Bisphosphonates in the management of osteoporosis in postmenopausal women

Bisphosphonates in the management of osteoporosis in postmenopausal women

Author
Hillel N Rosen, MD
Section Editors
Clifford J Rosen, MD
Kenneth E Schmader, MD
Deputy Editor
Jean E Mulder, MD



Last literature review version 16.3: October 2008 | This topic last updated: October 16, 2008 (More)


INTRODUCTION — Osteoporosis is caused by the cumulative effect of bone resorption in excess of bone formation. Bisphosphonates, one of the available therapeutic options for the management of osteoporosis, inhibit bone resorption with relatively few side effects. As a result, they are widely used for the prevention and treatment of osteoporosis.

Bisphosphonates are also used in the management of hypercalcemia, Paget disease, and in a number of malignancies including multiple myeloma, breast cancer, and prostate cancer. These topics are all reviewed separately in the appropriate topic reviews.

The use of bisphosphonates for osteoporosis in women is reviewed here. The pharmacology of bisphosphonates, role of bisphosphonates for osteoporosis in men and premenopausal women, and an overview of other treatment options for osteoporosis in women are reviewed separately. (See "Pharmacology of bisphosphonates" and see "Overview of the management of osteoporosis in postmenopausal women" and see "Treatment of osteoporosis in men", section on Bisphosphonates and see "Evaluation and treatment of premenopausal osteoporosis").

ALENDRONATE — Alendronate is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Alendronate is also effective for African-American women [1] and for men with osteoporosis. (See "Treatment of osteoporosis in men").

Treatment — A number of randomized, clinical trials have demonstrated that alendronate increases bone mineral density (BMD) and decreases the risk of osteoporotic fractures [2-7]. The optimal suppression of bone turnover and increase in bone density with minimal side effects is achieved at an alendronate dose of approximately 10 mg/day (show figure 1) [2,4].

In one trial of 994 women with postmenopausal osteoporosis who were randomly assigned to receive placebo or different doses of alendronate (all groups also were supplemented with calcium (500 mg/day) [2]), the results at three years were (show figure 1):

Bone density fell slightly in the placebo group but increased in the alendronate groups.

The differences in bone density between alendronate (10 mg/day) and placebo were 8.8 percent in the spine, 5.9 percent in the femoral neck, and 7.8 percent in the greater trochanter. Thus, alendronate increased bone density at sites rich in cortical bone (mid-forearm and femoral neck) and at sites rich in trabecular bone (spine).

Alendronate was associated with fewer vertebral fractures (3.2 versus 6.2 percent), less loss of height, and, at the dose of 10 mg/day, no increase in side effects as compared with placebo.

The Fracture Intervention Trial (FIT), a larger, randomized trial in postmenopausal women with low bone density, had two study arms comparing daily alendronate and placebo.

In the vertebral fracture study arm, in 2027 women with a low femoral neck bone density (T-score < -2.1) and at least one vertebral fracture at baseline, alendronate therapy increased femoral neck and spine BMD by 4.1 and 6.2 percent, respectively, and reduced the risk of vertebral fracture by approximately 50 percent, and hip and wrist fractures by approximately 30 percent [6].

The clinical fracture study arm included 4432 postmenopausal women with a low femoral neck bone density (T-score < -1.6), but no vertebral fracture at baseline [8]. Alendronate therapy (5 mg per day for two years followed by 10 mg per day for the remainder of the trial) increased bone mineral density and reduced the risk of vertebral fractures (diagnosed by x-ray) by 44 percent, but did not significantly decrease the risk of hip, wrist, or all clinical fractures. However, in a subgroup of the subjects who had osteoporosis (baseline femoral neck T score of -2.5 or less), alendronate reduced the risk of hip and all clinical fractures by 56 and 36 percent, respectively.

