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Open Access Journal of Urology & Nephrology Research Article 27 min read

Late Onset Hypogonadism [LOH]. Current Concepts and Controversies - A Review

Prasanna Ram, Bala Bhaskar Reddy and Joseph Philipraj S*
* Corresponding author
ISSN: 2578-4676  10.23880/oajun-16000158  Received: February 20, 2019  Published: March 06, 2019
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Keywords
Male Hypogonadism Testosterone Deficiency Lower Serum Testosterone Erectile Dysfunction
Abstract

Male hypogonadism is a clinical syndrome complex, which includes symptoms-with or without signs and biochemical evidence of testosterone deficiency. Lower serum testosterone (T) is common in ageing men, but only a small proportion of them develop the syndrome of low T with diffuse sexual physical and psychological symptoms. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations. This syndrome is also known as male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late onset hypogonadism (LOH) describes it best and is therefore the preferred term. A problem with the diagnosis is that often the symptoms of hypogonadism and low circulating T do not coincide in the same individual. The European Male Ageing Study (EMAS) has suggested a strict diagnostic criterion for LOH that includes the simultaneous presence of low serum T and three sexual symptoms (erectile dysfunction, and reduced libido and morning erections). By these criteria, only 2% of 40 to 80 year old men have LOH. Evidence based information on treatment is limited. The easiest approach is lifestyle modification, weight reduction and good treatment of comorbid diseases. T replacement is also widely used as a treatment modality, but evidence-based information about its benefits and short and long term risks, is not yet available. In this review, we will summarize the current concepts and controversies in the pathogenesis, diagnosis and treatment of LOH.

Introduction

United Nations (UN) estimates that the population on Earth will have increased fourfold from two and a half billion in 1950 to almost ten billion by 2050 [1]. The average life span has also increased due to improved hygiene, reduction of new-born mortality, and more effective prevention and therapy of diseases in adult age globally. Consequent to this phenomenon is a systematically growing population of older people and the emergence of age-related health problems that have not been seen before. These changes have increased the focus on the health and quality of life of older people.

Aging is a slow physiological process which is inevitable. During the process of aging, the humans undergo a series of morphological and functional modifications within all organs, tissues, and cells. This is characterised by a general tendency towards reduced physiological efficiency and atrophy of various organs and systems [2, 3]. Involutional processes occur in both peripheral glandular secretions as well as in the hypothalamus and pituitary gland which reflects in the fundamental change in the secretion of most hormones. There is a slow gradual decline in testicular testosterone production as the man ages which is a well-documented fact [4, 5]. Factors contributing to this are obesity and deteriorating health upon aging [6]. When the decrease of Testosterone is associated with symptoms of androgen deficiency the condition is known as late-onset hypogonadism (LOH). The trend of decline of Testosterone is 0.5–2% per year, and it remains within the reference range of young men in most elderly men. In some men the decrease is more profound which may be biochemical (<200ng/dl) or even clinical.

Definition

The Sexual Medicine Society of North America defines adult-onset hypogonadism (AOH) as a clinical and biochemical syndrome characterized by a deficiency of testosterone (T) with symptoms and signs that can be caused by testicular and/or hypothalamic-pituitary (HP) dysfunction. Manifestations of Low testosterone levels include symptoms of sexual dysfunction, muscle weakness, obesity, osteoporosis, hot flushes, insomnia, fatigue, poor concentration and depression. The combination of low T and an array of the above symptoms have been termed with many names, including male menopause or climacterium, partial androgen deficiency of the aging male (PADAM), andropause and late‑onset hypogonadism (LOH). The current definition ‘LOH is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum T levels (below the young healthy adult male reference range)’.

