have shown that Exenatide</p><p>may act as an emerging therapeutic option in PCOS. Nonetheless,</p><p>more extensive studies with larger sample size and longer study</p><p>duration should be taken into consideration. Moreover, lean to</p><p>moderate weight PCOS patients must be included along with obese</p><p>in order to further assess the safety and efficacy of the therapy.</p><p>DPP-4 inhibitors: DPP-4 inhibitors are another class of Antidiabetic</p><p>drugs that help in regulating the blood glucose, by increasing the</p><p>levels of incretin in the body [72]. Thus DPP-4 inhibitors have a new</p><p>support for their use in PCOS. Three DPP-4 inhibitors have been</p><p>studied in PCOS so far which include- Sitagliptin, Alogliptin and</p><p>Linagliptin.</p><p>Recent studies have shown that treatment with Sitagliptin</p><p>(100 mg/day for 1 month) decreased blood glucose, and visceral fat</p><p>in PCOS [73]. The Study further revealed that treatment with Sita-</p><p>gliptin improved growth hormone secretion, a possible mechanism</p><p>for visceral fat mass reduction. In Metformin intolerant obese PCOS</p><p>patients, Sitagliptin (100 mg, four times/day) has shown promising</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>results. Sitagliptin has shown improvement in beta-cell function</p><p>and prevented impaired glucose tolerance [74]. Thus, Sitagliptin</p><p>can likely be used as an alternative in PCOS womenwho failed with</p><p>lifestyle interventions and are intolerant to metformin. In another</p><p>study, Metformin treated obese PCOS patients were treated with</p><p>DPP-4 inhibitor Alogliptin [75]. In this 12 week study, 30 obese</p><p>PCOS patients were randomly given either, Alogliptin (25mg OD) or</p><p>Alogliptin þ Pioglitazone (25 mg þ 30mgOD). These patients had</p><p>already received Metformin 1000 mg, two times/day. It was</p><p>revealed that Alogliptin alone or in combination with Pioglitazone</p><p>improved b-cell function along with IR.</p><p>In an in-vivo study, Linagliptin/indole-3-carbinol (I3C) combi-</p><p>nation has shown a significant improvement in ovarian</p><p>morphology and biochemical/hormonal parameters in PCOS rats</p><p>[76]. The changes in lipid profile, IR and oxidative stress were also</p><p>seen. Further, the suppression of Nrf2/HO-1 pathway in PCOS was</p><p>also improved with combination therapy, suggesting that Lina-</p><p>gliptin/I3C combination therapy ameliorate PCOS condition. The</p><p>Combination of the drugs therefore can provide a synergistic effect</p><p>in order to tackle the core defects in this metabolic syndrome.</p><p>SGLT2 inhibitors: SGLT2 inhibitors are the class of oral anti-</p><p>hyperglycemic drugs that differ from other classes by providing</p><p>insulin-independent mechanism of action. SGLT2 inhibitors with</p><p>their unique mechanism of action decrease blood glucose in the</p><p>body through glycosuria and natriuresis. They target the glucose</p><p>reabsorption from the proximal tubules of the kidneys [77]. SGLT2</p><p>inhibitors increase urinary glucose excretion, weight loss and</p><p>improve cardiovascular risks in patients with type 2 diabetes [78].</p><p>Only one drug of SGLT2 inhibitors (Empagliflozin) has been studied</p><p>in PCOS so far. In a 12 week, open labelled, randomized study,</p><p>Empagliflozin (25 mg, once daily) treatment was compared with</p><p>Metformin (1500 mg, once daily) treatment in obese women with</p><p>PCOS [79]. In this study, Empagliflozin showed significant</p><p>improvement with respect to weight loss, BMI, waist/Hip ratio, fat</p><p>mass reduction and other anthropometric parameters when</p><p>compared to Metformin. However, changes in IR and testosterone</p><p>levels were comparable between both the treatments. Moreover,</p><p>RCT, long-term study duration and treatment with other SLGT2 in-</p><p>hibitors are needed to provide further insights for their use in PCOS.</p><p>Recently, licogliflozin, an SGLT1/2 dual inhibitor, has proven</p><p>effective in PCOS treatment [80]. An RCT concluded that licogli-</p><p>flozin at a dose of 50 mg three times a day decreases hyper-</p><p>insulinemia and hyperandrogenemia in women with PCOS. This</p><p>explored efficacy of licogliflozin in PCOS can make it a promising</p><p>novel treatment option for these patients [81].