Infertility Chapter Notes | Gynaecology and Obstetrics - NEET PG PDF Download

Introduction

• Infertility is a significant issue for many couples, causing them considerable emotional distress.
• Most couples facing childlessness experience reduced fertility rather than complete sterility, which means they may still have the potential to conceive naturally.
• Treatment methods for infertility are often based on intuition due to the lack of solid evidence.
• These methods are frequently influenced by traditional practices and individual preferences.
• The field of assisted reproduction is advancing rapidly, leading to the incorporation of new techniques into clinical practice without thorough prior evaluation.

Epidemiology

• In the general population, it is expected that 84% of women will conceive within 12 months and 92% within 24 months (te Velde et al. 2000).
• Infertility is defined as the failure to conceive after one to two years of unprotected intercourse (Hull et al. 1985).
• Studies indicate that 10-15% of couples in the Western world experience infertility (Templeton et al. 1990; Evers, 2003).
• Half of these couples ( 8%. will conceive without needing specialist advice or treatment.
• Among the remaining 8%who seek help from fertility clinics:
  • Half ( 4%. have primary infertility (no previous pregnancies).
  • The other half have secondary infertility (difficulty conceiving after an initial pregnancy).

Categories of Infertility

• Infertility is typically classified into five main categories based on the cause, investigation findings, and prognosis.
• The distribution of couples in each category varies according to environmental factors and referral practices.
• The chances of spontaneous live birth in infertile couples are affected by:
  • Female age
  • Duration of infertility
  • Previous pregnancies
  • Cause of infertility
• Unexplained infertility has the most positive outcome.
• For instance, a couple with primary unexplained infertility for 2 years, with the female partner aged 28 years, has a 36% chance of live birth within the next 12 months (Collins et al. 1995).
• Factors such as a history of previous pregnancy, shorter infertility duration, and being under 30 years old enhance a woman’s chances of live birth.
• On the other hand, issues like male factor infertility, tubal disease, and endometriosis significantly reduce these chances.
• Some categories, like anovulation and male factor infertility, may coexist, which should be taken into account when planning investigations or treatment.

Classification of Disorders of Ovulation

• * FSH stands for follicle-stimulating hormone.
• This classification is adapted from Templeton et al. (2000) Management of infertility for the MRCOG and beyond, published by RCOG Press London.

Ovulatory Disorders

• Anovulation (absence of ovulation) or oligo-ovulation (infrequent ovulation) affects about one-fifth of women experiencing infertility.
• Anovulatory infertility can be classified into different types, including:
• Hypogonadotropic Hypogonadism (WHO Type I)
• Normogonadotropic Anovulation
• Hypergonadotropic Hypogonadism (WHO Type III)
• Hyperprolactinaemia
• HYPOTHALAMUS AND PITUITARY (HYPOGONADOTROPIC HYPOGONADISM) (WHO TYPE I)
• NORMOGONADOTROPIC HYPOGONADISM
• HYPERGONADOTROPIC HYPOGONADISM (WHO TYPE III)
• HYPERPROLACTINAEMIA

Understanding Male Factor Infertility

Male factor infertility accounts for 25% of infertility cases and is believed to contribute to another 25%. This condition occurs when there are insufficient healthy sperm to fertilize a normal egg. The World Health Organization (WHO) has established criteria for normal semen parameters, which serve as a reference for laboratory results. Table 45.5 outlines these reference values.

Reference Values for Semen Analysis

Note: Grade a refers to rapid progressive motility, while Grade b indicates slow or sluggish motility.

Idiopathic Impairment of Semen Quality

• In many cases of male infertility, the cause of poor semen quality remains unknown.
• Azoospermia (absence of sperm) or significant oligozoospermia (sperm concentration less than 20 million per ml) may be associated with small, soft testes and elevated follicle-stimulating hormone (FSH) levels.
• Histological examination of the testicular tubules may reveal:
• Absence or reduced number of germ cells.
• Asthenozoospermia refers to reduced motility (less than 50% ). Poor or absent motility may result from structural abnormalities such as:
• Absence of dynein arms, radial spokes, nexin bridges, or dysplasia of the fibrous sheath.
• Similar structural defects can be observed in respiratory cilia in conditions like Immotile Cilia Syndrome, which is characterized by respiratory infections, sinusitis, and bronchiectasis. If a male has situs inversus, he may be diagnosed with Kartagener’s Syndrome.
• Teratozoospermia refers to abnormal sperm shape as observed under a microscope. While the assessment of sperm morphology is somewhat subjective, strict criteria can ensure consistency in reporting within each laboratory. Sperm morphology is believed to reflect the maturity and functionality of sperm and is associated with acrosomal defects and motility issues.

Causes of Male Infertility

Table 45.6 presents various factors contributing to male infertility, including:

• Varicocele
• Idiopathic oligozoospermia
• Accessory gland infection
• Idiopathic teratozoospermia
• Idiopathic asthenozoospermia
• Isolated seminal plasma abnormalities
• Suspected immunological infertility
• Congenital abnormalities
• Systemic diseases
• Sexual inadequacy
• Obstructive azoospermia
• Idiopathic necrozoospermia
• Ejaculatory inadequacy
• Iatrogenic causes
• Karyotype abnormalities
• Partial obstruction of the ejaculatory duct
• Retrograde ejaculation
• Immotile cilia syndrome
• Pituitary lesions
• Gonadotrophin deficiency

Varicocele

• A varicocele is characterized by a group of swollen veins in the pampiniform plexus of the spermatic cord, typically appearing as a tangle of enlarged blood vessels in the scrotum.
• Varicoceles are usually left-sided, develop during puberty, and affect approximately 15% of otherwise healthy men. Observational data suggest that clinically noticeable varicoceles are found in 12% of normal men and 25% of men with semen abnormalities.
• Impaired blood drainage from the testis due to increased scrotal temperature, hypoxia, high testicular pressure, and reflux of adrenal metabolites may hinder spermatogenesis. However, the presence of varicoceles in fertile men with normal sperm counts has led some researchers to question the causal link between varicoceles and infertility.

Genetic Causes

• Chromosomal abnormalities have been identified in 2.1–8.9% of men attending infertility clinics and are correlated with the severity of male factor infertility.
• Azoospermia is associated with karyotypic abnormalities in 15% of cases, with the majority being 47XXY (Klinefelter’s Syndrome). Structural changes in the Y chromosome, such as deletions of distal fluorescent heterochromatin, may also contribute to poor sperm production.
• Deletions affecting a gene family on the Y chromosome occur in 10% of non-obstructive azoospermia and some severe cases of oligozoospermia. Microdeletions have been identified in three regions of the Y chromosome: AZF a-b-c, with the most common abnormality being a microdeletion in the AZFc region, which includes the DAZ gene.

