Polycystic Ovary Syndrome
Overview
Polycystic ovary syndrome (PCOS) is a set of symptoms due to elevated androgen's[[1]] (male hormones) in females.[4][14] Signs and symptoms of PCOS include irregular or no menstrual periods[[2]], heavy periods[[3]], excess body and facial hair[[4]], acne, pelvic pain, difficulty getting pregnant[[5]], and patches of thick, darker, velvety skin.[3] Associated conditions include type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.[4]
PCOS is due to a combination of genetic and environmental factors.[6][7][15] Risk factors include obesity, a lack of physical exercise, and a family history of someone with the condition.[8] Diagnosis is based on two of the following three findings: no ovulation, high androgen levels, and ovarian cysts.[4] Cysts may be detectable by ultrasound[[6]].[9] Other conditions that produce similar symptoms include adrenal hyperplasia[[7]], hypothyroidism, and high blood levels of prolactin.[9]
PCOS has no cure as of 2020.[5] Treatment may involve lifestyle changes such as weight loss and exercise.[10][11] Birth control pills[[8]] may help with improving the regularity of periods, excess hair growth, and acne.[12] Metformin[[9]] and anti-androgen's may also help.[12] Other typical acne treatments and hair removal techniques may be used.[12] Efforts to improve fertility include weight loss, clomiphene, or metformin.[16] In vitro fertilization is used by some in whom other measures are not effective.[16]
PCOS is the most common endocrine disorder among women between the ages of 18 and 44.[17] It affects approximately 2% to 20% of this age group depending on how it is defined.[8][13] When someone is infertile due to lack of ovulation, PCOS is the most common cause.[4] The earliest known description of what is now recognized as PCOS dates from 1721 in Italy.[18]
Causes
PCOS is a heterogeneous disorder[[10]] of uncertain cause.[26][27] There is some evidence that it is a genetic disease. Such evidence includes the familial clustering of cases, greater concordance in monozygotic compared with dizygotic twins and heritability of endocrine and metabolic features of PCOS.[7][26][27] There is some evidence that exposure to higher than typical levels of androgens and the anti-Müllerian hormone (AMH) in utero increases the risk of developing PCOS in later life.[28]
Genetics The genetic component appears to be inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and, if a daughter receives the variant(s), the daughter will have the disease to some extent.[27][29][30][31] The genetic variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early baldness and/or excessive hair) and daughters, who will show signs of PCOS.[29][31] The phenotype appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells[[11]] from women with the allele.[30] The exact gene affected has not yet been identified.[7][27][32] In rare instances, single-gene mutations can give rise to the phenotype of the syndrome.[33] Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.[34]
The severity of PCOS symptoms appears to be largely determined by factors such as obesity.
PCOS has some aspects of a metabolic disorder, since its symptoms are partly reversible. Even though considered as a gynecological problem, PCOS consists of 28 clinical symptoms.
Even though the name suggests that the ovaries are central to disease pathology, cysts are a symptom instead of the cause of the disease. Some symptoms of PCOS will persist even if both ovaries are removed; the disease can appear even if cysts are absent. Since its first description by Stein and Leventhal in 1935, the criteria of diagnosis, symptoms, and causative factors are subject to debate. Gynecologists often see it as a gynecological problem, with the ovaries being the primary organ affected. However, recent insights show a multisystem disorder, with the primary problem lying in hormonal regulation in the hypothalamus, with the involvement of many organs. The name PCOD is used when there is ultrasonographic evidence. The term PCOS is used due to the fact that there is a wide spectrum of symptoms possible, and cysts in the ovaries are seen only in 15% of people.[36]
Environment PCOS may be related to or worsened by exposures during the prenatal period, epigenetic factors[[12]], environmental impacts (especially industrial endocrine disruptors,[37] such as bisphenol A and certain drugs) and the increasing rates of obesity.
Diganosis
Doctors typically diagnose PCOS in women who have at least two of these three symptoms
.high androgen levels .irregular menstrual cycles,[[13]] .cysts in the ovaries Your doctor should also ask whether you’ve had symptoms like acne, face and body hair growth, and weight gain.
A pelvic exam[[14]], can look for any problems with your ovaries or other parts of your reproductive tract. During this test, your doctor inserts gloved fingers into your vagina and checks for any growths in your ovaries or uterus.
Blood tests check for higher-than-normal levels of male hormones. You might also have blood tests to check your cholesterol, insulin, and triglyceride levels to evaluate your risk for related conditions like heart disease and diabetes.
An ultrasound uses sound waves to look for abnormal follicles and other problems with your ovaries and uterus.
Pathophysiology
The endocrinologic abnormality of PCOS begins soon after menarche. Chronically elevated luteinizing hormone (LH) and insulin resistance are 2 of the most common endocrine aberrations seen in PCOS. The genetic cause of high LH is not known. It is interesting to note that neither an elevation in LH nor insulin resistance alone is enough to explain the pathogenesis of PCOS.[7,8,9] In vitro and in vivo evidence offer support that high LH and hyperinsulinemia work synergistically, causing ovarian growth, androgen production, and ovarian cyst formation.
