Epidemiology of Male Hypogonadism

Synopsis:

The epidemiology of male hypogonadism has been understudied. Of the known causes of endogenous androgen deficiency, only Klinefelter syndrome is common with a likely population prevalence of > 5:10,000 men (possibly as high as 10–25:10,000). Mild traumatic injury might also be a common cause of androgen deficiency (prevalence 5–10:10,000 men), but large, long-term studies must be completed to confirm this prevalence estimation that might be too high. The classic causes of male androgen deficiency—hyperprolactinemia, pituitary macroadenoma, endogenous Cushing syndrome and iron overload syndrome are rare (prevalence < 10,000 men). Of the iatrogenic causes of male androgen deficiency, androgen deprivation therapy for prostate cancer, radiation and chemotherapy for testicular cancer, lymphoma and leukemia, and radiation therapy for primary brain tumors and head and neck cancers are common (prevalence > 5:10,000 men).

Introduction

There are many benefits to understanding the epidemiology of male hypogonadism. The benefits include determining the merits of screening for androgen deficiency in large populations, the predictive value of diagnostic testing for male hypogonadism in specific patients, and the calculation of the potential socioeconomic cost of the disorder to the society. This information is useful to clinicians providing care for patients, researchers developing and recruiting for clinical and translations studies, biomedical research and industry leaders making decisions about financial investments in research and development, and government officials making public health decisions around the world.

In the past three decades, testosterone therapy prescription and use has greatly expanded in some countries, and it has become a topic of great public and government interest. There have been developments in the diagnostic tools (e.g., chromatography-tandem mass spectrometry assays and methods for accurate assessment for free, unbound testosterone) and therapies (e.g., transdermal and long-acting testosterone formulations) during that period. However, despite this broad fascination with a hormone that has multiple systemic effects, there is relatively little known about the global epidemiology of male hypogonadism.

The testes have two primary functions: production of sperm and androgens (and estrogens via aromatization of androgens). Male hypogonadism encompasses abnormal sperm production (in quantity and/or quality) and androgen deficiency. The prevalence of male infertility is generally quoted to be 10–15%, and the vast majority of these men have dysspermatogenesis.¹ However, a 2017 systematic review commissioned by the World Health Organization concluded that due to the very low quality of evidence, “it is not possible to determine an unbiased prevalence of male infertility within global, regional or national populations”.² Dysspermatogenesis is consistently present in men with male hypogonadism, but the majority of infertile men have normal Leydig cell function and normal serum testosterone concentrations. We will focus on the epidemiology of androgen deficiency in our review, and we will use the terms “male hypogonadism” and “androgen deficiency” interchangeably. We will use the standard epidemiological definitions for “prevalence” and “incidence rate”; note that prevalence and incidence rate often do not correlate.

As with male infertility, there are many barriers to understanding the global epidemiology of male hypogonadism. First, there are many pathophysiological processes that lead to suppression of the hypothalamic-pituitary gonadal axis and lead to symptoms, signs, biochemical findings and clinical outcomes that are similar to or overlap with male hypogonadism. Any severe chronic or acute systemic illness or disorder including malnutrition, infections, cancer, inflammatory diseases, sleep apnea, and uncontrolled metabolic disorders (e.g., diabetes mellitus) may suppress the gonadal axis.³ Second, aging is associated with declines in serum testosterone in men starting their 4^th and 5^th decades. Although testosterone therapy might be beneficial to some or even many older men with low serum testosterone concentrations and no identifiable cause of hypogonadism, age-related declines in serum androgen should not be considered a disorder or a disease and therefore should not be described as hypogonadism per se. Third, the definition of low serum total testosterone concentrations in epidemiological studies has been fraught with problems because of the use of inaccurate total and free testosterone assays and inconsistent and non-uniform normal ranges in serum testosterone assays. Furthermore, the lower limit of the normal serum testosterone concentration has not been agreed upon (even in national and international guidelines including the two guidelines that used systematic review and systematic analysis in their methodology) or connected to clinical outcomes.^3–5 In addition, there has been no harmonization and standardization of testosterone assays (although there has been a recent effort to do so).⁶ Unlike the epidemiological studies of diabetes mellitus that are based on serum hemoglobin A1c and glucose concentrations that have low variability between assays and laboratories in different geographical areas, there has been significant inter-assay variability of serum testosterone measurements in published epidemiological studies. A fourth impediment to the accurate determination of the prevalence and incidence rate of male hypogonadism is the variability of iatrogenic causes. Drugs that cause hyperprolactinemia (e.g., psychotropic drugs), exogenous corticosteroids and opioids may cause hypogonadism, and the use of these drugs fluctuates by geographic region and over time. Furthermore, there is no clear dosage threshold for these drug-induced causes of hypogonadism, and the documentation of dose and duration is problematic. A fifth barrier to understanding the epidemiology of male hypogonadism has been the lack of large, systematic studies of the prevalence of male hypogonadism in younger and older males in large areas of Africa, Asia, and South America.

This final limitation is very important because it precludes the accurate assessment of the global and the locoregional epidemiology of male hypogonadism. For example, sickle cell disease is cited as a cause of hypogonadism in endocrinology textbooks and review articles, but it has only been reported as a cause of hypogonadism in small case series, and the prevalence of hypogonadism in sickle disease is not known.^7–9 However, 300,000–400,000 children are born each year with sickle cell disease, and ~2/3 are born in sub-Saharan Africa.¹⁰ Immigration patterns have increased the prevalence of sickle disease in certain regions including in India, Europe and North America. The incidence rate of sickle cell disease in men born in Africa or from ancestors from Africa is approximately 1:500 male births. Thus, sickle cell disease could be a significant, but unidentified, contributor to the incidence and prevalence of male hypogonadism in many areas of the world.

There is controversy about the diagnosis of male hypogonadism in the large number of men with nonspecific symptoms and signs of androgen deficiency, slightly low to low-normal serum testosterone concentrations who do not have an identifiable cause of dysfunction of the hypothalamus pituitary or testes. This constellation is more common in older men, men with diabetes mellitus and men with high body mass indices. We will not identify these men as hypogonadal in this review, but we will include them as “possible hypogonadism”.

There have been a number of approaches to estimating the prevalence or incidence rate of male hypogonadism. Most investigators have used a definition of hypogonadism of an arbitrary threshold based on a low serum testosterone concentrations or symptoms of male hypogonadism and a low serum testosterone concentration. A second approach would be to define hypogonadism based on testosterone replacement therapy prescriptions in large population databases, but that method overestimates the prevalence of male hypogonadism (due to secular trends of androgen therapy for indications other than male hypogonadism) and underestimates the prevalence of bona fide hypogonadism (due to under-recognition of causes such as Klinefelter syndrome; see the discussion in the section on Congenital and genetic causes of primary hypogonadism). In a third approach, we also attempt in this review to estimate the prevalence and incidence rate of male hypogonadism based on the epidemiology of known causes of primary and secondary causes.

