TOC  |  ENDO

Hypogonadism

Hypogonadism             REF:  Cecil Texbook of Medicine 2006  | Ferri's Clinical Advisor: Instant Diagnosis and Treatment 2006 | UpToDate 2006  

 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |     hypogonadism2008.pdf     

Hypogonadism in a man refers to a decrease in either of the two major functions of the testes: sperm production and testosterone production.

Diminished testosterone secretion during adulthood leads to decreases in energy, libido, sexual hair, muscle mass, and bone mineral density, & possible erectile dysfunction.

These abnormalities usually result from

  1. Primary Hypogonadism (Disease of the Testes)
    - Decreased Testosterone  (AM fasting total testosterone <200 ng/dL on at least 2 separate occasions) & sperm count, Increased LH or FSH
    - Check testes size.  
      If small  testes size - suspect Klinefelter's syndrome and check chromosome;
      if normal testes size - prob. acquired primary hypogonadism
  2. Secondary Hypogonadism (Disease of the Pituitary or Hypothalamus )
    - Decreased Testosterone & sperm count, Normal or Decreased LH or FSH  --> check Prolactin or Brain MRI

In occasional cases, however, a defect in the ability to respond to testosterone is the cause of hypogonadism.

Primary hypogonadism is more common than secondary hypogonadism and differs in two characteristics:

  • Primary hypogonadism is more likely to be associated with a decrease in sperm production than in testosterone production.
    Although many testicular diseases damage both the seminiferous tubules and the Leydig cells, they usually damage the seminiferous tubules to a greater degree. In contrast, there is a proportionate reduction in testosterone and sperm production in secondary hypogonadism.
  • Primary hypogonadism is more likely to be associated with gynecomastia, presumably due to the stimulatory effect of the supranormal serum FSH and LH concentrations on testicular aromatase activity. This results in increased conversion of testosterone to estradiol and enhanced testicular secretion of estradiol relative to testosterone.

Secondary hypogonadism is less common than primary hypogonadism and differs in two characteristics:

  • Secondary hypogonadism is usually associated with an equivalent decrease in sperm and testosterone production. This occurs because the primary reduction in LH secretion results in a decrease in testicular testosterone production and therefore in intratesticular testosterone, which is the principal hormonal stimulus to sperm production. In contrast, there is generally a greater fall in sperm production (the seminiferous tubules) than in testosterone secretion (the Leydig cells) in primary hypogonadism because the seminiferous tubules are damaged to a greater degree than the Leydig cells.
  • Secondary hypogonadism is less likely to be associated with gynecomastia, presumably because serum FSH and LH concentrations are not high and therefore do not stimulate testicular aromatase to increase the conversion of testosterone to estradiol.

   
 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |  
PRIMARY HYPOGONADISM (TESTICULAR HYPOGONADISM)
Primary hypogonadism refers to a condition of androgen deficiency with or without infertility in which the pathologic process lies at the testis level.
- Decreased Testosterone & sperm count, Increased LH or FSH  

Causes of Primary Testicular Failure & End Organ Resistance  

I.  Congenital Abnormalities:

  • Klinefelter's & related syndromes (XXY, XXy/XY, XYY, XX males)
  • Other Chromosomal disorders
  • Cryptorchidisim (developmental disorder)
  • Varicocele
  • Disorders of testosterone/androgen biosynthesis  & secretion
    — can result from rare mutations of the genes that encode the enzymes necessary for testosterone biosynthesis. These mutations, all rare, involve the cholesterol side chain cleavage enzyme, 3 beta-hydroxysteroid dehydrogenase, and 17 alpha-hydroxylase, both of which are present in the adrenal glands as well as the testes, and 17 beta-hydroxysteroid dehydrogenase, which is present only in the testes. Each of these mutations results in decreased testosterone secretion, beginning in the first trimester of pregnancy, and therefore in incomplete virilization.
  • Myotonia dystrophy  
    an autosomal dominant disorder that leads to muscle atrophy, is accompanied by hypogonadism that is usually not recognized until adulthood. Small testes and decreased sperm production are more common than decreased serum testosterone levels. In one study of 39 men with myotonic dystrophy, for example, all had supranormal serum FSH concentrations, and about one-half had subnormal serum testosterone and supranormal serum LH concentration.
  • Prenatal diethylstilbestrol syndrome (developmental disorder)

II.  Acquired defects or diseases:
The manifestations of acquired causes of primary hypogonadism also depend upon whether sperm production, testosterone secretion, or both are impaired; and, if testosterone secretion is diminished, when this occurs.

  • Decreased sperm production results in infertility.
  • Reduced testosterone secretion during childhood is associated with incomplete pubertal changes.
  • Diminished testosterone secretion during adulthood leads to decreases in energy, libido, sexual hair, muscle mass, and bone mineral density.
  1. Infections:  Orchitis, Mumps,  other viruses as HIV, AIDS; Granulomatous (as Tuberculosis, leprosy)
    - Testicular involvement of mumps causes painful swelling of the testes followed by atrophy. The seminiferous tubules are almost always severely affected, often resulting in infertility, especially when both testes are involved; the Leydig cells also may be damaged, resulting in decreased testosterone production.
    - HIV — Men who have HIV infection may be hypogonadal to some degree, as judged by generally lower serum testosterone concentrations than men without HIV. However, the serum FSH and LH can be elevated or not, indicating both primary and secondary hypogonadism. The frequency with which hypogonadism accompanies HIV infection, and its severity, appear to have diminished since the introduction of antiretroviral therapy.
  2. Irradiation
  3. Drugs:  
    - Alkylating and antineoplastic agents
    - Inhibitors of testosterone synthesis & antiandrogens (ketoconazole, cimetidine, flutamide, cryproterone, spironolactone)
    - Ethanol (alcohol), opiods & other recreational drugs - Marijuana, heroin, methadone, medroxyprogesterone acetate, other progestins, and estrogens all lower testosterone.
    - Acute alcohol ingestion also may cause secondary hypogonadism, as manifested by subnormal serum testosterone concentrations levels without increases in either LH or FSH
    - Medical treatment or illicit use (e.g., in athletes, body builders) with androgens such as testosterone, dihydrotestosterone, and synthetic anabolic steroids will lower serum LH and FSH and lower sperm counts in the absence of clinical signs and symptoms of androgen deficiency. Serum testosterone levels will be normal to elevated after testosterone treatment but will be low after use of DHT and synthetic anabolic agents.
    - Suramin is an antiparasitic drug now being evaluated as chemotherapy for various cancers; when given to 14 patients with refractory cancer, 8 of the 14 had a rise in serum FSH or LH concentrations to above the normal range. This effect is probably due to blockade of testosterone synthesis by the Leydig cell
  4. Toxins: alcohol, fungicides, insecticides (DBCP, metabolites of DDT), heavy metals (lead, cadmium), cottonseed oil (gossypol), DDT & other environmental estrogens  
  5. Trauma, Surgical, and torsion of testes
    - Testicular torsion is a twisting of the testis on the spermatic cord, which results in acute loss of the blood supply to the testis.  
  6. Infiltrative diseases (hemochromatosis, amyloidosis)
  7. Chronic Systemic disease  
    -     Many chronic, systemic illnesses cause hypogonadism both by a direct testicular effect and by decreasing gonadotropin secretion.
    -     Abnormalities of the hypothalamic-pituitary-testicular axis occur in a number of systemic diseases, as:
          cirrhosis, chronic renal failure (The mean serum FSH and LH concentrations were supranormal, while the serum testosterone response to exogenous hCG was impaired.), sickle cell disease, AIDS, amyloidosis, cystic fibrosis, advanced malignancies, severe malnutrition.  
  8. Autoimmune testicular failure - antibodies against microsomal fraction of the Leydig cells
    - Many men with idiopathic infertility have antisperm antibodies. It is not known, however, if these antibodies are the result of an autoimmune process or a response to damage by some other mechanism .  The hypogonadism that accompanies autoimmune polyglandular disease is also characterized by hypothyroidism and hypoadrenalism. It is much less common than idiopathic infertility, but is more likely to be the result of an autoimmune process.  
    - Isolated; Associated with other ortan-specific disorders (Addison's disease, Hashimoto's thyroiditis, inulin-dependent diabetes); Androgen resistance syndromes; 5 alpha-reductase deficiency
  9. Idiopathic

