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Slide 1 | First Slide:

Slide 2 | Current State of Understanding:

Epidemiology:
most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this age group.
PCOS manifests as various phenotypes that likely differ between ethnic groups (ex. high body mass index (BMI) is a feature in Caucasians. In contrast, lower BMI and mild hirsutism are features in East Asians
no significant differences across ethnic groups in the prevalence of PCOS itself have been identified when diagnoses are made using the Rotterdam criteria.

Slide 3 | Clinical Signs and Symptoms:

phenotype A, in which all three characteristics are present, and phenotypes B–D, in which two out of three characteristics are present
phenotype B, hyperandrogenism and ovulatory dysfunction
phenotype C, hyperandrogenism and PCOM
and phenotype D, ovulatory dysfunction and PCOM.
Clinical Signs and Symptoms:
he most common symptom of PCOS is irregular menstrual periods. Women with PCOS may also have excess hair growth, acne, and weight gain.
PCOS is typically diagnosed using a combination of medical history, physical examination, and laboratory testing.
Infertility
One of the most common symptoms of PCOS is infertility. PCOS can cause a woman’s ovaries to produce too much of the hormone testosterone, which can interfere with ovulation. As a result, women with PCOS may have difficulty becoming pregnant.
Irregular Menstrual Periods
Another common symptom of PCOS is irregular menstrual periods. Women with PCOS may have periods that are lighter or heavier than normal, or they may skip periods altogether. In some cases, women with PCOS may only have a period once every few months.
Excess Hair Growth
Excess hair growth is another symptom of PCOS that can be extremely distressing for women. Women with PCOS may develop excess facial and body hair, and the hair may be coarse and dark. This symptom is caused by an increase in testosterone levels in the body.
Weight Gain
Weight gain is another common symptom of PCOS, and it can be difficult to lose weight if you have the condition. Women with PCOS often have insulin resistance, which means that their bodies are less able to process sugar. This can lead to weight gain and an increased risk for type 2 diabetes.
Acne
Acne is another symptom of PCOS that can be very frustrating for women to deal with. The increase in testosterone levels associated with PCOS can cause an increase in sebum production, which can lead to clogged pores and acne breakouts
Androgen Excess
One of the primary features of PCOS is androgen excess. Androgens are male hormones that are present in both men and women, but women typically have lower levels of androgens than men. In women with PCOS, there is an imbalance in the ratio of androgens to estrogen, resulting in higher levels of androgens. This hormonal imbalance can lead to a variety of symptoms, including acne, hirsutism, and irregular periods.
Insulin Resistance
Insulin resistance is another key feature of PCOS. Insulin is a hormone that helps to regulate blood sugar levels. In people who are insulin resistant, the body does not respond properly to insulin, resulting in higher than normal blood sugar levels. Women with PCOS are often insulin resistant, which can lead to weight gain and an increased risk for type 2 diabetes.
Infertility
Infertility is a common problem in women with PCOS. The hormonal imbalance associated with PCOS can interfere with ovulation, making it difficult for women to become pregnant. Additionally, the high levels of insulin associated with PCOS can also contribute to fertility problems.
Cysts on the Ovaries
Another hallmark of PCOS is the presence of cysts on the ovaries. These cysts are small sacs that contain fluid and are typically benign (non-cancerous). In women with PCOS, the cysts can cause the ovaries to become enlarged and can lead to pain or discomfort.
Increased Risk for Other Health Problems
Women with PCOS are also at an increased risk for other health problems, including type 2 diabetes, high blood pressure, heart disease, and sleep apnea.
Complications:
Infertility
One of the most common complications of PCOS is infertility. PCOS can cause a woman to have irregular or absent menstrual periods, which can make it difficult to become pregnant. In addition, PCOS can also cause the ovaries to produce too much of the hormone testosterone, which can interfere with ovulation.
Gestational Diabetes
Gestational diabetes is a type of diabetes that occurs during pregnancy and can be dangerous for both the mother and the child. Women with PCOS are at an increased risk for developing gestational diabetes, as the condition can cause insulin resistance.
Hypertension
Hypertension, or high blood pressure, is another common complication of PCOS. High blood pressure can damage the arteries and increase the risk for heart disease and stroke.
Sleep Apnea
Sleep apnea is a condition in which a person stops breathing for brief periods during sleep. It can be caused by excess weight, which is a common symptom of PCOS. Sleep apnea can lead to fatigue and other health problems.
Anxiety and Depression
Anxiety and depression are two mental health conditions that are commonly associated with PCOS. The hormonal changes that occur with PCOS can cause mood swings and feelings of sadness or anxiety. In addition, the physical symptoms of PCOS, such as excess weight or acne, can also lead to low self-esteem and depression.
Endometrial Cancer
Endometrial cancer is a type of cancer that affects the lining of the uterus. Women with PCOS are at an increased risk for developing endometrial cancer due to the hormonal changes that occur with the condition.
Acanthosis Nigricans
Acanthosis nigricans is a skin condition that causes dark patches on the skin, typically on the neck or armpits. The patches often have a velvety texture and may be itchy or painful. Acanthosis nigricans is often caused by insulin resistance, which is a common symptom of PCOS
Miscarriage
Another complication of PCOS is miscarriage. Studies have shown that women with PCOS are at an increased risk of miscarrying a pregnancy. This may be due to the hormonal imbalances associated with PCOS, which can interfere with the normal development of the fetus.
Hypertension
Hypertension, or high blood pressure, is another complication that can occur in women with PCOS. This may be due to the hormonal imbalances associated with PCOS, which can cause an increase in blood pressure.
Skin Problems
Skin problems such as acne, hirsutism, and alopecia are common in women with PCOS. The hormonal imbalances associated with PCOS can cause an increase in sebum production, which can lead to acne breakouts. Hirsutism is excess hair growth on the face, chest, or back, while alopecia is hair loss on the scalp or elsewhere on the body

Slide 4 | Current Diagnostic Options:

PCOS is diagnosed according to several criteria: the 1990 National Institutes of Health (NIH) criteria, the 2003 Rotterdam criteria, the 2006 Androgen Excess & PCOS (AE-PCOS) Society criteria (worldwide), and the 2007 Japan Society of Obstetrics and Gynecology (JSOG) criteria (Japan).2,4,5
However, this is a matter of debate. The implementation of diagnostic criteria varies around the globe and between ethnicities, owing to variations in the prevalence of the components of PCOS, such as clinical and/or biochemical hyperandrogenism and ovulatory dysfunction.
The Rotterdam criteria, published by the European Society for Human Reproduction & Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM), require at least two out of the following three characteristics to be present for a diagnosis of PCOS to be made: clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology (PCOM)
The first international evidence-based guidelines, published in 2018, pose various problems for the diagnosis and understanding of the epidemiology and etiology of PCOS.3 The NIH criteria require the presence of two characteristics, hyperandrogenism and ovulatory dysfunction, while the AE-PCOS criteria require two characteristics, hyperandrogenism and ovarian dysfunction, which may be indicated by ovulatory dysfunction or PCOM.
modified Ferriman-Gallway (mFG) score for the definition of hirsutism in ethnic groups with less dense villus hair has not been established, nor has it even been determined whether it is appropriate to use the mFG score in these groups for the diagnosis of hirsutism
of direct free testos- terone, such as the radiometric and enzyme-linked assays that are frequently used in the clinical setting, are not particularly sensitive or accurate.
Furthermore, the serum androgen concentration does not necessarily reflect local hyperandrogenism in the ovary: high testosterone concentrations in the follicular fluid were found to be present in two-thirds of East Asian patients with PCOS and a nor- mal serum testosterone concentration using radioimmunoassay.
Furthermore, body composition varies substantially among ethnic groups, with East Asian people showing less adiposity than other ethnicities.3 However, the prevalence of impaired glucose tolerance is higher in patients with PCOS, independent of obesity, than in indi- viduals who do not have PCOS, by five-fold in Asia, four-fold in the Americas, and three-fold in Europe.13
Hyperandrogenism and insulin resistance together contribute to the pathophysiology, but their individual contributions differ from patient to patient, which accounts for the heterogeneous nature of PCOS and its presentation.

Slide 5 | Pathophysiology

What is PCOS?

difficulties in understanding the pathophysiology of PCOS is its heterogeneous and complex nature
Individual contributions of hyperandrogenism and insulin resistance differ from patient to patient, which accounts for the heterogeneous nature of PCOS and its presentation.
Simply PCOS is shaped by the interaction between reproductive dysfunction and metabolic disorders and has lifelong effects on the health of affected women.

What drives PCOS? Simply we do not fully know

multifactorial etiology
the exposure of individuals with predisposing genetic factors to potent environmental factors causes the development of various PCOS phenotypes.
The origin of this vicious cycle of disorders that comprises the pathology of PCOS remains unknown.
The simplest explanation for this complex and heterogeneous syndrome would be that hyperandrogenism is a predisposing factor, while insulin resistance triggers the development of PCOS.4,6,7,18,

Hallmarks of PCOS:

(1) Hyperandrogenism, (2) ovulatory dysfunction, (3) aberrant gonadotropin-releasing hormone (GnRH) pulsation and the (4) resulting abnormal gonadotropin secretion, and (5) insulin resistance have been implicated in the pathophysiology PCOS; these factors interact and exacerbate one another
Hyperandrogenism:
caused by intrinsic dysfunction of theca cells and/or the hypothalamus-pituitary-ovarian axis and is exacerbated by high AMH concentrations.8–11,20,21
synergistic effect with insulin resistance to induce the development of PCOS.
Hyperandrogenism is further aggravated by hyperinsulinemia, which develops secondary to insulin resistance.
hyperandrogenism causes abnormal GnRH pulsation and gonadotropin secretion through the aberrant negative or positive feedback of progesterone and estrogen.
Ovarian Dysfunction:
characterized by aberrant follicular growth → early stage and arrests at the antral stage
a failure of the selection of dominant follicles to ovulate leads to fluid accumulation
High AMH secreted by pre−/ small antral follicles that accumulate in PCOS ovaries → exacerbate ovarian dysfunction increasing hyperandrogenism by altering the follicular microenvironment and GnRH pulsation.
Abnormal GnRH pulsation:
Abnormal LH/FSH:
abnormal gonadotropin secretion in patients with PCOS is characterized by a high luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, which induces ovarian dysfunction, including the hypersecretion of androgens
Insulin resistance:
Insulin resistance is another key component of the pathophysiology of PCOS, although it is not included in the diagnostic criteria.12
Excess androgen secretion increases the level of insulin resistance, and hyperinsulinemia, which develops secondary to the insulin resistance, further increases androgen secretion and induces the production of sex hormone-binding globulin (SHBG) in the liver, thereby increasing the circulating concentration of bioactive free testosterone and further aggravating the disorders associated with hyperandrogenism.14–18
Insulin resistance in tissues such as the liver and muscle: is associated with visceral adiposity and adipocyte dysfunction, which are exacerbated by hyperandrogenism
The hyperandrogenism and insulin resistance exacerbate one another: excess androgen secretion induces visceral adiposity and adipocyte dysfunction, while the hyperinsulinemia that develops secondary to the insulin resistance stimulates andro- gen secretion by theca cells and modulates the effects of gonadotropins on theca cells.14–18

Genetics:

A high level of familial aggregation has been observed for PCOS
5x risk of PCOS if mother has PCOS
a cohort of twins studied in the Netherlands estimated the heritability of PCOS to be ~70%.
More recently, the prevalence of all three traits of PCOS, hyperandrogenism, ovulatory dysfunction, and PCOM was compared in the daughters born to women with and without PCOS several years after menarche. This was found to be 16.2% (7/43) in the daughters born to women with PCOS, while none of those born to women without PCOS (0/28) exhibited all of these three characteristics.26
Candidate genes suggested by genome-wide association studies (GWAS) include genes that regulate gonadotropin secretion and action and ovarian function, such as FSHB (follicle-stimulating hor- mone B polypeptide), LHCGR (luteinizing hormone/choriogonado- tropin receptor), FSHR (follicle-stimulating hormone receptor), AMH, and DENND1A (DENN domain containing 1A); and genes associated with metabolism, such as THADA (thyroid adenoma-associated gene) and INSR (insulin receptor).
12 PCOS loci identified by GWAS in Chinese individuals in patients of Northern European descent showed similar effect sizes and directions in both ethnic groups.
implying that PCOS was present at least 50 000–60 000 years ago, when their ancestors migrated out of Africa and then racially diverged, and further implies a common genetic risk profile across populations.32–34
These findings are consistent with the absence of differences in the prevalence of PCOS in people of differing ethnic- ity when identical diagnostic criteria are used
estimated that the loci identified by GWAS account for less than 10% of its high heritability.
include prenatal exposure to the intrauterine environment of mothers with PCOS, the follicular microenvironment, and lifestyle following birth.
The intrauterine environment of mothers with PCOS features high concentrations of androgens because of high circulating androgen concentrations and functional abnormalities of the placenta.35,3
Excess andro- gen production by the fetal ovaries in response to the intrauterine environment of mothers with PCOS may further exacerbate the androgen-richness of the intrauterine environment