In a meta-analysis of 11 trials of alendronate therapy in postmenopausal women, the relative risk (RR) of vertebral fractures in patients given 5 mg or more of alendronate was 0.52 [95% CI 0.43-0.65] [7]. The RR of nonvertebral fractures in patients given ≥10 mg of alendronate was 0.51, a greater reduction than with 5 mg (RR 0.87). Improvements in bone density with alendronate increased with both dose and time. The risk of side effects was similar for 5 mg and doses ≥ 10 mg. For all doses combined, there was no evidence of an excess risk of gastrointestinal side effects.

Elderly women — Alendronate appears to be equally effective in older and younger postmenopausal women with osteoporosis. In the FIT trial, alendronate reduced fracture rate even in women at highest risk for fracture (older than age 75 years, or severe osteoporosis) [9]. The reduction in fracture rate was similar in women older and younger than age 75 years, suggesting that even elderly women benefit from treatment of their osteoporosis [9]. In a randomized, trial of 327 elderly women with osteoporosis in long-term care facilities, alendronate increased bone density when compared to placebo and was well-tolerated [10].

Long-term efficacy — Alendronate is well tolerated and effective for at least 10 years. In an extension study of 247 postmenopausal women with osteoporosis, alendronate (5 or 10 mg/day) resulted in continued increases in bone mineral density over a 10-year period [11].

The total 10-year increase in lumbar spine density was 13.7 and 9.3 percent for the 10 and 5 mg/day groups, respectively. Increases in bone mineral density were greatest in the initial five years of the study (10 and 6.8 percent for the 10 and 5 mg/day groups, respectively).

Fractures were not a primary outcome, and were captured only as adverse events. However, fracture reduction appeared to be maintained throughout the study.
The safety and tolerability of alendronate were similar to those of placebo.
How long to treat? — There is currently no consensus on how long to continue bisphosphonate therapy. However, for some women, stopping therapy after five years may be reasonable, as there appears to be a residual benefit on BMD and fractures for up to five years. This was illustrated in the Fracture Intervention Trial Long-term Extension (FLEX), in 1099 postmenopausal women who had previously received alendronate for five years in the Fracture Intervention Trial (FIT) [12].

At the completion of FIT, women were randomly assigned to an additional five years of alendronate (5 or 10 mg daily) or placebo. Women at highest risk for fracture were excluded from FLEX (those with FLEX baseline T-scores either below -3.5, or below their FIT baseline). The BMD, bone marker, and fracture data in the women who continued alendronate for ten years were similar to those described above [11].

In women who were switched to placebo after five years of alendronate, the following results were seen:

There was a gradual decline in BMD (-2.4 and -3.7 percent, at the total hip and spine, respectively), but mean BMD remained at or higher than levels 10 years earlier.

There was a gradual rise in biochemical markers of bone turnover. However, the values were still lower than ten years previously.

In the placebo compared to alendronate groups, the rate of nonvertebral fracture (19 and 18.9 percent) or morphometric vertebral fractures (detected by lateral spine radiographs) (11.3 and 9.8 percent) were not significantly different. However, there was a slightly higher risk of clinically detected vertebral fractures (by participant's physician and spine radiograph) (5.3 and 2.4 percent for placebo and alendronate, respectively).

There were no differences in adverse events between the groups, and there were no cases of osteonecrosis of the jaw. No qualitative abnormalities were seen on bone biopsy in either group.

In summary, stopping alendronate after five years of therapy results in a gradual decline in BMD and increase in biochemical markers of bone turnover, but no significantly higher risk of fracture (except for clinical vertebral fracture). Thus, stopping bisphosphonate therapy after five years (with careful BMD and risk factor assessment follow-up) may be reasonable for some women.

However, the FLEX trial does not address the impact of stopping therapy in women at highest risk for fracture as they were excluded from the trial. In these women, we suggest continuing alendronate for up to ten years, as BMD and fracture benefits were maintained with no increased risk of adverse events.

Weekly dosing — Weekly administration of alendronate is as effective as daily dosing. In a two-year randomized trial comparing once-weekly (70 mg) and daily alendronate (10 mg), the regimens were similar for increasing BMD and had similar low rates of side effects [13]. The rates of clinical fractures were captured as adverse experiences, and were similar among the groups.

