|Year : 2019 | Volume
| Issue : 4 | Page : 229-235
Polycystic ovary syndrome: An updated review
Muthusamy Ranga Priya, A Nanthini, KP Bini
Department of Pharmacy Practice, Swamy Vivekanandha College of Pharmacy, Namakkal, Tamil Nadu, India
|Date of Submission||08-Mar-2019|
|Date of Acceptance||09-Jul-2019|
|Date of Web Publication||15-Oct-2019|
Dr. Muthusamy Ranga Priya
Department of Pharmacy Practice, Swamy Vivekanandha College of Pharmacy, Namakkal - 637 205, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Polycystic ovary syndrome (PCOS) is one of the most common metabolic and reproductive disorders among the reproductive age women. PCOS presents with the symptoms of androgen excess, menstrual dysfunction, hirsutism, acne, and obesity, which significantly impacts their quality of life. It not only a reproductive problem but also as a severe metabolic disease that carries crucial health risks as age increases. PCOS has an increased risk of multiple morbidities, including insulin resistance, type II diabetes mellitus, obesity, cardiovascular disease, cancer, infertility, and psychological disorders. This review summarizes that the literature has so far provided from guidelines to diagnosis of PCOS and also this review gives a general overview about the morbidities associated with PCOS, specifically with its more severe classic form. Finally, the review will stress on the various aspects of treatment currently used in the management of this condition.
Keywords: Diabetes, insulin, obesity, ovary, polycystic ovary syndrome
|How to cite this article:|
Priya MR, Nanthini A, Bini K P. Polycystic ovary syndrome: An updated review. Int J Health Allied Sci 2019;8:229-35
| Introduction|| |
Polycystic ovary syndrome (PCOS) is one of the most common gynecologic endocrinologic disorders found in reproductive-age women. PCOS is typically defined as hyperandrogenism associated with chronic anovulation oligo- or amenorrhea, hirsutism, and insulin resistance (IR); obesity is also common in women without other underlying disease. Described since 1935 by Stein and Leventhal, it represents a condition, in which an estimate of ten small cysts of a diameter ranging between 2 and 9 mm develop on one or both ovaries and/or the ovarian volume in at least one ovary exceeds 10 ml. Patients with this syndrome are at higher risk of developing IR, obesity, dyslipidemia, cardiovascular disease (CVD), and endometrial carcinoma. IR and hyperinsulinemia are responsible for low-grade chronic systemic inflammation.
The prevalence of PCOS is traditionally estimated at 4%–8% from studies performed in Greece, Spain, and the USA. In fact, according to the Rotterdam diagnostic criteria, the prevalence of PCOS in adolescents varies between a minimum of 3% and a maximum of 26%. Most of the studies in India reported the prevalence of PCOS as 9.13%–36%. In 2011, the prevalence of PCOS in Indian adolescents was 9.13%. In 2018, a cross-sectional community-based study was conducted among the school-going girls in five schools of Ahmedabad Gujarat region selected by cluster sampling. A total of 881 school-going girls of age 13–18 years were involved in the study and reported the prevalence of PCOS is 13.54%. Another study was carried out in Bhopal shows 8.20% of the prevalence of PCOS.
The economic burden of PCOS is significantly huge. Around 4 billion dollars are spent annually in the United States to screen for the disease and treat its various morbidities, including hirsutism, infertility, and diabetes mellitus The Australian Health System spends >800 million dollars every year to account for the disease. Therefore, accurate and early diagnosis of PCOS is necessary not only to prevent future health comorbidities but also to reduce financial cost and burden.