Slide 6 | Potential Intersting Targets

AMH:
Pregnant mothers have high AMH and hyperinsulinemia due to metabolic abnormalities leading to abnormal intrauterine environment.
The local concentration of AMH is high, reflecting the larger number and altered function of pre−/small antral follicles, which secrete AMH.40–43
Follicular Microenvironment:
abnormal follicular microenvironment in the ovaries of women with PCOS hyperandrogenism b/c of abnormalities in thecal cell function and hypothalamus-pituitary-ovarian axis.
A proinflammatory state in the follicular microenviron- ment, as well as low-grade systemic inflammation, is a key feature of PCOS.
Local oxidative stress and ER stress are features of PCOS.44–48
Inflammation, oxidative stress, and ER stress —> vicious circle; adversely affects the follicular microenvironment —> local hyperandrogenic conditions further activate these pathways.
metabolic abnormalities, including hyperinsulinemia, have deleterious effects on the follicular microenvironment.45,49–53
Accumulation of several exogenous toxins has also been identified in the ovaries of women with PCOS—> endocrine-disrupting chemicals (EDCs) and advanced glycation end products (AGEs).54,55
unfavorable lifestyle, including a poor diet, which also increases the risk of metabolic disease, drives the pathogenesis of PCOS.11,19
the accumulation of exogenous toxins in the follicular environment: EDCs, and the consumption of AGE-rich food —> drive the development of PCOS
AGEs can form either endogenously or exogenously, but most originate exogenously, from smoking or a high-fat and/or high-protein diet, especially if this includes food items cooked at high temperature and in a low-moisture environment.56

ER stress

ER is the organelle responsible for the folding and assembly of secretory proteins
ER stress —> condition which unfolded or misfolded proteins —> accumulate in the ER due to imbalance in the demand for protein folding and the protein-folding capacity of the ER.49,53,57,58
the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which affect and regulate various cellular functions.
the UPR exists to restore homeostasis and keep the cell alive in three ways: by reducing the translation of proteins; by increasing the synthesis of ER chaperones, thereby increasing protein-folding capacity; and by generating ER-associated degradation (ERAD) factors that remove irreparably misfolded proteins.
ER stress cannot be resolved,the UPR induces programmed cell death.

follicular microenvironment —> regulated by gonadotrophins and intraovarian factors in a spatially and temporally coordinated manner.
Intraovarian factors have regulatory roles during the entire process of follicular growth and play crucial roles in pathological conditions of the ovary, including PCOS.39,53,60,61
AGEs are produced by the Maillard reaction, in which the carbonyl groups of carbohydrates react non-enzymatically with the primary amino groups of proteins.
that ER stress pathways are activated in the granulosa cells of both a mouse model of PCOS induced by the continuous administration of androgen and in humans, and this finding has been confirmed by other groups.48,62–67 W
local inflammation and oxidative stress, which are closely connected with ER stress and form a vicious circle, and the local hyperandrogenic conditions further activate these pathways.45,49
Accumulation of AGEs and lipid observed in the follicular microenvironment of PCOS may also account for activation of ER stress.68,69 thus activate ER stress.
The ovarian dysfunction in PCOS is characterized by aberrant follicular growth, which accelerates in the early stage and arrests at the antral stage; a failure of the selection of dominant follicles to ovulate; and an ovulatory disorder.70
The ovarian morphology of patients with PCOS is characterized as PCOM with interstitial fibrosis.
We demonstrated that ER stress contributes to the pathophysiology of PCOS through multiple functional alterations in granulosa cells48,52,53,72–74 (Figure 3). E
ER stress stimulates the production of transforming growth factor-β1 (TGF-β1), a profibrotic growth factor, in granulosa cells and accelerates interstitial fibrosis in the ovary, which is a characteristic of PCOS.
testosterone-induced apoptosis of granulosa cells via the induction of the proapoptotic factor death receptor 5 (DR5) and is associated with follicular growth arrest at the antral stage, which is another characteristic of PCOS.52
the testosterone-induced expression of receptor for advanced glycation end products (RAGE) in granulosa cells, resulting in the accumulation of AGEs in these cells.
aryl hydrocarbon receptor (AHR), a representative receptor for EDCs, and its downstream signaling in granulosa cells, by which means it could plausibly alter steroid metabolism in these cells.
associated with cumulus oocyte-complex (COC) expansion in granulosa cells via Notch signaling, one of the most evolutionarily highly conserved signaling systems, which regulates various cellu- lar processes via juxtacrine cell–cell interactions.76
Takahashi, N. et al. (2019) ‘Accumulation of advanced glycation end products in follicles is associated with poor oocyte developmental competence’, Molecular Human Reproduction, 25(11), pp. 684–694. Available at:
https://doi.org/10.1093/molehr/gaz050
⁠
.
level of free AGEs in follicular fluid was increased in follicles containing oocytes that developed into poor morphology embryos, and that AGEs stimulated IL-6 and IL-8 production in GCs by activating the UPR factor ATF4. Our findings suggest that AGE accumulation in follicles reduces oocyte competence by triggering inflammation via the activation of ER stress in the follicular microenvironment. The AGE-RAGE axis and ER stress may be potential therapeutic targets to improve oocyte developmental competence in patients exhibiting ovarian accumulation of AGEs

FIGURE 3 Endoplasmic reticulum stress (ER stress) develops in the follicles and forms a key component of the pathophysiology of polycystic ovary syndrome (PCOS). Local hyperandrogenism in the follicular microenvironment activates ER stress in PCOS. ER stress contributes to the pathophysiology of PCOS by affecting the function of granulosa cells (GCs) in a number of ways. ER stress stimulates the production of transforming growth factor-β1 (TGF-β1), a profibrotic growth factor, in GCs and accelerates interstitial fibrosis in the ovary. ER stress mediates the testosterone-induced apoptosis of granulosa cells by inducing expression of the proapoptotic factor death receptor 5 (DR5) and is associated with follicular growth arrest at the antral follicle stage. ER stress also mediates the effects of testosterone to induce the expression of receptor for advanced glycation end products (RAGE) in GCs, which results in the accumulation of advanced glycation end products (AGEs), thereby affecting various cellular processes. ER stress also activates the aryl hydrocarbon receptor (AHR), a representative receptor for endocrine-disrupting chemicals (EDCs), and its downstream signaling in GCs, which may alter steroid metabolism in these cells. Furthermore, ER stress induces the expression of multiple genes that are associated with cumulus oocyte-complex (COC) expansion in GCs via notch signaling

