aace guidelines

Reference Section

a report by

T h e Ame r i c a n A s s o c i a t i o n o f C l i n i c a l E n d o c r i n o l o g i s t s H y p og o n ad i sm Ta s k Fo r c e

A b s t r a c t

In these clinical practise guidelines1, specificrecommendations are made for determining the mosteffective methods of diagnosing and treatinghypogonadism in adult male patients. The targetpopulations for these guidelines include:

• men with primary testicular failure requiringtestosterone replacement (hypergonadotropichypogonadism);

• male patients with gonadotropin deficiency ordysfunction who may have received testosteronereplacement therapy or treatment for infertility(hypogonadotropic hypogonadism); and

• aging men with symptoms relating to testosteronedeficiency who could benefit from testosteronereplacement therapy.

Initial hormonal evaluation generally consists of atestosterone determination, in conjunction with a freetestosterone or sex hormone-binding globulin level, inpatients with clear symptoms and signs but normal-range total testosterone, follicle-stimulating hormone,luteinizing hormone, and prolactin levels.

Other possible tests include semen analysis, pituitaryimaging studies, genetic studies, bone densitometry,testicular ultrasonography, testicular biopsy, andspecialized hormonal dynamic testing.

Therapeutic options generally consist of testosteronereplacement by injections, patches or topically appliedgel in hypergonadotropic patients and inhypogonadotropic patients not interested in fertility. Inhypogonadotropic patients interested in fertility,gonadal stimulation options can be considered,including human chorionic gonadotropin stimulationtherapy, with or without human menopausalgonadotropin (or follicle-stimulating hormone), orgonadotropin-releasing hormone pump therapy.

These therapies may be combined with assistedreproductive technologies such as in vitro fertilizationwith intracytoplasmic sperm injection, which may allowpregnancy to occur with very low numbers of sperm2.

Fo r ewo rd

Guidelines are systematically developed statements toassist healthcare professionals in medical decision-making for specific clinical conditions. Most of thecontent therein is based on literature reviews. In areas ofuncertainty, professional judgment was applied.

These guidelines are a working document that reflectsthe state of the field at the time of publication. Becauserapid changes in this area are expected, periodicrevisions are inevitable.The authors encourage medicalprofessionals to use this information in conjunctionwith their best clinical judgment.

The presented recommendations may not be appropriatein all situations. Any decision by practitioners to applythese guidelines must be made in light of local resourcesand individual patient circumstances.

M i s s i o n S t a t emen t

Hypogonadism is defined as “inadequate gonadalfunction, as manifested by deficiencies in gametogenesisand/or the secretion of gonadal hormones”3.

Men with hypogonadal disorders have symptoms that areoften denied by the patient and ignored by the physician.

In addition, diagnostic evaluation and therapeuticoptions are poorly understood. With a longer lifespanand with advances in the treatment of cardiovasculardisease, some aging men suffer from associated decreasesin testosterone levels that may increase the risk ofosteoporosis, sexual dysfunction, fatigue, cardiovasculardisease, and mood disturbances. Prostate cancer in menremains a common problem that demands furtherresearch efforts and also is an issue in the considerationof testosterone replacement therapy.

Of prime consideration is the paucity of long-termresearch studies on the identification of men at riskfor complications related to a decreased testosteronelevel, optimal assessment of such patients, optimaltreatment, and potential complications relating tolong-term therapy.

Amer i can Assoc ia t ion o f C l in i ca l Endocr ino log i s t s Med ica l Gu ide l ines forC l in i ca l Prac t i ce for the Eva luat ion and Treatment o f Hypogonad i sm inAdu l t Ma le Pat ient s – Update

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B U S I N E S S B R I E F I N G : N O R T H A M E R I C A N P H A R M A C O T H E R A P Y

ChairmanSteven M Petak, MD, JD, FACE

Committee MembersHoward R Nankin, MD, FACERichard F Spark, MD, FACE

Ronald S Swerdloff, MDLuis J Rodriguez-Rigau, MD, FACE

ReviewersRobert J Anderson, MD, FACE, FACP

Donald A Bergman, MD, FACEJeffrey R Garber, MD, FACE

Carlos R Hamilton, Jr, MD, FACEKenneth S Hershon, MD, FACE

Lois G Jovanovic, MD, FACEMichael Kleerekoper, MD, FACEJeffrey I Mechanick, MD, FACE,

FACP, FACNPasquale J Palumbo, MD, MACE

Anne L Peters, MDHerbert I Rettinger, MD MBA, FACE

Helena W Rodbard, MD, FACEHarvey A Rubenstein, MD, FACE

John A Seibel, MD, MACEJohn B Tourtelot, MD, FACE,

CDR, USN

These guidelines on the evaluation and treatment ofhypogonadism in adult male patients represent not onlya source of guidance for healthcare professionals butalso an appeal to clinicians to increase their awareness ofthe problem and to discuss these issues with their at-riskpatients.With growing awareness and increased researchefforts, both the duration and the quality of life foraging men will improve.

Ame r i c a n A s s o c i a t i o n o f C l i n i c a lE n d o c r i n o l o g i s t s M ed i c a l G u i d e l i n e s f o rC l i n i c a l P r a c t i s e f o r t h e E va l u a t i o n a n dTre a tmen t o f H y p og o n ad i sm i n A d u l tM a l e P a t i e n t s – 2 0 0 2 Upd a t e 4

G e n e r a l M a n i f e s t a t i o n s

Hypogonadism may manifest itself with testosteronedeficiency, infertility, or both conditions. Symptoms ofhypogonadism depend primarily on the age of the malepatient at the time of development of the condition.

Hypogonadism is often unrecognized before the age ofpuberty, unless it is associated with growth retardationor other anatomic or endocrine abnormalities.

When hypogonadism develops before the age of puberty,the manifestations are those of impaired puberty:

• small testes, phallus, and prostate;• scant pubic and axillary hair;• disproportionately long arms and legs (from delayed

epiphyseal closure);• reduced male musculature;• gynecomastia; and • persistently high-pitched voice.

Postpubertal loss of testicular function results inslowly evolving, subtle, clinical symptoms and signs.In aging men, these symptoms and signs may bedifficult to appreciate because they are oftenattributed to ‘getting older.’The growth of body hairusually slows, but the voice and the size of the phallususually remain unchanged. Prostate size may decreasein hypogonadal men, but the amount of change isrelated to the severity of testosterone deficiency.Typical, temporal hair recession and balding usuallydo not occur and if they did, these manifestationswould not be expected to prompt a patient to seekmedical attention. Patients with hypogonadism mayhave the following findings:

• progressive decrease in muscle mass;• loss of libido;• impotence;• oligospermia or azoospermia;• occasionally, menopausal-type hot flushes (with

acute onset of hypogonadism); and• poor ability to concentrate.

The risk of osteoporosis and attendant fractures isincreased. Many cases of hypogonadism are diagnosedduring the course of infertility evaluations.

E v a l u a t i o n

A comprehensive history should be elicited and a complete physical examination should be performedto help determine the cause and extent of the hypogonadism.

Histor y

Any history of loss of libido, sexual dysfunction, a low-volume ejaculate, or impotence should generally benoted. A history of use of medications, herbalpreparations, or home remedies and any history ofpossible exposure to diethylstilbestrol in utero should beelicited. A history of anosmia or hyposmia, mid-linedefects, or cryptorchidism may be suggestive ofKallmann’s syndrome or other types of hypo-gonadotropic hypogonadism.A family history may alsoindicate an underlying genetic basis.

Primary testicular failure is usually associated withgenetic syndromes such as Klinefelter’s syndrome orcongenital disorders such as anorchism.Testicular failuremay also be associated with a history of testiculartrauma, certain surgical procedures in the area,cryptorchidism, mumps orchitis, and, occasionally, toxicexposures, radiation treatment or chemotherapy.

A postpubertal onset of hypogonadotropichypogonadism, generally manifesting as a loss of libido,sexual dysfunction, or impotence, should suggest thepossibility of hypothalamic or pituitary disease.Evidence of other endocrine deficiencies such ascentral hypothyroidism or secondary adrenalinsufficiency, visual field disturbances, headaches, orseizures may also be associated with pituitary tumors orother central disorders.

Physical Examination

The amount and distribution of body hair, includingbeard growth, axillary hair, and pubic hair, should benoted, as should the presence of a male patternescutcheon.The ethnic origin of the patient should beconsidered in this assessment.Any decrease in body hairor beard growth should also be noted.The presence anddegree of gynecomastia should be recorded. Thepresence of galactorrhea would suggest pronouncedhyperprolactinemia, usually associated with somedegree of hyperestrogenism.

