William T. Sheahan, MD

Total hip arthroplasty (THA) is considered to be one of the most successful orthopedic interventions of its generation.¹ In 2010, 332,000 THAs were performed in the U.S.² Although used to correct advanced joint diseases in the elderly, the THA procedure has become increasingly common in a younger population for posttraumatic fractures and conditions that lead to early onset secondary arthritis such as avascular necrosis, juvenile rheumatoid arthritis, hip dysplasia, Perthes disease, and femoro-acetabular impingement.

Current hip replacements are expected to function at least 10 to 20 years in 90% of patients.³ As increasing numbers of young patients have these procedures and as seniors continue to live longer, patients will outlast their implants. Younger and more active patients have a higher rate of revision, because the longevity of the prosthesis is usually a function of usage.³ The number of revision THAs is projected to increase 137% by 2030.⁴

Hip resurfacing has been developed as a bone preserving surgical alternative to THA. The first system for use in the U.S. received FDA approval in 2006, but concerns about the metal on metal bearing surfaces, high failure and revision rates, and early catastrophic modes of failure compared with THAs has resulted in the recall of many of these devices. Hip resurfacing may offer some advantages compared with those of a THA in a carefully selected population, but its use will not be further discussed in this case study.⁵ Periprosthetic osteolysis and aseptic loosening are 2 of the long-term consequences of THA.⁶ Bone loss is felt to be secondary to a biologic reaction to particulate debris from implants.⁶ Some patients, especially those with loosening, complete wear, or fracture, will be symptomatic with pain. However, wear and osteolysis is a silent disease unless there is mechanical failure. Other patients may not experience discomfort. Radiographic studies may reveal significant changes, which warrant the recommendation for a hip revision.

Hip revision surgery has 3 major purposes: relieving pain in the affected joint, restoring the patient’s mobility, and removing a loose or damaged prosthesis before irreversible harm is done to the joint. It’s anticipated that most primary care providers (PCPs) will encounter patients who seek advice on the need for a revision hip arthroplasty.

This case will present an asymptomatic patient who underwent a THA in 1997 at age 37, to address developmental dysplasia of the hip (DDH) and was advised to undergo a revision hip arthroplasty due to abnormal radiographic findings at age 55 years. A discussion will follow that includes a brief review of the history of THA, the materials and bearings commonly used, the presenting symptoms or radiographic changes that signal the need for a revision, and the current options available for a patient such as this.

Case Report

A man aged 55 years presented to a new orthopedic surgeon for his first orthopedic appointment in 10 years. The patient had a left metal-on-polyethylene (M-on-PE) THA 18 years prior due to early onset secondary degenerative joint disease from DDH. The patient’s M-on-PE THA was a titanium acetabular socket and femoral stem with a cobalt-chromium alloy femoral head and a polyethylene liner. The patient remained physically active with an exercise routine consisting of walking, swimming, and weight training.

The patient’s orthopedic history was notable for a right knee arthroscopy for intervention due to a torn medial and lateral meniscus, and birth history was noteworthy for a breech presentation. The physical exam was unremarkable except for a slight leg length discrepancy, but the patient did not exhibit a Trendelenburg gait.

Plain X-rays and a computed tomography (CT) scan showed eccentric PE wear and superior migration of the femoral head, which was indicative of significant PE liner wear. No significant osteolysis or periprosthetic loosening was observed on the X-rays or CT scan. He was advised that a hip revision procedure would need to be done, optimally, within the next 6 months to a year.

Discussion

Hip dysplasia represents a broad group of disorders and generally means abnormal development of the hip joint. The term is most commonly used to refer to DDH with inadequate coverage of the femoral head. In one study, 25% of hip replacements performed in patients aged ≤ 40 years were due to underlying hip dysplasia.⁷

Developmental dysplasia of the hip occurs more often in children who present in the breech position.⁸ One theory argues that packaging issues in utero may account for the increased incidence of DDH.⁹ The earliest recorded attempts at hip replacement occurred in Germany, in 1891, when ivory was used to replace the femoral heads of patients whose hip joints had been destroyed by tuberculosis.¹

The orthopedic surgeon Sir John Charnley, who worked at the Manchester Royal Infirmary, is considered the father of the modern THA.¹ His low friction arthroplasty, designed in the early 1960s is identical, in principle, to the M-on-PE prosthesis used today.¹ The PE liner used was ultrahigh molecular weight polyethylene (UHMWPE).¹

