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klinefelter syndrome histopathology

Image: “Micrograph of testis showing atrophic hyalinised seminiferous tubules and prominent Leydig cells. H&E stain.” by Department of Pathology, Calicut Medical College – Government Medical College, Kozhikode. License: CC BY-SA 4.0

Definition of Male Hypogonadism

Male hypogonadism implies decreased functioning of the male gonads, the testes, which is associated with either decreased production of testosterone and sperm or a decrease in testosterone’s effects on other organs.


Primary hypogonadism, also known as primary testicular failure, means the problem is thought to originate from the testes. 

Secondary hypogonadism, on the other hand, implies that a problem in the hypothalamus or the pituitary gland is responsible for testicular failure.

Each type of hypogonadism may be present at birth (congenital) or acquired later in life through injury or infection of the gland involved in hormone secretion.

Sex steroids LH (Luteinizing Hormone) FSH (Follicular Stimulating Hormone)
Primary hypogonadism (hypergonadotropic hypogonadism)
Pituitary hypogonadism (Hypogonadotropic hypogonadism)

Epidemiology of Male Hypogonadism

Male hypogonadism is common, especially in men over 45 years of age, with an estimated prevalence of 39%. The prevalence of hypogonadism in men can differ from one study to another, depending on the definition of low testosterone.

When hypogonadism is defined as a total testosterone level lower than 325 ng/dL, the prevalence can range from 12% to 49%, depending on the population’s age under study. Approximately half of the men over 80 have hypogonadism.

Etiology and Pathophysiology of Male Hypogonadism

To understand the etiologies and the different pathophysiological mechanisms of hypogonadism, it is helpful to classify patients into primary and secondary hypogonadism.

Primary male hypogonadism

klinefelter's syndrome

Image: “Signs of Klinefelter’s syndrome.” No machine-readable author provided. The cat~commonswiki assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims). License: CC BY-SA 3.0

Klinefelter’s syndrome is associated with primary male hypogonadism. The male has more than one X chromosome in addition to his Y chromosome. A normal male karyotype should include only one X and one Y chromosome. An extra X chromosome affects testicle development; it is associated with decreased testosterone production and eventually male hypogonadism.

Undescended testicles or cryptorchidism is also associated with an increased risk of infertility due to hypogonadism. The risk is highest when the child does not undergo corrective surgery early in childhood.

Mumps orchitis is a viral infectious disease that involves different glands, including the salivary glands, the pancreas, and the testicles.

Patients with hemochromatosis have an increased iron overload, which is believed to be responsible for abnormal testicular function in a subset of patients. Hemochromatosis can be linked to decreased testosterone production and hypogonadism.

Finally, patients with previous chemotherapy or radiotherapy treatment for any form of cancer can affect sperm production and testosterone. When no cause can be identified and the patient is over 80, it is very likely that hypogonadism is part of the normal aging process.

Secondary male hypogonadism

Secondary hypogonadism may be traced to a hormone deficiency. The hypothalamus produces a gonadotropin-releasing hormone to stimulate the pituitary gland, which releases the follicle-stimulating hormone and luteinizing hormone. These hormones activate the testis to produce testosterone. Kallmann syndrome is associated with anosmia and an underdeveloped hypothalamus, thus leading to hypogonadism. Patients with pituitary tumorsmicroadenomas, or brain tumors who undergo radiotherapy, are at risk of pituitary gland dysfunction and abnormal release of follicle-stimulating hormone and luteinizing hormone, which can cause hypogonadism.

Inflammatory diseases, such as sarcoidosis and tuberculosis, can involve either the hypothalamus or the pituitary and can cause dysfunctional release of the different hormones described above and eventually hypogonadism.

HIV/AIDS infection is associated with low testosterone levels because the virus affects the hypothalamus-pituitary testicular axis.

The use of opiate-based medication has also been associated with hypogonadism.

Clinical Presentation of Male Hypogonadism

Men with hypogonadism usually present with a history of infertility or because of absence or regression of secondary sexual characteristics, such as facial hair growth, body hair growth, or a change in the voice or libido. Patients can also present with muscle pain and reduced bone mass because testosterone is protective against osteoporosis.