Incidence

It is well‑documented phenomenon that testicular testosterone (T) production decreases in men with ageing, by 1%–2% per year after the age of 40 years. However, on average serum levels of T remain within the normal range of young men [5, 6, 7, 8]. The age‑dependent reference range for T has not been defined and the criteria on cut off levels for hypogonadism remain somewhat controversial. When only hormonal criteria are used (i.e. T below the lower limit of the reference range of young men (about 10 nmol−1), the prevalence of ‘biochemical hypogonadism’ is high, 23.3% in 40‑ to 79‑year‑old men of the European Male Ageing Study (EMAS) [9] In another study, the incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 years of age, and the prevalence of low free T in each age group was even higher due to the ageing‑related increase of sex hormone binding globulin (SHBG) levels. This may not manifest clinically, because most men with low T remain asymptomatic [10]. Age-related hypogonadism is a clinically and biochemically defined disease of older men with serum testosterone level below the reference parameters of younger healthy men and with symptoms of testosterone deficiency, manifested by pronounced disturbances of the quality of life and harmful effects on multiple organ systems [11]. In middle-aged men, the incidence of biochemical hypogonadism varies from 2.1% to 12.8% [12]. The incidence of low testosterone and symptoms of hypogonadism in men aged 40-79 years varies from 2% to 6% [12, 13]. Hypogonadism is more prevalent in older men, in obesity, in those with co- morbidities, and in men with a poor health status [14].

Pathogenesis of LOH

Ageing and Hypothalamic-pituitary‑Testicular axis: Testicular function declines somewhat with advancing age [15]. Purely age‑dependent change is usually small and probably of the same magnitude as that of other organs of the body [16]. The morphological changes in the testis upon ageing include degeneration of the germinal epithelium and increased proportion of connective tissue. The total number of Sertoli and Leydig cells decreases to around half of that of the young testis [17, 18]. LOH is a consequence of the aging process, deterioration of hypothalamic-pituitary function, and Leydig cell function in the testes [19]. As the men age there is disorder of pulsed secretion of GnRH by dysregulation of the hypothalamic pulse generator and reduction of the frequency and amplitude of LH pulses. The amount and activity of Leydig cells decreases mainly by progression of atherosclerosis and degenerative changes in Leydig cells. Only the free, unbound testosterone is biologically active. SHBG levels increase with age, so the proportion of bioactive free testosterone decreases. In older men, it often leads to an increase in aromatase activity, which metabolises testosterone to oestradiol. This phenomenon is compounded by the co-occurrence of obesity, diabetes mellitus, cardiovascular disease, and cancer [20].

The concentration of serum T reaches its maximum around 25–30 years of age and starts a slow steady decline thereafter at a rate of about 1% per year. A recent longitudinal study showed that serum total T decreases between 55 and 68 years of age by 1.4% per year, free T by 2.7%, while SHBG increased at the same time by 2.7% [21]. The aging‑related decline of T shows great inter individual variability, with about 20% on men over 60 years having serum T in the upper normal range of young men, and about 20% being below the reference range, and even a larger proportion of men have their bioavailable T in the subnormal range [22]. About half of circulating T is bound to SHBG, and another half to albumin, and only 0.5%-3% of T remains in free, non-protein‑bound form, representing the biologically active fraction [23]. The concentration of SHBG increases with ageing which results in proportionate decrease in free T.

Impact of Low Testosterone on Health

LOH and its Association with Systemic Diseases

Since LOH is more common in older men with chronic diseases it becomes difficult to separate the influence of comorbidities from the influence of aging. High BMI, central adiposity, and MetS are associated with low serum total T and to a lesser extent low free T level. Low serum total T level is a predictor of the development of central obesity. Lowering the serum T levels in men with prostate cancer by treatment with GnRH analogues resulted in increased body fat mass. Prospective studies indicated that men with higher T levels had a 42% lower risk of DM2, also men with higher SHBG levels had a 52% lower risk of DM Type II. Estradiol levels were significantly elevated in the diabetic group.

Low serum SHBG, low total T, and clinical AD were significantly associated with increased risk of developing MetS. In the EMAS, BMI was significantly associated with the risk for secondary hypogonadism [24]. The patients with a BMI of 30 kg/m2 were 3 times more likely to develop LOH [25]. The presence of 1 or more comorbidities was significantly associated with secondary hypogonadism in the EMAS.

In the Hypogonadism in Males study- Significant presence of hypogonadism in patients who also suffered from diabetes, hypertension, hyperlipidemia, asthma/chronic obstructive pulmonary disease, and/or prostate disease in comparison to men without these conditions. The presence of low T level, therefore, may be a marker of poor health and the possible presence of comorbidities.

