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Reproductive Sciences (Thousand Oaks,... Apr 2024Clomiphene citrate (CC) and letrozole are the predominant medical interventions for the management of infertility in patients with polycystic ovary syndrome (PCOS). To... (Meta-Analysis)
Meta-Analysis Review
Clomiphene citrate (CC) and letrozole are the predominant medical interventions for the management of infertility in patients with polycystic ovary syndrome (PCOS). To comprehensively summarize the evidence, a systematic review and meta-analysis of randomized clinical trials (RCTs) was carried out to assess the effect of letrozole and CC on pregnancy outcomes in PCOS patients. We searched PubMed/MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials from inception to January 2023. We included RCTs conducted on PCOS women comparing letrozole to CC and assessing endometrial thickness, the number and size of follicles, and ovulation and pregnancy rates. The endpoints were summarized as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI) using the random-effects model. Heterogeneity was examined using the I statistic. Fifty trials met our inclusion criteria. The mean endometrial thickness was significantly higher in the letrozole group compared to CC group (SMD: 0.89; 95% CI: 0.49, 1.28; I=97.72%); however, the number of follicles was higher in the CC group (SMD: -0.56; 95% CI: -0.96, -0.17; I=96.34%). Furthermore, letrozole intake induced higher ovulation rate (RR: 1.20; 95% CI: 1.13, 1.26; I=54.49%) and pregnancy rate (RR: 1.44; 95% CI: 1.28, 1.62; I=65.58%) compared to CC. Compared to CC, letrozole has a positive effect on endometrial thickness, monofollicular development, and ovulation and pregnancy rates suggesting that letrozole may be a strong alternative to CC as a first-line medical intervention for chronic anovulation in PCOS women. Larger studies are warranted to further clarify these findings.
Topics: Pregnancy; Female; Humans; Letrozole; Pregnancy Outcome; Polycystic Ovary Syndrome; Fertility Agents, Female; Infertility, Female; Birth Rate; Ovulation Induction; Clomiphene; Pregnancy Rate
PubMed: 38030814
DOI: 10.1007/s43032-023-01404-8 -
Cureus Oct 2023In females with polycystic ovarian syndrome (PCOS), the most prevalent endocrine condition is chronic anovulation and hyperandrogenism. This illness influences females... (Review)
Review
In females with polycystic ovarian syndrome (PCOS), the most prevalent endocrine condition is chronic anovulation and hyperandrogenism. This illness influences females from conception to death, posing several risks to the health of a female, thus reducing the quality of life. It also increases the rates of mortality and morbidity. The first years of puberty are when PCOS symptoms first show. Menstrual irregularities, anovulation, and acne are features of both PCOS and typical puberty in females. There are many various phenotypes that fall under the same illness, so it is necessary to examine each one independently because they may need different treatments and result in different outcomes. Depending on the diagnostic criteria, approximately 6%-20% of females in the reproductive age group are believed to be affected by PCOS. As long as PCOS is still a syndrome, no single diagnostic indicator, such as hyperandrogenism or polycystic ovary (PCO), can be used to make a clinical diagnosis. The management of females with PCOS depends on the symptoms. These could include menstruation problems, androgen-related symptoms, or infertility caused by ovulatory disruption. In females with PCOS, anovulation is linked to low follicle-stimulating hormone (FSH) levels and a halt in antral follicle growth during the last stages of maturation. The condition may be treated surgically with laparoscopic ovarian drilling or medically with medications such as aromatase inhibitors, metformin, glucocorticoids, clomiphene citrate (CC), tamoxifen, or gonadotropins. Patients will experience different androgenic symptoms, such as hirsutism, acne, and/or baldness. Patients who appear with these troubling symptoms need to receive appropriate care. The review emphasizes the role it plays in the management of various conditions.
PubMed: 38021970
DOI: 10.7759/cureus.47408 -
Human Reproduction (Oxford, England) Jan 2024What is the current burden of infertility attributable to PCOS at global, regional, and national levels by age and socio-demographic index (SDI) across 21 regions and...
STUDY QUESTION
What is the current burden of infertility attributable to PCOS at global, regional, and national levels by age and socio-demographic index (SDI) across 21 regions and 204 countries and territories?