Epidemiology of male hypogonadism based on low serum testosterone concentrations

Early epidemiological studies focused on middle-aged and older men and defined male hypogonadism based on low serum testosterone concentrations without or with symptoms and signs of androgen deficiency (Table 1). The Baltimore Aging Longitudinal Study demonstrated a prevalence of low serum total testosterone concentrations in ~10% in men 50–59, 20% in men 60–69 and 70% in men 70–80 years old.¹¹ Other studies of American, European and Asian men (Framingham, European Male Ageing Study [EMAS] and Osteoporotic Fractures in Men [MrOs]) have confirmed age-related decreases in serum total testosterone concentrations with a prevalence of low serum total testosterone in ~10% in men with a mean age of 40 years and ~24% and 40% in men with mean ages of ~60 and 73 years, respectively.^12–14 A more recent (2015) large study of Australia confirmed the age-related decline in serum testosterone.¹⁵

Table 1.

Epidemiology of possible causes of male hypogonadism

Causes of possible hypogonadism*	Comments	Prevalence
Aging	Additional research must be done to determine if this is a cause of androgen deficiency and if the benefit of androgen replacement therapy exceeds the risk.	Unknown 2–8%? References: 13, 15–18
Obesity	Mean BMI has continually increased in countries and regions that have adopted diets with more processed foods and more sedentary lifestyles. The possible association of obesity and male hypogonadism has been inadequately studied. No definitive comments can be made about the possible prevalence of male hypogonadism due to obesity.	Unknown
Diabetes mellitus	The incidence and prevalence of diabetes mellitus has increased in parallel to global obesity. As with obesity, no definitive comments can be made about the possible prevalence of male hypogonadism due to obesity.	Unknown

^*Possible hypogonadism indicates a disorder associated with low serum testosterone concentrations without clear evidence that there is evidence of end-organ androgen deficiency.

The prevalence of hypogonadism is much lower in older men when low serum testosterone concentrations are coupled with symptoms suggestive of hypogonadism. For example, the EMAS study of over 3000 men ages 40–79 years demonstrated an overall prevalence of 2.1% when using a combination of 3 sexual symptoms (erectile and decreased frequency of morning erections and sexual thoughts) and a low total testosterone concentration.¹³ There was an age-related increase in male hypogonadism (0.1% for 40–49 years, 0.6% for 50–59 years, 3.2% for 60–69 years and 5.1% for 70–79 years). Similarly, two smaller cohort studies in Massachusetts (United States) demonstrated a baseline prevalence of hypogonadism of ~6% in men ages 30–79 and 40–69 years old respectively, based on a definition of hypogonadism that included a low serum testosterone and symptoms or signs of hypogonadism. In these studies, the prevalence increased with age.^16,17 Finally, a 2021 cohort study of more than 6000 Chinese men ages 40–79 years old (mean age 57) demonstrated similar findings with an ~8% prevalence of hypogonadism based on a low serum testosterone concentration and sexual symptoms suggestive of androgen deficiency.¹⁸

There are important limitations to the above epidemiological studies. Men with known causes of hypogonadism were excluded. Thus, these epidemiological studies form the basis for the estimation of “possible hypogonadism” due to the effects of aging (with attendant obesity and co-morbidities). The studies used different testosterone assays and different (and somewhat arbitrary) thresholds to define a low serum testosterone concentration. Furthermore, no men who were 18–30 years old and few men under age 40 were included in these studies.

Epidemiology of male hypogonadism based on the epidemiology of specific causes

The epidemiology of androgen deficiency might also be estimated based on the prevalence and incidence rate of known causes of primary and secondary male hypogonadism (Table 2). This estimation is confounded by the variation in the expression of androgen deficiency with known causes of male hypogonadism, the implausibility of including all causes of primary and secondary hypogonadism, the imperfect knowledge of the epidemiology of these causes, and the secular and geographic variation in acquired causes of primary hypogonadism and secondary hypogonadism. Acquired causes of primary hypogonadism and secondary hypogonadism vary across regions and over time due to a broad range of factors such as genetic clustering, differences in environmental exposure (e.g., infections), differences in use of therapeutic drugs or drugs of abuse. Nonetheless, this approach is a useful exercise to describe the epidemiology of male hypogonadism due to known pathological causes.

Table 2.

Incidence rate and prevalence of known causes of male hypogonadism

	Incidence rate of the disorder	Prevalence of androgen deficiency
Congenital and genetic causes of primary hypogonadism
Klinefelter syndrome	9–22;10,000 births	> 5:10,000 Possibly 0.2–0.3% prevalence in men
Congenital bilateral anorchia	0.5:10,000 births	Rare*
Down syndrome (trisomy 21)	10–30:10,000 births	Unknown
Noonan syndrome	4–10:10,000 births	Rare
Myotonic dystrophy	1–4:10,000 births	Rare
Autoimmune polyglandular syndromes	<5:100,000 births	Rare
46 XY disorders of sexual development with male genitalia	<1:10,000 births	Rare
Wolfram syndrome	<1:10,000 births	Rare
Ataxia-telangiectasia	<1:10,000 births	Rare
Prader Willi syndrome		Rare
Non-iatrogenic acquired causes of primary hypogonadism
Bilateral testicular trauma	<<1:10,000 patient-yrs	Likely rare
Testicular torsion	<<1:10,000 patient-yrs	Rare
Bilateral orchidectomy (for causes other than testicular cancer)	Likely < 1:10,000 patient-yrs	Likely rare
Infectious orchitis	Likely < 1:10,000 patient-yrs	Likely rare
Congenital and genetic causes of secondary hypogonadism
Kallmann syndrome/congenital hypogonadotropic hypogonadism	1:4000–1:30,000 male births	Likely rare
Holoprosencephalopathy	1:10,000 births	Likely rare
Septo-optic dysplasia	1:10,000 births	Likely rare
Congenital hypopituitarism	1–3:10,000 births	Likely rare
Congenital hypogonadotropic hypogonadism with adrenal hypoplasia	<1:10,000 births	Likely rare
CHARGE syndrome	<1:10,000 births	Likely rare
Bardet Biedel syndrome	<1:10,000 births	Likely rare
Selective defects in synthesis of luteinizing hormone	<1:10,000 births	Likely rare
	Incidence rate of the disorder	Prevalence of male androgen deficiency **
Non-iatrogenic acquired causes of secondary hypogonadism
Non-prolactin producing macroadenoma	< 1:10,000 patient-yrs	Rare
Traumatic brain injury	40:10,000 patient-yrs	Unknown Possibly > 5:10,000
Subarachnoid hemorrhage	0.6–1:10,000 patient-yrs	Likely rare
Pituitary apoplexy	<1:10,000 patient-yrs	Rare
Primary empty sella syndrome	Unknown; much higher in women	Likely rare
Iron overload syndromes	Rare; see text	Rare; see text
Endogenous Cushing syndrome	<1:1,000,000 male patient-years	Rare
Iatrogenic causes of hypogonadism
Prostate cancer treatment	See text	Up to 2–3% interval prevalence for men 5570 years old
Testicular cancer treatment	See text	Up to 0.06% lifetime prevalence in men
Systemic chemotherapy	See text	Likely rare
	Rare	Likely rare
Radiation therapy of benign brain tumor
Pituitary adenoma	< 1:10,000 patient-years	Rare
Benign non-pituitary brain tumor	1:10,000 patient-years	Rare
Radiation therapy of malignant brain tumor	Unknown	Unknown
Radiation therapy of brain metastasis	10–30:10,000 patient-years	Unknown
Total body irradiation for bone marrow transplantation	Rare	Rare
Radiation therapy for head and neck cancer	Unknown	Unknown
Iatrogenic Cushing syndrome	Unknown	Unknown
(Iatrogenic) opioid abuse	Unknown	Unknown
Iatrogenic medication-induced hyperprolactinemia	Unknown	Unknown

