POLYCYSTIC OVARIAN SYNDROME- A MULTIFACETED DISEASE: A REVIEWHTML Full Text
POLYCYSTIC OVARIAN SYNDROME- A MULTIFACETED DISEASE: A REVIEW
Mudasir Maqbool, Imran Gani and Mohammad Ishaq Geer *
Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal Srinagar - 190006, Jammu and Kashmir, India.
ABSTRACT: Polycystic ovarian syndrome (PCOS) is one of the most prevalent endocrine disorders in females of reproductive age. Globally, it has been found that PCOS affects 10% of reproductive-age women when using the NIH criteria for diagnosis, and up to 18% of reproductive-age women are diagnosed with PCOS as per the Rotterdam criteria. Mostly symptoms of PCOS include irregular menstrual cycles, signs of hyperandrogenism and insulin resistance. Women with PCOS are at increased risk for developing reproductive, metabolic and cardiovascular disorders. The measures for management of PCOS targets the symptoms which are present in a patient such as lowering body weight and insulin levels, restoring fertility, treating hirsutism or acne, restoring regular menstruation and preventing complications. Early detection of long-term morbidities through appropriate screening tests constitutes an essential part of the management of this condition. Future research has to focus on the missing blocks in our growing knowledge about this condition, following that physicians will be able to provide the finest care for patients.
PCOS, Insulin resistance, Hyperandrogenism, Menstrual irregularity
INTRODUCTION: Polycystic ovarian syndrome is one of the most prevalent female endocrine disorders. It is a complex heterogeneous disease of unusual etiology, but there is enough evidence that it can, to a large extent, be classified as a genetic disease 1, 2. As per various studies, PCOS affects 10% of reproductive-age women when using the NIH criteria for diagnosis, and up to 18% of reproductive-age women as per the Rotterdam criteria 3. However, about 70% of PCOS cases remain undiagnosed in primary care 4. PCOS is a metabolic disease, and mainly life style changes predispose it.
The percent of PCOS affected persons are mostly from diabetic family background, and genetically it has proved that if a mother or sister has PCOS then mostly that women can be affected. In the case of diabetics, the person develops resistance towards insulin which in turn hampers the LH and FSH hormones which causes alterations in menstrual cycle 5-20. Polycystic Ovarian Syndrome presents with menstrual irregularities, infertility, high levels of masculinizing hormones manifested by acne and hirsutism and metabolic syndrome and other symptoms associated with insulin resistance.
It has been found that serum insulin, insulin resistance, and homocysteine levels are higher in females with PCOS than in the normal females 21. PCOS leads to a significantly huge economic burden. About 4 billion dollars are spent every year in the United States on screening for the disease and treating its various morbidities, including hirsutism, infertility, and diabetes mellitus 22.
Various predisposing factors for PCOS include 23: genetic factors; high maternal androgen; endocrinal factors and drugs: such as anti-epileptic drugs (e.g., Valproate). Women with PCOS are at increased risk of presenting with insulin resistance (IR), impaired glucose tolerance (IGT), Type 2 Diabetes mellitus (DM2), obesity, and dyslipidemia 24-26.
Pathophysiology: The pathophysiology of PCOS as a multifaceted disease shows the involvement of uncontrolled ovarian steroidogenesis, aberrant insulin signaling, excessive oxidative stress, and genetic/environmental factors. In PCOS, ovaries are incited to produce increased amounts of male hormones (androgens), such as testosterone, by either the release of excessive luteinizing hormone, higher levels of insulin in the blood (hyperinsulinaemia) in females whose ovaries are sensitive to this stimulus or decreased levels of sex-hormone binding globulin (SHBG) resulting in excessive free androgens 27. Females with PCOS have increased gonadotrophin-releasing hormone (GnRH), which leads to an increase in LH/FSH ratio. Majority of patients with PCOS show insulin resistance and central obesity 27, 28.
