Low Testosterone in Men

Typically, hypogonadism is categorized as either primary if the problem lies at the level of the testes (the testes just can’t make enough testosterone), or secondary, if the dysfunction is due to a hypothalamic or pituitary issue (the body’s hormone is not stimulating the testes enough to make testosterone). Tertiary, functional, and late onset hypogonadism are other terms used within some settings to describe specific subtypes of hypogonadism. Disease onset can happen at any point in life. Some individuals are born with the condition, while others may develop it during puberty or even later in adulthood. In many cases, the earlier the onset of symptoms, the more severe the manifestation. Late-onset hypogonadism is frequently masked by and mistaken for other symptoms linked to aging.

Primary Hypogonadism

Low testosterone caused by impaired testicular function is termed primary hypogonadism. This condition commonly arises from various factors such as testicular injury, genetic disorders, autoimmune or viral diseases, infections, or exposure to chemotherapy and radiation.

The most prevalent genetic disorder linked to primary hypogonadism is Klinefelter syndrome. This condition is characterized by an extra X chromosome in individuals typically assigned male at birth. Additionally, issues like improper testicular development or failure of the testicles to descend can contribute to primary hypogonadism.

Viral infections, such as mumps, which can lead to mumps orchitis (inflammation of the testes), as well as HIV, are also associated with primary hypogonadism.

Primary hypogonadism is also called hypergonadotropic hypogonadism as the brain (pituitary gland) attempts to compensate for the reduced testosterone and sperm productio within the testes by overproducing (hyper-producing) the gonadotropins FSH and LH.

Patients with elevated LH levels but testosterone levels within the normal range may have a condition referred to as compensated or subclinical hypogonadism, sometimes referred to as mild primary hypogonadism. In this scenario, although there is a slight deficiency in testosterone, the overall levels may still fall within the normal range and the accompanying increase in LH is a result of the body's effort to stimulate the testes to produce more testosterone, compensating for the deficiency. Compensated hypogonadism has the potential to progress into primary hypogonadism over time.

Secondary Hypogonadism

Low testosterone resulting from issues in the hypothalamus or pituitary gland is termed secondary hypogonadism, also known as central hypogonadism. Various factors can lead to this condition, including conditions that you are born with (congenital), infections, traumatic brain injuries, tumors of the hypothalamus or pituitary gland, certain drugs like anabolic steroids and opiates, and exposure to radiation.

Additionally, chronic systemic diseases such as metabolic syndrome, type 2 diabetes mellitus, and HIV infection can also contribute to secondary hypogonadism.

Secondary hypogonadism is also called hypogonadotropic hypogonadism because in this case, the brain is not producing enough (hypo-producing) of the gonadotropins FSH and LH and thus understimulating the production of testosterone in the testes.

Primary and secondary hypogonadism both stem from some pathological condition involving the HPG axis and are together known as organic or classical hypogonadism.

Functional Hypogonadism

Some men may exhibit hypogonadism symptoms and low testosterone levels without apparent issues in their hypothalamic-pituitary-gonadal (HPG) axis, a condition known as functional hypogonadism. This condition is often linked with factors like excess weight, other health concerns, or the use/withdrawal of medications such as opioids, glucocorticoids, and anabolic steroids. While functional hypogonadism, also termed non-gonadal illness (NGI), lacks universal recognition as a distinct category among medical societies, specific guidelines distinguish between organic and functional hypogonadism/NGI. These guidelines emphasize lifestyle interventions to improve overall health as the primary approach.

According to the European Association of Urology (EAU), organic hypogonadism is characterized by a proven pathology affecting the HPG axis, typically necessitating conventional medication such as gonadotropins or testosterone therapy which we discuss in detail later in this course. On the other hand, functional hypogonadism occurs when there aren't any clear physical changes in the HPG axis, and testosterone levels remain within normal range. In these situations, the main focus of treatment is usually on managing any conditions that may contribute to the hypogonadal symptoms and related health issues first, before considering any hormone-related treatments.

Late Onset Hypogonadism (LOH)

As men get older, it's common for their testosterone levels to decrease, usually starting in their thirties and continuing into their forties and beyond. Clinical terms associated with this natural decline include androgen deficiency of the aging male (ADAM), late-onset hypogonadism (LOH), and symptomatic LOH (SLOH).

It's important to highlight that not all aging men undergo a decline in testosterone levels. Some smaller studies propose that in healthy aging men, there might not be a significant decrease in testosterone levels. However, factors such as chronic illness and obesity, which often worsen with age, might contribute to observed declines in testosterone levels.

Some symptoms associated with LOH, such as fatigue, decreased libido, and mood fluctuations, can often be multifactorial, and may be related to other medical conditions, not low testosterone alone. Consequently, diagnosing and deciding on treatment options for LOH can be challenging. This variability sometimes leads to differing levels of willingness among physicians to diagnose LOH, especially considering its potential reversibility through lifestyle interventions, particularly aimed at weight loss. Prioritizing a healthy lifestyle is essential for aging individuals, as it not only supports hormonal health but also contributes significantly to overall well-being.

As men age, the relationships between factors such as weight and hormonal balance becomes more noticeable. Low testosterone levels can contribute to weight gain and increase the risk of developing metabolic syndrome. Conversely, being overweight or having metabolic syndrome can further decrease testosterone levels. This creates a cycle where each factor exacerbates the others, leading to a higher risk of health complications such as diabetes, cardiovascular disease, and reduced quality of life.

Several large, long-term research studies have uncovered an association between body mass index (BMI) and testosterone levels, suggesting a complex relationship with significant implications for men's health and well-being. Two large studies showed that testosterone levels decrease with age and that this decrease is augmented by a high BMI.

The Massachusetts Male Aging Study (MMAS) and the European Male Aging Study (EMAS) concluded that higher body mass index (BMI) correlates strongly with decreasing testosterone levels in men aged 40 to 70. MMAS, spanning from 1987 to 1997, revealed an annual testosterone decline of 1.6%, while EMAS, conducted between 2003 and 2009, confirmed BMI as a key predictor of low testosterone. These findings highlight the significant impact of lifestyle factors on hormonal changes with age, which we discuss in more detail in the Treatment section.