Infertility: Epidemiology and Etiology

Definitions

Definition of infertility: a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after ≥12 months of regular unprotected sexual intercourse★

Classification

Primary vs. secondary
- Primary male infertility: male who has never initiated a clinical pregnancy and meets the criteria of being classified as infertile
- Secondary male infertility: couple where the man is unable to initiate a clinical pregnancy, but who had previously initiated a clinical pregnancy (with the same or different sexual partner)
  - Evaluation of secondary infertility should include a focus on conditions or exposures that have developed or occurred after initiation of the earlier pregnancy(ies).

Epidemiology of Infertility

Prevalence
- Varies depending on definition of infertility, source of data, and population
- Prevalence in Canada: ≈11%
  - Data from the Infertility component in the 2009–2010 Canadian Community Health Survey
  - Definition of infertility: did not become pregnant after exposure to the risk of conception during the previous 12 months.
    - Risk of conception: did not use any form of birth control within the past 12 months, reported having sexual intercourse in the past 12 months, and reported ever having tried to become pregnant with their current partner.
    - Bushnik, Tracey, et al. "Estimating the prevalence of infertility in Canada." Human reproduction 27.3 (2012): 738-746.

Age of the female partner is the single most important factor when predicting the chances of conception for a couple.
- Fertility decreases by almost 50% in women in their late 30’s compared to women in their 20’s.
- In women under 35 years of age, infertility is considered present after 12 months of attempting to conceive. This duration is shortened in women over the age of 35 years to 6 months.
Male factors[1]
- Solely responsible in ≈20% of all infertile couples
- Contributes to 30-40% of all infertile couples
- ≈30% female factor solely responsible, ≈10% unexplained
For those who ultimately become pregnant, cumulative pregnancy rate at:[2]
- 6 months: 75%
- 12 months: 85%
- 24 months: >90%

Semen parameters peak after 1 or 2 days of abstinence, then decline.
- To increase the probability of pregnancy, intercourse every day around the time of ovulation is optimal
- To assess bulk seminal parameters, a single day of abstinence is optimal
Female fecundity declines precipitously after age 35

Etiology of Male Infertility

Most common causes

Idiopathic (33%)
Varicocele (27%)
Obstruction (15%)
Endocrinopathy (10%), hypogonadism being most common

See Table 66-1 CW 12th edition for distribution of final diagnoses from a male infertility clinic
Idiopathic vs. unexplained§
- Idiopathic infertility: unable to identify etiology of the abnormal semen analysis
- Unexplained infertility: normal semen analysis and normal partner evaluation with unclear reason for infertility
  - In some cases, patients with normal semen analyses have sperm that do not function in a manner necessary for fertility

Classified (3):

Pre-testicular
Testicular
Post-testicular

Pre-testicular (hypogonadotropic hypogonadism)

Congenital

Kallmann syndrome
- Characterized by decreased pituitary hormone secretion
- Presence can be evaluated with smell test
- Management:
  - Replacing LH with hCG
  - Replacing FSH with recombinant FSH or hMG, which exhibits both LH and FSH-like activity
Prader-Willi syndrome
- Features: hypogonadism, small testes, dysmorphic facies, growth hormone deficiency with short stature, small hands and feet, pain insensitivity, cognitive disorders Acquired

Acquired

Hyperprolactinemia
- See 2018 AUA Testosterone Deficiency Guideline Notes
Pituitary trauma, infection, tumour, hemochramotosis, pituitary surgery, Sheehan's syndrome

Testicular

Congenital

DUNKY XX:
1. Down syndrone
2. Undescended testis/cryptorchidism
3. Noonan’s syndrome
4. Kleinfelters syndrome
5. Y-microdeletions
6. XX-male
- Klieinfelters
  - Most commonly identified genetic cause of male infertility
  - See Disorders of Sexual Differentiation Chapter Notes
- Cryptorchidism
  - If underwent orchidopexy and had unilateral cryptorchidism, 96% paternity rate; 70% if bilateral.
  - The sooner orchidopexy the better, but age unknown. Better if done prior to age 10.
- Androgen-receptor (AR) resistance
  - See Disorders of Sexual Differentiation Chapter Notes
  - Diagnosis and Evaluation: significantly elevated testosterone associated with impaired male fertility. LH is mildly elevated, FSH is normal
- Cystic Fibrosis
  - Associated with obstructive azoospermia, pulmonary problems, pancreatic deficiency, and dental carries
- Sertoli Cell Only syndrome
  - Patients present with normal levels of LH and testosterone. The low level of inhibin-B leads to elevated levels of follicle-stimulating hormone FSH.§
- Hypoandrogenism caused by Leydig cell insufficiency
  - Exogenous testosterone not indicated since insufficient testicular testosterone concentrations are achieved for spermatogenesis
  - If azoospermia, low testosterone, and elevated LH, perform surgical sperm extraction [consider biopsy if low-normal/normal T and normal LH, may be due to obstruction or testicular failure]

