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Causes of secondary hypogonadism in males

Causes of secondary hypogonadism in males
Author:
Peter J Snyder, MD
Section Editors:
Alvin M Matsumoto, MD
Mitchell E Geffner, MD
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 25, 2022.

INTRODUCTION — Hypogonadism in a male refers to a decrease in either or both of the two major functions of the testes: sperm production and testosterone production (see "Male reproductive physiology"). These abnormalities can result from disease of the testes (primary hypogonadism) or disease of the pituitary or hypothalamus (secondary hypogonadism). The distinction between these disorders is made by measurement of the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH):

The patient has primary hypogonadism if his serum testosterone concentration and/or sperm count are low and/or his serum LH and FSH concentrations are high.

The patient has secondary hypogonadism if his serum testosterone concentration and/or the sperm count are low and/or his serum LH and FSH concentrations are not elevated, as they would be if gonadotroph cell function were normal.

Secondary hypogonadism differs from primary hypogonadism in two characteristics:

Secondary hypogonadism is usually associated with similar decreases in sperm and testosterone production. This occurs because the reduction in LH secretion results in a decrease in testicular testosterone production and, therefore, in intratesticular testosterone, which is the principal hormonal stimulus to sperm production. In contrast, primary hypogonadism is usually associated with a greater decrease in sperm production than testosterone production because the seminiferous tubules are damaged to a greater degree than the Leydig cells. Men with primary hypogonadism, therefore, might have normal serum testosterone and LH concentrations even when the number of ejaculated sperm is very low or zero and the FSH concentration is elevated.

Primary hypogonadism is more likely to be associated with gynecomastia, presumably because elevated serum FSH and LH concentrations stimulate testicular aromatase to increase the conversion of testosterone to estradiol.

The major causes of secondary hypogonadism in males will be reviewed here (table 1). The causes of primary hypogonadism and of male infertility, which may or may not be associated with hypogonadism, and the manifestations and diagnosis of hypogonadism in males are discussed separately. (See "Causes of primary hypogonadism in males" and "Causes of male infertility" and "Clinical features and diagnosis of male hypogonadism".)

CONGENITAL ABNORMALITIES — Congenital abnormalities that cause decreased gonadotropin secretion are rare but well recognized and easy to diagnose.

Sexual differentiation in all of these disorders is that of a normal male because testosterone secretion by the fetal Leydig cells in the first trimester of pregnancy, when sexual differentiation occurs, is stimulated by placental human chorionic gonadotropin (hCG) that binds to and stimulates luteinizing hormone (LH) receptors on Leydig cells.

In contrast, phallic development during the third trimester is subnormal because testicular testosterone secretion at this stage is dependent upon fetal LH secretion, which is subnormal. This leads to diminished testosterone secretion by the fetal testes, resulting in birth with a small phallus, called micropenis.

Childhood growth is normal if gonadotropin deficiency is an isolated event or subnormal if it is associated with generalized hypopituitarism, including growth hormone and/or thyroid hormone deficiencies.

Pubertal development is incomplete or even absent, depending upon the degree of gonadotropin deficiency. Gonadotropin deficiency can occur in the absence of any other abnormalities or can be associated with other hormonal or nonhormonal abnormalities.

Eunuchoid proportions (greater arm span than height [>5 cm] and greater distance from pubis to floor than pubis to crown) result when epiphyseal closure is delayed because subnormal serum testosterone levels cause subnormal estradiol levels. An exception is if growth hormone is also subnormal.

Isolated hypogonadotropic hypogonadism — Congenital secondary hypogonadism that occurs in the absence of any other pituitary hormonal deficiencies may be the consequence of a number of disorders including congenital gonadotropin-releasing hormone (GnRH) deficiency or follicle-stimulating hormone (FSH) beta- or LH beta-subunit mutations. The cause of many cases has not yet been determined.

Congenital GnRH deficiency — The topic of congenital gonadotropin-releasing hormone (GnRH) deficiency, including its genetics, clinical manifestations, diagnosis, and management, is reviewed in detail separately. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

Leptin or leptin receptor mutations — Individuals with leptin receptor mutations have hypogonadotropic hypogonadism and obesity [1]. (See "Physiology of leptin", section on 'Leptin receptor deficiency'.)

