For couples of childbearing age, the conception rate per menstrual cycle is approximately 25%, with around 85%–90% of couples achieving pregnancy within one year. Infertility is defined as the inability to conceive after at least 12 months of regular, unprotected intercourse, applying to females. In males, the condition is referred to as sterility. Infertility can be classified into primary and secondary types. Primary infertility refers to cases where no prior pregnancies have occurred, whereas secondary infertility refers to cases where infertility develops after a previous pregnancy. Unlike irreversible sterility, infertility is a relative, time-dependent concept involving various causes that result in reproductive difficulties. There is no significant variation in infertility prevalence across different ethnicities or geographic regions.
Etiology
Female Factors
These include:
- Pelvic Factors: These are the most common causes of secondary infertility, accounting for approximately 35% of all infertility cases. Common causes include:
- Tubal Disorders: Tubal obstruction, adhesions around the tubes, hydrosalpinx, and impaired tubal function.
- Uterine Pathologies: Conditions such as endometrial abnormalities, uterine fibroids, adenomyosis, and intrauterine adhesions.
- Cervical Factors: Congenital abnormalities of the cervical canal, cervical stenosis or atresia, and abnormal cervical mucus.
- Endometriosis: The mechanism by which endometriosis causes infertility is not fully understood. Potential factors include abnormalities in ovulation, tubal function, fertilization, luteal function, or endometrial receptivity.
- Reproductive Tract Developmental Abnormalities: Conditions such as septate uterus, bicornuate uterus, double uterus, and congenital tubal malformations.
- Ovulation Disorders: These account for 25%–35% of female infertility cases. Causes include:
- Hypothalamic dysfunction, such as hypogonadotropic hypogonadism and anovulation.
- Pituitary disorders, such as hyperprolactinemia.
- Ovarian dysfunction, such as polycystic ovary syndrome, premature ovarian insufficiency, congenital gonadal dysgenesis, and ovarian failure caused by chemotherapy or radiotherapy.
- Other endocrine disorders, such as congenital adrenal hyperplasia or thyroid dysfunction.
- Ovarian Aging: With advancing age, especially after 35–37 years, there is a progressive depletion of FSH-sensitive follicles in the ovaries, while the proportion of FSH-insensitive aged follicles increases. This leads to a reduction in both the quantity and quality of oocytes.
Male Factors
These include:
- Abnormal Semen Parameters: Semen abnormalities can be categorized into issues involving sperm (quantity, quality, or morphology) and seminal fluid. Manifestations include oligospermia, asthenospermia, teratozoospermia, azoospermia, and isolated seminal plasma abnormalities.
- Sexual Dysfunction: Causes include organic or psychological conditions, such as erectile dysfunction, anejaculation, retrograde ejaculation, or insufficient coital frequency due to arousal disorders.
- Other Factors: Immune factors may contribute; however, no definitive clinical diagnostic criteria currently exist.
Unexplained Infertility
Couples may be diagnosed with unexplained infertility when routine infertility evaluations, including semen analysis, ovulation assessment, gynecological examination, and tubal patency tests, fail to identify any abnormalities. Unexplained infertility represents a condition of subfertility where neither male nor female factors can be clearly excluded; it accounts for 10%–20% of infertility cases. Potential causes may include immune factors, subtle tubal issues, underlying oocyte abnormalities, problems with fertilization, disrupted embryonic development, implantation failure, and genetic defects. Current clinical testing methods lack specificity to identify these underlying causes. Even when issues with gametes, embryos, or implantation are observed during in vitro fertilization and embryo transfer (IVF-ET), determining the precise etiology remains challenging.
Diagnosis
For individuals meeting the definition of infertility and exhibiting a history of diseases or clinical manifestations affecting fertility, evaluations for both partners are generally conducted concurrently. The diagnosis is primarily based on medical history, assessment of ovulation function, tubal patency, and semen analysis.
Male Evaluation
Medical History Collection
This includes the duration of infertility, the presence of sexual or ejaculatory dysfunction, prior infertility evaluations and treatments, history of illnesses such as mumps or diabetes, history of surgeries such as vasectomy, personal history (e.g., exposure to high-temperature environments, smoking, alcohol abuse, and drug use), and family history.
Physical Examination
Both general physical and reproductive system examinations are included.
Semen Analysis
This is the primary diagnostic test for infertile couples. It is conducted in accordance with the "World Health Organization Laboratory Manual for the Examination and Processing of Human Semen" (6th edition), requiring 2–3 separate analyses to confirm semen quality.
Additional Tests
These may include hormone testing, ultrasound imaging of the reproductive system, and genetic screening.
Female Evaluation
Medical History Collection
A comprehensive evaluation of infertility-related history is required, including current illness history, past medical history, menstrual history, sexual history, marital and reproductive history, personal history, family history, and other relevant medical history.
Physical Examination
General physical examination should evaluate physical development and nutritional status, including height, weight, body fat distribution, breast development, and thyroid condition. Observations for skin changes such as hirsutism, acne, or acanthosis nigricans are also necessary.