AACE Hypogonad i sm Guide l ines – Update


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The testes should be measured (length and width) byusing a Prader orchidometer or calipers. Some testiculardisorders may selectively affect production of spermwithout influencing production of testosterone. Thesedisorders may sometimes be detected by a carefulphysical examination, including a determination of thetesticular size and consistency.

Because approximately 85% of testicular mass consistsof germinal tissue, a reduced germinal cell masswould be associated with a reduced testicular size anda soft consistency.

Testicular growth is a reliable index of pubertalprogression in peripubertal boys, in whom hypogonadismmay frequently be difficult to distinguish from delayedpuberty5.Although ethnic and racial origin may influencetesticular size, approximate ranges are as follows:

• prepubertal testes are 3–4mL in volume and <2cm long;

• peripubertal testes are 4–15mL in volume and >2cmlong; and

• adult testes are usually 20–30mL in volume and4.5–6.5cm long x 2.8–3.3cm wide.

Testicular consistency should be noted. If the germinalepithelium was damaged before puberty, the testes aregenerally small and firm. If postpubertal damageoccurred, the testes are usually small and soft6. Onexamination of the scrotum, the presence of anymasses or varicoceles should be noted for furtherevaluation. For assessment of any potentiallysignificant varicocele, the patient should be asked toperform a Valsalva maneuver and the scrotal contentsshould be examined.

In prepuberty, the length of the stretched penis is about4–8cm and the width is less than 2cm in a flaccid state.In the adult, the length of the penis ranges from about10–17cm and the width in the flaccid state is morethan 3cm.

With the prepubertal onset of hypogonadism, thestature may assume eunuchoid proportions with acrown-to-pubis over pubis-to-floor ratio of less than0.92 and an arm span more than 3cm greater than theheight.These proportions vary according to racial andethnic background.

A non-palpable prostate suggests low testosteronelevels. A prostate that is normal for age suggestsreasonably normal testosterone levels. Of note, anenlarged prostate may not diminish substantially ifonce-normal testosterone levels have decreased.

Laborator y Studies

Testosterone

Testosterone levels vary from hour to hour; periodicdeclines below the normal range can occur in someotherwise normal men7. An overall diurnal rhythm isalso present, the highest levels of circulating testosteroneoccurring during the early morning hours. Therefore,testosterone levels should be determined in themorning and studies should be repeated in patientswith subnormal levels, especially those with no definitesigns or symptoms of hypogonadism.

Testosterone circulates principally in bound form,mainly to sex hormone-binding globulin (SHBG) andalbumin. It binds tightly to SHBG and is notbiologically available, whereas the testosterone fractionassociated with albumin is bound weakly and candissociate to become free, active testosterone8. In youngadult men, only about 2% of testosterone is in the freeform, 30% is bound tightly to SHBG, and 68% is boundweakly to albumin9.

Although a testosterone determination is the thresholdtest in the evaluation of suspected male hypogonadism,the total testosterone concentration may be within thenormal range in men with primary testicular disorderssuch as Klinefelter’s syndrome. Low production oftestosterone and increased estradiol stimulate theproduction of SHBG by the liver.The increased level ofSHBG results in higher circulating total testosteronethan would otherwise be present with low circulatingfree testosterone.An increased SHBG level may also beassociated with hyperthyroidism, liver disease, severeandrogen deficiency or estrogen excess. SHBG levelsincrease about 1% per year as men age. Male patientswith hypogonadism often have high SHBG levelsbecause of low serum testosterone levels and enhancedproduction of estradiol because of increases inintratesticular aromatization. Therefore, if the clinicalfindings indicate that hypogonadism is present and thetotal testosterone levels are normal or borderline low,the level of SHBG or free testosterone by equilibriumdialysis should be determined. The measurement oftotal testosterone values can be enhanced in borderlinecases with the measurement of SHBG levels. Freetestosterone assays are method-dependent and may bedifficult to interpret. Because albumin bindstestosterone weakly, the amount of free testosteronemeasured will vary with the technique. Determinationof the serum testosterone concentration by equilibriumdialysis is usually more reliable.

Equilibrium dialysis-free testosterone measurements aregenerally available and used to determine the amountof testosterone not bound to SHBG or albumin. Free3


Reference Section

testosterone measured by an analog displacement assayis probably not reliable and should not be used. Animportant research goal is to establish a consistentmethod for determining free testosterone levels and toverify the results so that these levels can be more widelyused and trusted. This issue arises frequently in theassessment of older men with impotence, in whom freetestosterone – or total testosterone interpreted withSHBG levels – may be useful for determining thethreshold of therapy10–12.

Conversely, a low testosterone level may also bemisleading under some circumstances. Slightlysubnormal levels of total testosterone may occur in menwith low levels of SHBG and normal circulating levelsof free testosterone.

A low SHBG level may be associated withhypothyroidism, obesity, or acromegaly. Determinationof the level of SHBG or free testosterone byequilibrium dialysis may be helpful for clarifying theunderlying disorder, especially when the clinicalfindings are not suggestive of hypogonadism13.

Another alternative is the use of the free testosteroneindex. The free testosterone index is the testosteronelevel (in nanomoles per liter) divided by the SHBG (innanomoles per liter)14.

Gonadotropins

If a low testosterone level has been established, furtherlaboratory testing is used to determine whether thehypogonadism is related to a primary testicular disorder(hypergonadotropic hypogonadism) or to pituitarydisease (hypogonadotropic hypogonadism).The primaryfeature of hypogonadotropic hypogonadism is the failureof a reciprocal increase in gonadotropins in the setting ofa substantially decreased testosterone level. In patientswith signs and symptoms indicative of hypogonadism,determining luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels together with theinitial testosterone level is usually most efficient.

FSH and LH may have variable biologic activity,depending on their carbohydrate content. Unlikestandard radioimmunoassays, highly sensitive, two-siteradioimmunometric assays for gonadotropins yieldresults that generally correlate well with biologic assays.Because the biologic-to-radioimmunologic ratio ofactivity of gonadotropins may vary according to ageand disease states, the15 most accurate results will beobtained with these highly sensitive assays9. Currently,many assays for gonadotropins lack the sensitivity todetect values below the normal range, unlike themodern thyrotropin assays for thyroid disease.Additional studies, such as gonadotropin-releasing

hormone (GnRH) testing by an endocrinologist, mayhelp in the further assessment of these patients.

Both FSH and LH are secreted in short pulses. FSHhas a longer half-life than does LH and is more likelyto provide adequate results on a single blood sample.In addition, most patients with progressivehypogonadism will have increased FSH levels wellbefore LH levels increase.

Because LH has a shorter half-life than does FSH,errors may be introduced in measurements made onsingle samples. Pooled samples for LH taken 20 to 30minutes apart are more accurate than single-sampledeterminations, albeit less convenient. Persistentborderline values may be evaluated further withdynamic endocrine testing.These tests may include theGnRH stimulation test, the clomiphene stimulationtest, and the human chorionic gonadotropin (hCG)stimulation test. These specialized, dynamic studiesshould be conducted and interpreted by anendocrinologist and may have limited clinical value.

D y n a m i c Te s t s

GnRH St imulat ion Test

In the GnRH stimulation test16,17, intravenous injectionof 100µg of GnRH causes serum LH levels to increasebetween threefold and sixfold during a period of 30 to45 minutes and FSH levels to increase between 20%and 50%. Various degrees of primary testicular failurecause higher than expected peak values for LH andFSH. Men with hypothalamic or pituitary disease mayhave a reduced or normal response that is ofteninadequate for distinguishing between a pituitary and ahypothalamic disorder. If the pituitary gland is primedwith repeated doses of GnRH, this stimulation test mayprovide a more sensitive and reliable result.

Clomiphene St imulat ion Test

In the clomiphene stimulation test, 100mg ofclomiphene citrate are given for five to seven days as anevocative test of the hypothalamic-pituitary axis.Clomiphene acts by interrupting the negative feedbackloop and thereby stimulating release of gonadotropinfrom the pituitary.A doubling of LH and a 20% to 50%increase in FSH are normal results indicative of anintact hypothalamic-pituitary response18.

hCG St imulat ion Test

Various protocols are used for hCG stimulation testing.In general for postpubertal male patients, a single doseof hCG (5,000 international units (IU) takenintramuscularly) is administered and pre-therapy and



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72-hour, post-therapy testosterone measurements areconducted (some protocols use 1,000 to 4,000IU ofhCG, or multi-day dosing)19.

Prolact in Level

In men with acquired hypogonadotropichypogonadism, who usually have a reduced libido andimpotence, a prolactin level should be determined toevaluate for the presence of a prolactinoma or othercause of hyperprolactinemia.