Syndromes associated with developmental delay — Several congenital syndromes, such as Prader-Willi syndrome, have been described in which hypogonadotropic hypogonadism is associated with developmental delay and other abnormalities, including obesity [2]. (See "Prader-Willi syndrome: Management".)

Gonadotropin subunit mutations

Beta-subunit of LH — Several different mutations of the luteinizing hormone (LH) beta-subunit gene have been reported, all leading to hypogonadotropic hypogonadism. In all of them, the clinical presentation was delayed puberty and low testosterone in the men in the families, but the LH and FSH concentrations differed. In one family, LH secretion was not impaired, but its binding to its receptor was impaired, so serum LH concentrations were elevated [3]. In a second family, the mutation prevents dimerization of LH, so it is not secreted and the serum LH is low [4]. In a third family, the mutation prevents normal intracellular processing of mRNA, so the serum LH concentration is undetectably low [5]. Two different mutations were described in an additional patient with delayed puberty and azoospermia [6].

Beta-subunit of FSH — Another rare cause is a mutation in the gene for the beta-subunit of follicle-stimulating hormone (FSH). A man with this mutation had delayed puberty with low serum testosterone and FSH concentrations, but a high serum LH concentration. The low serum testosterone concentration is hard to explain because Leydig cells do not have FSH receptors. However, this finding may indicate that normal human Leydig cell function is dependent on normal function of Sertoli cells, which do have FSH receptors [7].

Hypogonadotropic hypogonadism associated with other hypothalamic pituitary hormonal deficits — Secondary hypogonadism that occurs in association with impaired secretion of other pituitary hormones has been shown to result from impaired expression of transcription factors necessary for early differentiation of the pituitary during embryogenesis, including LHX3, LHX4, HESX1, and PROP-1 [8]. Some are associated with nonpituitary defects. Another genetic cause of multiple pituitary hormonal deficits is the stalk interruption syndrome [9]. (See "Causes of hypopituitarism", section on 'Genetic diseases'.)

ACQUIRED DISEASES — Hypogonadotropic hypogonadism can be caused by any disease that affects the hypothalamic-pituitary axis (see "Hypothalamic-pituitary axis"). One or more of the following mechanisms may be involved:

Disease or suppression of the hypothalamus, which impairs gonadotropin-releasing hormone (GnRH) secretion

Disease of the pituitary stalk, which interferes with the ability of GnRH to reach the pituitary

Disease or suppression of the pituitary, which directly diminishes luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion

In general, a mass lesion in the pituitary or hypothalamus is more likely to diminish the secretion of gonadotropins than that of corticotropin (ACTH) and thyroid-stimulating hormone (TSH). Patients may present, therefore, with hypogonadism without either adrenal or thyroid deficiency.

Suppression of gonadotropins

Hyperprolactinemia — Hyperprolactinemia of any cause can suppress gonadotropin secretion and thereby suppress testicular function [10]. (See "Clinical manifestations and evaluation of hyperprolactinemia".)

GnRH analogs — Prolonged administration of gonadotropin-releasing hormone (GnRH) analogs, as commonly used in the treatment of prostate cancer, causes a decrease in LH secretion and, consequently, in testosterone secretion. (See "Physiology of gonadotropin-releasing hormone" and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

Gonadal steroids — Androgens, estrogens, and progestins can suppress gonadotropins and thereby suppress testicular function. The high doses of androgens that athletes take cause suppression of gonadotropins after discontinuation, sometimes for many months, and during this time the man is hypogonadal (see "Use of androgens and other hormones by athletes"). The progestogen, megestrol, used for appetite stimulation, also causes secondary hypogonadism.

Glucocorticoid treatment — Chronic treatment with glucocorticoids can lead to hypogonadism. In one study, 16 men with chronic pulmonary disease who received high-dose glucocorticoid therapy for at least one month had a mean serum testosterone concentration of 211 ng/dL (7.3 nmol/L), compared with 449 ng/dL (15.6 nmol/L) in 11 men matched for age and disease [11]. This probably represents an effect on the hypothalamus or pituitary since serum LH concentrations do not increase during chronic glucocorticoid treatment.