SUMMARY ANSWER
The burden of infertility attributable to PCOS increased from 6.00 million prevalent cases in 1990 to 12.13 million in 2019 globally and increased sharply in most regions and nations.
WHAT IS KNOWN ALREADY
PCOS is the most common cause of anovulatory infertility, affecting up to 80% of women with anovulation. No comprehensive and detailed epidemiological estimates of infertility attributable to PCOS in reproductive women aged 15-49 years by age and SDI, at the global, regional, and national level, have been reported.
STUDY DESIGN, SIZE, DURATION
An age- and SDI-stratified systematic analysis of the prevalence and years lived with disability (YLD) of infertility attributable to PCOS across 21 regions and 204 countries and territories from 1990 to 2019 has been performed.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The prevalence and YLD of female infertility attributable to PCOS in reproductive women aged 15-49 years from 1990 to 2019 were retrieved directly from the Global Burden of Diseases 2019. The number, rates per 100 000 persons, and average annual percentage changes (AAPCs) of prevalence and YLD were estimated at the global, regional, and national levels.
MAIN RESULTS AND THE ROLE OF CHANCE
Globally, the prevalent cases of infertility attributable to PCOS among women of reproductive age (15-49 years) doubled from 1990 to 2019, with 6.00 million prevalent cases in 1900 and 12.13 million in 2019. The global age-standardized prevalence rates (ASPRs) of infertility attributable to PCOS were 223.50/100 000 persons in 1990 and 308.25/100 000 persons in 2019. At global level, the YLDs of infertility attributable to PCOS increased by 98.0% from 35.20 thousand in 1990 to 69.70 thousand in 2019. The burden of infertility attributable to PCOS in the high SDI region was significantly higher than that in the other four SDI regions. The greatest annual increases in rates of ASPR and age-standardized YLD rate were observed in the middle SDI region (AAPC 1.96 [95% CI 1.87-2.06], 1.94 [1.87-2.00], respectively) and the low-middle SDI region (AAPC 1.96 [1.90-2.03], 1.90 [1.85-1.94], respectively). The regional highest ASPR and the age-standardized YLD rate of infertility were observed in High-income Asia Pacific. The national highest ASPR and the age-standardized YLD rate of infertility were observed in Italy. Positive associations were observed between these burden estimates and the SDI level (all P < 0.001).
LIMITATIONS, REASONS FOR CAUTION
Although the Global Burden of Diseases 2019 has tried its best to collect all available data, some countries have limited data, which may result in an underestimation of the burden of infertility attributable to PCOS. The diagnostic criteria of PCOS are constantly changing, which may induce bias in infertility attributable to PCOS. No information on the PCOS phenotype is provided in the Global Burden of Diseases 2019, so we cannot estimate the infertility attributable to a specific PCOS phenotype. Detection bias would lead to a higher prevalence of PCOS and infertility attributable to PCOS in developed countries with well-established medical systems and greater willingness of the populace to seek medical attention. Thus, health resource allocation for infertility attributable to PCOS in low-prevalence areas should not be ignored.
