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Male hypogonadism, acquired or congenital, can be caused by defects that interfere with the hypothalamic-pituitary-testicular axis. It is essential to distinguish between primary hypogonadism and secondary hypogonadism. Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, and reduced testicular volume. Clinicians participating in this activity can expect to gain a comprehensive understanding of male hypogonadism. This activity covers the etiology, emphasizing the impact of hypothalamic-pituitary-testicular axis defects and accentuating the crucial differentiation between primary and secondary hypogonadism. Participants learn to recognize key symptoms and appreciate evaluation and management strategies, including patient selection for screening. Additionally, clinicians will gain insights into testosterone level interpretation, diagnostic criteria, and the nuanced approach required for patients with persistent symptoms despite normal testosterone levels. This activity also highlights the interprofessional team's role in enhancing care for patients with male hypogonadism. Objectives: Identify the signs and symptoms of male hypogonadism. Implement current guidelines in the evaluation of male hypogonadism. Apply best practices for the treatment of male hypogonadism. Select interprofessional team strategies for improving care coordination for patients with male hypogonadism. Access free multiple choice questions on this topic.

Ninety-five percent of the total testosterone in males is synthesized in the Leydig cells of the testes. Defects that interfere with interactions in the hypothalamic-pituitary-testicular axis can cause male hypogonadism as well as primary testicular disorders. Such defects may be acquired or congenital. It is helpful to distinguish between primary hypogonadism (which originates in the testes) and secondary (which originates in the hypothalamus or pituitary gland). Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, reduced nocturnal penile tumescence, infrequent morning erections, low libido, unexplained fatigue, and smaller testicular volume. The normal range for early morning testosterone in a male is generally between 300 ng/dL to 1000 ng/dL, although this varies by laboratory.[1] Hypogonadism is usually diagnosed when the morning serum testosterone level is <300 ng/dL on at least 2 occasions.[2] Morning levels are used because testosterone levels are typically the highest. However, clinical judgment can be exercised in diagnosing hypogonadism for patients with persistent symptoms of testosterone deficiency despite having testosterone levels in the normal range.[3] Total testosterone <405.9 ng/dL is below the fifth percentile.[4] Elderly males should optimally reach testosterone levels between 500 and 800 ng/dL, while young adults should expect levels between 600 and 900 ng/dL. Low testosterone levels alone do not require treatment unless they are associated with symptoms of hypogonadism.

Primary hypogonadism (testicular failure) is diagnosed by persistently low testosterone measurements with above-normal LH levels. Some causes of primary hypogonadism include Klinefelter syndrome, undescended testicles, mumps orchitis, hemochromatosis, cancer treatment, and normal aging. Secondary hypogonadism (pituitary failure) is characterized by low serum testosterone with normal or low LH levels. Causes of secondary hypogonadism include Kallman syndrome, pituitary disorders, HIV, obesity, surgery, trauma, and stress-induced hypogonadism.[5] Both primary and secondary hypogonadism can cause significant abnormalities in sperm count and semen analyses. Mild changes in the semen analysis, together with severely abnormal sperm motility, are more closely associated with primary hypogonadism. Hypogonadism can be due to congenital or acquired causes. Ambiguous genitalia, micropenis, and bilateral cryptorchidism are all signs of testosterone deficiency in pre-pubertal males. Karyotype testing should be performed in young adults to rule out conditions such as Turner and Klinefelter syndromes, which can result in testosterone deficiency.

Hypogonadism is often underreported, improperly diagnosed, and overtreated.[2] According to studies, approximately 40% of men older than 45 and 50% of men in their 80s are hypogonadal.[6][7][8] Testosterone levels have been found to decrease by 100 ng/dL every 10 years.[9] Hypogonadism does not appear to be affected by racial grouping or ethnic origin. A recent study in nonobese diabetic males found that 29% were testosterone deficient. The visceral adiposity index was the only reliable indicator of testosterone deficiency in this group of patients.[10] (The visceral adiposity index is a calculated value based on waist circumference, body mass index [BMI], serum triglycerides, and high-density lipoprotein [HDL level].)[11]

