Understanding Infertility: A Comprehensive Review

Understanding Infertility

Learning Objectives

By the end of this lecture, students should be able to:

• Define infertility and understand its epidemiological significance

• Identify the major causes of male and female infertility

• Describe the systematic approach to infertility evaluation

• Outline evidence-based treatment options for various causes of infertility

• Understand the psychological and social impact of infertility

• Recognize when to refer to reproductive endocrinology specialists

I. Definition and Epidemiology

Definition

Infertility is defined as the inability to conceive after 12 months of regular, unprotected sexual intercourse in women under 35 years of age, or after 6 months in women 35 years and older. Primary infertility refers to couples who have never conceived, while secondary infertility affects those who have previously achieved pregnancy but are currently unable to conceive.

Epidemiology

• Affects approximately 10-15% of reproductive-age couples globally

• Incidence increases with maternal age, particularly after age 35

• Male factors contribute to approximately 40-50% of cases

• Female factors account for 40-50% of cases

• Unexplained infertility comprises 10-15% of cases

• Combined male and female factors occur in 20-30% of couples

II. Female Factors in Infertility

A. Ovulatory Disorders (25-30% of female infertility)

1. Polycystic Ovary Syndrome (PCOS)

• Most common cause of anovulatory infertility

• Characterized by hyperandrogenism, irregular cycles, and polycystic ovarian morphology

• Associated with insulin resistance and metabolic dysfunction

• Diagnosis based on Rotterdam criteria (2 of 3): oligoovulation/anovulation, hyperandrogenism, polycystic ovaries on ultrasound

2. Hypothalamic Dysfunction

• Functional hypothalamic amenorrhea due to stress, excessive exercise, or low body weight

• Kallmann syndrome (congenital GnRH deficiency)

• Results in low FSH and LH levels

3. Pituitary Disorders

• Hyperprolactinemia (prolactinomas, medications, hypothyroidism)

• Pituitary adenomas affecting gonadotropin production

• Sheehan syndrome (postpartum pituitary necrosis)

4. Thyroid Disorders

• Both hyperthyroidism and hypothyroidism can affect ovulation

• Thyroid dysfunction may alter menstrual cycles and fertility

5. Premature Ovarian Insufficiency (POI)

• Onset of menopause before age 40

• May be idiopathic, genetic (Turner syndrome, FMR1 premutations), autoimmune, or iatrogenic

• Characterized by elevated FSH levels and low estradiol

B. Tubal and Pelvic Factors (25-35% of female infertility)

1. Tubal Occlusion

• Most commonly due to pelvic inflammatory disease (PID)

• Chlamydia trachomatis and Neisseria gonorrhoeae are primary pathogens

• Can result in complete or partial tubal blockage

• May cause hydrosalpinx formation

2. Endometriosis

• Affects 6-10% of reproductive-age women

• Can cause pelvic adhesions, ovarian cysts, and altered pelvic anatomy

• May impair egg quality and implantation

• Diagnosed definitively by laparoscopy, though imaging can be suggestive

3. Pelvic Adhesions

• Result from previous pelvic surgery, appendicitis, or PID

• Can distort normal pelvic anatomy and interfere with ovum pickup

4. Uterine Abnormalities

• Congenital anomalies: septate uterus, bicornuate uterus, unicornuate uterus

• Acquired conditions: fibroids (particularly submucosal), polyps, intrauterine adhesions (Asherman syndrome)

C. Cervical Factors (Rare, <5%)

• Cervical stenosis from previous procedures (LEEP, cone biopsy)

• Inadequate cervical mucus production

• Anti-sperm antibodies in cervical mucus

III. Male Factors in Infertility

A. Sperm Production Disorders (65-80% of male infertility)

1. Idiopathic Oligoasthenoteratozoospermia

• Most common cause of male infertility

• Characterized by decreased sperm concentration, motility, and/or morphology

• Often multifactorial etiology

2. Varicocele

• Present in 15% of general population, 35% of men with primary infertility

• Causes increased scrotal temperature and oxidative stress

• Most commonly affects left side due to venous anatomy

• Grade III varicoceles most likely to affect fertility

3. Cryptorchidism

• Undescended testes, affecting 1-4% of full-term males

• Risk of infertility increases with bilateral involvement and later surgical correction

• Associated with increased risk of testicular cancer

4. Genetic Causes

• Klinefelter syndrome (47,XXY) - most common genetic cause

• Y-chromosome microdeletions (AZF regions)

• Cystic fibrosis gene mutations (CFTR) - associated with congenital absence of vas deferens