WIDER IMPLICATIONS OF THE FINDINGS
The global burden of infertility attributable to PCOS increased sharply from 1990 to 2019. Effective health interventions and efficient preventative and managerial strategies should be established to reduce the burden of infertility attributable to PCOS. Weight control is suggested to reduce the burden of infertility attributable to PCOS, especially in the high SDI region.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the National Key Research and Development Program of China (grant number, 2022YFC2704100) and the National Natural Science Foundation of China (Nos 82001498 and 82371648). The authors declare no competing interests.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Humans; Female; Quality-Adjusted Life Years; Polycystic Ovary Syndrome; Global Burden of Disease; Prevalence; Global Health; Infertility
PubMed: 38011904
DOI: 10.1093/humrep/dead241 -
Clinics (Sao Paulo, Brazil) 2023PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would... (Review)
Review
PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would be a component of the environmental factor in the etiology of PCOS. Contamination by BPA can occur from food packaging (exposure during the diet) and through skin absorption and/or inhalation. It can be transferred to the fetus via the placenta or to the infant via breast milk, and it can be found in follicular fluid, fetal serum, and amniotic fluid. The phenolic structure of BPA allows it to interact with Estrogen Receptors (ERs) through genomic signaling, in which BPA binds to nuclear ERα or Erβ, or through nongenomic signaling by binding to membrane ERs, prompting a rapid and intense response. With daily and constant exposure, BPA's tendency to bioaccumulate and its ability to activate nongenomic signaling pathways can alter women's metabolic and reproductive function, leading to hyperandrogenism, insulin resistance, obesity, atherogenic dyslipidemia, chronic inflammatory state, and anovulation and favoring PCOS. The harmful changes caused by BPA can be passed on to future generations without the need for additional exposure because of epigenetic modifications. Not only high BPA levels can produce harmful effects, but at low levels, BPA may be harmful when exposure occurs during the most vulnerable periods, such as the fetal and neonatal periods, as well as during the prepubertal age causing an early accumulation of BPA in the body. Learning how BPA participates in the pathogenesis of PCOS poses a challenge and further studies should be conducted.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Anovulation; Phenols
PubMed: 38008036
DOI: 10.1016/j.clinsp.2023.100310 -
Reproductive Biology and Endocrinology... Nov 2023Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. This disorder affects 6-15% of women of childbearing age worldwide. It is diagnosed with...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. This disorder affects 6-15% of women of childbearing age worldwide. It is diagnosed with hyperandrogenism, polycystic ovaries, and chronic anovulation with insulin resistance. This study aimed to assess the prevalence of insulin resistance (IR) in 4 phenotypes of PCOS, and its relationship with demographic, clinical, and paraclinical individual characteristics in a sample of Iranian PCOS patients.
METHODS
This particular cross-sectional investigation involved 160 female participants, aged between 18 and 45 years, who were receiving care at gynecology clinics in Urmia, northwestern Iran. All the participants had been diagnosed with PCOS and were categorized into one of four phenotypes. All the participants underwent clinical evaluations, paraclinical assessments, and ultrasound scans. IR was defined as HOMA-IR > 2.5. The statistical significance level was 0.05.
RESULTS
Among the 160 participants, the prevalences of the 4 phenotypes were: A: 83 (51.9%), B: 37 (23.1%), C: 21 (13.1%), and D: 19 (11.9%). IR was detected in 119 participants (74.4%); its rate was significantly different between the 4 phenotypes (p-value: 0.008) as A: 62 (74.7%), B: 34 (91.9%), C: 12 (57.1%), D: 11 (57.9%). Linear and logistic regression analyses were performed to control confounding factors. In linear regression, PCOS phenotype, classic phenotype (A&B), economic status, and Hb levels were significantly related to HOMA-IR; in logistic regression Hb levels, exercise, economic status, and PCOS phenotypes were significantly associated with insulin resistance.
CONCLUSIONS
The most prevalent PCOS phenotype in this study was A. PCOS phenotypes were significantly related to insulin resistance and HOMA-IR, with the highest levels of insulin resistance and HOMA-IR observed in phenotype B. Determining the phenotype of PCOS may be helpful for better management of PCOS and its associated complications. However, further investigations are recommended in this regard.