Testosterone has 3 main hormonal effects.[12] Direct activity on specific androgen receptors Indirect activity through intracellular conversion to dihydrotestosterone by 5-alpha reductase, as in prostate cells Estrogen effect when converted to estradiol by aromatase Testosterone production by testicular Leydig cells depends on stimulation from the anterior pituitary gland, which secretes pulses of luteinizing hormone (LH) into the circulation. When LH binds to its receptors on Leydig cells, it causes cAMP levels to rise, which drives the expression of 2 proteins: StAR (the steroidogenic acute regulatory protein) and CYP11A1 (the cholesterol sidechain cleavage enzyme). StAR promotes the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, while CYP11A1 promotes the conversion of cholesterol to pregnenolone, the precursor of all steroid hormones. Pregnenolone can undergo 17α-hydroxylation to 17-hydroxypregnenolone, followed by dehydroepiandrosterone (DHEA), which is then converted into androstenediol in order to make testosterone.[13] Primary hypogonadism occurs when testicular steroidogenesis is insufficient to synthesize adequate testosterone levels, a testicular disorder. Secondary hypogonadism transpires when chemical signaling to the testes (either from the pituitary, through LH, or from the hypothalamus, through GnRH) cannot stimulate sufficient Leydig cell testosterone production. Low testosterone is a known risk factor for cardiovascular disease.[2][14]

Symptoms highly suggestive of androgen deficiency in men include reduced sexual desire, decreased spontaneous erections, fatigue, lethargy, loss of axillary and pubic hair, visual field changes (such as bitemporal hemianopsia), loss of smell (anosmia), declining or small testicular volume, hot flashes, and infertility with low or absent sperm counts. Other less suggestive symptoms include depressed mood, irritability, poor concentration, increased body fat, decreased physical performance, lower muscle mass, reduced endurance, weight loss, reduced energy, and loss of appetite.[2] Patients with a history of these conditions should be considered for hypogonadism testing even if they do not exhibit any specific symptoms of a low testosterone level.[2] A physical examination should identify the presence of bilateral testes and measure their size. A maximum measured testis size of <4 cm or volume <20 cc is considered small. Bilateral atrophic or missing testes would be highly suggestive of hypogonadism. Note should be made of the presence or absence of pubic, axillary, and facial hair. An examination of the breasts for gynecomastia or tenderness should also be performed.[2] Decreased muscle mass and body hair changes typically take years to manifest. Infertility, gynecomastia, and decreased testicular size are more typical of primary rather than secondary hypogonadism.

It has been estimated that up to 25% of men on testosterone therapy have not had their testosterone levels checked before starting treatment, and about half have not had their levels checked even after treatment has started.[2][15][16] Further, up to 33% of men on testosterone replacement therapy for hypogonadism do not meet the diagnostic criteria for the disorder.[2][15][16] Population screening is not recommended, but patients with HIV, end-stage renal disease, type 2 diabetes, infertility, severe COPD, unexplained anemia, and/or osteoporosis/osteopenia should consider screening.[17] Other risk factors include post-chemotherapy with testicular atrophy, post-testicular radiation therapy, chronic opioid use/abuse, infertility, pituitary dysfunction, and chronic steroid use. The Androgen Deficiency in Aging Males (ADAM) test can be a useful initial step in diagnosing male hypogonadism. It consists of a 10-item questionnaire intended to identify men exhibiting signs of testosterone deficiency.[18] However, some guidelines, such as the American Urological Association (AUA) Guideline on Testosterone Deficiency, do not currently recommend using validated questionnaires.[2] This is because questionnaires should not be substituted for a full patient evaluation with appropriate laboratory testing. Even validated questionnaires have highly variable reported sensitivities and specificities and are not a reliable alternative to formal laboratory testing.[2][19] Initial laboratory testing should include 2 early morning (8 AM to 10 AM) serum testosterone measurements.[20] Two total testosterone levels <300 ng/dL are generally considered sufficient to diagnose biochemical but not clinical male hypogonadism, although this may vary somewhat depending on the laboratory. The clinical diagnosis of male hypogonadism requires an associated symptom or sign of the disorder. Only patients with symptoms associated with clinical hypogonadism should be treated for low testosterone.[2] Since 2 total serum testosterone levels are required for a diagnosis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels can easily be added to the blood draw for the second testosterone level.

