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Hypogonadism

Hypogonadism is a condition characterized by decreased production of gonadal hormones.

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Presentation

The initial presentation of hypogonadism in men depends upon the age of onset. Prepubescent boys present with delayed secondary sex characteristics and puberty [16]. In men 20-50 years of age are often identified when undergoing evaluation for infertility and/or sexual dysfunction. Men over age 65 years are often diagnosed during evaluation for other health concerns [3].

Primary symptoms of hypogonadism include [11] [14]:

Other symptoms that may suggest low testosterone [11] [14]:

Testosterone deficiency alters metabolism and contributes to changes in body anthropometric features and body
composition [13] [14]. It is associated with decreased insulin sensitivity, central obesity, hyperlipidemia, hypertension, osteoporosis, muscle weakness and decreased strength, cognitive impairment, lethargy, and fatigue [2] [12]. These characteristics may explain, in part, the inter-relationship of hypogonadism with obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease [2] [14] [17].

Diagnosis of male post-pubescent hypogonadism is made by the presence of two or more symptoms and a low serum testosterone level [1]. Hypogonadism in men is often overlooked because symptoms are non-specific, often ignored, or attributed to other causes, including ageing [9].

Decreased Libido
  • Symptoms included flushing and sweating, amenorrhoea, impotence and decreased libido. Epidemiological studies have examined a possible link between hypogonadism and opioid use, in both patients and drug addicts.[ncbi.nlm.nih.gov]
  • Men develop testicular suppression with decreased libido, impotence, decreased ejaculate volume, loss of body and facial hair, weakness, fatigue and often anemia. On testing, blood levels of testosterone are low and should be replaced.[pituitary.org]
  • The clinical manifestations of hypogonadism in adult men include decreased libido, erectile dysfunction (inability to have or maintain an erection or to ejaculate), slowing of facial and pubic hair growth and thinning of hair in those regions, drying[britannica.com]
  • Post-pubescent hypogonadism results in sexual dysfunction: Erectile dysfunction, decreased libido, decreased sperm count, and, ultimately, infertility. Late-onset hypogonadism is often considered a normal process of aging.[symptoma.com]

Workup

The diagnosis of post-pubescent hypogonadism is based on clinical symptoms and low testosterone levels on at least 2 occasions [7]. Once testosterone deficiency is suspected physical examination should focus on [14]:

  • Evaluation of the testes: presence, position consistency, size
  • Examination of genitalia for abnormalities: hypospadias, micropenis
  • Digital rectal examination (DRE) 
  • Tanner staging
  • Muscle mass and strength
  • Body mass index, weight, and abdominal girth

Patient history should include [11]:

Laboratory studies [1] [11]:

  • Baseline screening
  • Complete blood count (CBC)
  • Renal function tests
  • Lipid profile 
  • DEXA scan
  • Prostate-specific antigen (PSA) test

Additional laboratory studies [1] [11]:

  • Testosterone levels
  • Follicle-stimulating hormone (FSH) levels
  • Luteinizing hormone (LH) levels
  • Prolactin levels
  • Thyroid function
  • Seminal fluid examination
  • Karyotyping
  • Testicular biopsy

Testosterone levels vary throughout the day, so serial testing is required. The best time is to draw blood in the early morning [11]. According to the Endocrine Society, total testosterone levels of 10.4 mmol ⁄ l (300 ng ⁄ dl ) and free testosterone levels of 50-65 pg ⁄ ml are considered the lower limit of normal [11] [14].

If the prostate-specific antigen (PSA) is abnormal, a transrectal ultrasound and prostate biopsy should be done before starting testosterone replacement therapy to rule out underlying prostate cancer [1].

Treatment

Treatment of male hypogonadism is testosterone replacement therapy. The aim of therapy is to return testosterone levels to a normal value, between 300–1000 ng ⁄ dl [11].

Studies have shown that this may reverse the symptoms of the disorder; increasing libido and sexual function, reducing the ratio of fat to lean body mass, and improving bone density [11]. It is even thought to decrease insulin resistance [11] [13] improve glycemic control, cholesterol levels, and hemoglobin A1C [9] [13] [13].