High prolactin levels can reduce GnRH andtestosterone levels. In addition, a high prolactin levelcan reduce libido and potency even in men treatedwith therapeutic doses of testosterone. About 5% ofmen who complain of impotence will have anincreased prolactin level20. Further endocrinologicevaluation with magnetic resonance imaging (MRI)scanning of the pituitary gland is indicated forunexplained hyperprolactinemia.

Semen Analys is

A semen analysis17 is the primary test to assess thefertility potential of the male patient. Semen should becollected by masturbation after two to five days ofabstinence and evaluated within two hours.Variabilitybetween specimens is common; with low or borderlinesamples, follow-up examinations evaluating three ormore samples should be carried out over a three-monthperiod. A fertile sample is usually associated with amotility of more than 50% and a sperm count thatexceeds 20 million/mL21. In general, semen volumeshould range from 1.5mL to 6mL.

Morphologic features should be examined forabnormalities.A fructose test should be carried out ona semen sample showing azoospermia. Becausefructose is secreted by the seminal vesicles, absence offructose may indicate a complete obstruction of theejaculatory ducts or a congenital absence of vasadeferentia and both ejaculatory ducts. Most often, asemen analysis is conducted in an otherwiseasymptomatic man during the course of an infertilityevaluation. For such an assessment, a semen analysisshould be taken early to determine appropriate furtherevaluation and therapeutic options.

O t h e r S t u d i e s

Bone Densitometr y

Because hypogonadism frequently results in low bonedensity and increased fracture risk, baseline hip andspine bone densitometry studies should be performedto assess the initial situation and allow future

interventions to be based on any deterioration in bonedensity that may occur over time. Such baseline studiesare especially important in men treated for prostatecancer and rendered hypogonadal.

In addition to addressing the underlying condition,treatment options to maintain bone mass may includetestosterone therapy (but not in the setting of prostatecancer) or bisphosphonates. At present, alendronate hasbeen approved by the US Food and DrugAdministration (FDA) for use on osteoporosis in malepatients. In addition, therapy should include sufficientcalcium, exercise, and vitamin D. Anabolic agents suchas parathyroid hormone may become therapeuticoptions in the future for men with osteoporosis.Regardless of treatment, bone density studies should berepeated in one to two years to determine whetherbone mass is being appropriately maintained22.

Pituitar y Imaging

In cases of acquired hypogonadotropic hypogonadism(low testosterone with low-normal FSH and LH levels)not clearly attributable to a specific cause, pituitaryimaging studies with MRI or computed tomographymay be needed to evaluate for structural lesions in thehypothalamic-pituitary region. MRI generally providesbetter pituitary images, but bony changes in the sellamay be better characterized by computed tomography.In general, MRI conducted both with and without acontrast agent is recommended as the initial pituitaryimaging study in patients requiring delineation of apituitary pathologic condition. Although no publishedstudies have indicated clearly a particular level oftestosterone in the setting of hypogonadotropichypogonadism that should prompt pituitary evaluation,a total testosterone concentration of 150 nanograms perdeciliter (ng/dL) or below has been considered areasonable level at which to pursue pituitary imaging,even in the absence of other symptoms. Certainly, othersymptoms suggestive of pituitary disease necessitateappropriate further evaluation.

A considerable proportion of aged men withhypogonadism of unknown cause have a central originfor this disorder. Possible contributing factors mayinclude aging itself, medications, and chronic illness.Further research in this area is clearly warranted.

Genetic Studies

Patients with hypergonadotropic hypogonadism andimpaired pubertal development associated with small,firm testes and often with gynecomastia are likely to haveKlinefelter’s syndrome or a variant. Classically, a buccalsmear was taken to establish the diagnosis by revealingBarr bodies.We currently recommend genetic karyotype5


Reference Section

testing to confirm the diagnosis in a patient with thesefindings at initial assessment. Fluorescent in situhybridization studies increase the sensitivity of detectingKlinefelter’s syndrome associated with mosaicism.

Test icular Biopsy and Scrotal Explorat ion

Since the advent of sensitive FSH assays, germinal cellfunction is now most often assessed through the FSHassay alone rather than testicular biopsy. In general,however, men with azoospermia, normal FSH levels,and normal testicular size should usually undergotesticular biopsy and scrotal exploration to determinewhether a germinal cell abnormality, an obstruction ora congenital abnormality of the vasa is present.

Test icular Ultrasonography

Testicular ultrasound examination should be conductedin patients with clinical findings suggestive of a scrotalor testicular mass.

D i f f e r e n t i a l D i a g n o s i s a n d S p e c i a l C o n s i d e r a t i o n s

The differential diagnosis of hypogonadism includes alarge and diverse group of disorders affecting thetesticles directly, or affecting hypothalamic-pituitaryregulation of the testes. The clinical setting, history,physical examination, and clinical judgment will, to alarge degree, determine which possible etiologic factorsare present. These guidelines summarize the variousdisorders, but are not intended to be comprehensive23.

H y p e r g o n a d o t r o p i c H y p o g o n a d i s m

Patients with hypergonadotropic hypogonadism mayhave some or all of the following characteristic findings:

• hypogonadism;• increased FSH level;• increased LH level;• low testosterone level; and/or• impaired production of sperm.

K l i n e f e l t e r ’ s S y n d r o m e

Klinefelter’s syndrome is caused by the presence of anextra X chromosome in the male karyotype and occursin about one in every 400 men9. The most commonkaryotype is 47,XXY and mosaicism is sometimespresent24. Men with Klinefelter’s syndrome classicallyhave small (less than 2.5cm), firm testes, gynecomastia,eunuchoid habitus, and increased gonadotropin levels.Although production of testosterone is low, high levelsof SHBG may result in normal-range testosterone levelsin about 40% of patients with Klinefelter’s syndrome.

These patients have azoospermia, but those withmosaicism may have some spermatogenesis and mayproduce some pregnancies early during theirreproductive lives.Virilization may begin with puberty,but frequently fails to progress. Gynecomastia is oftenpresent and frequently necessitates surgical therapy forcosmetic reasons or because of concerns about breastcancer, which occurs with an increased incidence inKlinefelter’s syndrome.The high levels of LH and FSHstimulate testicular aromatase activity; as a result,estradiol levels are increased.Bone density is significantlylower than for age-matched, male control subjects.

Learning disabilities are often present, as manifested bydyslexia and attention deficit disorder. Auto-immunedisorders are present with increased frequency inpatients with Klinefelter’s syndrome and may respondfavourably to testosterone therapy25.

O t h e r G e n e t i c S y n d r o m e s

47,XYY Syndrome

The 47,XYY karyotype, which occurs in about 0.1% ofmales, may be associated with hypogonadism. In somemen with this disorder, aggressive behaviour has beennoted. Affected patients may have azoospermia inassociation with maturation arrest of the germinalepithelium. Usually, serum FSH levels are increased, butLeydig cell function is normal, as are testosterone andLH levels.

Dysgenet ic Testes

Dysgenetic testes may occur in conjunction withmosaicism; the patient may have an XO karyotype, amixed XO/XY karyotype, or pure XY with gonadalstreaks. Occurrence of pure gonadal dysgenesis inassociation with an XY karyotype and gonadal streaks26

imposes a substantial risk of gonadoblastoma, whichnecessitates gonadectomy. Such patients generally havegenital ambiguity.

Androgen Receptor Defects

Patients with androgen receptor defects have an XYgenotype and variable phenotype, depending on thedegree of receptor defect. Such syndromes includetesticular feminisation, Reifenstein’s syndrome, and otherpartial defects, as discussed in the following paragraphs.

Test icular Feminizat ion

The most severe form of androgen resistance syndromeis testicular feminization. Patients with testicularfeminization have a female phenotype but a blindvaginal pouch. Testosterone receptors are non-



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functional or absent. Laboratory testing shows normalto high male range testosterone and increasedgonadotropin levels.The testes should be removed afterpuberty because of an increased risk of a malignantlesion due to cryptorchidism. Administration oftestosterone yields no response.

Reifenstein’s Syndrome

In Reifenstein’s syndrome, patients have a malephenotype with variable pseudohermaphroditism. Apartial androgen receptor defect is present; testosteroneand gonadotropin levels are increased.Abdominal testesshould be removed because of the risk of a malignantlesion. If hypospadias is present, surgical correction ofthe genitalia may be needed. Any significantgynecomastia may also need surgical correction.Patients may respond to high doses of testosterone.

Other Syndromes

Some male patients with gynecomastia or oligospermiamay have partial androgen insensitivity, in association withmild increases in testosterone and gonadotropin levels.