In this review, we will summarize the most relevant and recent reports related to PCOS, briefly addressing the pathophysiology of the disease, then dwelling in more depth into its diagnostic criteria and their limitations. Moreover, we will discuss morbidities associated with the classic form of PCOS, and we will provide information about the various treatment regimens and screening recommendations for women living with this condition. Throughout the review, we will emphasize the complexity of PCOS in terms of pathophysiology, diagnosis, morbidities, and the multidisciplinary treatment approach it requires.
| Etiology|| |
The exact pathophysiology of PCOS is complex and remains largely unclear. Detailed discussion is beyond the scope of this review, the underlying hormonal imbalance created by a combination of increased androgens and/or insulin under in PCOS. Genetic and environmental contributors to hormonal disturbances combine with other factors, including obesity, ovarian dysfunction, and hypothalamic pituitary abnormalities to contribute to the etiology of PCOS.
| Pathophysiology|| |
Many hypotheses emerged trying to explain the pathophysiology of PCOS. Recently, human studies showed neither an association between excessive prenatal androgen exposure and the development of PCOS in youth nor an elevation in androgen levels in the cord blood of females born to mothers with PCOS. The adipose tissue expandability hypothesis, suggested that infants with intrauterine growth restriction (IUGR) and spontaneous catch-up growth might develop decreased tissue expandability, meaning that they cannot store lipids appropriately in their fat tissues. Consequently, IR might ensue contributing to PCOS and hyperandrogenemia. However, this does not apply for patients with PCOS who did not have IUGR nor had it but without spontaneous catch-up growth.
A multifaceted disease
PCOS deals with it as a multifaceted disease involving uncontrolled ovarian steroidogenesis, aberrant insulin signaling, excessive oxidative stress, and genetic/environmental factors. An intrinsic defect in theca cells can partially explain the hyperandrogenemia in patients with PCOS. Indeed, women with PCOS have theca cells that, still secrete high levels of androgens due to an intrinsic activation of steroidogenesis even in the absence of trophic factors.
Oxidative stress can itself induce IR and hyperandrogenism in patients with PCOS.
Recently, multiple studies are suggesting that PCOS might start in utero, mainly in neonates with risk factors implicated in the development of PCOS. This includes low birth weight and high birth weight infants who later on catchup on their growth or constantly increase in weight postnatally.
The presentation of PCOS as a model that undergoes a step-wise evolution throughout development puts the complexity of this disease into perspective. Indeed, although science has provided an insight into the origins of PCOS, our understanding of it is still lacking. The adipose tissue expandability hypothesis cannot account for the disease in infants without IUGR.
| Diagnosis|| |
Diagnosis of PCOS in adults can be done by three different guidelines, which criteria are described in [Table 1]. Even though IR and obesity are considered intrinsic factor to PCOS, none of them is included in those guidelines and should, therefore, be used for diagnostic purposes.
|Table 1: Polycystic ovary syndrome diagnostic criteria, adapted from Teede et al., 2010|
Click here to view
In addition to the information described in [Table 1], each of the guidelines requires ruling out any pathological condition that might explain the hyperandrogenism or the menstrual irregularity. The disparity between the guidelines, although minor, has been associated with a variation in the diagnosis and the treatment of PCOS. Moreover, diagnosis in adolescent females is highly debatable.
Since PCOS tends to present as a spectrum of diseases, the Rotterdam criteria divided the disease into four phenotypes [Table 2].,
|Table 2: Diagnostic phenotypes of polycystic ovary syndrome, adapted from Moran and Teede|
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The variation in the symptomatology and presentation of PCOS can account for the presence of different diagnostic guidelines, as the phenotype may vary from being asymptomatic to having signs of all three components of the disease (anovulation, hyperandrogenism, and polycystic ovaries). One can argue that the different guidelines might lead to underdiagnosis or overdiagnosis of this condition. This clearly underlines the need for one new single guideline which encompasses all the different phenotypes of PCOS without missing the milder forms of the disease.
Signs and symptoms
A lack of ovulation prevents the uterine lining from shedding every month. Women with PCOS get fewer than eight periods a year.
This is more common in patients who are obese with PCOS. Sometimes, the small and primitive follicles produce enough estrogen to thicken the lining of the uterus, but the compacting and balancing hormone, progesterone, is absent. This can lead to the lining of the uterus becoming thicker and thicker and eventually undergoing a form of precancerous change. This may be associated with quite heavy bleeding or irregular, frequent, and even constant bleeding.
More than 70% of women with this condition grow hair on their face and body, including on their back, belly, and chest. Excess hair growth is called hirsutism.
