Primary Male Hypogonadism and Testosterone Therapy By Dr

Primary Male Hypogonadism and Testosterone Therapy By: Dr Salehidoost Assistant Prof. of Endocrinology Isfahan University Of Medical Sciences

Development of the male reproductive system Male sexual development starts between the 7 th and 12 th week of gestation. The undifferentiated gonads develop into a fetal testis through expression of the sex-determining region Y gene (SRY), a gene complex located on the short arm of the Y chromosome. The fetal testis produces two hormones: testosterone and anti-Müllerian hormone (AMH). Jungwirth A, et al. Eur Urol. 2012 Feb.

Development of the male reproductive system Testosterone is needed for the development of the Wolffian ducts, resulting in formation of the epididymis, vas deferens and seminal vesicle. AMH activity results in regression of the Müllerian ducts. Under the influence of intratesticular testosterone, the number of gonocytes per tubule increases threefold during the fetal period. Jungwirth A, et al. Eur Urol. 2012 Feb.

Development of the male reproductive system Testosterone is needed for development of the prostate, penis and scrotum. However, in these organs testosterone is converted into the more potent metabolite dihydrotestosterone (DHT) by the enzyme 5 a-reductase. The enzyme is absent in the testes, which explains why 5 areductase inhibitors do not have a marked effect on spermatogenesis. Jungwirth A, et al. Eur Urol. 2012 Feb.

Development of the male reproductive system Intratesticular testosterone is needed to maintain the spermatogenic process and to inhibit germ cell apoptosis. The seminiferous tubules of the testes are exposed to concentrations of testosterone 25 -100 times greater than circulating levels. Suppression of gonadotrophins (e. g. through excessive testosterone abuse) results in a reduced number of spermatozoa in the ejaculate and hypospermatogenesis. Complete inhibition of intratesticular testosterone results in full cessation of meiosis up to the level of spermatids. Jungwirth A, et al. Eur Urol. 2012 Feb.

Hypogonadism is defined as “inadequate gonadal function, as manifested by deficiencies in gametogenesis and/or the secretion of gonadal hormones. ” These abnormalities usually result from disease of the testes (primary hypogonadism) or disease of the pituitary or hypothalamus (secondary hypogonadism). In occasional cases, a defect in the ability to respond to testosterone is the cause of hypogonadism. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Hypergonadotropic Hypogonadism Patients with hypergonadotropic hypogonadism may have some or all of the following characteristic findings: • Increased FSH level • Increased LH level • Low testosterone level • Impaired production of sperm AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Hypogonadotropic Hypogonadism The condition of hypogonadotropic hypogonadism is generally associated with the following findings: • Low or low-normal FSH level • Low or low-normal LH level • Low testosterone level • Impaired production of sperm AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Hypogonadism Primary hypogonadism differs from secondary hypogonadism in two ways: ●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. As a consequence, the sperm count may be low, and the serum FSH concentration normal or high, yet the serum testosterone concentration remains normal. In contrast, in secondary hypogonadism, there is a proportionate reduction in testosterone and sperm production. Up. To. Date 2015, Causes of primary hypogonadism in males

Hypogonadism Primary hypogonadism differs from secondary hypogonadism in two ways: ●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. Up. To. Date 2015, Causes of primary hypogonadism in males

General Manifestations Symptoms of hypogonadism depend primarily on the age of the male patient at the time of development of the condition. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

General Manifestations When hypogonadism develops before the age of puberty, the manifestations are those of impaired puberty: ü • Small testes, phallus, and prostate ü • Scant pubic and axillary hair ü • Disproportionately long arms and legs (from delayed epiphyseal closure) ü • Reduced male musculature ü • Gynecomastia ü • Persistently high-pitched voice AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

General Manifestations In men in whom androgen deficiency develops after completion of pubertal maturation, symptoms of androgen deficiency include: Ø reduced sexual desire and activity, Ø decreased spontaneous erections, Ø loss of body hair and reduced frequency of shaving, Ø infertility, Ø reduced muscle bulk and strength, Ø hot flushes and sweats, Ø height loss due to atraumatic fracture, Ø small or shrinking testes, Ø breast enlargement or tenderness Less-specific symptoms include decreased energy, motivation, and initiative; sad or blue feelings, depressed mood, dysthymia; poor concentration and memory; sleep disturbance and increased sleepiness; increased body fat; and diminished physical or work capacity.

