Dr. med. Dirk Manski

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Male Hypogonadism: Causes, Diagnosis and Treatment

Definition and Classification of Male Hypogonadism

Hypogonadism is an endocrine dysfunction leading to testosterone deficiency.

Etiology (Causes) of Hypogonadism in Men

Primary Hypogonadism:

Hypergonadotropic hypogonadism results from bilateral diseases of the testes, diseases of a solitary testis, or from a disorder of testosterone biosynthesis.

Congenital diseases:

Klinefelter syndrome (47,XXY), disorders of sex development such as 46,XX male syndrome, disorders of testosterone biosynthesis, or anorchidia (vanishing testis syndrome).

Acquired conditions:

Testicular cancer (especially after chemotherapy), testicular torsion, testicular trauma, orchitis, or late-onset hypogonadism.

Systemic diseases:

Renal insufficiency, hepatic insufficiency, metabolic syndrome, or after chemotherapy.

Secondary Hypogonadism:

Hypogonadotropic hypogonadism results from a deficiency of the pituitary releasing hormones.

Pituitary insufficiency:

Causes of pituitary insufficiency include tumors, trauma, infarcts (vascular causes, sickle cell disease), infections (bacteria, tuberculosis, sarcoidosis), and hemochromatosis.


Hyperprolactinemia leads to hypogonadotropic hypogonadism and infertility. Other symptoms include decreased libido, erectile dysfunction, gynecomastia, and galactorrhea. Investigation of other pituitary hormones is mandatory (see also prolactin).

Isolated LH deficiency:

Isolated LH deficiency is an uncommon disorder. LH deficiency leads to testosterone deficiency and undervirilization, but adequate FSH enables spermatogenesis ("fertile eunuch" or Pasqualini syndrome).

Isolated FSH deficiency:

FSH deficiency leads to impaired spermatogenesis with infertility; virilization is normal.

Bardet-Biedl syndrome:

Hypogonadotropic hypogonadism with retardation, retinitis pigmentosa, and hand malformation (polydactyly).

Tertiary Hypogonadism:

Hypogonadotropic hypogonadism results from disorders of the hypothalamus with GnRH deficiency.

Kallmann syndrome:

Kallmann syndrome presents with anosmia (olfactory dysfunction) and absent GnRH due to a developmental disorder of neurons in the olfactory plate. Different genes with different modes of inheritance have been described (KAL1, FGFR1, PROK2). Kallmann syndrome may also occur spontaneously.

Leading symptoms are delayed puberty with testicular atrophy and hypogonadotropic hypogonadism. In addition, infertility, facial asymmetry, impaired color vision, microphallus, renal malformations, and cryptorchidism.

Idiopathic hypogonadotropic hypogonadism:

Like Kallmann syndrome, but without anosmia, many different genes with a wide spectrum of inheritance and accompanying symptoms are known.

Prader-Willi syndrome:

Prader-Willi syndrome is a genetic hypogonadotropic hypogonadism with obesity and retardation.

Signs and Symptoms of Male Hypogonadism

Symptoms of Prepubertal hypogonadism:

Symptoms include delayed or absent puberty, lack of penile growth, small scrotum, low testicular volume, straight pubescent hairline, tall stature, elongated arm span, gynecomastia, absent or reduced secondary sexual characteristics (voice change, body hair, beard growth, and musculature) [fig. prepubertal hypogonadism].

Symptoms of Postpubertal hypogonadism:

Visible physical symptoms are often not present. Early symptoms of hypogonadism are decreased libido and motivation, which can already occur in the lower normal range of testosterone concentration. Later symptoms include erectile dysfunction, infertility, depressed mood, and hot flashes.

Complications of Hypogonadism:

Muscle atrophy, anemia, osteoporosis, and metabolic syndrome.

Diagnosis of Male Hypogonadism

Laboratory tests:

Measure testosterone and FSH in the morning as a search test. Normal values exclude relevant hypogonadism; pathological values of these two hormones detect 99% of the above-mentioned disorders. The lower standard value for testosterone is 12 nmol/l (3 ng/ml). Laboratory tests are repeated for pathological values, and additional lab tests are ordered: SHBG, prolactin, LH, and TSH. Relevant systemic diseases are detected by determining blood count, HbA1C, CRP, liver enzymes and creatinine. A GnRH stimulation test is indicated in patients with decreased gonadotropins.

Semen analysis:

Hypogonadism leads to decreased ejaculate volume and low to absent spermatozoa. Semen analysis is only indicated in younger men (with a desire to have children).

Genetic testing:

Many different genes (KAL1, FGFR1, PROK2, GnRHR, GPR54) with a wide spectrum of inheritance and associated symptoms are known in familial hypogonadotropic hypogonadism. With the help of a pedigree analysis, a clinical geneticist can narrow down responsible genes and estimate the risk of recurrence in (assisted) reproduction (Tuettelmann et al., 2008).

Further examinations:

If the diagnosis is confirmed, a bone density examination and, in older men, the exclusion of prostate cancer before testosterone substitution is useful.

Treatment of Male Hypogonadism

For side effects, contraindications, and management of testosterone substitution, see the following section testosterone deficiency.

Hypogonadotropic hypogonadism with desire for fertility:

The substitution of GnRH with a subcutaneous drug pump may achieve fertility. Equal effectiveness is possible with subcutaneous gonadotropins: HCG (LH activity) 1000--2500 IE 3×/week combined with HMG (FSH activity) 75--150 IE 3×/week. Virilization without desire for fertility is achieved with testosterone substitution; see the following section testosterone deficiency.

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Tüttelmann, F.; Gromoll, J. & Kliesch, S. [Genetics of male infertility].
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  Deutsche Version: Ursachen und Diagnose des Hypogonadismus des Mannes