Prevention — In addition to its efficacy in the treatment of osteoporosis in postmenopausal women, alendronate is useful for the prevention of osteoporosis [14-18]. The approved prevention dose with alendronate is one-half the dose for treatment (5 mg/day or 35 mg/week).

As an example, in a double-blind, randomized trial of 447 women who had been menopausal for 6 to 36 months, alendronate for three years at 5, 10, and 20 mg/day increased bone mineral density at the lumbar spine, femoral neck, and trochanter by 1 to 4 percent [14]. In comparison, those receiving placebo lost 2 to 4 percent at these sites. The protective effect of alendronate disappeared relatively rapidly after cessation of therapy [15].

A second randomized study found similar efficacy (3.5 percent increase in bone mineral density at the lumbar spine and 1.9 percent increase at the hip) with the 5 mg dose of alendronate administered to postmenopausal women under the age of 60 years for two years [16]. In a follow-up study of this cohort for four [17] and six years [18], the positive effects of continued therapy on bone density were maintained (show figure 2) [17]. This dose was as, or perhaps slightly less, beneficial than estrogen-progestin therapy. Women receiving alendronate during years one and two who then received placebo in years three and four had the expected fall in bone density (show figure 2).

Although alendronate increases bone mineral density in postmenopausal women without osteoporosis [14,18], there is no consensus on when to initiate therapy in postmenopausal women with osteopenia (femoral neck T-scores between -1.5 and -2.4) and no other independent risk factors for fracture (previous fracture, age, tendency to fall). One group of investigators calculated that treating these women would not be cost-effective from a societal standpoint [19]. However, this does not imply that an individual postmenopausal woman with osteopenia would not derive fracture benefit.

Combination therapy — Although estrogen and bisphosphonates both inhibit bone resorption, they do so through different mechanisms. Their effects on BMD appear to be similar, and the combination of the two may be slightly more effective, although the additional benefit is modest [20-23]. The rate of bone loss may be accelerated after withdrawing estrogen therapy, but not after withdrawal of alendronate or combination therapy [24].

The combination of alendronate and raloxifene has a greater effect on bone mineral density and markers of bone turnover, when compared to either drug alone [25]. However, the benefit of combined versus monotherapy for fracture reduction is unknown.

We do not suggest combination bisphosphonate-estrogen therapy or bisphosphonate-raloxifene therapy, as the additional benefits are small. In addition, the indications for using estrogen have been diminished since the results of the Women's Health Initiative were published. (See "Postmenopausal hormone therapy: Benefits and risks" and See "Overview of the management of osteoporosis in postmenopausal women").

With PTH — Because teriparatide (PTH) stimulates bone formation and bisphosphonates reduce bone resorption, it has been hypothesized that combining the two therapies would increase bone density more than either therapy alone. However, addition of alendronate to teriparatide therapy provides no additional benefits for bone mineral density, and reduces the anabolic effect of teriparatide in both women and men. (See "Parathyroid hormone therapy for osteoporosis", section on Combination therapy, and see "Treatment of osteoporosis in men", section on Combination therapy).

Formulations — Several formulations of alendronate are available:

For treatment of osteoporosis, a 10 mg daily or 70 mg once weekly formulation are available. Most patients prefer the convenience of the once-weekly regimen.
For prevention of osteoporosis: 5 mg daily or 35 mg once-weekly tablets.
A liquid formulation of alendronate is also available (70 mg/75 mL). This may be useful for patients who are unable to swallow pills.

Instructions for administration are found below. (See "Oral regimen" below).

Other indications — Alendronate is also effective and approved for use in male osteoporosis, Paget disease (30 mg once daily dose), and glucocorticoid-induced osteoporosis. (See "Treatment of osteoporosis in men", section on Bisphosphonates, and see "Treatment of Paget disease of bone", section on Alendronate, and see "Prevention and treatment of glucocorticoid-induced osteoporosis", section on Alendronate).