B. Sperm Transport Disorders

1. Obstructive Azoospermia

• Congenital bilateral absence of vas deferens (CBAVD)

• Acquired obstruction from infection, trauma, or previous surgery

• Post-vasectomy status

2. Ejaculatory Dysfunction

• Retrograde ejaculation (diabetes, medications, surgery)

• Premature or delayed ejaculation

• Erectile dysfunction

C. Hormonal Disorders (1-2% of male infertility)

• Hypogonadotropic hypogonadism

• Hyperprolactinemia

• Thyroid disorders

• Androgen resistance

IV. Unexplained Infertility

Defined as infertility in couples with normal ovulation, patent fallopian tubes, adequate sperm parameters, and no other identifiable cause. Represents 10-15% of infertile couples. May involve subtle abnormalities in:

• Egg or sperm quality not detected by standard testing

• Fertilization process

• Implantation mechanisms

• Genetic factors

V. Infertility Evaluation

A. Initial Assessment

History Taking

• Female partner: menstrual history, previous pregnancies, contraceptive use, sexual history, medical/surgical history, medications, lifestyle factors

• Male partner: previous pregnancies with other partners, medical/surgical history, medications, occupational exposures, lifestyle factors

• Couple: duration of infertility, coital frequency and timing, lubricant use

Physical Examination

• Female: BMI, signs of hyperandrogenism, thyroid examination, breast examination, pelvic examination

• Male: BMI, secondary sexual characteristics, genital examination (testicular size, presence of vas deferens, varicocele)

B. Laboratory and Diagnostic Tests

Initial Testing (First-line)

1. Ovulation assessment:

• Serum progesterone level (mid-luteal phase)

• Basal body temperature charting or ovulation predictor kits

• Menstrual history

2. Ovarian reserve testing:

• Anti-Müllerian hormone (AMH)

• Day 3 FSH and estradiol

• Antral follicle count (AFC) via transvaginal ultrasound

3. Tubal patency assessment:

• Hysterosalpingography (HSG) - gold standard

• Sonohysterosalpingography (alternative)

• Laparoscopy with chromopertubation (if other pathology suspected)

4. Semen analysis (two samples, 2-7 days abstinence):

• Volume, concentration, motility, morphology

• WHO 2021 reference values should be used

5. Additional female hormonal testing (if indicated):

• TSH, prolactin

• Testosterone, DHEA-S (if PCOS suspected)

• Day 3 LH (if PCOS suspected)

Second-line Testing (If indicated)

• Hysteroscopy (if uterine abnormality suspected)

• Laparoscopy (if endometriosis or pelvic adhesions suspected)

• Genetic testing (if indicated by history or semen analysis)

• Specialized sperm function tests

• Immunological testing (anti-sperm antibodies)

VI. Treatment Approaches

A. Lifestyle Modifications

• Achieve and maintain healthy BMI (18.5-24.9 kg/m²)

• Smoking cessation for both partners

• Limit alcohol consumption

• Folic acid supplementation (400-800 mcg daily) for women

• Optimize coital timing (every 1-2 days during fertile window)

• Stress reduction techniques

B. Treatment of Specific Conditions

Female Factors

Ovulatory Disorders:

• PCOS: Lifestyle modification, metformin, clomiphene citrate, letrozole, gonadotropins

• Hypothalamic dysfunction: Address underlying causes, lifestyle modification, gonadotropins

• Hyperprolactinemia: Dopamine agonists (bromocriptine, cabergoline)

• Thyroid disorders: Appropriate hormone replacement or antithyroid therapy

Tubal Factors:

• Laparoscopic salpingostomy or salpingectomy

• In vitro fertilization (IVF) often preferred for significant tubal disease

Endometriosis:

• Laparoscopic excision or ablation of endometriotic lesions

• Medical suppression has limited role in fertility treatment

• IVF may be indicated for moderate to severe disease

Uterine Factors:

• Hysteroscopic resection of fibroids, polyps, or uterine septum

• Treatment of Asherman syndrome with hysteroscopic lysis

Male Factors

Varicocele:

• Surgical repair (varicocelectomy) or percutaneous embolization

• Consider if palpable varicocele with abnormal semen parameters

Hormonal disorders:

• Gonadotropin therapy for hypogonadotropic hypogonadism

• Treatment of hyperprolactinemia or thyroid disorders

Obstructive azoospermia:

• Surgical reconstruction when feasible

• Sperm retrieval with IVF/ICSI

C. Assisted Reproductive Technologies (ART)

Ovulation Induction

• Clomiphene citrate: First-line for ovulatory dysfunction, particularly PCOS

• Letrozole: Increasingly preferred first-line agent for PCOS

• Gonadotropins: Second-line therapy, requires careful monitoring

Intrauterine Insemination (IUI)

