Male Infertility.

Recently there was a news item that male fertility is reducing globally because of reducing sperm count? Is that how the human race is going to disappear with a small sizzle? Not a meteor or some natural disaster bringing our species to extermination in a dramatic event as happened to the dinosaurs? Just not having babies anymore? Potential grandparents tragically fading away?

The Nottingham study is just one in a mounting pile of research indicating that the quality and quantity of men’s sperm is on the decline and suggests that sperm counts have dropped by half in the last 50 years or so and that a higher percentage are poor swimmers – slow, ungainly or beset by genetic flaws. The exact cause of that decline is not well understood. … But many researchers suspect chemical residues in the environment may be partly to blame.May 24, 2019
http://www.theguardian.com › us-news › may › toxic-americ…

Being stressed out and sedentary is no good for sperm and it’s even worse if you smoke, drink alcohol or use recreational drugs. For example, a large review of studies from 26 regions across the world found that smoking decreased sperm by 13-17%. Another study found that smoking marijuana regularly (more than once weekly) lowers sperm count in young men and that the effect is exacerbated when they also use other recreational drugs.

There’s also a growing consensus that some chemicals found in everyday products such as plastic bottles, metal food cans, detergents, flame retardants, food, toys, cosmetics and pesticides can affect a man’s reproductive health. Those chemicals, referred to as “endocrine disruptors” interfere with the body’s natural hormone systems – by blocking production or effects of the male hormone testosterone, for instance.

Those effects may begin while babies are still developing in their mother’s womb says Niels Skakkebæk, professor at the University of Copenhagen and senior researcher at the Department of Growth and Reproduction at Rigshospitalet in Denmark. He points out that poor sperm quality is associated with an increased risk of testicular cancer and also a history of congenital reproductive defects, including undescended testes. One theory is that all those conditions are linked to the mother’s exposure to environmental contaminants at critical moments during pregnancy when the baby’s sex organs develop.

Endocrine disruptors may also affect sperm in adult men. A 2014 study of the effects of 96 of those chemicals on human sperm found that they affected sperm’s ability to swim, navigate and fertilize an egg.

How many sperm should there be? How many of them should be able to swim and what other characteristics make them healthy?

A study ” Sperm Morphology, Motility, and Concentration in Fertile and Infertile Men” was carried out by David S. Guzick, M.D., Ph.D., James W. Overstreet and their team and published in NEJM in November 8, 2001 (N Engl J Med 2001; 345:1388-1393). I am putting down some salient points.

Two semen specimens from each of the male partners in 765 infertile couples and 696 fertile couples were taken at nine sites. The female partners were all determined to be normal. The sperm concentration and motility were determined at the sites; semen smears were stained at the sites and shipped to a central laboratory for an assessment of morphologic features of sperm with the use of strict criteria.

The subfertile ranges were a sperm concentration of less than 13.5×106 per milliliter, less than 32 percent of sperm with motility, and less than 9 percent with normal morphologic features.

The fertile ranges were a concentration of more than 48.0×106 per milliliter, greater than 63 percent motility, and greater than 12 percent normal morphologic features. Values between these ranges indicated indeterminate fertility.

There was extensive overlap between the fertile and the infertile men within both the subfertile and the fertile ranges for all three measurements. Although each of the sperm measurements helped to distinguish between fertile and infertile men, none was a powerful discriminator. The percentage of sperm with normal morphologic features had the greatest discriminatory power.

The results of this study confirm that measurements of sperm concentration, motility, and morphology all provide useful information for diagnosing male infertility. Sperm morphology, as measured according to strict criteria, appears to be the most informative semen measurement for discriminating between fertile and infertile men. However, none of the measures, alone or in combination, can be considered diagnostic of infertility.

What is likely to be the cause of male infertility?

  • Idiopathic male infertility describes an infertile man with a normal semen analysis and no apparent cause for infertility,
  • Whereas infertile men with idiopathic dysspermatogenesis have abnormal semen analyses.
  • Secondary [hypogonadotropic] hypogonadism) – 2 to 5 percent.
  • Primary testicular defects in spermatogenesis – 65 to 80 percent (of which the majority have idiopathic dysspermatogenesis, an isolated defect in spermatogenesis without an identifiable cause).
  • Sperm transport disorders – 5 percent.