Clinical implications

ER stress and the UPR represent potential therapeutic targets for PCOS.
ER stress is activated in the granulosa cells of obese women.78
oxidative stress, AGEs, and inflammation, all of which are affected by lifestyle.
PCOS mice with ER stress inhibitors ameliorates their reproductive dysfunction by improving the estrous cycle and PCOM by reducing the number of atretic antral follicles.
Histologically, treatment with ER stress inhibitors reduces the levels of interstitial fibrosis and collagen deposition in the ovary, the apoptosis of granulosa cells of the antral follicles, and the accumulation of AGEs in these cells, with a concomitant reduction in ovarian ER stress
There are two means of modulating ER stress and the UPR
reduce ER stress by attenuating the protein misfolding
targeting of specific UPR factors.
chemical chaperones can be used as a pharmacological approach, and lifestyle interventions may also be effective.
low-molecular mass compounds that stabilize the folding of proteins and reduce abnormal protein aggregation, thereby reducing protein misfolding.77
Two chemical chaperones, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA), have been used clinically to treat liver diseases and urea cycle disorders, respectively, for a long time, and recent studies have shownthat they function as chemical chaperones
In contrast, there are no small molecules in clinical use that target specific UPR factors at present. Various promising molecules are in development, in particular targeting the UPR branch activated by double-stranded RNAactivated protein kinase-like ER kinase (PERK).59

Prenatal exposure to excess androgens in the daughters of women with PCOS and the development of PCOS in their later life

Daughters born to women with PCOS
have a larger anogenital distance, which serves as a biomarker of intrauterine exposure to excess androgens, during the fetal and neonatal periods as well as in adulthood
higher activity of 3β- hydroxysteroid dehydrogenase-1 (3β-HSD-1) and a lower activity of P450 aromatase than that from women without PCOS, which could also explain the hyperandrogenic intrauterine environment of preg- nant women with PCOS.36
hyperandro- genic intrauterine environment of pregnant women with PCOS. Metabolic dysfunction in women with PCOS can induce fetal hyper- insulinemia, which increases androgen production from the ovaries of the fetus after midgestation.37,3
higher serum AMH concentrations than women without, and this high AMH may result in maternal neuroendocrine- induced testosterone excess and less placental metabolism of tes- tosterone to estradiol, as shown in pregnant mice treated with AMH, leading to hyperandrogenism in utero.2
Numerous studies have shown that prenatally androgenized (PNA) animals, including rodents, sheep, and rhesus monkeys, ex- hibit PCOS-like reproductive and metabolic phenotypes in adult- hood, as extensively reviewed previously.85–
induction of epigenetic changes in fetal so- matic and/or germ cells by prenatal androgen exposure
induces specific epigenetic changes in the ovary, including in granulosa and theca cells, and in the key meta- bolic tissues, including liver, muscle, and visceral and subcutaneous adipose tissue.88,8
epigenetic modification of germ cells: PCOS-like reproductive and metabolic traits are observed in the granddaughters of female mice that are perinatally exposed to androgens, as well as in those exposed to AMH, which causes intrauterine hyperandrogenism.24
in utero exposure to androgens might cause abnormal ovarian and early follicular development.
exhibit high serum concentrations of AMH, which is produced by granulosa cells and reflects follicular develop- ment during infancy, prepuberty, and at the time of delivery, than those born to mothers without PCOS.35,9
a high density of small preantral follicles is present in the ovaries of women with PCOS, which may be the result of a larger population of germ cells in the fetal ovary, or a lower rate of loss of oocytes during late gesta- tion, childhood, and puberty.9

5.2  |  Potential role of the gut microbiome in the pathogenesis of PCOS

gut microbiome and various physiological and pathological conditions have been receiving an increasing amount of attention during the past decade.
important and causative roles of dysbiosis of the gut microbiome in metabolic disorders, such as obesity and type 2 diabetes.95
that sex steroid hormone concentration
is conceivable that changes in gut microbiome may play a role in the pathophysiology of PCOS.
gut microbiomes of adult patients with PCOS and in various models of PCOS differs from those of healthy individuals and control animals, respectively, as summarized in a recent review.
the transplantation of feces from or cohousing with healthy rodents ameliorates the PCOS-like phenotypes of such mode
gut microbiome plays a causative role in the pathogenesis of PCOS.100,101

5.3  |  Effects of prenatal exposure to high androgen concentrations on the gut microbiome and the development of the PCOS phenotype

We hypothesized that prenatal exposure to high concentrations of androgens would induce dysbiosis of the gut microbiome early in life and thus lead to the development of PCOS in later life
compared the gut microbiomes of PNA mice induced by the injection of dihydrotestosterone (DHT) into pregnant dams and control mice when they were prepubertal
We found that abnormalities appear in the gut microbiome as early as or even before PCOS-like phenotypes manifest in PNA offspring102 (Figure 4).
By contrast, alterations to the composition of the gut microbiome of female PNA offspring were apparent as early as before puberty and continued throughout the study, with a lower richness of bacterial taxa after young adulthood in PNA offspring, and significant differences in the microbial communities of the PNA and control groups during adolescence.
Relationship between the gut microbiome and polycystic ovary syndrome (PCOS). Accumulating evidence, in human studies and rodent models, indicates that there is an association between dysbiosis of the gut microbiome and PCOS. A–B: Gut microbes metabolize substrates that enter the gut, from the diet and the host, and produce metabolites that may act directly on the intestines or enter systemic circulation and influence various host tissues whose function is altered in PCOS, such as ovary, skeletal muscle, liver, and adipose tissue. Gut bacterial metabolites reported to be altered in PCOS include secondary bile acids, SCFAs, and TMA. For instance, bile acids bind to receptors, including FXR, in various tissues and activate intracellular signaling. C: Metabolic tissues, including skeletal muscle, liver, and adipocytes, produce metabolites (such as conjugated primary and secondary bile acids, TMAO, lactate, and glucose) that enter the gut and may alter the composition of gut bacteria by serving as substrates, thus providing selective advantages to certain strains of bacteria over others. D: The host reproductive axis regulates sex steroid hormone production. In PCOS, elevated levels of androgens may alter the composition of the gut microbial community. E: Crosstalk between host metabolic tissues and the reproductive axis also occurs independently of the gut microbiome and may be a driver of the pathology and development of PCOS. Further studies are needed to decipher how the interactions outlined in this figure occur mechanistically. Abbreviations: FSH, follicle-stimulating hormone; FXR, farnesoid X receptor; GnRH, gonadotropin-releasing hormone; IR, insulin resistance; LH, luteinizing hormone; SCFAs, short-chain fatty acids; TMA, trimethylamine; TMAO, trimethylamine N-oxide.