</p><p>Clomiphene citrate</p><p>Clomiphene citrate (CC) is the drug of first choice for ovulation</p><p>induction in women with PCOS [82]. It is often used in the treat-</p><p>ment of anovulation, because of its proven effectiveness in inducing</p><p>ovulation. High doses of CC are generally needed in obese patients</p><p>however these high doses have the potential to increase the risk of</p><p>multiple gestations [25]. Clomiphene citrate is a partially selective</p><p>estrogen receptor modulator. Its antiestrogenic activity at the hy-</p><p>pothalamus induces a change in gonadotropin releasing hormone</p><p>(GnRH) pulse frequency, leading to increased release of follicle</p><p>stimulating hormone (FSH) from the pituitary gland.</p><p>CC is generally administered for 5 days from the second or third</p><p>day of the menstrual cycle, starting with 50 mg/day and increased</p><p>to 250 mg/day [83,84]. When ovulation does not occur with CC</p><p>treatment at maximum dosage, a patient is classically defined</p><p>‘clomiphene citrate-resistant’ [83,85] and if pregnancy is not ach-</p><p>ieved after six ovulatory cycles, then the patient is said to have</p><p>44</p><p>clomiphene citrate failure [83]. CC administration increases the</p><p>ovulation rate by 60e85%, but the pregnancy rate is increased only</p><p>in 30e40% with an increased risk of multiple pregnancies (5e7%)</p><p>[86]. A systematic review and meta-analysis report in women with</p><p>WHO Group 2 anovulation, comparing clomiphene citrate with</p><p>placebo, demonstrated that CC improves the clinical pregnancy rate</p><p>per woman [87]. In a randomized controlled trial by yang et al., on</p><p>ovulation induction, clomiphene citrate compared with placebo/no</p><p>treatment showed a higher pregnancy and ovulation rate in WHO</p><p>Group 2 (including PCOS) anovulatory women [88].</p><p>Emerging therapeutics in PCOS</p><p>Statins</p><p>The newer treatment options that have been added to the</p><p>treatment protocols of PCOS are statins. They are useful in the</p><p>treatment of PCOS as they reduce sex steroid production and</p><p>improve dyslipidaemia and reduce ovarian androgen production</p><p>by inhibiting androgen production of thecal cells [89,90]. In</p><p>in vitro experiments on human thecal einterstitial cells, statins</p><p>have been shown to inhibit proliferation of human theca-</p><p>interstitial cells irrespective of the availability of cholesterol and</p><p>independently of leukocytes, both in normal and PCOS ovaries</p><p>[91]. Available</p><p>evidence supports the hypothesis that the meval-</p><p>onate pathway plays a major role in the function of theca-</p><p>interstitial cells and modulation of this pathway by statins, may</p><p>provide both cardiovascular (CV) and ovarian benefits in PCOS. In</p><p>PCOS, Statins have a potential approach in the medical manage-</p><p>ment of dyslipidaemia, increased oxidative stress and hyper-</p><p>androgenaemia [92]. In a RCTs, Prolonged use of Statins was</p><p>shown to cause an improvement in clinical and biochemical ab-</p><p>normalities with one ovulation dysfunction, in women with PCOS</p><p>[93]. Though, statin therapy has been shown to improve chronic</p><p>inflammation and lipid profile, however, its use worsens insulin</p><p>sensitivity in PCOS. In a study by Johana et al., atorvastatin therapy</p><p>was shown to impair insulin sensitivity in women with PCOS and</p><p>the study further suggested that statin therapy should be initiated</p><p>only on the basis of generally accepted criteria and individual risk</p><p>assessment of CVS, and not only on the basis of PCOS [94].