   
 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |  
SECONDARY HYPOGONADISM (HYPOGONADOTROPIC HYPOGONADISM)  
a deficiency in the secretion of gonadotropins (LH and FSH) due to an intrinsic or functional abnormality in the hypothalamus or pituitary glands.
- Decreased Testosterone & sperm count, Normal or Decreased LH or FSH
Such disorders result in the secondary Leydig cell dysfunction .  The clinical manifestations depend on the age of the patient at the onset of the disorder.

Hypothalamic-Pituitary Disorders (Secondary Hypogonadism)

  • Panhypopituitarism
  • Isolated gonadotropin deficiency
  • Complex congenital syndromes

Causes of Secondary Gonadal Insufficiency (Hypo-gonadotropic Hypogonadism)     - detail see the section below.

  1. Idiopathic or Congenital  
    • Isolated deficiency of GnRH
      - Associated with anosmia/hyposmia (Kallmann's syndrome) autosomal dominant
      - With other abnormlalities (Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, basal encephalocele)
    • Partial deficiency of GnRh (fertile eunuch syndrome)
    • Multiple hypothalamic/pituitary hormone deficiency
    • Pituitary hypoplasia or aplasia
  2. Acquired
    • Trauma, postsurgery, post-irradiation
    • Neoplastic
    • Pituitary adenomas (prolactinomas, other functional & nonfunctional tumors)
    • Craniopharyngiomas, germinomas, gliomas, leukemia, lymphomas
    • Pituitary infarction, carotid aneurysm
    • Infiltrative & infectious diseases of hypothalamus & pituitary
      - sarcoidosis, tuberculosis, coccidioidomycoses, histoplasmosis, shyphilis, abscess, histiocytosisX, hemochromatosis
    • Autoimmune hypophysitis
    • Malnutrition & systemic disease
    • Anorexia nervosa, starvation, renal failure, liver failure
    • Exogenous hormones & drugs
    • Antiandrogens, estrogens, & antiestrogens, progestrogens, glucocorticoids, cimetidine, spironolactone, digoxin, drug-induced hyperprolactinemia (metoclopramide, tranquilizers, antihypertensives)

   

Causes of Secondary hypogonadism

I.  CONGENITAL ABNORMALITIES
— Congenital abnormalities that cause decreased gonadotropin secretion are rare but well recognized and easy to diagnose.

  • Sexual differentiation in all of these disorders is normal male because testosterone secretion by the fetal Leydig cells in the first trimester of pregnancy, when sexual differentiation occurs, is stimulated by placental human chorionic gonadotropin (hCG).
  • In contrast, phallic development during the third trimester is subnormal because testicular testosterone secretion at this stage is dependent upon fetal LH secretion, which is subnormal. This leads to diminished testosterone secretion by the fetal testes, resulting in birth with a small phallus (micropenis).
  • Childhood growth is normal if gonadotropin deficiency is an isolated event or subnormal if it is associated with impaired growth hormone or thyroid hormone release.
  • Pubertal development is diminished or even absent, depending upon the degree of gonadotropin deficiency. Gonadotropin deficiency can occur in the absence of any other abnormalities or can be associated with other hormonal or nonhormonal abnormalities.
  1. Isolated idiopathic hypogonadotropic hypogonadism - IHH (Congenital secondary hypogonadism)
    — that occurs in the absence of any other abnormalities is usually the consequence of GnRH (gonadotropin-releasing hormone) deficiency, as judged by a normal response of serum LH to synthetic GnRH after repetitive administration of synthetic GnRH. However, families have been described who have isolated gonadotropin deficiency as a consequence of mutations of the GnRH receptor.  The presence of isolated gonadotropin deficiency may be suspected if micropenis is seen at birth; it is established by the findings of incomplete puberty, a subnormal serum testosterone concentration, a serum LH concentration that is either normal or below normal, and none of the hormonal and nonhormonal abnormalities found in patients with the other syndromes described below.
  2. Kallmann's syndrome
     — is characterized by hypogonadotropic hypogonadism and one or more nongonadal congenital abnormalities, including anosmia, red-green color blindness, midline facial abnormalities such as cleft palate, urogenital tract abnormalities, and neurosensory hearing loss.  Hypogonadism in this syndrome is a result of deficient hypothalamic secretion of GnRH, based upon the same kind of evidence described above for isolated IHH (Idiopathic Hypogonadotropic Hypogonadism). The hypogonadism may be severe, mild, or even transient and is diagnosed as described above. Inheritance is usually X-linked, as judged by the much greater number of cases in males than females. However, autosomal dominant or recessive transmission can occur.
  3. Idiopathic hypogonadotropic hypogonadism associated with mental retardation — Several syndromes, such as Prader-Willi syndrome, have been described in which hypogonadotropic hypogonadism is associated with retardation and other abnormalities, including obesity.
  4. Abnormal ß-subunit of LH
    — A rare but instructive cause of hypogonadotropic hypogonadism is caused by a point mutation in the LH ß-subunit gene.  In the single male described who was homozygous for this mutation, the secretion and serum concentration of testosterone were reduced, serum LH and FSH concentrations were high, and there was failure of spontaneous puberty. Three other men in the same family had low-normal serum testosterone concentrations, normal serum LH concentrations, normal virilization, and infertility.  The homozygous state could easily be confused with primary hypogonadism except for the family history of infertility and a normal serum testosterone response to hCG. The heterozygous state could easily be confused with idiopathic, isolated hypogonadotropic hypogonadism except for the family history of infertility.
  5. Abnormal ß-subunit of FSH
    — Another rare cause is a mutation in the gene for the ß-subunit of FSH. A man with this mutation had delayed puberty with low serum testosterone and FSH concentrations, but a high serum LH concentration. The low serum testosterone concentration is hard to explain because the Leydig cells do not have FSH receptors. However, this finding may indicate that normal human Leydig cell function is dependent on normal Sertoli cell function [16].
  6. Idiopathic hypogonadotropic hypogonadism associated with other hypothalamic pituitary hormonal deficits
    — Secondary hypogonadism that occurs in association with impaired secretion of other pituitary hormones has been shown to result from impaired expression of the transcription factor, PROP-1 [17]. (See "Causes of hypopituitarism").