RISEDRONATE

Treatment — Risedronate (Actonel) improves BMD, reduces fracture risk, and is well-tolerated in postmenopausal women with osteoporosis [26,27]. This was illustrated in the Vertebral Efficacy with Risedronate (VERT) study of 2458 postmenopausal women with osteoporosis (either two or more vertebral fractures, or one vertebral fracture and lumbar spine T-score of -2.0 or less) who were randomly assigned to risedronate (5 mg/day) or placebo for three years with the following results [28]:

Bone density at the lumbar spine, femoral neck, and trochanter increased by 5.4, 1.6, and 3.3 percent, respectively, in the risedronate group, as compared with 1.1 percent, -1.2 percent, and -0.7 percent, respectively, in the placebo group.
The risk of vertebral and nonvertebral fractures was reduced by 41 and 39 percent, respectively, with risedronate. The three-year rates of new vertebral fractures with risedronate versus placebo were 11 and 16 percent, respectively, and 5 and 8 percent, respectively, for nonvertebral fractures.

Gastrointestinal and other adverse effects occurred with similar (low) frequency in both groups.

In a two-year extension study in 265 subjects, the effects of risedronate on vertebral fracture and bone mineral density appeared to be maintained [29].
In a second three-year randomized trial in postmenopausal women with osteoporosis, a similar overall reduction in vertebral and nonvertebral fracture risk was observed; the vertebral fracture risk reduction was evident during the first year of the trial [30].

Risedronate reduces the risk of hip fracture among elderly women with confirmed osteoporosis, but not among elderly women selected primarily on the basis of risk factors. This was illustrated in a randomized trial of 5445 women aged 70 to 79 years with osteoporosis (Group 1), and 3886 women aged 80 years or older selected primarily on the basis of nonskeletal risk factors (poor gait, smoking, propensity to fall) (Group 2) [31]. Although risedronate decreased overall hip fracture risk by 30 percent, the rate of hip fracture was reduced only in Group 1 (1.9 and 3.2 percent of women experienced hip fracture in the drug and placebo groups, respectively, RR 0.6), but not in Group 2, where hip fracture rate was similar (4.2 and 5.1 percent of women, respectively).

A meta-analysis of eight randomized trials of risedronate confirmed the fracture risk reduction in early postmenopausal women and in women with established osteoporosis [26]. For risedronate versus placebo, the pooled relative risk (RR) for vertebral and nonvertebral fractures with risedronate was 0.64 and 0.73, respectively.

Long term efficacy — Risedronate is effective and well-tolerated for up to seven years, as illustrated in a trial of 164 women, in whom improvements in BMD continued over the seven years of therapy, with no apparent loss of fracture risk reduction [32].

How long to treat? — As discussed previously, there is currently no consensus on how long to continue bisphosphonate therapy. In the FLEX trial described above, stopping alendronate after five years of therapy resulted in a gradual decline in BMD and increase in biochemical markers of bone turnover over a five year period.

When risedronate is discontinued, its beneficial effects on BMD and markers of bone turnover appear to revert partially or completely within one year, as reported in an extension of the VERT trial [28,33]. In this extension study, women who received risedronate or placebo for three years were reassessed one year after stopping therapy (but continuing vitamin D supplementation) [33]. BMD of the lumbar spine and femoral neck decreased (0.83 and 1.23 percent, respectively) in the group previously taking risedronate, although mean values remained higher than baseline (lumbar spine) and placebo (lumbar spine and femoral neck). However, markers of bone turnover returned to baseline and were the same as the placebo group within one year. Nonetheless, the incidence of new vertebral fractures in patients previously treated with risedronate remained lower (6.5 versus 11.6 percent).

Given these results, stopping risedronate after three years of therapy may be an option for some women, but because bone turnover markers revert to the untreated state within one year, we do not suggest discontinuing risedronate after three years of use, especially in those individuals at high risk for fracture.

Weekly dose — Weekly risedronate (35 mg) is as effective and well tolerated as daily administration of 5 mg [34-36].