Due to the early success of the Charnley prosthesis, the M-on-PE prosthesis became the most widely used. Although PE is the most studied and understood of all acetabular liner materials, it will eventually wear and shed debris. Acetabular cup wear is the most frequent reason for mid-to-long-term revisions, especially in young and active patients.¹⁰ More active patients shed more debris.³ The PE debris instigates the release of inflammatory mediators, which results in chronic inflammation and tissue damage that erodes the supporting bone and can lead to implant loosening or fracture.⁶ Ongoing studies seek to optimize and improve properties of the UHMWPE and to develop alternative bearings. After FDA approval in 1999, highly cross-linked polyethylene liners (HXLPE) rapidly became the standard of care for THAs, at least in the U.S.¹¹ Highly cross-linked polyethylene liners are created from UHMWPE through a process of cross-linking by exposure to gamma radiation, and subsequent heat treatment to neutralize free radicals and limit oxidative degradation.¹²

In one study, the 5-year annual linear wear rate for a HXLPE liner was only 45% of that seen with the UHMWPE liner, although the qualitative wear pattern was the same.¹³ In a study that followed patients for 7 years postoperatively, the mean steady-state wear rate of the HXLPE was 0.005 mm/y compared with 0.037 mm/y for UHMWPE.¹⁴ In a long-term study (a minimum follow-up of 10 years) of 50 patients who were aged < 50 years and underwent THA using HXLPE liners, there was no radiographic evidence of osteolysis or component loosening, and liner wear was 0.020 ± 0.0047 mm/y.¹² In 2005, second-generation HXLPE liners were introduced clinically and have been shown to further reduce wear in vitro compared with both UHMWPE and first-generation HXLPE liners. Callary and colleagues calculated that the wear rates between 1 year and 5 years were all < 0.001 mm/y.¹⁵

The use of ceramic for THAs began in 1970, and ceramic heads on polyethylene (C-on-PE) liners and ceramic-on-ceramic (C-on-C) bearings have been in continual use for > 30 years in Europe. Premarket FDA approval based on European data was granted in 1983; however, the manufacturer voluntarily removed it from the market because of a high incidence of stem loosening (> 30% within 3 years in some series).¹⁶ FDA approvals came much later for C-on-PE (1989) and C-on-C (2003) bearings.

Ceramic is the hardest implant material used, and it can be concluded from many clinical and laboratory reports that C-on-PE and C-on-C combinations confer a potentially significant reduction in wear on THA bearings.¹⁶ Ceramic hips initially had 2 concerns: catastrophic shattering and squeaking. Current ceramic hips have been substantially improved, and some experts feel shattering has been essentially eliminated.¹⁶ Other experts note that ceramic brittleness remains a major concern.¹⁷ Squeaking remains a problem for some, but it usually abates over time. No study has correlated squeaking with impending failure or increased pain or disability.

While C-on-C bearings are now felt to be a good implant for young active patients, these bearings have generally not resulted in significantly lower wear rates and fewer revisions.¹⁸ High rates of wear and osteolysis have been sporadically documented over the 35-year history of ceramic implants.¹⁶ The FDA approved the first ceramic-on-metal total hip replacement system on June 13, 2011.

Metal-on-metal (M-on-M) implants have been used by some for decades, although they were not approved by the FDA until the late 1990s. However, some device recalls have brought negative attention to M-on-M implants.¹⁹ It was felt that they would generate less wear debris than PE, but reports of pseudotumors (from inflammatory mediators) and metallosis have significantly tempered enthusiasm for these products.^20,21 The wear rates are very low, estimated to be only 0.01 mm/y, but concerns about the carcinogenetic potential of systemically increased metal ions remains a possible and much debated concern.^19,22,23 In January 2013, FDA issued a safety communication on M-on-M implants.

Many experts feel that modern ceramic or metal on second-generation HXLPE represents the gold standard and the most predictable bearing choice for young, active patients.¹⁸ Others feel that the optimal choice of bearing surfaces in THA, particularly in the younger and more active patient, remains controversial.²⁴

Follow-Up

Intermittent orthopedic monitoring is recommended for all patients who have undergone a THA. The frequency of hip X-rays on follow-up appointments is left to the orthopedic surgeon. After the initial recovery, serial images every 2 to 5 years can identify progressive failure, and annual X-rays may be used for closer follow-up in high-risk patients.

Patients who experience dislocations, fractures, infections, or pain usually maintain close orthopedic follow-up. Significant wear of the prosthesis damages the socket; osteolysis can cause irreversible bone loss, fracture, and loosening. Massive acetabular bone loss is very difficult to reverse and creates major reconstruction challenges.

Figure 1A is a 2009 X-ray of a woman aged 44 years who underwent a THA after a motor vehicle accident in 1997 and who was advised to have a revision THA when seen in 2009.

Figure 3A is an X-ray of a man aged 71 years who had undergone THA 21 years earlier and had complied with routine follow-up. When his X-rays showed significant wear of the liner and some osteolysis, he was able to undergo a simple revision (Figure 3B).