Hypogonadism is associated with multiple comorbidities occurring in older men [3], such as obesity, type 2 diabetes, osteoporosis, cardiovascular disease, psychosocial function, and diminished quality of life [9]. Treatment with testosterone replacement is recommended in older men with low testosterone who are symptomatic [3] [9] [14].

Several formulations of testosterone are available. It is important, that the choice be geared to the individual by taking into consideration the patient’s needs and life circumstances [11].
Forms of testosterone replacement available include [11]:

  • Intramuscular injections are the most cost effective form. Injections are given every two weeks. Often produces fluctuations in hormone levels and recurrence of symptoms between doses.
  • Transdermal patches are the closest to normal hormone production. They need to be applied to the skin each night. Local skin irritation may occur. 
  • Transdermal gels 1% testosterone gel. Applied once a day. Can be transferred to others, partner or to children, through contact. 
  • Nasal testosterone gel recently approved in the United States [8]. This may resolve the issue of person to person transfer.

Contraindications to testosterone replacement therapy [11] [16]:

Caution when using testosterone replacement in the presence of [11] [16]:

Testosterone replacement therapy is not recommended in patients concerned with fertility issues. Therapy does not correct the causes of this disability [13] [18]. In fact, exogenous testosterone may affect the feedback mechanism of the hypothalamus-pituitary-gonad axis, resulting in impaired spermatogenesis [6] [18]. An alternative therapy is available. Clomiphene citrate has been used for these patients. This is an estrogen receptor modulator that increases gonadotropin levels and stimulates testosterone and sperm production [6]. Few studies are as yet available, however.

Follow-up care primarily involves the monitoring of treatment results and early identification of complications [1] [11] [16].

  • Prostate specific antigen levels and digital rectal exams should be perform before starting treatment and regularly during therapy. 
  • Liver function tests
  • Lipid profile
  • Repeat hematocrit levels. If hematocrit rises above 54% treatment should be stopped until the it returns to normal.
  • Bone density, baseline before treatment and regularly after therapy is discontinued.

Patients should also be regularly monitored for resolution of symptoms of testosterone deficiency and adverse reactions to therapy, specifically changes in mood and behavior and increased sleep apnea [1].

Prognosis

Greater longevity and the increasing incidence of type 2 diabetes and obesity predicts that male hypogonadism will become more prevalent in the future [11] [14].

Hypogonadism in both men and women can cause infertility.
This disorder increases the risk for diabetes, osteoporosis, and cardiovascular disease [13] [16]. Hormone replacement therapy reduces or prevents the symptoms and complications of hypogonadism [4] [11].

Etiology

Diagnosis of male hypogonadism requires the combination of low serum testosterone levels and the presence of the associated symptoms [11]. However the symptoms are vague and also occurring in other disorders. The symptoms are due to the effects of testosterone in the body [1]. Testosterone plays a role in carbohydrate and fat metabolism, bone mineralization, and adipogenesis [12].

Testosterone levels vary with age [11]. Levels of total testosterone level <8-10 mmol/l are considered deficient [1] in adult men. Level between 10 and 12nmol/l are considered borderline [6]. Values above 12mmol/l are normal [1].

A broader definition of hypogonadism considers the physiology of the hypothalamic-pituitary-testicular axis and its function [5] [13].
The symptoms of testosterone deficiency vary by the age of onset and may be classified as [1] [11] [12]:

Male hypogonadism may also be categorized by the underlying cause as congenital or acquired [1].

Causes of primary congenital hypogonadism [1] [15]:

Primary acquired hypogonadism may be [1] [14]:

Causes of secondary acquired hypogonadism [1]:

Early detection and treatment of hypogonadism may prevent the secondary effects of the disorder: Cardiovascular and cerebrovascular diseases, diabetes, and obesity [2] [14] [17]. This should prompt primary care providers to evaluate all men presenting with these disorders for hypogonadism [14].

Epidemiology

The prevalence of hypogonadism in men is estimated to be 38.7% in men over the age of 65 [9] [11]. Studies have shown the incidence to be approximately 25% in Caucasians, 30% in Hispanics, and perhaps higher in African Americans [4]. Exact prevalence is difficult because the disorder is underdiagnosed [1] [2]. Ethnic and geographical variations in the incidence of male hypogonadism are not clear, but may be associated with the incidence of comorbidities [14].

