From the Guidelines
Female infertility is primarily caused by disruptions in the complex reproductive process, with ovulatory disorders, tubal and pelvic pathology, uterine factors, and cervical factors being the main contributors to its pathophysiology. The pathophysiology of female infertility involves multiple systems and can be attributed to various factors, including hormonal imbalances, structural blockages, and age-related decline in egg quality and quantity. According to the most recent evidence 1, the most common causes of female infertility include ovulatory failure (21%), tubal damage (14%), and unexplained infertility (28%).
Key Factors Contributing to Female Infertility
- Ovulatory disorders, such as polycystic ovary syndrome (PCOS), which affects at least 7% of adult women 1 and is characterized by elevated androgens and insulin resistance
- Tubal and pelvic pathology, including structural blockages or damage to fallopian tubes from infections like pelvic inflammatory disease, endometriosis, or adhesions from previous surgeries
- Uterine factors, such as congenital abnormalities, fibroids, polyps, or adenomyosis, which can interfere with implantation
- Cervical factors, including abnormal mucus production that hinders sperm penetration
- Age-related fertility decline, with egg quality and quantity diminishing after age 35, and accelerating after 37
Diagnostic Approaches
Imaging techniques, such as transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI), can be used to diagnose polycystic ovarian morphology (PCOM) and other conditions contributing to female infertility 1. TVUS is considered the most reliable method for diagnosing PCOM, with criteria including 25 follicles that are 2 to 9 mm in diameter, in at least one ovary, and an ovarian volume >10 mL 1.
Clinical Considerations
It is essential to consider the clinical features and history of each patient when evaluating female infertility, as the diagnosis and treatment of underlying conditions can significantly impact fertility outcomes. The 2014 report by the Androgen Excess and Polycystic Ovary Syndrome Society provides updated criteria for diagnosing PCOS, which includes clinical features, such as hyperandrogenism and infertility, in addition to PCOM 1. A comprehensive evaluation, including medical history, physical examination, and imaging studies, is necessary to determine the underlying cause of female infertility and develop an effective treatment plan.
From the FDA Drug Label
CLINICAL PHARMACOLOGY Action Clomiphene citrate is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiphene citrate has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy Clomiphene citrate is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors Clomiphene citrate initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture.
The pathophysiology of female infertility related to anovulation involves a lack of estrogenic stimulus and subsequent failure to initiate a preovulatory gonadotropin surge. Clomiphene citrate works by interacting with estrogen-receptor-containing tissues, competing with estrogen for binding sites, and initiating a series of endocrine events that culminate in ovulation. Key factors in the pathophysiology of female infertility that clomiphene citrate addresses include:
- Hypothalamic-pituitary-ovarian axis dysfunction
- Anovulation due to lack of estrogenic stimulus
- Impaired folliculogenesis and steroidogenesis 2
From the Research
Pathophysiology of Female Infertility
The pathophysiology of female infertility is complex and multifactorial. It can be attributed to various causes, including:
- Ovulatory disorders: These disorders can be caused by hormonal imbalances, polycystic ovary syndrome (PCOS), or other factors 3, 4, 5, 6.
- Tubal disease: Damage to the fallopian tubes can prevent fertilization or implantation of the embryo 3, 7.
- Endometriosis: This condition can cause inflammation, scarring, and adhesions in the pelvic cavity, leading to infertility 3, 7.
- Uterine or cervical factors: Abnormalities in the uterus or cervix, such as leiomyomata or endometrial polyps, can affect implantation or fertility 3, 7.
- Pelvic adhesions: Scarring or adhesions in the pelvic cavity can prevent the ovaries from releasing eggs or the fallopian tubes from functioning properly 7.
- Mullerian anomalies: Congenital abnormalities of the reproductive tract can affect fertility 7.
Hormonal Imbalance and Ovulation
Hormonal imbalance is a common cause of ovulatory disorders, which can lead to infertility. PCOS is a hormonal disorder that affects 8-13% of women in their reproductive age and is a leading cause of female subfertility 4. Clomiphene citrate and letrozole are commonly used to induce ovulation in women with PCOS, with clomiphene being superior to metformin in achieving live birth 6. However, combination therapy of clomiphene and letrozole may potentially improve fertility outcomes in PCOS subfertility 4, 5.
Diagnostic Evaluation
A careful history and physical examination of each partner can suggest a single or multifactorial etiology and direct further investigation 3. Diagnostic tests, such as hysterosalpingography, pelvic ultrasonography, and hysteroscopy or laparoscopy, can be used to evaluate the female reproductive tract and identify any abnormalities 3, 7. Ovarian reserve testing, such as follicle-stimulating hormone and estradiol levels, can also be used to determine treatment options and the likelihood of success 3.