General Manifestations Postpubertal loss of testicular function results in slowly evolving subtle clinical symptoms and signs. In aging men, these symptoms and signs may be difficult to appreciate because they are often attributed to “getting older. ” AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

General Manifestations The growth of body hair usually slows. The voice and the size of the phallus usually remain unchanged. Prostate size may decrease in hypogonadal men, but the amount of change is related to the severity of testosterone deficiency. Typical temporal hair recession and balding usually do not occur, and if they did, these manifestations would not be expected to prompt a patient to seek medical attention. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Physical Examination The amount and distribution of body hair, including beard growth, axillary hair, and pubic hair, should be noted, as should the presence of a male pattern escutcheon. The presence and degree of gynecomastia should be recorded. The presence of galactorrhea would suggest pronounced hyperprolactinemia, usually associated with some degree of hyperestrogenism. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Physical Examination The testes should be measured (length and width) by using a Prader orchidometer or calipers. Some testicular disorders may selectively affect production of sperm without influencing production of testosterone. These disorders may sometimes be detected by careful physical examination, including determination of testicular size and consistency. Because approximately 85% of testicular mass consists of germinal tissue, a reduced germinal cell mass would be associated with a reduced testicular size and a soft consistency. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Physical Examination Testicular consistency should be noted. If the germinal epithelium was damaged before puberty, the testes are generally small and firm. If postpubertal damage occurred, the testes are usually small and soft. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Physical Examination On examination of the scrotum, the presence of any masses or varicoceles should be noted for further evaluation. For assessment of any potentially significant varicocele, the patient should be asked to perform a Valsalva maneuver, and the scrotal contents should be examined. The stretched penis should be measured (length and width). With prepubertal onset of hypogonadism, the stature may assume eunuchoid proportions, with a crown-to-pubis divided by a pubis-to-floor ratio of <0. 92 and an arm span more than 3 cm greater than the height. A nonpalpable prostate suggests low testosterone levels. A prostate that is normal for age suggests reasonably normal testosterone levels. Of note, an enlarged prostate may not substantially diminish if once-normal testosterone levels have decreased. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Differential Diagnosis

Klinefelter's syndrome is the most common congenital abnormality causing primary hypogonadism, occurring in approximately 1 in 1000 live male births. This syndrome is the clinical manifestation of a male who has an extra X chromosome. The most common genotype is 47, XXY , 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. Up. To. Date 2015, Causes of primary hypogonadism in males

Klinefelter's syndrome The 47, XXY genotype results from nondisjunction of the sex chromosomes of either parent during meiotic division. While mosaicism probably results from nondisjunction during mitotic division after conception. The greater the number of extra X chromosomes, the greater the phenotypic consequences, both gonadal and extragonadal. Up. To. Date 2015, Causes of primary hypogonadism in males

Klinefelter's syndrome Damage to the seminiferous tubules and, usually, damage to the Leydig cells as well. The gonadal manifestations include almost invariably small, firm testes, severely subnormal sperm count, infertility, elevated (FSH) and (LH) concentrations, variably subnormal serum testosterone concentration and decreased virilization. The damage may be increased if the patient also has cryptorchidism, the incidence of which is increased in Klinefelter's. A psychosocial abnormality, unrelated to the hypogonadism, which causes difficulty in social interactions throughout life and has been characterized by "marked lack of insight, poor judgment, and impaired ability to learn from adverse experience". Up. To. Date 2015, Causes of primary hypogonadism in males