LOH in the Immune Suppressed

Testosterone deficiency is more common in human immunodeficiency virus (HIV)-infected males than in the general population [26]. The pathophysiology of HIV-associated AOH includes [27, 28, 29, 30]. (1) Poor clinical or nutritional status, (2) Use of certain prescription medications used to treat HIV, (3) Illicit drugs including opiates and methadone, (4) Pituitary dysfunction [31], (5) Hepatitis C and other opportunistic infections, (6) Advancing age and increasing length of time diagnosed with HIV, (7) Changes in body composition, (8) increased levels of estradiol and increased levels of SHBG, (9) Normal age-related declines, (10) Low CD4 cell count [32, 33, 34, 35, 36], (11) High HIV viral load and disease progression, (12) Lean body mass, (13) Metabolic syndrome, and (14) Wasting lipodystrophy

Medications and LOH

Opioids, glucocorticoids, cimetidine, tricyclic anti- depressants, nicotine, and marijuana are some of the examples of the drugs associated with hypogonadism men who use anabolic steroids often show T levels that are the same as castrate levels after stopping these drugs. Opiate medications inhibit the HPG axis, causing a decrease in T levels [37, 38]. Evidence that Statin drugs have been implicated in hypogonadism is still not definitive [39]. Chemotherapy affects the testes directly and has a toxic effect on the Leydig cells, decreasing T production [40].

LOH, Sleep Apnoea and Stress

Men with obstructive sleep apnea seem to have a higher incidence of secondary hypogonadism than age- matched controls. Obesity is the common link between the increased prevalence of sleep disorders and hypogonadism [41].

Literature suggests that sleep apnea is an independent risk factor for hypogonadism possibly due to the fact that men with sleep apnea secrete blunted levels of LH during sleep [42]. Stress often manifests physiologically as a pro inflammatory state, which may cause HPG axis disruption, which is why in conditions like acute myocardial infarction, elective surgery, and brain injury, T levels reduce. Psychosocial stress and work-related stress also decrease T levels [43, 44, 45].

Clinical Features: Common clinical symptoms of LOH are lethargy, fatigue, decreased sense of well-being, reduced physical and mental activity, diminished libido, increased sweating, depressive mood, reduced muscle and bone mass or even osteoporosis, erectile dysfunction, and mild anaemia. When clinical symptoms are present, the laboratory work-up should focus on total serum testosterone levels. Total testosterone levels <200ng/dl indicates hypogonadism. In cases of testosterone levels between 200 and 400ng/dl, measurement should be repeated and supplemented by determination of free testosterone, either by appropriate laboratory methods or the calculation of free testosterone index.

Management

Diagnosis

Diagnosis is based on the presence of three sexual symptoms combined with a total testosterone level of less than 11nmol per liter and a free testosterone level of less than 220pmol per liter. The application of these new criteria can guard against the excessive diagnosis of hypogonadism and curb the injudicious use of testosterone therapy in older men.

Testosterone Therapy (TTh)

Once LOH is accurately diagnosed, the physician must discuss all treatment options for TRT, including the option of no treatment. When considering TRT, the goals of therapy should include restoration of testosterone levels to the mid-normal range, approximation of endogenous production, avoidance or reduction of significant adverse effects, and alleviation of the associated the signs and symptoms of AOH. Overall, there is evidence suggesting improvement in physical condition, sexual libido, glucose control, lipid metabolism, mood, and cognition. TTh significantly improves erectile function and other sexual parameters as measured by IIEF in hypogonadal men [46]. These results argue that sexual dysfunction should be considered a hallmark manifestation of T deficiency, since those symptoms can be significantly improved with normalization of serum T. In addition, these results suggest that TTh alone may be considered a reasonable treatment for hypogonadal men with milder degrees of erectile dysfunction, whereas the addition of other treatments, such as phosphodiesterase type 5 inhibitors, may be more appropriate for men with more severe erectile dysfunction [47].

Oral

Oral testosterone undecanoate undergoes first-pass metabolism and is inactivated in the liver. An oral preparation was created to bypass first-pass metabolism with the methylation at the 17α. Significant hepatotoxic adverse effects have been noted long-term with this modality, and as such, its use is not recommended [48]. This formulation needs to be taken 2 to 4 times daily with a normal meal, but without adequate dietary fat content, absorption may be incomplete and testosterone levels may not equilibrate.

Buccal

The testosterone buccal system (Striant) is the only available oral testosterone therapy in the United States. Buccal systems are applied every 12 hours to the upper gum, overlying the incisor tooth, with patches alternating between the left and right sides [49]. Administration provides a steady delivery of testosterone, which is maintained in physiologic ranges. Two noninferiority trials comparing Striant to either a testosterone transdermal system (Androderm) or testosterone gel (Androgel) demonstrated equivalent physiologic testosterone levels [50, 51, 52]. Safety and tolerability data from two open-label phase III trials demonstrated a 12% rate of discontinuation over a 2-year period due to adverse events, most commonly altered taste and gum irritation.