• Indications: mild male factor, cervical factor, anovulation with ovulation induction, unexplained infertility

• Success rates: 10-20% per cycle depending on diagnosis and age

• Usually limited to 3-4 cycles before considering IVF

In Vitro Fertilization (IVF)

• Indications: tubal factor, severe male factor, endometriosis, failed ovulation induction/IUI, advanced maternal age, unexplained infertility

• Success rates vary by age and diagnosis

• May include intracytoplasmic sperm injection (ICSI) for severe male factor

Other ART Procedures

• Preimplantation genetic testing: For couples with genetic disorders or recurrent pregnancy loss

• Donor gametes: When own gametes are not viable

• Gestational surrogacy: For uterine factor infertility or medical contraindications to pregnancy

VII. Age and Fertility

Female Age Effects

• Fertility begins to decline gradually after age 30, more rapidly after 35

• Decreased ovarian reserve and increased aneuploidy rates

• Increased risk of pregnancy complications

• Accelerated evaluation recommended for women ≥35 years

Male Age Effects

• Gradual decline in sperm quality with advancing age

• Increased DNA fragmentation and genetic abnormalities

• Associated with increased time to conception and pregnancy complications

VIII. Psychological and Social Aspects

Emotional Impact

• Infertility creates significant psychological stress for couples

• Higher rates of anxiety and depression compared to fertile couples

• Grief response similar to other major losses

• Relationship stress and sexual dysfunction common

Counseling and Support

• Referral to mental health professionals experienced in fertility issues

• Support groups and online communities

• Stress reduction techniques and coping strategies

• Decision-making support regarding treatment options

IX. Special Considerations

Cancer and Fertility Preservation

• Fertility preservation options before gonadotoxic treatments

• Embryo, oocyte, and sperm cryopreservation

• Ovarian tissue cryopreservation (experimental)

• GnRH agonist co-treatment during chemotherapy

Recurrent Pregnancy Loss

• Defined as two or more consecutive pregnancy losses

• Evaluation includes genetic, anatomic, endocrine, immunologic, and thrombophilic factors

• Treatment depends on underlying cause

X. When to Refer

Reproductive Endocrinology and Infertility (REI) Specialist

• Failed first-line treatments

• Complex cases requiring ART

• Recurrent pregnancy loss

• Suspected genetic causes

• Advanced maternal age (≥35 years) after 6 months of trying

Other Specialists

• Urologist for male factor evaluation and treatment

• Reproductive psychiatrist/psychologist for counseling

• Genetic counselor for hereditary conditions

Key Points for Clinical Practice

1. Early evaluation is crucial, especially for women ≥35 years

2. Both partners should be evaluated simultaneously

3. Evidence-based treatments should be offered in a stepwise approach

4. Lifestyle modifications are important adjuncts to medical treatment

5. Emotional support and counseling should be integral to care

6. Realistic expectations about success rates should be discussed

7. Cost-effectiveness should be considered in treatment planning

8. Patient autonomy in decision-making should be respected

Key References

1. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020;113(3):533-535.

2. Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril. 2020;113(2):305-322.

3. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-50.

4. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril. 2015;103(3):e18-25.

5. Zegers-Hochschild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

6. World Health Organization. WHO laboratory manual for the examination and processing of human semen. 6th ed. Geneva: World Health Organization; 2021.

7. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-379.

8. Practice Committee of the American Society for Reproductive Medicine. Management of endometriosis-associated infertility: a committee opinion. Fertil Steril. 2017;108(5):739-743.

9. Practice Committee of the American Society for Reproductive Medicine. Report on varicocele and infertility: a committee opinion. Fertil Steril. 2014;102(6):1556-1560.

10. Practice Committee of the American Society for Reproductive Medicine. Optimizing natural fertility: a committee opinion. Fertil Steril. 2017;107(1):52-58.

11. Practice Committee of the American Society for Reproductive Medicine. Role of tubal surgery in the era of assisted reproductive technology: a committee opinion. Fertil Steril. 2015;103(6):e37-43.

12. Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016;106(7):1634-1647.

13. Carson SA, Kallen AN. Diagnosis and management of infertility: a review. JAMA. 2021;326(1):65-76.

14. Thoma ME, McLain AC, Louis JF, et al. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril. 2013;99(5):1324-1331.

15. Practice Committee of the American Society for Reproductive Medicine. Fertility evaluation of infertile women: a committee opinion. Fertil Steril. 2021;116(5):1255-1265.