Initial laboratory testing should include 2 early morning (8 AM to 10 AM) serum testosterone measurements.[20] Two total testosterone levels <300 ng/dL are generally considered sufficient to diagnose biochemical but not clinical male hypogonadism, although this may vary somewhat depending on the laboratory. The clinical diagnosis of male hypogonadism requires an associated symptom or sign of the disorder. Only patients with symptoms associated with clinical hypogonadism should be treated for low testosterone.[2] Since 2 total serum testosterone levels are required for a diagnosis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels can easily be added to the blood draw for the second testosterone level. If both testosterone levels are reduced, further testing, including TSH (thyroid-stimulating hormone), free T4 (thyroxine), vitamin D, complete blood count (CBC), comprehensive metabolic panel, iron, transferrin, estradiol, and cortisol, are suggested. A prostate-specific antigen (PSA) level should be drawn in all patients with hypogonadism older than 40 years before initiating therapy.[2] Estradiol should be checked in male hypogonadal patients with breast symptoms (gynecomastia, pain, tenderness, nipple sensitivity, or discharge).[2] If estradiol is elevated, an endocrinology referral is suggested. Testosterone therapy is not recommended if the hematocrit (Hct) is greater than the upper normal limit. Testosterone supplementation should be reduced or discontinued. Injectable testosterone has been associated with the highest risk of polycythemia from hypogonadal therapy.[2][21] Elevated prolactin levels (usually considered to be 2 to 3 times the normal upper limit), and patients with severe hypogonadism (testosterone <150 ng/dL) together with a low or normal LH may have a prolactinoma and an MRI of the pituitary should be performed.[2][22] Male hypogonadal patients interested in fertility should have a full reproductive evaluation (semen analyses, FSH, LH) performed.[2] Hypogonadal patients with hypogonadotropic hypogonadism interested in fertility should be offered genetic testing. Measurement of free testosterone levels is generally unnecessary unless a problem with sex hormone-binding protein is suspected. This may occur as patients age but is most closely associated with obesity and can be corrected by weight loss.

Hypogonadal patients with hypogonadotropic hypogonadism interested in fertility should be offered genetic testing. Measurement of free testosterone levels is generally unnecessary unless a problem with sex hormone-binding protein is suspected. This may occur as patients age but is most closely associated with obesity and can be corrected by weight loss. It may also be affected by type 2 diabetes, hypothyroidism, and liver disease. Morbid obesity (BMI >40) has been linked to hypothalamic hypogonadism.[23] An equilibrium dialysis assay most accurately performs laboratory analysis of free serum testosterone, as other methods are generally considered unreliable.[24]

Asymptomatic hypogonadal patients do not require treatment. Only patients with symptoms possibly associated with low testosterone levels should be considered candidates for therapy. Patients with symptoms of hypogonadism but normal testosterone levels will not see any symptomatic relief from testosterone supplementation. Rather, lifestyle modifications such as weight loss and increased exercise are generally recommended.[25] Oral testosterone supplements, such as methyltestosterone, are not recommended due to their associated liver toxicity, including jaundice, cholestasis, and abnormal hepatic function tests.[2] Testosterone therapy in proven hypogonadal men has been shown in clinical trials to produce statistically significant improvements in libido, anemia, bone mineral density, lean body mass, depression, and erectile function.[2][26][27][28][29][30] Improvements in energy, fatigue, hyperlipidemia, diabetes control, cognitive function, energy level, and quality of life scores are possible, but studies proving this have been inconclusive.[2][31][32][33][34] The use of testosterone supplementation in the treatment of depression in hypogonadal men has generally yielded positive results although some studies have shown no difference in outcomes when compared to placebo.[35] Excessive use of testosterone is consistently associated with multiple adverse events and complications.[35] More research on this potential beneficial use of testosterone supplementation in treating depression is needed. An increased risk of significant cardiovascular events and venous thromboembolism has been suggested by anecdotal reports in patients on testosterone supplementation, but this has not been proven in clinical studies as the available data is conflicting or inconclusive.[2][36] However, the AUA Guideline on Testosterone Deficiency recommends that exogenous testosterone therapy not be initiated even with close monitoring and optimal dosing until at least 3 to 6 months after any major cardiovascular event.[2]