Transdermal

Multiple transdermal systems of testosterone delivery are currently available with similar pharmacokinetic and adverse event profiles. Although the sites of delivery vary between formulations, all therapies achieve normal physiologic concentrations of testosterone in over 75% of patients, with slight differences in the rates and peak levels of testosterone achieved [53, 54, 55, 56, 57]. Dose adjustment is important because transdermal absorption varies between men, and may vary in an individual over time, depending on long-term skin changes at administration sites. Skin irritation with blisters is more common with patches compared to gels. Patients undergoing transdermal testosterone supplementation should be cautioned to the potential for direct transference to others, particularly to women and children. As direct skin- to skin contact is required for transference, this may be avoided by placement of clothing over the administered site and thorough hand washing following topical application.

Injections

Injection therapies with testosterone provide an alternative method for testosterone supplementation. Deep intramuscular injections are performed every 1 to 4 weeks in the gluteal or quadricep areas. A characteristic of injectable testosterone is the rapid rise to supraphysiologic levels of testosterone within 1 to 2 days of administration, with a gradual decline into the hypogonadal range at the end of the dosing interval. Testosterone Enanthate 200 mg administered intramuscularly every 2 weeks achieves normal physiologic testosterone levels for 72% of the treatment interval compared to 82% with the testosterone transdermal system. Although costs vary, in general, intramuscular therapies are currently the least expensive alternative for testosterone supplementation. Adverse events with injectable testosterone include local pain and higher levels of polycythemia secondary to the supraphysiologic surge of testosterone associated with the injections.

Pellets

A long-lasting option for testosterone supplementation is subcutaneous testosterone pellets inserted into the lateral buttock or lower abdomen every 3 to 4 months. Different pellet presentations are available around the world. The procedure involves local anesthetic, with the pellets inserted into subcutaneous fat with a small trocar. Subcutaneous testosterone pellet insertion achieves peak testosterone levels approximately 12 hours following insertion, with a half-life of approximately 71 days. The total and duration of physiologic testosterone levels vary based on the number of pellets inserted and the patient’s body mass index. Patients with elevated body mass indices achieve lower peak concentrations and may require a larger number of pellets compared to men in the low or normal body mass index range [58, 59, 60, 61]. Common adverse events associated with testosterone pellet administration include, local pain, erythema, pellet extrusion, and ecchymosis.

Monitoring

Monitoring for treatment efficacy and possible adverse events should be based on the Endocrine Society’s guidelines for monitoring patients on TRT [62]. Once this started, follow-up should be set up for 3 to 6 months, at which time symptoms can be assessed, testosterone levels can be rechecked, and monitoring can be continued for weight, Hct, and PSA. Should TT remain <400ng/dL, consideration to increase dosing may be pursued. If Hct >54%, TRT should be stopped until it returns to a normal level, and TRT may be reinitiated at a lower dose. In men older than 40 years with a baseline PSA >0.6ng/mL, one should perform a PSA and digital rectal exam before TRT and at intervals of 3 and 6 months once TRT is initiated. If PSA remains stable, follow-up can continue annually thereafter. If the patient has tolerated TTh well with no laboratory abnormalities, follow-up can continue annually. After 1 to 2 years of TTh in men with osteoporosis or history of low trauma fracture, a bone mineral density test should be pursued. If no improvement is noted after 3 to 6 months of TTh, one should consider other causes of the initial presenting symptoms.

Risks of TRT

Testosterone Replacement Therapy and Cardiovascular Events

There has been an increased use of testosterone therapy (TTh) in the last decade. This increase in usage has been attributed to many factors including age, poor general health and medical conditions such as obesity and diabetes. Many studies in the last 20 years have published data that TD is associated with an increased risk of developing atherosclerosis, CV disease, worsening osteoporosis and increased mortality and TTh has been found to have a beneficial effect on multiple risk factors. Diabetes, dyslipidemia, hypertension and obesity are risk factors for CV disease, and that TD contributes to increased fat mass and insulin resistance, it is reasonable to believe that TD increases CV disease by potentiating these risk factors. Any therapeutic modality that mitigates these risk factors is expected to reduce the risk of developing CV disease. Many intervention studies with the use of TTh demonstrate improvements in lipid profile, inflammation, obesity, waist circumference, glycemic control and blood pressure [63, 64, 65, 66].