^*A prevalence < 5:10,000 is considered rare.^{Reference 19}

^**Prevalence = % men in general population with hypogonadism due to this cause yrs = years

In this section, a prevalence of 5:10,000 is considered a rare disease (the United States definition is closer to 8–9:10,000), and incidence rate of < 1:10,000 per live birth or patient-years is considered low frequency.¹⁹ We will estimate the prevalence of androgen deficiency when possible. We will err on the side of overestimation of hypogonadism to highlight that the majority of the causes of male hypogonadism affect a very small percentage of the overall male population. Our estimations are often crude and imprecise, but they provide a reasonable assessment of the overall prevalence of male hypogonadism

Congenital and genetic causes of primary hypogonadism

Primary hypogonadism with low serum testosterone concentrations and high serum gonadotropins is generally accepted as incontrovertible evidence of androgen deficiency. By far, the most common cause is Klinefelter syndrome. The incidence rate of Klinefelter syndrome is ~9–22:10,000 male births (0.09–0.22%) and only 25–50% are diagnosed during their lifetimes.^20–24 The prevalence of Klinefelter syndrome is likely to be lower in slightly lower in older men because the average longevity of men with Klinefelter syndrome appears to be reduced by 5–6 years; the prevalence is still likely to exceed 5:10,000 overall.^23,24 Although it is generally assumed that virtually all men with Klinefelter syndrome will eventually develop androgen deficiency, this assumption has not been proven.

In addition to Klinefelter syndrome, there are a number of structural and genetic causes of congenital primary hypogonadism. Men with congenital bilateral anorchia have severe androgen deficiency. This condition is found in only 0.5:10,000 male births, and the cause is unknown.²⁵ There are a number of genetic syndrome and syndromes that occasionally present with androgen deficiency. Down syndrome (trisomy 21) affects 10–30:10,000 births (12–14 in the United States because of 50% elective abortion rate), and the prevalence in the United States and Europe is ~6–14 per 10,000.^26,27 Most males with Down syndrome have hypospermatogenesis, and many have elevated serum FSH and LH concentrations, but they have normal serum testosterone concentrations and go through puberty normally.^28–32 The incidence rate and prevalence of androgen deficiency in this supernumerary chromosomal syndrome is not known, but it is likely much rarer in older men because the life expectancy is shorter by 10–15 years compared to men without Down syndrome.³² Males with Noonan syndrome and myotonic dystrophy commonly have isolated defects in spermatogenesis and have normal serum testosterone concentrations. For example, Noonan syndrome is found in 4:10,000–10:10,000 births, but males with Noonan syndrome commonly have cryptorchidism but typically have normal serum testosterone concentrations after puberty.^33–36 Myotonic dystrophy occurs in ~1:10,000–1.4:10,000 male births of European ancestry, but even less common in other populations with different gene pools.^37–39 About 80% of men with myotonic dystrophy have primary hypogonadism with spermatogenic defects, but only ~20%−40% have low testosterone concentrations.^38,39 Autoimmune polyglandular syndrome type 1 and type 2 are rare (<5:100,000 births) and may cause primary hypogonadism in females, but seldom in males.^40–42. Males with 46, XY disorders of sexual development (DSD) due to partial androgen insensitivity syndrome or gonadal dysgenesis (e.g., congenital abnormalities in androgen production) may rarely present with incomplete or small male genitalia and primary hypogonadism. There are no comprehensive epidemiological studies for these rare clinical syndromes, but the prevalence and incidence rate of males with male genitalia and primary hypogonadism due to any 46, XY DSD appears to be much lower than 1 per 10,000.⁴³ Finally, there are many complex genetic syndromes that are associated multiple congenital anomalies and disorders that may include primary hypogonadism as a manifestation. These disorders include Wolfram syndrome, ataxia-telangiectasia (with gonadal dysfunction more common in females), Prader-Willi syndrome (that is associated with mixed primary and secondary hypogonadism), and other very rare disorders.^44–46 The incidence rate of these complex genetic syndromes is 0.25:10,000 to < 0.1:10,000 births worldwide, and many of the patients with these syndromes are infertile but may not have primary hypogonadism. Overall, only Klinefelter syndrome is a common cause of congenital primary hypogonadism, but Down syndrome might be a more common cause of male hypogonadism than recognized (Box 1).

Box 1.

Of the known congenital causes of primary hypogonadism, Klinefelter syndrome is the only common cause of hypogonadism with an incidence rate of 10–25:10,000 males. The prevalence of Kallmann syndrome in adult men is not known, but it is likely > 5:10,000. All other congenital causes of hypogonadism appear to be rare, but none of these congenital causes have accurate assessments of prevalence of hypogonadism. Karyotyping for Klinefelter syndrome should be considered in a male that presents with primary hypogonadism. Perinatal screening for Klinefelter might be considered, too.

Non-iatrogenic acquired causes of primary hypogonadism

Non-iatrogenic acquired causes of primary hypogonadism with androgen deficiency include severe bilateral testicular trauma, testicular torsion, bilateral orchidectomy, and infectious orchitis. The epidemiology of acquired primary hypogonadism varies significantly due to secular trends, temporal changes in medical therapies and differences related to geography, cultural mores and other factors.