II. ACQUIRED DISEASES
— Hypogonadotropic hypogonadism can be caused by any disease that affects the hypothalamic-pituitary axis.
One or more of the following mechanisms may be involved:

  • Involvement of the hypothalamus, which impairs GnRH secretion.
  • Disease of the pituitary stalk, which interferes with the ability of GnRH to reach the pituitary.
  • Involvement of the pituitary, which directly diminishes LH and FSH secretion.

In general, a mass lesion in the pituitary or hypothalamus is more likely to diminish the secretion of gonadotropins than that of ACTH and TSH. Thus, patients may present with hypogonadism without either adrenal or thyroid deficiency.

  1. Benign tumors and cysts — Any kind of pituitary adenoma or cyst can cause sufficient pressure on the gonadotroph cells to interfere with their function and decrease LH and FSH secretion. In addition, hyperprolactinemia caused by lactotroph adenomas inhibits gonadotropin secretion.
  2. Malignant tumors — Malignant tumors are more likely to affect the hypothalamus than the pituitary. These include both primary (eg, meningiomas) and metastatic tumors (eg, breast in women and lung and prostate in men).
  3. Infiltrative diseases — Sarcoidosis and Langerhans cell histiocytosis (eosinophilic granuloma) can cause hypothalamic hypogonadism, while iron deposition hemochromatosis can cause pituitary hypogonadism. Treatment of the underlying disease may improve gonadotropin secretion. The age of the patient is important in hemochromatosis, since reversal of hypogonadism with venesection therapy is more likely to occur in men under the age of 40 years.
  4. Infections — Meningitis is a rare cause of hypogonadism in the United States. Tuberculous meningitis can lead to hypopituitarism; this problem is more often seen in countries where tuberculosis is common, such as India .
  5. Pituitary apoplexy — Sudden and severe hemorrhage into the pituitary can result in permanent impairment of pituitary function, including hypogonadism.
  6. Trauma — Trauma to the base of the skull can sever the hypothalamic-pituitary stalk and interrupt the portal circulation, thereby preventing GnRH from reaching the gonadotroph cells in the pituitary and decreasing LH and FSH release.
  7. Critical illness — Any critical illness, such as surgery, myocardial infarction, or head trauma can cause hypogonadotropic hypogonadism. One study of 35 critically ill men, for example, found that the serum testosterone concentration fell 43 to 58 percent within the first few days after the onset of the illness. This effect could not be attributed to a decrease in binding of testosterone to sex hormone-binding globulin because the percentage of free testosterone did not change. Thus, the low serum testosterone concentration was probably due to decreased secretion. Serum LH concentrations in these men also fell, indicating a pituitary or, more likely, hypothalamic cause of the hypogonadism.
  8. A subsequent study of 59 men with critical illness demonstrated that the degree of hypogonadism was directly related to the severity of the illness and that the hypogonadism resolved as the patient recovered from the illness. An unanswered question is whether or not the hypogonadism is helpful or harmful to recovery from the critical illness.
  9. Chronic, systemic illness — Several chronic and systemic illnesses, including cirrhosis, chronic renal failure, and AIDS, cause hypogonadism by a combination of primary and secondary effects.
  10. Glucocorticoid treatment — Chronic treatment with glucocorticoids can lead to hypogonadism. In one study, 16 men with chronic pulmonary disease who received high-dose glucocorticoid therapy for at least one month had a mean serum testosterone concentration of 211 ng/dL (7.3 nmol/L), compared with 449 ng/dL (15.6 nmol/L) in 11 men matched for age and disease. This probably represents an effect on the hypothalamus or pituitary, since serum LH concentrations do not increase during chronic glucocorticoid treatment as would be expected with primary hypogonadism.
  11. Chronic opiate administration — When opiates are administered chronically, especially when they are administered continuously for relief of chronic pain, they often cause pronounced hypogonadism. In one study of 29 men receiving morphine or hydromorphone intrathecally for chronic pain not due to malignancy, 25 had a subnormal serum testosterone concentration, whereas only 1 of 10 men, who had comparable chronic pain but were not receiving opioid treatment, had a subnormal value.
  12. In men being treated for opioid dependence, methadone, but not buprenorphine is associated with low serum testosterone concentrations and sexual dysfunction.
  13. Idiopathic — No cause can be identified in some pubertal-age boys or young men with acquired secondary hypogonadism. The severity can range from mild to severe, as in congenital idiopathic hypogonadotropic hypogonadism. This entity is not documented in the medical literature, but it is probably the kind of hypogonadotropic hypogonadism that is most commonly encountered by endocrinologists.
  14. Occasionally, excessive amounts of exercise can cause hypothalamic hypogonadism in men as it does in women with hypothalamic amenorrhea.
  15. Adult-onset idiopathic hypogonadotropic hypogonadism is a distinct disorder that is important to recognize since it is potentially treatable. A report investigated 10 men with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone due to isolated GnRH deficiency. Long-term GnRH therapy was given to five of these patients; all had a reversal of hypogonadism with the restoration of fertility.
  16. Intentional secondary hypogonadism — Prolonged administration of GnRH analogs, as commonly used in the treatment of prostate cancer, causes a decrease in LH secretion and, consequently, in testosterone secretion.

   
ANDROGEN RESISTANCE (ANDROGEN-SENSITIVE END ORGAN DEFICIENCY)
Certain conditions have clinical phenotypes mimicking testosterone deficiency in the absence of lowered testosterone levels. These are either drug induced (antiandrogens) or congenital defects in the androgen receptor, postreceptor defects, or 5a-reductase deficiency

Defects in Androgen Action

  • Testicular feminization (complete androgen insensitivity)
  • Incomplete androgen insensitivity
  • 5a-Reductase deficiency

* From Andreoli TE (ed): Cecil essentials of medicine, ed 4, Philadelphia, 1997, WB Saunders.

Lab. Evaluation:

  • Blood Testosterone, FSH, LH, sperm count analysis
  • Low Testosterone, FSH, LDH, & sperm count -> Hypothalamic-Pituitary abnormality -> check prolactin & Brain MRI
  • Low sperm count & Testosterone (or normal) with elevated FSH & LDH -> Primary Testicular abnormality -> check testes
  • Low sperm count, Normal Testosterone & LH, Normal or elevated FSH -> Acquired primary hypogonadism, spermatogenic failure or testicular ductal obstruction.