Obesity, which is seen in 50% to 65% of PCOS patients, may increase the insulin resistance and hyperinsulinemia. One important caveat is that the correlation between hyperandrogenism and insulin resistance has been recognized in both obese and nonobese anovulatory women. Thus, it is important to realize that a nonobese patient may also have insulin resistance. However, the insulin levels in obese women are higher than their nonobese counterparts. Clinically, though, both groups will have evidence of hyperandrogenism and oligo-ovulation or anovulation.[6,7]
Insulin resistance can be characterized as impaired action of insulin in the uptake and metabolism of glucose.[6] https://www.wikidoc.org/index.php/Hyperprolactinemia-I) and sex hormone binding globulin (SHBG). IGFBP-I binds to IGFBP-II and SHBG binds to sex steroids, especially androgens. The triad of hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome appears in a subgroup of patients with PCOS.[6,10,11]
Acanthosis nigricans, a dark and hyperpigmented hyperplasia of the skin typically found at the nape of the neck and axilla, is a marker for insulin resistance. Acanthosis nigricans is usually found in about 30% of hyperandrogenic women. Figure 1 illustrates acanthosis nigricans evident in a patient's axilla.
Differentiating PCOS from other Diseases
Polycystic ovary syndrome must be differentiated from other causes of irregular or absent menstruation[[15]], and hirsutism[[16]], such as,[[17]]Congenital_adrenal_hyperplasia congenital adrenal hyperplasia, cushing's syndrome[[18]], hyperprolactinemia[[19]], and other pituitary[[20]], or adrenal disorders[[21]].
Symptoms
.irregular periods or no periods at all
.difficulty getting pregnant (because of irregular ovulation or failure to ovulate)
.excessive hair growth (hirsutism) – usually on the face, chest, back or buttocks
.weight gain
.thinning hair and hair loss from the head
.oily skin or acne
Treatment
The primary treatments for PCOS include: lifestyle changes and medications.[76]
Goals of treatment may be considered under four categories:
Lowering of insulin resistance levels Restoration of fertility Treatment of hirsutism or acne Restoration of regular menstruation, and prevention of endometrial_hyperplasia[[22]], and endometrial Endometrial cancer[[23]], In each of these areas, there is considerable debate as to the optimal treatment. One of the major reasons for this is the lack of large-scale clinical trials comparing different treatments. Smaller trials tend to be less reliable and hence may produce conflicting results.
General interventions that help to reduce weight or insulin resistance can be beneficial for all these aims, because they address what is believed to be the underlying cause.
As PCOS appears to cause significant emotional distress, appropriate support may be useful.[77]
Diet Where PCOS is associated with overweight or obesity, successful weight loss is the most effective method of restoring normal ovulation/menstruation. The American Association of Clinical Endocrinologists guidelines recommend a goal of achieving 5 to 15% weight loss or more, which improves insulin resistance and all hormonal /Endocrine_disease[[24]].[78] However, many women find it very difficult to achieve and sustain significant weight loss. A scientific review in 2013 found similar decreases in weight and body composition and improvements in pregnancy rate[[25]], menstrual regularity, ovulation, hyperandrogenism, insulin resistance, lipids, and quality of life to occur with weight loss independent of diet composition.[79] Still, a low GI diet, in which a significant part of total carbohydrates are obtained from fruit, vegetables, and whole-grain sources, has resulted in greater menstrual regularity than a macronutrient-matched healthy diet.[79]
Vitamin D deficiency may play some role in the development of the metabolic syndrome, so treatment of any such deficiency is indicated.[80][81] However, a systematic review of 2015 found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS.[82] As of 2012, interventions using dietary supplements to correct metabolic deficiencies in people with PCOS had been tested in small, uncontrolled and nonrandomized clinical trials; the resulting data is insufficient to recommend their use.[83]
Medications Medications for PCOS include oral contraceptives and metformin. The oral contraceptives increase sex hormone binding globulin production, which increases binding of free testosterone. This reduces the symptoms of hirsutism caused by high testosterone and regulates return to normal menstrual periods. Metformin is a medication commonly used in type 2 diabetes mellitus to reduce insulin resistance, and is used off label (in the UK, US, AU and EU) to treat insulin resistance seen in PCOS. In many cases, metformin also supports ovarian function and return to normal ovulation.[80][84] Spironolactone can be used for its antiandrogenic effects, and the topical cream eflornithine can be used to reduce facial hair. A newer insulin resistance medication class, the thiazolidinediones (glitazones), have shown equivalent efficacy to metformin, but metformin has a more favorable side effect profile.[85][86] The United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results.[87][88] Metformin may not be effective in every type of PCOS, and therefore there is some disagreement about whether it should be used as a general first line therapy.[89] In addition to this, metformin is associated with several unpleasant side effects: including abdominal pain, metallic taste in the mouth, diarrhoea and vomiting.[90] The use of statins in the management of underlying metabolic syndrome remains unclear.[91]
It can be difficult to become pregnant with PCOS because it causes irregular ovulation. Medications to induce fertility when trying to conceive include the ovulation inducer clomiphene or pulsatile leuprorelin. Metformin improves the efficacy of fertility treatment when used in combination with clomiphene.[92] Metformin is thought to be safe to use during pregnancy (pregnancy category B in the US).[93] A review in 2014 concluded that the use of metformin does not increase the risk of major birth defects in women treated with metformin during the first trimester.[94] Liraglutide may reduce weight and waist circumference more than other medications.[95]
Infertility Main article: Infertility in polycystic ovary syndrome Not all women with PCOS have difficulty becoming pregnant. For those that do, anovulation or infrequent ovulation is a common cause. Other factors include changed levels of gonadotropins, hyperandrogenemia and hyperinsulinemia.[96] Like women without PCOS, women with PCOS that are ovulating may be infertile due to other causes, such as tubal blockages due to a history of sexually transmitted diseases.[97]
For overweight anovulatory women with PCOS, weight loss and diet adjustments, especially to reduce the intake of simple carbohydrates, are associated with resumption of natural ovulation.
