Azoospermia Treatment Ankara

Male infertility is one of the important health problems seen with increasing frequency every decade.

In industrialized society, waste products produced in industrialized and mechanized societies, environmental toxins, radiation, electromagnetic fields, GMO foods, alcohol, smoking, drugs, medications, and many other causes are gradually decreasing male reproductive potential with each passing day.

As a result, the sperm count is gradually decreasing with each ejaculation and even reaching zero.

Azoospermia stands before us as an important problem in this regard. It is the name given to the complete absence of sperm in semen. It can be seen in approximately 10-15% of all infertile patients.

It can occur due to congenital genetic problems or can develop later through various toxins.

In the articles below, medical information cited from various articles is provided in a way that provides detailed answers to all possible questions in your mind, starting with “what is azoospermia?”.

What is Azoospermia?

Azoospermia is the complete absence of sperm in the semen provided through ejaculation after appropriate sexual abstinence. Normal sperm testi a sperm test is generally given on the 4th day after 3 days of sexual abstinence.

When there are no sperm cells with fertilization potential in this provided amount (ejaculate), it is called azoospermia. However, at least 2 different sperm tests must be performed to confirm the absence of sperm, and the absence of sperm must be determined in both.

How Common is Azoospermia?

Azoospermia is observed at a rate of 1% when all men are considered. Among infertile men who consult a doctor with the desire to have children, this rate is observed at around 10-15%. This rate is quite significant, especially in patients who desire children.

Types of Azoospermia

Azoospermia is roughly evaluated under two categories:

• Obstructive Azoospermia:

Azoospermia can be seen when there is a stricture in the vas deferens (the seminal duct), at the point where the seminal duct opens into the channel inside the penis called the urethra, or anywhere in the channel inside the penis through which sperm produced in the testicles travels.

These strictures can be congenital or can develop after previous infections, surgeries, and certain medications.

• Non-Obstructive Azoospermia:

It is the condition where sperm cannot be produced as a result of congenital or acquired damage to anatomical structures without any stricture at any point from the testicles to the expulsion from the tip of the penis. This condition is observed more frequently than obstructive azoospermia.

Causes of Azoospermia

There are many factors that cause azoospermia. The testicles are the production center of sperm cells related to reproduction. However, problems related to the testicle alone do not cause azoospermia. However, other factorswith the addition of other factors, the causes of azoospermia are examined under 3 main headings:

• Pre-Testicular Causes:

The term pre-testicular is used for azoospermia that occurs as a result of disorders in reproductive-related structures before the testicles. What is often meant by this expression is endocrine disorders. The hormones that trigger reproduction are produced in organs called the hypothalamus and pituitary gland in the brain.

The hormones produced here enter the systemic circulation through brain vessels and reach the testicles to stimulate the reproductive cells in the testes. Therefore, diseases of the hypothalamus or pituitary gland prevent sufficient stimulation from reaching the testicles, and this can result in azoospermia.

• Testicular Causes:

The male reproductive cell that fertilizes the female egg to enable having children is the sperm. The production site of sperm is the testicles. Therefore, congenital or all factors that develop later can also cause azoospermia. Among the leading congenital pathologies are undescended testicle occurs.

The complete lack of testicular development from birth or the failure of the formed testicle to descend into the scrotum can impair sperm production.

This condition can also result in azoospermia.Additionally, subsequently occurring traumas, medications used, chemotherapy medications, radiotherapy, and Varicocele Surgery Ankaravaricocele many such conditions are also known as testicular causes among azoospermia causes.

• Post-Testicular Causes:

Post-testicular factors can also cause azoospermia. The main point here is that stricture in the vas deferens, the anatomical canal that carries semen, along with ejaculatoryejaculatory dysfunctions (ejaculation disorders) are also examined in this group. Briefly, this condition is evaluated in 2 groups within itself.

• Vas Deferens Pathologies:

Duktus deferens, is an anatomical structure that functions in the ejection of sperm formed in the testicles into the canal within the penis. It has a firmer consistency compared to other anatomical structures around it. It is quite effective in the transport of sperm.. Sometimes this structure is completely absent from birth.

Sometimes, obstruction occurs within it due to various diseases or traumas and sperm cannot be transported. Male birth control method voluntary azoospermia can also be created by surgically tying the vas deferens.