Klinefelter's syndrome Predisposition to develop morbidities later in life that are unrelated to testosterone deficiency. These include: Ø pulmonary diseases such as chronic bronchitis, bronchiectasis, and emphysema ; Ø cancers, including germ cell tumors (particularly extragonadal tumors involving the mediastinum) , breast cancer , and possibly non-Hodgkin lymphoma ; Ø varicose veins, leading to leg ulcers ; Ø systemic lupus erythematosus, probably due to the extra X chromosome ; Ø and diabetes mellitus Mortality from breast cancer has been reported to be much higher in Klinefelter syndrome than in the general population but that from prostate cancer lower. Up. To. Date 2015, Causes of primary hypogonadism in males

Klinefelter's syndrome 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. Fertility has been achieved with assisted reproductive technologies , but there are important genetic implications of these procedures. Up. To. Date 2015, Causes of primary hypogonadism in males

Other Chromosomal Abnormalities ●The 46, XY/XO karyotype leads to a syndrome characterized by short stature and features typical of Turner syndrome. The gonads vary from streak to dysgenetic to normal testes; as a result, the sexual phenotype varies from complete female to complete male. If the patient has both a streak gonad and a dysgenetic testis ("mixed gonadal dysgenesis"), the risk of gonadoblastoma is about 20 percent. Gonadectomy should therefore be performed in these patients. ●The 47, XYY karyotype was initially thought to be associated with hypogonadism, but subsequent reports have not confirmed this relation. ●Microdeletions in specific regions of the long arm of the Y chromosome are occur in up to 20 percent of men with azoospermia or severe oligospermia. Some of these men have no other testicular lesions, but others have cryptorchidism.

Mutation in the FSH and LH receptor genes Another rare cause of primary hypogonadism is a mutation in the FSH receptor gene. One report described five men found to be homozygous for an inactivating mutation of the FSH receptor. These subjects had variably low sperm counts and inhibin B concentrations and high serum FSH concentrations. LH receptor mutations result in Leydig cell hypoplasia and testosterone deficiency in the first trimester in utero, resulting in varying degrees of male pseudohermaphroditism.

Cryptorchidism refers to testes that are undescended. Unilateral or bilateral cryptorchidism can occur. The incidence of this condition is 3 to 4% at birth, but most testes ultimately descend. Thus, the 1 -year incidence is about 0. 8%. Because normal testicular descent requires normal pituitary function and dihydrotestosterone levels, the incidence of cryptorchidism is increased in patients with Kallmann’s syndrome. Generally, the objective is to bring the undescended testicle into the scrotum before 1 to 2 years of age to improve fertility potential. Because a slight risk of a malignant lesion is associated with undescended testicles, surgical placement into the scrotum offers the opportunity for thorough examination. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Cryptorchidism may affect one or both testes. 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. ●If both testes are undescended, the sperm count will usually be severely subnormal and the serum testosterone may also be reduced. Up. To. Date 2015, Causes of primary hypogonadism in males

Disorders of androgen biosynthesis A congenital decrease in testosterone synthesis and secretion can result from 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 alphahydroxylase, 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.

Myotonic Dystrophy Classically, myotonic dystrophy is an autosomal dominant disorder, characterized by hypogonadism, muscle weakness, and frontal balding, that occurs only in male patients. Testicular failure usually occurs after age 40 years; thus, patients often have children at risk for the disease. Testosterone levels may be variably decreased in the setting of azoospermia and high gonadotropin levels. Small testes and decreased sperm production are more common than decreased serum testosterone levels. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Vanishing Testes Syndrome (Congenital Anorchism or Prepubertal Functional Castrate) The initial manifestation of the vanishing testes syndrome is sexual immaturity in a male patient. The cause is unclear, but the syndrome may be due to testicular torsion during fetal life after sufficient testosterone exposure to produce masculinization of the reproductive tract. Impalpable testes suggest the possibility of cryptorchidism. FSH and LH levels are increased, and testosterone levels are low. If the LH levels are only minimally increased, h. CG stimulation testing of the gonad should be done. With vanishing testes syndrome, no response would be demonstrated. A response to h. CG stimulation would raise the possibility of intra-abdominal testes, which would necessitate further evaluation because of the potential for malignant transformation. In this setting, MRI is recommended to assess the possibility of a retained intraabdominal dysgenetic gonad because this would be associated with an increased risk of a malignant lesion and would necessitate removal. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

