Editing Polycystic ovary syndrome (section)

== Diagnosis ==
Not every person with PCOS has polycystic ovaries (PCO), nor does everyone with [[ovarian cyst]]s have PCOS; although a [[pelvic ultrasound]] is a major diagnostic tool, it is not the only one.<ref name=emedicine_imaging /> The diagnosis is fairly straightforward using the Rotterdam criteria, even when the syndrome is associated with a wide range of symptoms.<ref>{{cite journal | vauthors = Lujan ME, Chizen DR, Pierson RA | title = Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies | journal = Journal of Obstetrics and Gynaecology Canada | volume = 30 | issue = 8 | pages = 671–9 | date = August 2008 | pmid = 18786289 | pmc = 2893212 | doi = 10.1016/S1701-2163(16)32915-2 }}</ref>
<gallery mode="packed" widths="360px" heights="220">
File:Polycystic_ovary.jpg|Transvaginal ultrasound scan of polycystic ovary
File:PCO polycystic ovary.jpg|Polycystic ovary as seen on sonography
</gallery>

=== Differential diagnosis ===
Other causes of irregular or absent menstruation and hirsutism, such as [[hypothyroidism]], [[congenital adrenal hyperplasia]] (21-hydroxylase deficiency) (which may cause excessive body hair, deep tone voice and others symptoms similar to [[hyperandrogenism]]), [[Cushing's syndrome]], [[hyperprolactinemia]] (leading to [[anovulation]]), androgen-secreting neoplasms, and other pituitary or adrenal disorders, should be investigated.<ref name=BMC2010 /><ref name=HumRep_Rotterdam /><ref name=emedicine_workup />

===Assessment and testing===
==== Standard assessment ====
* History-taking, specifically for menstrual patterns, obesity, hirsutism, and acne. A [[clinical prediction rule]] found that these four questions can diagnose PCOS with a [[sensitivity (tests)|sensitivity]] of 77.1% (95% [[confidence interval]] [CI] 62.7%–88.0%) and a [[specificity (tests)|specificity]] of 93.8% (95% CI 82.8%–98.7%).<ref name="pmid17872783">{{cite journal | vauthors = Pedersen SD, Brar S, Faris P, Corenblum B | title = Polycystic ovary syndrome: validated questionnaire for use in diagnosis | journal = Canadian Family Physician | volume = 53 | issue = 6 | pages = 1042–7, 1041 | date = June 2007 | pmid = 17872783 | pmc = 1949220 }}</ref>
* [[Gynecologic ultrasonography]], specifically looking for small [[ovarian follicles]]. These are believed to be the result of disturbed ovarian function with failed ovulation, reflected by the infrequent or absent menstruation that is typical of the condition. In a normal [[menstrual cycle]], one egg is released from a dominant follicle&nbsp;– in essence, a cyst that bursts to release the egg. After ovulation, the follicle remnant is transformed into a [[progesterone]]-producing [[corpus luteum]], which shrinks and disappears after approximately 12–14 days. In PCOS, there is a so-called "follicular arrest"; i.e., several follicles develop to a size of 5–7&nbsp;mm, but not further. No single follicle reaches the preovulatory size (16&nbsp;mm or more). According to the Rotterdam criteria, which are widely used for the diagnosis of PCOS,<ref name=Mor2015/> 12 or more small follicles should be seen in a suspect ovary on ultrasound examination.<ref name=emedicine_main /> More recent research suggests that there should be at least 25 follicles in an ovary to designate it as having polycystic ovarian morphology (PCOM) in women aged 18–35 years.<ref name="DewaillyLujan2013">{{cite journal | vauthors = Dewailly D, Lujan ME, Carmina E, Cedars MI, Laven J, Norman RJ, Escobar-Morreale HF | title = Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society | journal = Human Reproduction Update | volume = 20 | issue = 3 | pages = 334–352 |date= 2013 | pmid = 24345633 | doi = 10.1093/humupd/dmt061 | doi-access = free }}</ref> The follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'.<ref name="O'Brien2011">{{cite book |vauthors = O'Brien WT |title=Top 3 Differentials in Radiology |url=https://books.google.com/books?id=l9BmkWhvcXYC&pg=PA369 |access-date=30 August 2014 |date=1 January 2011 |publisher=Thieme |isbn=978-1-60406-228-1 |page=369 |quote=Ultrasound findings in PCOS include enlarged ovaries with peripheral follicles in a "string of pearls" configuration. |url-status=live |archive-url=https://web.archive.org/web/20160419092632/https://books.google.com/books?id=l9BmkWhvcXYC&pg=PA369 |archive-date=19 April 2016 }}</ref> If a high-resolution transvaginal ultrasonography machine is not available, an ovarian volume of at least 10 ml is regarded as an acceptable definition of having polycystic ovarian morphology, rather than follicle count.<ref name="DewaillyLujan2013" />
* [[laparoscopic surgery|Laparoscopic]] examination may reveal a thickened, smooth, pearl-white outer surface of the ovary. (This would usually be an incidental finding if laparoscopy were performed for some other reason, as it would not be routine to examine the ovaries in this way to confirm a diagnosis of PCOS.)<ref>{{cite journal | vauthors = Bordewijk EM, Ng KY, Rakic L, Mol BW, Brown J, Crawford TJ, van Wely M | title = Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 2 | pages = CD001122 | date = February 2020 | pmid = 32048270 | pmc = 7013239 | doi = 10.1002/14651858.CD001122.pub5 }}</ref>
* Serum (blood) levels of [[androgen]]s, including [[androstenedione]] and [[testosterone]] may be elevated.<ref name="BMC2010" /> [[Dehydroepiandrosterone sulfate]] (DHEA-S) levels above 700–800&nbsp;μg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made exclusively by the adrenal glands.<ref name="pmid18844715">{{cite journal | vauthors = Somani N, Harrison S, Bergfeld WF | title = The clinical evaluation of hirsutism | journal = Dermatologic Therapy | volume = 21 | issue = 5 | pages = 376–391 |date= 2008 | pmid = 18844715 | doi = 10.1111/j.1529-8019.2008.00219.x | s2cid = 34029116 }}</ref><ref name=emedicine_workup>{{EMedicine|article|256806|Polycystic Ovarian Syndrome|workup}}</ref> The [[free testosterone]] level is thought to be the best measure,<ref name=emedicine_workup /><ref name="pmid17603706">{{cite journal | vauthors = Sharquie KE, Al-Bayatti AA, Al-Ajeel AI, Al-Bahar AJ, Al-Nuaimy AA | title = Free testosterone, luteinizing hormone/follicle stimulating hormone ratio and pelvic sonography in relation to skin manifestations in patients with polycystic ovary syndrome | journal = Saudi Medical Journal | volume = 28 | issue = 7 | pages = 1039–43 | date = July 2007 | pmid = 17603706 | id = {{INIST|18933286}} | oclc = 151296412 }}</ref> with approximately 60 per cent of PCOS patients demonstrating supranormal levels.<ref name="huang" />