5.4  |  Clinical implications

PCOS-like phenotypes manifest in PNA off-
imply that female PNA offspring that are susceptible to PCOS already have an abnormal gut microbial composition soon after weaning, and this may be amplified by the consumption of certain foods and sex steroid action after puberty, contributing to the development of the reproductive and metabolic phenotypes of PCOS.
currently no preventive strategy for use in girls at a high risk of subsequently developing PCOS,
life. To clarify the role of alterations of gut microbiome in the development of PCOS in later life, intervention studies are needed
mechanism by which dysbiosis is induced in PNA offspring as early as just after weaning should provide insight into whether interventions in pregnant women with PCOS or in daughters born to such mothers would be effective
Alternatively, the gut, skin, and/or milk microbiome of PNA dams might be altered by DHT treatment, and this altered microbial population might be transmitted to their pups during delivery and feeding
of fecal metabolites that are affected by dysbiosis in PNA offspring would be helpful in guiding the selection of novel pre-/pro-/postbiotics that might help prevent the development of PCOS.

Slide 7 | Treatment

Slide 8 |

The pathogenesis is shaped by interactions between reproductive dysfunction and metabolic disorders: hyperandro- genism and insulin resistance exacerbate one another in the de- velopment of PCOS, which is also affected by altered function of hypothalamus-pituitary-ovarian axis. P
loci identified using GWAS appear to only account for a small pro- portion of this heritability.
PCOS is a multifactorial disorder, like type 2 diabetes, with the exposure to environmental factors causing individuals with predisposing ge- netic factors to develop PCOS.
These environmental factors may include the intrauterine environment during the pre- natal period, the follicular microenvironment, and lifestyle follow- ing birth.
identify the factors that induce the development and progression of PCOS, and to elucidate the underlying mechanisms. mechanism connecting the reproductive and metabolic abnormali- ties that comprise the pathophysiology of PCOS is of great interest because such knowledge could be used to target the interruption of the vicious cycle involved, but research in this area to date has been limited.
environmental factors that are known to drive the development of PCOS throug
the identification of novel factors, which may include psychosocial factors, would add to our under- standing of the pathophysiology.
The second area for further research is the elucidation of the mechanisms underlying the high heritability of PCOS
part attributable to the ‘common dis- ease, common variants’ rationale of GWAS, which means that the etiology of common and complex diseases cannot be explained by the limited number of common variants of moderate-to-low effect size that can be detected using this method.1
Investigation of the mechanisms by which the intrauterine envi- ronment during the perinatal period predisposes toward the devel- opment of PCOS in later life has only just started, and this is definitely a promising area of research, given that accumulating evidence im- plies that this phenomenon is important in humans rather than just in experimental animals.
induction of epigenetic changes in fetal somatic and/or germ cells, and of dysbiosis of the offspring's gut microbiome, requires investigation.
With respect to the gut microbiome, the identification of the fecal metabolite con- centrations that are affected by dysbiosis and an exploration of the functional links between the gut and other organs should improve our understanding of the pathophysiology of PCOS as a systemic disorder
The third area for further research is the identification of biomarkers that could be used to identify individuals early in life who are at high risk of developing PCOS in later life.
only 3.3% (78/2275) of daughters born to mothers with PCOS were subsequently diagnosed as having PCOS, while the remaining 96.7% were not.
in the Swedish cohort, 67.1% (159/237) of all daughters diagnosed with PCOS were born to mothers who did not have PCOS
Evaluation of maternal metabolic and/or hormonal status during pregnancy may be help- ful for distinguishing daughters at high and low risk
metabolic and/or hormonal status of daughters themselves at their early stage of life, that is at infancy or childhood, may serve as a biomarker identifying those who may develop PCOS in later life.
Totally novel biomarkers, including fecal metabolites or gut micro- bial composition, would be of special interest for future research.

(A) FOH is nearly universal in PCOS and can account for all of the cardinal clinical features of the syndrome: hyperandrogenemia, oligo-anovulation, and polycystic ovaries (step 1). Pituitary LH secretion is necessary to sustain the ovarian androgen excess but is not sufficient to cause it. (B) Approximately one-half of patients with FOH have an abnormal degree of insulin-resistant hyperinsulinism (step 2). Insulin-resistant hyperinsulinism acts on theca cells to aggravate hyperandrogenism, synergizes with androgen to prematurely luteinize granulosa cells, and stimulates fat accumulation. The increased hyperandrogenemia provokes LH excess, which then acts on both theca and luteinized granulosa cells to worsen hyperandrogenism (step 3). LH also stimulates luteinized granulosa cells to secrete estradiol (step 4), which suppresses FSH secretion. These hyperinsulinism-initiated changes in granulosa cell function further exacerbate PCOM and further hinder ovulation. Obesity increases insulin-resistance, and the resultant increased hyperinsulinism further aggravates hyperandrogenism (step 5). Bold and enlarged fonts represent greater severity. Both FOH and insulin resistance typically have an intrinsic basis. This model does not exclude the possibility that the unknown intrinsic ovarian defects that underpin the ovarian steroidogenic dysfunction also involve granulosa cell folliculogenesis and other systems as well. The figure also does not depict other associated defects, such as the functional adrenal hyperandrogenism that often accompanies the ovarian hyperandrogenism and the contribution of excess adiposity to peripheral androgen production and gonadotropin suppression.
Notes in Document
'Barbieri and Ehrmann - Clinical manifestations of polycystic ovary syndro.pdf':
Follicular development and function are abnormal in PCOS ovaries, including abnormal patterns of follicular fluid hormone production (low follicular fluid estradiol concentrations and high levels of follicular fluid androgens
be arrested at 5 to 8 mm in diameter, much smaller than a mature follicle destined
is evidence for an abnormal ovarian endocrine environment, it is also possible that there is an intrinsic defect in ovarian folliculogenesis.
the density of small preantral follicles was sixfold greater in anovulatory women with polycystic ovaries compared with normals
preantral follicular pool, the percentage of early growing (primary) follicles was significantly greater, the percentage of primordial (resting) follicles significantly lower, and there was a trend towards a greater percentage of atretic follicles in the anovulatory polycystic ovary patients compared with controls.
greater initial pool of follicles in women with PCOS, a higher percentage get recruited and then become atretic.
Serum anti-müllerian hormone (AMH) is expressed by small (<8 mm) preantral and early antral follicles; serum concentrations reflect the size of the primordial follicle pool.
In adult women, AMH levels gradually decline with age (as the primordial follicle pool decreases) and become undetectable at menopause [21]
In one study, serum concentrations of AMH were two-to-threefold higher in women with PCOS compared with normal ovulatory women