An increased risk of significant cardiovascular events and venous thromboembolism has been suggested by anecdotal reports in patients on testosterone supplementation, but this has not been proven in clinical studies as the available data is conflicting or inconclusive.[2][36] However, the AUA Guideline on Testosterone Deficiency recommends that exogenous testosterone therapy not be initiated even with close monitoring and optimal dosing until at least 3 to 6 months after any major cardiovascular event.[2] Patients actively trying to conceive should not be started on testosterone therapy.[2] Those interested in preserving future fertility should be carefully counseled that testosterone supplementation therapy significantly reduces sperm count and would need to be stopped before any reasonable expectation of a return of fertility. While spermatogenesis eventually returns after discontinuing testosterone supplementation, two-thirds of men will recover after 6 months, and 10% will not recover until after 1 year.[2][37] Clomiphene citrate is an effective therapy for both biochemical and clinical male hypogonadism through a unique mechanism of action.[38][39][40] Clomiphene is an anti-estrogen and can trick the body into thinking testosterone levels are lower than they are by preventing estradiol from lowering gonadotropin-releasing hormone (GnRH) production in the hypothalamus.[38] This causes the pituitary gland to release more FSH and LH.[38] The increased FSH helps maintain fertility and sperm counts, and the LH helps increase testosterone levels.[38][39][41] It also explains why clomiphene will not be effective in raising testosterone levels in patients with primary hypogonadism who already have high LH titers.[38][42] Clomiphene should be considered first-line therapy in hypogonadal men who wish to maintain their sperm counts and fertility.[38][43] The recommended dosage of clomiphene in male hypogonadism is 25 to 50 mg daily, and testosterone levels can be checked after 30 days of treatment.[42][44]

The increased FSH helps maintain fertility and sperm counts, and the LH helps increase testosterone levels.[38][39][41] It also explains why clomiphene will not be effective in raising testosterone levels in patients with primary hypogonadism who already have high LH titers.[38][42] Clomiphene should be considered first-line therapy in hypogonadal men who wish to maintain their sperm counts and fertility.[38][43] The recommended dosage of clomiphene in male hypogonadism is 25 to 50 mg daily, and testosterone levels can be checked after 30 days of treatment.[42][44] Human chorionic gonadotropin (hCG) works similarly to clomiphene in that it will stimulate testosterone production by the Leydig cells of the testes without affecting sperm counts or spermatogenesis.[45] HCG is similar to LH but has a much longer half-life (36 hours compared to 30 minutes), which is why it is often the preferred agent used in symptomatic testosterone-deficient men with hypogonadotropic hypogonadism.[45] Clomiphene or hCG therapy may be used together with testosterone supplementation to help maintain testicular size and fertility. Neither clomiphene nor hCG will be effective if FSH and LH are already elevated (primary hypogonadism).[38][42] Tamoxifen appears to act similarly, but there is minimal data on its use in hypogonadism.[42] Clomiphene is considered safe, has few adverse effects, and does not lower sperm counts the way testosterone supplements do.[38] The recommended clomiphene dosage for male hypogonadism is 25 mg to 50 mg daily; it requires about 1 month to be effective.[42] The dosage of hCG would be 3000 IU subcutaneously or intramuscularly every other day. Of these, only hCG is FDA-approved for use in men.[46] A short trial of clomiphene therapy can "reboot" or "restart" native testosterone production in about 25% of hypogonadal patients.[47] Preservation of fertility in hypogonadal men may also be achieved by using aromatase inhibitors, but there is less data available on this application.[48] Testosterone Replacement Therapy There are several options for testosterone replacement, including oral, intranasal, transdermal (gel, solution, subcutaneous pellets), and intramuscular injections.[49] Among these, transdermal gels and intramuscular injections are the most widely used in the US. Buccal testosterone tablets are no longer available in the US.