Clinical Trials Reporting Increased Cardiovascular Risk

The first trial which reported adverse CV effects after TTh was the Testosterone in Older Men with Mobility Limitations (TOM) trial [67] This was a prospective, placebo-controlled, randomized trial that was designed to determine the effects of 6 months of TTh on lower- extremity strength and physical function in older men (n=209) with TD and limited mobility. The study a benefit for functional status and muscular strength response but the trial was terminated early because of increased CV

adverse effects in the treatment group (21.6% vs. 4.8% in placebo group). Of the 23 reported CV events, only four were considered major adverse cardiac events (MACE).

Prostate Cancer

No adequately designed or appropriately powered study has been conducted to date to assess prostate cancer related risks of TTh. The detrimental effect of testosterone in locally advanced or metastatic prostate cancer has been well established, with early studies demonstrating significant progression of disease following exogenous testosterone administration [67, 68, 69]. Hsing [70] noted no difference in the incidence of prostate cancer in patients undergoing TTh compared to the general population. Two meta analyses of placebo- controlled TRT studies revealed no increased risk of the development of prostate cancer for patients undergoing TRT [71, 72]. As such, the available evidence suggests it is safe to administer testosterone in the setting of LOH without increasing an individual’s long-term risk of prostate cancer. Several retrospective studies have studied TRT in patients who have undergone definitive therapy for their prostate cancer and have demonstrated no increased risk of prostate cancer recurrence. Current evidence recommends against TRT in the setting of untreated prostate cancer but permits administration at a prudent interval following successful definitive local therapy with no evidence of recurrence.

Lower Urinary Tract Symptoms (LUTS)

Although androgens are thought to play a large role in prostate development, no difference in prostatic androgens has been noted in men with and without benign prostatic hyperplasia (BPH). Multiples studies have demonstrated either no change or improved parameters of voiding and LUTS in patients with BPH undergoing TTh, and thus, BPH should not be a contraindication to TTh in the setting of LOH [73, 74, 75, 76, 77].

Polycythemia

Polycythemia (erythrocytosis) is a common adverse event associated with TRT, that is both dose and serum- level dependent [78, 79]. The overall effect noted varies by dose and patient age, but the risk of an increase in Hct >50% has been noted to be 3 to 4 times higher in patients receiving TRT compared to controls [68, 69]. The initial rise in hemoglobin and Hct is seen in the first 5 to 6 months, with a decline noted 3 to 12 months after TRT discontinuation [80]. Although it has been hypothesized that enhance blood viscosity may be a risk for CVE, a causal relationship for TRT and its related erythrocytosis with CVE and mortality have not been well-defined through current studies, as described noted. As such, the Endocrine Society’s Clinical Practice Guidelines are used to guide clinical management of TRT-related polycythemia and state that Hct values >54% warrant discontinuation of TRT until further assessment. In cases of extremely elevated or persistent polycythemia, therapeutic phlebotomy has been described as a management option.

Conclusion

Late-onset hypogonadism is a new entity afflicting elderly men. Evidence supports the authenticity of this entity and its health relevance. However, it is important to realise the presence of gaps in the understanding of this syndrome and its treatment. Improved clinical management can be expected to result from rigorous investigation of diagnostic criteria and demonstration of efficacy and safety of treatments for this syndrome.