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. Up. To. Date 2015, Causes of primary hypogonadism in males

Infections — Mumps orchitis is the infection most closely associated with testicular damage. Orchitis is a much more common manifestation when mumps occurs in adulthood than in childhood. The median age of men who got mumps orchitis in one study was 29. 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. Up. To. Date 2015, Causes of primary hypogonadism in males

Radiation Direct radiation to the testes, as in treatment for leukemia, will damage the testes. Even indirect radiation to the testes when they are shielded (as with radiation to the inguinal lymph nodes for lymphoma) will damage the seminiferous tubules. The degree of damage is proportionate to the amount of radiation exposure. Radioactive iodide has been reported to cause a decrease in the sperm count when doses of several hundred m. Ci are administered to treat thyroid cancer. Up. To. Date 2015, Causes of primary hypogonadism in males

• Trauma — Trauma to the testes can be sufficiently severe to damage both seminiferous tubules and Leydig cells. • Testicular torsion — Testicular torsion is one of the most common reasons for the loss of a testicle before puberty. Testicular torsion is a twisting of the testis on the spermatic cord, which results in acute loss of the blood supply to the testis. Torsion lasting more than eight hours can lead to sufficient damage to the seminiferous tubules to lower the sperm count. • Bilateral orchiectomy — Orchiectomy is standard treatment for testicular cancer, which is often bilateral, although it often occurs at different times on each side. Up. To. Date 2015, Causes of primary hypogonadism in males

Alkylating and antineoplastic agents Alkylating agents, such as cyclophosphamide, chlorambucil, cisplatin, and busulfan can damage the seminiferous tubules to a degree sufficient to cause azoospermia and markedly elevated serum follicle-stimulating hormone (FSH) concentrations . Concurrent administration of testosterone might protect against long-term gonadal injury in adults. Up. To. Date 2015, Causes of primary hypogonadism in males

Drugs • Ketoconazole — The antifungal drug directly inhibits testosterone biosynthesis, thereby causing testosterone deficiency. • Glucocorticoids — Chronic glucocorticoid use can also lower testosterone levels by about one-third; the mechanism is not clear, but inhibition may occur at both the testis and pituitary. Up. To. Date 2015, Causes of primary hypogonadism in males

Autoimmune Syndromes Anti-Leydig cell antibody-associated disorders or conditions associated with anti-sperm antibodies are autoimmune syndromes related to hypogonadism. The hypogonadism that accompanies autoimmune polyglandular disease is also characterized by hypothyroidism and hypoadrenalism. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Chronic systemic diseases • Many chronic, systemic illnesses cause hypogonadism both by a direct testicular effect and by decreasing gonadotropin secretion. • Cirrhosis • Chronic renal failure • HIV AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Hemochromatosis Iron overload may lead to primary gonadal failure or hypothalamic-pituitary dysfunction that results in secondary gonadal failure. The diagnosis is made in the setting of associated findings of hemochromatosis in conjunction with an increased ferritin level. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Idiopathic Primary hypogonadism may be idiopathic, whether it is severe, resulting in testosterone deficiency and azoospermia, or mild, resulting only in oligospermia/azoospermia and an elevated FSH.

