Polycystic ovary syndrome is the most common endocrinopathy among reproductive-aged women in the United States, affecting approximately 7% of female patients. Although the pathophysiology of the syndrome is complex and there is no single defect from which it is known to result, it is hypothesized that insulin resistance is a key factor. Metabolic syndrome is twice as common in patients with polycystic ovary syndrome compared with the general population, and patients with polycystic ovary syndrome are four times more likely than the general population to develop type 2 diabetes mellitus. Patient presentation is variable, ranging from asymptomatic to having multiple gynecologic, dermatologic, or metabolic manifestations. Guidelines from the Endocrine Society recommend using the Rotterdam criteria for diagnosis, which mandate the presence of two of the following three findingshyperandrogenism, ovulatory dysfunction, and polycystic ovaries-plus the exclusion of other diagnoses that could result in hyperandrogenism or ovulatory dysfunction. It is reasonable to delay evaluation for polycystic ovary syndrome in adolescent patients until two years after menarche. For this age group, it is also recommended that all three Rotterdam criteria be met before the diagnosis is made. Patients who have marked virilization or rapid onset of symptoms require immediate evaluation for a potential androgen-secreting tumor. Treatment of polycystic ovary syndrome is individualized based on the patient's presentation and desire for pregnancy. For patients who are overweight, weight loss is recommended. Clomiphene and letrozole are first-line medications for infertility. Metformin is the first-line medication for metabolic manifestations, such as hyperglycemia. Hormonal contraceptives are first-line therapy for irregular menses and dermatologic manifestations.
Tadesse TM, 2026·Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
To review the mechanism of action, epidemiology, clinical efficacy, factors influencing treatment outcomes, and limitations of clomiphene citrate (CC). A systematic literature search was conducted using electronic databases. The search strategy employed a combination of relevant MeSH terms and keywords. The final selection was limited to complete, peer-reviewed articles. Clomiphene citrate (CC) is the first-line oral ovulation induction agent for WHO Group II anovulation, most commonly polycystic ovary syndrome. It acts primarily at the hypothalamus, depleting estrogen receptors to increase gonadotropin-releasing hormone pulsatility and stimulate gonadotropin release. Although effective in restoring ovulation in approximately 73% of treated women, pregnancy rates remain significantly lower (\~36%), highlighting a pronounced ovulation‒pregnancy gap. This discrepancy is largely attributed to CC's peripheral anti-estrogenic effects, which can cause endometrial suppression and hostile cervical mucus, thereby impairing implantation. Treatment success is influenced by factors such as obesity, insulin resistance, and hyperandrogenism, which are key predictors of CC resistance. While generally well-tolerated, side effects include hot flashes, mood swings, headaches, visual disturbances, and a notable risk of multiple pregnancies (8%-10%). While CC remains a cornerstone for inducing ovulation, its peripheral anti-estrogenic effects and significant rate of resistance necessitate adjunctive strategies, careful patient selection, and a transition to advanced therapies when needed to improve live birth outcomes.
Is sequential letrozole/human menopausal gonadotrophin (HMG) superior to letrozole alone in ovulation induction and pregnancy promotion among infertile women with polycystic ovary syndrome (PCOS)?
This open-label randomized controlled trial comparing sequential letrozole/HMG and letrozole alone included 174 participants enrolled from August 2019 to January 2020 at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. Infertile women aged between 18 and 40 years who met Rotterdam criteria for PCOS and without other known causes of infertility were selected for this study. Patients were randomly assigned at a 1:1 ratio to receive 2.5 mg letrozole on cycle days 3-7 (n = 87) or 2.5 mg letrozole on cycle days 3-7 with a sequential injection of 75 IU HMG on cycle days 8-10 for one treatment cycle (n = 87). The pregnancy outcome was recorded after one treatment cycle.
Women receiving sequential treatment achieved a significantly higher ovulation rate than those in the letrozole group (90.8% versus 70.1%, P = 0.001) and the live birth rate of the sequential group was significantly higher than that of the letrozole protocol (23.0% versus 10.3%, P = 0.025); there was no statistical variation with respect to adverse events. The data suggest that the sequential letrozole/HMG protocol may be superior to the letrozole alone protocol in terms of ovulation induction and pregnancy promotion among infertile women with PCOS.
Costello MF et al., 2019·Aust N Z J Obstet Gynaecol
Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where firstor second-line ovulation induction therapies have failed. This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.
PCOSOvulation InductionLetrozole vs ClomipheneRandomized Controlled Trial