   

 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |                   

TREATMENT OF TESTOSTERONE / ANDROGEN DEFICIENCY

INDICATIONS:

  • The main medical indication for androgen replacement therapy is male hypogonadism.
    The diagnosis is based on clinical symptoms and signs and a reduced serum testosterone level.

The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range.

The most available and commonly used blood measurement of testosterone is serum total testosterone. The normal range of a young adult male population varies for different laboratories but should be in the general range of 300 to 1000 ng/dL (10 to 38 nmol/L). Total testosterone measurements may be misleading indicators of Leydig cell status in conditions in which SHBG levels are abnormal (see earlier section). Under these circumstances, a measurement of free testosterone (by dialysis method), bioavailable testosterone (free + albumin bound), or calculated free testosterone (utilizing total testosterone and SHBG measurements) is useful to characterize circulating bioactive testosterone levels.

The following rules apply to most young and middle-aged men suspected of hypogonadism.

  • If a morning serum total testosterone level is repeatedly less than 250 ng/dL (8.5 nmol/L), the patient is most probably hypogonadal, and testosterone replacement is indicated.
  • If the serum testosterone level is between 250 and 300 ng/dL with normal serum LH levels, the patient may not be hypogonadal, and androgen replacement may not improve the symptoms (e.g., sexual dysfunction).

Thus, when serum total testosterone is borderline and LH is not increased, measurement of one of the bioactive testosterone level levels is indicated. The guidelines for men over the age of 60 years are less certain; since SHBG levels are increased in this age group, total testosterone levels may overestimate the biologically active forms of circulating testosterone. In men older than 60 years with signs and/or symptoms of androgen deficiency, a serum total testosterone level greater than 400 ng/dL argues strongly against hypogonadism; a serum level less than 200 ng/dL is almost always a clinically significant level, and total testosterone concentrations between 200 and 400 ng/dL deserve further testing with one of the tests of bioactive testosterone.

Indications for Testosterone/Androgen Therapy  

  1. Androgen deficiency (male hypogonadism)
  2. Microphallus (neonatal)
  3. Delayed puberty in boys
  4. Elderly men with low total or bioavailable or free testosterone levels
  5. Angioneurotic edema
  6. Other possible uses or under investigans:
    • Homonal male contraception
    • Wasting diseases associated with cancer/HIV/chronic infection
    • Postmenopausal female

CONTRAINDICATIONS TO TESTOSTERONE THERAPY:

  • Absolute contraindications for androgen replacement therapy include carcinoma of the prostate and the male breast.
    These cancers are androgen dependent for growth and proliferation.
    Androgens should be used with caution in older men with enlarged prostates and urinary symptoms, elevated hematocrit, and sleep-related breathing disorders.

BENEFITS VERSUS RISKS OF ANDROGEN THERAPY:

Table 247-7 shows the benefits and potential side effects of androgen treatment. In hypogonadal men, androgen replacement leads to the development and maintenance of secondary sexual characteristics. Testosterone has important anabolic effects on muscle and bone and improves libido and sexual dysfunction. It has less effect on erectile dysfunction (see later section on sexual dysfunction).

Table 3 Benefits vs Risks

Benefits of Testosterone/Androgen Therapy

  • Development or maintenance of secondary sex characteristics
  • Improves lbido & sexual function
  • Increases muscle mass & strength
  • Increases body & visceral fat
  • Improves mood
  • Effect on cognition (?)
  • Effect on quality of life (?)

Risks of Testosterone/Androgen Therapy  

  • Fluid retention
  • GynecomastiaAcne/oily skin
  • Increases hematocrit
  • Decreases HDL cholesterol (cardiovascular risk?)
  • Sleep apnea
  • Prostate diseases: BPH, prostate carcinoma
  • Aggressive behavior (?)

 
 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |  
TESTOSTERONE/ANDROGEN PREPARATIONS:  
  1. Injectable (Intramuscular):
    Testosterone enanthate (or cypionate)     100 mg /mL IM per week or 150-200 mg IM per 2-3 weeks
    Intramuscular injection of testosterone esters
    The data suggests that testosterone enanthate doses from IM 100 mg per week to 300 mg per three weeks are biologically effective, but that 400 mg per four weeks is not. Less information is available for testosterone cypionate, but the few studies that have been performed suggest that its characteristics are similar to those of testosterone enanthate.
  2. Transdermal skin patches of testosterone
    a high incidence of skin irritability (redness, swelling, and blisters)
    • Androderm 2.5 - 5 mg patch  (non-scrotal):  2 patches delivering 2.5 mg testosterone each per day or 1 patch delivering 5 mg testosterone per day (the physiologic production rate)
      AndroGel 1%       apply 5 g daily (1 foil packet or 4 pumps from 75 g dispense). may increase dose to 6.5 -10 g after 2 weeks.
      -       A metered-dose pump that delivers 1.25 g per pump depression is also available.
      Testim       5 g (1 tube) daily, may increase to 2 tubes (10 g) after 2 weeks.
    • Transdermal TTS - 1 patch delivers 5 mg testosterone per day  
    • Scrotal patch - 1 patch delivering 4 mg or 6 mg testosterone per day
  3. Implants:  
    Testosterone implants 200 mg pellets, three inserted once every 4-6 months
    Testopel     2-6 pellets (150-450 mg testosterone) SC q 3-6 months;
    2 pellets for each 25 mg testosterone propionate weekly    
  4. Buccal:
    Striant 30 mg q12h on upper gum  
  5. Oral: Testosterone undecanoate 40-80 mg PO 2-3x/day  is not available in the United States  
    Alkylated androgens
    — Decades ago, investigators discovered that adding an alkyl group in the 17-alpha position of the testosterone molecule retarded its catabolism by the liver.  Many endocrinologists who treat male hypogonadism think that these preparations are not fully effective in producing virilization, although no studies have tested these observations. In addition, several reports have described hepatic side effects with these preparations, including cholestatic jaundice, a hepatic cystic disease called peliosis, and hepatoma . For both of these reasons, and because better preparations are available, the 17-alkylated androgens should generally not be used to treat testosterone deficiency.

MONITORING THE EFFECTS OF TESTOSTERONE TREATMENT — Patients who are treated with testosterone should be monitored to determine that normal serum testosterone concentrations are being achieved.

The serum testosterone should be measured midway between injections in men who are receiving testosterone enanthate, and the value should be mid-normal, eg, 600 to 700 ng/dL (20.8 to 24.3 nmol/L). The dose should be reduced if higher values are obtained.

The serum testosterone can be measured at any time in men who are using any of the transdermal preparations, with the recognition that the peak values occur three to five hours after application of the scrotal patch and six to eight hours after application of the nonscrotal patch. The concentrations fluctuate when the gel is used, but not in a predictable way, so at least two measurements should be made at any dose of gel; the time of measurement does not appear to matter. The value should be well within the normal range (400 to 800 ng/dL [13.9 to 27.7 nmol/L]).

