Evaluation of clinical manifestations, health risks, and quality of life among women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), which affects 6%–20% of women of reproductive age, has been the most debatable female endocrine disorder in the developed world [ 1 ], with Pakistan being no exception. It is one of the leading causes of female infertility and is characterized by menstrual irregularities, hirsutism, cystic acne, seborrhea, hair loss, and obesity [ 2 ]. The prevalence of PCOS in higher among Pakistani women (52%) than among Western Caucasian women, e.g., 20%–25% in UK [ 3 ]. PCOS is associated with significant short- and long-term health problems; these include many metabolic and cardiovascular complications [ 4 , 5 ] as well as psychological disorders [ 6 ] such as depression, anxiety, sexual dysfunction, and social problems, which affect a woman’s identity and health-related quality of life (QOL). The increasingly high incidence of PCOS can be attributed to genetic factors, environmental factors, and intermarriages [ 7 ]; however, it is considered an amalgamation of insulin resistance, hyperandrogenemia, and factors causing follicular abnormalities [ 8 ]. PCOS has been strongly associated with the future development of type 2 diabetes mellitus, glucose intolerance, hyperinsulinemia, cardiovascular disorders, and hypertension [ 9 , 10 ]. Insulin resistance has been reported in >60% of patients with PCOS [ 11 ], including obese and non-obese populations, and 10% of women with PCOS may develop type 2 diabetes by the age of 40 years [ 8 ]. Elevated luteinizing hormone levels have been found to be significantly associated with PCOS-associated ovulation disorders and elevated anti-Müllerian hormone (AMH) levels in patients with PCOS [ 12 ]. The National Institutes of Health (NIH) diagnostic criteria for PCOS defined in 1990 include hyperandrogenism and oligoovulation but exclude other disorders mimicking PCOS such as adult-onset congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting neoplasms [ 13 – 16 ]. However, the Endocrine Society recommends that PCOS should be diagnosed when adult women present with two of the following features: excess androgen production, anovulation, and pearl-sized cysts in the ovaries [ 17 ]. PCOS has pronounced effects on the QOL of affected patients. In a multivariate analysis, patients with depression reported low QOL [ 18 ]. A randomized controlled trial showed that a stress management program yielded significant reductions in stress and depressive and anxiety symptoms as well as improvements in QOL [ 19 ]. Nonetheless, the aspects of PCOS that have a strong influence on affected women remain unclear; thus, it is highly recommended that patient assessment include the evaluation of reproductive and metabolic health and health-related QOL. Various long-term complications and comorbidities have been associated with PCOS, and early diagnosis and therapeutic intervention are warranted in such cases [ 20 ]. Moreover, apart from the lack of disease awareness and management as well as medical therapy according to the guidelines, women, mostly in rural areas, are reluctant to visit gynecologists or endocrinologists for treatment despite having symptoms of the disease. This reluctance results in most patients remaining untreated, leading to various future complications. Therefore, the purpose of this study was to investigate the clinical aspects and QOL related to PCOS.