Hyperinsulinemia massively increases sebum production and enhance the ability of androgens to do the same. Male hormones can make the skin oilier than usual and cause breakouts on areas such as the face, chest, and upper back.
Up to 80% of women with PCOS are overweight or obese
Due to androgen excess, male-pattern hair loss called alopecia will occur in middle-age women which is thinning hair on the top of the head or hair recession, something that may be more severe in middle-aged women. Hairs on the scalp get thinner and fall out.
Darkening of the skin
Dark patches of the skin can form in body creases like those on the neck, in the groin, and under the breasts.
Hormone changes can trigger headaches in some women.
| Morbidities in Polycystic Ovary Syndrome|| |
The clinical and/or biochemical signs of androgen excess in PCOS result from increased synthesis and release of ovarian androgens. Elevated luteinizing hormone and insulin synergistically increase androgen production. IR reduces sex hormone-binding globulin (SHBG) and raises free circulating testosterone and together, cause the hyperandrogenism and hyperinsulinemia, thereby impairs ovarian follicle development. Clinical hyperandrogenism primarily includes hirsutism, acne, and male-pattern alopecia.
Obesity increases hyperandrogenism, hirsutism, infertility, and pregnancy complications both independently and by exacerbating PCOS. In general populations, obesity and IR further increase type 2 diabetes mellitus (DM2) and CVD. Likewise, in PCOS patient with obesity worsens the IR and exacerbates reproductive and metabolic features. Furthermore, women with PCOS have increased risk factors for DM2 and CVD, increased impaired glucose tolerance (IGT), DM2, and potentially increased CVD.
A great deal of attention has been given to the metabolic disturbances that accompany PCOS, as well as to the consequences of these disturbances later in life. Today, IR is considered the main pathogenic factor in the background of increased metabolic disturbances in women with PCOS.
In fact, recent studies show that hyperinsulinemia is present in 85% of patients with PCOS, including 95% of obese and 65% of lean affected women increased insulin levels in patients with PCOS may, along with the high levels of luteinizing hormone, trigger the arrest of follicular growth which contributes to anovulation hyperinsulinemia also alters the gonadotropin-releasing hormone pulse secretion pattern, suppresses the SHBG, and potentiates ovarian androgen production in women with PCOS.
Other studies showed that 6 months of lifestyle modifications enhanced insulin sensitivity by 70% and significantly reduced anovulation in affected obese women.
Type II diabetes mellitus
PCOS confers a substantially increased risk for DM2 and gestational diabetes from early ages. About 1 in 5 women with PCOS will develop DM2 making IGT a common abnormality in this disease. Cross-sectional and prospective longitudinal studies have consistently shown that women suffering from PCOS have a higher risk of developing DM2 or IGT compared to control populations matched for age and ethnic background. Furthermore, prospective longitudinal studies in young- and middle-aged women with PCOS show a higher risk for developing diabetes even though family history and obesity are major contributors in the development of diabetes in PCOS patients, diabetes can still occur in lean PCOS patients who have no family history, mainly secondary to IR.
There is increasing evidence that patients with PCOS have increased cardiovascular risk compared with age-matched controls. It has been estimated that myocardial infarction is seven times more likely in patients with PCOS, and cardiac catheterization studies have shown more extensive coronary artery disease in these patients than in women with normal ovaries. Furthermore, significant subclinical carotid atherosclerosis has been demonstrated on carotid artery ultrasound in women with PCOS. This increased cardiovascular risk is probably the result, in part, of the metabolic disturbance associated with PCOS. Dyslipidemia, diabetes, and obesity are all potent cardiovascular risk factors that tend to cluster in women with PCOS. However, it is not known whether the increased cardiovascular risk seen in PCOS is mediated through obesity or is independent of body mass index and the result of other metabolic factors.
More recent data showed that patients with PCOS have significantly elevated levels of circulating biomarkers of CVD, including C-reactive protein and lipoprotein A in comparison to matched controls., Other studies demonstrated a higher burden of indicators of atherosclerosis with early-onset cardiovascular dysfunction, i.e., arterial stiffness, endothelial dysfunction, and coronary artery calcification.