Three-dimensional CT is useful for quantifying the presence and severity of osteolytic lesions, because plain radiographs may underestimate the amount of bone loss that is present.²⁵ The CT in Figure 3C shows the magnitude of osteolysis that was underestimated by the preoperative plain X-rays (Figure 3A). Computed tomography scans are crucial for surgical planning in the setting of severe acetabular bone loss.

There is a wide spectrum of signs and symptoms that can occur in the setting of acetabular component failure. Pain is a common presenting symptom. Groin pain can represent acetabular failure; thigh pain may be correlated to femoral component failure.²⁵ The clinical patient presentation ultimately depends on the underlying cause: an infection, polyethylene wear, instability, or aseptic loosening.²⁵ Leg-length discrepancy, joint deformity, location of prior incisions, functional status, and baseline neurologic status should be evaluated and documented during the preoperative evaluation as well.²⁵

Case Study Revision Options

The X-rays and CT scans for this case study patient showed that he was a possible candidate for the simplest revision surgery; an isolated liner exchange and replacement of the femoral head. When the original surgery was performed (1997), the only FDA approved PE liner was UHMWPE. To justify isolated liner exchange, the modular acetabular metallic shell also should be well-fixed and appropriately oriented.²⁶ This is evaluated both preoperatively and intraoperatively.

If found to be well fixed with an appropriate orientation and locking mechanism, the UHMWPE liner could be replaced with a HXLPE liner and a larger metal femoral head for improved wear and stability. Acetabular revision is indicted for an asymptomatic patient who has progressive osteolysis, severe wear, or bone loss that would compromise future reconstruction.

Conclusions

Over the past several decades, THA has become recognized as an effective treatment option for the reduction of pain and disability associated with hip joint disease and is associated with successful clinical outcomes. The most frequently noted recommendations for trying to increase the life expectancy of an artificial hip replacement include maintaining a normal weight, keeping leg muscles strong, and avoiding repetitive squatting and kneeling.

As the number of primary THAs has increased and the average age of those undergoing a primary THA has decreased, the need for revisions has risen. Reviews have demonstrated that the most common causes for early total hip revision, regardless of component, included infection, instability/dislocation, and fracture, whereas wear is the most common reason for mid to late revisions.

The wear of all materials used has been shown to be greatest in the most active patients.

Studies continue to identify ways to potentially prevent or reverse osteolysis from wear debris. Alendronate therapy has been shown to prevent and treat PE debris-induced periprosthetic bone loss in rats.²⁷ It also was successfully used in a case report of an asymptomatic woman aged 39 years who had rapid PE wear and aggressive periprosthetic osteolysis within just 2 years of a bilateral THA.²⁸ Other areas of research on decreasing osteolysis in THA recipients include trials with mesenchymal stem cells, bone morphogenic proteins, and gene therapy.⁶

In the U.S., 46,000 revisions were performed in 2004 and this number is expected to more than double by 2030.⁴ Primary care providers are sure to encounter patients who will be in need of a hip revision procedure. It’s important for them to make sure that their patients who have undergone a THA are periodically seen for orthopedic follow-up. Despite the long history of primary THAs, there is still not a single technique and material to suit all patient characteristics.¹ Unfortunately, the same currently applies to hip revision procedures.

Total hip arthroplasty (THA) is considered to be one of the most successful orthopedic interventions of its generation.¹ In 2010, 332,000 THAs were performed in the U.S.² Although used to correct advanced joint diseases in the elderly, the THA procedure has become increasingly common in a younger population for posttraumatic fractures and conditions that lead to early onset secondary arthritis such as avascular necrosis, juvenile rheumatoid arthritis, hip dysplasia, Perthes disease, and femoro-acetabular impingement.

Current hip replacements are expected to function at least 10 to 20 years in 90% of patients.³ As increasing numbers of young patients have these procedures and as seniors continue to live longer, patients will outlast their implants. Younger and more active patients have a higher rate of revision, because the longevity of the prosthesis is usually a function of usage.³ The number of revision THAs is projected to increase 137% by 2030.⁴

Hip resurfacing has been developed as a bone preserving surgical alternative to THA. The first system for use in the U.S. received FDA approval in 2006, but concerns about the metal on metal bearing surfaces, high failure and revision rates, and early catastrophic modes of failure compared with THAs has resulted in the recall of many of these devices. Hip resurfacing may offer some advantages compared with those of a THA in a carefully selected population, but its use will not be further discussed in this case study.⁵ Periprosthetic osteolysis and aseptic loosening are 2 of the long-term consequences of THA.⁶ Bone loss is felt to be secondary to a biologic reaction to particulate debris from implants.⁶ Some patients, especially those with loosening, complete wear, or fracture, will be symptomatic with pain. However, wear and osteolysis is a silent disease unless there is mechanical failure. Other patients may not experience discomfort. Radiographic studies may reveal significant changes, which warrant the recommendation for a hip revision.