</p><p>Aromatase inhibitors</p><p>Aromatase inhibitors are new promising ovulation-inducing</p><p>agents. Selective aromatase inhibitors such as anastrozole and</p><p>letrozole block the conversion of testosterone and androstenedione</p><p>to estradiol and estrone, respectively. They decrease estrogenic</p><p>activity, release the hypothalamus from negative feedback and in-</p><p>crease the FSH release [95]. In PCOS patients Letrozole is admin-</p><p>istered usually at doses of 2.5e7.5/day between days 3e7 of the</p><p>menstrual cycle [96,97] or as a single dose of 20 mg on day 3 of the</p><p>cycle. Initial studies on its use in infertility treatment have shown</p><p>teratogenic effect, however in a recent study by wang et al., con-</p><p>tradictory results have been obtained (no foetal abnormalities)</p><p>[88]. After clomiphene citrate failure, Mitwally and Casper, firstly</p><p>experimented the use of letrozole in PCOS anovulatory patients,</p><p>and reported ovulation in 75% of patients and pregnancy in 25% of</p><p>cases [98].</p><p>In a Meta-analysis study of comparison of aromatase inhibitors</p><p>with clomiphene citrate, statistical significant results were seen in</p><p>favour of the aromatase inhibitors both in pregnancy and in live</p><p>births [99,100], however data were not confirmed by RTC, signi-</p><p>fying no clear evidence of using aromatase inhibitors over clomi-</p><p>phene citrate in infertile cases. However, recent systematic review</p><p>and meta-analysis reports on ovulation induction, have shown</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>letrozole superior to clomiphene citrate in terms of live birth,</p><p>pregnancy and ovulation rates for WHO Group 2 (including PCOS)</p><p>anovulatory women and for pregnancy rate in therapy naïve WHO</p><p>Group 2 (including PCOS) anovulatory women [88]. A more</p><p>recently published RCTs comparing letrozole with clomiphene</p><p>citrate in PCOSwomen also demonstrated a significantly higher live</p><p>birth and clinical pregnancy rate per woman randomized with</p><p>Letrozole [101]. Letrozole has also been shown to be more effective</p><p>than metformin in terms of live birth rate for WHO Group 2</p><p>(including PCOS) anovulatory women [88]. As per the Australian</p><p>Therapeutic Goods Administration (AU TGA), Letrozole is consid-</p><p>ered pregnancy category D drug and should not be given to the</p><p>pregnant women. Also, health care providers should counsel and</p><p>give information to the PCOS patient before their Letrozole use.</p><p>Bromocriptine</p><p>The inhibitory effect of dopamine and dopamine agonists on LH</p><p>release in females has long been established [102,103]. Dopamine</p><p>agonist bromocriptine, has a potential usefulness in patients with</p><p>PCOS by reducing LH hypersecretion. Decrease in LH pulse fre-</p><p>quency leads to restoration of cyclical activity to the hypothalmo-</p><p>pituitary-ovarian axis, decrease in androgen synthesis [104],</p><p>restoration of normal menstrual cycle and regular ovulation</p><p>(30e60%) in PCOS patients. In a double blind RCTs study comparing</p><p>bromocriptine with placebo, it was seen that serum prolactin level</p><p>fell significantly in the bromocriptine groupwith a significant fall in</p><p>the serum LH response to GnRH in both groups, further no hor-</p><p>monal measurement or response predicted the clinical response to</p><p>treatment [105].</p><p>Vitamin D and calcium</p><p>Vitamin D and calcium supplementation have therapeutic im-</p><p>plications in improving menstrual regularity, hyperandrogenism</p><p>and follicle maturation in women with PCOS [106,107]. Serum 25-</p><p>hydroxyvitamin D level was improved in obese PCOS patients, on</p><p>daily supplementationwith vitamin D and elemental calcium [108].</p><p>In a study, significant reduction in total testosterone and androgen</p><p>levels (by 12% and 17%, respectively) was seen after three month</p><p>supplementation of 530 mg elemental Ca and 3533 IU vitamin D</p><p>which was later increased to 8533 IU [109]. VDR-mediated signal-</p><p>ling pathways and vitamin D levels seem to (deeply) affect the risk</p><p>of several gynaecological diseases, such as polycystic ovary syn-</p><p>drome (PCOS), endometriosis, and ovarian and even breast cancer.</p><p>Vitamin D plays an important role in ovarian follicular develop-</p><p>ment, luteinization (altering anti-müllerian hormone (AMH)</p><p>signaling), follicle-stimulating hormone (FSH) sensitivity and pro-</p><p>gesterone production in human granulosa cells [110]. AMH levels</p><p>are elevated inwomenwith PCOSwhich cause an abnormal ovarian</p><p>folliculogenesis. Vitamin D therapy normalizes the serum AMH</p><p>levels and thereby, can be linked to an improvement in folliculo-</p><p>genesis [111].