Objective

Undescended testes that are not treated by the age of 2 are likely to have abnormal tissue. Delaying surgery can lower fertility and increase the risk of testicular cancer by 4 to 10 times.

Symptomatic orchitis occurs in 27–30% of mumps cases in males. In 17% of these cases, orchitis affects both sides and leads to damage of the seminiferous tubules. If bilateral orchitis happens after puberty, it can affect fertility.

Toxic factors from radiation, medication, and chemicals can harm the quickly dividing germ cells, which develop into sperm. Some heavy metals and chemicals can also negatively impact fertility.

Pesticides have been linked to issues in sperm development. Additionally, tobacco, cannabis, alcohol, and lifestyle choices such as wearing tight underwear are also associated with male infertility. However, evidence for some of these links is conflicting.

Several commonly used drugs can reduce sperm quality, as listed in Table 45.7, along with their actions.

Azoospermia with normal testicular size and normal FSH levels suggests a possible blockage in the genital tract. Major causes include:

• Previous vasectomy
• Congenital abnormalities
• Infections like tuberculosis and gonorrhoea, which are more common in certain regions

Congenital issues leading to blockages may include:

• Agenesis or malformations of the Wolffian ducts, affecting the epididymis and seminal vesicles
• Congenital bilateral absence of the vas deferens (CBAVD), which occurs in 2% of obstructive azoospermia cases and is often associated with cystic fibrosis
• Young ’ s Syndrome, characterised by obstruction where the caput meets the body of the epididymis, chronic lung infections, and bronchiectasis

Infections from Gram-negative enterococci, chlamydia, and gonococcus can cause:

• Urethral discharge
• Painful ejaculation
• Dysuria
• Haematospermia
• Tenderness in the epididymis and prostate

Diagnosis is confirmed by:

• Semen culture
• Urethral swabs
• Presence of over 1 million polymorphonuclear leucocytes per ml of semen

The role of subclinical infections in male infertility is unclear, and there is no agreement on diagnostic criteria.

Hypogonadotrophic hypogonadism is a rare condition due to congenital or acquired failure of the hypothalamus and pituitary. In congenital cases, signs of androgen deficiency usually appear at puberty. A lack of GnRH results in:

• Absence of secondary sexual characteristics
• Total testicular failure
• Many affected men may have anosmia (Kallman ’ s syndrome)

Symptoms are less severe in those with partial deficiency. Diagnosis is confirmed by:

• Low or undetectable levels of gonadotrophins (LH and FSH)
• Low testosterone

Adult-onset hypothalamic hypogonadism can be caused by:

• Trauma
• Tumours
• Chronic inflammation

Male infertility may also result from issues with intercourse. Causes of coital dysfunction in men are shown in Table 45.8.

Antisperm antibodies are found in one in six men visiting infertility clinics. They are either IgG or IgA types and can be present in:

• Serum
• Seminal fluid
• Bound to various parts of the spermatozoa

Risk factors for developing antisperm antibodies include:

• Vasectomy reversal
• Prior infections such as epididymitis
• Sexually transmitted diseases
• Orchitis

The effect of antisperm antibodies on infertility is not fully understood and requires more research. It is thought they can:

• Affect sperm motility
• Cause abnormalities in the acrosomal reaction
• Inhibit binding to the zona pellucida

Antisperm antibodies can also be found in fertile men, and current methods do not allow for meaningful differentiation between various epitopes (Paradisi et al. 1995).

Tubal Factor Infertility

Tubal disease is responsible for 15-20% of primary infertility cases and about 40% of secondary infertility cases. It usually occurs after pelvic infections or surgeries that damage the tissue, causing scarring and adhesions. This damage can impair the fallopian tubes' function, leading to partial or complete blockage. In some cases, fluid accumulates in the tubes, resulting in a condition called hydrosalpinx. For the fallopian tubes to function properly, they need to be open and have a healthy mucosal lining. Unfortunately, damage to the tubes is often permanent, making treatment difficult. Currently, we can only assess the visible condition and openness of the fallopian tubes.

Infection

Pelvic inflammatory disease (PID) is the primary cause of tubal disease and can occur on its own or following miscarriage, childbirth, medical procedures, or pelvic surgery. The risk of future tubal factor infertility increases with PID, especially when caused by Chlamydia trachomatis or Neisseria gonorrhoeae. Chlamydia, the most common sexually transmitted disease (STD) in Europe, is responsible for at least 50% of PID cases. Many women with chlamydia are asymptomatic, but about three-quarters have antibodies against it in their blood. Risk factors for chlamydia include:

• Multiple sexual partners
• Younger age at first sexual intercourse
• Poor socio-economic status
• Heavy alcohol consumption
• Cigarette smoking

There are differing opinions on the impact of previous terminations of pregnancy on infertility risk, with some studies suggesting no increased risk when other factors are considered.

Surgery

Lower abdominal surgeries elevate the risk of tubal infertility due to the potential for adhesions. Most abdominal and pelvic surgeries, including gynaecological procedures, appendicectomy, bowel resection, and urological interventions, are believed to increase the risk of tubal disease.

Other Causes

The link between intrauterine contraceptive devices (IUCDs) and tubal disease is contentious. In the 1980s, studies suggested a higher risk of PID in IUCD users compared to non-users. However, recent research indicates that low-risk IUCD users do not face an increased risk of PID. Rare congenital defects can result in tubal issues, often associated with urinary system abnormalities. Conditions such as endometriosis, cornual fibroids, or polyps can obstruct or distort the fallopian tubes. Another rare cause, salpingitis isthmica nodosa, involves nodular thickening of the fallopian tube, though its etiology is unknown.

Endometriosis is a condition where uterine tissue grows outside the uterus, primarily affecting the pelvic peritoneum, ovaries, and rectovaginal septum. Research indicates that 21% of women with infertility have pelvic endometriosis (Mahmood and Templeton, 1991 ).

The association between endometriosis and infertility is evident in some studies but not universally accepted. Women with endometriosis undergoing assisted reproduction often experience worse outcomes. A systematic review shows that pregnancy rates in endometriosis cases are about half of those with tubal infertility (Barhart et al. 2002 ). Data from in vitro fertilisation (IVF) programmes reveal lower ovarian reserve, poor egg and embryo quality, and diminished implantation rates in severe endometriosis cases (Brosens, 2004 ). Peritoneal fluid from women with endometriosis, containing elevated levels of cytokines and activated macrophages, has been shown to adversely affect sperm function and embryo survival (Guidice and Kao, 2004 ). Moreover, there is increasing evidence that abnormal endometrial tissue may lead to implantation failures (Guidice and Kao, 2004 ).