Hyperinsulinaemia contributes to abnormalities in the hypothalamic-pituitary-ovarian axis leading to PCOS. The sequence various events that precede in PCOS pathogenesis include; increased insulin levels increase GnRH pulse frequency, LH over FSH dominance, excessive ovarian androgen production, diminished follicular maturation and reduced SHBG binding. All these factors lead to the development of PCOS 27, 28. Various other factors such as exposure to environmental toxins, like endocrine-disrupting chemicals that mimic endogenous hormones and advanced glycation end products, might programme reproductive and metabolic function, leading to PCOS and its associated metabolic dysfunctions, especially if such exposure is persistent and occurs during developmental periods such as fetal life, infancy or childhood 29.
Similar consequences might result from exposure to certain pharmaceutical drugs during critical developmental windows, especially the anti-epileptic and mood stabilizer valproate 30, which is frequently associated with a PCOS-like phenotype in premenopausal women and induces a genomic and molecular signature in theca cell cultures that is similar to that of PCOS 31, 32. PCOS is indicated by complex positive feedback of insulin resistance and hyperandrogenism 33. In humans, adipose tissue contains aromatase enzyme, which converts androstenedione to estrone and testosterone to estradiol. Since obese patients possess excessive adipose tissue, it leads them to have both increased androgens and estrogens. The androgens are responsible for hirsutism and virilization whereas estrogens inhibit FSH via negative feedback 34. The ovaries at the time of production have tiny fluid-filled sacs called cysts 35-37.
As the egg grows, the follicle builds up fluid, and once the egg matures, the follicle breaks open, and the egg is released, and this egg travels through the fallopian tube to the uterus (womb) for fertilization that is called ovulation, but in case of women with PCOS, the ovary is unable to produce all the essential hormones which are needed for an egg to fully mature. The follicles may start to grow and build up fluid; however, ovulation does not develop. Rather, a few follicles may remain as cysts 35-37. Thus, ovulation does not happen, and the hormone progesterone is not made. Without progesterone, a woman's menstrual cycle is sporadic or missing. Furthermore, the ovaries make male hormones, which additionally counteract ovulation 38-53.
Diagnosis of PCOS: 54 Although, pelvic ultrasound is a major diagnostic tool, however, is not the only one. Certain definitions are used for diagnosis of PCOS such as National Institutes of Health (NIH) criteria, Rotterdam Criteria, and Androgen Excess PCOS Society Criteria.
Hyperandrogenism: It is a major patho-physiological feature of PCOS showing the prevalence of 60-80% 55. Excessive ovarian androgen production by theca cells is the main culprit to androgen excess in women of reproductive age with PCOS 56, whereas about 20-60% of women with classic anovulatory PCOS have adrenal androgen excess, as determined by elevated dehydroepiandrosterone sulphate (DHEAS) levels 57. The latter originates mainly from the zona reticularis of the adrenal cortex 58. Adrenal androgen hypersecretion in PCOS women of reproductive age is also observed after adrenal stimulation 59-61. Hyperandrogenism is the main criterion in the diagnostic work-up of PCOS. According to the current criteria, it can be indistinctly defined by either hirsutism and excess of blood testosterone (T) levels. However, most but not all PCOS women are hirsute, and no more than 50% have increased T levels measured by commonly used immunoassay methods. This implies that the population of PCOS is rather heterogeneous in displaying its hyperandrogenic phenotype, which may be related to the relative unreliability of the diagnostic criteria used to define hyperandrogenism 62.
The current definition of hirsutism by the modified Ferriman-Gallwey (mF-G) score is largely Unsatisfactory due to a poor interobserver agreement and the intrinsic variability of the scoring system. Also, although most women with hirsutism have high T levels, and some correlation is found between hirsutism scores and T levels in women with PCOS, this relationship becomes only marginally significant when T is measured by more appropriate techniques. According to one hypothesis for the pathogenesis of PCOS, increased peripheral aromatization of androstenedione to estrone leads to excessive secretion of Luteinizing Hormone which leads to a further increase in ovarian androgen production 62.
