HomeENGLISH MAGAZINEAbout low sperm count: natural history, diagnostics and possible interventions

About low sperm count: natural history, diagnostics and possible interventions

Introduction

A low sperm count, or oligospermia, is a condition in which the concentration of sperm in the ejaculated semen is too low to encourage natural fertilization of an egg. It is usually defined as having a sperm count of less than 20 million / ml of sperm, although more recent research puts the threshold below 15 million. Male infertility occurs in about 7% of humans and is commonly due to sperm deficiency. It is the cause of male infertility in one third of couples who seek assisted reproductive techniques to conceive. It can have multiple causes in the reproductive and non-reproductive systems, but most cases are idiopathic.

Causes of oligospermia

Some common etiologies include:

Absence or insensitivity to testosterone

  • low androgen levels as in hypogonadism (congenital or acquired): secondary testicular failure, congenital or acquired, can result from low gonadotropin secretion with reduced testosterone production.
  • Congenital hypogonadotropic hypogonadism (CHH): this form is characterized by a deficiency in the production of gonadotropin (LH, FSH) by the hypothalamus or anterior pituitary. This form is most commonly caused by a developmental disorder called Kallmann’s syndrome, which manifests as a number of phenotypic abnormalities.
  • primary testicular failure, with small, soft testicles and a high level of FSH
  • genetic diseases such as Klinefelter’s syndrome

Obstructive disorders

  • testicular trauma causing obstruction
  • obstruction of the testicular spermatic ducts as a result of damage, disease, inflammation or congenital causes
  • previous testicular surgery

Testicular toxicity

  • transient oligozoospermia which often occurs following a serious illness, with the count returning to normal within three to six months
  • testicles retained in infancy
  • post-inflammatory testicular dysfunction: chronic infections or inflammation of the testicles or genital tract lead to an increase in the concentrations of reactive oxygen species that can damage the sperm membrane, resulting in impaired fertilization.
  • some drugs such as testosterone, anabolic steroids, chemotherapy and some antibiotics or antidepressants can reduce sperm count if used for a long time, but the effect is usually reversible within one year of stopping the drug.
  • radiation damage (radiotherapy) can also cause oligospermia
  • in utero exposure to estrogenic compounds, such as diethyl stilbestrol or bisphenol A, has been associated with abnormal testicular development and oligospermia in adults
  • lifestyle or environmental factors, including:
  • Sexually transmitted infections caused by chlamydia, gonorrhea or prostatitis: these cause infection of the accessory glands and lead to epididymitis, prostatitis (typically subclinical) and obstruction of the testicular ducts
  • local temperature increase of the testicles due, for example, to excessively tight inner clothing
  • abuse of tobacco, alcohol or drugs (especially cocaine or marijuana)

Genetic causes

Men with severe oligozoospermia, when the sperm count is less than 5 million per ml of semen, have a higher (7-10 percent) risk of genetic abnormalities. These can cause structural or functional testicular abnormalities. Only 20-30 percent of men with azoospermia or severe oligospermia are ultimately diagnosed with a specific disorder, while the vast majority of genetic abnormalities leading to male infertility remain unknown to this day. The identified genetic causes of male subfertility include:

  • Klinefelter syndrome (47 XXY): is characterized by testicular atrophy and reduced testosterone production, with azoospermia. Leydig cells are reduced, germ cell lines are atretic, and signs of masculinization are deficient, such as body hair, muscle development, bone density and breast enlargement, often with learning difficulties and social dysfunction
  • Y chromosome microdeletion (YCMD): is common in primary or incomplete testicular failure. It involves three regions of the azoospermic factor (AZF) which are essential for normal spermatogenesis. They are detected in 5-10 percent of men with severe oligospermia. Many of these make testicular sperm recovery impossible, but others can be circumvented with intracytoplasmic sperm injection (ICSI).
  • Congenital hypogonadotropic hypogonadism (CHH): is due to the deficiency of gonadotropin secretion in the pituitary and is present from birth. It is mainly due to Kallman’s syndrome, which occurs in 1 in 10,000 men. It is caused by aberrant migration of olfactory and GnRH-producing (GnRH) neurons from the pituitary, resulting in anosmia and hypogonadism. However, a number of clinical manifestations have been described, including isolated CHH, and more than a few genetic abnormalities have also been reported. CHH can also occur as a result of other autosomal mutations (FGFR1 or FGF8, for example) without anosmia.
  • mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR), which manifests itself with the congenital absence of the vessels and the atresia of the seminal vesicles, resulting in a low volume of sperm. More than 1700 mutations have been reported with a corresponding diverse spectrum of clinical disorders, ranging from isolated vessel absence to classic cystic fibrosis. In the latter, both vas deferens are absent in over 95% of males.
  • abnormalities of various genes that regulate testicular maturation, such as mutations in the MLH1 or MSH2 genes.
  • Karyotype abnormalities may show structural abnormalities, mostly Robertsonian translocations and inversions of entire chromosomes, found in 6% of infertile males. These changes are eight times more frequent in infertile men than in the control group of fertile men.
  • The 46, XX karyotype is a rare translocation found in azoospermia, with the absence of most of the Y chromosome making sperm production impossible.
  • X-linked mutations such as the androgen receptor Xq11.2-12 mutation can cause androgen insensitivity and azoospermia
  • As the number of X chromosomes increases, the number of spermatozoa decreases leading to male subfertility