Theories on the Pathogenesis of Endometriosis

• Retrograde menstruation/transplantation
• Coelomic metaplasia
• Altered cellular immunity
• Metastasis
• Genetic basis
• Environmental basis
• Multifactorial inheritance involving genes and environmental factors

Adapted from: [Guidice and Kao, 2004 ].

Unexplained infertility is identified when standard tests, including semen analysis, tubal evaluation, and ovulation assessments, yield normal results. The reported rates of unexplained infertility vary widely due to differences in population characteristics and testing methods, with most clinics reporting incidences between 20-30%. The limitations of routine tests in pinpointing obvious causes have led clinicians to explore various potential factors contributing to unexplained infertility (Table 45.10). However, the practical significance of these factors has diminished with the rising prominence of assisted reproduction techniques that circumvent many of these possible issues.

Investigations of Infertility

When to Investigate

• Couples should seek assistance when they suspect a fertility problem. The initial consultation can take place in primary care without the need for a referral to a specialist clinic.
• Often, it may be sufficient to rule out obvious medical issues, explain normal conception patterns, and offer lifestyle advice.
• Referral to a fertility clinic depends on the age of the female partner and the duration of trying to conceive.
• Couples without known reproductive issues should be investigated after trying for 1–2 years.
• Early intervention is crucial for specific high-risk factors in either partner:
• For men, this includes a history of azoospermia, testicular surgery, vasectomy, or coital failure.
• For women, early referral is necessary for oligoamenorrhoea, known endocrine problems affecting ovulation, history of tubal disease, endometriosis, or salpingectomy.
• Couples should attend fertility appointments together, as it is a joint decision.
• Investigations and treatments should be explained clearly with both verbal and written information.
• It is important to consider the social and psychological needs of couples throughout the process.

Luteal Phase Deficiency

• Luteal phase deficiency is thought to arise from issues in folliculogenesis and luteal function. These problems may be linked to gonadotrophin secretion, endometrial steroid receptors, and luteal rescue mechanisms.

Luteinized Unruptured Follicle (LUF) Syndrome

• Luteinized Unruptured Follicle (LUF) Syndrome is diagnosed through serial ultrasound scans, although the criteria for this syndrome can vary.
• High levels of prolactin may be associated with poor luteal function.
• Mild endometriosis without significant pelvic distortion is often linked to unexplained infertility and is treated in a similar manner.

Subclinical Pregnancy Loss

• The occurrence of subclinical pregnancy loss is similar to that in the general population.

Anatomical Factors

• Tubocornual polyps and minor anatomical variations have minimal impact on unexplained infertility. Treating these conditions shows little effect on fertility outcomes.

Occult Infection

• Previous infections may potentially impair tubal function, but research on definitive links between occult infections and unexplained infertility is ongoing.

Sperm Dysfunction

• Unexplained infertility may be related to subtle issues with sperm function, as well as interactions between sperm, cervical mucus, and oocytes. These interactions can only be thoroughly examined through in vitro fertilization (IVF).

Immunological Causes

• Antiphospholipid antibodies, including those against various phospholipid antigens, have been associated with infertility, suggesting a potential immunological factor in some cases.

Psychological Factors

• There is currently no direct evidence linking stress levels with unexplained infertility. Further research is needed to understand the relationship between psychological factors and fertility.

History and Examination

• Detailed History:Both partners should provide a comprehensive history, including:
  • Duration of infertility
  • General health status
  • Past medical and surgical history
  • Specific questions about sexual history
• Examination: Both partners need to undergo a physical examination according to established guidelines.

Purpose of Diagnostic Tests

• Diagnostic tests for infertility aim to:
  • Screen for individuals requiring further investigation
  • Identify the underlying cause of infertility
  • Make prognostic assessments
• Considerations in Test Planning:When planning diagnostic tests, it is important to consider:
  • The relevance of each test to future clinical decisions
  • The limitations of commonly used tests
  • Balancing the risks and potential benefits of the tests

Initial Investigations

Male

• Semen analysis is the most common test for males.
• To account for changes in semen quality, at least two samples should be taken 4 weeks apart.
• Samples need to be collected after 2–7 days of abstinence.
• There is some disagreement about how accurate routine semen analysis is.
• The WHO reference values for semen quality are based on studies of fertile men and can serve as guidelines (WHO, 2000).
• Large labs might have their own normal ranges based on local populations.
• The standard semen analysis has a sensitivity of 89.6%, identifying 9 out of 10 men with real issues.
• However, it is not very specific, and a single test may incorrectly label 10% of men as abnormal.
• Repeating the test can lower this chance to 2%.

Female

• A normal menstrual cycle suggests that ovulation is occurring.
• Ovulation is usually confirmed by a mid-luteal serum progesterone level above 30 nmol/l, 7 days before menstruation starts (day 21 of a 28-day cycle).
• Each woman should also have a rubella screening.
• There is little proof that using temperature charts and LH detection kits improves outcomes.
• Regular testing of FSH, LH, prolactin, and thyroid function in ovulating women is not necessary.

Further Investigations of Female Infertility

Investigations for Anovulation

• When the menstrual cycle is not the typical 28 days, a single progesterone test on day 21 might not accurately indicate whether ovulation has occurred. In such cases, multiple progesterone tests over time, known as progesterone tracking, may be required to confirm ovulation. For example, in cycles ranging from 28 to 35 days, progesterone tracking can be initiated to assess ovulation more accurately.

Tests for Tubal Obstruction

HSG (Hysterosalpingography) is a test used to check for blockages in the fallopian tubes. It has a sensitivity of 0.65, meaning it correctly identifies open tubes 65% of the time, and a specificity of 0.83, indicating it accurately identifies blocked tubes 83% of the time. This test can suggest whether the tubes are open but may not reliably detect blockages.

A review of 23 studies found that testing for chlamydia antibodies using an enzyme-linked immunofluorescent assay is as effective as HSG for diagnosing tubal problems. The HyCosy method, which involves ultrasound and a special contrast medium injected through the cervix, is mentioned as a potential alternative but is not widely used in standard practice. Early studies comparing HyCosy with laparoscopy or HSG show good agreement, but more research is needed on endoscopic tests like fertiloscopy and falloposcopy.