3b. Ejaculatory dysfunction (ejaculation disorders):

Azoospermia can also be seen in cases of anejaculation, the inability to ejaculate. Here, even if sperm has been produced and the transport channels are normal, no sperm appears in the semen due to the inability to ejaculate.

What Genetic Diseases are Associated with Azoospermia?

Genetics is the biological heritage passed down to us from our parents. Our genetic infrastructure forms the foundation of our biological building blocks. Unfortunately, the basis for the development of certain diseases is formed while we are still in the womb.

We roughly know that this genetic infrastructure is also intact in men with reproductive potential. However, the situation is somewhat different in patients with azoospermia. In some of these patients, certain disorders can be found in the genetic infrastructure that forms reproductive potential.

Genetic disorders seen in patients with azoospermia are examined under 4 main headings, and separate evaluations are required for each.

1. Kromozom anomalileri:

There are chromosome anomalies that disrupt testicular function. In normal individuals, there are a total of 46 chromosomes: 22 pairs of autosomes (44 total) and 1 pair of sex chromosomes (2 total). One of the sex chromosomes, called gender chromosomes, is X and the other is Y (46XY).

Chromosome anomalies are observed at a rate of approximately 0.5% in the normal population. However, when compared with the normal population, this incidence gradually increases in infertile couples and is approximately 5.8%.

Chromosome anomalies are observed at different rates in autosomal chromosomes or sex chromosomes separately. While sex chromosome anomalies are seen at a rate of 4.2% in infertile individuals, autosomal anomalies are observed at a rate of 1.5%. As can be understood from these rates, sex chromosome anomalies are observed more frequently than autosomal anomalies in infertile individuals.

Chromosome anomalies are also examined in 2 groups within themselves:

1a. Structural anomalies:

This refers to disorders seen in the elements that form the basic building blocks of chromosomes. These occur in the following forms:

• Delesyon
• Inversion: 8 times more common in infertile men.
• Duplikasyon
• Translocation: 8.5 times more common in infertile men.

1b. Numerical anomalies:

It is used to express deficient or excess numbers in chromosomes.

• Polyploid, containing more than one copy of all chromosomes
• Cells containing an addition or deletion of one or more chromosomes are in aneuploid form.

The frequency of numerical chromosome anomalies is high in infertile men. These are frequently seen in the following forms:

• Klinefelter Syndrome
• Mixed gonadal dysgenesis
• XYY males

Klinefelter Syndrome, is the most common sex chromosome disorder. It is observed 30 times more frequently in infertile men compared to the male population in the general society. This syndrome is found at a rate of 14% in patients with azoospermia.da is observed.

Important note!!!

Autosomal trisomy and sex chromosome aneuploidies can be seen at higher rates in pregnancies resulting from IVF (ICSI).

Therefore, when numerical or structural chromosome anomalies are detected in patients before ICSI, if your doctor deems it appropriate, genetic counseling, preimplantation genetic diagnosis, and amniocentesis or chorionic villus sampling may be needed.

2. Y Kromozom Mikrodelesyonu:

A deletion point has been identified on the long arm of the Y chromosome in azoospermic men, and this region has been specifically named the AZF region. The genes in this region are specifically related to sperm formation. These deletions are classified under 3 headings:

• AZFa deletions
• AZFb deletions
• AZFc deletions

One of the important causes of defects seen in the sperm formation stage is deletions occurring in these AZF regions. The prevalence in idiopathic azoospermia (where the cause cannot be exactly determined) is approximately 15-20%. while in patients with idiopathic oligozoospermia (low sperm count of unknown cause), this rate is approximately 7-10%.

3. Cystic fibrosis gene mutations causing congenital vas deferens agenesis:

One of the important genetic diseases with autosomal recessive inheritance is Kistik Fibrozis disease. This disease Cystic Fibrosis Transmembrane Regulator (CFTR) is caused by mutations in the gene. In these patients, there is generally no bilateral development of the vas deferens (semen duct). On physical examination, bilateral vas deferens cannot be palpated.memesi in case of infertil bir in the patient must always be considered and investigated in this regard.