 

The disorders in many infertile men are characterized primarily by descriptions of observed abnormalities, such as decreased sperm number, movement, or egg-penetrating and fusion capabilities. Even testicular biopsies rarely shed insight on the underlying etiology; they simply indicate the extent of spermatogenic impairment.
How do you start the evaluation of an infertile man? The history should include details of recreational drugs, alcohol intake, any diseases like diabetes, cystic fibrosis, spermatocele or obvious signs of hypogonadism or use of medical drugs which could affect the endocrine system. The frequency and timing of intercourse should be discussed.
A thorough physical examination should follow and then a semen analysis should be done after 2-7 days abstinence from intercourse with any partner. Repeat a semen analysis one week later.
More details of the history should include:
  • Sexual developmental history, including testicular descent, pubertal development, loss of body hair, or decrease in shaving frequency

  • Chronic severe systemic illness and history of major head or pelvic trauma

  • Infections, such as mumps orchitis, sinopulmonary symptoms, sexually transmitted infections, and genitourinary tract infections (including prostatitis)

  • Surgical procedures involving the inguinal and scrotal areas, such as vasectomy or orchiectomy

  • Drugs and environmental exposures, including alcohol, tobacco, marijuana, opioids, radiation therapy, anabolic steroids, corticosteroids, cytotoxic chemotherapy (current or past), drugs that cause hyperprolactinemia, and exposure to toxic chemicals (eg, pesticides)

  • Sexual history, including libido, frequency of intercourse, and previous fertility assessments of the man and his partner

    The physical examination should include a general medical examination to determine overall health, obesity, and overt signs of endocrinopathies that are uncommon causes of male infertility (eg, thyroid dysfunction or Cushing’s syndrome).

    Because some infertile men have combined defects in testosterone and sperm production, the examination should also focus on findings suggestive of androgen deficiency. The clinical manifestations of androgen deficiency depend upon the age of onset. Androgen deficiency during early gestation presents as atypical genitalia; in late gestation as micropenis; in childhood as delayed pubertal development; and in adulthood as decreased sexual function, infertility, and, eventually, loss of secondary sex characteristics. The examination of the man should include the following components.

    Skin – Men with iron overload syndromes as the cause of infertility may have diffuse or patchy hyperpigmentation. Men with Cushing’s syndrome may have thin skin, ecchymoses, and/or broad purple striae. Loss of pubic, axillary, and facial hair, decreased oiliness of the skin, and fine facial wrinkling suggest long standing testosterone deficiency.

    External genitalia – Several abnormalities that affect fertility can be recognized by examination of the external genitalia:

    • Incomplete sexual development can be recognized by examining the phallus and testes and finding small testes and other findings of incomplete pubertal development.

    • Diseases that affect sperm maturation and transport can be detected by examination of the scrotum for absence of the vasa, epididymal thickening, and large varicoceles.

    • Decreased volume of the seminiferous tubules can be detected by measuring testicular size by Prader orchidometer or calipers. The Prader orchidometer consists of a series of plastic ellipsoids with a volume from 1 to 35 mL. In an adult man, a testicular volume below 15 mL or a testicular length (measured on the longest axis) less than 3.6 cm are considered small.

Look for
  • Semen volume and pH
  • Microscopy for:
    • Sperm concentration, count, motility, and morphology
    • Debris and agglutination
    • Leukocyte count
    • Immature germ cells

What are the reference norms that WHO has set?