Patients who present with infertility can have oligospermia. Patients might also complain of erectile dysfunction, and lower ejaculate volume. These patients also experience symptoms of depression, reduced stamina, and fatigue.

Diagnostic Work-up for Male Hypogonadism

Laboratory investigations for male hypogonadism

Early diagnosis is important to help the patient avoid problems associated with hypogonadism, which include delayed puberty and osteoporosis due to low estrogen levels.
Male hypogonadism can be diagnosed only when total serum testosterone levels fall below 300 ng/dL; hence, laboratory assessment of testosterone is needed. Testosterone sampling should be performed early in the morning since levels are highest during the morning and vary throughout the day.

The next step is to differentiate between primary and secondary hypogonadism. In primary hypogonadism, follicle-stimulating hormone and luteinizing hormone levels will be normal or elevated. In secondary hypogonadism, the hormone levels will be low.

If the diagnosis is secondary hypogonadism, the next step is to determine whether the condition is hypothalamic or pituitary related. Low follicle-stimulating hormone and luteinizing hormone levels with an elevated gonadotropin-releasing hormone indicate a pituitary problem. When all hormone levels, including gonadotropin-releasing hormone, are low, a hypothalamic etiology needs to be excluded.

Imaging and more advanced evaluation for male hypogonadism

Ultrasonography is helpful in patients with a suspected history of mumps orchitis or abnormal development of the testis. Patients without secondary sexual characteristics should undergo karyotype testing to exclude Klinefelter’s syndrome.

Patients suspected of having secondary hypogonadism due to a pituitary disorder should undergo a brain magnetic resonance imaging study to evaluate the pituitary gland and the hypothalamus.

A seminal analysis is also indicated to identify azoospermia, oligospermia, and/or abnormal sperm quality in terms of motility, configuration, or shape, which are common in men with hypogonadism and infertility.

A testicular biopsy might be indicated in a few patients to confirm abnormal testicular development, testicular inflammation, or necrosis, which can occur with mumps orchitis.

Treatment of Male Hypogonadism

Men who will undergo chemotherapy or radiotherapy for any form of cancer should be advised about the possible effects on future fertility. If fertility is an issue, they should be provided the option to collect and store sperm samples. However, this does not mean that men who have chemotherapy or radiotherapy will be infertile; it happens to a minority of patients.

The best treatment for male hypogonadism is testosterone replacement therapy. Different forms of testosterone replacement therapy exist. The choice of therapy depends on the patient’s preference, age, and expected goals.

Transdermal testosterone patches are more convenient than injection therapy but can put the patient at an increased risk of skin irritation, allergies, and contact dermatitis. Therefore, this option should be used with caution in the elderly who are more likely to have skin irritation.

Topical testosterone gels also can be used to restore normal testosterone levels and a normal circadian testosterone rhythm. They have also been associated with improved bone density and a lower risk of osteoporosis-related fractures.

Buccal testosterone tablets result in sudden increases in blood levels of testosterone, which resembles the endogenous pulsatile release mechanism. They are better tolerated than patches or gels.

Similar to progesterone implantable pallets, testosterone pallets have also been developed and successfully alleviated hypogonadism symptoms. The pallets can work for up to 6 months.

Intramuscular testosterone injections result in large fluctuations in testosterone blood levels. This can be associated with symptom fluctuations, but the treatment is successful overall. The advantages are less dosing, as the injections are usually taken every four weeks, and the injections are the most cost-effective option. The disadvantages include repeat clinic visits, injection site reactions, and abnormal testosterone fluctuations.

Oral testosterone tablets are also available for patients with Klinefelter syndrome or pituitary tumors. While most patients respond well to this therapy, they should be monitored for side effects, such as elevated blood pressure, increased red blood cell count, and nausea.

Patients with pituitary tumors should undergo microsurgery or endoscopic surgery to remove the pituitary adenoma. Hormonal replacement therapy of other hormones, such as growth hormone, prolactin, and gonadotropins, may also be recommended for patients with secondary hypogonadism.

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