Hypogonadism due to severe bilateral testicular trauma (blunt or penetrating) is rare.^47,48 In a national database analysis, only ~8,000 of 3.5 million men who had trauma requiring evaluation at a United States trauma center had scrotal or testicular trauma between 2007–2016.⁴⁹ Of these, ~45% had blunt trauma, and ~55% had penetrating trauma. Only 1–2% of men with blunt testicular trauma and ~30% of men with penetrating testicular trauma have bilateral testicular trauma that might result in sufficient loss of Leydig cells to cause androgen deficiency. Thus, the incidence rate of androgen deficiency of severe bilateral testicular trauma is < 1:10,000 patient-years, and the lifetime prevalence of androgen deficiency due to testicular trauma can be inferred to be < 5:10,000. Hypogonadism due to testicular torsion is even rarer. Testicular torsion typically occurs in males under age 25, and the annual incidence rate is 4:100,000 with an estimated lifetime prevalence of 3–7:10,000 by age 25.^50,51 Unilateral orchidectomy may be required in 25–45%.^50,51 Although decreased spermatogenesis may occur as a long-term consequence, androgen deficiency seldom, if ever, occurs as a result of testicular torsion or its treatment.⁵²

Mumps orchitis commonly causes dysspermatogenesis, particularly when there is postpubertal infection.^53,54 Androgen deficiency due to Leydig cell dysfunction only occurs with severe bilateral orchitis in postpubertal males. Mumps causes bilateral orchitis in ~30% of postpubertal adolescents and men, and few cases are severe. The mumps vaccine effectively prevents bilateral mumps orchitis. Thus, despite a recent increase in mumps infections in regions of the world where there are barriers to vaccination, mumps orchitis is now a very rare cause of primary hypogonadism with androgen deficiency. Other, even rarer, infectious causes of androgen deficiency due to orchitis include toxoplasma gondii, mycobacteria, brucella, echovirus, (undertreated) human immunodeficiency virus and arbovirus infections. Overall, the non-iatrogenic causes of acquired primary hypogonadism appear to be very uncommon (Box 2).

Box 2.

The prevalence of non-iatrogenic causes of acquired primary hypogonadism is not well described, but causes such as traumatic testicular injury and infectious orchitis appear to be rare (lifetime prevalence likely ≤ 5:10,000) and does not significantly affect the overall incidence rate and prevalence of hypogonadism.

Congenital and genetic causes of secondary hypogonadism

There are various uncommon causes of congenital/genetic causes of secondary hypogonadism. These include congenital developmental disorders that are variably associated with hypogonadotropic hypogonadism such as holoprosencephaly and septo-optic dysplasia that both have incidence rates of 1:10,000 births and Kallmann syndrome.^55,56 There is a genetic overlap with between holoprosencephaly and Kallmann syndrome that has a quoted incidence rate of approximately 1:10,000 males births (1:4000 to 1:30,000).^55,57 Congenital hypopituitarism with multiple pituitary deficiencies (including gonadotropin deficiency) occurs in 1.25:10,000–2.5:10.000 births.^55,58–60 There are very rare causes (<1;10,000 births) of congenital/genetic hypogonadotropic hypogonadism including congenital hypogonadotropic hypogonadism with adrenal hypoplasia, CHARGE syndrome (that may overlap genetically with Kallmann syndrome), Bardet Biedel syndrome (a ciliopathy that also overlaps with Kallmann syndrome), and selective defects in synthesis of luteinizing hormone.^60–66

Acknowledging that some of these syndromes might overlap, the overall incidence rate of congenital causes of secondary hypogonadism is quite low, but the prevalence of these syndromes is unknown (Box 3).

Box 3.

The incidence rate of congenital causes of secondary hypogonadism is very low. The prevalence rate of these congenital causes is unknown, but they collectively are rare (< 5:10,000 males). Congenital causes of hypogonadotropic hypogonadism should be considered in infant boys with micropenis or boys who fail to go through puberty and have low serum testosterone and gonadotropins. Boys and young men with secondary hypogonadism with extragonadal symptoms or signs such as impairment of hearing or sense of smell, coloboma, polydactyly or cerebellar findings (e.g., synkinesias) suggest rare genetic syndromes associated with congenital secondary hypogonadism.

Non-iatrogenic acquired causes of secondary hypogonadism

Acquired causes of secondary hypogonadism include macroadenomas and other pituitary masses, traumatic brain injury, intracranial hemorrhage, empty sella syndrome, hyperprolactinemia, iron overload syndromes, and endogenous Cushing syndrome.

Pituitary macroadenomas and sellar masses and empty sella syndrome

The overall incidence rate of pituitary adenomas is ~0.3–0.7:10,000 patient-years, but the prevalence is ~8–12:10,000.^67–70 About 40–60% of these adenomas are macroadenomas with a higher percentage of macroadenomas reported in men; the remainder are mostly small pituitary microadenomas that do not cause secondary hypogonadism. About 50% of the macroadenomas are prolactinomas, and the vast majority of the remainder are nonfunctional (gonadotrope or corticotrope) macroadenomas. (The macroprolactinomas are also discussed in the hyperprolactinemia section below.) Of the males with nonfunctional macroadenomas, 25–50% will present with hypogonadism.^71–74 Based on limited data, large sellar masses (e.g., large Rathke’s cysts) other than pituitary macroadenomas are rare (prevalence likely <1:10,000 people), but they appear to have similar associations with secondary hypogonadism (10–60%).^74,75 Thus, the prevalence of hypogonadism due to non-prolactin-producing macroadenomas and other benign sellar masses is very low (rare; ~1–1.5 per 10,000 men; Box 4).

Box 4. Calculation:

The estimated prevalence of male hypogonadism due to pituitary nonfunctional macroadenomas and benign sellar masses times is the prevalence of adenomas in men (8–12:10,000) times the percentage of adenomas in men that are macroadenomas (50%) times the percentage that are nonfunctional (50%) times the percentage of male patients with nonfunctional macroadenomas that have secondary hypogonadism (50%) equals 1–1.5:10,000 men.

Traumatic brain injury, subarachnoid hemorrhage and pituitary apoplexy

The incidence rate of traumatic brain injury (TBI) is approximately 40:10,000 patient-years in men, and it is more common in younger men.⁷⁶ There is some modest geographic variation in the incidence rates. Most (80–90%) of the TBI worldwide is classified as mild (i.e., a brain injury leading to a concussion with transient loss of consciousness without focal neurological deficits or injury on brain imaging).⁷⁶ Although chronic pituitary dysfunction including secondary hypogonadism (28–32% with some reports as high as 55–70% with more severe trauma) has been reported after moderate to severe TBI, mild TBI is associated with much lower rates (<10%) with growth hormone deficiency being the most common deficit.^77–80 Minor TBI commonly causes a biochemical pattern consistent with secondary hypogonadism early after the traumatic event, but the hypothalamus-pituitary-testicular axis typically returns to normal within one year of mild TBI.⁸¹ Based on these data, the incidence rate of hypogonadism due to all TBI might be 6.0–8.2:10,000 patient-years (Box 5). This estimated incidence rate is probably too high.^77,78

Box 5. Calculation:

The incidence rate of hypogonadism due to mild traumatic brain injury (TBI) is the incidence rate of TBI in men (40:10,000 patient-years) times the percentage that is mild TBI (80–90%) times the percentage of hypogonadism due to mild TBI (10%) plus the incidence rate of TBI in men (40:10,000 patient-years) times the percentage that is moderate to severe TBI (10–20%) times the incidence rate of hypogonadism due to moderate to severe TBI (70%) equals 6.0–8.2:10,000 patient-years. This estimate is probably too high.