4. Genetic syndromes directly affecting sperm functions

Certain genetic syndromes directly affect the stages of sperm formation, leading to infertility and azoospermia. Some of these syndromes are listed below:

• Primary ciliary dyskinesia
• Myotonic dystrophy
• Usher Syndrome
• Noonan Syndrome
• Sickle Cell Anemia
• Genetic endocrine disorders
  • GnRH production and release disorders (Kallman syndrome and Prader-Willi Syndrome)
  • FSH and LH function disorders
  • Androgen synthesis and function disorders

As a result;

As listed above, azoospermia is observed in many genetic diseases, primarily Klinefelter Syndrome and Y Chromosome Microdeletions in the AZF regions.

What are the Symptoms of Azoospermia?

We can say that azoospermia symptoms normally do not exist since it can only be understood when a sperm test is given. More accurately, there is no direct clinical symptom indicating azoospermia.

However, the presence of a pre-existing genetic disease, trauma to the testicles for any reason, or having received chemotherapy, surgery, or radiotherapy may suggest a risk of azoospermia.

What are the Risk Factors for Azoospermia?

Rather than findings directly pointing to azoospermia, risk factors that may suggest it are more meaningful. Therefore, we can list some of the following conditions as risk factors for azoospermia:

• Bilateral vas deferens agenesis
• Testicular trauma
• Genetic syndromes
• Chromosome disorders
• Presence of Y chromosome microdeletions
• Bilateral congenital absence of testicles
• Bilateral undescended testicle
• Kemoterapi
• Radyoterapi

What Should Be Considered During Azoospermia Examination?

The most important aspect to pay attention to during examination in azoospermia patients is the testicles. Normally, two testicles are located within the skin called the scrotum. The points to pay attention to during testicular examination are:

• Are both testicles present?
• Are both testicles in their proper position?
• Is there a size difference between the two testicles?
• Is there a consistency difference between the two testicles?
• Is there dilation (varicocele) in the vessels surrounding both testicles?
• Is there swelling or redness in the skin surrounding both testicles?
• Is there pain on palpation of both testicles?
• Is there increased warmth on palpation of both testicles?
• Is there swelling in both testicles?
• Is there redness in both testicles?

In addition to the testicles, the structure of the epididymis and vas deferens should also be evaluated in detail during examination. It should not be forgotten to also check for penile diseases during the examination.

Which Hormonal Diseases are Associated with Azoospermia?

There are many different hormonal diseases that cause azoospermia. Some of these are diseases mainly related to the central nervous system (brain) that we listed among pretesticular causes. Another part is related to the production of testosterone (male hormone) from the testicles.

• Hypothalamic diseases
• Pituitary gland diseases
• Thyroid disorders
• Hypogonadotropic hypogonadism
• Kallman Syndrome
• Klinefelter Syndrome
• Isolated FSH Deficiency Syndrome
• Bilateral undescended testicle

Is Azoospermia Genetic?

Not all azoospermia cases develop due to genetic disorders. However, various genetic disorders are observed in approximately 15-20% of men with azoospermia.

Can Azoospermia Be Treated?

It completely depends on the cause of the azoospermia. While improvement in azoospermia is not expected in certain genetic diseases (such as complete AZF deletions), in some hormonal diseases (such as hypogonadotropic hypogonadism), the azoospermia condition can be completely resolved with treatment.

The essential thing to predict whether azoospermia will resolve is to identify the cause of the azoospermia.

What Genetic Diseases are Associated with Azoospermia?

Klinefelter syndrome is among the most commonly seen genetic diseases. Y chromosome microdeletions, Primary ciliary dyskinesia, Myotonic dystrophy, Usher Syndrome, Noonan Syndrome, Sickle Cell Anemia, Genetic endocrine disorders, and many other genetic diseases show association with azoospermia.

How is Azoospermia Diagnosed?

To diagnose azoospermia, a diagnosis is made when no sperm cells can be seen in the semen test given on the 4th day following a 3-day sexual abstinence period. However, to confirm the azoospermia diagnosis, if no sperm is seen in the first semen test, a second test must definitely be performed.

What Genetic Tests are Used in Azoospermia Diagnosis?

There are 2 important tests routinely used today in evidence-based medicine for azoospermic men:

• Chromosome Analysis
• Y Chromosome microdeletion

In addition to these tests, many recommended genetic tests have been identified. While certain genetic markers provide information about the spermatogenetic process, they are used for research purposes and are not tests whose clinical validity has been confirmed.