The WHO has published lower reference limits for semen analyses  The following parameters represent the generally accepted 5th percentile (lower reference limits and 95% CIs in parentheses), derived from a study of over 1900 men whose partners had a time to pregnancy of ≤12 months:

  • Volume – 1.5 mL (95% CI 1.4-1.7)
  • Sperm concentration – 15 million spermatozoa/mL (95% CI 12-16)
  • Total sperm number – 39 million spermatozoa per ejaculate (95% CI 33-46)
  • Morphology – 4 percent normal forms (95% CI 3-4), using “strict” Tygerberg method
  • Vitality – 58 percent live (95% CI 55-63)
  • Progressive motility – 32 percent (95% CI 31-34)
  • Total (progressive and nonprogressive) motility – 40 percent (95% CI 38-42)

After the initial evaluation (history, physical exam, and two semen analyses), men with infertility should undergo the following evaluation: look for a couples infertility factor if there is idiopathic male infertility i.e. normal semen, recommend ART (assisted reproductive technology) such as IVF (in vitro fertilisation). Intracytoplasmic sperm injection (ICSI) refers to a technique in which a single sperm is injected directly into the cytoplasm of a mature oocyte. This procedure is performed as part of an in vitro fertilization (IVF) cycle, and provides an effective method for assisting fertilization in men with suboptimal semen parameters or who experienced no or low fertilization rates after conventional IVF.

Sperm concentration <10 million/mL — Because Klinefelter syndrome is common in men presenting with infertility and sperm concentrations <10 million/mL, serum total testosterone (on a blood sample obtained between 8 and 10 AM), serum follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

Severe oligozoospermia or azoospermia: genetic testing is required. Karyotyping is recommended for infertile men with elevated serum FSH and LH concentrations and a sperm concentration less than 10 million/mL

Evaluation of obstructive azoospermia (those who have normal endocrine testing, normal testicular volume, palpable vasa deferentia on examination, and azoospermia: ejaculatory duct obstruction can be diagnosed by a scrotal or transrectal ultrasound showing dilated seminal vesicles. Transrectal ultrasound might be modestly more sensitive in detecting obstructive azoospermia. Patients with obstructive azoospermia should be referred to a urologist who specializes in infertility for further evaluation and treatment.

Genetic testing.

The common genetic abnormality found is Klinefelter’s syndrome. This syndrome is the clinical manifestation of a male who has an extra X chromosome. The most common genotype is 47,XXY but greater and lesser numbers of X chromosomes have also been reported, resulting in karyotypes such as 48,XXXY and 46,XY/47,XXY mosaicism. Only the most severe phenotypes of Klinefelter syndrome are recognized before puberty. Neonates with Klinefelter syndrome may present with micropenis (<1.9 cm for neonate) or clinodactyly, hypospadias, or cryptorchidism. Prepubertal boys with Klinefelter syndrome may present with behavioral abnormalities, language delay, learning disabilities, or hypertelorism. Boys of pubertal age with Klinefelter syndrome tend to be taller than expected based on mid-parental height and have legs that grow out of proportion to arm length. Their leg length is, on average, 4 to 8 cm greater than men without Klinefelter syndrome. Adult men with Klinefelter syndrome may present with infertility due to azoospermia or symptoms and signs of androgen deficiency (gynecomastia, sexual dysfunction, or osteoporosis). Men with classic Klinefelter syndrome have very small, firm testes (≤4 cc each). The small testicular volume is due to progressive fibrosis and destruction of both functional (steroidogenic and spermatogenic) compartments of the testes. Sperm may be harvested and preserved at attaining puberty. The use of gonadotropins, aromatase inhibitors, or selective estrogen receptor modulators to increase spermatogenesis are ineffective. ART may be tried.

Genetic testing is also done to look for Y chromosome microdeletion or testing for cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Other chromosomal abnormalities that result in testicular hypofunction have been reported.

  • The 46,XY/XO karyotype leads to a syndrome characterized by short stature and features typical of Turner syndrome. The gonads vary from streak to dysgenetic to normal testes; as a result, the sexual phenotype varies from complete female to complete male. If the patient has both a streak gonad and a dysgenetic testis (“mixed gonadal dysgenesis”), the risk of gonadoblastoma is approximately 20 percent. Gonadectomy should therefore be performed in these patients.
  • The 47,XYY karyotype was initially thought to be associated with hypogonadism, but subsequent reports have not confirmed this relationship.