Subarachnoid hemorrhage is associated with similar rates of panhypopituitarism (25–35%), but only ~5–20% patients with incident subarachnoid hemorrhage have secondary hypogonadism after 6 months to 5 years of follow-up.^82,83 The annual incidence rate of subarachnoid hemorrhage is only 0.6–1:10,000 patient-years and has a high mortality (~35% mortality at a median of 4 years); the prevalence of secondary hypogonadism due to subarachnoid hemorrhage is likely to be very low.^83–85 Pituitary apoplexy has a similarly very low incidence rate (0.2:10,000 patient-years) and lifetime prevalence (~0.6 per 10,000 people).^86,87 Despite a reported association with secondary hypogonadism in up to 70% of men, pituitary apoplexy--like subarachnoid hemorrhage—is a rare cause of acquired secondary hypogonadism.^86–88

A primary empty sella is a highly prevalent anatomic finding (2–20%) in autopsy and radiology series. The clinical incidence rate and prevalence of primary empty sella syndrome (characterized by the anatomic finding plus headaches and/or pituitary hormone deficiency) appears to be much lower, and it is much more common in women than men (4–6:1).^89–91 The prevalence of hypogonadism has been reported to be 10–55% in patients with primary empty sella syndrome. The overall prevalence of some form of hypopituitarism due to primary empty sella syndrome has been estimated to be approximately 5:10,000 people, but it is likely lower in men.⁹¹ There could be a significant underestimation of empty sella syndrome due to under-detection, but the best (albeit weak) evidence indicates that empty sella syndrome is probably found primarily in women and is a rare cause of secondary male hypogonadism.⁹¹

Iron overload syndromes: hereditary hemochromatosis and blood dyscrasias.

Iron deposition due to any iron overload syndrome may cause secondary hypogonadism. The most well-known iron overload syndrome is hereditary hemochromatosis, but any disorder associated chronic and frequent blood transfusions might result in an iron overload syndrome.

The incidence rate of homozygosity for hereditary hemochromatosis is common (up to 25:10,000–50:10,000 births) with significant variation among populations, but the penetrance of this disorder is much lower.^92–94 In one long-term Irish retrospective study over 20 years, only 6% (9/141) developed secondary hypogonadism.⁹⁵ Hypogonadism due to overload has been reported in males with beta thalassemia major and other congenital anemias who receive frequent transfusions.^96,97 However, this complication of iron overload occurs in only uncommon, severe blood dyscrasias and is fully preventable (and treatable with iron chelation therapy). Overall, iron overload syndromes are associated with a low incidence rate of secondary hypogonadism that is preventable, and these syndromes likely do not contribute significantly to the overall life-time prevalence of hypogonadism.

Hyperprolactinemia

A 2017 Scottish study demonstrated that the prevalence of hyperprolactinemia in men increased from 0.6:10,000 in 1993 to 9.4:10,000 in 2012.⁹⁸ This study defined as hyperprolactinemia as >1000mU/L (> ~50 ng/mL) a threshold that is often used clinically to trigger further evaluation. The increased prevalence of hyperprolactinemia was attributable primarily to the increased prescription of antipsychotics and antidepressants that increase serum prolactin concentrations. The most common cause was medication-induced hyperprolactinemia that accounted for almost 50% of the cases followed by pituitary causes (e.g., adenomas) that accounted for ~25% of the cases. (Hypogonadism due to drug-induced hyperprolactinemia is discussed in the Iatrogenic causes section below.). The incidence rate of pituitary causes of hyperprolactinemia remained ~0.1–0.2:10,000 patient-years for men over the 20-year period except a slight increase to 0.26:10,000 patient-years in the last 5-year interval that the investigators attributed to increased testing. In this study, 45% of pituitary causes of hyperprolactinemia in men were due to a macroadenoma, and case series of prolactinomas generally report that 50–75% of men with prolactin-producing adenomas have macroadenomas. About 75–90% men are hypogonadal at the time of presentation with a macroprolactinomas, a rate that is higher than nonfunctional gonadotrope or corticotrope adenomas.^99–101 About 35–40% will remain hypogonadal after surgery and ~30–50% after medical therapy.^99–101

Based on the 2017 Scottish study, the prevalence on male hypogonadism due to non-iatrogenic hyperprolactinemia (i.e., all causes of hyperprolactinemia minus drug-induced hyperprolactinemia) is likely low enough to qualify as a “rare disease” (< 5:10,000 men; Box 6).

Box 6. Calculation:

According to a 2017 Scottish study⁹⁴, the prevalence of male hypogonadism due to non-iatrogenic hyperprolactinemia is the overall male prevalence of hyperprolactinemia (9.4:10,000 in 2012) minus the portion attributed to medications and macroprolactin (~ 50% or 4.7:10,000) times the percentage of men who developed hyperprolactinemia-induced secondary hypogonadism. Assuming that 100% of all men with hyperprolactinemia not due to medications become hypogonadal (clearly an assumption that is too high; see text), the male prevalence of hypogonadism due to non-iatrogenic hyperprolactinemia is still rare (< 5:10,000).

Cushing syndrome due to endogenous causes

It has been well known for decades that corticosteroids suppress pituitary secretion of LH and FSH and may cause secondary hypogonadism in men.¹⁰² However, there appears to be variation between individuals as not all men with endogenous Cushing syndrome have secondary hypogonadism.^102,103 Remarkably little is published about the effects of endogenous Cushing syndrome (i.e., the degree of hypercortisolism) on the gonadal axis or the dose-response of exogenous corticosteroids on the male gonadal axis.^100,101 This lack of knowledge is in part due to epidemiology of this syndrome. The incidence rate is only 0.7–2.4:1,000,000 patient-years (0.0024:10,000 patient-years) and it is much more common in women than men.^104–106Because it has a very low incidence rate in men and its high morbidity and reduced longevity, endogenous Cushing syndrome is likely to be a very rare cause of male hypogonadism.¹⁰⁷

Summary of the congenital secondary and non-iatrogenic acquired secondary causes of hypogonadism

Of the known causes of congenital and non-iatrogenic acquired causes of secondary hypogonadism, traumatic brain injury is likely the most common cause (estimated incidence rate 6.0–8.2:10,000 patient-years). Congenital causes and non-iatrogenic acquired secondary causes of hypogonadism other than trauma are likely to be rare (Box 7). Important gaps in knowledge include lack of high-quality studies on the incidence rate and prevalence of persistent androgen deficiency in males with traumatic brain injury, men with primary empty sella syndrome and men who are taking drugs that raise serum prolactin concentrations, chronic corticosteroids, or opioids.