If the patient has primary hypogonadism, normalization of the serum LH concentration should also be used to judge the adequacy of the testosterone dose, no matter which testosterone preparation is used.

Desirable effects — Normalization of the serum testosterone concentration should lead to normal virilization in men who are not virilized and maintenance of virilization in those who already are. Men who become hypogonadal in adulthood and are still normally virilized, but whose hypogonadism is manifested by a decrease in libido and energy, should note a marked improvement in these symptoms. Failure of improvement when the serum testosterone concentration has been restored to normal suggests another cause of the symptoms.

Testosterone replacement also leads to substantial improvements in muscle strength and bone density. In one report, for example, the administration of 100 mg of testosterone enanthate once a week for ten weeks to hypogonadal men increased their strength in the bench press by 22 percent and their squat strength by 45 percent. In another series, the effect of testosterone replacement on bone density was assessed in 72 hypogonadal men. The increase in bone density averaged 39 percent in the first year of testosterone replacement and eventually reached and was maintained in the normal range. The response was greatest in the first year in previously untreated patients and was most pronounced in those with lowest bone density measurements at baseline.

Undesirable effects — Testosterone enanthate and the testosterone patch and gels have virtually no side effects unrelated to the action of testosterone. Testosterone enanthate rarely leads to infection at the injection site, while the scrotal patch occasionally leads to mild to moderate scrotal itching, which remits spontaneously or after the application of hydrocortisone cream.

The patch, Androderm, often causes skin rashes, some very mild and others quite severe, requiring discontinuation of this treatment. The rash may sometimes be prevented by pretreatment of the skin with a corticosteroid cream.

However, some of the actions of testosterone itself, while not side effects, are undesirable.

  • During the first few months after the initiation of testosterone replacement, some of the undesirable effects of normal puberty, such as acne and gynecomastia, can be seen.
  • When testosterone is first administered to hypogonadal adolescent boys, physically aggressive behavior may increase.
  • Prostate volumes and serum prostate specific antigen (PSA) increase in response to testosterone treatment. On average, values increase to those of age-matched eugonadal men.
  • Some men, especially those over the age of 50, experience an exacerbation of benign prostatic hyperplasia (BPH), a testosterone-dependent disease. Symptoms, predominantly urinary outflow obstruction, may increase.
  • Because prostate cancer is, at least to some degree, testosterone dependent, it seems theoretically likely that the risk of prostate cancer is less in hypogonadal men than eugonadal men and the risk increases to normal, but not above, when testosterone is replaced. However, no data are available to support or refute this assumption. It seems prudent, nonetheless, to screen hypogonadal men for prostate cancer before beginning testosterone replacement and to monitor them for prostate cancer during treatment, just as one would monitor a eugonadal man.
  • Sleep apnea and erythrocytosis may be worsened.

There is no reason to think that men who rely on medication to maintain a normal serum testosterone concentration are more likely to develop these conditions than men who produce their own testosterone.
Nevertheless, the physician who prescribes testosterone for a man over age 50 should monitor him as follows:

  • For BPH, the symptom score should be assessed and, if warranted by symptoms, the urine flow rate and post-void residual urine in the bladder by ultrasonography should be measured.
  • For prostate cancer, digital rectal examination and measurement of serum PSA should be performed three months after initiation of treatment and then annually. The patient should be referred for prostate biopsy if a prostate nodule is palpated at any time or if the serum PSA concentration is above 4.0 ng/mL initially or if it rises by more than 0.75 ng/mL per year. The latter recommendations assume that the patient does not have prostatitis and that the values are confirmed by repeat measurement.
  • For erythrocytosis, the hemoglobin and hematocrit should be measured initially after three months and then yearly.
  • For sleep apnea, the physician should inquire about symptoms, such as daytime sleepiness, and, if indicated, polysomnography should be performed.

RECOMMENDATIONS
— We usually recommend transdermal testosterone to most hypogonadal men, especially a gel, because it usually produces normal serum testosterone concentrations, and most patients find it the most convenient. Some men, however, prefer Androderm and others prefer injections of testosterone enanthate because of the freedom from daily application.

Men who begin using a transdermal preparation need to be seen two to three months after the initiation of therapy to measure the serum testosterone concentration and evaluate the possibility of undesirable effects. Men who use the body patch or a 50 mg dose of the gel, but whose serum testosterone concentration is not high enough, can try wearing two patches or applying 75 or 100 mg of the gel.

The initial regimen of testosterone enanthate should be 200 mg IM every two weeks, which can be administered either by someone in the patient's household or by the patient himself. The patient should be seen approximately two to three months later and, if he is bothered by fluctuations in energy, mood, or libido, the regimen can be changed to 100 mg once a week or transdermal testosterone can be offered again.

   
 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |  

Klinefelter’s syndrome
is a congenital disorder in which an extra X chromosome 47, XXY chromosome complement is associated with hypogonadism and infertility, but greater and lesser numbers of X chromosomes have also been reported, resulting in karyotypes such as 48 XXXY and 46,XY/46,XXY mosaicism. 46,XX males also have Klinefelter's syndrome; the development of testes in this setting is presumably due to translocation of a small portion of chromosomal material containing the testis-determining factor to an X chromosome.

Diagnosis of Klinefelter's syndrome usually can be made by determining the karyotype of the peripheral leukocytes. Testosterone deficiency and the resulting hypogonadism, if present, can be treated with testosterone. Hormone replacement is unlikely to improve the other abnormalities.

INCIDENCE:  1 in 1000 men (most common sex chromosome disorder causing primary hypogonadism)

GENETICS: The most common mosaic complement is 46,XY/47,XXY. 47,XXY karyotype and occasional 48,XXYY; 48,XXXY; or 49,XXXXY have been reported. The manifestations vary in severity in patients. It is this sex chromosome mosaicism that is thought to account for the variable presentation. Fertility, although very rare, has been reported in men with Klinefelter’s syndrome.

PHYSICAL FINDINGS CLASSIC TRIAD:  Small firm testes, azoospermia, and gynecomastia  (others: infertility tall long legs)

Postpubertal:  Gynecomastia (periductal fat growth) with small, firm, pea-sized testes.  Exaggerated growth of the lower extremities results in a decreased crown-to-pubis:pubis-to-floor ratio There are diminished strength, diminished ability to grow a full beard or mustache, infertility; decreased intellectual development and antisocial behavior are thought to occur with high frequency.

