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★
For those who ultimately become pregnant, cumulative pregnancy rate at:[1]
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)
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.
Age of the female partner is the single most important factor when predicting the chances of conception for a couple.
Female fecundity declines precipitously after age 35
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.
Replacing FSH with recombinant FSH or hMG, which exhibits both LH and FSH-like activity, after testosterone levels are normalized on hCG
If medical therapy fails to result in a pregnancy, but some sperm are found in the ejaculate, referral for ART is recommended.
Prader-Willi syndrome
Features: hypogonadism, small testes, dysmorphic facies, growth hormone deficiency with short stature, small hands and feet, pain insensitivity, cognitive disorders
Males with Klinefelter syndrome should be counseled that few non-mosaic XXY men will have sperm in the ejaculate and medically-unassisted paternity is rare.§
Y chromosome microdeletion
Second most common known genetic cause of infertility in the male
Can result from errors that occur during homologous recombination during meiosis due to the palindromic structure of the chromosome
Majority of (but not all) genes on the Y chromosome encode proteins involved in testis determination or spermatogenesis
Consists of three areas encoding genes involved in spermatogenesis (AZFa, AZFb, AZFc)
AZFa (also known as AZF1) or AZFb complete microdeletion: generally result in absence of spermatogenesis.
Common phenotypic manifestations of deletions in AZFa region are azoospermia and Sertoli cell-only syndrome
Genes in the AZFb region have been found to support the growth and maturity of sperm and are critical for efficient progression of spermatogenesis. Common phenotypic manifestations of deletions in this region are spermatogenic arrest and azoospermia
AZFc microdeletion: may result in spermatogenic impairment but not necessarily absence of spermatogenesis
Genes in the AZFc region have a diverse role, but overall, they are essential to complete spermatogenesis. AZFc deletions have been associated with drastic reduction in sperm count, and there are subsets of men with AZFc microdeletions that experience progressive declines in their sperm count.
Originally, the AZFb and AZFc genes were identified and thought to be separate regions. They were later found to be overlapping and are now referred to as AZF2.
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.
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.§
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
5 mg/day is associated with reduced semen volume, but 1 mg/day data are inconclusive
Exogenous testosterone/anabolic steroids
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
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.
Should be ceased as the initial step
Majority 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
Time to recovery slower in
Older males
Low-normal sperm count prior to starting exogenous testosterone
High dose exogenous testosterone
Probabilities of recovery at 6, 12, 16, and 24 months to be 67%, 90%, 96% and 100%, respectively.
Older males less likely to recover
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
Low-quality evidence for no impact of anabolic steroids/exogenous testosterone on permanent infertility[3]
Other medications mentioned in Campbell's 11th edition:
Spironolactone
HIV medications
Protease inhibitors (indinavir) and nucleoside reverse transcriptase inhibitors (stavudine)
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
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.
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
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§
Alcohol use
Drinkers have slightly lower semen volume and slightly poorer sperm morphology, but drinking does not adversely affect sperm concentration or sperm motility[5]
Caffeine
Moderate quality evidence of no association (except possibly sperm aneuploidy) between caffeine and male infertility[6]
Environmental exposure
Some heavy metals (e.g. lead) and pesticides are associated with increased risk of infertility§
For those patients thought to be at risk for heavy metal toxicity, serum testing may be performed; however, lead levels in the blood may not reflect the total lead burden throughout the body§
Diet
Poor diet results in reduced fertility
Stress
Associated with reduced sperm progressive motility, but has no association with semen volume; data were inconclusive for sperm concentration and sperm morphology[7]
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§
Testicular cancer
Impacts sperm count and concentration, but evidence is inconclusive regarding impact on motility and morphology§
Increased scrotal temperature
Scrotal temperature is maintained 2-4°C below body temperature.
Increasing testis temperature impairs spermatogenesis; safe scrotal temperature is not known
Age
Older men have slightly reduced fertility
All 7 parameters, except concentration, are associated with small age-dependent declines (i.e., semen parameters decrease as age increases)[8]
Obesity
Moderately reduced fertility
Mechanisms related to infertility (4):
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.
Partial retrograde ejaculation may exist concurrently with partial antegrade ejaculation. If the antegrade specimen is sufficient for reproduction either naturally or with medical assistance, no treatment may be necessary. However, if the antegrade ejaculate is poor and a substantial RE is present as demonstrated by post-ejaculatory urinalysis, various therapies may be required.
Regulates anion transport and fluid secretion in the excurrent ducts
The mutations more likely to cause obstructive azoospermia may be different than those that cause cystic fibrosis[10]
Characterized by
Pulmonary obstruction and infection
Exocrine pancreatic insufficiency
Obstructive azoospermia
Dental carries
Mutations in the CFTR gene can lead to vasal and seminal vesicle agenesis/atresia[11]
Thought that dysregulation of proper fluid dynamics leads to obstruction and/or atrophy in the epididymis and vas deferens during embryogenesis
Mutations in the CFTR gene are present in up to
80% of men with congenital bilateral absence of the vas deferens (CBAVD)
20% of men with CUAVD
21% of men with idiopathic epididymal obstruction
While vasal abnormalities are apparent on physical examination, epididymal obstruction may only be diagnosed at the time of surgical exploration. As such, CFTR testing may necessarily occur after surgical treatment in some men.
Not all cystic fibrosis patients have vasal agenesis
Some men with otherwise idiopathic genital tract obstruction are found to harbor mutations in the CFTR gene
