By Aysha Uddin, MRes Reproductive Science & Women's Health, University College London, reviewed by Jack Fertility Chief Scientific Officer, Maryam Rahbar.
Klinefelter syndrome ("KS") is one of the most common genetic disorders affecting people with sperm, with a prevalence of 1 in 500 live male births globally [1]. Those with Klinefelter syndrome are born with an additional X chromosome resulting in a chromosomal variation of 47, XXY as opposed to the usual 46, XY karyotype in most men.
Klinefelter syndrome is the main chromosomal disorder associated with male infertility. Many of those with KS will only receive a diagnosis in adulthood, which is, in many cases, a result of fertility testing. At Jack Fertility, we are committed to ensuring that people with sperm are provided with the knowledge to better understand and test their unique fertility potential.
In this post we will cover:
Common symptoms of Klinefelter syndrome that contribute to infertility, such as, low testosterone levels, small testes, and lack of sperm
Diagnosis through hormonal blood tests and chromosomal analysis
Treatment options to manage Klinefelter syndrome such as Testosterone Replacement Therapy
Fertility treatment options for those with Klinefelter’s including surgical sperm retrieval techniques and hormonal stimulation
What are Common Symptoms of Klinefelter Syndrome?
Common symptoms of Klinefelter syndrome vary depending on the age of the individual. In infancy children may display signs such as lack of energy, undescended testes, and delayed development in speech, or motor skills like learning to crawl [2]. Klinefelter’s is not commonly diagnosed in children as symptoms are typically mild, and can go unnoticed in childhood. However, undescended testes can be problematic later in life with regards to fertility.
During puberty and adolescence common symptoms of Klinefelter’s include small firm testes or a small penis, gynecomastia (enlarged breast tissue), weaker bones, speech and learning difficulties [2]. Young people with Klinefelter syndrome may also experience difficulty navigating social interactions and display signs of low confidence. This may discourage individuals from exploring their fertility potential earlier on in life. At Jack Fertility we look to provide at home sperm test kits which provide a comfortable, discreet, and confidential alternative to traditional fertility checks.
Symptoms that are often associated with Klinefelter’s include having broader hips, longer limbs and being taller than the average height. However, such symptoms are not usually apparent in most patients and are very rarely the cause for diagnosis.
In adulthood, additional symptoms that men with Klinefelter syndrome may also experience are a low sex drive, lack of facial and body hair and erection problems [2]. In comparison with their peers or family members, individuals with Klinefelter’s may also display a lack of muscle.
The symptoms described are experienced by many and in most cases are not caused by Klinefelter syndrome. Symptoms of Klinefelter’s being common amongst men and relatively harmless, leads to most Klinefelter diagnoses being made in adulthood, which is in many instances a result of fertility testing.
How does Klinefelter Syndrome Affect Fertility?
Men with Klinefelter’s typically struggle to conceive without assisted technologies due to hypogonadism, defined as a lack of sufficient sex hormone in the body, and non-obstructive azoospermia (no sperm in the ejaculate).
Male hypogonadism, affecting approximately 35% of men over the age of 45, is the term used to describe low testosterone levels. Hypogonadism is of two types, primary and secondary. Primary hypogonadism is caused by a problem with the testes. Secondary hypogonadism is caused by a problem in the hypothalamus or pituitary gland, which are parts of the brain responsible for testosterone production in the testes.
Those with Klinefelter syndrome are mainly affected by primary hypogonadism, due to underdeveloped testes resulting in lower levels of testosterone being produced.
Azoospermia, defined as the absence of sperm in the ejaculate, also consists of two types. Obstructive azoospermia (OA) and non-obstructive azoospermia (NOA). Obstructive azoospermia is when an obstruction caused by a physical abnormality such as blocked tubes or a missing connection in the reproductive tract, prevent sperm from passing through to the ejaculate. Non-obstructive azoospermia, which affects many of those with Klinefelter syndrome, occurs when there is a hormonal imbalance which is responsible for the lack of sperm production in the testes, resulting in the absence of sperm in the ejaculate.
Men with Klinefelter syndrome typically have very low sperm counts or produce no sperm at all. However, sperm can still be present in the testes of 50% of men with Klinefelter’s who may experience other lowered sperm parameters [3]. Fertility investigations where hormone testing and karyotype analysis is conducted diagnoses the majority of Klinefelter patients. Karyotype analysis is a form of genetic testing, also known as chromosomal screening, it is a test conducted to confirm the diagnosis of Klinefelter’s by checking the size, structure, and number of chromosomes.
Abnormal semen analysis could result in further testing including hormonal blood tests which may help to diagnose Klinefelter’s. A blood sample can highlight abnormal hormone levels, such as low testosterone, high luteinising hormone (LH) and follicle stimulating hormone (FSH) as well as high sex hormone binding globulin (SHBG).