There is ongoing debate about routinely checking tubal status, especially in cases where knowing if the tubes are open would not change the treatment approach. For instance, in severe male factor infertility where intracytoplasmic sperm injection is necessary, tubal status may not be relevant.

Uterine Pathology

Uterine issues such as adhesions, polyps, submucous leiomyomas, and septae are found in 10–15% of women seeking fertility treatment. It is unclear if hysteroscopy should be a standard test along with laparoscopy or HSG. While there is evidence linking uterine fibroids to infertility, the routine use of hysteroscopy for diagnosing uterine pathology in all women undergoing fertility evaluations is still under discussion.

Investigation Parameters

• Baseline (day 1–3) FSH, LH
• Serum prolactin
• Raised prolactin
• Raised FSH/LH
• Low FSH/LH
• Normal FSH/LH
• Pituitary imaging
• Karyotype
• Autoantibody
• BMI
• Ultrasound scan of ovaries
• Serum androgens, SHBG
• If required, DHEA, DHEAS, 17–OH progesterone

Effectiveness of Surgical Treatment

The effectiveness of surgical treatment for uterine abnormalities in enhancing pregnancy rates is not clearly established and requires further investigation. Transvaginal pelvic ultrasound (TVS) offers superior visualization of pelvic structures compared to a bimanual examination. It is capable of identifying conditions such as endometriomas, ovarian cysts, polycystic ovaries, fibroids, and hydrosalpinges. However, the routine application of TVS in women without a history of pelvic disorders has not been validated.

Role of the Post-Coital Test

The post-coital test (PCT) is a subject of debate regarding its utility in detecting motile sperm. Some studies suggest it may help predict spontaneous conception in couples with less than 3 years of infertility, provided female infertility factors have been ruled out. However, a systematic review found insufficient evidence supporting the predictive value of PCT, and a trial involving 444 women demonstrated no benefits in routine PCT concerning pregnancy rates.

Ovarian Reserve and Endometrial Biopsy

Women are born with a finite number of primordial ovarian follicles, which decline with age. Tests for ovarian reserve aim to assess how the ovaries will respond to stimulation during fertility treatments. Factors such as day-3 FSH, serum inhibin, and antral follicle count have been linked to ovarian response. However, current ovarian reserve tests lack sufficient sensitivity and specificity for routine use in all infertile women.

The necessity of an endometrial biopsy in standard practice is not well-established. It may be beneficial when endometrial issues are suspected due to menstrual irregularities, but it should not be used to evaluate the luteal phase. There is no evidence to support that treating luteal phase defects improves pregnancy rates.

Chlamydia Screening

Screening for chlamydia trachomatis can reduce the risk of pelvic inflammatory disease (PID) in women at higher risk. Procedures involving the uterus during investigations or treatments can reactivate upper genital tract infections. Therefore, women scheduled for such procedures should undergo screening for chlamydia trachomatis.

Further Investigations of Male Infertility

If the semen analysis reveals abnormalities or if the medical history and examination indicate the need for further investigation, additional tests may be necessary.

Endocrine Tests

• For men with azoospermia, measuring serum FSH (follicle-stimulating hormone) levels helps differentiate between obstructive and non-obstructive causes.
• Normal FSH levels suggest obstructive azoospermia, while elevated levels indicate non-obstructive causes.

Methods for Sperm Retrieval

• Percutaneous Epididymal Sperm Aspiration (PESA). An outpatient procedure performed under local anaesthesia to retrieve sperm from the epididymis.
• Testicular Sperm Aspiration (TESA). Used for men with non-obstructive azoospermia to obtain sperm directly from the testis.
• Testicular Sperm Extraction (TESE). A surgical procedure requiring general anaesthesia to extract sperm from testicular tissue.
• Microsurgical Sperm Extraction (MESA). Indicated in cases of elevated FSH levels suggesting spermatogenesis failure, involving microscopic techniques to retrieve sperm.

In rare instances, undetectable FSH levels may indicate hypogonadism, where treatment with exogenous FSH could be beneficial. Testosterone and LH testing is useful when androgen deficiency is suspected or to rule out sex steroid abuse or tumours in the testes or adrenal glands. Men with hyperprolactinaemia often face sexual dysfunction, so checking for high prolactin levels is crucial in cases of low libido and impotence. Persistently high prolactin levels require further tests, including imaging of the pituitary gland.

Chromosomal and Genetic Studies

• Men with azoospermia or severe oligozoospermia should undergo chromosomal analysis to identify potential genetic causes of infertility.
• A cystic fibrosis screen is recommended for men with congenital bilateral absence of the vas deferens (CBAVD), a condition linked to defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Microbiology of Semen

• The role of asymptomatic infections in the male reproductive system, indicated by the presence of white blood cells in the ejaculate, is not fully understood.
• Semen cultures are advised for men showing microscopic signs of infection to identify potential pathogens.
• Male partners of women with chlamydia should be screened for infections to prevent transmission and potential infertility issues.

Imaging of the Male Genital Tract

• Various imaging techniques have been used to detect varicoceles, but the routine need for varicocele treatment has diminished the enthusiasm for these tests.
• Retrograde venography is considered the gold standard in specific clinical situations despite its high cost. Other imaging options include:
• Ultrasound and Doppler. Non-invasive methods to assess blood flow and detect abnormalities in the male genital tract.
• Radionucleotide angiography. A nuclear medicine technique to evaluate blood flow in the male reproductive system.
• Thermography. A technique to detect temperature variations in the male genital area, potentially indicating abnormalities.
• Scrotal ultrasounds. Useful for evaluating suspected testicular tumours or other abnormalities in the scrotal region.
• Vasography. A procedure to identify obstruction sites in the male reproductive tract, although its clinical use has decreased with advancements in surgical sperm extraction and intracytoplasmic sperm injection (ICSI).

In Vitro Tests of Sperm Function

• The advent of assisted reproduction techniques such as IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) has reduced the significance of in vitro tests of sperm function.
• Tests like acrosome reaction tests and zona-free hamster egg penetration tests are now less commonly used in clinical practice.

Testicular Biopsy

• Testicular biopsy has been used in the past to differentiate between obstructive and non-obstructive azoospermia.
• However, its invasive nature and associated risks, such as reduced testicular mass and potential autoimmune responses, limit its use.
• The risks of testicular biopsy often outweigh the potential benefits, leading to a decline in its routine application.