Some other blood tests are suggestive but not diagnostic. The ratio of LH ([[luteinizing hormone]]) to FSH ([[follicle-stimulating hormone]]), when measured in [[international unit]]s, is elevated in women with PCOS. Common [[cut-off (reference value)|cut-off]]s to designate abnormally high LH/FSH ratios are 2:1<ref name=Banaszewska2003/> or 3:1<ref name=emedicine_workup /> as tested on day 3 of the menstrual cycle. The pattern is not very sensitive; a ratio of 2:1 or higher was present in less than 50% of women with PCOS in one study.<ref name=Banaszewska2003>{{cite journal | vauthors = Banaszewska B, Spaczyński RZ, Pelesz M, Pawelczyk L | title = Incidence of elevated LH/FSH ratio in polycystic ovary syndrome women with normo- and hyperinsulinemia | journal = Roczniki Akademii Medycznej W Bialymstoku | volume = 48 | pages = 131–4 |date= 2003 | pmid = 14737959 | citeseerx = 10.1.1.410.676 }}</ref> There are often low levels of [[sex hormone-binding globulin]],<ref name=emedicine_workup /> in particular among obese or overweight women.<ref>{{cite book | vauthors = Macpherson G |title=Black's Medical Dictionary |date=2002 |publisher=Scarecrow Press |location=Lanham, MD |isbn=0-8108-4984-4 |page=496 |edition=40}}</ref>
[[Anti-Müllerian hormone]] (AMH) is increased in PCOS, and may become part of its diagnostic criteria.<ref name="pmid26691645">{{cite journal | vauthors = Dumont A, Robin G, Catteau-Jonard S, Dewailly D | title = Role of Anti-Müllerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review | journal = Reproductive Biology and Endocrinology | volume = 13 | page = 137 | date = December 2015 | pmid = 26691645 | pmc = 4687350 | doi = 10.1186/s12958-015-0134-9 | type = Review | doi-access = free }}</ref><ref name="pmid24430863">{{cite journal | vauthors = Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C, Mason H, Nelson SM, Visser JA, Wallace WH, Anderson RA | title = The physiology and clinical utility of anti-Mullerian hormone in women | journal = Human Reproduction Update | volume = 20 | issue = 3 | pages = 370–385 |date= 2014 | pmid = 24430863 | doi = 10.1093/humupd/dmt062 | type = Review | doi-access = free | hdl = 10023/7488 | hdl-access = free }}</ref><ref name="BroerBroekmans2014">{{cite journal | vauthors = Broer SL, Broekmans FJ, Laven JS, Fauser BC | title = Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications | journal = Human Reproduction Update | volume = 20 | issue = 5 | pages = 688–701 |date= 2014 | pmid = 24821925 | doi = 10.1093/humupd/dmu020 | doi-access = free }}</ref>