However, we know that especially the sperm FISH test, determination of haploid/diploid cell ratios, and certain genetic markers are prominent.

What Testicular Diseases Cause Azoospermia?

When we look at testicular diseases that cause azoospermia, many factors negatively affect the testicles and lead to azoospermia, including congenital absence of testicles, undescended testicle, any trauma to the testicles, varicocele, testicles being affected during childhood mumps infection, testicular cancers, chemotherapy drugs used during various cancer treatments, and radiotherapy.

What is the Relationship Between Azoospermia and FSH?

Follicle Stimulating Hormone (FSH) is a hormone secreted from the anterior part of the pituitary gland in the brain. This hormone enters the systemic circulation from the brain, reaches the testicles, and initiates and maintains sperm formation.

In azoospermic men, especially in cases of primary testicular failure (e.g., Klinefelter Syndrome), when there is insufficient production in the testicles, more stimulation is sent from the brain to the testicles. Therefore, excessive FSH secretion occurs and consequently, FSH is found at high levels in the blood.

However, there is no rule that elevated FSH will be found in every azoospermia patient. FSH levels vary according to the cause of the azoospermia. For example, in men with azoospermia due to hypogonadotropic hypogonadism, FSH is actually low.

Can Azoospermia Be Temporary?

This condition can vary depending on the cause of the azoospermia. Therefore, a diagnosis of azoospermia is made when sperm cannot be found despite at least two semen tests. In the first sample, sometimes when the patient does not fully know how to provide a sperm sample, sperm may not appear when the ejaculate is spilled.

Due to a very simple sample-providing error, the patient may be told they have azoospermia. In addition, azoospermia can sometimes be temporarily seen during urogenital or systemic infections.

Does Azoospermia Resolve on Its Own?

This situation is closely related to why the azoospermia occurred. When the cause of the azoospermia resolves spontaneously or improvement is achieved with various treatments, improvement in azoospermia is also seen.

However, this information should not encourage patients to wait for spontaneous improvement and should not delay consulting a doctor to fully understand the cause.

Because in terms of determining the process and planning treatment, there is also a race against time.

What Radiological Methods are Used in Azoospermia Diagnosis?

There is no specific radiological method used for azoospermia diagnosis. However, there are some radiological imaging methods that can be performed while investigating the cause of azoospermia through indirect means.

• Skrotal Ultrasonografi

Scrotal ultrasonography may be needed to determine the location and size of both testicles and to identify causes of azoospermia that may occur in extra-testicular anatomical structures.

• Transrektal Ultrasonografi:

It may be needed especially in patients with obstructive azoospermia to demonstrate seminal vesicle and distal ejaculatory duct pathologies.

• Magnetic Resonance Imaging

In addition to being useful for demonstrating hypothalamic and pituitary pathologies in the brain, MRI may also be preferred for demonstrating distal ejaculatory duct obstructions in obstructive azoospermia. MRI may also be needed for investigating the presence of undescended testicles or demonstrating the presence of bilateral vas deferens.

How is Duct Obstruction Detected in Azoospermia?

There are some clues that suggest duct obstruction:

• Semen analysis checking volume: If the amount of semen provided is under 1.5 ml
• Investigating biomarkers in semen: Obstruction can be predicted by determining various genetic or biochemical biomarkers in semen. For example, checking fructose in semen.
• Radiological imaging methods: Obstruction can be investigated with various methods such as scrotal ultrasonography, transrectal ultrasonography, or magnetic resonance imaging (MRI).

What is the purpose of ultrasound use in azoospermia?

Ultrasonography is of great importance in azoospermia investigation. Therefore, it is mostly preferred in azoospermia investigations. In addition to being inexpensive, being non-invasive is also a separate reason for preference. To summarize all this information, ultrasonography is mostly requested for the following:

• Investigating whether the testicles are in their proper position
• Determining the size of the testicles
• Obtaining information about the organ called the epididymis outside the testicles
• Information about the sperm transport channels known as the vas deferens
• Examination of the vessels feeding the testicles
• Evaluation of seminal vesicles when performed rectally
• Demonstration of distal ejaculatory duct cysts via rectal route

Can azoospermia occur by blocking sperm exit?

Yes, it can occur. This condition is called obstructive azoospermia in medicine. When there is an anatomical barrier blocking sperm exit, it can be seen as azoospermia.