Women with PCOS may have reduced fertility due to the associated endocrine and gynecologic abnormalities that impact ovarian quality and function.
Approximately 20% of couples in Western society experience infertility. Infertility occurs due to the ovulatory disturbances in PCOS, and 100% of patients with PCOS suffer from ovulatory dysfunction according to the National Institutes of Health 1990 Criteria. Of this, 75% of women with PCOS will experience infertility. In fact, one study reported a 3.4-fold incidence of concern using the Child Health Questionnaire-Child Self-Report Form-87. Concerning the effects on the embryo, women with PCOS are 2.5 times at a higher risk of giving birth to small for gestational age children in comparison to healthy females and offspring show an increased morbidity and mortality compared to control.,
Females suffering from PCOS present many risk factors associated with the development of endometrial cancer, such as obesity, IR, DM2, and anovulation. Anovulation triggers an unopposed uterine estrogen exposure. This can subsequently trigger the development of endometrial hyperplasia and ultimately endometrial cancer. In fact, studies show that women with PCOS have a 3-fold increased risk of developing endometrial cancer.
The psychiatric aspects of PCOS have grown. According to previous studies, 56.9% of women with PCOS have at least one psychiatric disorder, and higher incidences of psychiatric disorders have been observed in women with PCOS, particularly depressive disorder, bipolar disorder, and anxiety disorder. Furthermore, a study reported that these comorbid psychiatric problems affect the quality of life of PCOS patients.
| Treatment|| |
The treatment section will mainly focus on two major treatment guidelines: the American Task Force and the PCOS Australian Alliance Guidelines.
| Lifestyle Changes|| |
As a crucial part of the management of obesity in women with PCOS, the guidelines recommend exercise therapy and calorie-restricted diet. In fact, lifestyle modifications are considered as a cost-effective first-line treatment and as a necessary adjunct to medication.
| Drug Treatment|| |
The drug of choice for inducing ovulation in PCOS is clomiphene citrate, although the precise mechanism of action is unknown. Initially, a dose of 50 mg/day for 5 days is given. Clomiphene results in successful pregnancies, approximately 30% of the time; however, 20% of these pregnancies result in spontaneous abortions or stillbirths. Adverse effects may include ovarian enlargement, ovarian hyperstimulation syndrome, multiple pregnancies, hot flashes, and gastrointestinal distention, bloating, and discomfort.
Metformin (Glucophage) is an oral antidiabetic biguanide drug. It acts by impeding hepatic glucose production and increasing the peripheral insulin sensitivity. It is also a reasonable treatment option for those women to whom oral contraceptives (OCs) may not be recommended, such as PCOS patients presenting moderate-to-severe high blood pressure, high triglycerides levels, Class II or III obesity, and/or metabolic syndrome. The usual dose of metformin for PCOS is 1500–2500 mg/day. Antidiabetic drugs can be used to improve fertility, decrease IR, and reduce circulating androgen levels. More data are available for metformin than for the thiazolidinediones in treating PCOS. The role of metformin for the treatment of infertility with PCOS was compared with placebo in a study that enrolled 320 women and reported that significantly higher pregnancy rates (53.6% vs. 40.4%, respectively) and live birth rates (41.9% vs. 28.8%, respectively; P = 0.014) compared with placebo.
Human menopausal gonadotropin and follicle-stimulating hormone (FSH) can also be used to induce ovulation if clomiphene and/or metformin therapy fails. In one study of 302 women, 132 received low-dose FSH (50 units subcutaneously) on cycle day 4 with weekly incremental increases of 25 units, and 123 patients received clomiphene 50 mg for 5 days starting on day 4 with the dose titrated upward to 150 mg/day. Pregnancy rates were higher with FSH than with clomiphene (58% vs. 44%, respectively; P = 0.03), and there were more live births with FSH (52% vs. 39%, respectively; P = 0.04).