Antisperm Antibodies

• Testing for antisperm antibodies is not a routine procedure in the evaluation of male infertility.
• If sperm agglutination (clumping) is observed in a semen sample, it may indicate the presence of antisperm antibodies, prompting further testing.
• Further tests on a fresh semen sample should include:
• MAR (Mixed Agglutination Reaction) Test: This test involves incubating semen with red blood cells coated with non-specific antibodies to IgA or IgG. Sperm with antisperm antibodies will stick to the treated red blood cells, indicating the presence of these antibodies.
• Immunobead Test: This test uses polyacrylic beads with bound albumin IgA and IgG antibodies. Sperm binding to these beads indicates the presence and location of antisperm antibodies in the semen sample.

Treatment of Infertility

All couples trying to conceive can benefit from general advice, such as:

• Stopping smoking
• Limiting alcohol intake

Pre-treatment counseling should cover lifestyle changes, including achieving an ideal BMI. This may involve:

• Weight loss for women with a BMI over 30
• Weight gain for some women experiencing weight-related amenorrhea and anovulation

Taking folate supplements before conception has been shown to lower the risk of neural tube defects (OR 0.28, 95% CI 0.13–0.58). A daily dose of 0.4 mg is recommended for all women planning to conceive (NICE guideline, 2004). Investigating infertility in couples leads to various diagnostic categories, each with a specific management pathway ( Fig. 45.3 ). Management details for each group are discussed below. For prolonged infertility that does not respond to standard treatment, in vitro fertilization is the recommended approach.

Women must be informed about the potential risks of:

• Multiple pregnancies
• Ovarian hyperstimulation

It is important to rule out male factor issues and tubal problems. If there is no history indicating tubal disease, it might be reasonable to wait for three cycles before conducting formal tests for tubal patency, allowing for less invasive treatments like clomiphene.

WHO Type I

For women with weight loss-related amenorrhea, treatment should be postponed until a target BMI of 20 kg/m² is achieved. The most natural treatment for WHO type I anovulation or hypothalamic amenorrhea is:

• Pulsatile administration of GnRH agonists via a portable battery-operated pump (Filicori et al. 1994).

Studies suggest that cumulative pregnancy rates of 80–90% can be achieved over 12 treatment cycles using GnRHa at doses of 15–20 µg subcutaneously or 2.5–5 µg intravenously. The intravenous method requires lower doses of GnRH, maintains a better hormonal balance, and results in higher ovulation rates. Monitoring is done through serum oestrogen levels and pelvic ultrasound. Support during the luteal phase is provided with human chorionic gonadotropin (hCG) injections. Despite high success rates and lower risks of multiple pregnancies, some women may find GnRH pumps inconvenient or fear pump failure.

WHO Type II (PCOS)

Weight loss and dietary measures are essential:

• Weight loss should be the first step for obese women with anovulation due to PCOS.
• Central obesity and high BMI contribute significantly to insulin resistance, hyperinsulinaemia, and hyperandrogenaemia.
• Effectively treating obesity can reverse these conditions.

Severe Male Factor

• Unknown Cause
• Obstructive Azoospermia: Surgery (MESA, PESA, TESA, RESE)
• Non-Obstructive Azoospermia: Surgical sperm retrieval in selected cases
• Ejaculatory Failure: Drug treatment, sperm recovery
• Hypothalamic Hypogonadism: Gonadotrophins, ICSI, DI
• Anovulation: Male factor, mild male factor, IUI
• Endometriosis: Unexplained
• WHO I: Pulsatile GnRHa, Gonadotrophins
• WHO II: Clomifene or tamoxifen, Metformin, Gonadotrophins, Ovarian drilling
• Hyperprolactinaemia: Bromocriptine, Cabergoline
• WHO III: Ovarian failure, Oocyte donation, IVF
• Mild: Tubal surgery
• Proximal Tubal Obstruction: Tubal cannulation
• Moderate to Severe: IVF
• Minimal: Surgical ablation, SO/IUI
• Moderate, Severe: Surgery
• Tubal Empirical Treatment: Clomiphene, IUI, SO/IUI

Treatment of Infertility

In women with obesity and PCOS, losing 5-10% of body weight can restore reproductive function in 55-100% of cases within 6 months.

Clomifene Citrate

• Clomifene citrate is an oral medication used to treat women with anovulatory polycystic ovary syndrome (PCOS). It works as both an oestrogen and anti-oestrogen by blocking oestrogen receptors in the hypothalamus and pituitary gland, leading to increased secretion of gonadotropin-releasing hormone (GnRH).
• Dosage and Administration. Clomifene is typically prescribed at an initial dose of 50 mg daily from day 2 to day 6 of the menstrual cycle. The dosage can be increased by 50 mg daily until ovulation occurs, with a maximum of 150 mg per day. Couples are advised to have intercourse every other day starting from day 9 for at least one week.
• Treatment Duration. A course of 6 to 12 cycles may be recommended for women who respond to the medication.
• Monitoring. Follicular response should be monitored with transvaginal (TV) scans during the first treatment cycle to minimize the risk of multiple pregnancies. Mid-luteal progesterone levels are assessed in each cycle.
• Success Rates. Ovulation is expected in 80% of women, with pregnancy rates ranging from 35% to 40%.
• Non-responders. About 20% to 25% of women do not respond to clomifene and are considered resistant to the treatment.

Adverse Reactions

• Common Side Effects. Thickening of cervical mucus and hot flushes occur in 10% of women.
• Other Side Effects. Abdominal distension (2%), abdominal pain, nausea and vomiting, headaches, breast tenderness, reversible hair loss.
• Ocular Effects. Blurred vision and scotomas in 1.5% of women, which are reversible.
• Ovarian Effects. Significant ovarian enlargement in 5% of women, with ovarian hyperstimulation syndrome (OHSS) being rare.
• Multiple Pregnancies. The rate of multiple pregnancies with clomifene is 7% to 10%, with most being twins.
• Ovarian Cancer Risk. There is a potential link between multiple clomifene cycles and an increased risk of ovarian cancer.

Tamoxifen

• Dosage and Administration. The recommended dose of tamoxifen is 20-40 mg per day from day 3 of the menstrual cycle for 5 days.
• Efficacy. Pregnancy rates with tamoxifen are similar to those with clomifene, with an odds ratio of 1.00 (95% confidence interval 0.48 to 2.09).
• Cervical Mucus. Tamoxifen may have a milder effect on cervical mucus compared to clomifene.