</p><p>Vitamin D supplementation increases insulin sensitivity in PCOS</p><p>patients with vitamin D deficiency. In a prospective study by kar-</p><p>adag et al., 67 vitamin-D-deficient PCOS patients were matched</p><p>with 54 vitamin-D-deficient non-PCOS volunteers. It was seen that</p><p>Vitamin D supplementation showed a considerable improvement</p><p>in vitamin-D-deficient PCOS but did not have any effect in vitamin-</p><p>D-deficient non-PCOS women, indicating the possible role of</p><p>vitamin D in the pathogenesis of PCOS [112]. Similar studies carried</p><p>out by Hahn et al. [113], Li et al. [114],Wehr et al. [115] and S.K. Patra</p><p>et al. [116], demonstrated a positive role of hypovitaminosis of</p><p>vitamin D in the etiology of insulin resistance in PCOS. In a study by</p><p>Patra et al., HOMA-IR values (Homeostatic Model Assessment of</p><p>45</p><p>Insulin Resistance) were compared in three groups for the assess-</p><p>ment of insulin resistance with the highest HOMA levels i.e.</p><p>maximum insulin resistance in the groupwith vitamin D deficiency</p><p>and lowest with vitamin D sufficiency. Steroids, such as Vitamin D</p><p>and Progesterone play an important role in different biological</p><p>processes. A Recent study has shown that vitamin D exerts pro-</p><p>gesterone like activity [117]. Vitamin D like Progesterone mimics</p><p>several activities during pregnancy, helps endometrium to be</p><p>receptive and supports implantation through similar pathways as</p><p>by progesterone. Vitamin D levels and VDR (Vitamin D receptor)-</p><p>mediated signalling pathways affect the risk of several other</p><p>gynaecological diseases, such as endometriosis, ovarian and even</p><p>breast cancer.</p><p>Vitamin D receptors are expressed in human and murine ovary</p><p>and endometrium. A study by ozkan et al., found that women with</p><p>higher levels of vitamin D in their serum and follicular fluid were</p><p>significantly more likely to achieve pregnancy from IVF compared</p><p>to women with lower levels of vitamin D [118]. A retrospective</p><p>cohort study, concluded that vitamin D deficiency results in low</p><p>pregnancy rates with an effect mediated via endometrium. Besides</p><p>this correlation, the study did not find any association between</p><p>vitamin D and ovarian stimulation or with markers of embryo</p><p>quality [119]. However study by Firouzabadi et al., concluded that</p><p>there was no correlation between the serum and follicular vitamin</p><p>D level and the pregnancy rate in the IVF [120]. Besides Vitamin C</p><p>and D, Vitamin E and omega 3 fatty acids have also shown bene-</p><p>ficial effects in the management of PCOS [121e124].</p><p>Cosmetic interventions in PCOS</p><p>Permanent hair removal methods</p><p>Electrolysis is the type of permanent hair removal</p><p>method that</p><p>is approved by FDA for hirsutism. Formany years it has been used to</p><p>remove unwanted hair. In Electrolysis, each hair is treated indi-</p><p>vidually and electrical current is applied through a fine needle</p><p>inserted into the hair follicle. It is usually applied for localized areas</p><p>and can be used for any hair or skin colour. Electrolysis can ease the</p><p>problem of hirsutism; however, it is a painful and costly technique.</p><p>Further erythema, postinflammatory pigment changes may occur</p><p>[125]. No scientific data and controlled trials with respect to</p><p>effectiveness of electrolysis in PCOS has been reported so far.