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Male Hypogonadism


Semir A. S. Al Samarrai

 

Definition:

Male hypogonadism is a clinical syndrome caused by testosterone deficiency which may adversely affect multiple organ functions and quality of life(1). 

Introduction:

Testosterone deficiency increase with age, an annual decline in circulating testosterone of 0,4-2,0% has been repeated (2,3). In middle-aged men, the incidence was found be 6 % (4). It is more prevalent in older men, in men with obesity, those with co-morbidities, and in men with poor health status.

Aetiology:

Hypogonadism results from testicular failure, or is, due to the disruption of one or several levels of the hypothalamus-pituatary-gonadal axis.

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

  • The hypothalamus and pituitary (secondary hypogonadism);
  • The testes (primary hypogonadism);
  • The hypothalamus/pituitary and gonads (late-onset hypogonadism);
  • Androgen target organs (androgen insensitivity/resistance);
Male hypogonadism of hypothalamic-hypopituitary origin: the most relevant forms of secondary hypogonadism are:
  • Hyperprolactinemia (HP) caused by prolactin-secreting pituitary adenomas (prolactinomas) (microprolactinomas <10mm in diameter vs. macroprolactinomas) or drug-induced (by dopamine-antagonistic effects of substances such as phenothiazine, imipramine and metoclopramide), additional causes may be chronic renal failure or hypothyroidism
  • Isolated hypogonadotrophic hypogonadism (IHH)
  • Kallmann Syndrome (hypogonadotrophic hypogonadism with anosmia, genetically determined, prevalence one in 10,000 males)
These disorders are characterized by disturbed hypothalamic secretion or action of 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 neurons results in Kallmann Syndrome (5,6).

2.) Male hypogonadism of gonadal origin: (Primary Hypogonadism)

Primary testicular failure results in low testosterone levels, impairment of spermatogenesis and elevated gonadotrophins.

The most important clinical forms of primary hypogonadism are Klinefelter Syndrome (47,XXY) (1 in 500 males) and testicular tumours (12 in 100,000 males) 

3.) Male hypogonadism due to mixed dysfunction of hypothalamus/pituitary and gonads:

Combined primary and secondary failure results in low testosterone levels, impairment of spermatogenesis and variable gonadotrophin levels.

4.) Male hypogonadism due to defects of androgen target organs:

There are androgen receptor defects with complete, partial and minimal androgen insensitivity syndrome, Reifenstein Syndrome, bulbospinal muscular atrophy (Kennedy disease), as well as 5 a-reductase deficiency. 

The classification of hypogonadism has therapeutic implications. In patients with secondary hypogonadism, hormonal stimulations with HCG and FSH or alternatively GnRH can restore fertility in most cases (7,8).


Combined forms of Primary and Secondary Hypogonadism can be observed in aging men between 40-70 years, with a concomitant age-related decline in testosterone levels resulting from defects in testicular as well as hypothalamic-pituitary function.

A significant percentage of men over the age of 60 years have serum testosterone levels below the lower reference limits in young adults (9-13).

Diagnosis: 

Hypogonadism is diagnosed on the basis of persistent symptoms and signs related to testosterone deficiency and assessment of consistently low testosterone levels (at least on two occasions) with reliable method (14-18).

Symptoms: 

Low levels of circulating testosterone may be associated with signs and symptoms as:
  • 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
  • Diminished nocturnal erections
  • Hot flushes
  • Changes in mood, fatigue and anger
  • Sleep disturbances
  • Metabolic Syndrome
  • Insulin resistance and type 2 diabetes mellitus
  • Diminished cognitive function
The most prevalent symptoms of male hypogonadism in aging men are reduced sexual desire and sexual activity, erectile dysfunction, and hot flushes (14).

In men aged 40-79 years, the threshold for total testosterone was 8 nmol/L for decreased frequency of sexual thoughts, 8.5 nmol/L for erectile dysfunction, 11 nmol/L for decreased frequency of morning erections and 13 nmol/L for diminished vigour (19).

The strongest prediction for hypogonadism in this age was three sexual symptoms:
  • Decreased sexual thoughts.
  • Weakened morning erections
  • Erectile dysfunction.
Early onset of hypogonadism causes a lack or minimal pubertal development, lack of development of secondary sex characteristics, possibly eunuchoid body proportions and a high-pitched voice. These signs and symptoms strongly suggest hypogonadism.

Post pubertal development of hypogonadism causes a loss of androgen-dependent functions and symptoms that may have other etiological backgrounds with low testosterone levels.