5-α Reductase Def ic iency

An autosomal recessive condition, 5-α reductasedeficiency syndrome is associated with an XYgenotype. Affected patients, however, have femalegenitalia until puberty, when increasingly male featuresdevelop. The diagnosis is based on clinicalmanifestations and an increased testosterone-to-dihydrotestosterone ratio, both after puberty and inresponse to hCG before puberty. Sexual assignment isan issue and patients may need corrective surgicalprocedures that necessitate specialty consultation.

Myotonic Dystrophy

Classically, myotonic dystrophy is an autosomaldominant disorder, characterized by hypogonadism,muscle weakness, and frontal balding, that occurs onlyin male patients. Recent studies have demonstratedrepeat sequences of CTG in an untranslated region ofthe dystrophia myotonica-protein kinase (DMPK) genein many of these patients, but the disorder seems to begenetically and phenotypically heterogeneous27.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 thesetting of azoospermia and high gonadotropin levels.

Cr yptorchidism

Unilateral or bilateral cryptorchidism can occur. Theincidence of this condition is 3% to 4% at birth, but

most testes ultimately descend. Thus, the one-yearincidence is about 0.8%. Because normal testiculardescent requires normal pituitary function anddihydrotestosterone levels, the incidence ofcryptorchidism is increased in patients withKallmann’s syndrome. Problems associated with themanagement of cryptorchidism includedistinguishing between cryptorchidism and retractiletestes and recommending medical treatment withhCG or surgical therapy in an infant28. Generally, theobjective is to bring the undescended testicle into thescrotum before one to two years of age to improvefertility potential. Because a slight risk of a malignantlesion is associated with undescended testicles,surgical placement into the scrotum offers theopportunity for thorough examination. Inprepubertal boys, treatment with hCG may be usedfor four weeks to determine whether testiculardescent occurs before operative intervention isconsidered. Discussion of these problems is beyondthe scope of these guidelines; appropriate specialtyconsultation should be obtained.

Vanishing Testes Syndrome (Congenital Anorchism

or Prepuber tal Funct ional Castrate)

The initial manifestation of the vanishing testessyndrome is sexual immaturity in a male patient. Thecause is unclear, but the syndrome may be due totesticular torsion during fetal life after sufficienttestosterone exposure to produce masculinization of thereproductive tract.

Impalpable testes suggest the possibility ofcryptorchidism. FSH and LH levels are increased, andtestosterone levels are low. If the LH levels are onlyminimally increased, hCG stimulation testing of thegonad should be done.With vanishing testes syndrome,no response would be demonstrated. A response tohCG stimulation would raise the possibility of intra-abdominal testes, which would necessitate furtherevaluation because of the potential for malignanttransformation. In this setting, MRI is recommended toassess the possibility of a retained, intra-abdominal,dysgenetic gonad, because this would be associated withan increased risk of a malignant lesion and wouldnecessitate removal.

Hemochromatosis

Iron overload may lead to primary gonadal failure orsometimes hypothalamic-pituitary dysfunction thatresults in secondary gonadal failure29. The diagnosis ismade in the setting of associated findings ofhemochromatosis in conjunction with an increasedferritin level and is generally confirmed with a liver orbone marrow biopsy.7


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External Test icular Insults Trauma

The patient may have a history of direct traumaticinjury.Testicular torsion sometimes is associated with a‘bell-clapper’ abnormality, in which the testes liehorizontally because of incomplete closure of thesurrounding tissues.

Mumps Orchit i s

In patients with post-pubertal mumps, a 25% risk oforchitis exists. More than 50% of those patients withorchitis will be infertile. Increased FSHconcentrations and oligospermia or azoospermia arepresent. Mumps orchitis can progress to produce lowtestosterone and high LH levels in some men.Unilateral, testicular atrophy can progress to bilateralfailure over the years.

Radiat ion Treatment or Chemotherapy

With irradiation or chemotherapy, testicular exposurecan occur from treatment of another disease orinadvertently.A dose-dependent recovery potential anda variable Leydig cell dysfunction have been noted. Pre-treatment sperm banking is possible if future ‘fertility’ isdesired and sperm counts are normal.

Auto- immune Syndromes

Anti-Leydig cell, antibody-associated disorders, orconditions associated with anti-sperm antibodies areautoimmune syndromes related to hypogonadism.These syndromes are poorly characterized and furtherresearch is needed to determine diagnostic criteria andpossible treatment options.

Ser tol i -cel l -only Syndrome

The absence of germ cells in patients with small testes,high FSH levels, azoospermia, and normal testosteronelevels should suggest the presence of Sertoli-cell-onlysyndrome. The diagnosis can be made only bytesticular biopsy.

The presence of Leydig cell hyperplasia is commonand may be responsible for high serum estradiol levels.The cause of this syndrome is currently unknown.

Hypogonadotropic Hypogonadism

The condition of hypogonadotropic hypogonadism isgenerally associated with the following findings:

• low or low-normal FSH level;• low or low-normal LH level; and• low testosterone level.

Kal lmann’s Syndrome

Classic Kallmann’s syndrome is a congenital disorderinherited as a sporadic condition or generally as an X-linked, recessive trait manifesting as prepubertalhypogonadism.The incidence of this syndrome is about1 in 10,000 male births. Low testosterone levels arepresent because of an impaired release of LH and FSHas a result of variable GnRH deficiency. LH and FSHare released in response to priming followed bystimulation with GnRH.

The gene on the X chromosome for classic Kallmann’ssyndrome and associated anosmia has been identifiedand cloned30. Autosomal recessive and autosomaldominant variants of hypogonadotropic hypogonadismalso exist and are referred to as idiopathichypogonadotropic hypogonadism.

Classically, Kallmann’s syndrome is associated withanosmia as a result of defective development of theolfactory tract in the brain. The GnRH-containingneurons originate in the developing olfactory tractand therefore do not develop properly in thissyndrome9. This defective development of theolfactory tract can be diagnosed by MRI scanning. Insome cases, other defects such as cerebellardysfunction, red-green color blindness, cleft palate,and congenital deafness are present31. Cryptorchidismmay occur because gonadotropins contribute tonormal testicular descent.

The prepubertal testes in patients with Kallmann’ssyndrome tend to be larger than in patients withKlinefelter’s syndrome and are appropriate up untilpuberty, in as much as normal initial amounts ofgerminal tissue are present. Partial pubertaldevelopment may be present in patients with partialdefects; thus, Kallmann’s syndrome may be difficult todistinguish from delayed puberty up through theteenage years. Once a patient with Kallmann’ssyndrome has been identified, other family members atrisk (on the basis of their mode of inheritance) shouldbe assessed, if possible.

Other Related Syndromes

Congenital, hypogonadotropic syndromes areassociated with secondary hypogonadism and othersomatic findings. Prader-Willi syndrome ischaracterized by hypogonadism, short stature, mentalretardation, hypotonia at birth, and obesity. Laurence-Moon-Bardet-Biedl syndrome is an autosomalrecessive trait characterized by mental retardation,retinitis pigmentosa, polydactyly, and hypogonadism.These syndromes may be due to a hypothalamicdeficiency of GnRH.



8

Fer t i le Eunuch Syndrome

Hypogonadotropic hypogonadism in patients who havemodest FSH secretion and selective LH deficiency isknown as the fertile eunuch syndrome. Fertility may bepresent in some of these patients. These men usuallyrespond to hCG therapy.

Pituitar y Disorder s

Acquired hypogonadotropic hypogonadism mayindicate the presence of pituitary insufficiency or apituitary tumor. Unless the reason for the pituitarydefect is clear, imaging studies of the pituitary gland andthe hypothalamus are indicated to determine whether atumor or an infiltrative disorder is present. Metastatictumors, granulomas, abscesses, and hemochromatosismay also be discovered.

Hyperprolactinaemia is a potential cause of hypo-gonadotropic hypogonadism and generally manifests itselfwith a low libido and impotence.

A serum prolactin level should be determined in men with acquired hypogonadotropichypogonadism. High prolactin levels are usuallyassociated with a prolactinoma, but certain medicationsmay also cause hyperprolactinemia.

Hypogonadotropic hypogonadism from pituitarydisease may also occur with granulomatous andinfiltrative disorders, cranial trauma with or withoutpituitary stalk transection, irradiation, and hypophysitis.

Hemochromatosis

See earlier discussion of hemochromatosis inHypergonadotropic Hypogonadism section.

Ser ious I l lness , AIDS and Stress

Transient hypogonadotropic hypogonadism may occurin patients with serious disorders or malnutrition32.AIDS may be associated with low testosterone levelsand generally low gonadotropin levels (consistent withhypothalamic-pituitary involvement).

In some patients with AIDS, gonadotropin levels areincreased (consistent with testicular disease)33.