Laboratory Studies

Testosterone concentrations may be affected by illness and certain medications (e. g. opiates and glucocorticoids). Total testosterone concentrations are also influenced by alterations in SHBG concentrations. Serum testosterone levels exhibit a circadian variation with peak values in the morning; this circadian rhythm is blunted with aging. Because of this circadian variation in testosterone levels and the fact that normal ranges for serum testosterone are usually established using morning blood samples, testosterone measurement for the diagnosis of androgen deficiency should be performed in the morning. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Testosterone It is important to confirm low testosterone concentrations in men with an initial testosterone level in the mildly hypogonadal range because 30% of such men may have a normal testosterone level on repeat measurement. Also, 15% of healthy young men may have a testosterone level below the normal range in a 24 -h period (day-to-day variations) Single testosterone measurements were inadequate to characterize an individual’s levels, and at least two testosterone measurements were needed to diagnose androgen deficiency with greater confidence. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Testosterone Serum total testosterone concentration represents the sum of unbound and protein-bound testosterone in circulation. Most of the circulating testosterone is bound to SHBG and to albumin ; only 0. 5– 3% of circulating testosterone is unbound or “free. ” The term “bioavailable testosterone” refers to unbound testosterone plus testosterone bound loosely to albumin. Free or bioavailable testosterone concentrations should be measured when total testosterone concentrations are close to the lower limit of the normal range and when altered SHBG levels are suspected, e. g. in older men and in men with obesity, diabetes mellitus, chronic illness, or thyroid disease. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Gonadotropins Both FSH and LH are secreted in short pulses. FSH has a longer half-life than does LH and is more likely to provide adequate results on a single blood sample. Because LH has a shorter half-life than does FSH, errors may be introduced in measurements made on single samples. Pooled samples for LH done 20 to 30 minutes apart are more accurate than single-sample determinations (albeit less convenient). Persistent borderline values may be further evaluated with dynamic endocrine testing. These tests may include the Gn. RH stimulation test, the clomiphene stimulation test, and the human chorionic gonadotropin (h. CG) stimulation test. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Semen Analysis A semen analysis is the primary test to assess the fertility potential of the male patient. Semen should be collected by masturbation after 2 to 5 days of abstinence and evaluated within 2 hours. Variability between specimens is common; with low or borderline samples, follow-up consisting of evaluation of three or more samples should be done during a 3 -month period. A fructose test should be done on a semen sample showing azoospermia. Because fructose is secreted by the seminal vesicles, absence of fructose may indicate complete obstruction of the ejaculatory ducts or congenital absence of both vasa deferens and both ejaculatory ducts. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Genetic Studies Patients with hypergonadotropic hypogonadism and impaired pubertal development associated with small, firm testes and often with gynecomastia are likely to have Klinefelter’s syndrome or a variant. Classically, a buccal smear was done to establish the diagnosis by revealing Barr bodies. We currently recommend genetic karyotype testing to confirm the diagnosis. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Testicular Biopsy and Scrotal Exploration Since the advent of sensitive FSH assays, germinal cell function is now most often assessed through the FSH assay alone rather than testicular biopsy. Men with azoospermia, normal FSH levels, and normal testicular size should usually undergo testicular biopsy and scrotal exploration to determine whether a germinal cell abnormality, an obstruction, or a congenital abnormality of the vasa is present. AACE Hypogonadism Guidelines, Endocr Pract. 2002; 8(No. 6)

Diagnosis We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels between 8 and 10 AM on at least two occasions. . J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Diagnosis If a single 8 to 10 AM value is well within the normal range, testosterone production can be assumed to be normal. If a single 8 to 10 AM value is low or borderline low or does not fit with the clinical findings, the measurement should be repeated once or twice before making the diagnosis of hypogonadism. The normal range in adult men in most laboratories is about 300 to 800 ng/d. L.

Diagnosis We suggest the measurement of morning total testosterone level as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating measurement of total testosterone. We suggest measurement of free or bioavailable testosterone level, using an accurate and reliable assay, in some men in whom total testosterone concentrations are near the lower limit of the normal range and in whom alterations of SHBG are suspected. We suggest that an evaluation of androgen deficiency should not be made during an acute or subacute illness. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Case finding