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[[Sadeghi_et+al_PolycysticOvarySyndromeComprehensiveReview_2022]]
# [Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775814/)
## [[Hosna Sadeghi]]; [[Ida Adeli]]; [[Daniela Calina]] et al.
## Abstract Polycystic ovary syndrome (PCOS) is an endocrine-gynecology disorder affecting many women of childbearing age. Although a part of the involved mechanism in PCOS occurrence is discovered, the exact etiology and pathophysiology are not comprehensively understood yet. We searched PubMed for PCOS pathogenesis and management in this article and ClinicalTrials.gov for information on repurposed medications. All responsible factors behind PCOS were thoroughly evaluated. Furthermore, the complete information on PCOS commonly prescribed and ==repurposed medications is summarized through tables==. Epigenetics, environmental toxicants, stress, diet as external factors, insulin resistance, hyperandrogenism, inflammation, oxidative stress, and obesity as internal factors were investigated. Lifestyle modifications and complementary and alternative medicines are preferred first-line therapy in many cases. Medications, including 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents, and some supplements have supporting data for being repurposed in PCOS. Since there are few completed clinical trials with a low population and mostly without results on PCOS repurposed medications, it would be helpful to do further research and run well-designed clinical trials on this subject. Moreover, understanding more about PCOS would be beneficial to find new medications implying the effect via the novel discovered routes.
## Key concepts #polycystic_ovary_syndrome; #oxidative_stress; #insulin_resistance; #complementary_and_alternative_medicine; #endocrine; #pathogenesis; #luteinizing_hormone; #metformin; #hyperandrogenism; #endocrine_disrupting_chemical; #tumor_necrosis_factor_α; #sex_hormone_binding_globulin; #etiology; #pioglitazone; #gonadotropin_releasing_hormone; #follicle_stimulating_hormone; #united_states_food_and_drug_administration; #pathophysiology; #c_reactive_protein; #insulin_receptor_substrate; #polycystic_ovarian_syndrome; #traditional_chinese_medicine; #body_mass_index; #national_health_service; #reactive_oxygen_species; #reactive_nitrogen_species; #american_heart_association; #11β_hydroxysteroid_dehydrogenase; #united_states_environmental_protection_agency; #national_center_for_complementary_and_integrative_health
## Quote > The most crucial step is to lose at least 5% of the weight; having a regular exercise plan and fat and sugar-free diets are recommended to every woman with Polycystic ovary syndrome
## Key points - Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder that impacts many women of the reproductive age worldwide [^1] - The most crucial step is to lose at least 5% of the weight; having a regular exercise plan and fat and sugar-free diets are recommended to every woman with PCOS - The United States Environmental Protection Agency (USEPA) defines endocrine-disrupting chemical (EDC) as “an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behavior” [^24] - One of the significant merits of Complementary and Alternative Medicine (CAM) is that people often tend to accept these methods due to their beliefs and cultures; this leads to their improved adherence or tolerance to the therapy - The pathogenesis of PCOS is not fully understood, it is believed that different factors from epigenetic alterations to obesity, inflammation, and inactivity may aggravate this syndrome - Many studies demonstrate that even a 5% to 10% reduction in weight can restore the regular menstruation cycle [^87] - All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas—that is, revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work
## Synopsis A review of the most commonly prescribed and repurposed medications for PCOS. Polycystic ovary syndrome is a heterogeneous endocrine disorder that impacts many women of the reproductive age worldwide. The most crucial step is to lose at least 5% of the weight. Having a regular exercise plan and fat and sugar-free diets are recommended to every woman with PCOS. PubMed, Google Scholar, ScienceDirect, TRIP database, and UpToDate were comprehensively searched for publications including PCOS relevant keywords in different areas. Clinicaltrials.gov was searched to find data about completed or running trials of repurposed drugs in PCOS over the past five years.<br/><br/>They recommend that medications, including thiazolidinedinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents.<br /><br />
## Summary
### Introduction Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder that impacts many women of the reproductive age worldwide [^1]. Apart from the essential need for improvement in the research and development of new drug molecules and new drug discovery, novel medications could be found with drug repurposing methods [^9] On this very spot, there are plenty of medications, previously approved by USFDA for indications rather than PCOS; and, today, there is a desire to implement them as the therapeutic options in the management of PCOS. Given that PCOS is a growing issue that is followed by many unwanted complications and that available methods and medications are not 100% effective, it is essential to investigate its pathogenesis and find out new pharmacological targets carefully This could be done through repositioning approaches, saving time and cost. A couple of repurposed medications are mentioned thoroughly, reviewing the related clinical trials over the past five years
### Methods PubMed, Google Scholar, ScienceDirect, TRIP database, and UpToDate were comprehensively searched for publications including PCOS relevant keywords in different areas, focusing on the new ones and excluding those with a language rather than English or animal studies. Clinicaltrials.gov was searched to find data about completed or running trials of repurposed drugs in PCOS over the past five years
### Diagnosis PCOS is among the conditions that cannot be diagnosed with basic diagnostic tests, including blood tests, culture, and biopsy; there is no certain test for PCOS diagnosis. Differential diagnosis is called excluding the relevant disorders according to the symptoms and narrowing the choices. In order to establish a differential diagnosis for PCOS, hyperprolactinemia, thyroid disease, Cushing’s syndrome, and hyperplasia of adrenal should be excluded based on the associated investigations [^10],[^11]. According to the National Health Service (NHS), irregular or infrequent periods, high levels of androgenic hormones or symptoms, and scans showing polycystic ovaries are the specified criteria for PCOS [^13]. Rotterdam PCOS diagnostic criteria in adults are the most commonly used method. The presence of two clinical or biochemical hyperandrogenism, ovulatory dysfunction, or polycystic ovaries would finalize a PCOS diagnosis [^14]
### Epigenetic Mechanism Epigenetic refers to inheritable alterations in genome and gene expression without any changes in DNA sequence [^15],[^16]. LH/choriogonadotropin receptor (LHCGR) is responsible for the steroidogenesis process in theca