LABORATORY TESTS

  • Diagnosis by Buccal smear: one sex chromatin body
  • Normal to low serum testosterone
  • Elevated sex hormone binding globulin (SHBG) (acts to further suppress any available free testosterone)
  • Normal to increased estradiol (a result of augmented peripheral conversion of testosterone to estradiol)
  • Testis biopsy shows azoospermia, Leydig cell hyperplasia, hyalinization, and fibrosis of the seminiferous tubules. Mosaics may have focal areas of spermatogenesis, and, on rare occasions, a sperm may appear in the ejaculate. It is the extra X chromosome that is the pivotal factor controlling spermatogenesis as well as affecting neuronal function directly leading to the behavioral abnormalities related to decreased IQ.
  • PREPUBERTAL MALE: Gonadotropin levels are normal.
  • POSTPUBERTAL MALE: Gonadotropin levels are elevated even when the testosterone level is normal

   
Cryptorchidism
Cryptorchidism refers to one or both testes that are undescended; specifically, to testes that are in the abdominal cavity or in the inguinal canal and cannot be manipulated manually to within the scrotum by the age of one year. In comparison, testes that can be manipulated manually into the scrotum are called retractile.  The etiology of cryptorchidism is unknown in most cases, but gonadotropin deficiency in utero appears to be one cause, as evidenced by the frequency of cryptorchidism in association with congenital hypogonadotropic hypogonadism.

Some clinical consequences of cryptorchidism depend upon whether one or both testes are cryptorchid:

  • If only one testis is undescended,
    the sperm count will be subnormal in 25 to 33 percent, and the serum FSH concentration will be slightly elevated. The presence of these abnormalities suggests that both testes are abnormal, perhaps congenitally, even though only one fails to descend. The undescended testis may be damaged further by constant exposure to the heat of the abdomen, as suggested by decreased sperm counts in normal men whose testes were experimentally pushed into their inguinal canals for 6 to 12 months.
  • If both testes are undescended,
    the sperm count will usually be severely subnormal and the serum testosterone may also be reduced     .

Another clinical consequence of a cryptorchid testis is an approximately 3- to 14-fold increased risk of testicular cancer.

Treatment of cryptorchidism is designed to minimize heat-induced testicular damage by moving the cryptorchid testis into the scrotum, as well as to reduce the risk of malignancy and make the testis easier to palpate.

  1. Common initial therapy has been the administration of small doses of human chorionic gonadotropin (hCG) or a gonadotropin-releasing hormone (GnRH) analog, based upon the rationale that descent is dependent upon testosterone. However, one study showed that this regimen led to testicular descent only if the testis is retractile, not if it is cryptorchid.
  2. If hormonal therapy fails, the next step is orchiopexy, in which the cryptorchid testis is surgically manipulated into and attached to the scrotum. Orchiopexy may reduce the risk of malignancy, but biopsy at the time of orchiopexy may increase the risk. There is no documentation that orchiopexy actually improves testicular function. In addition, the operated testes usually remain small in adulthood.

   
Varicocele
Varicosity of the venous plexus within the scrotum, called a varicocele, has long been considered a possible cause of damage to the seminiferous tubules and thereby of infertility. As a result, ligation of varicoceles has long been practiced as a treatment for infertile men.  The proposed mechanism by which a varicocele damages the seminiferous tubules is increased blood flow, which raises the testicular temperature.

However, infertile men who do not have a varicocele have scrotal temperatures similar to those in infertile men who have a varicocele.

Many series have reported an improvement in semen qualities following varicocele ligation, but these studies were uncontrolled. Controlled trials have not demonstrated improvement in sperm count or fertility after varicocele correction. As a result, we cannot conclude that a varicocele impairs spermatogenesis or that correcting it will improve spermatogenesis.

   
 Primary Hypogonadism | Secondary Hypogonadism | Rx of Hypogonadism |  

        2011

Screening and Workup for Testosterone Deficiency

Martin M. Miner, MD

Medscape CME Released: 09/21/2011; Valid for credit through 09/21/2012  
This program is jointly sponsored by New York Medical College and Continuing Education Alliance.

Introduction

Estimates of the prevalence of testosterone deficiency (TD) in men vary widely, from 2.8% in community-dwelling men to 39% in men in patient populations.[1-3] Going by the higher estimate, which is based on biochemical evidence of TD, roughly 14 million men =45 years of age who visit a primary care provider (PCP) each year may be testosterone deficient.[2] Not all men with biochemical TD also have hypogonadal symptoms. Many do, however, have nonspecific, nonsexual symptoms that may suggest TD. Therein lies a major obstacle to identifying men with TD in primary care. A multitude of comorbidities have been found in conjunction with TD in prevalence studies—comorbidities seen with great frequency in primary care, including metabolic syndrome and diabetes, cardiovascular disease and hypertension, chronic inflammatory states including autoimmune diseases and chronic obstructive pulmonary disease (COPD), and long-term opiate use. The role of low testosterone as a cause or marker of these comorbidities is not clear, but as research continues to explore the question, the associations themselves mandate increased awareness of TD symptoms and clinician confidence in the screening and workup of at-risk patients.

Understanding Pathophysiology

Most patients who are experiencing TD want to know why they have the condition and where it originated. Although it is sometimes possible for the clinician to arrive at a definitive etiology of individual cases, more often the cause is multifactorial and complex.[4,5] The possible sites of origin are the testes, where testosterone is produced; and the brain, where the production process is regulated by means of the hypothalamic-pituitary-gonadal (HPG) axis. These 2 sites are the basis of a general classification scheme for TD in which hypogonadism is considered primary if it is testicular in origin and secondary if it results from hypothalamic or pituitary dysfunction (Table 1).[4,6] Each type of hypogonadism can be inherited or acquired, and each type can occur in men of any age.[7] However, most cases of hypogonadism in men aged 30 to 50 years are a mixed form, involving testicular failure as well as central defects of the HPG axis.[4,6,7] This form corresponds to what is often called adult-onset or late-onset hypogonadism (LOH).[5]

Table 1. Primary and Secondary Forms of Hypogonadism  [4,6,8-10]

• Primary hypogonadism (testicular dysfunction)  

• Secondary hypogonadism (hypothalamic or pituitary dysfunction)

• Mixed hypogonadism (seen chiefly in men aged 30 to 50 years old)

Relatively few cases of TD are primary; those that occur are usually congenital in origin, such as Klinefelter syndrome, the most common primary form.[4] Other primary causes include mumps orchitis, cryptorchidism, chemotherapy/radiation therapy, and testicular trauma.[6]

Causes of secondary hypogonadism include hypothalamic or pituitary lesions, cranial trauma, hyperprolactinemia, and Kallmann syndrome (genetic). Aging, acute illnesses, certain medications, and chronic illnesses including alcoholism, diabetes, cardiovascular disease, and sickle cell disease are believed to play causative roles in mixed hypogonadism.[6,10]

Although all forms of hypogonadism involve TD, they differ somewhat in their characteristic gonadotropin profiles. Primary hypogonadism is marked by increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the result of reduced feedback from testosterone; secondary hypogonadism is characterized by low or low-normal levels of LH and FSH; and the mixed form varies according to the predominance of primary or secondary hypogonadism. All forms also involve impaired spermatogenesis.[7,11] The clinical guidelines of the Endocrine Society recommend measurement of LH and FSH in hypogonadal men to distinguish between primary and secondary hypogonadism.[11] A more rational approach is to reserve FSH measurement for hypogonadal patients who have fertility concerns. LH is directly relevant to testosterone production and, in the absence of fertility questions, is the only gonadotropin of interest for TD classification. Measurement of serum prolactin, for insight on pituitary function, is appropriate when the serum testosterone level is <150 ng/dL or when secondary hypogonadism is suspected.[12]

Identifying Candidates for Screening

Signs and symptoms typical of TD do not figure into the hypogonadism classification scheme because they do not distinguish one form from another; symptoms can be similar regardless of the etiology of TD. Nonetheless, both symptoms and biochemical evidence of hypogonadism are prerequisites for the diagnosis and treatment of TD. This principle presents the core challenge to clinicians, because the symptoms of TD are not specific to hypogonadism, and can, at best, raise suspicion of TD when they are present.