Case finding In men with chronic diseases such as diabetes mellitus, end-stage renal disease, and chronic obstructive lung disease, measurement of testosterone may be indicated by symptoms such as sexual dysfunction, unexplained weight loss, weakness, or mobility limitation. In men with some other conditions, such as a pituitary mass, HIV-associated weight loss, low trauma fracture, or treatment with medications that affect testosterone production, measurement of testosterone may be indicated regardless of symptoms. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Testosterone Therapy We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Testosterone Therapy We suggest that when clinicians prescribe testosterone therapy, therapeutic target should be to raise serum testosterone levels into a range that is mid-normal for healthy, young men. In men receiving testosterone enanthate or cypionate, serum testosterone levels vary during the dosing interval; We suggest aiming for testosterone levels between 400 and 700 ng/dl midway between injections. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Monitoring men receiving testosterone therapy Evaluate the patient 3 to 6 months after treatment initiation and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering from any adverse effects. Monitor testosterone level 3 to 6 months after initiation of testosterone therapy: Therapy should aim to raise serum testosterone level into the mid-normal range. Injectable testosterone enanthate or cypionate: measure serum testosterone level midway between injections. If testosterone is 700 ng/dl (24. 5 nmol/liter) or 400 ng/dl (14. 1 nmol/liter), adjust dose or frequency. Transdermal patches: assess testosterone level 3– 12 h after application of the patch; adjust dose to achieve testosterone level in the mid-normal range. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Monitoring men receiving testosterone therapy Buccal testosterone bioadhesive tablet: assess level immediately before or after application of fresh system. Transdermal gels: assess testosterone level any time after patient has been on treatment for at least 1 wk; adjust dose to achieve serum testosterone level in the mid-normal range. Testosterone pellets: measure testosterone levels at the end of the dosing interval. Adjust the number of pellets and/or the dosing interval to achieve serum testosterone levels in the normal range. Oral testosterone undecanoatea: monitor serum testosterone level 3 to 5 h after ingestion. Injectable testosterone undecanoate: measure serum testosterone level just prior to each subsequent injection and adjust the dosing interval to maintain serum testosterone in mid-normal range. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Monitoring men receiving testosterone therapy Check hematocrit at baseline, at 3 to 6 months, and then annually. If hematocrit is 54%, stop therapy until hematocrit decreases to a safe level; evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose. Measure bone mineral density of lumbar spine and/or femoral neck after 1– 2 yr of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture, consistent with regional standard of care. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Monitoring men receiving testosterone therapy In men 40 yr of age or older with baseline PSA greater than 0. 6 ng/ml, perform digital rectal examination and check PSA level before initiating treatment, at 3 to 6 months, and then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient. Obtain urological consultation if there is: Ø An increase in serum PSA concentration 1. 4 ng/ml within any 12 month period of testosterone treatment. Ø A PSA velocity of 0. 4 ng/ml yr using the PSA level after 6 months of testosterone administration as the reference (only applicable if PSA data are available for a period exceeding 2 yr). Ø Detection of a prostatic abnormality on digital rectal examination. Ø An AUA/IPSS of 19. J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Testosterone therapy in men with sexual dysfunction We suggest that clinicians offer testosterone therapy to men with low testosterone levels and low libido to improve libido and to men with ED who have low testosterone levels after evaluation of underlying causes of ED and consideration of established therapies for ED. Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

HIV-infected men with weight loss We suggest that clinicians consider short-term testosterone therapy as an adjunctive therapy in HIVinfected men with low testosterone levels and weight loss to promote weight maintenance and gains in LBM and muscle strength. Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Glucocorticoid-treated men We suggest that clinicians offer testosterone therapy to men receiving high doses of glucocorticoids who have low testosterone levels to promote preservation of LBM and bone mineral density. Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol Metab, June 2010, 95(6): 2536– 2559

Time course of effects The time course of the effects of testosterone replacement is variable. Increases in fat-free mass, prostate volume, erythropoiesis, energy, and sexual function occurred within the first three to six months. In contrast, the full effect on bone mineral density (BMD) did not occur until 24 months.

In general, the benefits of TRT are more consistent in men with very low testosterone concentrations than in those with concentrations just below the normal range. Health care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy. TRT should not be provided to men who have untreated or metastatic prostate cancer or breast cancer. Testosterone and Cardiovascular Risk, Endocr Prac. 2015; 21(No. 9)

Relative contra-indications include : Ø untreated severe sleep apnea, Ø a hematocrit >50%, Ø severe lower urinary tract symptoms with an International Prostate Symptom Score above 19, Ø uncontrolled or poorly controlled heart failure, Ø a MI or cerebrovascular accident within the past 6 months, Ø a personal or family history of a procoagulant state, Ø or a personal history of thromboembolism Testosterone and Cardiovascular Risk, Endocr Prac. 2015; 21(No. 9)