In total, 440 patients with PCOS were studied; among these, 274 (62.3%) were aged 15–30 years and 166 (38%) aged 31–44 years. Weight measurements revealed that a large proportion (74.5%) of the patients were normal to nearly obese; approximately, a quarter (24.5%) of the patients were morbidly obese, whereas only a few (0.9%) were underweight. Among the study patients, 364 (82.7%) were married and 76 (17.3%) were unmarried. Table 1 shows that 263 (59.8%) patients had PCOS alone, whereas 177 (40.2%) had PCOS with other gynecological and endocrine disorders. Among the study patients, 278 (63.2%) had hyperglycemia, including 106 (24.1%) with diabetes. Ultrasonography revealed that the majority (n = 268, 61%) of the patients had multiple cysts (diameter > 10 mm) and 34 (8%) had PCOS and endometriosis. Regarding the cardinal symptoms of PCOS, 316 (71.8%) patients had irregular menstruation, 301 (68.4%) had hirsutism, and 296 (67.3%) had acne. Furthermore, depression was reported by 272 (61.8%) patients. Among the comorbidities reported with PCOS, hypertension (7.0%) was the most common, followed by diabetes (22.7%). QOL analysis showed that 374 (85%) patients had poor QOL and 66 (15%) had good QOL ( Table 2 ). PCOS, polycystic ovary syndrome; QOL, quality of life If not treated properly, PCOS can lead to various serious complications and result in possible aggravation of the syndrome. In the present study, >5 complications were observed in 42 (10%) patients, with the most common complications being obesity (79.8%), hyperandrogenism (77.7%), and diabetes (60.9%). The details of all complications observed in the study population are provided in Fig 1 . Among the 440 patients with PCOS, metformin was prescribed to 358 (81%), contraceptives to 261 (59.4%), infertility drugs to 196 (44.6%), spironolactone to 79 (18%), anti-hirsutism drugs to 21 (4.8%), anti-acne drugs to 34 (7.7%), antihypertensive drugs to 47 (10.7%), anti-obesity drugs to 21 (4.8%), and antidepressant drugs to 35 (8%). Significant drug–drug interactions were observed in 115 (26.1%) patients, which required close monitoring. In addition, the presence of ADRs due the use of these drugs was determined. Accordingly, 433 (98.4%) patients had an ADR rate of >10%, whereas 13 (3%) had an ADR rate of >50%. Detailed description of data regarding prescribed drugs, drug–drug interactions, and ADRs are provided in Table 3 . PCOS, polycystic ovary syndrome QOL was determined and analyzed against the cardinal symptoms of PCOS and other variables, with significant differences observed among the disease outcomes; detailed results are presented in Table 4 . QOL was found to differ significantly ( p < 0.05) among patients with menstrual irregularities, hirsutism, acne, obesity, depression, comorbidities, and increased number of complications, including hyperlipidemia, obesity, and hyperandrogenism. Poor QOL scores were observed among patients with menstrual irregularities, hirsutism, acne, hyperglycemia, and obesity. Similarly, poor QOL scores were observed in patients with depression, comorbidities, ovarian cysts, and complications including hyperlipidemia, hyperandrogenism, and insulin resistance. QOL, quality of life After analyzing the mean QOL scores according to the clinical conditions associated with PCOS, it was observed that depression was the largest contributor to low QOL among patients with PCOS, followed by acne and obesity. The mean QOL scores are presented in Fig 2 . QOL, quality of life; PCOS, polycystic ovary syndrome. The association between ADRs and prescribed drug use is shown in Table 5 . The table presents the major ADRs associated with prescribed drug use. The most common ADR was diarrhea, which was observed in 81.4% of the patients, followed by nausea in 65.9%, mood changes in 64.1%, and abdominal pain and breast tenderness in 59.3%. A significant difference ( p < 0.05) was observed in terms of the occurrence of diarrhea with metformin and clomiphene use; abdominal pain with metformin, combined oral contraceptive (COC), clomiphene, and letrozole use; and breast tenderness with clomiphene, letrozole, and spironolactone use. Metformin was found to significantly affect the occurrence of diarrhea, vomiting, abdominal pain, dysuria, hot flashes, and reduced libido. Progestin was found to be associated with vaginal/uterine bleeding, dysuria, reduced libido, weight changes, headaches, and confusion. COCs were most commonly associated with abdominal pain, nausea, mastalgia, hot