</p><p>Another technique called photoepilation uses laser and nonlaser</p><p>light sources to damage hair follicles. Nowadays, it has become one</p><p>of the most common dermatological procedures used for hair</p><p>reduction. Laser hair removal treatment has proven much effica-</p><p>cious than other forms of hair removal (ref facial hait QOL). It has</p><p>improved the quality of life in PCOS patients [126]. Reports have</p><p>shown that in PCOS, laser treatment has improved quality of life up</p><p>to 6 months after treatment. Study by A. Roche et al., on 63 hirsute</p><p>women reported 30 months post laser benefit on quality of life</p><p>[127]. Study has further shown a significant decrease in the</p><p>emotional burden on patients. Long term sustainability of laser</p><p>treatment in PCOS condition need to be further ascertained with</p><p>more clinical relevance. This treatment is much expensive, but less</p><p>painful and much faster than other methods of hair removal [128].</p><p>Nowadays newer topical hair removal creams are available and</p><p>added along with laser therapy for additional benefits in hirsutism</p><p>treatment.</p><p>Topical treatment</p><p>Eflornithine hydrochloride, a topical cream, is the newer inter-</p><p>vention used for removal of unwanted hair in females. It has been</p><p>approved by Food and Drug Administration for reduction of facial</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>hirsutism [129]. Eflornithine, irreversibly inhibits the enzyme</p><p>ornithine decarboxylase in the human skin, which inhibits cell di-</p><p>vision and synthetic functions, thus reducing the rate of hair</p><p>growth [28,29]. Randomized clinical studies have reported Eflor-</p><p>nithine as an effective treatment in reducing facial hair along with</p><p>the improvements in quality of life of patients [130]. It is recom-</p><p>mended to use twice daily and can also be combined with laser</p><p>treatment. In a study Eflornithine cream combined with laser</p><p>treatment for a period of 6 months enhanced the efficacy of hair</p><p>removal with rapid and complete reduction of facial hair [131]. This</p><p>study was further supported by Stacy et al., which demonstrated</p><p>rapid hair removal of Eflornithine when combined with laser</p><p>treatment [132]. Unwanted hair which is considered as the thief of</p><p>womanhood now can be resolved by these new cosmetic tech-</p><p>niques. Even though these treatments have limitations, yet, they</p><p>can provide a high esteem and confidence among women.</p><p>Lifestyle interventions</p><p>Lifestyle interventions are the first line treatment for PCOS</p><p>[133,134]. A healthy diet with caloric restriction and exercise (to aid</p><p>in weight loss and prevention of future weight gain) are best at</p><p>reducing body mass index and improving insulin sensitivity. Even a</p><p>small amount of weight loss (5%) can help in alleviating the signs</p><p>and symptoms of PCOS e. g, menstrual cycle regularity, ovulation,</p><p>decrease in the risk of diabetes in high risk groups, prevention of</p><p>future cardio-metabolic risk and in mental wellbeing [135e138].</p><p>The Endocrine society clinical practice guidelines 2013 suggest the</p><p>use of exercise therapy in the management of overweight and</p><p>obesity in PCOS [139]. According to guidelines, Exercise therapy</p><p>alone or in combinationwith dietary intervention, improvesweight</p><p>loss, reduces cardiovascular risk factors and diabetes risk in the</p><p>general population.</p><p>Short-term meal substitution is now recognized as a dietary</p><p>option for women with PCOS [140]. A number of dietary compo-</p><p>sitions have been investigated for PCOS, with recent studies rec-</p><p>ommending macronutrient intake. Fat restriction to �30% of total</p><p>calories, less intake of high GI (Glycemic index) carbohydrate, cal-</p><p>orie intake distribution between several meals per day with low</p><p>intake from snacks and drinks should be given a thought [141]. The</p><p>pilot study by Mavropoulos et al., reported that the intake of low</p><p>carbohydrate, ketogenic diet (LCKD) resulted in significant reduc-</p><p>tion inweight, free testosterone, LH/FSH ratio, and fasting insulin in</p><p>women with obesity and PCOS [142].</p><p>Various studies regarding fasting, have gained popularity in</p><p>terms of PCOS. The recent study by chiofalo et al., have reported</p><p>ameliorative effects of fasting on metabolic and hormonal dys-</p><p>functions in PCOS [143].