Hip revision surgery has 3 major purposes: relieving pain in the affected joint, restoring the patient’s mobility, and removing a loose or damaged prosthesis before irreversible harm is done to the joint. It’s anticipated that most primary care providers (PCPs) will encounter patients who seek advice on the need for a revision hip arthroplasty.

This case will present an asymptomatic patient who underwent a THA in 1997 at age 37, to address developmental dysplasia of the hip (DDH) and was advised to undergo a revision hip arthroplasty due to abnormal radiographic findings at age 55 years. A discussion will follow that includes a brief review of the history of THA, the materials and bearings commonly used, the presenting symptoms or radiographic changes that signal the need for a revision, and the current options available for a patient such as this.

Case Report

A man aged 55 years presented to a new orthopedic surgeon for his first orthopedic appointment in 10 years. The patient had a left metal-on-polyethylene (M-on-PE) THA 18 years prior due to early onset secondary degenerative joint disease from DDH. The patient’s M-on-PE THA was a titanium acetabular socket and femoral stem with a cobalt-chromium alloy femoral head and a polyethylene liner. The patient remained physically active with an exercise routine consisting of walking, swimming, and weight training.

The patient’s orthopedic history was notable for a right knee arthroscopy for intervention due to a torn medial and lateral meniscus, and birth history was noteworthy for a breech presentation. The physical exam was unremarkable except for a slight leg length discrepancy, but the patient did not exhibit a Trendelenburg gait.

Plain X-rays and a computed tomography (CT) scan showed eccentric PE wear and superior migration of the femoral head, which was indicative of significant PE liner wear. No significant osteolysis or periprosthetic loosening was observed on the X-rays or CT scan. He was advised that a hip revision procedure would need to be done, optimally, within the next 6 months to a year.

Discussion

Hip dysplasia represents a broad group of disorders and generally means abnormal development of the hip joint. The term is most commonly used to refer to DDH with inadequate coverage of the femoral head. In one study, 25% of hip replacements performed in patients aged ≤ 40 years were due to underlying hip dysplasia.⁷

Developmental dysplasia of the hip occurs more often in children who present in the breech position.⁸ One theory argues that packaging issues in utero may account for the increased incidence of DDH.⁹ The earliest recorded attempts at hip replacement occurred in Germany, in 1891, when ivory was used to replace the femoral heads of patients whose hip joints had been destroyed by tuberculosis.¹

The orthopedic surgeon Sir John Charnley, who worked at the Manchester Royal Infirmary, is considered the father of the modern THA.¹ His low friction arthroplasty, designed in the early 1960s is identical, in principle, to the M-on-PE prosthesis used today.¹ The PE liner used was ultrahigh molecular weight polyethylene (UHMWPE).¹

Due to the early success of the Charnley prosthesis, the M-on-PE prosthesis became the most widely used. Although PE is the most studied and understood of all acetabular liner materials, it will eventually wear and shed debris. Acetabular cup wear is the most frequent reason for mid-to-long-term revisions, especially in young and active patients.¹⁰ More active patients shed more debris.³ The PE debris instigates the release of inflammatory mediators, which results in chronic inflammation and tissue damage that erodes the supporting bone and can lead to implant loosening or fracture.⁶ Ongoing studies seek to optimize and improve properties of the UHMWPE and to develop alternative bearings. After FDA approval in 1999, highly cross-linked polyethylene liners (HXLPE) rapidly became the standard of care for THAs, at least in the U.S.¹¹ Highly cross-linked polyethylene liners are created from UHMWPE through a process of cross-linking by exposure to gamma radiation, and subsequent heat treatment to neutralize free radicals and limit oxidative degradation.¹²

In one study, the 5-year annual linear wear rate for a HXLPE liner was only 45% of that seen with the UHMWPE liner, although the qualitative wear pattern was the same.¹³ In a study that followed patients for 7 years postoperatively, the mean steady-state wear rate of the HXLPE was 0.005 mm/y compared with 0.037 mm/y for UHMWPE.¹⁴ In a long-term study (a minimum follow-up of 10 years) of 50 patients who were aged < 50 years and underwent THA using HXLPE liners, there was no radiographic evidence of osteolysis or component loosening, and liner wear was 0.020 ± 0.0047 mm/y.¹² In 2005, second-generation HXLPE liners were introduced clinically and have been shown to further reduce wear in vitro compared with both UHMWPE and first-generation HXLPE liners. Callary and colleagues calculated that the wear rates between 1 year and 5 years were all < 0.001 mm/y.¹⁵

The use of ceramic for THAs began in 1970, and ceramic heads on polyethylene (C-on-PE) liners and ceramic-on-ceramic (C-on-C) bearings have been in continual use for > 30 years in Europe. Premarket FDA approval based on European data was granted in 1983; however, the manufacturer voluntarily removed it from the market because of a high incidence of stem loosening (> 30% within 3 years in some series).¹⁶ FDA approvals came much later for C-on-PE (1989) and C-on-C (2003) bearings.