Gonadotrophins

• Indication. Treatment with gonadotrophins is considered for women who do not respond to clomifene or do not conceive after 6-12 ovulatory cycles.
• Common Preparations. Recombinant follicle-stimulating hormone (FSH) or purified urinary human menopausal gonadotrophin (HMG), which contains both FSH and luteinizing hormone (LH).
• Gonadotrophin Regimens. Includes standard step-up, chronic low-dose step-up, and step-down protocols.
• Standard Step-Up Treatment. Starting at 150 IU/day, this regimen has achieved acceptable cumulative conception rates.
• Risks. Standard step-up treatment has a 34% risk of multiple pregnancy and a 4.6% risk of OHSS.

Risk Factors for OHSS

• Age: Women under 30 years old are at higher risk.
• Body Mass Index (BMI): Low BMI in women with PCOS increases risk.
• Use of GnRH Agonists: Combining GnRH agonists with gonadotrophins raises risk.
• Use of Exogenous hCG: Triggering ovulation or providing luteal support with exogenous hCG increases risk.
• Endogenous hCG Surge: An endogenous surge of hCG due to pregnancy increases risk.
• Follicle Count: Having many small and intermediate follicles increases risk.
• Estradiol Levels: High E2 levels (>9000 pmol/l) increase risk.
• Rapid Estradiol Increase: A rapid increase in estradiol levels (over 75% from previous day) increases risk.
• Oocyte Count: Collecting a large number of oocytes (>20) in IVF/ICSI cycles increases risk.

Adapted from: Whelan and Vlahos, 2000.

• Low-Dose Step-Up Regimen. This regimen is used to lower the risk of multiple follicular development. A starting dose of 75 IU is given for 14 days, with small increases as needed at intervals of at least 7 days until follicular development begins. The dose continues until 1-2 leading follicles >17-18 mm are identified.
• Success Rates. The low-dose step-up regimen has shown slightly better pregnancy rates (40% vs 24%) while reducing the incidence of OHSS and multiple pregnancies. Unifollicular ovulation occurs in 74% of cases.
• Comparison of Gonadotrophins. A systematic review found no significant difference between human menopausal gonadotrophin (HMG) and urinary FSH regarding pregnancy rates per cycle. No differences in pregnancy rates have been observed between recombinant FSH and urinary FSH.
• Cumulative Pregnancy Rates. Treatment with gonadotrophins in women with PCOS results in cumulative pregnancy rates of 40-50%, a miscarriage rate of 25-30%, and a 1-2% risk of serious OHSS.

GnRH Analogues in Ovulation Induction

GnRH agonists have been used in conjunction with gonadotrophins for pituitary downregulation and cycle control during ovulation induction. However, evidence supporting the routine use of this combination is limited. A systematic review of three randomized controlled trials (RCTs) found no significant improvement in pregnancy rates when GnRH agonists were used alongside gonadotrophins (OR 1.50; 95% CI 0.72–3.12) (Hughes et al. 2000).

The strong association between anovulation and insulin resistance in women with PCOS has led to the hypothesis that reducing insulin levels could enhance their health profile. While weight loss can be beneficial, the use of an insulin-sensitizing agent like metformin may be particularly effective. Metformin is an oral biguanide primarily used to manage high blood sugar in type 2 diabetics. It has several benefits for women with PCOS, including:

• Lowering insulin levels
• Reducing both total and free androgen levels
• Alleviating symptoms related to hyperandrogenism

A systematic review (Lord et al. 2003) indicated that metformin is more effective than a placebo in inducing ovulation in women with PCOS (OR 3.88, 95% CI 2.25–6.69). When used in combination with clomifene, metformin outperforms clomifene alone in terms of ovulation (OR 4.41, 95% CI 2.37–8.22) and pregnancy rates (OR 4.40, 95% CI 1.96–9.85). Metformin positively impacts:

• Fasting insulin levels
• Blood pressure
• Low-density lipoprotein (LDL) cholesterol

However, there is insufficient evidence regarding its effects on body mass index (BMI) or waist/hip ratio. Potential side effects of metformin include nausea, vomiting, and gastrointestinal disturbances. It may also pose a risk of lactic acidosis in individuals with impaired kidney function. While the evidence supporting the safety and efficacy of metformin is encouraging (Homburg 2003), it remains uncertain whether it will become the preferred treatment for all infertile women with PCOS. Currently, metformin is not licensed for use in PCOS, and although preliminary studies suggest it is safe during pregnancy (and may reduce miscarriage rates) (Homburg, 2003), further data from randomized trials is necessary. Other insulin-lowering agents, such as glitazones (rosiglitazone and pioglitazone) and d-chiro-inositol, are being investigated for their potential benefits in PCOS.

Laparoscopic Ovarian Drilling

Laparoscopic ovarian drilling (LOD) is a treatment option for women experiencing anovulation due to PCOS. This procedure seems to be more effective in slimmer women with elevated LH levels, although the exact mechanism behind its effectiveness is not fully understood. During LOD, a unipolar coagulating current is used to create four punctures in each ovary, with each puncture being approximately 4 mm deep.

A Cochrane review (Farquhar et al. 2000) found that the ongoing cumulative pregnancy rates following LOD were comparable to those achieved after 3–6 cycles of gonadotrophin treatment (OR 1.27, 95% CI 0.77, 1.98). One notable finding was that the rate of multiple pregnancies was significantly lower in women who underwent ovarian drilling (OR 0.16, 95% CI 0.03, 0.98). The main advantages of ovarian drilling include:

• Inducing monofollicular ovulation
• Reducing the incidence of multiple pregnancies

Aromatase Inhibitors

Aromatase inhibitors are increasingly being used as alternatives to clomifene for inducing ovulation. Unlike clomifene, aromatase inhibitors do not have anti-oestrogenic effects. These medications work by reducing oestrogen production, thereby mimicking the natural decrease in negative feedback from ovarian oestrogen. Among the available aromatase inhibitors, Letrozole is the most commonly used and has shown promise in early trials (Homburg 2003). However, more extensive evidence from larger trials is still awaited to confirm its effectiveness and safety.

Egg Donation

For patients experiencing ovarian failure, egg donation may be the only viable option for achieving pregnancy. This topic is explored in greater detail in the chapter on assisted reproduction (Chapter 46).

Prolactin Regulation

Prolactin secretion is primarily regulated by the inhibitory action of dopamine. In cases of hyperprolactinaemia, Bromocriptine, a medication that mimics dopamine, has proven effective. It can shrink 80% of macroadenomas, normalize prolactin levels in 80-90% of cases, and restore ovulation in 70-80% of women. Long-term use of bromocriptine is associated with pregnancy rates ranging from 35-70% per woman.