However, “when sperm exit is blocked” what is meant is deliberately preventing semen from coming out by blocking its flow during masturbation, this has no relation to the obstructive azoospermia mentioned above.

How is Azoospermia Treated?

The treatment of azoospermia varies depending on the cause. In obstructive azoospermia, if possible, removing the obstruction through medical or surgical means can treat the disease.

In non-obstructive azoospermia, treatment also varies depending on the cause. In this group of patients, medical and hormonal medications can be used, and in case of failure of such treatments, it is possible to search for sperm from within the testicles using a method called micro-TESE.

What Medications are Used in Azoospermia?

Some of the medications frequently used in azoospermic patients are listed below. Who these medications will be used by, at what dose, and for how long is entirely under the knowledge and control of the physician.

• Antioxidant medication treatments
• Hormonal medication treatments

Which Surgical Methods are Used in Azoospermia Treatment

The surgical method frequently applied in azoospermia treatment is searching for sperm from both testicles with surgeries such as micro-TESE, TESA, MESA, and PESA. However, in cases of obstructive azoospermia, TURED surgery can also be performed to open the distal ejaculatory duct obstruction.

Additionally, in cases of clinically significant and advanced varicocele (venous dilation) accompanied by testicular shrinkage, although the chance of success is low, it may sometimes be preferred depending on the patient’s characteristics. In addition to the surgical procedures above, if a specifically identifiable cause is found, specific surgical options for that condition are also available for the relevant structure.

What is the Most Successful Method in Azoospermia Treatment?

The important criterion determining success in azoospermia treatment is identifying the cause of the azoospermia.

When this cause is identified, success will also be achieved in the treatment initiated for it. While success can be achieved with medication treatment alone in some patients (such as hypogonadotropic hypogonadism), surgical methods may be the solution in others.

IVF Chances in Azoospermia

The essential issue in the treatment of azoospermic patients is obtaining sperm. This sperm can be obtained through spontaneous ejaculation, or in case sperm cannot be found in the semen, by opening the inside of the testicle mikroTESE method can also be used to obtain it.

Since the conditions that cause azoospermia have many different reasons, each must be addressed separately and IVF chances must be evaluated accordingly. If sperm has been obtained as a result of treatment, it certainly means there is a chance for IVF.

Is Natural Pregnancy Possible in Azoospermia?

Of course it is possible. However, it is closely related to the cause of the azoospermia and its successful treatment. Especially azoospermia resulting from congenital disorders such as hypogonadotropic hypogonadism can be successfully treated, and natural pregnancy may be possible afterward.

What is the Association Between Azoospermia and Varicocele?

Varicocele is the advanced dilation of the vessels carrying deoxygenated blood to the testicles. This dilation negatively affects sperm functions in terms of the toxins it contains and the increase in temperature. Varicocele is found in a portion of azoospermic patients.

However azospermisi olan ve beraberinde varicocelei olan in patients, varicocele surgery treatment, reported studies on spontaneous sperm production report increases in sperm counts at quite low rates.

Azoospermia and Testicular Biopsy Applications

Testicular biopsy solely for diagnostic purposes in azoospermia patients has been abandoned today. If a biopsy is planned in these patients, there is a consensus among experts that it would be appropriate to search for sperm using the micro-TESE method and use the obtained sperm in IVF treatment in the same session.

What Surgeries are Performed in Azoospermia Cases?

There are many centers performing azoospermia and infertility treatment in the Cukurambar area of Ankara.

Micro-TESE is one of the most commonly performed surgeries in these centers and worldwide. In addition, many surgeries such as TESA, PESA, MESA, TURED, or to a lesser extent microscopic varicocelectomy are applied.

Can Azoospermia Be Treated with Alternative Medicine and Herbal Methods?

Today, the term “alternative medicine” is no longer used by many physicians. Instead, the term “complementary medicine” is used more commonly. The essential approach in azoospermia treatment is evidence-based medicine that uses methods whose effectiveness and reliability have been proven.

It is important to know that treatments outside of this cannot form the basis of azoospermia treatment. It should not be forgotten that all methods that can be used in this scope can however be “complementary”.

What Side Effects May Occur in Patients Who Have Azoospermia Surgery?

What is often meant by this question is micro-TESE surgery. Although side effects that may occur after these surgeries are few, hematoma, bleeding, or infection in the testicles may still be seen in the early period. In the late period, decreased testicular volume and related symptoms are prominent.

