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]:

• Low testosterone 
• Sexual dysfunction: Reduced libido, erectile dysfunction
• Decreased muscle mass and strength
• Depression
• Decreased energy and increased fatigue
• Osteoporosis or low bone mass

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

• Delayed/absence of sexual development
• Decreased sperm count, infertility
• Gynaecomastia/breast discomfort
• Lack/loss of axillary, facial, and pubic hair
• Small or shrinking testes
• Poor concentration and memory
• Sleep disturbances, insomnia
• Increased body fat and body mass index
• Menopausal-type hot flushes

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].

• Asymptomatic

  It is also important to note that many men with low blood levels of testosterone are completely asymptomatic and appear completely healthy. [urology.ucsf.edu]

  ESR, 10 mm/h; B27 (-) Normal None 47,XXY(68%)/46,XY(32%) 7 21 Gonadal dysgenesis with Asymptomatic ESR, 15 mm/h; B27 (-) Normal None mosaicism; 45,X/47,XYY 8 17 Bilateral cryptorchidism, Asymptomatic ESR, 15 mm/h; B27 (-) Normal None orchidectomy; 46 [arthritis-research.biomedcentral.com]

  Both parents were asymptomatic, had a normal ECG, and presented no hearing problems. [revespcardiol.org]

  Mild-to-moderate testosterone elevations are usually asymptomatic in males, but can cause distressing symptoms in females. The exact causes for mild-to-moderate elevations in testosterone often remain obscure. [mayomedicallaboratories.com]

• Dentist

  Oral manifestations of celiac disease: a clinical guide for dentists. J. Mich. Dent. Assoc. 93, 42–46 (2011). 142. Cheng, J., Malahias, T., Brar, P., Minaya, M. T. & Green, P. H. [dx.doi.org]

• Anosmia

  […] hormone (GnRH) and/or gonadotropin release at the hypothalamic-pituitary axis Genetic disorders Kallmann syndrome Idiopathic hypogonadotropic hypogonadism (IHH): genetic disorder characterized by a defect in GnRH production/action in the absence of anosmia [amboss.com]

  Kallmann syndrome (anosmia and GnRH deficiency)15 GnRH receptor mutation and deficiency16 Genetic mutations associated with pituitary hormone deficiencies, eg, PROP-1 mutation.17 [mdedge.com]

  Two subtypes of IHH have been defined: Kallmann syndrome (CHH with anosmia; see this term) mainly associated with abnormal embryonic migration of the Gn-releasing hormone (GnRH)-synthesizing neurons, and normosmic IHH (nIHH; see this term), in which HH [orpha.net]

  Results: Normal olfaction, hyposmia and anosmia were defi ned. An age related decline in olfaction was observed, especially among males aged 59 years or more. [mendeley.com]

  Kallmann syndrome (KS) is a rare genetic disorder characterized by hypogonadotropic hypogonadism associated with anosmia or hyposmia. When anosmia is absent it is simply referred to as idiopathic hypogonadotropic hypogonadism (IHH). [radiopaedia.org]

• Hyposmia

  Results: Normal olfaction, hyposmia and anosmia were defi ned. An age related decline in olfaction was observed, especially among males aged 59 years or more. [mendeley.com]

  Results: Normal olfaction, hyposmia and anosmia were defined. An age related decline in olfaction was observed, especially among males aged 59 years or more. [scielo.conicyt.cl]

  KISS1, TAC3, TACR3 have also been found to be associated with hyposmia on detailed testing on UPSIT and MRI for olfactory structures revealed absent OB. [scirp.org]

  Kallmann syndrome (KS) is a rare genetic disorder characterized by hypogonadotropic hypogonadism associated with anosmia or hyposmia. When anosmia is absent it is simply referred to as idiopathic hypogonadotropic hypogonadism (IHH). [radiopaedia.org]

  IHH Fail to undergo puberty with incomplete sexual maturation low FSH,LH and low testosterone(absent pulsatile LH) 60%present with hyposmia isolated Gntr defeciency with otherwise normal pituitary function. IHH(hypogonadotropic eunuchoidism) 27. [slideshare.net]