However, due to its short half-life, bromocriptine needs to be taken two to three times daily. To minimize side effects such as nausea, headache, vertigo, postural hypotension, fatigue, and drowsiness, it is recommended to start with a low dose of bromocriptine (1.25 mg) at bedtime with a snack and gradually increase the dosage to 2.5 mg three times a day with food over a period of 2 to 3 weeks. Newer dopamine agonists like cabergoline and quinagolide have recently been licensed for the treatment of hyperprolactinaemia. These medications have fewer side effects and longer half-lives, allowing for more convenient dosing schedules, such as once-daily doses of quinagolide and twice-weekly doses of cabergoline. Data from randomized controlled trials suggest that cabergoline is more effective than bromocriptine in restoring normal prolactin levels and promoting ovulation.

Management of Hyperprolactinemia

Hyperprolactinemia is typically managed through medication. Surgery is only considered in rare instances, such as for women with pituitary tumors who have normal prolactin levels but do not show sufficient tumor shrinkage. Surgery may also be an option for patients with large macroadenomas who cannot tolerate or do not respond to drug treatment.

Surgical Considerations

• Although surgery is invasive, its outcomes are modest.
• After surgery, prolactin levels normalize in:
  • 50% of cases with microadenomas
  • 10-15% of cases with macroadenomas

Management of Male Factor Infertility

• General measures include stopping smoking and reducing alcohol consumption.
• Targeted treatment should be considered when a specific cause is found.
• In most cases, the cause of abnormal semen parameters is unclear.
• Assisted reproduction is the primary option for men wanting biological children.

Intrauterine Insemination (IUI)

• IUI with washed sperm is suitable for mild to moderate semen abnormalities.
• IUI offers higher pregnancy rates compared to timed intercourse:
  • Natural cycles: OR 2.5
  • Stimulated cycles: OR 2.2
• No significant difference between stimulated and unstimulated cycles: OR 1.8
• IUI in natural cycles may be preferable due to the risk of multiple pregnancies with stimulated cycles.
• While IUI enhances pregnancy chances, the overall outlook for male infertility without assisted reproduction is still poor.

In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI)

• IVF is recommended for men with very low sperm concentrations ( 5 million/ml ).
• In obstructive azoospermia cases with normal testicular volume and FSH levels, surgical sperm retrieval followed by ICSI is an option.
• Non-obstructive azoospermia with small atrophied testes and high FSH levels may indicate poor prognosis or the need for donor insemination.

Donor Insemination

• Thawed frozen donor sperm may be used if surgical sperm retrieval or ICSI is not possible.
• Donors are screened for hereditary conditions and blood-borne viruses.
• Confirming tubal patency in the female partner is necessary, and ovulation induction should be considered for irregular cycles.
• Monitoring LH levels helps time insemination shortly after ovulation.
• IUI is more effective than intra-cervical insemination (ICI) for higher pregnancy rates: OR 2.4
• Controlled ovarian stimulation during donor insemination can increase the risk of multiple births and is generally avoided.
• National donor insemination programs report live-birth rates per cycle between 10.3-11.6%
• Cumulative pregnancy rates do not significantly improve after the sixth treatment cycle, suggesting options like IVF with donor sperm should be considered.

Traditional Approaches to Treat Male Infertility

Hormonal Treatments

• Gonadotropin therapy can lead to improvements in hypogonadotrophic hypogonadism.
• However, this treatment has not been thoroughly assessed in randomised controlled trials (RCTs).
• Observational studies indicate that treatment with FSH and hCG is generally well tolerated.
• Around 80% of men undergoing this treatment achieve a satisfactory sperm count.
• Pulsatile GnRH may be as effective as hCG and hMG in boosting sperm production.

Surgical Interventions

• Data on success rates for surgical procedures addressing post-infective blocks, such as epididymovasotomy, is limited.
• Observational studies suggest a post-surgical patency rate of 52%.
• The pregnancy rate following such surgeries is estimated to be around 38%.
• A systematic review of seven RCTs found no evidence that varicocele repair enhances pregnancy rates in couples facing male or unexplained infertility (Evers, 2002).

Addressing Ejaculatory Issues

• Sildenafil has been proven effective for men experiencing erectile dysfunction (Burls et al. 2001).
• Treatments for ejaculatory issues have included alpha-agonists like imipramine and pseudoephedrine, as well as parasympathomimetic drugs such as neostigmine.
• Alpha-agonists have shown lower success rates compared to parasympathomimetics (19% versus 51%) (Kamischke and Nieschlag, 1999).
• Treatment for retrograde ejaculation focuses on enhancing sympathetic stimulation of the bladder.
• There has been no significant difference in effectiveness between alpha-agonists and anticholinergic drugs in this context.
• Sperm recovery from urine has been successful in certain cases of retrograde ejaculation.
• Electroejaculation may be considered for men with neurological impairments.
• In cases where other treatments are ineffective, surgical sperm retrieval followed by IVF/ICSI could be an option.

Other Treatments for Male Factor Infertility

• Gonadotrophins do not increase pregnancy rates in men with unexplained low sperm count (idiopathic oligozoospermia).
• Treatments that have been found ineffective include:
  • Anti-oestrogens such as clomifene and tamoxifen
  • Androgens
  • Bromocriptine
  • Medications that boost kinin activity
• Antioxidants like Vitamins C, E, and glutathione may enhance semen quality, but there is insufficient evidence to recommend them due to lack of data on important outcomes such as pregnancy or live-birth rates.
• Mast cell blockers have shown potential benefits in men with severe oligozoospermia, as noted in the 2004 guideline by the National Collaborating Centre for Women’s and Children’s Health (NICE).

Treatment of Tubal Factor Infertility

Women with moderate to severe damage to their fallopian tubes are unlikely to conceive naturally. In such cases, In Vitro Fertilization (IVF) is often considered the best treatment option. Although there are no randomised trials to support this approach, evidence from observational studies suggests its effectiveness.

Surgical Techniques for Tubal Repair

• Various surgical techniques are available to repair damaged or blocked fallopian tubes.
• Reports indicate that women who undergo tubal surgery have higher pregnancy rates compared to those who do not, with rates of 29% versus 12% over three years.

Factors Influencing Surgical Success

• The success of tubal surgery depends on several factors, including:
• The extent of tubal damage
• The woman’s age
• The surgeon’s experience and training
• The availability of appropriate equipment

Efficacy of Surgery

• Surgery can be effective for minor to moderate tubal damage.
• However, it is not beneficial for women with severe tubal disease.
• Some data suggest that pregnancy rates after surgical treatment of proximal blockages, mild distal blockages, and light adhesions can be comparable to those achieved through IVF.