Menstrual Irregularity: Menstrual disorders and physical manifestations of excessive androgen production is the leading cause of consultation in the adolescent group. Other than metabolic syndrome and primary infertility they are also at high risk for insulin resistance and impaired glucose tolerance. Therefore it is important to identify adolescent at risk, early because diabetes mellitus is asymptomatic at the early stage of insulin resistance and impaired glucose tolerance. Modification in life style can avert the development of metabolic syndrome and diabetes mellitus in these adolescents 63, 64. The menstruation patterns that follow menarche, especially during the first 2 years, are usually anovulatory, irregular, and occasionally abundant, due to the immaturity of the hypothalamus-pituitary-ovary axis in adolescents 65-67. After two years of menarche, the hypothalamus-pituitary-ovary axis usually acquires normal functioning. The persistence of anovulatory cycles for more than 24 months after menarche, especially in association with other characteristics of hormonal disorders, suggests ovulatory dysfunction of pathologic origin 68, 69.
As such, menstrual irregularity can sometimes be an unreliable criterion for the diagnosis of PCOS in adolescents 70. Clinicians monitor the menstrual cycle patterns closely to differentiate physiological anovulation associated with adults from pathological anovulation as an abnormality identified in PCOS 71, 72. It has been suggested to postpone diagnosis at least 2 years after menarche to establish a persistent menstrual irregularity 73. However, this may delay the initiation of appropriate treatment 74.
Polycystic Ovaries on Ultrasonography: During puberty, ultrasonography findings are controversial for the diagnosis, as the ovaries show normal physiological changes and variations in the volume and size of the ovaries 75. Researchers noted that the diagnosis of polycystic ovaries requires strict criteria 76, 77 and should not be assigned based solely on a polycystic or multicystic appearance of the ovary. The diagnosis of polycystic ovaries has been recently reviewed 79. For diagnostic purposes, normal ovarian volume in female adolescents is considered equal to or less than 10 ml 80.
Management of PCOS: Management of PCOS is based on the aspect of correcting the symptoms present in patients usually such as anovulation, infertility, hirsutism, etc. Treatment of PCOS acts to reduce hyperinsulinemia, restore fertility, treat hirsutism or acne, correct menstrual irregularity and prevent endometrial hyperplasia and endometrial cancer 81. A lifestyle program that addresses healthy diet with caloric restriction, exercises to aid in weight loss and prevention of future weight gain and behavior change support is the best first-line treatment for PCOS 82. Weight loss reduces hyperinsulinemia and subsequently hyperandrogenism. Even a small amount of weight loss (5%) can help to restore ovulation and menstrual cycle regularity, assist in mental well-being, decrease the risk of diabetes in high-risk groups and help prevent future cardio-metabolic risk 83-86. Those who smoke should be offered support to help them quit. Pharmacotherapies are based on whether the patient's main complaint is an irregularity in menstrual cycles, infertility, acne or hirsutism, etc. The most common prescribing drugs and therapeutic options used in the management of PCOS include hormonal contraceptives/oral contraceptives, insulin sensitizers, ovulation-inducing agents and anti-androgens 87.
Typically, oral contraceptive pills (OCP’s) are first-line agents for Pharmacological management of hirsutism in premenopausal women 87. Combined OCPs are a good treatment option to regularize menstruation in those not desiring pregnancy, and they are often considered the first line for the treatment of PCOS related hirsutism and acne. Apart from these positive effects on PCOS, OCPs are believed to slightly worsen insulin sensitivity 88-90, and for this reason, their use may aggravate the already impaired glucose metabolism of women with PCOS. However, studies estimating the role of OCPs on glucose tolerance 91 or insulin sensitivity 92-98 in women with PCOS have obtained conflicting results, and either no effect or a negative modification 91, 94, 96, 97 was reported. There may be some negative influence on lipids also, and a low dose COCP may be preferable 99, 100.
Antiandrogens such as Spironolactone, cyproterone acetate (CPA) or Flutamide work by competitive inhibition of androgen-binding receptors or by decreasing androgen production 101. Spironolactone shows moderate antiandrogenic action when administered in large doses; however, it has promising effects on hirsutism 102. It is generally well tolerated, but it occasionally causes fatigue, postural hypotension, and dizziness. CPA is a progestational antiandrogen. CPA is generally well tolerated, though it may cause headaches, nausea, breast tenderness and weight gain. A combination of ethinyl estradiol and CPA is very effective in treating hirsutism and acne. CPA has a marked progestational property apart from its antiandrogenic effect, thus preventing ovulation 103. Flutamide is a non-steroidal, selective anti-androgenic agent without any progestogenic effect. It is very effective in treating hirsutism. However, it is rarely used alone due to its high cost and the risk of hepatocellular toxicity. Finasteride is a type 2(5-α-reductase) activity inhibitor that inhibits the production of dihydrotestosterone. Hirsutism scores were lower in studies of Finasteride 104. In comparison to Finasteride, Spironolactone has shown equal or lesser efficacy than Finasteride. It has also been used in combination with a CPA containing OCP. Finasteride as such has a low side effect profile, but its feminizing effects on a male fetus preclude its use in most patients 87.