Ceramic is the hardest implant material used, and it can be concluded from many clinical and laboratory reports that C-on-PE and C-on-C combinations confer a potentially significant reduction in wear on THA bearings.¹⁶ Ceramic hips initially had 2 concerns: catastrophic shattering and squeaking. Current ceramic hips have been substantially improved, and some experts feel shattering has been essentially eliminated.¹⁶ Other experts note that ceramic brittleness remains a major concern.¹⁷ Squeaking remains a problem for some, but it usually abates over time. No study has correlated squeaking with impending failure or increased pain or disability.

While C-on-C bearings are now felt to be a good implant for young active patients, these bearings have generally not resulted in significantly lower wear rates and fewer revisions.¹⁸ High rates of wear and osteolysis have been sporadically documented over the 35-year history of ceramic implants.¹⁶ The FDA approved the first ceramic-on-metal total hip replacement system on June 13, 2011.

Metal-on-metal (M-on-M) implants have been used by some for decades, although they were not approved by the FDA until the late 1990s. However, some device recalls have brought negative attention to M-on-M implants.¹⁹ It was felt that they would generate less wear debris than PE, but reports of pseudotumors (from inflammatory mediators) and metallosis have significantly tempered enthusiasm for these products.^20,21 The wear rates are very low, estimated to be only 0.01 mm/y, but concerns about the carcinogenetic potential of systemically increased metal ions remains a possible and much debated concern.^19,22,23 In January 2013, FDA issued a safety communication on M-on-M implants.

Many experts feel that modern ceramic or metal on second-generation HXLPE represents the gold standard and the most predictable bearing choice for young, active patients.¹⁸ Others feel that the optimal choice of bearing surfaces in THA, particularly in the younger and more active patient, remains controversial.²⁴

Follow-Up

Intermittent orthopedic monitoring is recommended for all patients who have undergone a THA. The frequency of hip X-rays on follow-up appointments is left to the orthopedic surgeon. After the initial recovery, serial images every 2 to 5 years can identify progressive failure, and annual X-rays may be used for closer follow-up in high-risk patients.

Patients who experience dislocations, fractures, infections, or pain usually maintain close orthopedic follow-up. Significant wear of the prosthesis damages the socket; osteolysis can cause irreversible bone loss, fracture, and loosening. Massive acetabular bone loss is very difficult to reverse and creates major reconstruction challenges.

Figure 1A is a 2009 X-ray of a woman aged 44 years who underwent a THA after a motor vehicle accident in 1997 and who was advised to have a revision THA when seen in 2009.

Figure 3A is an X-ray of a man aged 71 years who had undergone THA 21 years earlier and had complied with routine follow-up. When his X-rays showed significant wear of the liner and some osteolysis, he was able to undergo a simple revision (Figure 3B).

Three-dimensional CT is useful for quantifying the presence and severity of osteolytic lesions, because plain radiographs may underestimate the amount of bone loss that is present.²⁵ The CT in Figure 3C shows the magnitude of osteolysis that was underestimated by the preoperative plain X-rays (Figure 3A). Computed tomography scans are crucial for surgical planning in the setting of severe acetabular bone loss.

There is a wide spectrum of signs and symptoms that can occur in the setting of acetabular component failure. Pain is a common presenting symptom. Groin pain can represent acetabular failure; thigh pain may be correlated to femoral component failure.²⁵ The clinical patient presentation ultimately depends on the underlying cause: an infection, polyethylene wear, instability, or aseptic loosening.²⁵ Leg-length discrepancy, joint deformity, location of prior incisions, functional status, and baseline neurologic status should be evaluated and documented during the preoperative evaluation as well.²⁵

Case Study Revision Options

The X-rays and CT scans for this case study patient showed that he was a possible candidate for the simplest revision surgery; an isolated liner exchange and replacement of the femoral head. When the original surgery was performed (1997), the only FDA approved PE liner was UHMWPE. To justify isolated liner exchange, the modular acetabular metallic shell also should be well-fixed and appropriately oriented.²⁶ This is evaluated both preoperatively and intraoperatively.

If found to be well fixed with an appropriate orientation and locking mechanism, the UHMWPE liner could be replaced with a HXLPE liner and a larger metal femoral head for improved wear and stability. Acetabular revision is indicted for an asymptomatic patient who has progressive osteolysis, severe wear, or bone loss that would compromise future reconstruction.