cells [^19] This receptor hypomethylation leads to higher gene expression and sensitivity to LH [^18],[^20]. Hypermethylation of PPARγ, hypomethylation of nuclear co-repressor 1 [^19],[^22], and alteration in acetylation of histone deacetylase 3, for which both are PPARγ co-repressors [^15], are observed in PCOS patients showing HA [^15],[^19],[^22]. These alterations were noticed in PCOS women’s granulosa cells [^18],[^23]
### Environmental Toxicants The United States Environmental Protection Agency (USEPA) defines endocrine-disrupting chemical (EDC) as “an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behavior” [^24]. A higher body mass index corresponds to a lower extent of soluble RAGEs, which is responsible for glycotoxin clearance and deposition of AGEs in the reproductive system, especially in ovaries [^21],[^29] This bilateral relation worsens inflammatory processes and metabolic syndrome in PCOS [^21]. These compounds disrupted glucose transport in the human granulosa KGN cell line [^21] and reduced glucose uptake by adipocytes in previous research [^21],[^29] They involve IR by causing oxidative stress, inflammation, and glycation of proteins, which considerably diminishes insulin sensitivity [^21]. Increased concentration of AGEs changes the insulin signaling pathway and interferes with glucose transporter 4 (GLUT-4) translocation [^23]
### Physical and Emotional Stress There is minimal information on the role of stress in PCOS, it is known that PCOS possesses adverse effects on self-esteem and mental health. Chronic stress is associated with adipokine secretion, attraction, and activation of stromal fat immune cells [^33]. It is responsible for making an inflammatory condition by leading to high levels of inflammatory cytokines like IL-6 and TNF-α, along with disrupting oxidant-antioxidant balance [^33]. Chronic stress plays a vital role in IR. Calcitriol upregulates insulin receptors at mRNA and protein levels. It increases insulin sensitivity directly and indirectly. Vitamin D deficiency may result in insulin resistance by causing an inflammatory response [^37],[^39]. Vitamin D downregulates the AMH promoter [^39]
### Insulin Resistance IR means an insufficient cells response to insulin [^40]. IR is independent of patients’ adiposity, body fat topography, and androgen levels [^18],[^41]; i.e., it has been reported in lean patients as well [^18],[^42]. Hyperinsulinemia inhibits IGF-1 binding protein production in the liver. IGF-1 is responsible for triggering the production of androgens in thecal cells. Inhibition of the production of IGF-1 binding proteins leads to a higher concentration of this substance in blood circulation and higher production of androgens in thecal cells [^18],[^46]. HA [^46] and hyperinsulinemia [^45],[^46],[^57] both play a role in stopping follicles growth [^45],[^46]. This stoppage is attributed to menstrual irregularity, anovulatory sub-fertility, and amassing of immature follicles [^46]
### Hyperandrogenism Hyperandrogenism (HA) reduces the SHBG level, leading to a higher concentration of free testosterone [^18],[^59]. It was observed that PCOS women have higher concentrations of testosterone in plasma which can convert to estrone in adipose tissue. Estradiol and progesterone are responsible for GnRH and LH secretion via negative feedback [^58],[^61],[^62]. HA disrupts the negative feedback on secretion [^18],[^23],[^61],[^62] resulting in increased LH levels [^18],[^62]. Interaction of androgen and its receptor interferes with progesterone receptor transcription This receptor is involved in converting high levels of androgens to compounds that modulate the gamma-aminobutyric acid A (GABAA). It is assumed that androgens might decrease hepatic nuclear factor-4α (HNF-4α) levels by inhibiting lipid synthesis. One way androgen results in oxidative stress is by increasing MNC sensitivity to glucose and aggravating glucose-stimulated oxidative stress [^65]. HA is a cause of adipocyte hypertrophy and consequential damages to adipokine secretion [^55]
### Inflammation High levels of white blood cell [^46],[^66], C-reactive protein (CRP) [^4],[^46],[^50],[^66],[^67], and other inflammatory biomarkers in peripheral blood are associated with PCOS [^4],[^46],[^66],[^67],[^68]. Some studies showed that the insulin receptor substrate (IRS) serine residue phosphorylation inhibits insulin receptor signaling [^32],[^70]. This phenomenon results in the prevention of GLUT-4 translocation and glucose reuptake [^70]. IL-1 hinders the FSH and LH receptors Inhibition of these receptors leads to inhibition of follicular development and ovulation [^66]. An increase in CRP level is another cause of IR in insulin-sensitive tissues. Another study approved the higher-than-normal level of IL-6 mRNA in granulosa cells [^66]
### Oxidative Stress Oxidative stress (OS) is an imbalance between pro-oxidants and antioxidants [^71],[^72],[^73]. Oxidative molecules include different chemicals such as reactive oxygen species (ROS) [^73],[^74],[^75] (e.g., O2−, H2O2, and OH−) [^76] and reactive nitrogen species (RNS) [^74],[^75]. ROS plays a role in different mechanisms like signaling pathways [^71],[^73],[^76], cell growth [^71],[^73], and differentiation, as well as RNS [^73]. NF-κB is involved in inflammatory pathways [^75] and affects the production of pro-inflammatory cytokines like TNF-α and IL-6 [^72],[^80]; the effect in IR and PCOS was explained above. It increases mature adipocyte size and stimulates pre-adipocyte proliferation and adipocyte differentiation. OS imposes a major effect on obesity [^71]
### Obesity Accumulation of adipocytes in visceral fat leads to hypoxia and consequent necrosis, which causes inflammatory cytokines production [^66]. The lipolytic response of visceral fat to catecholamines causes lipotoxicity [^44] and impairment of insulin clearance and activity [^81]. Increased FFAs reduce insulin and glucose uptake sensitivity in intramyocellular lipids [^52]. The adiponectin insulin-sensitizing effect causes a reduction in FFA uptake and gluconeogenesis It plays a role in progesterone and estrogen production, ovulation, and decreased GnRH secretion [^52]. 17β-HSD converts androstenedione to testosterone [^44],[^81] and estrone to estradiol [^81] This enzyme is expressed in adipose tissue [^44],[^81].
