Hypogonadism

Physiology and Pathophysiology 

Testosterone is the most important steroid produced by the testis. 5–7 mg testosterone are produced each day by the Leydig cells of an adult man. As testosterone is lipophilic, it passes easily through membranes and leaves the Leydig cells by diffusion. In the blood, 98% of testosterone is bound to transport proteins, and only 2% is free and hence biologically active.

Approximately 60% of the circulating testosterone is bound with high affinity to the ?-globulin sex hormone binding globulin (SHBG), and 38% is loosely bound and transported by albumin. SHBG shows a higher affinity for testosterone than estradiol. Thus, increased production of SHBG by the liver causes a shift in the ratio of testosterone to estradiol by reducing the amount of free testosterone.1

Several lines of evidence suggest that not only free testosterone but also albumin bound testosterone is available to the target tissues, in case of an increased testosterone need. Therefore, the non-SHBG-bound testosterone is called “the bioavailable testosterone”. Free testosterone mediates androgenic effects, which are exerted at target organs via stimulation of the androgen receptor, a member of the superfamily of nuclear receptors.3 The actions of testosterone are also mediated through conversion to active metabolites, such as dihydrotestosterone (DHT), derived from testosterone through reduction of the Δ 4-bond. Aromatization of testosterone results in the formation of estradiol, a chemical process of considerable importance for the balance between both hormones.

Hypogonadism represents a state of impaired testosterone secretion which may have its origin at the different levels of the hypothalamic-pituitarygonadal axis:

Testicular failure with compensatory upregulation of the gonadotropins (primary or hypergonadotrophic hypogonadism)
Malfunction at the hypothalamus-pituitary level (secondary or hypogonadotrophic hypogonadism)

Additionally, enzyme defects in the testosterone biosynthesis or luteinizing hormone (LH) receptor defects may be causative factors for hypogonadism.

Enzyme defects

Figure 1. Classification of Hypogonadism.2

Testosterone blood levels are often found to be decreased in systemic diseases such as renal failure, liver cirrhosis and diabetes.4 Although a target organ resistance may imply the clinical features of hypogonadism, it is not primarily caused by hypogonadism, but, for exampls, by a loss of androgen receptor function. This androgen insensitivity syndrome manifests as genetic (XY) males who are phenotypical, though sterile, females.5 Interestingly, these persons accept their sexual identity as women. This suggests that the androgen receptor is crucial not only for the male morphologic development but also for the configuration of the male CNS.6

Relating to the main physiological roles of testosterone,7 its deficiency manifests in several ways, many of which are unspecific, particularly in the adult male. This renders the diagnosis of testosterone deficiency as the cause even more difficult:

in children or adolescents, androgen deficits, which are mainly genetical or congenital, are diagnosed if puberty is missing or retarded
after puberty, hypogonadism of the young adult, which is most often acquired (trauma, malignancy, hypophyseal, hypothalamic or general diseases), has unspecific symptoms and is often only diagnosed when infertility becomes obvious
in men over 50 years of age, an androgen deficit is in most cases a consequence of the neuroregulatory defects at hypothalamic and pituitary level, of the decreased size of the pituitary gland with aging and the decrease in number of Leydig cells and / or their ability to produce testosterone. The declined secretion of testosterone with age can become clinically apparent depending on the endocrine capacity of the testes and the individual sensitivity for androgens. The resulting relative androgen deficiency is often aggravated by the increasing SHBG levels with age8 which lead to a further decrease of the free, biologically active fraction of testosterone. The clinical signs are heterogeneous and of little specificity and hence not always recognized.

References:
1. Jockenhövel F: Male Hypogonadism. UNI-MED Verlag Bremen 2004.
2. Schering AG: Classification of hypogonadism and selected syndroms. www.get-back-on-track.com/en/professionals/00_meta/07_praesentationen/p_con_0007_01_02.php, accessed on 28 th July 2004
3. Howell S, Shalet S: Testosterone deficiency and replacement. Horm Res 2001; 56 (suppl 1): 86–92.
4.Zitzmann M, Nieschlag E: Hormone substitution in male hypogonadism. Mol Cell Endocrin 2000; 161: 73–88.
5. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HFL, Gearhart JP, Berkovitz GD, Brown TR, Money J: Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosocial outcome. J Clin Endocrinol Metab 2000; 85: 2664–2669.
6. Gelman EP: Molecular biology of the androgen receptor. J Clin Oncol 2002; 20: 3001–3015.
7. Nehra A: Treatment of endocrinologic male sexual dysfunction. Mayo Clin Proc 2000; 75 (suppl): 40–45.
8. Kim YC: Testosterone supplementation in the aging male. Int J Impot Res 1999; 11: 343–352.

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