Gynecological examination should assess the development of the external genitalia, pubic hair distribution, clitoral size, the condition of the vagina and cervix (e.g., discharge or abnormal secretions), and the position, size, texture, mobility of the uterus, as well as pelvic conditions such as thickened adnexa, masses, or tenderness. Additional checks include rectouterine pouch tenderness or nodules, as well as any abdominal tenderness, rebound tenderness, or palpable masses.
Infertility-Related Auxiliary Examinations
Ultrasound Examination
Gynecological ultrasound is used to assess uterine and ovarian size, position, shape, and the presence of abnormalities such as nodules, cysts, or solid masses.
Ovulation monitoring involves counting antral follicles measuring 2–9 mm in diameter to evaluate ovarian reserve, tracking the development of dominant follicles, and assessing the concurrent thickness and morphology of the endometrium.
Hormone Testing
Anti-Müllerian hormone (AMH) serves as an effective indicator of ovarian reserve.
For women with ovulatory dysfunction or those aged ≥35 years, measurements of baseline levels of FSH, LH, E2, T, PRL, and P should be performed on days 2–4 of the menstrual cycle.
Assessment of LH levels during the ovulatory phase aids in predicting ovulation timing, while P levels during the luteal phase help determine whether ovulation occurs and evaluate luteal function.
Tubal Patency Assessment
Hysterosalpingography (HSG) is the preferred method for evaluating tubal patency and is generally performed 3–7 days after menstruation has ended, in the absence of contraindications. HSG also provides insights into uterine cavity abnormalities. In addition, three-dimensional real-time ultrasound hysterosalpingography is another reliable method for assessing tubal patency.
Other Examinations
Basal body temperature monitoring may suggest ovulation with biphasic patterns, but it is insufficient as a standalone diagnostic tool.
Hysteroscopy and laparoscopy are appropriate for patients whose examinations (physical, ultrasound, and/or tubal patency tests) indicate uterine cavity or pelvic abnormalities. These procedures help define the location and severity of lesions and enable treatment if necessary.
Chromosomal karyotype analysis is applicable for couples with unexplained infertility, recurrent pregnancy loss, or a history of births involving congenital anomalies.
Treatment of Female Infertility
Female fertility is closely associated with age, and treatment plans should account for the patient's ovarian physiological age to devise individualized approaches that are reasonable, safe, and effective. Patients with obesity, low body weight, unhealthy lifestyle habits (such as smoking), or a history of exposure to harmful environments may benefit from lifestyle modifications as a primary step. Systemic diseases affecting the body should be corrected or treated as part of the management. For patients without organic diseases, addressing abnormal sexual practices may involve providing guidance to help them understand ovulation patterns, regulate sexual frequency, and optimize timing to improve the chances of conception.
For individuals with a clear etiological diagnosis, treatment options should target the underlying causes.
Correction of Organic Pelvic Disorders
Tubal Disorders
Expectant Management
For younger couples with a infertility duration of less than three years, normal semen parameters, and well-functioning ovaries, expectant management involving natural conception attempts for 3–6 months may be considered if there is mild obstruction at the tubal fimbriae.
Tubal Reconstruction Surgery
For cases involving peri-tubal adhesions, distal obstruction, or mild hydrosalpinx, laparoscopic procedures such as tubal salpingostomy or adhesion lysis may restore normal tubal anatomy and improve functional patency. For obstruction of the intramural or isthmic segments, transcervical tubal recanalization procedures may be performed. Post-surgery, natural conception is typically attempted for 6–12 months, and assisted reproductive technologies like intrauterine insemination (IUI) or in vitro fertilization and embryo transfer (IVF-ET) are considered for patients who remain infertile. Severe hydrosalpinx, particularly cases accompanied by significant vaginal discharge, may warrant tubal removal or ligation to mitigate adverse effects of inflammatory hydrosalpinx on the endometrium and create favorable conditions for subsequent IVF-ET.
Uterine Disorders
Submucosal fibroids, larger intramural fibroids, endometrial polyps, intrauterine adhesions, and uterine septa significantly affecting uterine cavity morphology may necessitate surgical intervention. Following surgery, the choice between natural conception attempts and assisted reproductive technologies should be guided by infertility evaluations. For patients with adenomyosis resulting in uterine enlargement without significant cavity distortion, treatment with GnRH agonists for 2–3 cycles is recommended to reduce uterine size prior to assisted reproductive approaches. In cases involving marked cavity distortion, insufficient uterine miniaturization, or poor IVF-ET outcomes, adenomyosis lesions and uterine reconstruction may be needed before IVF-ET is undertaken.
Ovarian Tumors
Non-neoplastic ovarian cysts or benign ovarian tumors presenting surgical indications may require removal. Any ovarian mass with uncertain nature should first undergo diagnostic clarification, and exploratory surgery is performed if necessary. Pathological findings guide the choice of surgical approach, and depending on outcomes, natural conception efforts or assisted reproductive technologies may follow.