Selective aromatase inhibitors such as anastrozole and letrozole are promising new ovulation-inducing agents. They are reversible and highly potent. Letrozole is an aromatase inhibitor approved for patients with hormone-responsive breast cancer, but it has also been studied for the induction of ovulation in PCOS. The difference between the efficacy of anastrozole and letrozole was studied for ovulation induction; the difference in pregnancy rates was not considered statistically significant.
In a phase 2 dose-finding study, a 5-day regimen of various doses of anastrozole was compared with clomiphene 50 mg/day. Clomiphene resulted in higher rates of ovulation compared with all three doses of anastrozole.
Aromatase inhibitors may be considered for patients with clomiphene resistance or for women who are not candidates for clomiphene or gonadotropins because of the risk of congenital abnormalities associated with this class of medications.
Spironolactone, flutamide, and finasteride are antiandrogens that work in PCOS by decreasing androgen levels, thereby reducing the signs of hirsutism and acne. These antiandrogens may also improve lipid levels, which can be elevated in patients with PCOS. The effects of spironolactone 100 mg, flutamide 250 mg, and finasteride 5 mg daily were compared in 40 women with hirsutism for 6 months. All three drugs were found to be efficacious, although there was no significant difference between the groups.
Spironolactone, at a dose of 25–100 mg twice daily, is the most commonly used antiandrogen because of its safety, availability, and low cost. Due to the increased risk of teratogenicity to the male fetus (opposing genital formation), contraception is recommended when patients are using antiandrogens for the treatment of PCOS.
The mechanism of action for OCs in the treatment of PCOS is primarily through the regulation of menstrual periods. These drugs also reduce hirsutism, acne, and androgen levels. Estrogen and progestin combinations are the primary OCs used in the treatment of hirsutism and acne associated with PCOS. Although data are sparse, some newer OCs contain antiandrogenic progestins, such as Bayer's drospirenone and dienogest. Theoretically, these drugs are more effective for treating androgenic symptoms compared with older formulations. Women with hirsutism usually notice clinical improvement after approximately 6 months of treatment with OCs. The data also suggest that OCs can be combined with antiandrogens for synergy.
| Other Treatment|| |
Medroxyprogesterone acetate (MPA) can be used to treat amenorrhea or dysfunctional uterine bleeding in women with PCOS who do not wish to conceive and who are not at risk for pregnancy. Monthly progestin therapy obviates abnormal endometrial proliferation but does not suppress ovarian androgen production. MPA may also improve insulin sensitivity and lipid profiles in patients with PCOS.
Statins are considered to have a place in the treatment of PCOS because of their ability to reduce testosterone levels, as well as low-density lipoprotein-cholesterol, triglycerides, and total cholesterol. In a comparison of simvastatin and metformin in women with PCOS, total testosterone levels were reduced by 17.1% and 13.6%, respectively. Simvastatin had a superior effect compared with metformin alone, but the combination was not found to be superior to simvastatin alone, at 15.1%.
| Conclusion|| |
An extent amount of knowledge learned about PCOS, since it was initially described by Stein and Leventhal. Yet, we are still lacking knowledge about many of its aspects, including its etiology, progression throughout life, spectrum of symptoms, and various morbidities.
Morbidities, more common in the frank PCOS phenotype, emphasize the complexity of this disease as a condition that affects many bodily systems, whether endocrine, gynecological, cardiac, or psychological. Therefore, the management of this varied entity requires a skilled and knowledgeable multidisciplinary team who can achieve the best patient outcomes. It is imperative to remember that the treatment of PCOS changes throughout age and should be guided by symptomatology. Early detection of long-term morbidities through appropriate screening tests constitutes an essential part of the management of this condition.
Guidelines strongly recommend lifestyle modifications as a critical part of the management. OC pills are the main medication of choice for anovulation and hyperandrogenism; clomiphene citrate is the drug of choice for infertility. Studies assessing inositol stereoisomers' effectiveness should carry on, as they may become the new drug of choice for treatment. The other treatment options like MPA and statins are helpful in the management of PCOS.
In conclusion, we hope this review provided an updated summary that sheds light over the complex nature of PCOS. Future research has to focus on the missing blocks in our growing knowledge about this condition, for that physicians will be able to provide the finest care for patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]