References

  1. US Census Bureau, International Date Basa. Access: (2015) July.
  2. Warszawa (2015) Główny Urząd Statystyczny. Trwanie życia w 2014 r. 15-17.
  3. Warszawa (2014) Główny Urząd Statystyczny Prognoza ludności na lata 2014-2050. 4: 78.
  4. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, et al. (2009) Investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Androl 32(1): 1-10.
  5. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, et al. (2008) European male aging study Group. 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 93(7): 2737-2745.
  6. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, et al. (2002) 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 87(2): 589-598.
  7. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86(2): 724-731.
  8. Morley JE, Kaiser FE, Perry HM, Patrick P, Morley PM, et al. (1997) Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 46(4): 410-413.
  9. Tajar A, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, et al. (2012) Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab 97(5): 1508-1516.
  10. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, et al. (2010) Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 363(2): 123-135.
  11. Wang C, Nieschlag E, Swerdloff R, Behrec HM, Hellstrom WJ, et al. (2009) Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 55(1): 121-130.
  12. Hall SA, Esche GR, Araujo AB, Travison TG, Clark RV, et al. (2008) Correlates of low testosterone and symptomatic androgen deficiency in a population- based sample. J Clin Endocrinol Metab 93(10): 3870- 3877.
  13. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, et al. (2008) 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 93(7): 2737- 2745.
  14. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, Mcwhirter C (2006) Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 60(7): 762-769
  15. Perheentupa A, Huhtaniemi I (2009) Aging of the human ovary and testis. Mol Cell Endocrinol 299(1): 2-13.
  16. Lamberts SW, van den Beld AW, van der Lely AJ (1997) The endocrinology of aging. Science 278(5337): 419-424.
  17. Neaves WB, Johnson L, Porter JC, Parker CR Jr, Petty CS (1984) Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab 59(4): 756-763.
  18. Johnson L, Zane RS, Petty CS, Neaves WB (1984) Quantification of the human Sertoli cell population: its distribution, relation to germ cell numbers, and age-related decline. Biol Reprod 31(4): 785-795.
  19. Tüttelmann F, Nieschlag E (2010) Classification of Andrological Disorders. In: Andrology: male reproductive health and dysfunction. Springer-Verlag, Berlin Heidelberg, 87-92.
  20. Rabijewski M (2011) Hipogonadyzm u mężczyzn. In: Wielka Interna, Endokrynologia, Część 2. Zgliczyński W (ed.), 1st (Edn.), Warsaw: 633-646,774.
  21. Travison TG, Araujo AB, Kupelian V, O’Donnell AB, McKinlay JB (2007) The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 92(2): 549-555.
  22. Kaufman JM, Vermeulen A (2005) The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26(6): 833-876.
  23. Belchetz PE, Barth JH, Kaufman JM (2010) Biochemical endocrinology of the hypogonadal male. Ann Clin Biochem 47(Pt 6): 503-515.
  24. Tajar A, Forti G, O’Neill TW, Lee DM, Silman AJ, et al. (2010) Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Aging Study. J Clin Endocrinol Metab 95(4): 1810-1818.
  25. Corona G, Vignozzi L, Sforza A, Mannucci E, Maggi M (2015) Obesity and late-onset hypogonadism. Mol Cell Endocrinol 418(2): 120-133.
  26. Ashby J, Goldmeier D, Sadeghi-Nejad H (2014) Hypogonadism in human immunodeficiency virus- positive men. Korean J Urol 55(1): 9-16.
  27. Crum-Cianflone NF, Bavaro M, Hale B, Amling C, Truett A, et al. (2007) Erectile dysfunction and hypogonadism among men with HIV. AIDS Patient Care STDS 21(1): 9-19.
  28. De Ryck I, Van Laeken D, Apers L, Colebunders R (2013) Erectile dysfunction, testosterone deficiency, and risk of coronary heart disease in a cohort of men living with HIV in Belgium. J Sex Med 10(7): 1816- 1822.
  29. Moreno-Pérez O, Picó Alfonso AM, Portilla J (2009) Hypogonadism, erectile dysfunction and endothelial dysfunction among HIV-infected men [in Spanish]. Med Clin (Barc) 132(8): 311-321.
  30. Richardson D, Goldmeier D, Frize G, Lamba H, De Souza C, et al. (2007) Letrozole versus testosterone: a single-center pilot study of HIV-infected men who have sex with men on highly active anti-retroviral therapy (HAART) with hypoactive sexual desire disorder and raised estradiol levels. J Sex Med 4(2): 502-508.