flashes, reduced libido, and mood changes. Clomiphene significantly affected the occurrence of diarrhea, vomiting, abdominal pain, vaginal/uterine bleeding, breast tenderness, mastalgia, hot flashes, headaches, and confusion. Letrozole significantly affected the incidence of abdominal pain, breast tenderness, dysuria, weight changes, mood changes, and headache. Further, spironolactone significantly affected the occurrence of vaginal/uterine bleeding, breast tenderness, dysuria, reduced libido, mood changes, and headaches. ADR, adverse drug reaction; COC, combined oral contraceptive Table 6 describes the appropriateness of administered drug therapy for the management of PCOS symptoms and complications and its association with QOL. It was observed that various symptoms and complications were left untreated, which led to reduced QOL scores. Accordingly, 32.9% of the patients with infertility remained untreated; thus, all these patients had poor QOL. Menstrual irregularities remained untreated in 109 (34.5%) patients, among whom 103 had poor QOL. Hirsutism and acne remained untreated in 286 (95%) and 262 (88.5%) patients, among whom 249 and 225 patients had poor QOL, respectively. Hyperandrogenism remained untreated in 273 (79.8%) patients, among whom 248 had poor QOL. Depression, obesity, and hypertension were not appropriately managed in 247 (90.8%), 330 (94%), and 43 (49.4%) patients, among whom 215, 293, and 35 patients had poor QOL, respectively. Significant associations were determined using chi-square test (using nominal scale QOL scores such as poor and good) and one-way ANOVA (using QOL score of each patient). Chi-square test showed that QOL scores significantly differed ( p < 0.05) among patients taking infertility drugs, contraceptives, anti-acne drugs, and metformin. Meanwhile, one-way ANOVA revealed that QOL scores significantly differed ( p < 0.05) among patients taking infertility drugs, anti-hirsutism drugs, anti-acne drugs, metformin, and antidepressants. a Chi-square test b One-way analysis of variance In the present study, 33.2% of the patients had infertility; among these, 67.1% were administered clomiphene and letrozole. To determine differences in terms of mean QOL scores between patients receiving clomiphene and those receiving letrozole, one-way ANOVA and Tukey’s post hoc analysis were performed. The results of the post hoc analysis are summarized in Table 7 , and the comparison between mean scores is presented in Fig 3 . ANOVA, analysis of variance; QOL, quality of life; df, degrees of freedom; F; Sig. One-way ANOVA confirmed a significant difference ( p < 0.05) in terms of QOL scores between patients receiving clomiphene and those receiving letrozole. Post hoc analysis revealed differences in terms of mean scores and showed that patients receiving letrozole had higher QOL scores than those receiving clomiphene.

The strengths of the current study include a large, multi-centric patient population, detailed study of all relevant clinical aspects and conditions, and research focus on the clinical and statistical significance of each variable. Moreover, this study is unique because it developed an association of psychometric assessment including QOL with clinically significant conditions. The information collected during a literature review revealed that most currently available studies lack these strengths. The major limitation of the present study is its cross-sectional design, which did not enable a longitudinal study of the long-term effects of drugs and various complications. Another limitation of this study is the lack of adequate financial resources to determine the levels of various significant biochemical parameters, including those of AMH, androgens, triglycerides, high-density lipoproteins, and glucose tolerance. Furthermore, the body mass index could not be determined due to a lack of patient height data. All patients were declared obese/overweight according to their body weight as per the local practices of the participating hospitals.

Patients with PCOS exhibit poor QOL, which is associated with depression, acne, and hirsutism. Therefore, PCOS management guidelines should review the recommendations regarding the use of pharmacological agents for these conditions. The clinical conditions and complications associated with PCOS should be given due importance while selecting appropriate management plans for each patient considering the effects of these conditions on overall morbidity and QOL.