Prevalence increases with age [4]. The incidence of testosterone deficiency, in some studies, was 6% in men ages 40 to 69 years [10] and 6 to 10%in men 40 to 65 [1] [11]. Below the age of 40, less than 1% of men have low testosterone levels [1]. Male hypogonadism occurs in 25 to 40% of individuals with type 2 diabetes and increases to near 50% when obesity and type 2 diabetes occurred together [14].

Sex distribution
Age distribution

Pathophysiology

Male hypogonadism is related to the functioning of the hypothalamic–pituitary–testicular (HPT) axis which maintains and regulates testosterone levels [5] [14]. The hypothalamus releases gonadotropin-releasing hormone (GnRH). This activates the pituitary to release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Luteinizing hormone then stimulates testicular Leydig cells to produce testosterone. Follicle-stimulating hormone initiates spermatogenesis in testicular Sertoli cells.

Normal functioning of the hypothalamic-pituitary-gonadal axis is needed for normal gonadal development and sex hormone production [7] [16] [18]. Male hypogonadism is due to dysfunction of the axis [14]. Two biomarkers can be used to measure Leydig cell function, serum testosterone and insulin-like factor 3 (INSL3) levels [5].

Normal circulating testosterone levels provide a negative biofeedback to inhibit hypothalamus and pituitary gland hormone production [11] [14].

The physiologic effects of testosterone include [11] [13]:

  • Maintenance of reproductive tissues
  • Stimulation of spermatogenesis
  • Maintenance of sexual function
  • Regulation of lean body mass
  • Maintenance of bone mass
  • Promotion of axillary and body hair growth
  • Stimulation of erythropoiesis

Primary hypogonadism is due to testicular failure and is indicated by low serum testosterone with high luteinizing hormone and follicular stimulating hormone levels [11].

Secondary hypogonadism is associated with defects in the hypothalamus or pituitary gland and results in low testosterone due to insufficient stimulation of the Leydig cells [11].

Hypogonadism may be caused by a combination of primary and secondary factors, mixed hypogonadism [11]. This is
seen in sickle-cell disease, thalassemia, alcoholism, glucocorticoid treatment, and in older men [11].

Testosterone regulates body composition (fat and lean muscle mass), and its deficiency produces impaired glucose metabolism and hypercholesterolemia [13]. This predisposed individuals with hypogonadism to type 2 diabetes and cardiovascular disease [11] [13] [14].

Prevention

Complications of hypogonadism can be prevented or limited by early diagnosis of testosterone deficiency and institution of testosterone replacement therapy.

Current studies point to the possibility of reducing the prevalence of hypogonadism by controlling possible risk factors; preventing obesity, maintaining healthy weight, and controlling type 2 diabetes.

Summary

Hypogonadism refers to a decrease in the sexual hormones produced by the gonads, primarily testosterone and estrogen. However, the term is most often used to refer to a group of characteristic clinical symptoms and the evidence of testosterone deficiency in men (<10.4nmol/l) [1] [2] [3] [4]. The diagnosis is difficult because lower normal testosterone levels used to identify the disorder vary widely and the signs and symptoms are vague [3] [4].

Although hypogonadism is most common in older males [5], it can occur in younger men and, rarely, in women [6] [7]. Hypogonadism occurs before and after the onset of puberty [1] [7]. In pre-pubescent males without testosterone replacement, individuals have signs of eunuchoidism, sparse body hair, poor muscles development, and delayed epiphyseal closure [1] [5]. In post-pubescent males, symptoms include fatigue and impaired sexual function [1]. Females with hypogonadism, due to genetic abnormalities, fail to develop through puberty and experience primary or secondary amenorrhea [7] [8].

Hypogonadism is associated with increased cardiovascular risk, obesity, type 2 diabetes, decreased bone density [9], sexual dysfunction and infertility [2] [4] [6]. It is also associated with behavioral changes and cognitive deficits [10].

Standard treatment for symptomatic hypogonadism is hormone (testosterone and estrogen) replacement therapy. However studies have suggested that, despite the large number of men affected by the disorder, only 5 to 10 % of them are routinely treated [6] [10].

Patient Information

What is hypogonadism?

Hypogonadism is defined as an deficiency of sex hormones, specifically testosterone in men. It is associated with a variety of symptoms that occur with many other conditions. It is seen more often in men who are obese or have type 2 diabetes.
Hypogonadism can result in many physical, psychological, and life altering complications.