### Management The management approach and selection of the best therapy option depend on the target patient and her priorities [^4]. The complications may vary from seeking fertility, regulation of menstrual disturbances to weight reduction or relief from hyperandrogenic symptoms, including acne, hirsutism, or androgenic alopecia [^84]. The approach should be individualized for each person to meet the optimal result [^8]. There is no one ideal treatment for all women diagnosed with PCOS, which leaves physicians no choice but symptomatic therapy [^85]
### Weight Loss Elevated androgenic hormone levels lead to weight gain in women with PCOS, mainly in the abdominal area. The first step for women diagnosed with PCOS would be weight reduction and calorie intake restriction [^86]. Many studies demonstrate that even a 5% to 10% reduction in weight can restore the regular menstruation cycle [^87]. For obese women, it would be best if they could reach their normal range of body mass index (BMI). Low glycemic index carbohydrates are at the top of the agenda; they include foods and vegetables like broccoli, raw carrot, lentils, soy, bran breakfast cereals, whole-grain bread, etc. Patients should be aware that foods with a high glycemic index for prevention, white rice, cakes and cookies, fries or chips, and some fruits such as pineapple or watermelon are actual examples [^37]
### Exercise Exercise and physical activity play a key role in weight reduction. They may be beneficial to improve insulin sensitivity [^88]. Different studies suggest various times for exercise during the week, but the American Heart Association (AHA) recommends approximately 150 min of moderate or 75 min of vigorous and intense exercise per week [^84]. Several studies show that exercise, with or without being on a diet, can resume ovulation in women with PCOS. Exercise probably can affect ovulation through modulation of the hypothalamic-pituitary-gonadal (HPG) axis. In overweight and obese women, exercise leads to lower insulin and free androgen levels, inducing the restoration of HPA regulation of ovulation [^88]
### Complementary and Alternative Medicine (CAM) Current management and accessible medications are only moderately effective in PCOS, and there are still some cases left untreated despite non-pharmacological and pharmacological treatments. Recent studies have demonstrated that using complementary and alternative medicine (CAM) as adjunctive therapy may benefit the management [^89]. Today, CAM is a well-known approach that has been used at least at one point in more than 70% of PCOS patients during their diseases [^90]. One of the significant merits of CAM is that people often tend to accept these methods due to their beliefs and cultures; this leads to their improved adherence or tolerance to the therapy. Taking a look at prior studies, various methods of CAM including traditional Chinese medicine (TCM), immunotherapy, diet therapy, psychotherapy, spa, yoga, Tai Chi, and oxygen therapy have been considered as effective strategies in reducing the severity of PCOS and its complications [^89],[^91],[^92],[^93],[^94],[^95]. Two critical subgroups of CAM effective in PCOS management are discussed
### Acupuncture Acupuncture, a fundamental part of CAM, has been used in China for more than 3000 years [^89]. It is a kind of sensory stimulation in which thin needles are placed into the skin and muscles. Acupuncture improves clinical manifestations of PCOS by activating somatic afferent nerves of the skin and muscles, modulating somatic and autonomic nervous system activity and endocrine/metabolic functions [^91]. Β-endorphin production increases, affecting the secretion of gonadotropin-releasing hormone, ovulation, and menstrual cycle. This means that acupuncture may induce ovulation and restore the menstrual cycle [^64]
### Pharmacological Treatments Before heading to pharmacological approaches, healthy lifestyle advice must be given to all women diagnosed with PCOS regardless of their weight, complaint, or anything else. The physician can choose the best oral contraceptive with a look on other symptoms rather than menstruation irregularity; for example, Yasmin®, Yaz®, or some other agents can show antiandrogenic effects and can, on the other hand, result in the reduction of androgen production. As a result, they might be helpful in those with hirsutism and/or acne complications. Metformin, from the biguanides category, is usually prescribed along with the first-choice drugs (COCs) to restore the ovulation cycle in PCOS women because of its insulin sensitivity-increasing properties.
### Drug Repurposing in PCOS In other terms drug repositioning or drug re-tasking, means finding new indications in other diseases or conditions for a medication that has previously been in the market and has USFDA approval for a specific therapeutic goal [^9]. Using this method has shortened the duration of the research and development process, given the thought that the medicines have passed pre-clinical and clinical, safety, and immunological tests. Taking a look at other drugs—mostly diabetes agents—may be helpful to recognize some new medications for women with PCOS-related complications.
### Conclusions The pathogenesis of PCOS is not fully understood, it is believed that different factors from epigenetic alterations to obesity, inflammation, and inactivity may aggravate this syndrome. In terms of the repurposing, there is a good chance that other approved agents could exert beneficial effects on PCOS. There is still very much to discover and examine for a better understanding of the pathogenesis, and, as a result, targeting the mechanism by proper medication. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas—that is, revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript
### Findings Many studies demonstrate that even a 5% to 10% reduction in weight can restore the regular menstruation cycle [^87]. Today, CAM is a well-known approach that has been used at least at one point in more than 70% of PCOS patients during their diseases [^90]
### Conflicts of Interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. European Society of Human Reproduction and Embryology International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.
## Findings - Many studies demonstrate that even a 5% to 10% reduction in weight can restore the regular menstruation cycle [^87] - Today, CAM is a well-known approach that has been used at least at one point in more than 70% of PCOS patients during their diseases [^90]
## Contributions - Although the pathogenesis of PCOS is not fully understood, it is believed that different factors from epigenetic alterations to obesity, inflammation, and inactivity may aggravate this syndrome. Since there is still no certain medication or definite cure for this condition, the routine approach after advising on some lifestyle modification and supplementary tips is symptomatic therapy with plenty of agents, including contraceptives, oral antidiabetics, or antiandrogens. In terms of the repurposing, there is a good chance that other approved agents could exert beneficial effects on PCOS. Since the complete profiles of these agents are available, and their efficacy and safety have already been comprehensively studied, the pathway for finding novel treatments becomes a little more straightforward. However, there is still very much to discover and examine for a better understanding of the pathogenesis, and, as a result, targeting the mechanism by proper medication.<br/><br/>Author Contributions
## Future work - Medications, including 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents, and some supplements have supporting data for being repurposed in PCOS. Since there are few completed clinical trials with a low population and mostly without results on PCOS repurposed medications, it would be helpful to do further research and run well-designed clinical trials on this subject. Understanding more about PCOS would be beneficial to find new medications implying the effect via the novel discovered routes.

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