Topics: Humans; Female; Adolescent; Young Adult; Adult; Middle Aged; Polycystic Ovary Syndrome; Insulin Resistance; Cross-Sectional Studies; Iran; Phenotype; Insulin
PubMed: 38001527
DOI: 10.1186/s12958-023-01160-z -
Reproductive Biology and Endocrinology... Nov 2023Polycystic ovary syndrome (PCOS) is a heterogeneous functional endocrine disorder associated with a low-grade, chronic inflammatory state. Patients with PCOS present an... (Review)
Review
Polycystic ovary syndrome (PCOS) is a heterogeneous functional endocrine disorder associated with a low-grade, chronic inflammatory state. Patients with PCOS present an increased risk of metabolic comorbidities and often menstrual dysregulation and infertility due to anovulation and/or poor oocyte quality. Multiple mechanisms including oxidative stress and low-grade inflammation are believed to be responsible for oocyte deterioration; however, the influence of nitric oxide (NO) insufficiency in oocyte quality and ovulatory dysfunction in PCOS is still a matter for debate. Higher production of superoxide (O) mediated DNA damage and impaired antioxidant defense have been implicated as contributory factors for the development of PCOS, with reported alteration in superoxide dismutase (SOD) function, an imbalanced zinc/copper ratio, and increased catalase activity. These events may result in decreased hydrogen peroxide (HO) accumulation with increased lipid peroxidation events. A decrease in NO, potentially due to increased activity of NO synthase (NOS) inhibitors such as asymmetric dimethylarginine (ADMA), and imbalance in the distribution of reactive oxygen species (ROS), such as decreased HO and increased O, may offset the physiological processes surrounding follicular development, oocyte maturation, and ovulation contributing to the reproductive dysfunction in patients with PCOS. Thus, this proposal aims to evaluate the specific roles of NO, oxidative stress, ROS, and enzymatic and nonenzymatic elements in the pathogenesis of PCOS ovarian dysfunction, including oligo- anovulation and oocyte quality, with the intent to inspire better application of therapeutic options. The authors believe more consideration into the specific roles of oxidative stress, ROS, and enzymatic and nonenzymatic elements may allow for a more thorough understanding of PCOS. Future efforts elaborating on the role of NO in the preoptic nucleus to determine its influence on GnRH firing and follicle-stimulating hormone/Luteinizing hormone (FSH/LH) production with ovulation would be of benefit in PCOS. Consequently, treatment with an ADMA inhibitor or NO donor may prove beneficial to PCOS patients experiencing reproductive dysfunction and infertility.
Topics: Female; Humans; Polycystic Ovary Syndrome; Luteinizing Hormone; Anovulation; Nitric Oxide; Follicle Stimulating Hormone; Reactive Oxygen Species; Hydrogen Peroxide; Infertility; Oxidative Stress
PubMed: 37996893
DOI: 10.1186/s12958-023-01159-6 -
Journal of Ovarian Research Nov 2023The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout...
The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout mice have irregular cycles and subfertility and variants in or around the PRLR gene were associated in humans with female testosterone levels and recurrent miscarriage. We tested 40 variants in the PRLR gene in 212 Italian families phenotyped by type 2 diabetes (T2D) and PCOS and found two intronic PRLR-variants (rs13436213 and rs1604428) significantly linked to and/or associated with the risk of PCOS. This is the first study to report PRLR as a novel risk gene in PCOS. Functional studies are needed to confirm these results.
Topics: Humans; Female; Animals; Mice; Polycystic Ovary Syndrome; Receptors, Prolactin; Prolactin; Diabetes Mellitus, Type 2; Infertility; Hyperandrogenism
PubMed: 37993904
DOI: 10.1186/s13048-023-01280-5 -
Journal of Ovarian Research Nov 2023The objective of this study is to investigate the effects of an ethanolic extract derived from Agaricus subrufescens on rat models exhibiting Polycystic Ovarian Syndrome...
OBJECTIVE
The objective of this study is to investigate the effects of an ethanolic extract derived from Agaricus subrufescens on rat models exhibiting Polycystic Ovarian Syndrome (PCOS) induced by Letrozole.
METHODS
A total of thirty female Wistar rats were divided into five groups, each consisting of six rats. The negative control group was administered a volume of 1 mL of a 0.5% solution of carboxy methylcellulose (CMC). Letrozole (1 mg/kg) was administered to additional groups for a duration of 21 days in order to induce polycystic ovary syndrome (PCOS). Animals designated as positive controls were euthanized on the 22nd day. Both the test group and the standard group were subjected to treatment from the 22nd day to the 36th day. The experimental group was administered ethanolic extract of Agaricus subrufescens at doses of 200 mg/kg and 400 mg/kg p.o, while the control group received clomiphene citrate at a dose of 1 mg/kg. The study observed various physiological markers in individuals with polycystic ovarian disease, including estimated blood glucose levels, total cholesterol levels, triglyceride levels, and hormonal fluctuations such as increased testosterone and estrogen levels, as well as decreased progesterone levels. The presence of menstrual irregularities was confirmed through the examination of vaginal smears and histopathological changes in the ovaries.