• Vascular Disease

  DIABETES CARE References ↵ Kapoor D, Malkin CJ, Channer KS, Jones TH: Androgens, insulin resistance and vascular disease in men. [care.diabetesjournals.org]

  peripheral vascular disease, cerebrovascular disease, transient ischemic attack, renal disease, obesity, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, alcohol-induced liver disease, alcohol dependence, and rheumatoid arthritis [doi.org]

  The elevations in hemoglobin can result in adverse outcomes, particularly in elderly due to increases in viscosity that can exacerbate vascular disease (coronary, cerebrovascular, or peripheral vascular circulation) [27, 193, 200–202]. [hindawi.com]

  […] low BMD Etiologies of Hypogonadism Causes of hypogonadism may be separated into diseases of the testis (primary), and diseases of the hypothalamic-pituitary axis (secondary). [clinicaladvisor.com]

  Risk of vascular disease in adults with diagnosed coeliac disease: a population-based study. Aliment. Pharmacol. Ther. 20, 73–79 (2004). 129. Wolf-Maier, K. et al. [dx.doi.org]

• Hirsutism

  In adult women, excess testosterone production results in varying degrees of virilization, including hirsutism, acne, oligo-amenorrhea, or infertility. [mayomedicallaboratories.com]

  […] investigation, transdermal testosterone administration to women with HIV and low baseline free testosterone concentrations was very well tolerated and did not result in adverse events, including lipid or liver abnormalities or significant differences in hirsutism [healio.com]

  Analyst 128 : 363 – 368 13 1994 Hirsutism and acne in women: coordinated radioimmunoassays for eight relevant plasma steroids. Clin Chem 40 : 2296 – 2305 14 2003 Limitations of direct estradiol and testosterone immunoassay kits. [doi.org]

• Loss of Libido

  In adult women, hypogonadism causes: amenorrhea infertility loss of libido vaginal dryness hot flashes Prolonged periods of hypogonadism can cause osteoporosis. [ccpd.ucsf.edu]

  A 55-year-old patient presented for erectile dysfunction, loss of libido and fatigue. The biochemical evaluation showed very high FSH serum levels in the presence of central hypogonadism. [ncbi.nlm.nih.gov]

  Adult women with the condition may stop menstruating or develop infertility, loss of libido, vaginal dryness and hot flashes. Prolonged periods of hypogonadism can cause osteoporosis. [ucsfhealth.org]

  In the adult men, one can often observe fatigue, decrease in physical capacity, loss of libido and erectile dysfunction. At the physical examination, genitalia have always to be assessed in search of a testes/penis atrophy. [econtent.hogrefe.com]

• Anorchia

  CRYPTORCHIDISM B/L CONGENITAL ANORCHIA(Vanishing testes syn. [slideshare.net]

  Acquired causes (due to damage to or dysfunction of the gonads) include ovarian torsion, vanishing/anorchia, orchitis, premature ovarian failure, ovarian resistance syndrome, trauma, surgery, autoimmunity, chemotherapy, radiation, infections (e.g., sexually-transmitted [en.wikipedia.org]

  Hypergonadotropic hypogonadism (primary hypogonadism) Definition: insufficient sex steroid production in the gonads Primary gonadal insufficiency; : Turner syndrome; (females), Klinefelter syndrome (males), androgen insensitivity syndrome, anorchia Secondary [amboss.com]

  Causes of primary hypogonadism include: Karyotype abnormalities—Klinefelter syndrome (47, XXY syndrome) is the most common Toxin exposure, chemotherapy Congenital defects—anorchia, cryptorchidism13 Orchitis (mumps, autoimmune) Testicular trauma or infarction [mdedge.com]

  Anorchia, the absence of both testicles at birth. Cryptorchidism, where one or both testicles do not descend into the scrotum. A separate lesson covers the details of this condition. Mumps, chemotherapy, and certain medications. [study.com]

• Prostatic Disease

  Prostate disease, hematocrit higher than 50 %, uncontrolled heart failure and severe obstructive sleep apnea are contraindications of a testosterone replacement therapy. [econtent.hogrefe.com]