Proximal Tubal Blockages

• Tubal catheterisation or cannulation guided by imaging techniques or hysteroscopy can be used to treat proximal tubal obstructions.
• Observational studies suggest higher pregnancy rates with cannulation (49%) compared to catheterisation (21%).
• However, tubal cannulation carries risks, including a 2-5% chance of tubal perforation and a 3-9% risk of ectopic pregnancy.

Tubal Surgery vs. Assisted Reproductive Technologies (ART)

• The increased availability of assisted reproductive technologies has reduced the role of tubal surgery in treating infertility.
• Uncontrolled data show that around 50% of women with proximal tubal blockage can achieve a full-term pregnancy after microsurgical tubocornual anastomosis.

Treatment of Endometriosis in Infertility

Due to the lack of evidence from randomised trials, the treatment for endometriosis is primarily based on observational studies. The treatment options include:

• Expectant management
• Medical treatment
• Surgical treatment
• Conventional fertility methods
• Assisted reproduction

Expectant Management (No Treatment)

• Endometriosis decreases the chances of natural pregnancy.
• The prognosis varies with the severity of endometriosis, as per the revised American Fertility Society Guidelines.
• Initially, minimal and mild endometriosis can be managed with expectant management.

Medical Treatment

• Medications for endometriosis include:
• Combined oral contraceptives
• Progestogens
• Danazol
• Gestrinone
• GnRH analogues
• Ovulation suppression agents have not been proven to improve pregnancy rates compared to no treatment or danazol.
• Many of these medications have side effects like weight gain, hot flushes, and bone loss.
• Current evidence does not support medical treatment for infertility associated with endometriosis.
• The role of medical treatment alongside surgery is still unclear.

Surgical Treatment

• Laparoscopic surgical treatment of minimal and mild endometriosis may improve ongoing pregnancy or live-birth rates.
• The benefits of laparoscopic surgery must be weighed against the risks and costs.
• Surgical treatment for moderate to severe endometriosis can improve pregnancy rates, with laparoscopic surgery showing better outcomes compared to laparotomy.

Comparison of Surgical Approaches

• Observational studies indicate pregnancy rates of:
• 81% after laparoscopy, 84% after laparotomy, and 54% following medical treatment.
• Laparoscopic surgery is associated with higher pregnancy rates (54-66%) compared to laparotomy (36-45%) in women with moderate and severe endometriosis.

Conclusion

• The treatment of endometriosis and tubal factor infertility involves a range of options, including IVF, surgical interventions, and medical management.
• The choice of treatment depends on individual circumstances, severity of the condition, and potential risks and benefits of each approach.

Post-Operative Medical Treatment

According to the National Institute for Health and Care Excellence (NICE) guidelines from 2004, it is not advisable to routinely use medical treatments such as GnRH agonists (like naferelin, goserelin, or luprolide) or danazol after surgery for endometriosis. There is still some debate about the most effective treatment for endometriomas. One study suggested that women have better chances of getting pregnant within two years after laparoscopic cystectomy (removal of the cyst) compared to drainage and coagulation methods. However, more clinical trials are necessary to assess the effectiveness and safety of both existing and new surgical interventions. There are concerns that widespread removal or destruction of endometriotic tissue might harm healthy ovarian cortex, potentially reducing ovarian reserve. This concern was highlighted in a study by Guidice and Kao in 2004.

Controlled Ovarian Hyperstimulation

Controlled ovarian hyperstimulation combined with intrauterine insemination (IUI) has been a treatment option for women with minimal or mild endometriosis, provided their fallopian tubes are open. A meta-analysis encompassing two trials indicated that stimulated IUI significantly improved live-birth rates in such cases.

Despite its widespread use, the role of in vitro fertilization (IVF) in the context of endometriosis has not been thoroughly evaluated through rigorous studies. For more information on assisted reproduction, refer to Chapter 46.

In instances of unexplained infertility, any treatment approach remains speculative. It's crucial to consider the possibility of spontaneous pregnancy, as even invasive assisted reproduction techniques yield modest success rates. Generally, a minimum duration of 3 years of unexplained infertility is accepted before initiating active intervention, although this timeframe may vary based on individual circumstances. The decision to commence treatment should also factor in the woman's age. Clear communication with the couple is vital, and the significance of detailed discussions, supported by written information materials, cannot be emphasized enough. Many couples experience frustration when their request for early treatment seems denied, necessitating careful counselling.

Empirical Clomifene

Clomifene citrate is known to increase the number of follicles produced in each cycle, thereby improving the chances of a fertilised embryo successfully reaching the uterine cavity. However, its use in cases of unexplained infertility remains a topic of debate. A meta-analysis has indicated a significant benefit from using clomifene in such cases, with a combined odds ratio for clinical pregnancy per patient being 2.37. Due to the small sample sizes of the included trials, future studies may lead to different conclusions. Traditionally, clomifene is considered to be inexpensive and relatively safe, which is why many practitioners prefer its empirical use over more invasive techniques. However, concerns about the potential for multiple pregnancies resulting from clomifene use and the unresolved question of a possible link to ovarian cancer underscore the importance of carefully weighing the risks and benefits.

The approach to using clomifene in unexplained infertility differs from its use in women with anovulatory conditions. The treatment typically starts with a dose of 50 mg, and a scan on day 12 of the cycle is conducted to assess the ovarian response. If the response is found to be very strong, the dose may be reduced to 25 mg. The goal is to achieve no more than two preovulatory follicles measuring over 17 mm.

Intrauterine Insemination with or without Superovulation

Intrauterine insemination (IUI), whether in natural (unstimulated) cycles or in conjunction with superovulation (SO/IUI), has been employed as a treatment for unexplained infertility. However, neither of these treatment approaches has been thoroughly evaluated against expectant management. Among these options, IUI with superovulation is the more frequently used intervention. Evidence supporting its effectiveness comes from a systematic review indicating that the combination of gonadotrophins and IUI resulted in higher pregnancy rates compared to gonadotrophins with timed intercourse.

A specific randomised trial has shown comparable pregnancy rates between women undergoing IUI alone and those receiving SO/IUI or in vitro fertilization (IVF). Furthermore, a larger multi-centre trial conducted in the United States found SO/IUI to be more effective than IUI alone in terms of live-birth rates, although it also presented a significantly higher risk of multiple pregnancies. Consequently, while IUI in an unstimulated cycle offers a safer alternative, SO/IUI may enhance success rates at the expense of a higher likelihood of multiple pregnancies.