3.1.Epidemiology

Definition: male hypogonadism is a clinical syndrome caused by androgen deficiency which may adversely affect multiple organ functions and quality of life (QoL) [1].

Androgen deficiency increases slightly with age also in healthy men [2,3]. In middle-aged men, the incidence of biochemical hypogonadism varies from 2.1-12.8% [4]. The incidence of low testosterone and symptoms of hypogonadism in men aged 40-79 varies form 2.1-5.7% [3,4]. Hypogonadism is more prevalent in older men, in men with obesity, those with co-morbidities, and in men with a poor health status.

Androgens, which are produced by the testis and by the adrenal glands, play a pivotal role in male reproductive and sexual function. Androgens are crucial for the development of male reproductive organs, such as the epididymis, vas deferens, seminal vesicle, prostate and penis. In addition, androgens are needed for puberty, male fertility, male sexual function, muscle formation, body composition, bone mineralisation, fat metabolism, and cognitive functions [5].

Male sexual development starts between the 7th and 12th week of gestation. The undifferentiated gonads develop into a foetal testis through expression of multiple genes located on the short arm of the Y chromosome, including the sex-determining region of the Y chromosome (SRY gene complex) and the SOX gene on chromosome 17 [6]. The foetal testis produces three hormones: testosterone, insulin-like peptide 3 (INSL3) and anti-Mllerian hormone (AMH). Testosterone is needed for the stabilisation of the Wolffian ducts, resulting in formation of the epididymis, vas deferens and seminal vesicle. AMH activity results in regression of the Mllerian ducts (Figure 1). INSL3 and AMH regulate testicular descent.

Under the influence of intratesticular testosterone, the number of gonocytes per tubule increases threefold during the foetal period [7]. In addition, testosterone is needed for development of the prostate, penis and scrotum. However, in these organs testosterone is converted into the more potent metabolite 5a-dihydrotestosterone (DHT) by the enzyme 5a-reductase. Testosterone and DHT are required for penile growth, both activating the androgen receptor [8].

Intratesticular testosterone is needed to maintain the spermatogenic process and to inhibit germ cell apoptosis [9]. The seminiferous tubules of the testes are exposed to concentrations of testosterone 25-100 times greater than circulating levels. Suppression of gonadotropins (e.g. through excessive testosterone abuse) results in a reduced number of spermatozoa in the ejaculate and hypospermatogenesis [10]. Complete inhibition of intratesticular testosterone results in full cessation of meiosis up to the level of round spermatids [11,12]. Testosterone does not appear to act directly on the germ cells, but functions through the Sertoli cells by expression of the androgen receptor (AR) and influencing the seminiferous tubular microenvironment [11]. Testosterone can also be metabolised into oestradiol by aromatase, present in fat tissue, the prostate, the testes and bone. Oestradiol is also essential for bone mineralisation in men [13]. The production of testosterone is controlled in the foetus by placental choriongonadotropin (hCG) and after birth by luteinising hormone (LH) from the pituitary gland. Immediately after birth, serum testosterone levels reach adult concentrations over several months (mini puberty). Thereafter and until puberty, testosterone levels are low, thus preventing male virilisation. Puberty starts with the production of gonadotropins, initiated by gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus and results in testosterone production, male sexual characteristics and spermatogenesis [14]. Figure 1 shows the development of the male reproductive system.

Testosterone exerts its action through the AR, located in the cytoplasm and nucleus of target cells. During the foetal period, testosterone increases the number of ARs by increasing the number of cells with the AR and by increasing the number of ARs in each individual cell [8,13]. The AR gene is located on the X chromosome (Xq 11-12): defects and mutations in the AR gene can result in male sexual maldevelopment, which may cause testicular feminisation or low virilisation (i.e. disorder of sexual development (DSD)). Less severe mutations in the AR gene may cause mild forms of androgen resistance and male infertility [15]. In exon 1 of the gene, the transactivation domain consists of a trinucleotide tract (cytosine-adenine-guanine (CAG) repeats)) of variable length. Androgen sensitivity may be influenced by the length of the CAG repeats in exon 1 of the AR gene [15]. The AR CAG repeat length is inversely correlated with serum total and bioavailable testosterone and oestradiol in men. Shorter repeats have been associated with an increased risk for prostate disease, and longer repeats with reduced androgen action in several tissues [16]. CAG repeat number may influence androgenic phenotypical effects, even in case of normal testosterone levels [17].

Summary of evidence

Testosterone is essential for normal male development.

Figure 1: Development of the male reproductive system

FSH=follicle-stimulating hormone; LH=luteinising hormone; SRY=sex determining region of the Y chromosome; INSL3=insulin-like peptide 3.

Hypogonadism results from testicular failure, or is due to the disruption of one or several levels of the hypothalamic-pituitary-gonadal axis (Figure 2).

Male hypogonadism can be classified in accordance with disturbances at the level of:

Primary testicular failure is the most frequent cause of hypogonadism and results in low testosterone levels, impairment of spermatogenesis and elevated gonadotropins. The most important clinical forms of primary hypogonadism are Klinefelter syndrome and testicular tumours.

The main reasons for primary testicular failure are summarised in Table 1.

Central defects of the hypothalamus or pituitary cause secondary testicular failure. Identifying secondary hypogonadism is of clinical importance, as it can be a consequence of pituitary pathology (including prolactinomas) and can cause infertility, which can be restored by hormonal stimulation in most patients with secondary hypogonadism.

The most relevant forms of secondary hypogonadism are:

These disorders are characterised by disturbed hypothalamic secretion or action of gonadatropin-releasing hormone (GnRH), as a pathophysiology common to the diseases, resulting in impairment of pituitary LH and FSH secretion. An additional inborn error of migration and homing of GnRH-secreting neurons results in Kallmann syndrome [23,24]. The most important symptom is the constitutional delay of puberty: it is the most common cause of delayed puberty (pubertas tarda) [25]. Other rare forms of secondary hypogonadism are listed in Table 2.