==== Glucose tolerance testing ====
* Two-hour oral [[glucose tolerance test]] (GTT) in women with risk factors (obesity, family history, history of gestational diabetes)<ref name=BMC2010 /> may indicate impaired glucose tolerance (insulin resistance) in 15–33% of women with PCOS.<ref name=emedicine_workup /> Frank diabetes can be seen in 65–68% of women with this condition.<ref>{{cite journal | vauthors = Andersen M, Glintborg D | title = Diagnosis and follow-up of type 2 diabetes in women with PCOS: a role for OGTT? | journal = European Journal of Endocrinology | volume = 179 | issue = 3 | pages = D1–D14 | date = September 2018 | pmid = 29921567 | doi = 10.1530/EJE-18-0237 | s2cid = 49315075 | doi-access = free }}</ref> Insulin resistance can be observed in both normal weight and overweight people, although it is more common in the latter (and in those matching the stricter NIH criteria for diagnosis); 50–80% of people with PCOS may have insulin resistance at some level.<ref name=BMC2010 />
* Fasting insulin level or GTT with insulin levels (also called IGTT). Elevated insulin levels have helped predict response to medication and may indicate women need higher doses of metformin or a second medication to significantly lower insulin levels. Elevated [[blood sugar]] and insulin values do not predict who responds to an insulin-lowering medication, low-glycemic diet, and exercise. Many women with normal levels may benefit from combination therapy. A hypoglycemic response in which the two-hour insulin level is higher and the blood sugar lower than fasting is consistent with insulin resistance. A mathematical derivation known as the HOMAI, calculated from the fasting values in glucose and insulin concentrations, allows a direct and moderately accurate measure of insulin sensitivity (glucose-level x insulin-level/22.5).<ref>{{cite book |vauthors=Muniyappa R, Madan R, Varghese RT |chapter=Assessing Insulin Sensitivity and Resistance in Humans |date=2000 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK278954/ |veditors=Feingold KR, Anawalt B, Boyce A, Chrousos G |title=Endotext |place=South Dartmouth (MA) |publisher=MDText.com, Inc. |pmid=25905189 |access-date=19 October 2022 |archive-date=16 June 2022 |archive-url=https://web.archive.org/web/20220616022426/https://www.ncbi.nlm.nih.gov/books/NBK278954/ |url-status=live }}</ref>

=== Stem cell models ===
[[Human embryonic stem cell]]s (hESCs) derived from the inner cell mass of blastocyst-stage embryos of women with PCOS have shown abnormal lipid metabolism, consistent with the pathophysiology of the disease.<ref name=":6">{{Cite journal |last1=Khatun |first1=Masuma |last2=Lundin |first2=Karolina |last3=Naillat |first3=Florence |last4=Loog |first4=Liisa |last5=Saarela |first5=Ulla |last6=Tuuri |first6=Timo |last7=Salumets |first7=Andres |last8=Piltonen |first8=Terhi T. |last9=Tapanainen |first9=Juha S. |date=January 2024 |title=Induced Pluripotent Stem Cells as a Possible Approach for Exploring the Pathophysiology of Polycystic Ovary Syndrome (PCOS) |journal=Stem Cell Reviews and Reports |language=en |volume=20 |issue=1 |pages=67–87 |doi=10.1007/s12015-023-10627-w |pmid=37768523 |pmc=10799779 |issn=2629-3269}}</ref> When the hESCs are differentiated into adipocytes, gene expression data from these fat cells reveal a downregulation or a decrease in genes linked to glucose, lipid, and steroid metabolism.<ref>{{Cite journal |last1=Li |first1=Peng-fen |last2=Wang |first2=Fang |last3=Kong |first3=Hui-juan |last4=Zhao |first4=Fang |last5=Bai |first5=Ai-hong |last6=Chen |first6=Xue-mei |last7=Sun |first7=Ying-pu |date=January 2012 |title=Establishment of polycystic ovary syndrome-derived human embryonic stem cell lines |url=http://www.tandfonline.com/doi/full/10.3109/09513590.2011.588748 |journal=Gynecological Endocrinology |language=en |volume=28 |issue=1 |pages=25–28 |doi=10.3109/09513590.2011.588748 |pmid=21780950 |issn=0951-3590}}</ref> Despite the significant findings provided by hESC research to understand the earliest stages of PCOS development, there are limitations in studying human embryos due to legal prohibitions and ethical concerns.