Monthly dose — Monthly risedronate (150 mg once monthly or 75 mg tablets on two consecutive days each month) has similar efficacy for increasing spine and hip BMD as daily administration of 5 mg [37-39].

Prevention — Risedronate is also effective for prevention of bone loss in postmenopausal women with normal bone density [40], and postmenopausal women with low bone density but no fractures [26,41].

Other indications for risedronate include osteoporosis in men, glucocorticoid-induced osteoporosis, and Paget disease. (See "Treatment of osteoporosis in men", section on Bisphosphonates, and see "Prevention and treatment of glucocorticoid-induced osteoporosis", section on alendronate, and see "Treatment of Paget disease of bone", section on alendronate).

Combination therapy — Addition of estrogen therapy to risedronate may provide a modest additional benefit [42], but we do not suggest the routine use of combined risedronate-estrogen therapy, given the known risks of estrogen therapy. (See "Postmenopausal hormone therapy: Benefits and risks").

Formulation — Risedronate formulations available for clinical use include: a daily (5 mg), weekly (35 mg) and monthly (single 150 mg tablet or 75 mg tablets on two consecutive days each month) dose (all used for the treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis).

In addition, a 30 mg once daily formulation is available for the treatment of Paget disease. (See "Treatment of Paget disease of bone", section on Bisphosphonates).

Risedronate may also be effective for men with osteoporosis, but it is less well studied. (See "Treatment of osteoporosis in men", section on Bisphosphonates).

Instructions for administration are found below. (See "Oral regimen" below).

Alendronate versus risedronate — Alendronate and risedronate have been compared in one prospective randomized and some retrospective observational trials. In the randomized trial, alendronate increased bone density more than risedronate at all sites after 12 months [43]. Results persisted in year two of the study [44]. However, there were no differences in the incidence of fractures, which were reported only as adverse events. In one observational study, treatment with risedronate was associated with a decreased risk of fracture in the first year of therapy [45]. However, this study was limited by the inability to accurately characterize fracture risk at baseline between the two groups. Thus, although alendronate may have a greater effect on bone mineral density when compared to risedronate, the clinical relevance of this finding is unclear. A prospective randomized trial with fracture as a defined endpoint is necessary to determine if there is a difference in fracture prevention efficacy between the two bisphosphonates.

IBANDRONATE — Ibandronate is a newer bisphosphonate that is approved for prevention and treatment of osteoporosis [46]. A daily regimen (2.5 mg/day), and intermittent regimen (20 mg every other day for 12 doses every 3 months) are equally effective for increasing bone mineral density and reducing vertebral fracture risk, when compared to placebo [47]. However, a significant reduction in hip fracture was not seen. The daily formulation was approved for use in 2003, but was never marketed.

Monthly dose — A once-monthly 150 mg oral formulation is available for both prevention and treatment of osteoporosis [48]. In a trial of 1609 postmenopausal women with osteoporosis randomly assigned to receive daily ibandronate (2.5 mg), ibandronate 50 + 50 mg once-monthly [single doses given on consecutive days], 100 mg once-monthly, or 150 mg once-monthly, the following results were seen after two years of follow-up [49]:

Increases in lumbar spine bone density were observed in all treatment groups (5.0, 5.3, 5.6, and 6.6 percent in the daily, 50 + 50 mg, 100 mg, and 150 mg groups, respectively). The increases in the 50 + 50 and 100 mg group were not statistically different from the daily 2.5 mg group, while the increase in the 150 mg group was significantly greater than the 2.5 mg daily group.
Similar results were seen for hip bone density.
No differences in adverse events were noted.
Fracture data were not reported.

Thus, monthly ibandronate (150 mg) appears to improve BMD more than daily administration (2.5 mg). The manufacturer of the monthly formulation will also provide monthly reminders for patients. The monthly formulation may therefore increase overall compliance with therapy [49].