  31. Rochira V, Zirilli L, Orlando G, Santi D, Brigante G, et al. (2011) Premature decline of serum total testosterone in HIV-infected men in the HAART-era. PLoS One 6(12): 28512.
  32. Sadeghi-Nejad H, Wasserman M, Weidner W, Richardson D, Goldmeier D (2010) Sexually transmitted diseases and sexual function. J Sex Med 7(2): 389-413.
  33. Tripathy SK, Agrawala RK, Baliarsinha AK (2015) Endocrine alterations in HIV-infected patients. Indian J Endocrinol Metab 19(1): 143-147.
  34. Zona S, Guaraldi G, Luzi K, Beggi M, Santi D, et al. (2012) Erectile dysfunction is more common in young to middle-aged HIV-infected men than in HIV- uninfected men. J Sex Med 9(7): 1923-1930.
  35. Rahnema CD, Lipshultz LI, Crosnoe LE, Kovac JR, Kim ED (2014) Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril 101(5): 1271- 1279.
  36. Birthi P, Nagar VR, Nickerson R, Sloan PA (2015) Hypogonadism associated with long-term opioid therapy: a systematic review. J Opioid Manag 11(3): 255-278.
  37. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ (2013) The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 11: 57.
  38. Howell SJ, Shalet SM (2005) Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr 34: 12-17.
  39. Attal P, Chanson P (2010) Endocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab 95(2): 483-495.
  40. Luboshitzky R, Aviv A, Hefetz A, Herer P, Shen-Orr Z, et al. (2002) Decreased pituitarygonadal secretion in men with obstructive sleep apnea. J Clin Endocrinol Metab 87(7): 3394-3398.
  41. Woolf PD, Hamill RW, McDonald JV, Lee LA, Kelly M (1985) Transient hypogonadotropic hypogonadism caused by critical illness. J Clin Endocrinol Metab 60(3): 444-450.
  42. Nilsson PM, Møller L, Solstad K (1995) Adverse effects of psychosocial stress on gonadal function and insulin levels in middle-aged males. J Intern Med 237(5): 479-486.
  43. Singer F, Zumoff B (1992) Subnormal serum testosterone levels in male internal medicine residents. Steroids 57(2): 86-89.
  44. Corona G, Rastrelli G, Morgentaler A, Sforza A, Mannucci E, et al. (2017) Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. Eur Urol 72(6): 1000-1011.
  45. Rizk PJ, Kohn TP, Pastuszak AW, Khera M (2017) Testosterone therapy improves erectile function and libido in hypogonadal men. Curr Opin Urol 27(6): 511-515.
  46. Dean JD, McMahon CG, Guay AT, Morgentaler A, Althof SE, et al. (2015) The International Society for Sexual Medicine's process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med 12(8): 1660-1686.
  47. Korbonits M, Kipnes M, Grossman AB (2004) Striant SR: a novel, effective and convenient testosterone therapy for male hypogonadism. Int J Clin Pract 58(11): 1073-1080.
  48. Dobs AS, Matsumoto AM, Wang C, Kipnes MS (2004) Short-term pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men. Curr Med Res Opin 20(5): 729-738.
  49. Columbia Laboratories Inc. Data on file: a combined report of two open-label phase III, multicenter studies of COL 1621, The long-term safety, tolerability and efficacy in testosterone-deficient patients 2004.
  50. Wang C, Swerdloff R, Kipnes M, Matsumoto AM, Dobs AS, et al. (2004) New testosterone buccal system (Striant) delivers physiological testosterone levels: Pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab 89(8): 3821-3829.
  51. Mazer N, Bell D, Wu J, Fischer J, Cosgrove M, et al. (2005) Comparison of the steady state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men. J Sex Med 2(2): 213-226.
  52. Wang C, Ilani N, Arver S, McLachlan RI, Soulis T, et al. (2011) Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen-deficient men. Clin Endocrinol (Oxf) 75(6): 836-843.
  53. Kaufman JM, Miller MG, Garwin JL, Fitzpatrick S, McWhirter C, et al. (2011) Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med 8(7): 2079-2089.
  54. McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA (2003) A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 91(1): 69-74.
  55. Dobs AS, McGettigan J, Norwood P, Howell J, Waldie E, et al. (2012) A novel testosterone 2% gel for the treatment of hypogonadal males. J Androl 33(4): 601- 607.
  56. Jockenhövel F, Vogel E, Kreutzer M, Reinhardt W, Lederbogen S, et al. (1996) Pharmacokinetics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal men. Clin Endocrinol (Oxf) 45(1): 61-71.
  57. Pastuszak AW, Mittakanti H, Liu JS, Gomez L, Lipshultz LI, et al. (2012) Pharmacokinetic evaluation and dosing of subcutaneous testosterone pellets. J Androl 33(5): 927-937.
  58. Handelsman DJ, Conway AJ, Boylan LM (1990) Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 71(1): 216-222.