Box 7.

The most common non-iatrogenic cause of secondary hypogonadism is likely to be moderate to severe traumatic brain injury; mild traumatic brain injury infrequently causes hypogonadism that persists beyond one year. Congenital secondary causes are rare although there are no high-quality data on prevalence. Classic causes of non-iatrogenic acquired causes of hypogonadism such as nonfunctional macroadenomas, prolactinomas, iron overload syndromes and endogenous Cushing syndrome are also rare.

Iatrogenic causes of male hypogonadism

Treatment of prostate cancer

Androgen deprivation therapy is commonly prescribed for men with prostate cancer. Androgen deprivation therapy may cause primary hypogonadism (e.g., surgical castration or medical therapy that inhibits androgen synthesis such as abiraterone), secondary hypogonadism (e.g., suppression of gonadotropin secretion by a gonadotropin-releasing hormone analog) or decreased androgen effect (e.g., an androgen receptor blockade with enzalutamide).

Prostate cancer is the second most commonly diagnosed cancer in men worldwide.¹⁰⁸ In 2020, the cumulative risk of prostate cancer between birth and age 75 was 3.86%, and the cumulative risk of death by age 75 was 0.63%.^109,110 There are three categories of men with prostate cancer who might benefit from androgen deprivation therapy. First, men with intermediate- or high-risk prostate cancer treated with radiation therapy benefit with adjuvant androgen therapy (for 4–36 months depending on the perceived risk of recurrent disease).^111–114 Second, men with high-risk prostate cancer treated with radical prostatectomy might benefit from neoadjuvant and/or adjuvant androgen therapy; there is no consensus on the recommended duration of androgen deprivation therapy for this group of men.^111–114 Third, men with metastatic or recurrent prostate cancer after primary therapy are considered candidates for life-long androgen deprivation therapy.^111,114 Thus, androgen deprivation therapy for prostate cancer represents a major potential cause of hypogonadism.

Although we do not have data on the incidence rate and prevalence of this potential cause of hypogonadism, we can estimate a range of the upper limit of the potential use of androgen deprivation therapy for prostate cancer based on current evidence. We will use the data obtained from the core age group of the ERSCP study, the best long-term study of active prostate cancer screening.^115–118 The core-age group of this multi-site study consisted of more than 240,000 European men aged 55–69 years who were randomized to no study intervention or active prostate cancer screening with serum prostate specific antigen measurement at regular intervals. After up to 16 years of follow-up, 13.3% of the men who were enrolled in the active screening group were diagnosed with prostate cancer. In the control group, 10.3% of men were diagnosed with prostate cancer during the same time of follow-up. In the active screen group, 79% of the men were diagnosed with prostate cancer had low-risk or intermediate-risk prostate cancer (low risk = stage ≤ T2a, PSA ≤ 10 ng/ml and Gleason score ≤ 6; intermediate-risk = stage T2b, a Gleason score of 7 or a PSA level of ≥ 10 and ≤ 20 ng/ml); 21% had high-risk prostate cancer. Current evidence and guidelines support the use of long-term androgen deprivation therapy only for patients with high-risk prostate cancer.^111,113,114 Thus, in men (aged 55–69 years) who are offered prostate-cancer screening at regular intervals for up to 16 years, there is approximately a 2.8% screening-interval incidence rate of androgen deprivation therapy for aggressive prostate cancer. Assuming that prostate cancer screening was widely offered to men between 55–69 years old, uniformly accepted and performed, then the life-time prevalence of hypogonadism due to androgen deprivation therapy could be as high as 2–3% in men between ages 55–70 (Box 8).

Box 8. Calculation:

The life-time prevalence or risk of hypogonadism due to androgen deprivation therapy in men ages 55–69 who are undergoing prostate-cancer screening at regular intervals is the ERSCP screening-interval 13.3% incidence rate of prostate cancer time the percentage of ERSCP equals a lifetime prevalence of 2.8% for men between ages 55–70.^112. Age 70 was chosen because a man diagnosed with prostate cancer at age 69 might not receive androgen deprivation therapy until at least age 70.

Treatment of testicular cancer

Global data indicate that the risk of development of testicular cancer is 0.14% between birth and 79^.110 Testicular cancer treated with orchidectomy, but only 0.5–1.0% of testicular cancers include both testes.¹¹⁹ Testicular cancer is often treated with alkylating chemotherapy. Patients with testicular cancer are often treated with chemotherapy (for nonseminomas) or irradiation (for seminomas), and these therapies may result in androgen deficiency. The definition of androgen deficiency (and therefore prevalence) varies greatly in the studies of long-term of survivors, but a prevalence of 20–40% appears to be a reasonable estimation of the upper limit of androgen deficiency due to chemotherapy and/or radiation therapy for testicular cancer.^120–127 Thus, the upper limit of the life-time prevalence of androgen deficiency due to treatment of testicular cancer is 0.06% (Box 9).

Box 9. Calculation:

The life-time prevalence of androgen deficiency in men due to treatment of testicular cancer is the 0.14% lifetime prevalence of testicular cancer times 1% incidence of therapeutic bilateral orchidectomy plus 0.14% lifetime prevalence times 40% incidence of chemotherapy- or radiation-induced hypogonadism equals 0.06% life-time prevalence.

Systemic chemotherapy for non-prostatic and non-testicular cancers

Long-term survivors of cancer treated with systemic chemotherapy may develop androgen deficiency due to primary, secondary hypogonadism or combined primary and secondary hypogonadism. Pelvic and cranial irradiation may cause androgen deficiency due to primary and secondary hypogonadism, respectively.

Systemic chemotherapy (particularly alkylating agents) commonly causes damage to germ cells and dysspermatogenesis, but few long-term male survivors of non-prostatic, non-testicular cancer develop primary or secondary hypogonadism with androgen deficiency due to systemic chemotherapy. About 10–11% of all male childhood survivors develop secondary hypogonadism with androgen deficiency.^128–133 However, male survivors of childhood (or early adulthood) cancer treated with systemic chemotherapy and radiation for lymphoma or leukemia develop androgen deficiency of 10–25%; radiation therapy (of the testes or brain) appears to be more important than systemic chemotherapy for the development of androgen deficiency.^129,132,133 Although the scope and prevalence of secondary hypogonadism (and other pituitary dysfunction) in long-term survivors of childhood and early adulthood cancers is unknown, it is likely that the prevalence will significantly increase as the treatments of these relatively rare childhood and early adult cancers (<1% of all new cancers annually) continue to improve, and survival and longevity increases.¹³³

Androgen deficiency due to radiation therapy for benign and malignant tumors

Radiation therapy that directly or indirectly (by scatter) affects the testicles, pituitary or hypothalamus may cause hypogonadism. The testes are generally shielded during pelvic radiation for treatment of non-testicular cancer. Although there are reports of androgen deficiency after pelvic radiation for rectal cancer, this adverse effect is rare.^134,135 However, brain tumors or head and neck cancers are commonly treated with external radiation that might cause damage to hypothalamic or pituitary dysfunction and lead to secondary hypogonadism. The frequency of radiation therapy for treatment of brain tumors is not known, but we shall attempt to estimate the range of secondary hypogonadism due to this treatment modality for intracranial neoplasms.