Clinical diagnosis

Oligospermia is diagnosed on the basis of a semen analysis, in which the quantity and quality of sperm in a human-collected semen sample is analyzed in the laboratory. If the results are deemed abnormal, a repeat test is performed three months later for confirmation. Home kits are available for sperm counting, but a lot of research on their accuracy is lacking. In addition, other sperm parameters are not checked, including sperm morphology and motility, both of which are important factors affecting male fertility. For this reason they can be falsely reassuring and delay treatment when required. They can also give falsely low counts in some cases. Non-obstructive azoospermia or severe oligospermia (less than 5 million / mL) may be associated with increased gonadotropin levels and small, soft testes.

Semen analysis

Semen analysis is the primary technique for testing male fertility and is often the benchmark. Two ejaculated samples are taken from the male, either by masturbation, or if there are objections to this practice, in a non-spermicidal condom. Samples are best taken six weeks apart if the former is somehow abnormal. Three days of sexual abstinence will ensure that the sample is representative of the true constitution of the semen. Semen analysis can help detect the following:

  1. Abnormalities in the number of spermatozoa
  • Azoospermia – absence of sperm in semen
  • Oligozoospermia – the presence of less than 15 million spermatozoa / ml
  1. Abnormalities of sperm function and motility (asthenospermia)

Sperm with a progressive forward motility of less than 25 microns / second must make up at least 50% of the semen sample. When the sperm in the sample are constantly immobile or poorly mobile, fertilization is unlikely to occur as they cannot pass cervical mucus to reach the uterine cavity.

  1. Abnormalities of sperm morphology (teratospermia)

Sperm are classified morphologically using the WHO classification or strict Kruger criteria, and this provides additional information to the other parameters in determining sperm quality. When spermatozoa are showing gross anomalies like bicephalic (two heads, one tail), bicaudal (one head, two tails) and other related anomalies, these are labeled as teratospermia (from the greek “theratos=monster”).

  1. Home fertility test kit

Many men consider it an insult to their manhood to have their fertility tested, although both need not be related. For this reason many men prefer to test their semen at home instead. While, these tests can accurately provide sperm count but fail to follow recent guidelines, which define oligospermia as less than 15 million sperm / mL.

Second, they control sperm count but not morphology or motility, which are equally important in determining the success of fertilization. In this way they can provide false reassurance, unnecessarily delaying the patient’s visit for the treatment needed to aid conception. Conversely, the test kit may give the impression that the sperm count is low when it is within normal limits.

Personal medical history

Men with oligospermia must have a careful medical history, including:

  • Erectile dysfunction
  • Professional toxicants (e.g. heavy metals, organic solvents)
  • Symptoms of the urinary tract
  • Past illnesses and testicular surgery
  • Heavy smoking, alcohol or drug abuse
  • Past and current medications that can reduce sperm count or motility

Laboratory medicine

Imaging tests such as scrotal ultrasound may be needed to rule out a testicular tumor or varicocele. The prostate and seminal vesicles may require visualization by transrectal ultrasound, such as when the sperm volume is very low. Humoral testing, including testing for serum follicle-stimulating hormone (FSH) levels, may be needed as an indicator of poor sperm production. High levels of FSH with low levels of testosterone indicate lack of testicular response, but low levels of FSH and testosterone indicate deficiency of gonadotropin. FSH may be normal in the case of some mutations that cause late maturation arrest. This evaluation will reveal the difference between obstructive and non-obstructive azoospermia by providing data on testis size and consistency, other signs of hypogonadism, and gonadotropin levels. About seven out of ten men with infertility will be offered an etiological diagnosis at this stage.