Conclusions

Over the past several decades, THA has become recognized as an effective treatment option for the reduction of pain and disability associated with hip joint disease and is associated with successful clinical outcomes. The most frequently noted recommendations for trying to increase the life expectancy of an artificial hip replacement include maintaining a normal weight, keeping leg muscles strong, and avoiding repetitive squatting and kneeling.

As the number of primary THAs has increased and the average age of those undergoing a primary THA has decreased, the need for revisions has risen. Reviews have demonstrated that the most common causes for early total hip revision, regardless of component, included infection, instability/dislocation, and fracture, whereas wear is the most common reason for mid to late revisions.

The wear of all materials used has been shown to be greatest in the most active patients.

Studies continue to identify ways to potentially prevent or reverse osteolysis from wear debris. Alendronate therapy has been shown to prevent and treat PE debris-induced periprosthetic bone loss in rats.²⁷ It also was successfully used in a case report of an asymptomatic woman aged 39 years who had rapid PE wear and aggressive periprosthetic osteolysis within just 2 years of a bilateral THA.²⁸ Other areas of research on decreasing osteolysis in THA recipients include trials with mesenchymal stem cells, bone morphogenic proteins, and gene therapy.⁶

In the U.S., 46,000 revisions were performed in 2004 and this number is expected to more than double by 2030.⁴ Primary care providers are sure to encounter patients who will be in need of a hip revision procedure. It’s important for them to make sure that their patients who have undergone a THA are periodically seen for orthopedic follow-up. Despite the long history of primary THAs, there is still not a single technique and material to suit all patient characteristics.¹ Unfortunately, the same currently applies to hip revision procedures.

Total hip arthroplasty (THA) is considered to be one of the most successful orthopedic interventions of its generation.¹ In 2010, 332,000 THAs were performed in the U.S.² Although used to correct advanced joint diseases in the elderly, the THA procedure has become increasingly common in a younger population for posttraumatic fractures and conditions that lead to early onset secondary arthritis such as avascular necrosis, juvenile rheumatoid arthritis, hip dysplasia, Perthes disease, and femoro-acetabular impingement.

Current hip replacements are expected to function at least 10 to 20 years in 90% of patients.³ As increasing numbers of young patients have these procedures and as seniors continue to live longer, patients will outlast their implants. Younger and more active patients have a higher rate of revision, because the longevity of the prosthesis is usually a function of usage.³ The number of revision THAs is projected to increase 137% by 2030.⁴

Hip resurfacing has been developed as a bone preserving surgical alternative to THA. The first system for use in the U.S. received FDA approval in 2006, but concerns about the metal on metal bearing surfaces, high failure and revision rates, and early catastrophic modes of failure compared with THAs has resulted in the recall of many of these devices. Hip resurfacing may offer some advantages compared with those of a THA in a carefully selected population, but its use will not be further discussed in this case study.⁵ Periprosthetic osteolysis and aseptic loosening are 2 of the long-term consequences of THA.⁶ Bone loss is felt to be secondary to a biologic reaction to particulate debris from implants.⁶ Some patients, especially those with loosening, complete wear, or fracture, will be symptomatic with pain. However, wear and osteolysis is a silent disease unless there is mechanical failure. Other patients may not experience discomfort. Radiographic studies may reveal significant changes, which warrant the recommendation for a hip revision.

Hip revision surgery has 3 major purposes: relieving pain in the affected joint, restoring the patient’s mobility, and removing a loose or damaged prosthesis before irreversible harm is done to the joint. It’s anticipated that most primary care providers (PCPs) will encounter patients who seek advice on the need for a revision hip arthroplasty.

This case will present an asymptomatic patient who underwent a THA in 1997 at age 37, to address developmental dysplasia of the hip (DDH) and was advised to undergo a revision hip arthroplasty due to abnormal radiographic findings at age 55 years. A discussion will follow that includes a brief review of the history of THA, the materials and bearings commonly used, the presenting symptoms or radiographic changes that signal the need for a revision, and the current options available for a patient such as this.

Case Report

A man aged 55 years presented to a new orthopedic surgeon for his first orthopedic appointment in 10 years. The patient had a left metal-on-polyethylene (M-on-PE) THA 18 years prior due to early onset secondary degenerative joint disease from DDH. The patient’s M-on-PE THA was a titanium acetabular socket and femoral stem with a cobalt-chromium alloy femoral head and a polyethylene liner. The patient remained physically active with an exercise routine consisting of walking, swimming, and weight training.

The patient’s orthopedic history was notable for a right knee arthroscopy for intervention due to a torn medial and lateral meniscus, and birth history was noteworthy for a breech presentation. The physical exam was unremarkable except for a slight leg length discrepancy, but the patient did not exhibit a Trendelenburg gait.