In the absence of consistent clinical trial data that ibandronate reduces hip fracture risk, we continue to suggest alendronate or risedronate as our first choice for bisphosphonate therapy in patients at high risk for fractures.

Intravenous — An intravenous formulation of ibandronate (3 mg every three months) appears to improve BMD to a similar or greater degree than daily oral ibandronate (2.5 mg/day) [50,51]. This formulation provides an alternative option for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill.

Meta-analyses of phase III studies, in which fracture data were collected as adverse effects, have shown a reduction in nonvertebral fractures with higher doses of ibandronate (pooled data from IV dosing [2 or 3 mg every two to three months] and oral dosing [150 mg monthly]) [52,53]. However, there is no direct fracture efficacy data for IV ibandronate. In the absence of this data, zoledronic acid is our first choice for IV bisphosphonate therapy in patients who cannot tolerate oral therapy. (See "Zoledronic acid" below).

ZOLEDRONIC ACID — Zoledronic acid (ZA) is another intravenous bisphosphonate, which is administered once yearly (as a 15 minute infusion) rather than quarterly. It increases BMD and reduces fracture risk. It is approved in many countries, including the United States, for the treatment of osteoporosis.

The efficacy of ZA for the treatment of osteoporosis is demonstrated in the following studies:

In a study of five regimens of intravenous ZA infused over five minutes (1 to 4 mg administered as one to four doses over one year), lumbar spine bone density increased similarly in all five groups (4.3 to 5.1 percent) [54].

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, 7765 postmenopausal women with osteoporosis were randomly assigned to 5 mg of ZA or placebo, administered intravenously once yearly for three consecutive years [55]. Bone mineral density increased at the spine, total hip, and femoral neck and markers of bone turnover decreased in the ZA group compared with placebo.

In addition, there was a significant reduction in fracture. The three-year incidence of vertebral fracture was 10.9 percent in the placebo group versus 3.3 percent in the ZA group, a reduction of 70 percent (RR 0.30, 95% CI 0.24-0.38). The incidence of hip fracture was 2.5 and 1.4 percent in the placebo and ZA groups, respectively, a 41 percent reduction (hazard ratio 0.59, 95%CI 0.42-0.83).

In the HORIZON Recurrent Fracture Trial, 2127 men and women with hip fracture were randomly assigned to receive yearly ZA (5 mg) or placebo within three months of surgical repair [56]. Subjects also received vitamin D (50,000 to 125,000 IU 14 days prior to infusion, if 25OHD concentration was <15 mg/dl or unknown, and 800 to 1200 IU daily thereafter) and calcium. After a median follow-up of 1.9 years, new fractures occurred in 8.6 and 13.9 percent of individuals in the ZA and placebo groups, respectively, representing a relative risk reduction of 35 percent (HR 0.65, 95% CI 0.5-0.8). All-cause mortality, a secondary safety endpoint, was lower in the ZA compared with placebo group (HR 0.72, 95% CI 0.56-0.93).

Although there were no differences in serious adverse events or discontinuation because of adverse events, ZA was associated with an expected increase in post-infusion flu-like symptoms and mild transient hypocalcemia in both HORIZON studies. In addition, in the Pivotal Fracture Trial there was an unexpected increase in atrial fibrillation, which was not seen in the Recurrent Fracture Trial. There were no long-term adverse effects on renal function. A thorough search of the safety database yielded two cases of potential osteonecrosis of the jaw, one in the ZA group and one in the placebo group. (See "Adverse effects" below).

Thus, in the HORIZON studies, yearly IV ZA was associated with an improvement in BMD, a decrease in spine and hip fractures in postmenopausal women with osteoporosis (Pivotal Fracture Trial) , and a decrease in recurrent clinical fractures in men and women with recent hip fracture (Recurrent Fracture Trial). The infusions were relatively well tolerated, given the known association between intravenous bisphosphonates and flu-like symptoms.