For those women that after weight loss still are anovulatory or for anovulatory lean women, then the medications letrozole and clomiphene citrate are the principal treatments used to promote ovulation.[98][99][100] Previously, the anti-diabetes medication metformin was recommended treatment for anovulation, but it appears less effective than letrozole or clomiphene.[101][102]
For women not responsive to letrozole or clomiphene and diet and lifestyle modification, there are options available including assisted reproductive technology procedures such as controlled ovarian hyperstimulation with follicle-stimulating hormone (FSH) injections followed by in vitro fertilisation (IVF).
Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4–10 small follicles with electrocautery, laser, or biopsy needles), which often results in either resumption of spontaneous ovulations[80] or ovulations after adjuvant treatment with clomiphene or FSH.[citation needed] (Ovarian wedge resection is no longer used as much due to complications such as adhesions and the presence of frequently effective medications.) There are, however, concerns about the long-term effects of ovarian drilling on ovarian function.[80]
Depression Although women with PCOS are far more likely to have depression than women without, the evidence for anti-depressive use in women with PCOS remains inconclusive.[103]
Hirsutism and acne Further information: Hirsutism When appropriate (e.g., in women of child-bearing age who require contraception), a standard contraceptive pill is frequently effective in reducing hirsutism.[80] Progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.[80]
Other medications with anti-androgen effects include flutamide,[104] and spironolactone,[80] which can give some improvement in hirsutism. Metformin can reduce hirsutism, perhaps by reducing insulin resistance, and is often used if there are other features such as insulin resistance, diabetes, or obesity that should also benefit from metformin. Eflornithine (Vaniqa) is a medication that is applied to the skin in cream form, and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face.[80] 5-alpha reductase inhibitors (such as finasteride and dutasteride) may also be used;[105] they work by blocking the conversion of testosterone to dihydrotestosterone (the latter of which responsible for most hair growth alterations and androgenic acne).
Although these agents have shown significant efficacy in clinical trials (for oral contraceptives, in 60–100% of individuals[80]), the reduction in hair growth may not be enough to eliminate the social embarrassment of hirsutism, or the inconvenience of plucking or shaving. Individuals vary in their response to different therapies. It is usually worth trying other medications if one does not work, but medications do not work well for all individuals.
Menstrual irregularity If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.[80] The purpose of regulating menstruation, in essence, is for the woman's convenience, and perhaps her sense of well-being; there is no medical requirement for regular periods, as long as they occur sufficiently often.
If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required. Most experts say that, if a menstrual bleed occurs at least every three months, then the endometrium (womb lining) is being shed sufficiently often to prevent an increased risk of endometrial abnormalities or cancer.[106] If menstruation occurs less often or not at all, some form of progestogen replacement is recommended.[105] An alternative is oral progestogen taken at intervals (e.g., every three months) to induce a predictable menstrual bleeding.[citation needed]
Alternative medicine A 2017 review concluded that while both myo-inositol and D-chiro-inositols may regulate menstrual cycles and improve ovulation, there is a lack of evidence regarding effects on the probability of pregnancy.[107][108] A 2012 and 2017 review have found myo-inositol supplementation appears to be effective in improving several of the hormonal disturbances of PCOS.[109][110] Myo-inositol reduces the amount of gonadotropins and the length of controlled ovarian hyperstimulation in women undergoing in vitro fertilization.[111] A 2011 review found not enough evidence to conclude any beneficial effect from D-chiro-inositol.[112] There is insufficient evidence to support the use of acupuncture, current studies are inconclusive and there's a need for additional randomized controlled trials.
Asthma
fast-acting
Short-acting beta2-adrenoceptor agonists (SABA), such as salbutamol
Reference