There are several options for testosterone replacement, including oral, intranasal, transdermal (gel, solution, subcutaneous pellets), and intramuscular injections.[49] Among these, transdermal gels and intramuscular injections are the most widely used in the US. Buccal testosterone tablets are no longer available in the US. Patches have an unacceptably high rate of undesirable skin reactions in up to a third of patients. Oral testosterone supplements, such as methyltestosterone, are not recommended due to their associated liver toxicity, including jaundice, cholestasis, and abnormal hepatic function tests (except for oral testosterone decanoate; see below).[2] An intranasal testosterone gel is available. A pump metered-dose applicator provides 5.5 mg of testosterone with each activation. The recommended dose is one in each nostril, 3 times a day. This method avoids possible androgen transfer from contact with others, but patients perceive the frequent dosing schedule as very inconvenient. There is also data indicating very high testosterone levels in the brain. The significance of this is uncertain. Surgically implantable long-duration testosterone pellets have the advantage of long therapeutic duration.[50] Up to 6 75 mg seeds or pellets are implanted every 3 to 6 months. They are placed into the subcutaneous fat of the lower abdominal wall, thighs, or buttocks using a trocar under a local anesthetic. There is currently limited data on long-term testosterone level maintenance using these pellets, and the need for repeated procedures also makes this treatment method less desirable. Testosterone gel applied to the skin daily is generally the preferred delivery modality due to overall patient preference, convenience, avoidance of injections, maintenance of stable androgen levels, and insurance coverage. Gels' primary advantage is maintaining stable serum testosterone concentrations, resulting in stable libido, energy, and mood. There are various commercial prescription testosterone gel products in varying concentrations available. Gels should only be applied to the shoulders, upper arms, or abdomen but not to the scrotum, which has enhanced absorption. After applying testosterone gels and creams, care should be taken to avoid skin contact with others, especially children and women, to minimize inadvertent transfer.[2]

Testosterone gel applied to the skin daily is generally the preferred delivery modality due to overall patient preference, convenience, avoidance of injections, maintenance of stable androgen levels, and insurance coverage. Gels' primary advantage is maintaining stable serum testosterone concentrations, resulting in stable libido, energy, and mood. There are various commercial prescription testosterone gel products in varying concentrations available. Gels should only be applied to the shoulders, upper arms, or abdomen but not to the scrotum, which has enhanced absorption. After applying testosterone gels and creams, care should be taken to avoid skin contact with others, especially children and women, to minimize inadvertent transfer.[2] Testosterone levels are more variable with gels than with injections. Therefore, 2 testosterone levels are suggested for monitoring testosterone levels for men on gel supplementation.[51] Miller and colleagues showed that the bioavailability of testosterone gel is 30% lower when applied to the abdomen compared to the arms or shoulders.[17][52] Testosterone injection therapy generally consists of intramuscular injections of testosterone cypionate or enanthate, starting initially as a 100 mg weekly dose and then adjusted according to follow-up laboratory testing and clinical response. This avoids excessive, potentially dangerous supernormal peak levels.[53] There is some controversy regarding when to check testosterone levels when using injections. Many experts check a mid-week sample, which would provide a median level. Other experts check 2 days after the injection to get a peak level. The rationale is that only an excessively high supernormal level is dangerous regarding stimulating prostate growth, aggravating anger issues, increasing Hct, promoting prostate cancer, etc. There is no need for a trough level as long as the patient's symptoms are relieved on supplemental therapy. Endocrinologists usually use the mid-week median levels, while many urologists typically favor monitoring the peak levels for treatment and dosage guidance. This is because, unlike endocrinologists, urologists deal with benign prostatic hyperplasia (BPH), PSA, and prostate cancer issues that overly aggressive testosterone therapy can produce.

Endocrinologists usually use the mid-week median levels, while many urologists typically favor monitoring the peak levels for treatment and dosage guidance. This is because, unlike endocrinologists, urologists deal with benign prostatic hyperplasia (BPH), PSA, and prostate cancer issues that overly aggressive testosterone therapy can produce. There is very little difference between testosterone cypionate and enanthate, the 2 most common formulations of injectable testosterone. Both are absorbed slowly, with similar absorption characteristics. The main difference is in the oil used as a carrier. Enanthate uses sesame oil, which is very viscous. This means it takes longer to mix and inject. It may also cause lumps. Cypionate uses olive oil, which is much less viscous and avoids these issues.[12] They can generally be used interchangeably.[12] Liquid testosterone formulations for injection are no longer available due to their high risk of potential abuse. Commercially produced testosterone products are recommended over compounded preparations.[2] While less expensive, compounded formulations do not have direct FDA oversight, and there is often considerable variability in concentration, potency, and quality between samples from the same pharmacy.[2] The goal of therapy is to avoid exceeding the normal maximum testosterone blood level (which peaks 2 days after a testosterone injection) while maintaining normal serum androgen levels and adequately treating the instigating symptom, which may take up to 6 months. For most patients, this requires 100 mg of testosterone cypionate or enanthate once a week or the equivalent daily testosterone gel. If possible, the lowest dose of testosterone supplementation that produces acceptable clinical results should be used. In 2014, the FDA approved an extra-long-acting intramuscular injectable form of testosterone called testosterone undecanoate. It is administered at an initial dose of 750 mg, followed by a second dose 4 weeks later. Subsequent doses are given at 10-week intervals. Testosterone undecanoate is not used as a first-line agent but rather in patients without access to other treatment forms. BPH is a testosterone-mediated event. Several trials and a meta-analysis have failed to show any significant harmful effects on BPH from testosterone supplementation in hypogonadal men.[26][54]