Despite the availability of effective oral bisphosphonates, such as alendronate and risedronate, poor adherence to oral drug regimens is common. IV ZA offers an alternative option for individuals who cannot tolerate oral bisphosphonates or who find the dosing regimen more convenient. Ideal durations of therapy and long-term safety (>3 years) have not been established.

OTHER BISPHOSPHONATES — A number of other bisphosphonates are available but are used less often (or not at all) for osteoporosis.

Etidronate — Etidronate was the first bisphosphonate used in the treatment of osteoporosis. It increased bone mineral density and decreased vertebral but not nonvertebral fractures, and it was never approved for treating postmenopausal osteoporosis. In addition, there was concern that long term use may cause osteomalacia. Therefore, it has been superseded by other bisphosphonates.

Tiludronate — Tiludronate, an effective therapy for Paget disease of bone, has not been demonstrated to be effective for the treatment or prevention of osteoporosis. (See "Treatment of Paget disease of bone").

Pamidronate — Pamidronate, an intravenous preparation, has been used primarily for the treatment of hypercalcemia, and prevention of skeletal complications in multiple myeloma, breast cancer, and prostate cancer. (See "Treatment of hypercalcemia" and see "Bisphosphonates in breast, prostate, and other solid tumors", section on Pamidronate).

Pamidronate is also effective for osteoporosis, and has been used for patients with osteoporosis who could not tolerate oral bisphosphonates [57]. However, it has been superseded by zolendronic acid and in some cases intravenous ibandronate.

ORAL REGIMEN — Bisphosphonates are poorly absorbed orally (less than one percent of the dose) [58], and must be taken on an empty stomach for maximal absorption. The following regimen is recommended to maximize absorption and minimize the risk of esophageal adverse effects. (See "Gastrointestinal" below).

Bisphosphonates should not be given to patients with active upper gastrointestinal disease.

Bisphosphonates should be discontinued in patients who develop any symptoms of esophagitis.

Bisphosphonates should be taken alone on an empty stomach first thing in the morning with at least 240 mL (8 oz) of water while sitting or standing to minimize the risk of the tablet getting stuck in the esophagus. After administration, the patient should not have food, drink, medications, or supplements for at least one-half hour (alendronate, risedronate) or one hour (ibandronate).

Bioavailability may be seriously impaired by ingestion with liquids other than plain water, such as mineral water, coffee, or juice, or by retained gastric contents, as with insufficient fasting time or gastroparesis, or by eating or drinking too soon after taking the bisphosphonate.

Patients should remain upright for at least 30 minutes before eating, both to minimize the risk of reflux and improve absorption of the drug.
Compliance is also important for optimal fracture reduction [59,60].

Timing of dose — Administration of bisphosphonates first thing in the morning, prior to breakfast, appears to be important for bioavailability and subsequent suppression of bone turnover. This was illustrated in a randomized trial of nursing home residents who were assigned to risedronate or placebo between meals (after a two-hour fast) for 12 weeks, rather than before breakfast or the first liquid of the day [61]. Markers of bone turnover were not suppressed as they typically would be with before-breakfast administration, suggesting that this alternative schedule may not provide the desired effects on bone mineral density.

IV REGIMEN — Intravenous bisphosphonates (zoledronic acid and ibandronate) provide an alternative option for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill. IV bisphosphonates may be associated with flu-like symptoms and hypocalcemia. Acetaminophen can be administered to prevent or treat flu-like symptoms.

Hypocalcemia is more likely to occur in those individuals with vitamin D deficiency, and therefore, it can be minimized by vitamin D and calcium supplementation. A serum calcidiol (25-hydroxyvitamin D) concentration should be assessed prior to IV bisphosphonate infusions. Individuals with vitamin D deficiency (25-hydroxyvitamin D <15 ng/mL [37 nmol/L]) should be treated prior to the infusion. (See "Treatment of vitamin D deficient states"). Increasing calcium supplementation (doubling of usual dose) for five to seven days, starting on the day of the infusion, may also minimize hypocalcemia. (See "Adverse effects" below).