A g i n g

Considerable controversy exists over the concept of amale climacteric or ‘andropause’34. Growing evidenceindicates that some aging men have a reducedproduction of testosterone associated with decreasedlibido, impotence, decreased growth of body hair,

decreased muscle mass, fatigue, increased risk ofmyocardial infarction35, and decreased bone mass inconjunction with osteoporosis.

Some early studies indicated that the problem may berelated to coexisting conditions, but more recentevidence supports the view that an age-related declinein testicular function may occur with associatedsymptoms and often responds to testosteronereplacement therapy36,37.

Measurements of SHBG in conjunction with totaltestosterone are usually needed to demonstrate theabnormality.Age-related declines in free testosterone, asmeasured by equilibrium dialysis, are more rapid thanthe decreases in total testosterone. The SHBG levelsincrease with advancing age, probably in relation tohigher serum estradiol levels from increased adiposetissue. Often, the FSH and LH levels are mildlyincreased, an indication that a primary testiculardisorder may be present in conjunction with asecondary abnormality in LH burst frequency38.

Dynamic testing may disclose more subtleabnormalities of hypothalamic function. The circadianvariation in serum testosterone levels, with highervalues in the morning, is generally lost with aging.

Data from long-term research studies is needed toclarify the criteria for therapeutic considerations inaging men. Short-term research studies havedemonstrated that testosterone replacement treatmentmay result in improved lean body mass, increasedhematopoiesis, decreased low-density lipoprotein(LDL) levels in conjunction with a constant ratio ofLDL to high-density lipoprotein (HDL), improvedlibido, and improved well-being in older men with lowtestosterone levels. Generally, prostate size and prostate-specific antigen (PSA) levels do not change incomparison with otherwise normal men, but PSA levelshave been found to increase in some men39.

Men with symptomatic hypogonadism and a totaltestosterone level of less than 200ng/dL may bepotential candidates for therapy, although no specificrecommendations have been established at this time.Some studies have used 2.5 standard deviations belowthe mean testosterone values for young normal malesubjects as the cut-off point for the initiation of therapy,resulting in intervention at values of about 319ng/dL40.With the use of this guideline, approximately 30% ofmen beyond 75 years of age would have testosteronevalues below this hypogonadism threshold. In general, ifthe potential benefit exceeds the potential risk, then thepatient may be a candidate for therapy. The lack ofknowledge about the exact nature of the benefit andrisk remains the main problem.9


Reference Section

T h e r a py

G o a l s o f T h e r a py

To Restore Sexual Funct ion, Libido,

Wel lbeing and Behavior

Many studies have been undertaken to evaluate theeffects of testosterone therapy on sexual function andwellbeing in men with hypogonadism41. Impairedsexual behavior and mood disturbances seem to occurbelow a certain threshold of circulating testosteronelevels and most studies have demonstrated improvedfunction with testosterone replacement.

In studies of testosterone treatment of men withhypogonadism, investigators have found that therapyresulted in increased sexual interest and an increasednumber of spontaneous erections.

On psychological testing, the men with untreatedhypogonadism tended to score high on depression,anger, fatigue, and confusion scales. Hormonalreplacement diminished most of these traits, butalthough the depression score improved, it remainedmore of a problem in men with hypogonadism than inmale control subjects42.

Further long-term studies are clearly needed in thisarea to establish definite criteria for therapy andresponse in borderline cases. Notably, erectiledysfunction associated with hypogonadism may notimprove after adequate androgen replacement if othersecondary causes for erectile dysfunction are present.For additional information, see the AmericanAssociation of Clinical Endocrinologists Clinical PracticeGuidelines for the Evaluation and Treatment of MaleSexual Dysfunction43.

With the onset of hypogonadism before puberty, aninitial low dose of testosterone should be used to avoidacute priapism, adverse psychological effects, andaggressive behavior.

To P r o d u c e a n d M a i n t a i n V i r i l i s a t i o n

Secondary sex characteristics such as increased musclemass, beard growth, growth of pubic and axillary hair,and phallus growth improve with testosterone therapy.

To O p t i m i z e B o n e D e n s i t y a n d P r e v e n t O s t e o p o r o s i s

In a study of elderly male nursing home residents, theincidence of hip fracture was between 5% and 15%44. Ofthose residents who had sustained a prior hip fracture,66% were found to have hypogonadism (serum

testosterone levels less than 300ng/dL). Hypogonadismwas present in up to 20% of men with vertebral crushfractures, even though many of these men did not haveother clinical features of hypogonadism.

In adolescent male patients with hypogonadotropichypogonadism, testosterone therapy increases bonemineral density in comparison with that in malepatients with hypogonadism not receivingtestosterone45,46. In men with prepubertal-onsethypogonadotropic hypogonadism, however,diminished bone mass may be only marginallyimproved by testosterone replacement47.

P o s s i b l y t o N o r m a l i z e G r ow t h H o r m o n eL e v e l s i n E l d e r l y M e n

In comparison with normal men, those withhypogonadism have significantly reduced meangrowth hormone pulse amplitude but normal pulsefrequency. Patients with adult-onset growth hormonedeficiency also have increased cardiovascular-relatedmortality48. Testosterone treatment results in asignificant increase in 24-hour mean serum growthhormone value and mean growth hormone pulseamplitude. Perhaps testosterone has an important rolein the control of growth hormone secretion inadulthood and testosterone therapy may have apositive clinical influence49. No specificrecommendations on this issue are possible untilfurther research clarifies the potential risks andbenefits of therapy.

P o t e n t i a l l y t o A f f e c t t h e R i s k o fC a r d i ov a s c u l a r D i s e a s e

Orally administered, alkylated androgens are non-aromatizable and result in increased LDL anddecreased HDL levels, which may increasecardiovascular risk25,50,51. Unlike orally administered,alkylated androgen preparations, testosterone isaromatised to estrogen.

In men with hypogonadism treated with replacementdoses of testosterone, total cholesterol and LDL levelsmay modestly decrease in conjunction with minimalchange in HDL; thus, investigators have speculatedthat the risk of cardiovascular disease may be higherin men with hypogonadism not receivingtestosterone replacement52.

Testosterone replacement therapy in men is notassociated with major adverse lipid changes53; in fact,endogenous testosterone and administration ofexogenous testosterone may lower the atherogenicLp(a) lipoprotein levels54. Other studies suggest thattestosterone replacement in men with hypogonadism



10

may be associated with adverse lipid effects and yetother studies have reported indeterminate findings34.

Other cardiovascular effects, apart from changes inlipids, may be attributable to testosterone replacementtherapy. A potential risk of testosterone therapy is thepropensity of testosterone to increase plateletaggregation and thrombogenicity55.

Currently, whether testosterone replacement therapy inmen with hypogonadism increases, decreases, or has aneutral effect on cardiovascular risk remains uncertain.Long-term prospective research must be conducted toassess the role of endogenous testosterone andtestosterone replacement therapy on cardiovascular riskin men.

No specific recommendations on this issue are possibleuntil further research clarifies the potential risks andbenefits of therapy.

To R e s t o r e F e r t i l i t y i n C a s e s o fH y p o g o n a d o t r o p i c H y p o g o n a d i s m

See subsequent sections relating to therapy forhypogonadotropic hypogonadism.

Con t r a i n d i c a t i o n s t o Te s t o s t e ro n e ,G nRH a n d G on ado t ro p i n T h e r a py

Testosterone replacement, pulsatile GnRH therapy,and gonadotropin therapy are contraindicated in men with prostate cancer, male breast cancer oruntreated prolactinoma. Treatment with thesemedications can stimulate tumor growth in androgen-dependent neoplasms. Careful examination of themale breast and prostate is required initially and atfollow-up visits.

In addition to prostate examination, baseline and follow-up PSA levels should be determined in older men atincreased risk for prostate cancer.Men with symptomaticprostatism should undergo evaluation and treatment forthis problem before testosterone replacement therapy isconsidered. Sleep apnea and polycythemia, which maycause hyperviscosity, are relative contraindications to theuse of testosterone therapy.

Testosterone treatment will tend to reduce spermcounts and testicular size and should not be used inmen currently seeking fertility.

Te s t o s t e ro n e T h e r a py i n A d u l t M a l ePa t i e n t s w i t h H y p og o n ad i sm

Ideally, testosterone therapy should provide physiologicrange serum testosterone levels (generally between 280

and 800ng/dL) and physiologic rangedihydrotestosterone and estradiol levels, which wouldallow optimal virilization and normal sexual function.

Testosterone therapy can be used in the male patientwith hypogonadism who is not interested in fertility ornot able to achieve fertility. In late teenage male patientswith delayed puberty, testicular size should bemonitored for evidence of the onset of puberty. In thissetting, short-term, low-dose testosterone therapyshould be withdrawn to determine whetherspontaneous puberty is occurring.