In 2014, the FDA approved an extra-long-acting intramuscular injectable form of testosterone called testosterone undecanoate. It is administered at an initial dose of 750 mg, followed by a second dose 4 weeks later. Subsequent doses are given at 10-week intervals. Testosterone undecanoate is not used as a first-line agent but rather in patients without access to other treatment forms. BPH is a testosterone-mediated event. Several trials and a meta-analysis have failed to show any significant harmful effects on BPH from testosterone supplementation in hypogonadal men.[26][54] A new oral testosterone undecanoate was recently FDA-approved. It delivers good serum testosterone levels without requiring injections, surgically implantable pellets, frequent nasal sprays, uncomfortable patches, or transferable gels. It is absorbed by the intestinal lymphatics, which bypasses the liver and, therefore, avoids the hepatic toxicity associated with other oral forms of testosterone supplementation.[55] It is a twice-daily medication that should be taken with food. Even in long-term studies, there appear to be no significant adverse effects or hepatic toxicity, and patient satisfaction with this new oral capsule is greater than for alternative supplementation therapies, except for its high cost.[55][56][57][58] The recommended initial starting dose is 237 mg or 225 mg BID with food and then titrated to obtain optimal, sustained testosterone levels. The available therapeutic choices depend on the patient's LH levels.[59] If LH levels are normal or low, clomiphene, hCG, and aromatase inhibitors may be tried, as well as testosterone supplementation. Only testosterone supplementation can restore normal androgen levels if LH levels are elevated. Contraindications to androgen replacement therapy include a history of breast cancer, prostate cancer (with exceptions, see below), uncontrolled heart failure, untreated obstructive sleep apnea, a pretreatment Hct over 50%, palpable undiagnosed prostate nodules, and an elevated PSA >4 ng/mL, especially in high-risk patients including African Americans and men that have a first-degree relative with prostate cancer.[17][60][61] Testosterone Supplementation and Prostate Cancer Although worrisome, there is no conclusive evidence that testosterone supplementation promotes the development of prostate cancer.[2][26][33][62][63]

Contraindications to androgen replacement therapy include a history of breast cancer, prostate cancer (with exceptions, see below), uncontrolled heart failure, untreated obstructive sleep apnea, a pretreatment Hct over 50%, palpable undiagnosed prostate nodules, and an elevated PSA >4 ng/mL, especially in high-risk patients including African Americans and men that have a first-degree relative with prostate cancer.[17][60][61] Testosterone Supplementation and Prostate Cancer Although worrisome, there is no conclusive evidence that testosterone supplementation promotes the development of prostate cancer.[2][26][33][62][63] Supplementation in patients with known prostate cancer is controversial. Such treatment in patients with low-grade disease on active surveillance or with premalignant lesions (high-grade prostatic intraepithelial neoplasia [PIN] and atypical small acinar proliferation (ASAP) should only be considered after careful counseling and shared decision-making with the patient regarding potential benefits along with our limited knowledge of the possible future risks.[2] Preliminary data suggests a minimal effect on PSA levels or prostate cancer detection rate in patients with high-grade PIN receiving testosterone therapy for hypogonadism.[64] There is limited data on the use of testosterone replacement therapy in men who are post-radical prostatectomy. However, there appears to be no significant increase in PSA levels or prostate cancer risk in carefully selected men with favorable pathology (negative seminal vesicles, margins, and lymph nodes) who also have undetectable PSA levels for at least 2 years postoperatively, although the data is very limited.[2][65][66] For patients who received definitive radiation therapy for prostate cancer, the available studies have suggested minimal effects of testosterone supplementation compared to controls in carefully selected patients whose PSA levels continue to lower or drop to <0.1 ng/mL.[2][67] Exogenous testosterone treatment in hypogonadal patients with higher-risk prostatic malignancy, locally advanced disease, or existing metastases carries correspondingly greater risks and should reasonably be considered only in research settings.[2] Monitoring:

For patients who received definitive radiation therapy for prostate cancer, the available studies have suggested minimal effects of testosterone supplementation compared to controls in carefully selected patients whose PSA levels continue to lower or drop to <0.1 ng/mL.[2][67] Exogenous testosterone treatment in hypogonadal patients with higher-risk prostatic malignancy, locally advanced disease, or existing metastases carries correspondingly greater risks and should reasonably be considered only in research settings.[2] Monitoring: Pretreatment: Hemoglobin (Hgb), Hct, digital rectal exam (DRE), PSA level, 2 early morning testosterone levels, prolactin, FSH, and LH. Consider a baseline dual-energy x-ray absorptiometry (DEXA) scan.[2] 1 month after initiating treatment: morning testosterone level. If the dosage requires adjustment, repeat the testosterone level 1 month after the change. Continue dosage adjustments until the level is optimal. The optimal testosterone level with treatment should be between 450 and 600 ng/dL. 3 to 6 months after the dosage optimization during the first year: morning testosterone level, liver function tests (LFTs), lipid profile, PSA, DRE, Hgb, and Hct. Testosterone levels should be measured every 6 to 12 months while on therapy. Patients who have achieved normal testosterone levels for 6 months but fail to improve their signs or symptoms may be considered clinical failures, and their testosterone therapy can be discontinued. Annually after the first year: testosterone level, LFTs, lipid profile, DRE, PSA, estradiol, Hgb, and Hct. Testosterone is converted to estrogen through aromatization, causing hyperestrogenism.[59][68] If this occurs, aromatase inhibitors may be necessary. This is why it is recommended that estradiol levels be checked periodically.

The differential diagnosis of male hypogonadism includes the following: 5-alpha-reductase deficiency Androgen insensitivity syndrome Anorexia nervosa Congenital adrenal hyperplasia Depression History of androgen abuse Hyperparathyroidism Hyperprolactinemia Infertility unrelated to hypogonadism Kallman syndrome (must be ruled out in males complaining of anosmia or hyposmia) Klinefelter syndrome Malnutrition Malignancy Micropenis Osteoporosis Pituitary gland masses (must be ruled out in patients complaining of visual disturbances) Testicular atrophy Turner syndrome

The prognosis is excellent for symptomatic men diagnosed with male hypogonadism who are treated according to guidelines and followed appropriately. While the condition is not usually curable, it is amenable to treatment with clomiphene or testosterone replacement therapy. Optimal results are obtained when proper follow-up is implemented and treatment is modified appropriately to utilize the minimal acceptable dose to relieve symptoms and avoid side effects.

The complications of male hypogonadism and its treatment include the following: Acne and similar skin problems Exacerbation of heart failure Gynecomastia and other breast disorders Infertility (low sperm count) Polycythemia Possible increased risk of blood clots (controversial as data is conflicting) Possible increased risk of cardiovascular events (controversial as data is conflicting) Prostate cancer growth acceleration Prostate growth stimulation (benign) Skin reaction to patches or gels Sleep apnea Steroid rage and emotional disorders Testicular atrophy There are conflicting trials on the cardiovascular risks of testosterone, most notably the TOM (Testosterone in Older Men) trial and the TEAAM (Testosterone's Effects on Atherosclerosis Progression in Aging Men) trial.[69][70] The TOM trial found that applying testosterone gel daily after 6 months was associated with increased cardiovascular events.[69] The TOM trial involved a sample of 209 men without monitoring serum testosterone levels. Recently, the TEAAM trial published in 2015 followed 308 men over 3 years and found that testosterone administration resulted in no difference in cardiovascular risk.[70] A randomized, double-blind, placebo-controlled, parallel study found that after 12 weeks of treatment, testosterone undecanoate reduced fasting glucose and waist circumference while improving carotid intima-media thickness and high sensitivity C-reactive protein.[71]