Hypogonadism symptoms
develop slowly and overlap with the symptom profiles of conditions such as depression, erectile dysfunction (ED), and normal aging. They may manifest as reduced libido, muscle mass, strength, and bone mass; or as increases in mood disturbances, body fat, and hot flashes, all of which can arise from causes other than TD. Their lack of specificity means that these symptoms require corroboration by testosterone measurement, and even a repeat measurement (ie, 2 low values), for final confirmation.[11,12]

As noted in the first Expert Column in this series on TD,[13] there is lack of agreement on the relevance of TD to ED, that is, whether ED is sufficiently symptomatic of hypogonadism to prompt screening and testosterone measurement. The Endocrine Society guidelines[11] do not specify ED as suggestive of TD. The American College of Physicians does not recommend for or against routine hormonal blood tests or hormonal treatment for ED, citing the wide-ranging prevalence rates of ED in hypogonadal men (12.5%-35%) and the lack of conclusive evidence about the impact of testosterone therapy on ED.[14,15] On the other hand, several other international medical societies[12] recognize ED as among the hallmark symptoms of TD requiring biochemical corroboration. Most primary care practitioners will know from their own experience that ED is the portal to testosterone measurement. It should by no means go unappreciated as a possible manifestation of TD.

National and international guidelines concur in recommending TD screening for men deemed at risk due to coexisting illnesses (Table 2). The conditions include infertility, type 2 diabetes, metabolic syndrome, chronic obstructive pulmonary disease, inflammatory arthritis, cardiovascular disease, and chronic use of glucocorticoids and opioids.[8,9,11,12] Clinicians should maintain a high index of suspicion of TD in patients with these comorbidities. Even those at-risk patients who report no symptoms typical of hypogonadism require a thorough clinical and biochemical workup for TD.

Table 2.  Conditions With a High Prevalence of Testosterone Deficiency and Requiring Measurement of Serum Testosterone [5,11,12]*

*For men with sellar mass, HIV-associated weight loss, low-trauma fracture, or use of medications that affect testosterone production, measurement of testosterone should be considered regardless of hypogonadal symptoms.

There is little support for the use of formal questionnaires as a screening method for TD, especially as an isolated method in the workup. The Aging Males' Symptoms and the Androgen Deficiency in Aging Men scales, 2 of the better known symptom inventories used in TD screening, demonstrate high sensitivity for identifying men with TD but very low specificity (<40%),[16,17] making them unreliable for screening. In a recent trial with 587 community-dwelling men aged 60 to 80 years with known TD, the scores from these scales correlated more closely with age than with testosterone, and they did not reflect changes in symptoms after a 6-month regimen of testosterone therapy.[16] This latter finding is unfortunate because some clinicians find the instruments useful as a reference for evaluating the effects of treatments.[9]

However, the screeners may be helpful in identifying patients with a high likelihood of TD, and for educating the clinician about high-yield questions to ask in the TD workup. Even so, the current array of questionnaires are too time-consuming for most primary care clinicians to use routinely, especially given the lineup of other screeners suggested for primary care (for depression, dementia, and cancer, to name a few) that compete for time and resources. Newer screeners for TD are in development with fewer questions, and thus shorter completion time; these are likely to become available in the next 2 years.

Signs and Symptoms

Practice guidelines suggest that clinicians measure or consider measuring the testosterone levels of men who manifest any of these symptoms.[11,12] Another practical way to look at TD symptoms is from the perspective of affected domains (Table 3),[18] the 3 chief domains being sexual; psychological, including sleep; and physiologic, relating to strength, muscle mass, visceral obesity, and mobility. However symptoms are approached, clinicians should be aware that most of our current knowledge of TD symptoms is derived from clinical observations, and their own clinical judgment will be their chief resource as they proceed with the workup of TD. Symptoms may be vague: a general lack of energy, loss of motivation, inability to concentrate, a cantankerous mood, muscular aches.[4] The symptoms will also be affected by patient age, comorbid illnesses, the severity and duration of TD, previous testosterone therapy, and genetic factors.[9,11] The concern is that clinicians will connect these symptoms to aging or chronic disease or unhealthy lifestyle, and fail to investigate them as part of hypogonadism.

Table 3. Domains and Clinical Manifestations of TD in Men  [8,11,12,18]

Sexual Domain

Psychological Domoain

Physiological Domain

In addition to testosterone measurement, the workup for hypogonadism should proceed with the patient's personal and family medical history and a physical examination that covers blood pressure, secondary sexual characteristics (body hair, beard, pubic hair), testicular examination, and measurement of waist circumference and fat distribution. Examination of the prostate is appropriate to assess prostate cancer (which will affect the decision and timing about testosterone repletion); a nonpalpable or small prostate suggests low testosterone. Small testes (<15 mL) suggest TD. Supplementary tests may be necessary to exclude conditions in the differential diagnosis of TD; for example, a bone density test for suspected osteoporosis, or magnetic resonance imaging (MRI) to detect a pituitary macroadenoma in men (especially those <50 years of age) with both low testosterone and low LH, or elevated prolactin. Older men with secondary hypogonadism should undergo MRI if their serum testosterone is very low (<150 ng/dL) and if LH is normal or low or prolactin is increased. Visual changes or headache should also prompt MRI scanning. Other conditions in the differential diagnosis of TD include diabetes insipidus, hypothyroidism, adrenocorticotropic deficiency, or acute infection. The clinician should also be vigilant regarding obstructive sleep apnea, which has been associated with TD as well as testosterone repletion and may require evaluation both before and after initiation of repletion therapy.[4,8]