When there is no clinical or laboratory evidence of testicular failure, genetic testing is not indicated. Similarly, if there is a clear etiological factor identified in the history and examination, it is not required, or if the man has secondary infertility. Genetic testing is indicated in men who have azoospermia or severe oligospermia, with suspected congenital obstruction. It is also suitable for those with primary or incomplete testicular failure and congenital hypogonadotropic hypogonadism, as well as those with normal FSH and testicular volume with non-obstructive azoospermia. These tests can include:

  • Karyotyping

Translocations or inversions are found in about 6% of infertile men. They are also found in cases of aneuploidy such as Klinefelter’s syndrome or 46XX with translocation of the distal tip containing SRY of the short arm of the Y chromosome into the corresponding region of the X chromosome. X-linked genes such as Xq11.2-12 that encode for the androgen receptor can be abnormal, resulting in varying degrees of insensitivity to androgens and leading to azoospermia with a chromosomal complement 46XY.

  • Microdeletions of the Y chromosome (YCMD)

YCMDs are usually on the Yq or long Y arm and lead to the loss of the azoospermic factor (AZF) regions involved in coding for spermatogenesis. In 60 percent of these men, spermatozoa cannot be found in the testicles. In the remainder, with AZFC microdeletions, although the spermatozoa are usually recovered, the mutation is passed on to the offspring via ICSI. YMCDs are usually detected by PCR.

  • Cystic fibrosis

A mutation of the transmembrane regulatory gene (CFTR) on chromosome 7q31.2 should be sought in all men with congenital bilateral absence of the vas deferens (CBAVD), as up to 80% have two abnormal copies of this gene. Cystic fibrosis (CF) can result from over 1,700 mutations, however, it cannot be said with certainty that up to a quarter of patients with CBAVD have CF. Female partners must be tested for the gene before ICSI – this is because heterozygous CF alleles that could put the offspring at risk for CF or infertility.

  • Genes associated with the maturation of spermatozoa

These MLH1 and MSH2 genes belong to a family of proteins that repair DNA damage by preventing abnormal recombinations that can lead to cell death.

  • Testicular microbiopsy

It may be required as a last resort to distinguish between obstructive and non-obstructive azoospermia if all other clinical and laboratory parameters are normal – this will confirm the presence of sperm.

Treatments for oligospermia

Individuals with borderline sperm counts can still successfully inseminate their partners. Some lifestyle changes and increasing the frequency of sexual intercourse to once every two or three days, especially around the time of the female’s ovulation, are advisable to increase the chances of conception. Other options are available for those who cannot conceive, such as in vitro fertilization (IVF). This involves retrieving the oocytes from the woman and mixing them with the man’s sperm outside the woman’s body to achieve fertilization, following which the embryo is cultured and returned to the woman’s uterus within a few days to implant and grow into a pregnancy.

Intracytoplasmic Sperm Injection (ICSI) is a newer in vitro fertilization technique that uses a single sperm that is injected into the cytoplasm of the oocyte to fertilize it directly, following which normal in vitro fertilization procedures are implemented. Avoid male low sperm count instead of treating it, and is appropriate for men with few or few sperm in their sperm, or if the sperm are dead or immobile.

Donor insemination is the use of another man’s sperm to fertilize a woman’s oocytes, either by artificial insemination or by in vitro fertilization, with the consent of both partners. It is most commonly used when humans have a genetic disease that could be passed on to offspring. Drugs that stimulate gonadotropins or gonadotropin substitutes (GnRH agonists) can be used to increase sperm production if the man is hypogonadal. But they are not helpful in idiopathic infertility.

Finally, if a lack of nutritional factors is suspected, supplements based on carnitine, coenzyme Q, zinc, omega-3, folic acid, arginine and other amino acids or nutritional factors can be used. Any deficiencies in antioxidants should also not be underestimated. For example, it is well recognized by the scientific community that vitamins C and E are protective of the reproductive system.

  • Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.

Scientific references

Pelzman DL et al. Transl Androl Urol. 2021; 10(3):1354–64.

Dong M, Li H et al. Front Genet. 2021 Mar 31; 12:617133. 

Dcunha R, Hussein RS et al. Reprod Sci. 2020 Dec 7:1-19.

Smits RM et al. Reprod Biomed Online 2019; 39(6):963-968.

Krausz C, Rieri-Escamilla A. Exp Suppl. 2019;111:341-366. 

KrausZ C, Rieri-Escamilla A. Nat Rev Urol 2018;15(6):369-84.

Wosnitzer MS. Transl Androl Urol. 2014 Mar; 3(1):17–26.

McLachlan RI. J Clin Endocrinol Metab 2013; 98(3):873-80.

Montjean D, Ravel C et a. Fertil Steril. 2013; 100(5):1241-47.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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