Can Klinefelter Syndrome be Treated?
Klinefelter syndrome has no cure or form of treatment to correct the chromosomal abnormality, however there are several treatment options to help reduce the effects of Klinefelter’s. A widely used and very common form of treatment is testosterone replacement therapy (TRT) [4]. This form of treatment targets and can minimise many of the symptoms of Klinefelter’s such as promoting development during puberty. Effects of TRT include the development of body and facial hair, voice change, increase of libido, and gaining of muscle mass. Aside from puberty, TRT also supports individuals throughout adulthood by increasing bone density and reducing the likelihood or severity of osteoporosis. TRT has also been shown to prevent low mood and increase energy. However, testosterone replacement therapy cannot treat, or reverse infertility caused by Klinefelter syndrome. In fact, TRT may inhibit fertility further and therefore many practitioners may choose to start Klinefelter patients on TRT post fertility treatment.
Many symptoms of Klinefelter syndrome associated with infertility are caused due to a lack of testosterone, namely the absence of sperm or low sperm count. However, Testosterone replacement therapy exogenously (externally) administers testosterone to the body [4]. This causes the body to cease in the production of FSH and LH. Which are hormones required for stimulating the production of sperm. Increasing your blood testosterone levels by taking exogenous testosterone does not increase sperm production. When the body detects exogenous testosterone, it stops sperm production because of the imbalance of hormones within the body.
What Fertility Treatment Options are there for Klinefelter’s?
For people with Klinefelter syndrome fertility treatment options include surgical sperm removal techniques known as a Conventional Testicular Sperm Extraction (cTESE) or a micro-TESE (mTESE). This is where sperm samples are extracted directly from the testes and is employed in instances where viable sperm is absent in an individual’s ejaculate.
If viable sperm is found in the extracted samples, they can be frozen or used immediately in an ICSI procedure. An intracytoplasmic sperm injection (ICSI) is where oocytes (eggs) are fertilised by injecting extracted sperm directly into the oocytes.
Recent studies have evaluated the use of hormonal stimulation to induce and increase sperm production in those with Klinefelter syndrome [5]. Such treatment aims to increase testosterone levels by administering human chorionic gonadotropin (hCG) or Clomiphene (Clomid) to patients prior to surgical sperm extraction, in the hopes of improving success rates of surgery for those with Klinefelter’s.
Clomid (clomiphene citrate) functions by blocking oestrogen and as a result stimulating increased LH production in the pituitary gland. LH causes testicles to make testosterone which in turn leads to increased sperm production.
hCG functions in the body as LH would do, by promoting the production of testosterone. By inducing increased testosterone production, hCG aides in improving sperm count. For patients undergoing surgical sperm extraction this may increase the likelihood of a successful outcome. This is different to TRT which directly increases testosterone levels using an external source but hinders fertility, whereas hCG stimulates testosterone production by mimicking LH in the body, promoting fertility.
Klinefelter patients may undergo surgical sperm removal techniques and still find no viable sperm present in their testes. This 2021 Study found that surgical sperm extraction success rates were 21.4% for patients with Klinefelter syndrome. However, when combined with hormonal stimulation, success rates have been shown to increase to 55%. For cases with less positive surgical outcomes, options such as a repeat TESE, the use of donor sperm and adoption may be explored.
Where to Begin?
Male fertility investigations begin with a semen analysis, which provides an in-depth examination of a variety of semen parameters. The results provide a clear picture of an individual’s current fertility potential and highlight any causes for concern, which can then be explored further with a specialist.
Klinefelter syndrome while being one of the most common genetic disorders in men, is still a relatively rare condition to be diagnosed with. If you suspect that you may have Klinefelter syndrome please visit your GP or primary care physician for further support.
At Jack Fertility we aim to provide a postal semen analysis test kit which can be carried out from the comfort of your home. Giving you lab-grade results that will provide you with what you need to know about your current fertility status. Sign up to be the first to know!
References
1. Plotton, I., et al., Fertility in men with Klinefelter's syndrome. Ann Endocrinol (Paris), 2022. 83(3): p. 172-176.
2. Nassau, D.E., et al., Androgenization in Klinefelter syndrome: Clinical spectrum from infancy through young adulthood. J Pediatr Urol, 2021. 17(3): p. 346-352.
3. Paduch, D.A., et al., New concepts in Klinefelter syndrome. Curr Opin Urol, 2008. 18(6): p. 621-7.
4. Gravholt, C.H., et al., Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr Rev, 2018. 39(4): p. 389-423.
5. Naylor, K.C., G.; Uddin, A.; Williamson, Elizabeth; Ralph, D.; Sangster, P., Does implementing a new protocol for the induction of the spermatogenesis pathway in Klinefelter patients result in improved sperm retrieval? European Urology, 2023. 83: p. S958.