What are the symptoms?

Symptoms of hypogonadism include:

Symptoms that suggest low testosterone include:

What causes hypogonadism?

The exact cause of hypogonadism is not known. However, this disorder can be classified as primary or secondary. Primary hypogonadism is the result of dysfunction of the gonads, sex organs, themselves, and causes decreased or absent hormone production. This may be congenital (a genetic abnormality) or acquired (tumor, infection, or injury). Secondary hypogonadism is due to an abnormality of the regulating mechanism of the body that controls hormone production. This may be due to defects of the hypothalamus or pituitary gland.

Who gets hypogonadism?

Hypogonadism may occur before or after puberty, at any age. However it is most common in men over the age of 65 years.
Those who are obese or have type 2 diabetes are at higher risk.

How is it diagnosed?

Hypogonadism is diagnosed by the presence of symptoms of testosterone deficiency and testosterone levels below 10 mmol/dl.
A simple blood test and a through health history are all that are required.

How is hypogonadism treated?

Hypogonadism is treated with testosterone as hormone replacement. Testosterone may be given by injection, transdermal patch, or topical gel.

What are the complications of Hypogonadism?

Complication of hypogonadism include increased cardiovascular disease (eg. hypertension), obesity, type-2 diabetes, decreased bone density, sexual dysfunction and possible infertility. It may also result in behavioral changes, loss of memory, and depression [7].

References

Article

  1. Muneer A. Hypogonadism: an underdiagnosed condition. Trends in Urology Gynaecology & Sexual Health March/April, 2010: 14-17.
  2.  Muraleedharan V, Hugh Jones T. Testosterone and mortality. Clinical Endocrinology. 2014; 0:1–11.
  3. Jones TH. ‘What should I do with a 60-year old man with a slightly low serum total testosterone concentration and normal levels of serum gonadotrophins’? Clinical Endocrinology. 2010; 72:584–588.
  4. Guay AT. The Emerging Link Between Review Hypogonadism and Metabolic Syndrome. J Androl. 2009;30:370–376.
  5. Rey RA, Grinspon RP, Gottlieb S, Pasqualini T, Knoblovits P, Aszpis S, et al. Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach. Andrology. 2013; 1: 3-16.
  6. Katz DJ, Nabulsi O, Tal R, Mulhall JP. Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU International. 2 011;110:573–578.
  7. Murphy KG. Kisspeptins: regulators of metastasis and the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2005;17(8):519-25.
  8. Tucker ME. FDA OKs Natesto, First-Ever Nasal Testosterone Treatment. Medscape Medical News [serial online]. May 29 2014.
  9. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, Mcwhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006; 60(7): 762–769. 
  10. Strasser F, Palmer JL, Schover LR, Yusuf SW, Pisters K, Vassilopoulou-Sellin R, et al. The Impact of Hypogonadism and Autonomic Dysfunction on Fatigue, Emotional Function, and Sexual Desire in Male Patients With Advanced Cancer. Cancer. 2006;107(12): 2950-9.
  11. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010; 64(6): 682–696.
  12. Yassin AA, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Obesity. 2013; 3: 73–83.
  13. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2014; 68(3):314–329.
  14. Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Clinical Endocrinology. 2013;78:330–337.
  15. AksglaedeLA, Link K, Giwercman A, Jørgensen N, Skakkebæk NE, Juul A. 47-XXY Klinefelter Syndrome: Clinical Characteristics and Age-Specific Recommendations for Medical Management. Am J Med Genet. 2013;163C:55–63.
  16. Viswanathan V, Eugster EA. Etiology and treatment of hypogonadism in adolescents. Endocrinol Metab Clin North Am. 2009;38(4):719-38.
  17. Lotti F, Corona G, Degli Innocenti S, Filimberti E, Scognamiglio V, Vignozzi L, et al. Seminal, ultrasound and psychobiological parameters correlate with metabolic syndrome in male members of infertile couples. Andrology. 2013; 1: 229–239. 
  18. Silveira LG, Noel SD, Silveira-Neto AP. Mutations of the KISS1 Gene in Disorders of Puberty. J Clin Endocrinol Metab. 2010; 95(5): 2276-80.

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Last updated: 2019-07-11 22:16