Recent studies have successfully developed in vitro PCOS disease models through [[Induced pluripotent stem cell]] technology (iPSC).<ref name=":6" /> Similar to hESCs, iPSC cells can be derived from patients and can differentiate into various cell types. Using adult somatic cells, iPSCs can reprogram the cells into a pluripotent state, which can then be specified to replicate PCOS-like traits. Furthermore, 3D “organoid” models of female reproductive tissue, such as the uterus and ovaries, produced from iPSCs, present a powerful way to stimulate the development of reproductive disorders such as PCOS in vitro.<ref name=":6" />
[[File:IPSC Model for PCOS.png|thumb|Induced pluripotent stem cell model for PCOS research]]

Although not widely utilized, some researchers have explored the use of this biotechnology to model PCOS. One study that characterized the link between obesity and PCOS reprogrammed PCOS-derived urine epithelial cells into adipocytes and found that iPSC lines had greater glucose consumption along with lower insulin response compared to controls.<ref>{{Cite journal |last1=Yang |first1=Sheng |last2=Ding |first2=Shufang |last3=Jiang |first3=Xianglong |last4=Sun |first4=Bolan |last5=Xu |first5=Qianhua |date=June 2016 |title=Establishment and adipocyte differentiation of polycystic ovary syndrome-derived induced pluripotent stem cells |journal=Cell Proliferation |language=en |volume=49 |issue=3 |pages=352–361 |doi=10.1111/cpr.12258 |pmid=27108524 |pmc=6496004 |issn=0960-7722}}</ref> These are results consistent with symptoms of the disease. Studies on iPSCs have also contributed significantly to understanding the behavior of ovarian [[granulosa cell]]s, which maintain follicular development and secrete steroid hormones.<ref>{{Cite journal |last1=Jozkowiak |first1=Malgorzata |last2=Piotrowska-Kempisty |first2=Hanna |last3=Kobylarek |first3=Dominik |last4=Gorska |first4=Natalia |last5=Mozdziak |first5=Paul |last6=Kempisty |first6=Bartosz |last7=Rachon |first7=Dominik |last8=Spaczynski |first8=Robert Z. |date=31 December 2022 |title=Endocrine Disrupting Chemicals in Polycystic Ovary Syndrome: The Relevant Role of the Theca and Granulosa Cells in the Pathogenesis of the Ovarian Dysfunction |journal=Cells |language=en |volume=12 |issue=1 |pages=174 |doi=10.3390/cells12010174 |doi-access=free |pmid=36611967 |issn=2073-4409|pmc=9818374 }}</ref> The transcriptome data from the PCOS-derived iPSCs indicate dysfunctions in folliculogenesis and disruptions in the oocyte microenvironment.

Current growing data shows a strong association between mitochondrial malfunction and PCOS. iPSCs from PCOS patients have provided some evidence of impairments in glycolytic and mitochondrial functions.<ref name=":6" /> Interestingly, these cells exhibited a higher number of copies of mitochondrial DNA compared to the control. This may support the idea that mitochondrial biosynthesis is elevated in these patients as a compensatory response to the aberrations seen in the metabolic processes.<ref name=":6" />

iPSC models have great advantages over the ethical concerns in hESC research. One challenge to using this technology is controlling or assessing the intra-human variability, especially with a multifaceted disease such as PCOS. Nonetheless, these stem cell models are a valuable approach to gaining more insights into the disease.