RESULTS
The consumption of Agaricus subrufescens was found to have a significant impact on various physiological parameters, including blood glucose levels, testosterone levels, anovulation, and menstrual irregularity. All therapeutic interventions significantly normalized the levels of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT). The rats with polycystic ovary syndrome (PCOS) that were induced by Letrozole exhibited increased levels of urea and creatinine. The findings of this study indicate that the administration of Agaricus subrufescens therapy has a protective effect on renal function, as evidenced by a reduction in serum levels of urea and creatinine. In rats with polycystic ovary syndrome (PCOS) induced by Letrozole, the inhibition of hepatic synthesis, promotion of ovarian follicle immaturity, and elevation of androgen secretions result in an increase in the weight of the liver and ovaries. The weight of endocrine organs exhibited a decrease across all treatment groups. The histopathological examination of PCOS specimens revealed an increased presence of cysts and theca lutein cells. The group of rats with polycystic ovary syndrome (PCOS) that did not receive treatment exhibited a higher number of cysts compared to the groups that received treatment.
CONCLUSION
This study demonstrated that the administration of Letrozole orally resulted in the development of polycystic ovarian disease. The results indicated heightened levels of blood glucose, total cholesterol, and triglycerides, as well as alterations in hormone levels such as increased testosterone and estrogen, and decreased progesterone. These hormonal changes were accompanied by menstrual irregularities, which were confirmed through the examination of vaginal smears and histopathological analysis of the ovaries in the control group with polycystic ovarian disease. The treatment groups that received Agaricus subrufescens exhibited a decrease in blood glucose, total cholesterol, and testosterone levels.
Topics: Humans; Rats; Female; Animals; Polycystic Ovary Syndrome; Letrozole; Progesterone; Blood Glucose; Creatinine; Rats, Wistar; Estrogens; Menstruation Disturbances; Testosterone; Cholesterol; Urea
PubMed: 37993900
DOI: 10.1186/s13048-023-01311-1 -
BMC Women's Health Nov 2023The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile women with ovulatory dysfunction.
METHODS
A randomized controlled trial was conducted at a single academic medical center between November 2020 and December 2021. Anovulatory infertility females, aged 18 to 40, were evenly distributed by a computer-generated block of four into two treatment groups. A "combination group" received a daily dose of CC (50 mg) and letrozole (2.5 mg), while a "CC-alone group" received a daily dose of CC alone (50 mg). The study medications were administered on days 3 through 7 of menstrual cycle. The primary outcome was the ovulation rate, defined by serum progesterone levels exceeding 3 ng/mL at the mid-luteal phase. The secondary outcomes were ovulation induction cycle characteristics, endometrial thickness, conception rate, and adverse events.
RESULTS
One hundred women (50 per group) were enrolled in the study. The mean age was not significantly different in both groups: 31.8 years in the combination group and 32.4 years in the CC-alone groups (P = 0.54). The prevalence of polycystic ovary syndrome in the combination and CC-alone groups was 48% and 44%, respectively (P = 0.841). According to intention-to-treat analysis, the ovulation rates were 78% and 70% in the combination and CC-alone groups, respectively (P > 0.05). There was no significant difference in the mean endometrial thickness or the number of dominant follicles of the groups. No serious adverse events were observed in either group.
CONCLUSIONS
Our study found no significant difference between the combination of CC and letrozole and CC alone in inducing ovulation in infertile women with ovulatory dysfunction in one cycle. The small number of live births precluded any meaningful statistical analysis. Further studies are needed to validate and extend our findings beyond the scope of the current study.
TRIAL REGISTRATION
The study was registered at https://www.thaiclinicaltrials.org with the following number: TCTR20201108004 and was approved on 08/11/2020.
Topics: Pregnancy; Female; Humans; Letrozole; Infertility, Female; Fertility Agents, Female; Pregnancy Rate; Clomiphene; Ovulation Induction; Polycystic Ovary Syndrome; Live Birth
PubMed: 37964246
DOI: 10.1186/s12905-023-02773-7 -
Human Reproduction (Oxford, England) Jan 2024The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained...
The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.
Topics: Pregnancy; Female; Adolescent; Humans; Adult; Endometriosis; Adenomyosis; Amenorrhea; Secondary Prevention; Menstruation
PubMed: 37951243
DOI: 10.1093/humrep/dead229