Deterrence and education on male hypogonadism are crucial components of public health initiatives aimed at preventing and mitigating the impact of this condition. Deterrence involves raising awareness about risk factors, emphasizing the importance of a healthy lifestyle, and promoting regular health check-ups to identify potential issues early on. Education plays a pivotal role in ensuring both healthcare professionals and the general public have accurate and up-to-date information about the causes, symptoms, and available treatments for male hypogonadism. Fostering an understanding of the condition among healthcare providers facilitates early diagnosis and appropriate management, contributing to improved patient outcomes and overall public health. By disseminating knowledge about the condition, its risk factors, and the benefits of timely intervention, educational efforts empower individuals to make informed decisions about their health. Patients must understand the diagnostic criteria required to warrant testosterone therapy. This includes at least 2 separate low testosterone levels and a specific hormone-related symptom that could be reasonably expected to improve with testosterone supplementation. Candidates should be carefully counseled that excessive use of androgens has many potentially harmful effects and can permanently affect fertility. Patients who wish to actively pursue fertility should consider alternative treatments to testosterone supplementation, such as clomiphene or hCG therapy. Inappropriate use of testosterone supplementation is strongly discouraged, and regular monitoring of testosterone levels, PSA, Hgb, and Hct is required. Failure to relieve or significantly improve symptoms after 6 months of therapy may result in discontinuation of the testosterone treatment.

Key facts to keep in mind regarding male hypogonadism are as follows: Consider a trial of clomiphene citrate or hCG therapy, especially in men who wish to maintain their fertility (sperm count). Available therapy choices depend on LH levels. If LH is high, only testosterone supplementation will effectively correct the patient's hypogonadism. Testosterone supplementation will decrease sperm count and fertility unless FSH levels are maintained with clomiphene citrate or hCG therapy. Do not start testosterone supplementation in men actively trying to achieve a pregnancy. Men wishing to preserve their fertility may consider adding clomiphene to their testosterone supplementation. The goal of treatment is to avoid peak testosterone levels above the normal range and to relieve symptoms associated with hypogonadism. Patients with normal testosterone levels will not have symptom relief from exogenous supplementation. Patients who fail to improve their symptoms after 6 months of testosterone supplementation should consider discontinuing therapy. Gels avoid the peaks and troughs associated with injections but require daily application and risk transference to others. Injections will produce some degree of daily serum hormonal variability. Most patients prefer a daily gel to weekly injections, although the shots are often less expensive. Most patients prefer the new oral testosterone decanoate to all other forms of androgen supplementation, although it is quite expensive compared to other supplemental testosterone therapies. Peak levels occur 2 days after a testosterone injection. Testosterone supplementation may be used cautiously in carefully selected patients with prostate cancer if, after shared decision-making discussions, the benefits are deemed sufficient despite the risks and unknowns. If injection therapy is selected, weekly injections are preferred, at least initially, as it is challenging to maintain adequate testosterone levels and control symptoms without exceeding normal range maximums in most patients. To adjust the peak level, change the dose rather than the interval. The duration between shots optimally depends on when symptoms from low testosterone begin.

Physicians, advanced care practitioners, nurses, pharmacists, and other health professionals can enhance patient-centered care, outcomes, patient safety, and team performance through a multifaceted strategy. Each professional should possess the necessary skills for assessing, diagnosing, and managing male hypogonadism. This includes competence in interpreting testosterone levels, recognizing symptoms, and understanding the complexities of the hypothalamic-pituitary-testicular axis. All interprofessional team members must understand the risks, benefits, and contraindications of testosterone therapy. A comprehensive strategy that ensures a cohesive and streamlined approach to patient care should be developed. This involves creating standardized protocols for evaluation, diagnosis, and treatment, promoting evidence-based practices, and fostering continuous education to stay updated on advancements in the field. A collaborative and patient-centered care model for male hypogonadism requires healthcare professionals to delineate clear responsibilities, communicate effectively, and coordinate care seamlessly. Physicians lead in diagnosis and treatment planning, while nurses, pharmacists, and other professionals contribute to patient education, medication management, and ongoing monitoring. Effective communication channels between team members facilitate information exchange and coordination of care. Regular interdisciplinary meetings can enhance understanding of patient cases, ensuring a holistic approach and avoiding gaps in care. This integrated interprofessional approach ensures optimal patient outcomes, safety, and team performance.