The following preparations of testosterone have beenapproved by the FDA for clinical use:

• long-acting, intramuscular preparations;• short-acting, intramuscular preparations;• scrotal patches;• transdermal patches;• transdermal gel; and• orally administered agents.

Orally administered testosterone is quicklymetabolized by the liver and cannot achieve sufficientblood levels over time to be useful. The orallyadministered, alkylated androgen preparationscurrently available in the US are generally notrecommended because of poor androgen effects,adverse lipid changes and hepatic side effects such as hemorrhagic liver cysts, cholestasis, andhepatocellular adenoma25.

In Europe, testosterone undecanoate may be a moreacceptable oral alternative, but erratic testosteronelevels, frequent dosing, and occasional gastrointestinalside effects may limit the usefulness of thispreparation in the US. Reformulation of thispreparation with testing in the US and elsewhere iscurrently under way.

Injectable testosterone pellets are sometimes used andfurther study may prove them to be suitable for manymen. For patients with hypogonadotropichypogonadism wishing fertility, hCG with or withouthuman menopausal gonadotropin (FSH) or pulsatileGnRH therapy and hCG with or without assistedreproduction are options.

Pa re n t e r a l Te s t o s t e ro n e P r e p a r a t i o n s

Testosterone enanthate and testosterone cypionate arelong-acting testosterone esters suspended in oil toprolong absorption. Peak levels occur about 72 hoursafter intramuscular injection and are followed by a slowdecline during the subsequent one to two weeks56. Forcomplete androgen replacement, the regimen should be11


Reference Section

between 50mg and 100mg of testosterone enanthate orcypionate administered intramuscularly every seven to10 days, which will achieve relatively normal levels oftestosterone throughout the time interval betweeninjections57. Longer time intervals are more convenient,but are associated with greater fluctuations intestosterone levels.

Higher doses of testosterone produce longer-termeffects but also higher peak levels and wider swingsbetween peak and nadir circulating testosterone levels;the result is fluctuating symptoms in many patients58.

The use of 100mg to 150mg of testosterone every twoweeks is a reasonable compromise. Use of 300mginjections every three weeks is associated with widerfluctuations of testosterone levels and is generallyinadequate to ensure a consistent clinical response.Withuse of these longer interval regimens, many men willhave pronounced symptoms during the week precedingthe next injection. In such instances, a smaller dose atcloser intervals should be tried.

As a guide, testosterone levels should be above the lowerlimit of normal, in the range of 250ng/dL to 300ng/dL,just before the next injection59. Excessive peak levelsand side effects should also be monitored and used toadjust the dosing regimens.

When full androgen replacement is not required,patients should receive lower doses of testosterone. Onesuch category includes adult male patients with aprepubertal onset of hypogonadism who are goingthrough puberty for the first time during therapy andwho frequently require psychological counseling,especially when a spouse is involved as well. In thesepatients, testosterone therapy should be initiated at50mg every three to four weeks and then graduallyincreased during subsequent months, as tolerated, up tofull replacement within one year.

Men with appreciable benign prostatic hypertrophywho have hypogonadism and symptoms may be given50mg to 100mg of testosterone every two weeks as aninitial regimen and maintained on this dosage withcareful monitoring of urinary symptoms and prostateexaminations; therapy can be withdrawn if necessary.

Attaining a full virilization in the patient withhypogonadism may take as long as three to four years.Follow-up intervals should be between four and sixmonths to monitor progress, review compliance, anddetermine whether any complications orpsychological adjustment problems are present.Often, patients can learn how to administer their owninjections. A spouse or significant other may also beinstructed in this technique.

Tr a n s d e rma l Te s t o s t e ro n e T h e r a py

Tr a n s d e r m a l Te s t o s t e r o n e D e l i v e r yS y s t e m – N o r m a l S k i n

A testosterone patch with permeability enhancementallows testosterone delivery through normal skin. Dailyevening application generally results in normal-rangeserum testosterone levels, which mimic the normaldiurnal changes in testosterone in normal men. Incontrast to the situation with use of the scrotal patch,dihydrotestosterone levels remain within the normalrange60. Estradiol and bioavailable testosterone levelsalso remain within the normal range. Skin irritationmay be a problem in some patients.Therapy consists ofone to two patches applied daily to normal skin. Aswith scrotal patches, this treatment is more expensivethan injections, but convenience of use, maintenance ofnormal diurnal testosterone levels, and elimination ofoffice visits for injections may make this form oftreatment useful in many patients. Testosterone levelsshould be monitored periodically to ensure theappropriate range is being maintained.

S c r o t a l Pa t c h Te s t o s t e r o n e D e l i v e r y S y s t e m

Scrotal testosterone patches are available in 40cm2 and60cm2 sizes, which deliver, respectively, 4mg and 6mgof testosterone daily. Scrotal skin absorbs testosteronebetter than does non-scrotal skin.The patch is appliedto the scrotal skin after preparation of the scrotum withdry shaving.The patch is non-adhesive and a new patchis applied each morning.The testosterone levels mimicthe diurnal rhythm present in normal men.Testosteronelevels are generally maintained in the normal range andare usually well tolerated.

These levels should be assessed in the morning beforepatch application to ensure that they are above thelower limit of the normal range at the nadir. If thescrotum is small or the skin surface is abnormal,absorption may be limited. Because genital skincontains high concentrations of 5α-reductase, thedihydrotestosterone levels in treated patients increaseinitially but may return to normal in some men. Inmost men treated with the scrotal patch, however, theselevels remain higher than normal61. The HDL-to-cholesterol ratio in treated patients does not changesignificantly from before to after therapy62.

The long-term potential effects of increased levels ofdihydrotestosterone are unknown at this time, andcareful monitoring of prostate growth is recommended.Further research may clarify any possible adverse effectsof such increased levels occurring in men who receivethis type of therapy.



12

The cost of using the scrotal patch exceeds that fortestosterone injections, but the convenience of usemay make this therapeutic option acceptable formany patients.

Tr a n s d e r m a l Te s t o s t e r o n e G e l

Transdermal testosterone in a hydroalcoholic gel foronce-daily administration to the nongenital skin isavailable in packets labeled 2.5 G (containing 25mg oftestosterone) and 5 G (containing 50mg oftestosterone).After application of the gel, blood levels oftestosterone seem to be constant over 24 hours andlevels are adequate in most patients63. Positive effects onlibido, mood by about 30 days of therapy, and musclemass and strength by 90 to 180 days of therapy havebeen noted64.The gel is well tolerated and is generallyassociated with minimal skin irritation in comparisonwith testosterone patches65. The gel dries quickly afterapplication. One potential problem is transfer of the gelfrom person to person if direct skin contact occurs.Transdermal testosterone use has been shown todecrease bone resorption markers and increase boneformation markers; in addition, small increases in bonedensity have been noted after six months of use66.

Mon i t o r i n g I s s u e s a n d S i d e E f f e c t s o fTe s t o s t e ro n e T h e r a py

Periodic follow-up of patients receiving testosteronetherapy is needed. During the first year of such therapy,the clinical response and side effects should bemonitored at three- to four-month intervals.

For patients receiving testosterone injections, a serumtestosterone level should be measured at the midpointbetween injections to ensure that the value is near themiddle of the normal range. Most patients usingtestosterone gel have constant blood levels oftestosterone over 24 hours; thus, the time ofmeasurement is usually not critical. The testosteronepatch preparations usually yield peak serumtestosterone values within four to eight hours afterapplication. Examination of the prostate should be doneroutinely, along with a prostate-related symptomassessment every six to 12 months. PSA levels should bedetermined annually in older men receivingtestosterone replacement therapy.

High PSA levels should be evaluated further with ahighly specific PSA assay, if available. If results areabnormal, a urologic consultation should be sought andtestosterone replacement therapy should be terminated.Men receiving testosterone replacement therapy andfinasteride should be considered for further evaluationeven with PSA values in the upper normal range.Testosterone treatment should not be administered to

men with high PSA values or significantly increasingPSA levels. Testosterone – and especially dihydro-testosterone – stimulates growth of the prostate andseminal vesicles. In a study that assessed the effect ofexogenous testosterone administration by patch or byinjection on the serum levels of PSA and prostate-specific membrane antigen in men with hypogonadism,the results demonstrated no correlation with therapyand thus no testosterone dependence of PSA orprostate-specific membrane antigen67. Testosteronetreatment of men with hypogonadism also resulted ingrowth of the prostate and seminal vesicles, but thisgrowth did not exceed the volumes expected in normalmen68. No clear relationship has been establishedbetween testosterone replacement therapy and prostatecancer, although anecdotal reports have beenpublished69. Men in whom symptomatic prostatismdevelops should undergo assessment before testosteronereplacement therapy is continued. Long-term studiesare needed to clarify this issue.