  • Microdeletions in specific regions of the long arm of the Y chromosome occur in up to 20 percent of men with azoospermia or severe oligospermia.

Mutation in the FSH and LH receptor genes

  • Another rare cause of primary hypogonadism is a mutation in the follicle-stimulating hormone (FSH) receptor gene. One report described five men found to be homozygous for an inactivating mutation of the FSH receptor. These subjects had variably low sperm counts and inhibin B concentrations and high serum FSH concentrations.
  • Luteinizing hormone (LH) receptor mutations result in Leydig cell hypoplasia and testosterone deficiency in the first trimester in utero, resulting in varying degrees of male pseudohermaphroditism.

Cryptorchidism may affect one or both testes.

  • If only one testis is undescended, the sperm count will be subnormal in 25 to 33 percent and the serum FSH concentration will be slightly elevated. The presence of these abnormalities suggests that both testes are abnormal, perhaps congenitally, even though only one fails to descend.
  • If both testes are undescended, the sperm count will usually be severely subnormal and the serum testosterone may also be reduced.

Disorders of androgen biosynthesis. This is associated with incomplete virilisation.

Myotonic dystrophy, an autosomal dominant disorder that leads to muscle atrophy, is accompanied by hypogonadism that is usually not recognized until adulthood. Small testes and decreased sperm production are more common than decreased serum testosterone levels.

Congenital anorchia. This form of testicular regression occurs after 20 weeks of gestation, so that at birth, male sexual differentiation is normal but testes are absent and hypogonadism is severe.

Varicocele 

Varicosity of the venous plexus within the scrotum, called a varicocele, has long been considered a possible cause of damage to the seminiferous tubules and thereby of infertility. As a result, ligation of varicoceles has long been practiced as a treatment for infertile men, although available data do not support this practice.

Acquired causes of male infertility.

Infections such as mumps and HIV affect the seminiferous tubules and the Leydig cells.

Alkylating agents, such as cyclophosphamide, chlorambucil, cisplatin, and busulfan, can damage the seminiferous tubules to a degree sufficient to cause azoospermia and markedly elevated serum follicle-stimulating hormone (FSH) concentrations. Cisplatin or carboplatin also can decrease the sperm count, but the count typically recovers, at least partially. Ketoconazole can also cause oligospermia. Chronic glucocorticoid use can also lower testosterone levels by approximately one-third; the mechanism is not clear, but inhibition may occur at both the testis and pituitary.

Radiation either directly to the testes or even through shielding for leukemia, lymphoma also damages the seminiferous tubules.

Environmental toxins such as the nematocide dibromochloropropane is known to decrease spermatogenesis in men in vivo.

Trauma and testicular torsion is one of the most common reasons for the loss of a testicle before puberty. Orchiectomy is standard treatment for testicular cancer, which is often bilateral.

Autoimmune damage — Many men with idiopathic infertility have antisperm antibodies. It is not known, however, if these antibodies are the result of an autoimmune process or a response to damage by some other mechanism.

The hypogonadism that accompanies autoimmune polyglandular disease is also characterized by hypothyroidism and hypoadrenalism.

Cirrhosis is occasionally associated with hypogonadism, as manifested by a reduction in the serum testosterone concentration. More than one mechanism appears to be involved. In some cases, primary gonadal injury appears to be more prominent, as suggested by increased serum FSH and LH concentrations. In others, suppression of hypothalamic or pituitary function appears to play a primary role, as suggested by serum LH concentrations that are not elevated. Hypogonadism due to cirrhosis is rapidly corrected following liver transplantation.

Acute alcohol ingestion also may cause secondary hypogonadism, as manifested by subnormal serum testosterone concentration levels without increases in either LH or FSH.

Severe chronic kidney disease may also be associated with hypogonadism.

As you can see that the health of the sperm is a delicate matter depending on genes, hormones, infections, alkylating agents and other agents used in chemotherapy and radiation, systemic illnesses. Restoring the sperm to health is not an easy task and there is a heavy reliance on RTA and IVF to help out the infertile man.

 

Published by

shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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