Androgen deficiency due to radiation therapy for benign brain tumors

The overall global lifetime prevalence of patients with primary benign brain tumors is unknown.¹³⁶ The prevalence of all benign (pituitary plus non-pituitary tumors) is not known, but the prevalence of patients with benign pituitary tumors (e.g., pituitary adenomas) is approximately 8–12:10,000 people.^{70,74, 136–138} About 50% of pituitary adenomas are macroadenomas^.67–70 Women are modestly more likely (~5:4) to be diagnosed with pituitary adenomas, but men are about modestly more likely to present with pituitary macroadenomas.⁶⁷ For our estimation, we will use a male prevalence of pituitary adenomas 12:10,000 and macroadenomas 6:10,000 respectively. (Microadenomas are not typically radiated.) The incidence rate of benign pituitary tumors (e.g., adenomas), is 0.4:10,000 patient-years, and the incidence rate for benign non-pituitary tumors is 1.3:10,000 patient-years.^{67, 136–138} Because patients with benign pituitary tumors have a generally excellent prognosis that is at least comparable to other benign brain tumors (e.g., meningioma), it is conservative to assume a similar prevalence to incidence ratio (30 to 1) for all benign non-pituitary brain tumors. (We acknowledge the crudeness of this assumption and estimation.) Using this assumption, the prevalence of benign non-pituitary brain tumors would be ~39:10,000 men (assuming equal prevalence between men and women).

Many of the benign extra-pituitary tumors and a majority of benign pituitary tumors will not be treated with external beam radiation. For example, a 2021 study of a United States national database indicated that external beam radiation therapy was used in only 3% of benign pituitary adenomas in 2014 (down from 8% in 2004).¹³⁹ The incidence of secondary hypogonadism is radiation-dose-dependent and increases for years after sellar radiation of pituitary tumors. In studies that include at least 5-year follow-up data of patients with pituitary macroadenomas treated with cranial radiation, the percentage men with androgen deficiency due to secondary hypogonadism ranged from ~5–25% of men.^140–146 Assuming that 5% of patients with benign pituitary tumors are treated with cranial radiation and 25% of patients will have developed permanent gonadotrope dysfunction 5 years after sellar radiation, the lifetime prevalence of secondary hypogonadism due to radiation of benign pituitary tumors is ≤1:10,000 men (Box 10).

Box 10. Calculation:

The life-time prevalence of male secondary hypogonadism due to radiation therapy of a benign pituitary tumor is the prevalence of macroadenomas in men (4–6:10,000) times the percentage of benign pituitary tumors treated with sellar radiation (5%) times the percentage of men with chronic gonadotrope dysfunction after radiation of a benign pituitary tumor (25%) equals 0.05–0.1:10,000 men. (Note that this range assumes that the androgen deficiency is due to radiation and not the macroadenoma. In addition, this calculation assumes that life-time prevalence of men who develop secondary hypogonadism due to cranial radiation does not significantly increase 5–10 years after radiation therapy.)

Similarly, a minority of benign non-pituitary primary brain tumors are treated with cranial radiation therapy. For example, meningiomas constitute >70% of all benign nonpituitary brain tumors, and intracranial radiation is used as primary or adjunctive therapy in < 10% of these tumors.^136,137,147 Up to 35% of patients with meningiomas (or other benign primary brain tumors) may develop hypogonadism after high dosages of radiation therapy (>30 cGy), but these high dosages are used primarily in the minority of tumors that are incompletely resected or recur after surgery.^148–151 Vestibular schwannomas, the second most common benign non-pituitary tumors, account for ~10–12% of the benign nonpituitary brain tumors.^136,137 Schwannomas are often treated with radiation therapy, but the dosage is typically < 20 cGy, a dosage that is not likely to cause pituitary dysfunction.^152–154 Assuming that 10% of patients with benign nonpituitary tumors (mostly meningiomas) are treated with high dosages (> 30 cGy) and that 35% of these patients develop secondary hypogonadism with long-term follow-up, the life-time prevalence of secondary male hypogonadism due to radiotherapy of benign-nonpituitary tumors is up to 1.4:10,000 men (Box 11).

Box 11 Calculation:

The life-time prevalence of secondary hypogonadism due radiation therapy of a benign non-pituitary brain tumor is the prevalence of benign non-pituitary brain tumors (39:10,000) times the percentage of benign non-pituitary tumors treated with cranial radiation (10%) times the percentage of patients with chronic gonadotrope dysfunction after radiation of a benign non-pituitary brain tumor (35%) equals 1.4:10,000. (Note that this calculation uses the same assumption as Box 9: the lifetime prevalence of secondary hypogonadism due to cranial radiation does not significantly increase 5–10 years after radiation therapy.)

Androgen deficiency due to radiation of primary malignant brain tumors, brain metastases or due to total body irradiation for bone marrow transplantation

The global prevalence of primary malignant brain tumors (estimated to be < 2:10,000) because the survival time after diagnosis is generally low.^136,155 The prevalence in the United State is higher, but still low (~6:10,000).¹³⁷ For example, glioblastoma, the most common primary brain malignancy (~50% of all primary brain malignancies), has an estimated prevalence of 0.5–1.0:10,000 and a median life expectancy of 8–14 months.^136,137,155 Although the incidence rate of brain metastases from solid tumors might be 10–30;100,000 patient-years, the prevalence of metastatic brain cancer is very low because the median time to death is just a few months.¹⁵⁶ However, hypopituitarism might occur within a few months of brain radiation for primary or metastatic brain cancer and might be clinically significant.¹⁵⁷ Similarly, total body irradiation for bone marrow transplantation is potentially associated with very high prevalence of androgen deficiency, but this procedure is too infrequently performed to affect the prevalence in androgen deficiency in the overall global male population.^{131,133,158,159} Thus, although radiation therapy for primary or metastatic brain cancer and total body irradiation for bone marrow transplantation do not significantly contribute to the overall prevalence of male hypogonadism, further investigation about the epidemiology and the potential risks and benefits of testosterone therapy to these patients would be valuable.