Gynecomastia may result from the aromatization oftestosterone to estradiol and changes in SHBG levels.

Surgical therapy may be considered for some patients.Men with a genetic susceptibility to alopecia may notea worsening of this problem with testosterone therapy.

Testosterone stimulates the bone marrow production oferythrocytes. The result is an increased hematocrit insome men, with the possibility of hyperviscosity sideeffects70. The hematocrit should be determined everysix months for the first 18 months and then yearlythereafter if it is stable and normal.Testosterone therapyshould be decreased or discontinued if the hematocritincreases to above 50%.

Lipid disturbances in testosterone-treated male patientsare generally not a problem because of thearomatisation of testosterone to estradiol. The ratio ofHDL to total cholesterol generally remains constant.Anabolic steroids, used in oral testosterone preparations,that are not aromatized increase LDL and lower HDLlevels and thus could increase cardiovascular risk. Aninitial lipid profile should be recorded and a follow-upprofile should be obtained after six to 12 months oftherapy and then yearly thereafter.

Sleep apnoea may also be a problem in some men andtestosterone therapy should be discontinued until thesleep apnoea problem can be adequately addressed71.The patient should be asked about fatigue during theday in addition to disordered sleep.A sleep study shouldbe undertaken if symptoms are present.

Because pharmacological use of testosterone willsuppress spermatogenesis, the use of testosterone13


Reference Section

preparations may substantially reduce fertility inotherwise normal men. This adverse effect is often anissue with the illicit use of testosterone.

Gon ad a l S t imu l a t i o n i nH ypog on ado t ro p i c H y p og o n ad i sm

Because gonadotropin or GnRH therapy is effectiveonly in hypogonadotropic hypogonadism, thisdiagnosis must be firmly established beforeconsideration of therapy.

Although these agents may also be used to inducepuberty in boys and to treat androgen deficiency inhypogonadotropic hypogonadism, the major use ofthese preparations is in the initiation and maintenanceof spermatogenesis in hypogonadotropic men whodesire fertility.

Gon ado t ro p i n T h e r a py i n A n d rog e n D e f i c i e n c y

It is known that hCG binds to Leydig cell LH receptorsand stimulates the production of testosterone.

Peripubertal boys with hypogonadotropichypogonadism and delayed puberty can be treated withhCG instead of testosterone to induce pubertaldevelopment. The initial regimen of hCG is usually1,000IU to 2,000IU administered intramuscularly twoto three times a week72. The clinical response ismonitored, and testosterone levels are measured aboutevery two to three months. Dosage adjustments of hCGmay be needed to determine an optimal schedule.

Increasing doses of hCG may reduce testicularstimulation by down-regulating the end-organ; thus, amore optimal result may occur with less frequent orreduced dosing.The half-life of hCG is long.

The advantages of hCG over testosterone in this settinginclude the stimulation of testicular growth, which maybe an important issue for some men. Use of hCG mayalso yield greater stability of testosterone levels andfewer fluctuations in hypogonadal symptoms73. Inaddition, hCG treatment is necessary for stimulatingenough intratesticular testosterone to allow theinitiation of spermatogenesis.

The disadvantages of hCG include the need for morefrequent injections and the greater cost.

Gon ado t ro p i n T h e r a py f o r I n d u c t i o n o f S p e rma t og e n e s i s

Male patients with an onset of hypogonadotropichypogonadism before completion of pubertal

development may have testes generally smaller than5mL.These patients usually require therapy with bothhCG and human menopausal gonadotropin (or FSH)to induce spermatogenesis.

Men with partial gonadotropin deficiency or who havepreviously (peripubertally) been stimulated with hCGmay initiate and maintain production of sperm withhCG therapy only. Men with postpubertal, acquiredhypogonadotropic hypogonadism who have previouslyhad normal production of sperm can also generallyinitiate and maintain spermatogenesis with hCGtreatment only74.

Fertility may be possible at sperm counts much lowerthan what would otherwise be considered fertile.Counts of less than one million/mL may be associatedwith pregnancies under these circumstances. It isimperative that the female partner undergo assessmentfor optimal fertility before or concurrently withconsideration of therapy in the man.

Therapy with hCG is generally begun at 1,000IU to2,000IU applied intramuscularly two to three times aweek and testosterone levels should be monitoredmonthly to determine whether any therapeuticadjustments are needed to normalize the levels. It maytake two to three months to achieve normal levels oftestosterone. When normal levels of testosterone areproduced, examinations should be conducted monthlyto determine whether any testicular growth hasoccurred. Sperm counts should also be assessedmonthly during a one-year period. Because of the highcost of human menopausal gonadotropin (or FSH)preparations, hCG should be the initial therapy ofchoice for at least six to 12 months. Use of hCG, in theabsence of exogenous FSH, can often completespermiogenesis in men with partial gonadotropindeficiency75. In general, the response to hCG can bepredicted on the basis of the initial testicular volume –the greater the initial testicular volume, the greater thechance of responding to hCG only76. In one study,however, investigators demonstrated that most patientswill respond to hCG alone regardless of initialtesticular volume77. Studies have shown that combiningpurified FSH and testosterone without LH or hCGdoes not stimulate spermatogenesis in trulyhypogonadotropic men78.

If spermatogenesis has not been initiated by the end of sixto 12 months of therapy with hCG or LH, administrationof an FSH-containing preparation is initiated in a dosageof 75IU, applied intramuscularly three times a week alongwith the hCG injections. After six months, if sperm arenot present or are present in very low numbers (less than100,000/mL), the human menopausal gonadotropin (orFSH) dosage can be increased to 150IU intramuscularly,



14

three times a week for another six months. If pregnancyoccurs, the patient’s regimen can be switched to onlyhCG to allow continued spermatogenesis for subsequentpotential pregnancies.

After delivery, if no further pregnancies are desired, thepatient can be switched to testosterone therapy if desired,or long-term hCG therapy can be continued inconjunction with appropriate contraceptive measures, ifneeded. Rarely, antibodies against hCG may arise andprevent any response to therapy; in such a case,human LHmay be effective79.Recombinant LH has recently becomeavailable and may be of use in selected patients.

GnRH T h e r a py

In patients with an otherwise intact pituitary gland andhypogonadotropic hypogonadism, synthetic GnRH canbe given in a pulsatile fashion, subcutaneously througha pump every two hours.

GnRH therapy is monitored by measuring LH FSH,and testosterone levels every two weeks until levels arein the normal range, at which point monitoring can beadjusted to every two months. GnRH can be used toinitiate pubertal development, maintain virilization andsexual function and initiate and maintainspermatogenesis.

In most patients, these effects may take from three to 15months to achieve sperm production80. As withgonadotropin therapy, fertility can be achieved withvery low sperm counts – often in the range of one million/mL.

GnRH may be more effective than gonadotropinstimulation in increasing testicular size and initiatingspermatogenesis in many patients with hypo-gonadotropic hypogonadism81.

O t h e r Tr e a tmen t C o n s i d e r a t i o n s

A n t i e s t r o g e n T h e r a py i n O l i g o s p e r m i a

Long-term use of low-dose clomiphene citrate at25mg daily to increase pituitary stimulation oftesticular function has often been attempted in menwith oligospermia82. Tamoxifen has been used incountries other than the US. The results areunpredictable and no long-term, prospective studieshave demonstrated efficacy. Studies have generallyshown no significant changes in semen variables orpregnancy rates83.

Currently, we do not recommend the general use ofclomiphene citrate or tamoxifen for the treatment ofoligospermia in male patients.

A s s i s t e d R e p r o d u c t i v e Te c h n o l o g y

The ability to perform in vitro fertilization withintracytoplasmic sperm injection directly into the egghas revolutionised the approach to male subfertility. Asingle sperm or immature form retrieved from thetesticle is sufficient to fertilise an egg and provide areasonable chance at pregnancy.

In vitro fertilization with intracytoplasmic sperminjection may be a viable option in many men withhypogonadism who cannot otherwise be induced toproduce enough sperm to result in pregnancy as wellas in the presence of a female factor that may furthermake pregnancy by the couple difficult or impossible.The procedure is expensive and seldom covered byhealth insurance; therefore, this technology willgenerally not replace conventional gonadal stimulationprotocols. Intrauterine insemination may also be a low-cost option in suitable women when the man has mildto moderate oligospermia.

P i t u i t a r y Tu m o r s

Patients with acquired, hypogonadotropichypogonadism may require assessment for a possiblepituitary tumor with appropriate pituitary imagingstudies such as MRI and determination of a prolactinlevel. Depending on the presence or absence of atumor, other hormonal testing may be indicated,including thyroid and adrenal function tests.