Insulin sensitizers such as Metformin and thiazolidinediones have insulin-lowering effects by improving insulin sensitivity, and thus, in turn, can decrease circulating androgen levels 87. Additionally, these agents have a role in the treatment of PCOS because women with PCOS are at an increased risk of insulin resistance, development of metabolic disorders and cardiovascular disease 105. The US Food and Drug Administration has not approved any antidiabetic agents for the treatment of PCO, but Metformin is preferred at this time because it appears to have the safest risk-benefit ratio, and it can cause weight loss, while as thiazolidinediones can increase weight as a result of fluid retention 105. The other insulin-sensitizing agents, such as D-chiro-inositol in PCOS treatment is currently under investigation. Inositolglycans have been described as interfering insulin action on thecal steroidogenesis 106.
Clomiphene citrate (CC) is the drug of the first choice for ovulation induction in women with PCOS 107. CC is a partially selective estrogen receptor modulator. It is the first-step therapy for anovulation; no consistent evidence suggests that Metformin is better than CC regarding cumulative ovulation, pregnancy or live birth rates 108, 109. Selective aromatase inhibitors like Anastrozole and Letrozole are new ovulation-inducing drugs. They are reversible and highly potent. The mean half-life of Anastrozole and Letrozole is ≈ 45 h only unlike CC, which has a half-life of 5-7 days. To date, Letrozole has been studied much more extensively than Anastrozole 110. Letrozole was introduced as an assisted reproduction treatment following the appearance of multiple adverse effects of CC, the complexity of gonadotropin treatment and CC’s scant therapeutic success. As per American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology 107, ovulation induction with gonadotropins and laparoscopic ovarian drilling (LOD) are considered to be second-line therapies for ovulation induction. The gonadotropin approach is less invasive and is best-preferred treatment in women who do not desire surgery. LOD is preferred only when the patient has other indications for surgery or when the patient is not able to comply with the frequent follow-up visits required with gonadotropin therapy 111. Bromocriptine, a dopaminergic agonist, may also be a useful treatment in women with PCOS associated with hyperprolactinemia 107. Eflornithine is a topical cream that has been approved by the US Food and Drug Administration for removal of unwanted facial hair in females 87, 105.
CONCLUSION: PCOS is an important endocrine disease that affects women of reproductive age and may cause serious complications. Further, research is needed to determine the exact etiology of PCOS, methods of prevention and proper management. Patients suffering from PCOS are at risk for the development of reproductive, metabolic and cardiovascular disorders, etc. Moreover, it may affect daily physical activities. Treatment of PCOS acts to reduce hyperinsulinemia, restore fertility, treat hirsutism or acne, and correct menstrual irregularity. A lifestyle program that addresses healthy diet with caloric restriction, exercise to aid in weight loss and prevention of future weight gain and behavior change support is the best first-line treatment for PCOS Early detection of long-term morbidities through appropriate screening tests constitutes an essential part of the management of this condition. Future research has to focus on the missing blocks in our growing knowledge about this condition. Following those physicians will be able to provide the finest care for patients.
CONFLICT OF INTEREST: None
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How to cite this article:
Maqbool M, Gani I and Geer MI: Polycystic ovarian syndrome- a multifaceted disease: a review. Int J Pharm Sci & Res 2019; 10(3): 1072-79. doi: 10.13040/IJPSR.0975-8232.10(3).1072-79.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
M. Maqbool, I. Gani and M. I. Geer
Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal Srinagar, Jammu and Kashmir, India.
12 July 2018
22 September 2018
05 October 2018
01 March 2019