Plain X-rays and a computed tomography (CT) scan showed eccentric PE wear and superior migration of the femoral head, which was indicative of significant PE liner wear. No significant osteolysis or periprosthetic loosening was observed on the X-rays or CT scan. He was advised that a hip revision procedure would need to be done, optimally, within the next 6 months to a year.

Discussion

Hip dysplasia represents a broad group of disorders and generally means abnormal development of the hip joint. The term is most commonly used to refer to DDH with inadequate coverage of the femoral head. In one study, 25% of hip replacements performed in patients aged ≤ 40 years were due to underlying hip dysplasia.⁷

Developmental dysplasia of the hip occurs more often in children who present in the breech position.⁸ One theory argues that packaging issues in utero may account for the increased incidence of DDH.⁹ The earliest recorded attempts at hip replacement occurred in Germany, in 1891, when ivory was used to replace the femoral heads of patients whose hip joints had been destroyed by tuberculosis.¹

The orthopedic surgeon Sir John Charnley, who worked at the Manchester Royal Infirmary, is considered the father of the modern THA.¹ His low friction arthroplasty, designed in the early 1960s is identical, in principle, to the M-on-PE prosthesis used today.¹ The PE liner used was ultrahigh molecular weight polyethylene (UHMWPE).¹

Due to the early success of the Charnley prosthesis, the M-on-PE prosthesis became the most widely used. Although PE is the most studied and understood of all acetabular liner materials, it will eventually wear and shed debris. Acetabular cup wear is the most frequent reason for mid-to-long-term revisions, especially in young and active patients.¹⁰ More active patients shed more debris.³ The PE debris instigates the release of inflammatory mediators, which results in chronic inflammation and tissue damage that erodes the supporting bone and can lead to implant loosening or fracture.⁶ Ongoing studies seek to optimize and improve properties of the UHMWPE and to develop alternative bearings. After FDA approval in 1999, highly cross-linked polyethylene liners (HXLPE) rapidly became the standard of care for THAs, at least in the U.S.¹¹ Highly cross-linked polyethylene liners are created from UHMWPE through a process of cross-linking by exposure to gamma radiation, and subsequent heat treatment to neutralize free radicals and limit oxidative degradation.¹²

In one study, the 5-year annual linear wear rate for a HXLPE liner was only 45% of that seen with the UHMWPE liner, although the qualitative wear pattern was the same.¹³ In a study that followed patients for 7 years postoperatively, the mean steady-state wear rate of the HXLPE was 0.005 mm/y compared with 0.037 mm/y for UHMWPE.¹⁴ In a long-term study (a minimum follow-up of 10 years) of 50 patients who were aged < 50 years and underwent THA using HXLPE liners, there was no radiographic evidence of osteolysis or component loosening, and liner wear was 0.020 ± 0.0047 mm/y.¹² In 2005, second-generation HXLPE liners were introduced clinically and have been shown to further reduce wear in vitro compared with both UHMWPE and first-generation HXLPE liners. Callary and colleagues calculated that the wear rates between 1 year and 5 years were all < 0.001 mm/y.¹⁵

The use of ceramic for THAs began in 1970, and ceramic heads on polyethylene (C-on-PE) liners and ceramic-on-ceramic (C-on-C) bearings have been in continual use for > 30 years in Europe. Premarket FDA approval based on European data was granted in 1983; however, the manufacturer voluntarily removed it from the market because of a high incidence of stem loosening (> 30% within 3 years in some series).¹⁶ FDA approvals came much later for C-on-PE (1989) and C-on-C (2003) bearings.

Ceramic is the hardest implant material used, and it can be concluded from many clinical and laboratory reports that C-on-PE and C-on-C combinations confer a potentially significant reduction in wear on THA bearings.¹⁶ Ceramic hips initially had 2 concerns: catastrophic shattering and squeaking. Current ceramic hips have been substantially improved, and some experts feel shattering has been essentially eliminated.¹⁶ Other experts note that ceramic brittleness remains a major concern.¹⁷ Squeaking remains a problem for some, but it usually abates over time. No study has correlated squeaking with impending failure or increased pain or disability.

While C-on-C bearings are now felt to be a good implant for young active patients, these bearings have generally not resulted in significantly lower wear rates and fewer revisions.¹⁸ High rates of wear and osteolysis have been sporadically documented over the 35-year history of ceramic implants.¹⁶ The FDA approved the first ceramic-on-metal total hip replacement system on June 13, 2011.

Metal-on-metal (M-on-M) implants have been used by some for decades, although they were not approved by the FDA until the late 1990s. However, some device recalls have brought negative attention to M-on-M implants.¹⁹ It was felt that they would generate less wear debris than PE, but reports of pseudotumors (from inflammatory mediators) and metallosis have significantly tempered enthusiasm for these products.^20,21 The wear rates are very low, estimated to be only 0.01 mm/y, but concerns about the carcinogenetic potential of systemically increased metal ions remains a possible and much debated concern.^19,22,23 In January 2013, FDA issued a safety communication on M-on-M implants.