Combined primary and secondary testicular failure results in low testosterone levels and variable gonadotropin levels. Gonadotropin levels depend predominantly on primary or secondary failure. What has been labelled as late-onset hypogonadism and age-related hypogonadism is comprised of three types of hypogonadism and formally secondary hypogonadism is the most prevalent [26,27]. It should however be stated that low testosterone and low gonadotropin levels do not exclude a compromised gonadal response to LH stimulation as has been demonstrated in obesity, corticosteroid induced hypogonadism etc.

These forms are primarily rare defects and will not be further discussed in detail in these guidelines. There are AR defects with complete, partial and minimal androgen insensitivity syndrome; Reifenstein syndrome; bulbospinal muscular atrophy (Kennedy disease); as well as 5a-reductase deficiency (for a review, see Nieschlag et al. 2010) [28].

The classification of hypogonadism has therapeutic implications. In patients with secondary hypogonadism, hormonal stimulation with human chorionic gonadotropin (hCG) and FSH or alternatively pulsatile GnRH treatment can restore fertility in most cases [29,30]. Detailed evaluation may for example detect pituitary tumours, systemic disease, or testicular tumours. Combined forms of primary and secondary hypogonadism can be observed in ageing, mostly obese men, with a concomitant age-related decline in testosterone levels resulting from defects in testicular as well as hypothalamic-pituitary function.

Table 1: Most common forms of primary hypogonadism

Disease

Causes of deficiency

Maldescended or ectopic testes

Failure of testicular descent, maldevelopment of the testis

Testicular cancer

Testicular maldevelopment

Orchitis

Viral or unspecific orchitis

Acquired anorchia

Trauma, tumour, torsion, inflammation, iatrogenic, surgical removal

Secondary testicular dysfunction

Medication, drugs, toxins, systemic diseases

(Idiopathic) testicular atrophy

Male infertility (idiopathic or specific causes)

Congenital anorchia (bilateral in 1 in 20,000 males,

unilateral 4 times as often)

Intrauterine torsion is the most probable cause

Klinefelter syndrome 47,XXX

Sex-chromosomal non-disjunction in germ cells

46,XY disorders of sexual development (DSD)

(formerly male pseudohermaphroditism)

Disturbed testosterone synthesis due to enzymatic defects of steroid biosynthesis (17,20- lyase defect, 17-hydroxysteroid dehydrogenase defect)

Gonadal dysgenesis (synonym streak gonads)

XY gonadal dysgenesis can be caused by mutations in different genes

46,XX male syndrome (prevalence of 1 in 10,000-20,000)

Males with presence of genetic information from the Y chromosome after translocation of a DNA segment of the Y to the X chromosome during paternal meiosis

Noonan syndrome (prevalence of 1 in 1,000 to 1 in 5,000)

Short stature, congenital heart diseases, cryptorchidism

Inactivating LH receptor mutations, Leydig cell hypoplasia (prevalence of 1 in 1,000,000 to 1 in 20,000)

Leydig cells are unable to develop due to the mutation [31]

Table 2: Most common forms of secondary hypogonadism

Disease

Causes of deficiency

Hyperprolactinemia

Prolactin-secreting pituitary adenomas (prolactinomas) or drug-induced

Isolated hypogonadotropic hypogonadism (IHH) (formerly termed idiopathic hypogonadotrophic hypogonadism, IHH)

Specific (or unknown) mutations affecting GnRH synthesis or action

Kallmann syndrome (hypogonadotropic hypogonadism with anosmia, prevalence 1 in 10,000)

GnRH deficiency and anosmia, genetically determined

Secondary GnRH deficiency

Medication, drugs, toxins, systemic diseases.

Hypopituitarism

Radiotherapy, trauma, infections, haemochromatosis and vascular insufficiency or congenital

Pituitary adenomas

Hormone-secreting adenomas; hormone-inactive pituitary adenomas; metastases tothe pituitary or pituitary stalk

Prader-Willi syndrome (PWS) (formerly Prader-Labhart-Willi syndrome, prevalence 1 in 10,000 individuals)

Congenital disturbance of GnRH secretion

Congenital adrenal hypoplasia with hypogonadotropic hypogonadism (prevalence 1 in 12,500 individuals)

X-chromosomal recessive disease, in the majority of patients caused by mutations in the DAX1 gene

Pasqualini syndrome

Isolated LH deficiency

Recommendation

LE

GR

Differentiate the two forms of hypogonadism (primary and secondary) (LH levels), as this has implications for patient evaluation and treatment and makes it possible to identify patients with associated health problems and infertility.

1b

B

Figure 2: The hypothalamic-pituitary-testes axis

FSH=follicle-stimulating hormone; GnRH=Gonadotropin-releasing hormone; LH=luteinising hormone.

Hypogonadism is diagnosed on the basis of persistent signs and symptoms related to androgen deficiency and assessment of consistently low testosterone levels (on at least two occasions) with a reliable method [4,32-35].

Low levels of circulating androgens may be associated with signs and symptoms (Table 3) [4,36,37]

Table 3: Clinical symptoms and signs suggestive for androgen deficiency

Delayed puberty

Small testes

Male-factor infertility

Decreased body hair

Gynaecomastia

Decrease in lean body mass and muscle strength

Visceral obesity

Decrease in bone mineral density (osteoporosis) with low trauma fractures

Reduced sexual desire and sexual activity

Erectile dysfunction

Fewer and diminished nocturnal erections

Hot flushes

Changes in mood, fatigue and anger

Sleep disturbances

Metabolic syndrome

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