Opioids — When opioids are administered chronically, especially when they are administered continuously for relief of chronic pain, they often cause pronounced secondary hypogonadism [12,13]. In one study of 29 men receiving morphine or hydromorphone intrathecally for chronic pain not due to malignancy, 25 had a subnormal serum testosterone concentration, whereas only 1 of 10 men, who had comparable chronic pain but was not receiving opioid treatment, had a subnormal value [13].

In men being treated for opioid dependence, methadone is more likely than buprenorphine to be associated with low serum testosterone concentrations and sexual dysfunction [14]. Hypogonadism occurs in over half of male opioid users. In a meta-analysis of 15 studies in 3250 men receiving opioid therapy, 63 percent had hypogonadism [15]. The use of testosterone therapy for men with opioid dependence is the same as for other men with hypogonadism and is discussed separately. (See "Testosterone treatment of male hypogonadism".)

Critical illness — Any critical illness, such as surgery, myocardial infarction, or head trauma, can cause hypogonadotropic hypogonadism. One study of 35 critically ill men, as an example, found that the serum testosterone concentration fell 43 to 58 percent within the first few days after the onset of the illness [16]. This effect could not be attributed to a decrease in binding of testosterone to sex hormone-binding globulin (SHBG), because the percentage of free testosterone did not change. Thus, the low serum testosterone concentration was probably due to decreased secretion. Serum LH concentrations in these men also fell, indicating a pituitary or, more likely, hypothalamic cause of the hypogonadism.

A subsequent study of 59 men with critical illness demonstrated that the degree of hypogonadism was directly related to the severity of the illness (figure 1) and that the hypogonadism resolved as the patients recovered from the illness (figure 2) [17]. An unanswered question is whether or not the hypogonadism is helpful or harmful to recovery from the critical illness.

Chronic, systemic illness — Several chronic and systemic illnesses, including cirrhosis, chronic kidney disease, chronic lung disease, and acquired immune deficiency syndrome (AIDS), cause hypogonadism by a combination of primary and secondary effects. (See "Causes of primary hypogonadism in males".)

Anorexia nervosa — Although anorexia is not nearly as common in adolescent boys and men as in adolescent girls and women, when it does occur, it may also be associated with marked secondary hypogonadism [18,19].

Diabetes mellitus — Men who have type 2 diabetes mellitus are more likely to have low serum testosterone concentrations than nondiabetic men, but the nature of the relationship is unclear. In a review of 43 studies comprising 6427 men, the cross-sectional studies showed that men with type 2 diabetes had a mean serum testosterone concentration 76 ng/dL lower than nondiabetic men [20]. In the same review, the longitudinal studies showed that men who had higher testosterone concentrations had a lower risk of developing type 2 diabetes. The relative roles of testosterone, obesity, and insulin resistance in this relationship, however, have not been delineated.

Not only is the total testosterone more likely to be low in men with diabetes, but the free testosterone concentration is more likely to be low as well [21].

Obesity — Men who are overweight (body mass index [BMI] 25 to 29 kg/m2) and obese (BMI ≥30 kg/m2) tend to have lower serum concentrations of SHBG and, therefore, lower serum concentrations of total testosterone. Some obese men with low total serum concentrations due to low SHBG have normal free testosterone concentrations.

However, men who are obese may also have low free testosterone concentrations. These abnormalities were shown in a report from the European Male Aging Study in which data from 3220 men ages 40 to 79 years at eight sites were analyzed [22]. At all ages, both total testosterone and SHBG concentrations were lower in overweight men than in men of normal weight and lower yet in obese men. Free testosterone, however, was similar in normal weight and overweight men, but lower in obese men. Serum LH concentrations were not elevated in the obese men, indicating that the overweight men had secondary hypogonadism. In short, obese men may have a low total serum testosterone concentration because of a combination of low SHBG and secondary hypogonadism. Measurement of the serum free testosterone concentration is necessary to determine if an obese man's low total testosterone is due only to low SHBG or to secondary hypogonadism as well.