Further evaluation and treatment options woulddepend on what hormonal deficits are present, the sizeand site of the tumor, the operability of the tumor, andthe patient’s preferences in specific circumstances.

If a prolactinoma is present, therapy is directed towardcorrecting this problem before the initiation of othertherapy. Medical therapy with bromocriptine,pergolide or cabergoline may effectively reduceprolactin levels sufficiently to allow gonadal functionto resume or allow stimulation with gonadotropins.Even when prolactin levels cannot be normalized,hCG therapy alone or in conjunction with humanmenopausal gonadotropin (or FSH) therapy maystimulate spermatogenesis in treated prolactinomasand result in pregnancies84.

Surgical therapy should especially be considered forsignificant pituitary tumors that are not prolactin-secreting microadenomas. Surgical treatment may alsobe an option in prolactin-secreting microadenomas ifpatients have severe side effects from medications, orprefer this approach after being appropriatelyinformed of the risks and benefits of medical versussurgical management.15


Reference Section

G y n e c o m a s t i a

Many men have psychological problems resultingfrom gynecomastia. This problem should be takenseriously and discussed with the patient.

Use of aromatase inhibitors such as testolactone hasbeen tried, but has yielded limited benefit. A breastreduction surgical procedure is often required forpsychological wellbeing.

P s y c h o l o g i c a l C o u n s e l i n g

Men with hypogonadotropic disorders frequently haveassociated mood disturbances, including depression,aggression, poor self-esteem, and learning problems.

In such cases, psychological counseling is often neededto allow proper identification and treatment of theseproblems. Counseling should also include significantothers, if possible.

S umma r y

The major objectives of the initial assessment of apatient with possible hypogonadism are to distinguishprimary gonadal failure (hypergonadotropichypogonadism with low testosterone and increasedFSH and LH levels) from hypothalamic-pituitarydisorders (hypogonadotropic hypogonadism with lowtestosterone and low to normal FSH and LH levels) andto make a specific diagnosis. The initial clinicalmanifestations may vary, depending on whether theonset of the disorder was prepubertal or postpubertal.

Men with hypogonadotropic disorders may achievefertility with gonadal stimulation. Men withhypergonadotropic disorders are treated withtestosterone to achieve virilization and are usually, butnot invariably, incapable of achieving fertility.

H i s t o r y a n d P h y s i c a l E x a m i n a t i o n

• A history of major medical problems, medications,toxic exposures, fertility problems, anddevelopmental milestones should especially benoted. Low libido, impotence, fatigue, impairedconcentration, and sexual dysfunction are importantpresenting problems and need to be asked aboutspecifically because most men will not seek medicalattention for these symptoms alone.

• The degree of pubertal development, eunuchoidproportions, anosmia, hyposmia, gynecomastia,abnormal hair growth and distribution, abnormalgenitalia, presence of varicocele, findings on prostateexamination, and testicular size and consistency, in

particular, are important physical manifestations fordifferential diagnosis.

L a b o r a t o r y a n d A n c i l l a r y E v a l u a t i o n

• Laboratory testing is directed toward determiningwhether the patient has abnormalities ofreproductive hormones and whether theabnormalities are indicative of testicular orhypothalamic-pituitary disease.The initial laboratorytesting should include a morning blood sample fortestosterone, prolactin, FSH and LH levels. A semenanalysis is needed if fertility potential is an issue.

• If testosterone levels are low to normal and thesymptoms and signs indicate hypogonadism, thetestosterone study should be repeated and SHBG ora free testosterone level by equilibrium dialysisshould be determined to help diagnose ahypogonadal state because total testosterone levelsmay be normal in the setting of hypogonadism if theSHBG levels are increased.

• To diagnose hypergonadotropic hypogonadism, FSHis especially important because FSH has a longer half-life, is more sensitive, and demonstrates less variabilitythan LH. Pooled LH samples (three preferred) mayhelp reduce problems with LH variability associatedwith a short half-life and pulsatile secretion.

• Dynamic testing of the hypothalamic-pituitary-testicular axis should be done by an endocrinologistand reserved for patients in whom the results ofbaseline diagnostic testing are equivocal, althoughinterpretation of the results of dynamic testing maybe poorly defined.

• In acquired hypogonadotropic hypogonadism, aprolactin level and pituitary imaging study should beundertaken to assess the patient for a possiblehypothalamic-pituitary disorder, such as a pituitarytumor. Testing of the thyroid, adrenal, and growthhormone axes is also indicated.

• Chromosomal analysis should be considered in menwith prepubertal-onset hypergonadotropic hypo-gonadism to evaluate for Klinefelter’s syndrome andrelated disorders.

• Bone densitometry should be taken in men withchronic, untreated hypogonadal disorders, to aid indecision making about treatment options to preventand treat osteoporosis.

• Testicular ultrasonography should be done inpatients with clinical findings suggestive of a scrotalor testicular mass.



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• In the evaluation of abnormal semen findings,testicular biopsy should be reserved for patients withnormal results of hormonal studies and azoospermiato evaluate for obstruction or congenital absence ofthe vasa and possible surgical repair or use of in vitrofertilization with intracytoplasmic sperm injection.

D i a g n o s i s a n d Tr e a t m e n t

An overall summary of clinical and laboratory findings,potential diagnoses, and recommended evaluation ortreatment strategies in adult male patients withhypogonadism is presented in Table 1.

Con c l u s i o n

The recognition, evaluation, and treatment ofhypogonadism in the male patient are often dismissedby the patient and overlooked by the physician. The

symptoms and signs of hypogonadism should beidentified through appropriate questioning of thepatient and a directed physical examination. Hormonaland ancillary testing should be performed in a cost-efficient and clinically appropriate manner to allowpertinent treatment considerations.

Testosterone replacement therapy can often enable thepatient to function in a more normal manner anddecrease the risk of future problems with fertility, mooddisturbances, fatigue, impaired virilization, andosteoporosis. Further studies are needed to determinethe influence of testosterone replacement therapy oncardiovascular risk. Importantly, these guidelinesdemonstrate the need for meaningful, long-term studiesof hypogonadal disorders in general and of aging menin particular. The ultimate goals are to improve bothduration and quality of life and to allow people to reachtheir full potential, regardless of age. ■


Reference Section

Testicular size† FSH LH Testosterone‡ Semen analysis Diagnosis Evaluation or treatmentNot palpable – – – Azoospermia Anorchism Surgical explorationNot palpable – – N‡ or Azoospermia Bilateral cryptorchidism Surgical exploration<5 mL – – – Azoospermia, Kallmann’s T for virilization;

oligospermia syndrome, hCG ±_hMG hypogonadotropic (or FSH) or GnRH hypogonadism for spermatogenesis

<5mL – – N‡ or Azoospermia Klinefelter’s Karyotype tosyndrome, other confirm;T forhypergonadotropic syndromes virilization

8–15mL – N N Azoospermia Germinal damage: Fertility: IVF witholigospermia toxins, idiopathic ICSI (?)

10–20mL – – – Oligospermia Adult-acquired, Pituitary MRI;hypogonadotropic treat pituitaryhypogonadism disorder with prolactin

if present; otherwisetreat as Kallmann’s syndrome

10–20mL N or N or N‡ or Variable Senescence – T if symptomatic(variable) (variable) l with low T‡

15–20mL N or N N Oligospermia Varicocele, drugs, Fertility: varicocele – idiopathic repair if significant

varicocele present.Optimize femalefactor; IVF with ICSI

Variable Phenotype – – – Variable T-receptor defects, Variable(variable) (variable) Reifenstein’s Syndrome (depending on degree):

medical or surgical therapy20–30mL N N N Azoospermia Obstruction Fertility: surgical repair;

IUI, IVF with ICSI

Table 1: Summary of Findings, Potential Diagnoses, and Recommended Strategies in Adult Male Patients With Hypogonadism

FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin; hMG = human menopausal gonadotropin; ICSI = intracytoplasmic sperm injection; IUI = intrauterine

insemination; IVF = in vitro fertilization; LH = luteinizing hormone; MRI = magnetic resonance imaging; N = normal; SHBG = sex-hormone-binding globulin;T = testosterone.

† Normal testicular size is 20–30mL.Testicular size is used here as a clinical finding to help narrow the differential diagnosis. Some variation beyond the listed ranges may exist for a specific condition. Use of this variable is

optional; the diagnosis should be based on the total clinical picture.

‡ Because of changes in SHBG levels, total testosterone may be in the normal range in the setting of low testosterone production. Level of SHBG or free testosterone should be used in this setting to determine whether

treatment options should be considered.

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