Androgen deficiency due to radiation therapy for primary head and neck cancer

Head and neck cancer is common worldwide, and it is often treated with radiation therapy.^160,161 The incidence rate of secondary hypogonadism after head and neck irradiation ranges from 10% to 35% (depending on the radiation dosage, radiation field size and exposure to the sella turcica, and length of follow-up interval).^151,162 A recent, exhaustive systematic review cited at least a 35% incidence of secondary hypogonadism in childhood cancer survivors who have been treated with cranial radiation including for head and neck cancers that are not primary brain tumors.¹³¹ However, the prevalence of androgen deficiency in survivors of head and neck cancers is unknown because we lack information on the global incidence of radiation therapy for head and neck cancer, and we need large, long-term follow-up studies of the gonadal function of these patients before and after head and neck irradiation.

Secondary hypogonadism due to medication-induced hyperprolactinemia, iatrogenic Cushing syndrome, (iatrogenic) opioids, and androgenic steroid abuse

There are few data on the dosage effects of exogenous corticosteroids, opioids or drugs that induce hyperprolactinemia on the male gonadal axis, and there are not accurate data about the worldwide frequency, dosage and duration of use of prescription corticosteroids, opioids or medications that raise prolactin concentrations. Unlike the other three drug classes above, chronic, current abuse of androgenic steroids does not cause hypogonadism during use, but cessation of chronic, long-term androgenic steroid abuse might cause persistent suppression of the gonadal axis and symptoms and signs of male hypogonadism in normal men, but recovery of normal gonadal function typically occurs (often within 1 year of discontinuation).¹⁶³ Because of the potential legal consequences and stigma attached to androgen abuse, there is even less known about the incidence, prevalence and long-term effects and withdrawal from androgen abuse than the epidemiology of hypogonadism due to use of corticosteroids, opioids or drugs that raise serum prolactin concentrations.¹⁶³

There is no basis to estimate the determine the regional and global prevalence of these iatrogenic causes of hypogonadism, but these drugs could have a significant effect on the epidemiology of androgen deficiency in men.

Summary of iatrogenic causes of male hypogonadism

In general, iatrogenic etiologies are probably the most common causes of male hypogonadism. Cancer therapies such as androgen deprivation therapy for the treatment of prostate cancer; surgical, medical and radiation treatment of testicular cancer; radiation therapy of malignant benign non-pituitary brain tumors and head and neck cancers; and systemic chemotherapy for lymphoma and leukemia may commonly cause androgen deficiency. Chronic medication-induced hyperprolactinemia, supraphysiologic corticosteroid therapy and opioid prescription are also likely common causes of secondary hypogonadism. High quality studies of incidence rate and prevalence of permanent androgen deficiency in men with these conditions or exposures would be invaluable.

Conclusions

The best available evidence indicates that the most common endogenous pathological cause of hypogonadism is Klinefelter syndrome (affecting up to ~0.2% of the male population). Common iatrogenic causes include systemic androgen deprivation for prostate cancer and surgical, medical and radiation therapy for testicular cancer are common causes of hypogonadism. There are many important gaps in knowledge about the epidemiology of male hypogonadism including a lack of data about the longitudinal incidence and lifetime prevalence of androgen deficiency in males with Klinefelter and Down syndrome and males with a history of traumatic brain injury or a history of chronic use of supraphysiological dosages of corticosteroids, drugs that raise serum prolactin concentrations, or opioids. In addition, we need better information about long-term follow-up of survivors who have been treated with radiation therapy (+/− chemotherapy) for cancers affecting the head, brain, neck and pelvis. Finally, we need high-quality long-term studies of middle-aged to older men with “possible hypogonadism”.

Overall, the prevalence of male hypogonadism due to known endogenous pathological causes is low (likely < 1%). Iatrogenic causes of male hypogonadism may significantly raise the prevalence of male hypogonadism, particularly in middle-aged and older men who are more likely to be affected by these iatrogenic causes. These iatrogenic causes are readily identified by taking a careful history. There is much to learn about the epidemiology of male hypogonadism (infertility and androgen deficiency), but the current evidence indicates that there is there is a discordance between the likely true (low) prevalence of endogenous male androgen deficiency and the widespread perception that it is a common malady in young and old men.

Key Points:

• Of the known pathological causes of hypogonadism, Klinefelter syndrome is the most common cause of male hypogonadism, and it is often undiagnosed (25–50%).

• Iatrogenic etiologies are the most common causes of male hypogonadism.

• Common iatrogenic etiologies include oncotherapy with the most important of these being the following: androgen deprivation therapy for prostate cancer; systemic chemotherapy and radiation for testicular cancer, leukemia and lymphoma; and radiation therapy for primary brain tumors and head and neck cancers.

• Medication-induced hyperprolactinemia, exogenous corticosteroids and opioids might also be common causes of iatrogenic hypogonadism in certain populations.

• Classic causes of hypogonadism including pituitary nonfunctional adenomas, prolactinomas, iron overload syndromes, and Cushing syndrome are uncommon or rare.

Clinics Care Points –

1. Klinefelter syndrome is by far the most common endogenous cause of male androgen deficiency is underdiagnosed (with 25–50% of affected males not being diagnosed during their lifetimes).

2. Serum karyotyping (for Klinefelter syndrome) should be considered in all men with primary hypogonadism.

3. Congenital causes of male hypogonadism (with androgen deficiency) are rare, and they generally have extragonadal symptoms or signs such as abnormalities affecting sight or the sense of smell, cerebellar abnormalities such as ataxia, dyskinesias synkinesias, and midline abnormalities such as coloboma or cleft palate.

4. The prevalence of male androgen deficiency due to known pathological causes is low, and the prevalence of low serum testosterone concentrations is high in men over age 40. Screening for male hypogonadism in adults is not warranted.

5. Iatrogenic etiologies are the most common causes of persistent or permanent male hypogonadism.

6. When evaluating a man with male hypogonadism (androgen deficiency) or suspected male hypogonadism, the clinician should query about any history of cancer and oncotherapy (particularly radiation therapy that might have affected the pelvis or brain), significant traumatic head injury (defined as loss of consciousness for at least several seconds), and a history of recent use of medications that increase serum prolactin, corticosteroids, or opioids.

7. Classic causes of secondary hypogonadism including nonfunctional pituitary macroadenomas, prolactinomas, endogenous Cushing syndrome, and iron overload syndromes (e.g., hereditary hemochromatosis or thalassemias) are rare.

8. For older men with isolated secondary hypogonadism (i.e., normal serum thyroxine and thyrotropin concentrations) and unsuppressed serum gonadotropins, sellar imaging is generally not necessary.

9. For men with secondary hypogonadism, the evaluation should include serum prolactin.

10. For men with secondary hypogonadism, the history and physical examination suffices to exclude Cushing syndrome as the cause.

11. Assessment of iron studies to exclude hemochromatosis is most useful for men who under age 40 and have secondary hypogonadism and other manifestations of hemochromatosis such as chondrocalcinosis of the hands or progressive hyperpigmentation of the skin.