  59. Kaminetsky JC, Moclair B, Hemani M, Sand M (2011) A phase IV prospective evaluation of the safety and efficacy of extended release testosterone pellets for the treatment of male hypogonadism. J Sex Med 8(4): 1186-1196.
  60. Bhasin S, Cunnignham GR, Hayes FJ, Matsumoto AM, Snyder PJ, et al. (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guidline. J Clin Endocrinol Metab 95(6): 2536-2559.
  61. Khera M (2015) Controversies in testosterone supplementation therapy. Asian J Androl 17(2): 175- 176.
  62. Bhattacharya RK, Khera M, Blick G, Kushner H, Miner MM (2012) Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS). Clin Interv Aging 7: 321-330.
  63. Malik RD, Lapin B, Wang CE, Lakeman JC, Helfand BT (2015) Are we testing appropriately for low testosterone? Characterization of tested men and compliance with current guidelines. J Sex Med 12(1): 66-75.
  64. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, et al. (2015) Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 90(2): 224-251.
  65. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, et al. (2007) Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPICNorfolk) Prospective Population Study. Circulation 116(23): 2694-2701.
  66. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, et al. (2005) Adverse events associated with testosterone replacement in middleaged and older men: a meta-analysis of randomized, placebo- controlled trials. J Gerontol A Biol Sci Med Sci 60(11): 1451-1457.
  67. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, et al. (2010) Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 95(6): 2560-2575.
  68. Fowler JE Jr, Whitmore WF Jr (1981) The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 126(3): 372-375.
  69. Fowler JE Jr, Whitmore WF Jr (1982) Considerations for the use of testosterone with systemic chemotherapy in prostatic cancer. Cancer 49(7): 1373-1377.
  70. Hsing AW (2001) Hormones and prostate cancer: what's next?. Epidemiol Rev 23(1): 42-58.
  71. van der Sluis TM, Vis AN, van Moorselaar RJ, Bui HN, Blankenstein MA, et al. (2012) Intraprostatic testosterone and dihydrotestosterone, part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer. BJU Int 109(2): 176-182.
  72. Pechersky AV, Mazurov VI, Semiglazov VF, Karpischenko AI, Mikhailichenko VV, et al. (2002) Androgen administration in middle-aged and ageing men: Effects of oral testosterone undecanoate ondihydrotestosterone, oestradiol and prostate volume. Int J Androl 25(2): 119-125.
  73. Amano T, Imao T, Takemae K, Iwamoto T, Nakanome M (2010) Testosterone replacement therapy by testosterone ointment relieves lower urinary tract symptoms in late onset hypogonadism patients. Aging Male 13(4): 242-246.
  74. Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A (2014) Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology 83(1): 167-173.
  75. Haider A, Gooren LJ, Padungtod P, Saad F (2009) Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia 41(1): 7-13.
  76. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, et al. (2010) Adverse events associated with testosterone administration. N Engl J Med 363: 109-122.
  77. Delev DP, Davcheva DP, Kostadinov ID, Kostadinova II (2013) Effect of testosterone propionate on erythropoiesis after experimental orchiectomy. Folia Med (Plovdiv) 55(2): 51-57.
  78. Ip FF, di Pierro I, Brown R, Cunningham I, Handelsman DJ, et al. (2010) Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. Eur J Endocrinol 162(2): 385-390.
  79. Swerdloff RS, Wang C (2003) Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male 6(3): 207-211.
  80. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, et al. (2004) Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 89(5): 2085-2098.
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@article{prasanna2019,
  title   = {Late Onset Hypogonadism [LOH]. Current Concepts and
Controversies - A Review},
  author  = {Prasanna Ram, Bala Bhaskar Reddy and Joseph Philipraj S},
  journal = {Open Access Journal of Urology & Nephrology},
  year    = {2019},
  volume  = {4},
  number  = {1},
  doi     = {10.23880/oajun-16000158}
}
Prasanna Ram, Bala Bhaskar Reddy and Joseph Philipraj S (2019). Late Onset Hypogonadism [LOH]. Current Concepts and
Controversies - A Review. Open Access Journal of Urology & Nephrology, 4(1). https://doi.org/10.23880/oajun-16000158
TY  - JOUR
TI  - Late Onset Hypogonadism [LOH]. Current Concepts and
Controversies - A Review
AU  - Prasanna Ram, Bala Bhaskar Reddy and Joseph Philipraj S
JO  - Open Access Journal of Urology & Nephrology
PY  - 2019
VL  - 4
IS  - 1
DO  - 10.23880/oajun-16000158
ER  -