Sleep apnea — Low testosterone levels have been reported in men with sleep apnea [23,24]. Treatment of sleep apnea with continuous positive pressure airway pressure (CPAP), however, does not appear to raise testosterone levels in these men, as shown by a meta-analysis [25]. This analysis comprised five observational studies and two clinical trials with a total of 232 men in whom testosterone values were available before and after initiation of CPAP. The standardized mean difference between the testosterone values before and after the initiation of CPAP was -0.14 (95% CI -0.63 to 0.34). These results suggest that the low testosterone levels in men with sleep apnea may be the result of the concomitant obesity and not sleep apnea itself.

Damage to gonadotroph cells

Benign tumors and cysts — Any kind of pituitary adenoma or cyst can cause sufficient pressure on the gonadotroph cells to interfere with their function and decrease LH and FSH secretion. (See "Causes, presentation, and evaluation of sellar masses".)

Malignant tumors — Malignant tumors are more likely to affect the hypothalamus than the pituitary. These include both primary (eg, meningiomas) and metastatic tumors (eg, lung and prostate).

Infiltrative diseases — Sarcoidosis and Langerhans cell histiocytosis (eosinophilic granuloma) can cause hypothalamic hypogonadism, while iron deposition in hemochromatosis can cause pituitary hypogonadism. Treatment of the underlying disease may improve gonadotropin secretion [26]. The age of the patient is important in hemochromatosis since reversal of hypogonadism with phlebotomy is more likely to occur in men under the age of 40 years [27]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Infections — Meningitis is a rare cause of hypogonadism in the United States. Tuberculous meningitis can lead to hypopituitarism; this problem is more often seen in countries where tuberculosis is common, such as India [28].

Pituitary apoplexy — Sudden and severe hemorrhage into the pituitary can result in permanent impairment of pituitary function, including hypogonadism. (See "Causes of hypopituitarism", section on 'Pituitary apoplexy'.)

Trauma — Trauma to the base of the skull can sever the hypothalamic-pituitary stalk and interrupt the portal circulation, thereby preventing hypothalamic releasing hormones from reaching the pituitary, resulting in hypopituitarism. When GnRH does not reach the gonadotroph cells in the pituitary, LH and FSH release decreases (see "Causes of hypopituitarism", section on 'Traumatic brain injury'). Traumatic brain injury of various causes, including subarachnoid hemorrhage, can also cause secondary hypogonadism [29].

Idiopathic — No cause can be identified in some men with acquired secondary hypogonadism. The severity can range from mild to severe, as in congenital idiopathic hypogonadotropic hypogonadism. When acquired secondary hypogonadism occurs in young and middle-aged men and is severe, as described in a report of 10 such men [30], there seems little question that it represents clearcut disease. When it occurs in older men and especially when it is of mild to moderate severity, it is not clear if it represents a disease. This is a common occurrence in older men. (See "Approach to older men with low testosterone".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Male infertility or hypogonadism".)

SUMMARY — Primary hypogonadism results from disease of the testes, while secondary hypogonadism results from disease of the pituitary or hypothalamus. The distinction between these disorders is made by measurement of the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). (See "Clinical features and diagnosis of male hypogonadism".)

The patient has primary hypogonadism if his serum testosterone concentration and sperm count are low and his serum LH and FSH concentrations are high. (See "Causes of primary hypogonadism in males".)

The patient has secondary hypogonadism if his serum testosterone concentration and sperm count are low and his serum LH and FSH concentrations are not elevated.

Secondary hypogonadism differs from primary hypogonadism in two characteristics:

Secondary hypogonadism is usually associated with a similar decrease in sperm and testosterone production. This occurs because the primary reduction in LH secretion results in a decrease in testicular testosterone production and, therefore, in intratesticular testosterone, which is the principal hormonal stimulus to sperm production. In contrast, primary hypogonadism is usually associated with a greater fall in sperm production than in testosterone secretion because in primary hypogonadism the seminiferous tubules are damaged to a greater degree than the Leydig cells.

Primary hypogonadism is more likely to be associated with gynecomastia, presumably because elevated serum FSH and LH concentrations stimulate testicular aromatase, which increases the conversion of testosterone to estradiol.

Causes of secondary hypogonadism can be divided into congenital abnormalities and acquired diseases. (See 'Congenital abnormalities' above and 'Acquired diseases' above.)

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