Comorbidities Associated With TD

The links between TD and other illnesses are still being explored at all levels, but epidemiologic research has by now established several critical associations. The strongest links relate to diabetes and metabolic syndrome. The cross-sectional Hypogonadism In Males (HIM) study reported several years ago that TD occurs frequently in men with type 2 diabetes in a primary care population; these men had more than twice the risk of hypogonadism than men without diabetes.[2] A more recent HIM analysis, based on free-testosterone measurement in more than 1800 men, found that the hormone's concentration in obese men with diabetes was significantly lower than in obese men without diabetes. Forty percent of the men without diabetes in the population and 50% of the men (=45 years) with diabetes were testosterone deficient. In a decade's time, the average decline in free testosterone was 7.8 pg/mL in the men without diabetes and 8.4 pg/mL in men with diabetes. The HIM investigators proposed that obesity and diabetes (in addition to age) exert independent effects on the prevalence of TD, with obesity perhaps the most closely associated comorbidity; and that the presence of either obesity or diabetes in a patient should prompt measurement of testosterone, especially if they occur together.[19] Furthermore, diabetes should be considered as a potential comorbidity in men with ED or with diminished libido, whether or not TD is also present.[12]

Obesity is but one component of the metabolic syndrome, which also includes hypertension, dyslipidemia, impaired glucose regulation, and insulin resistance, to show a close relationship with TD. In a population of 794 community-dwelling men aged 50 to 91 years who were prospectively followed for 20 years in the Rancho Bernardo Study, low testosterone levels were associated with central obesity, hyperinsulinemia, insulin resistance, hyperglycemia, dyslipidemia, hypertension, and other cardiovascular risk factors such as low adiponectin and elevated C-reactive protein. Surprisingly, TD maintained an independent association with increased mortality during follow-up: men with total testosterone levels in the lowest quartile (<241 ng/dL) were 40% more likely to die than the men with higher levels, regardless of age, adiposity, and other components of the metabolic syndrome and cardiovascular risk. The excess mortality was mainly due to cardiovascular and respiratory diseases, and the authors theorized that obesity could be a pathway by which TD influences and promotes these problems.[20]

A recent review of research on the links between hypogonadism, metabolic syndrome, and cardiovascular disease concluded that any connections remain clinically and pathophysiologically unclear.[21] Other findings suggest meaningful associations. In a randomized trial of 32 hypogonadal men with metabolic syndrome and newly diagnosed type 2 diabetes, the men who received testosterone repletion in addition to lifestyle therapy experienced greater improvement in components of the metabolic syndrome, with more than 80% of these men achieving reversal of syndrome parameters and reaching all specified targets for glycemic control.[22,23] In addition, a double-blind, placebo-controlled trial involving 50 men with metabolic syndrome found that testosterone therapy significantly reduced insulin resistance and C-reactive protein. Testosterone therapy was also credited with delaying the progression of atherosclerosis as assessed by intima-media thickness of the carotid artery.[24] Continued focus on the relationships between TD, metabolic disorders, and cardiovascular disease is an important research objective.

TD is one of numerous hormonal disorders associated with HIV and acquired immunodeficiency syndrome (AIDS), although its prevalence and pathogenesis have changed in the past 20 years. Originally associated with advanced AIDS, particularly wasting syndrome, hypogonadism is now less prevalent in the HIV/AIDS population and is now associated with aging, comorbidities (eg, hepatitis C), and drug side effects. There is no established connection between antiretrovirals and TD, but injection drug use and psychotropic medications are associated with TD in older men with HIV.[25] Drug use has also emerged as a comorbidity of TD in the general population. Given the known increase in both therapeutic and nonmedical uses of opioids in the past 10 years, it is not surprising that more men with a history of chronic use of these drugs (such as methadone, oxycodone, hydrocodone, morphine, and codeine) are presenting with associated complaints. Beyond the inherent risks of overuse and misuse, including death, the long-term effects of opioid medications are now believed to include hypogonadism, sexual dysfunction, and hyperalgesia.[26] Pituitary hormones may also be altered with continued use, and the risks of infertility and bone loss may rise (in men and women). Furthermore, opioids may increase or decrease food intake, cause hypoglycemia, and impair insulin secretion. This excessive stress is difficult for body systems to tolerate, so it is troubling that the rate of substance abuse has increased among adults aged 60 years and older, the aging baby boomers. Alcohol and prescription drug abuse may by now affect as many as 17% of older adults.[27]

Measuring Testosterone: What Do the Values Mean?

Total testosterone (TT) has been the traditional measure for use in corroboration of hypogonadism. Testosterone levels in healthy men follow a circadian rhythm, with levels peaking in the morning. Accordingly, guidelines recommend measurement of TT in a blood sample taken during morning hours, preferably after the patient has fasted. A positive finding should be repeated, especially if borderline.[9,11]

Values for "normal" testosterone vary among laboratories according to the assay in use. Even if assays were consistent, there is no clear clinically relevant dividing line between normal and deficient testosterone in the blood, despite the efforts of involved medical societies to define one (Table 4). It is generally agreed that a TT level of >350 ng/dL does not require treatment and suggests nontestosterone sources of symptoms. Otherwise, the recommendation is to consider treating men with "unequivocally low" testosterone along with symptoms. Clinicians should be aware that TT measurements do not necessarily correspond with the patient's clinical presentation. Some research supports symptom-specific levels of TT below which the prevalence of the symptom starts to increase.[28] Other research finds no symptom-specific thresholds but further evidence that the severity of symptoms increases with decreasing testosterone level, most clearly the severity of psychological symptoms.[29]

Table 4. Biochemical Definitions of Hypogonadism  [8,11,12,30]

                             Total Testosterone Level  
Society Guidelines  ng/mL    ng/dL   nmol/L  
EAA, ISA, ISSAM < 3.40   < 340  < 12 (mild)    
EAU, ASA, ISSM < 2.31 < 231  < 8 (severe)
ES < 3.00 < 300  < 10.4
AACE < 2.00 < 200  7

EAA = European Academy of Andrology; ISA = International Society of Andrology; ISSAM = International Society for the Study of the Aging Male; EAU = European Association of Urology; ASA = American Society of Andrology; ISSM = International Society for Sexual Medicine; ES = Endocrine Society; AACE = American Association of Clinical Endocrinologists.

TT represents the total of free testosterone plus hormone bound to sex hormone-binding globulin (SHBG) and albumin. TT levels are subject to alterations in SHBG that occur in association with obesity, old age, diabetes, medications, and other confounders.[11] Measurement of free testosterone can be of diagnostic value in cases where TT does not correspond with the clinical picture. However, this practice is limited by the availability of assays and, again, a lack of consensus on threshold values. Many clinicians who regularly see men with TD suggest a threshold of 8 ng/dL to define hypogonadism by calculated free testosterone. For measurement by means of the analog free-testosterone assay, values <1.5 ng/dL have been proposed as a lower limit of normal.[18]

Our upcoming Expert Column will discuss the treatment of TD, which has already achieved successes in improving sexual symptoms, body composition and strength, bone density, and glycemic parameters, effects with an indisputable relevance to quality of life and overall good health.

This article is a CME certified activity. To earn credit for this activity visit:  
http://www.medscape.org/viewarticle/749240  

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