Acquired

Toxins
- Chemotherapy
  - Cancer (especially testicular cancer) can negatively affect spermatogenesis, even before chemotherapy
  - It is unknown what duration of time after receiving chemotherapy is needed to have no residual DNA damage
    - Sperm DNA damage can be detected at least 2 years after chemotherapy.
    - Sperm banking should be prioritized early in the management of a patient with testicular cancer
- Radiation to testes if dose > 7.5 Gy
- Medications
  - If there is concern about the influence of a particular medication on fertility, clinicians may consult databases with data on reproductive effects of medications such as REPROTOX® for additional information.
  - Finasteride
    - Associated with decreased semen volume and appears to be dose-dependent
  - Exogenous testosterone
    - Testosterone is converted to estradiol by aromatase. This estradiol inhibits LH secretion. Consequently, there is decreased intratesticular testosterone synthesis and reduced spermatogenesis.
    - Testosterone abuse results in an acquired variant of hypogonadotropic hypogonadism characterized by extremely low or undetectable serum levels of FSH and LH, atrophic testes and severe oligozoospermia or azoospermia.
      - Anabolic androgenic steroid abuse was the most frequent cause of profound hypogonadism among young men.
      - Injections are the most toxic against spermatogenesis; nasal spray is the least toxic
      - While exogenous testosterone does not suppress luteinizing hormone or FSH during puberty in patients with Klinefelter syndrome, testosterone does suppress gonadotropins after puberty.16
    - Should be ceased as the initial step.
      - Majority of men recover fertility in a time-dependent manner.
      - Recovery begins on average 4 to 5 months after initiation of medical therapy but it can take up to 2 years
        Probabilities of recovery at 6, 12, 16, and 24 months to be 67%, 90%, 96% and 100%, respectively.
        Older males less likely to recover
        
        Time to recovery slower in older males, low-normal sperm count prior to starting exogenous testosterone, and with high dose exogenous testosterone.
      - Recovery of spermatogenesis can be improved with hCG +/- FSH
        Semen quality will be sufficient for intrauterine insemination in 70% of men within 12 months of medical therapy to promote spermatogenesis
  - Estrogen
  - Anti-androgens
  - Low-quality evidence, none of which had any significant impact:
    - Anti-rheumatic medications
    - Thiopurines
    - Methotrexate
    - Corticosteroids
  - Other medications mentioned in Campbell's 11th edition:
    - Spironolactone
    - HIV medications
      - Protease inhibitors (indinavir) and nucleoside reverse transcriptase inhibitors (stavudine)
    - Corticosteroids
    - Cimetidine
    - Sulfasalazine (should be substituted with mesalazine)
    - Opioids
      - Suppresses LH release resulting in decreased intratesticular testosterone synthesis and reduced spermatogenesis
    - Anti-psychotics
      - Dopamine antagonists can result in decreased libido
      - SSRIs are associated with anorgasmia and delayed or absent ejaculation
- Social habits
  - Cigarette smoking
    - Low-quality evidence (due to high risk of bias) exists to link smoking with a small impact on sperm concentration, motility, and morphology§
  - Cannabis decreases plasma testosterone and may affect the acrosome of the spermatozoa§
  - Heavy alcohol use increases the conversion of testosterone to estradiol
    - High-quality evidence exists on the mild impact of alcohol on semen volume, sperm morphology (although not clinically significant).§
- Environmental exposure
  - Some heavy metals (e.g. lead) and pesticides are associated with increased risk of infertility§

Infections and Inflammation
- History of infections of the GU tract (testis, epididymis, prostate, urethra) is associated with infertility
  - Viral orchitis can result in bilateral testicular atrophy
- No effect of HIV or hepatitis

Childhood
- Hydrocele or hernia surgery can cause obstruction
  - Moderate-quality evidence that found the impact of hernia repair on reproductive function to be inconclusive§
- Torsion
  - 11% of males develop anti-sperm antibodies after testicular torsion. However, fertility similar to general population
    - 2016 study from Israel reviewed torsion 63 patients, 41 with orchiopexy and 22 with orchiectomy, and found that pregnancy rates were similar to general population (≈90%). Mean time to pregnancy approx. 7 months, no difference between orchiopexy and orchiectomy§

Increased scrotal temperature
- Scrotal temperature is maintained 2-4°C below body temperature.
- Increasing testis temperature impairs spermatogenesis; safe scrotal temperature is not known
Testicular cancer
- Impacts sperm count and concentration, but evidence is inconclusive regarding impact on motility and morphology§

Obesity
- Mechanisms related to infertility:
  - Adipose tissue, which is the main source of aromatase in men and results in increased E2 levels, lowers T:E2 ratio and increases negative feedback on the HPG axis
  - Increased scrotal temperature
  - Increased total body surface area, effectively diluting testosterone concentration in testosterone sensitive areas.
  - Obesity and metabolic syndrome are associated with an overall increased inflammatory state, suppressing the HPG axis and causing mixed testicular/pituitary hypogonadism.

Post-testicular

Ejaculatory dysfunction
- Ductal obstruction
- Retrograde ejaculation
- Anejaculation
  - Causes include spinal cord injury, demyelinating neuropathies (multiple sclerosis), diabetes, iatrogenic (RPLND, pelvic surgery) transverse myelitis, and congenital neural tube defects
Sexual History
- Lubricants impair sperm motility.
  - Pre-seed is a lubricant that does not decrease motility.
- Saliva is toxic to sperm

Other syndromes associated with infertility
- Kartagener syndrome
  - Also known as primary ciliary dyskinesia
  - Associated with infertility and respiratory pathology due to absence of ciliary movement

Male Infertility. Source: Wikipedia

Recurrent pregnancy loss

Defined as two or more failed pregnancies
- Distinct from infertility
Most miscarriages are related to abnormalities within the fetus itself★
Causes of recurrent miscarriages (6)
1. Genetic causes (e.g., chromosomal translocations)
2. Anatomic abnormalities of the female uterus (e.g., septum, submucosal fibroids, adhesions)
3. Infections
4. Hematologic and immunologic disorders of the female partner
5. Female partner endocrine issues (e.g., thyroid and diabetes)
6. Male factor issues
  - Most common identified etiologic issues in males: karyotypic abnormalities and sperm DNA fragmentation.

Questions

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 24
Khan MA, Pagani RL, Ohlander SJ. 2019 AUA Update: Exogenous Testosterone and Male Reproduction