Endometriosis
Laparoscopy is effective for diagnosing and treating endometriosis. However, caution is required for recurrent endometriosis or cases accompanied by significant ovarian dysfunction. Medications aimed at ovarian suppression do not improve pregnancy rates in endometriosis-related infertility. For women at rASRM stage I/II with an EFI score >4 and patent fallopian tubes, ovulation induction combined with IUI is recommended over expectant management or standalone IUI. Women at rASRM stage III/IV with EFI ≤4, including those with deep infiltrating endometriosis, are better served by IVF-ET. In cases where tubal patency exists, ovulation induction with IUI may be considered, though its efficacy remains uncertain. For recurrent ovarian endometriotic cysts with no malignant signs based on clinical assessment, IVF-ET may be directly pursued. If the cyst's position impairs egg retrieval, ultrasound-guided aspiration may be performed.
Reproductive Tract Tuberculosis
During the active phase of pelvic tuberculosis, anti-tuberculosis therapy should be implemented, and pregnancy should be avoided during the drug treatment and sensitivity stages. For uterine and tubal sequelae resulting from pelvic tuberculosis, IVF-ET may be considered based on an evaluation of endometrial conditions.
Ovulation Induction
Clomiphene Citrate (CC)
Clomiphene citrate competitively binds to estrogen receptors in the hypothalamus and pituitary gland, inhibiting negative feedback induced by estrogen, thereby increasing gonadotropin secretion and promoting follicular growth. It is suitable for patients with an intact hypothalamic–pituitary–ovarian feedback mechanism and a baseline level of endogenous estrogen. The recommended dosage is 50 mg per day (maximum dose not exceeding 150 mg/day), starting on days 3–5 of the menstrual cycle and continuing for 5 days. The ovulation rate may reach 70%–80%, and the pregnancy rate per cycle is approximately 20%–30%. Vaginal ultrasound monitoring of follicle development is typically recommended, and, when necessary, urinary gonadotropins may be used during the follicular phase to further stimulate follicular growth. A single dose of human chorionic gonadotropin (hCG) may be administered to induce ovulation when follicles are mature. Luteal phase support is provided for 12–14 days post-ovulation using natural progesterone formulations.
Letrozole (LE)
Letrozole, an aromatase inhibitor, blocks the conversion of androgens to estrogens, resulting in lower estrogen levels that reduce negative feedback on the hypothalamus and pituitary gland, thereby increasing gonadotropin secretion and promoting follicular development. Letrozole's indications and usage mirror those of clomiphene citrate, with a typical dosage of 2.5–5 mg/day. Ovulation induction and luteal support protocols remain consistent with clomiphene citrate.
Human Menopausal Gonadotropin (hMG)
Derived from the urine of postmenopausal women, hMG is also known as postmenopausal gonadotropin. The medication theoretically contains 75 IU each of FSH and LH per 75 IU preparation. Treatment begins on days 2–3 of the menstrual cycle, with intramuscular injections of 75–150 IU administered daily or every other day until follicular maturity is achieved. Ultrasound monitoring of follicle growth, often accompanied by serum estrogen level measurement, is required during treatment. Once follicles mature, hCG is administered to induce ovulation and luteinization. Luteal support protocols post-ovulation are consistent with those outlined previously.
Human Chorionic Gonadotropin (hCG)
Similar in structure to LH, hCG is often used to simulate endogenous LH surges when follicles have reached maturity, thus inducing ovulation. A single dose of 5,000–10,000 IU is administered via intramuscular injection. hCG may also be used for luteal support therapy.
Bromocriptine
Bromocriptine, a dopamine receptor agonist, inhibits pituitary prolactin (PRL) secretion and is effective for treating ovulatory disorders caused by hyperprolactinemia. The starting dosage is 1.25 mg/day and may be increased to 2.5 mg/day as needed. Serum PRL levels are typically reevaluated every 3–6 months, with treatment continued for 1–2 years if necessary.
Treatment of Unexplained Infertility
For women younger than 35 years of age with an infertility history of less than 2 years, expectant management for 6–12 months may be considered. If conception does not occur during this period, active treatments should be undertaken. Couples who fail expectant management despite female age being under 35 years may consider ovulation induction combined with intrauterine insemination (IUI) using the husband’s sperm. If pregnancy is not achieved across 3–6 cycles of treatment, IVF-ET should be considered. For women over 35 years of age with a prolonged infertility history (>3 years), combinations of ovulation induction with IUI or direct IVF-ET may be considered.
Assisted Reproductive Technologies
These include methodologies such as intrauterine insemination (IUI), in vitro fertilization and embryo transfer (IVF-ET), and other derivative techniques.
Principles for the Treatment of Male Infertility
Given the diverse and complex causes of male infertility, treatment plans depend on the specific circumstances. Priority is typically given to less invasive treatments, such as medications or intrauterine insemination. More complex interventions, including epididymal and testicular surgeries or advanced assisted reproductive technologies like IVF-ET and related techniques, may be considered when necessary.