  Men aged over 50 years should have blood levels of prostate specific antigen evaluated, as high levels of PSA indicate prostate disease (e.g. prostate cancer). [healthengine.com.au]

  None of the men had had prostate disease before the study. Men with PSA levels above 4 ng/mL were excluded. The participants ranged in age from 18 to 85 years (mean age 52.5). [sexhealthmatters.org]

  Y Cui, H Zong, H Yan and Y Zhang, The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis, Prostate Cancer and Prostatic Diseases, 10.1038/pcan.2013.60, 17, 2, (132-143), (2014). [doi.org]

  […] and acceleration of benign or malignant prostatic disease [5]. [hindawi.com]

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]:

• Sexual history with particular attention to erectile dysfunction and libido
• Complaints of fatigue and lack of energy
• Depression and mood changes

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].

• Hyperprolactinemia

  BACKGROUND: Hyperprolactinemia causes hypogonadotrophic hypogonadism. Hyperprolactinemia can be pre-existing in some patients with schizophrenia. [ncbi.nlm.nih.gov]

  In the present article we discuss the case of a 38-years old male, in whom we confirmed the clinical and laboratory features of (hypogonadotropic) hypogonadism, as well as hyperprolactinemia and pituitary macroadenoma. [worldcat.org]

  Causes of secondary hypogonadism include hyperprolactinemia, severe obesity, iron overload syndromes, opioid use, glucocorticoids, or androgen-deprivation therapy, androgenic-anabolic steroid withdrawal syndrome, idiopathic hypogonadotropic hypogonadism [mdedge.com]

  Causes of secondary hypogonadism include: Congenital (the person is born with the condition): certain conditions, including Kallman’s syndrome, Prader Willi syndrome; idiopathic (cause unknown) Acquired : hyperprolactinemia; diabetes mellitus; obesity [my.clevelandclinic.org]

• Testosterone Increased

  Testosterone is essential for the changes seen in boys during puberty including increase in height, body and pubic hair, enlargement of the penis, and normal male libido. [diurnal.co.uk]

  increase FSH and LH. [slideshare.net]

  An increase in the activity of aromatase induced locally could explain the drop in androgen levels and the increase in estrogens observed in patients with RA [ 38 ]. However, in our group of patients, serum testosterone and E 2 were both decreased. [arthritis-research.biomedcentral.com]

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]:

• Male breast cancer
• Prostate cancer (known or suspected)
• Sensitivity to ingredients in the delivery system

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

• Benign prostatic hyperplasia (BPH)
• Lower urinary tract symptoms
• Preexisting cardiac, renal, or hepatic disease
• Gynaecomastia
• Sleep apnea
• Azoospermia
• Testicular atrophy
• Erythrocytosis

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].

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].

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]:

• Pre-pubescent hypogonadism causes delayed puberty and lack of secondary sex characteristics. Affected children are treated with testosterone replacement therapy. 
• 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. However, not all men experience low testosterone and its symptoms as they age [9] [14].

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

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

• Chromosomal abnormalities [14] (XX males, Turner syndrome, Klinefelter syndrome [15])
• Leydig cell aplasia
• Cryptorchidism
• Defects of the hypothalamus or pituitary [14]
• Impaired testosterone synthesis

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

• Idiopathic
• Gonadotoxic agents
• Radiotherapy
• HIV
• Testicular trauma/torsion/orchitis
• Systemic disease or medication

Causes of secondary acquired hypogonadism [1]:

• Tumors
• Infection
• Pituitary infarction
• Drug use
• Alcohol

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].

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].

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].

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.

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].

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:

• Sexual dysfunction: reduced libido, erectile dysfunction
• Decreased muscle mass and strength
• Depression
• Decreased energy and increased fatigue
• Osteoporosis or low bone mass

Symptoms that suggest low testosterone include:

• Delayed or absence of sexual development
• Decreased sperm count, infertility
• Gynaecomastia or breast enlargement in men
• Lack or loss of axillary, facial, and pubic hair
• Small or shrinking testes
• Poor concentration and memory
• Sleep disturbances, insomnia
• Increased body fat and body mass index
• Menopausal-type hot flushes

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].

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.