Can Azoospermia Be Improved with Acupuncture Treatment?

Although there are studies in the literature where acupuncture treatment was tried in patients with azoospermia and publications reporting success in a small number of them, there are no long-term, randomized studies with sufficient case numbers. Therefore, no improvement rate has been reported that could go beyond being a complementary medical method.

Is Azoospermia Related to Eating Habits?

There are studies indicating the relationship between dietary habits and sperm functions. Many dietary patterns such as obesity, increased weight gain, fast-food style food consumption, excessively fatty diet, and diets excessively rich or poor in carbohydrates negatively affect sperm functions.

However, it is known that various food products consumed, especially antioxidant foods, also have a positive effect on azoospermic patients.

What are the Recommendations for Individuals with Azoospermia?

• Doctor examination and check-up to investigate the cause of azoospermia
• Regulating eating habits
• Ensuring regular sleep patterns
• Avoiding environmental toxins
• Avoiding substances such as cigarettes, alcohol, and drugs
• Fighting obesity
• Regular exercise
• Reorganizing lifestyle habits
• Use of effective medications monitored by a specialist
• Full motivation for psychological recovery
• Limiting the use of various medications

How Can Azoospermia Be Prevented?

If the azoospermia is due to a congenital cause, treatments are planned to improve the current condition, not for new formation. In acquired azoospermia, the most critical event is clearly and definitively identifying the cause of the azoospermia.

When the cause of azoospermia is eliminated, the problem will also be resolved on its own. For example, removing a known environmental factor or adjusting medications that could lead to azoospermia may serve as a preventive measure.

What Factors Affect Success in Male Factor Infertility Treatment for Azoospermia?

Some of the factors affecting treatment success are listed below:

• Genetic factor
• Patient age
• Cause of azoospermia
• Testicular volume
• Initial FSH level
• Testosterone (male hormone) level

When Should Couples with Azoospermia Start IVF Treatment?

The clear answer to this question can be given by the physicians evaluating the couple. The exact date is determined after Andrological examination for the male factor and Gynecological examination and evaluations for the female factor are completed.

Which Hormone Tests are Checked for Azoospermia?

• FSH
• LH
• Estradiol
• Total testosterone (male hormone)
• TSH
• Prolaktin

Does Azoospermia Hormone Treatment Take Long?

While the duration of hormone treatment varies depending on the existing disease, it can range from 3-28 months, especially in azoospermia patients. It is appropriate for the relevant physician to make this decision.

Are There Congenital Diseases in Children of Those with Azoospermia?

There is no reported scientific difference in terms of congenital diseases between those who have azoospermia and have children and those who do not have azoospermia and have children.

Can Pathology Results Predict Treatment Success in Azoospermia?

In azoospermia patients, if sperm cannot be found during the micro-TESE procedure, pathological samples are often sent to investigate the presence of sperm precursor cells. The results from these pathological samples are expected to provide predictions about subsequent treatment success. Especially in results reported as hypospermatogenesis, more sperm can be obtained later with treatment.

Can Azoospermia Be Treated with the ROSI Technique?

Azospermili in patients mikroTESE in some cases where mature sperm cannot be obtained by this method, round sperm cells whose neck and tail parts have not yet formed are obtained, and their fertilization with the female egg can be performed.tedir.

References:

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• The management of obstructive azoospermia: a committee opinion. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology. Fertil Steril. 2019 May;111(5):873-880.
• Management of non-obstructive azoospermia. Chiba K, Enatsu N, Fujisawa M.Reprod Med Biol. 2016 Jan 18;15(3):165-173.
• Review of Azoospermia. Wosnitzer M, Goldstein M, Hardy MP. Spermatogenesis. 2014 Mar 31;4:e28218.
• Innovations in surgical management of nonobstructive azoospermia. Ran R, Kohn TP, Ramasamy R. Indian J Urol. 2016 Jan-Mar;32(1):15-20.
• A step-by-step guide to office-based sperm retrieval for obstructive azoospermia. Coward RM, Mills JN.Transl Androl Urol. 2017 Aug;6(4):730-744.
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• Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A; Klinefelter ItaliaN Group (KING).J Endocrinol Invest. 2017 Feb;40(2):123-134.