Ethical approval was obtained from the Ethics Review Board of each participating hospital namely Institutional review board for bioethics, (IRBB), KMU Institute of Medical Sciences Kohat, Dr syed javed hussain Abbottabad diabetes medical and infertility clinic, Dr Farzana Tabbasum Babu shifa doctors clinic, Dr Erum Rubab, PTCL health unit, Islamabad and Professor doctor tanveer Shafqat, Lady Reading Hospital, Peshawar. Informed consent was obtained from each patient after explaining the research and its objectives. Patients were included only after they signed the informed consent. All researchers ensured patient data confidentiality and compliance with the Declaration of Helsinki. In this prospective, cross-sectional, observational study, patients with PCOS were included who were admitted to any of the following hospitals or who visited their outpatient departments for a routine checkup: Khyber Medical University, Peshawar; KMU Institute of Medical Sciences, Kohat; PTCL Health Center, Islamabad; Abbottabad Diabetes Medical and Infertility Clinic, Abbottabad; Liaqat Memorial Hospital, Kohat; and Bab-ul-Shifa Clinic, Kohat. The study sample comprised females of reproductive age who met the inclusion criteria based on the NIH 1990 criteria for PCOS and were admitted to or visited the outpatient department of any of the participating hospitals for a routine checkup as well as those who had infertility problems or repeated miscarriages and visited infertility clinics from September 2016 to July 2017. The diagnostic criteria of PCOS on the basis of the NIH 1990 criteria [ 13 – 16 ] include hyperandrogenism and oligoovulation and exclude other disorders mimicking PCOS, such as adult-onset congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting neoplasms. Females were included in the study based on the following inclusion criteria: (a) reproductive age (15–44 years), (b) history of infertility or repeated miscarriage, and (c) diagnosis of PCOS by the consulting gynecologist/physician based on the NIH 1990 criteria. Females were excluded from the study if they met either of the following conditions: (a) age of 45 years and (b) no PCOS diagnosis by the consulting gynecologist/physician. Initially, all patients were diagnosed based on the NIH 1990 criteria as per local practices. The researchers further investigated each patient based on the Rotterdam criteria as well as conducted detailed investigation of menstrual history to identify irregular or absent ovulation and ultrasonography to identify ovarian morphology. The study sample size was determined using the Epi Info StatCalc software [ 21 , 22 ] and a confidence level of 95%. Accordingly, an approximate sample size of 387 was considered statistically significant. After considering 20% of non-response or missing data values, the final required sample size was determined to be 440. The present study used convenience sampling for patient selection. Clinical evaluation of all patients was performed to evaluate improvements in the cardinal symptoms of PCOS, including irregular menstruation, hyperglycemia, obesity, acne, and hirsutism. Furthermore, health risk assessment was performed using data on adverse drug reactions (ADRs), complications, irrational prescribing, underprescribing, and drug–drug interactions. The appropriateness of drug choice and drug–drug interactions were assessed using Physicians’ Desk Reference [ 23 ] and Stockley’s Drug Interaction [ 24 ]. A thorough and comprehensive review of literature was conducted to develop an evidence-based clinical checklist. Furthermore, variables included in the checklist were compared with those reported in previous studies [ 25 , 26 ] and discussed in a focus group comprising clinical researchers and practitioners. The final developed checklist was also subjected to content validity through a pilot study on 20 patients and to a focus group discussion to identify any overlooked variables or clinical scenarios. After validation, the final version of the checklist was used in the study. QOL of each patient was determined using the SF-12 questionnaire, which is a 12-point tool comprising mental and physical health-related aspects [ 27 , 28 ]. Responses obtained from each patient were used to calculate the QOL score following the standard method, with low scores indicating poor QOL and vice versa. All data collected using the clinical checklist and SF-12 questionnaire were recorded in an SPSS spreadsheet after coding and carefully defining all the studied variables. Analysis was then performed in two steps. The first step included descriptive analysis wherein patients’ clinical condition and various variables were analyzed for the respective frequencies, percentages, and measure of central tendency. In the second step, inferential statistics were used to determine the associations among patient- and therapy-related variables, clinical outcomes, and QOL using Pearson’s chi-square test, analysis of variance (ANOVA), and post hoc analysis, with a p -value of <0.05 indicating statistically significance.

(XLSX) Click here for additional data file.