Many experts feel that modern ceramic or metal on second-generation HXLPE represents the gold standard and the most predictable bearing choice for young, active patients.¹⁸ Others feel that the optimal choice of bearing surfaces in THA, particularly in the younger and more active patient, remains controversial.²⁴

Follow-Up

Intermittent orthopedic monitoring is recommended for all patients who have undergone a THA. The frequency of hip X-rays on follow-up appointments is left to the orthopedic surgeon. After the initial recovery, serial images every 2 to 5 years can identify progressive failure, and annual X-rays may be used for closer follow-up in high-risk patients.

Patients who experience dislocations, fractures, infections, or pain usually maintain close orthopedic follow-up. Significant wear of the prosthesis damages the socket; osteolysis can cause irreversible bone loss, fracture, and loosening. Massive acetabular bone loss is very difficult to reverse and creates major reconstruction challenges.

Figure 1A is a 2009 X-ray of a woman aged 44 years who underwent a THA after a motor vehicle accident in 1997 and who was advised to have a revision THA when seen in 2009.

Figure 3A is an X-ray of a man aged 71 years who had undergone THA 21 years earlier and had complied with routine follow-up. When his X-rays showed significant wear of the liner and some osteolysis, he was able to undergo a simple revision (Figure 3B).

Three-dimensional CT is useful for quantifying the presence and severity of osteolytic lesions, because plain radiographs may underestimate the amount of bone loss that is present.²⁵ The CT in Figure 3C shows the magnitude of osteolysis that was underestimated by the preoperative plain X-rays (Figure 3A). Computed tomography scans are crucial for surgical planning in the setting of severe acetabular bone loss.

There is a wide spectrum of signs and symptoms that can occur in the setting of acetabular component failure. Pain is a common presenting symptom. Groin pain can represent acetabular failure; thigh pain may be correlated to femoral component failure.²⁵ The clinical patient presentation ultimately depends on the underlying cause: an infection, polyethylene wear, instability, or aseptic loosening.²⁵ Leg-length discrepancy, joint deformity, location of prior incisions, functional status, and baseline neurologic status should be evaluated and documented during the preoperative evaluation as well.²⁵

Case Study Revision Options

The X-rays and CT scans for this case study patient showed that he was a possible candidate for the simplest revision surgery; an isolated liner exchange and replacement of the femoral head. When the original surgery was performed (1997), the only FDA approved PE liner was UHMWPE. To justify isolated liner exchange, the modular acetabular metallic shell also should be well-fixed and appropriately oriented.²⁶ This is evaluated both preoperatively and intraoperatively.

If found to be well fixed with an appropriate orientation and locking mechanism, the UHMWPE liner could be replaced with a HXLPE liner and a larger metal femoral head for improved wear and stability. Acetabular revision is indicted for an asymptomatic patient who has progressive osteolysis, severe wear, or bone loss that would compromise future reconstruction.

Conclusions

Over the past several decades, THA has become recognized as an effective treatment option for the reduction of pain and disability associated with hip joint disease and is associated with successful clinical outcomes. The most frequently noted recommendations for trying to increase the life expectancy of an artificial hip replacement include maintaining a normal weight, keeping leg muscles strong, and avoiding repetitive squatting and kneeling.

As the number of primary THAs has increased and the average age of those undergoing a primary THA has decreased, the need for revisions has risen. Reviews have demonstrated that the most common causes for early total hip revision, regardless of component, included infection, instability/dislocation, and fracture, whereas wear is the most common reason for mid to late revisions.

The wear of all materials used has been shown to be greatest in the most active patients.

Studies continue to identify ways to potentially prevent or reverse osteolysis from wear debris. Alendronate therapy has been shown to prevent and treat PE debris-induced periprosthetic bone loss in rats.²⁷ It also was successfully used in a case report of an asymptomatic woman aged 39 years who had rapid PE wear and aggressive periprosthetic osteolysis within just 2 years of a bilateral THA.²⁸ Other areas of research on decreasing osteolysis in THA recipients include trials with mesenchymal stem cells, bone morphogenic proteins, and gene therapy.⁶

In the U.S., 46,000 revisions were performed in 2004 and this number is expected to more than double by 2030.⁴ Primary care providers are sure to encounter patients who will be in need of a hip revision procedure. It’s important for them to make sure that their patients who have undergone a THA are periodically seen for orthopedic follow-up. Despite the long history of primary THAs, there is still not a single technique and material to suit all patient characteristics.¹ Unfortunately, the same currently applies to hip revision procedures.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.