</p><p>Acupuncture</p><p>Acupuncture is an ancient therapeutic approach in which nee-</p><p>dles are used for sensory stimulation of somatic afferent nerves that</p><p>innervate skin and muscles [144]. Worldwide, acupuncture has</p><p>gained popularity in terms of reproduction and endocrinology</p><p>[145]. Various clinical and pre-clinical studied have suggested</p><p>acupuncture as a useful technique in anovulatory dysfunction, IR</p><p>and hyperandrogenism in PCOS [146,147]. Studies from China, have</p><p>reported that acupuncture regulates the hypothalamic-pituitary-</p><p>ovarian axis, hence, it may be of relevance in improving hormon-</p><p>al and metabolic profile in hyperandrogenism [144]. In a RCT of 17</p><p>overweight/obese PCOS patients, electroacupuncture (5 week</p><p>treatment) improved glucose tolerance and decreased adipose</p><p>tissue androgens [148,149]. An In- vivo study on rat PCOSmodel has</p><p>reported better efficacy of electroacupuncture in terms of insulin</p><p>46</p><p>sensitivity when compared with exercise [150]. Recently a study</p><p>has shown that acupuncture ameliorates anxiety and depression in</p><p>PCOS via decreasing serum b-endorphin and androgen [151].</p><p>However, more vigorous clinical and preclinical studies with high</p><p>quality systematic research should be conducted to give more</p><p>robust evidence in treatment of PCOS.</p><p>Altered gut microbiome treatment in PCOS</p><p>Over the past few years, various studies have shown the link</p><p>between PCOS and changes in the gut microbiome. A compelling</p><p>difference in composition of gut microbiome is documented among</p><p>normal and PCOS patients [152,153]. Studies have reported a spe-</p><p>cific increase in harmful bacteria (Escherichia and Shigella) [152]</p><p>and reduction in beneficial bacteria (Lactobacilli and Bifidobacteria)</p><p>in women with PCOS [154,155]. Reduction in glycodeoxycholic and</p><p>tauroursodeoxycholic acid levels has also been reported with</p><p>altered Interlukin-22 (IL-22) level [156].</p><p>The therapeutic options to treat altered gut microbiome</p><p>responsible of PCOS consists of probiotics (live micro-organisms),</p><p>prebiotics (source of food for healthy gut bacteria), symbiotic, and</p><p>newer therapies that include fecal microbiota transplantation and</p><p>exogenous IL-22 administration [157].</p><p>Probiotic supplementation has shown a beneficial effect on</p><p>metabolic profile in PCOS [158,159]. A significant decline in weight,</p><p>BMI, plasma glucose and serum insulin levels were seen in PCOS</p><p>patients compared with the placebo [158,160]. Prebiotics that alter</p><p>the composition of the microbiota of the host have shown some</p><p>positive health benefits. Reduction in fasting plasma glucose, total</p><p>cholesterol and a significant increase in HDL cholesterol levels were</p><p>seen with prebiotics use [161,162]. Studies have reported that</p><p>probiotic consumption could improve hyperandrogenism and</p><p>menstrual irregularities in women with PCOS [163].</p><p>Fecal microbiota transplantation (FMT), a new therapeutic op-</p><p>tion for PCOS, consists of administration of microorganisms from</p><p>the feces of healthy donors to the intestinal tract of the recipient.</p><p>This therapy changes the composition of the gut microbiome and</p><p>can treat disease in recipients [164]. An In vivo study has shown</p><p>that FMT alleviates serum androgen levels, increases estrogen</p><p>levels and helps to regulate the normal menstrual</p><p>cycle [165].</p><p>Similarly, exogenous administration of intestinal immune factor IL-</p><p>22 has been shown to be effective in the treatment of PCOS-induced</p><p>murine models [166]. The decrease in hyperandrogenism, IR, and</p><p>improved ovary morphology has been reported with IL-22</p><p>administration. However, so far no clinical study has reported the</p><p>use of FMT and Exogenous IL-22 for the treatment PCOS, never-</p><p>theless, continued research and clinical trials need to be conducted</p><p>to prove the efficacy of FMT in humans [167].