It is important to assess and exclude systemic illnesses:
  • Signs of malnutrition and malabsorption
  • Ongoing acute disease
  • Pharmaceological treatments with Corticosteroids
  • Abuse of drugs such as marihuana
  • Opiates and alcohol
  • Previous treatment or use of testosterone
  • Abuse of anabolic steroids
Physical Examination:

  • Assessment of body mass index (BMI).
  • Measurement of the waist-hip ratio (or sagittal abdominal diameter),
  • Assessment of the body hair
  • Assessment of malepattern hair loss
  • Assessment of the presence of gynaecomastia
  • Measurement of the testicular size. (measured with an ultrasound (US).
  • Structural examination of the penis
  • Digital rectal examination (DRE) of the prostate.
Treatments:

Testoterone treatment aims to restore testosterone levels to the physiological range in men with consistently low levels of serum testosterone and associated symptoms of androgen deficiency. The aim is to improve quality of life, sense of well-being, sexual function, muscle strength and bone mineral density.

Indication for testosterone treatment:
  • Delayed puberty (idiopathic, Kallmann Syndrome),
  • Klinefelter Syndrome with hypogonadism
  • Sexual dysfunction and low testosterone,
  • Low bone mass in hypogonadism,
  • Adult men with consistent and preferably multiple signs and symptoms of hypogonadism.
  • Hypopituitarism.
  • Testicular dysgenesis and hypogonadism
Contraindication against testosterone treatment:

  • Prostate cancer
  • PSA >4mg/dl
  • Male breast cancer
  • Severe sleep apnoea
  • Male infertility
  • Haematocrit >50%
  • Severe lower urinary tract symptoms (LUTS) due to prostatic enlargement (BPH).
The benefits of receiving (TRT) by hypogonadal men are:

  • Reduction in BMI
  • Reduction of waist size
  • Improvement of glycemic control
  • Improvement of lipid profile
Testosterone replacement therapy (TRT) is safe and effective and the agents are available as oral preparations, intramuscular injections and transdermal gel or patches (20).

By the treatment of hypogonadism by infertility it is recommended hCG therapy to consider, because exogenous testosterone therapy reduces endogenous testosterone production by negative feedback on the hypothalamic pituitary-gonadal axis.

Human chorionic gonadotrophin (hCG) stimulates testosterone production of leydig cells in the testes. Its administration should be restricted to patients with secondary hypogonadism, if fertility issues are important.

Reference:

1. Nieschlag E, Behre HM (eds). Andrology: male reproductive health and dysfunction. 3rd edn. Heidelberg: Springer, 2010.

2. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005 Oct;26(6):833-76.

3. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008 Jul;93(7):2737-45.

4. Hall SA, Esche GR, Araujo AB, et al. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab 2008 Oct;93(10):3870-7.

5. Behre HM, Nieschlag E, Partsch CJ, et al. Diseases of the hypothalamus and the pituitary gland. In: Nieschlag E, Behre HM, Nieschlag S (eds). Andrology – male reproductive health and dysfunction. 3rd edn. Berlin: Springer, 2010:169-92.

6. Pitteloud N, Durrani S, Raivio T, et al. Complex genetics in idiopathic hypogonadotrophic hypogonadism. Front Horm Res 2010;39:142-53.

7. Büchter D, Behre HM, Kliesch S, et al. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotrophic hypogonadism: a review of 42 cases. Eur J Endocrinol 1198 Sep;139(3):298-303. 

8. Sykiotis GP, Hoang XH, Avbelj M, et al. Congenital idiopathic Hypogonadotrophic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab 2010 Jun;95(6):3019-27.

9. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 2007 Nov;92(11):4241:7.

10. Gray A, Feldman HA, McKinlay JB, et al. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991 Nov;73(5):1016-25.

11. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002 Feb;87(2):589-98.

12. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001 Feb;86(2):724-31.

13. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older man are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008 Jul;93(7):2737-45.

14. Hall SA, Esche GR, Araujo AB, et al. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab 2008 Oct;93(10):3870-7.

15. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Cline Endocrinol Metab 2010 Jun;95(6):2536-59.

16. Wang C, Catlin DH, Demers LM, et al. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2004 Feb;89(2):534-43.

17. Rosner W, Auchus RJ, Azziz R, et al. Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007 Feb;92(2):405-13.

18. Rosner W, Vesper H. Toward excellence in testosterone testing: a consensus statement. J Clin Endocrinol Metab 2010 Oct;95(10):4542-8.

19. Vesper HW, Bhasin S, Wang C, et al. Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods. Steroids 2009 Jun;74(6):498-503.

20. Zitzman M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscolar testosterone undecanoate therapy in hypogonodal men. J Clin Endocrinol Metab 2007 Oct;92(10):3844-53.

Correspondence:
Prof. Dr. SEMIR AHMED SALIM AL SAMARRAI
Professor Doctor of Medicine-Urosurgery, Andrology, and Male Infertility
Dubai Healthcare City, Dubai, United Arab Emirates.
Mailing Address: Dubai Healthcare City, Bldg. No. 64, Al Razi building, Block D,
2nd floor, Dubai, United Arab Emirates, PO box 13576
Email: fmcalsam@emirates.net.ae