</p><p>Traditional/folk medicine in PCOS</p><p>In recent times focus has been shifted towards traditional/</p><p>herbal medicine for their beneficial role in PCOS. Various natural</p><p>remedies have been tried in PCOS which include- Cinnamon</p><p>[168e171], Flaxseeds [172e174], Chestberry [175,176], Liquorice</p><p>[177], Berberine [178,179] and many others. Flavonoids, flavanones</p><p>and other polyphenolic compounds such as resveratrol, quercetin</p><p>and naringenin are suggested as a potential therapeutic agents in</p><p>the treatment of PCOS [180e182].</p><p>Studies found that Cinnamon (Cinnamomum verum) supple-</p><p>mentation decreased insulin resistance, fasting insulin and anti-</p><p>Mullerian hormone levels in women with PCOS [169,171].</p><p>Another plant based product, Flaxseed (Linum usitatissimum) is a</p><p>rich source of lignin, which comes under phytoestrogens [183]. A</p><p>significant reduction in BMI and weight loss has been noted in</p><p>R. Rashid, S.A. Mir, O. Kareem et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 40e50</p><p>PCOS patients treated with flaxseed [172]. In an in vivo study,</p><p>flaxseed in combination with spearmint improved ovarian and</p><p>endocrine profile in PCOS rat model [173]. Chasteberry (Vitex</p><p>agnus-castus), with many pre-clinical and clinical evidences has</p><p>been shown to lower prolactin level, improve menstrual regu-</p><p>larity and treat infertility [175,184]. It contains a variety of com-</p><p>pounds that bind to dopamine type 2 (DA-2) receptors in the</p><p>brain; reduce cyclic adenosine mono phosphate (cAMP) and lower</p><p>prolactin secretion [177].</p><p>Italian researchers have found that Liquorice (Glycyrrhiza gla-</p><p>bra) root can help reduce serum testosterone inwomenwith PCOS</p><p>[185]. Liquorice with its active constituent glycyrrhizin, can also</p><p>be used as an adjuvant therapy for hirsutism [186,187]. Berberine,</p><p>the major active constituent of Rhizoma coptidis has shown posi-</p><p>tive effects on insulin resistance in PCOS [145,188]. When</p><p>compared with metformin, berberine was more efficacious in</p><p>improving IR and dyslipidemia. Decrease in androgen levels and</p><p>LH/FSH ratio was also seen in PCOS patients when compared with</p><p>Metformin [189].</p><p>Nicker Bean (Caesalpinia bonducella) a medicinal shrub is the</p><p>new spotlight for its encouraging results in the treatment of PCOS.</p><p>Its seed extracts have shown anti-androgenic, hypoglycemic and</p><p>anti-inflammatory properties with regularization of normal hor-</p><p>monal milieu in PCOS state [190,191].</p><p>The above data, derived mainly from in vivo and small clinical</p><p>trials, indicate that herbal treatment might be of some benefit in</p><p>women with PCOS. However, the current literature should be</p><p>enhanced with better study design, with more clinical relevance</p><p>and patient data. Studies should test active constituents from</p><p>herbal drugs, rather than extract as a whole, before any definite</p><p>conclusions on the role of herbal treatment on PCOS can be drawn.</p><p>Conclusion</p><p>Polycystic ovarian syndrome (PCOS) is a common endocrine</p><p>system disorder in women of reproductive age. A wide variety of</p><p>risk factors have been investigated in relation to PCOS, including</p><p>obesity, glucose intolerance, and dyslipidemia. Insulin resistance is</p><p>known to play a critical role in the pathophysiology of PCOS. Several</p><p>studies suggest the use of new or modified therapies for the</p><p>treatment of obesity and metabolic syndrome associated with</p><p>PCOS. Recent clinical trials have focused on inositols, statins,</p><p>Letrozole and vitamin D for treating PCOS. Clinical studies with</p><p>GLP-1 agonists, DPP-4 inhibitors and SGLT2 antagonists have</p><p>shown promising results however, the trials are ambiguous, and</p><p>larger clinical investigations are still needed. The addition of laser</p><p>and other cosmetic interventions for removal of unwanted hair</p><p>have improved the physical appearance in these patients and thus</p><p>the quality of life. However, studies on traditional/folk medicine in</p><p>treatment of PCOS are inconclusive and need to be fully investi-</p><p>gated with reference to their efficacy and safety profiles. 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