KIDNEY DISEASE — Patients with chronic kidney disease with creatinine clearance (CCr) above 30 to 35 mL/min are usually managed similarly, with appropriate modification of bisphosphonate doses based upon level of kidney function [62-64]. However, there is little data about fracture prevention efficacy and long-term adverse effects in subjects with reduced renal function, and bisphosphonates are generally not recommended for those with CCr below 30 to 35 mL/min.

Retrospective analyses of the Fracture Intervention Trial (FIT) data and pooled data from nine risedronate studies revealed that 7 to 10 percent of subjects had severe renal impairment (defined as an eGFR <30 to 45 ml/min) and 37 to 45 percent had moderate impairment (eGFR ≥30 to 59 ml/min) as estimated by the Cockcroft-Gault formula [64,65]. Compared with placebo treated women, alendronate and risedronate increased BMD and prevented vertebral fracture regardless of degree of renal impairment.

There were no differences in the adverse event rate between subjects with normal or reduced renal function in either study. In the FIT study, there was a small increase in creatinine during the three year study, but the increase was similar in those with and without reduced renal function (mean increase in both groups 0.01 +/- 0.10) and in those taking placebo or alendronate. There was no increase in serum creatinine in the risedronate studies (mean exposure of two years).

Thus, bisphosphonates appear to be effective in individuals with moderately reduced renal function. However, women with serum creatinine >1.27 mg/dl (112 mmol/liter) or serum PTH >85 pg/ml were excluded from participation in FIT, ie, women with renal dysfunction resulting in secondary hyperparathyroidism were not treated with alendronate. Therefore, there is inadequate data with regard to fracture prevention efficacy in those with more severe kidney disease resulting in secondary hyperparathyroidism and in end-stage renal failure.

With progression of renal failure, serum PTH concentrations rise, and the bone morphologic features of renal osteodystrophy [osteitis fibrosis cystica (due to secondary hyperparathyroidism), osteomalacia, adynamic bone disease, and/or mixed osteodystrophy], rather than osteoporosis, become predominant. The principal goal with regard to bone disease in patients with significant renal dysfunction is to prevent or manage renal osteodystrophy, largely by controlling secondary hyperparathyroidism. In this setting, the diagnosis of osteoporosis should be made only after excluding renal osteodystrophy. The diagnosis and management of renal osteodystrophy and secondary hyperparathyroidism are discussed in detail elsewhere. (See "Active vitamin D analogs and calcimimetics to control hyperparathyroidism in chronic kidney disease").

MONITORING THE RESPONSE — Serial BMD measurements are performed to assess the clinical response to therapy. This topic is reviewed in detail elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on Monitoring the response to therapy, and see "Overview of dual-energy x-ray absorptiometry", section on Interpretation of BMD changes, and see "Use of biochemical markers of bone turnover in osteoporosis").

ADVERSE EFFECTS

Gastrointestinal — Gastrointestinal side effects have been the primary concern for patients taking oral bisphosphonates. However, the incidence of these side effects is very low if proper administration instructions are followed. (See "Oral regimen" above).

Alendronate — In clinical trials, the incidence of upper gastrointestinal problems in women receiving alendronate daily [6,66] or once weekly [67] was not different from those receiving placebo. However, pill-induced esophagitis and esophageal ulcers can occur, and may be disabling and require hospitalization or rarely lead to esophageal stricture [68,69]. In addition, endoscopically apparent gastric ulcers have been described in patients receiving a bisphosphonate [70]. The risk may be potentiated by concomitant use of a nonsteroidal antiinflammatory drug [71].

Esophageal complications are infrequent if patients follow the recommendations outlined above [2,4-6]. (See "Oral regimen" above). There has been concern that these complications may be more frequent in ordinary practice than in clinical trials, because patients with dyspepsia were excluded from the trials [72]. However, in a study of 72 patients who discontinued alendronate because of gastrointestinal side effects and who were then randomly assigned to a rechallenge with either alendronate or placebo, 15 percent of the patients taking alendronate and 17 percent of those taking placebo stopped treatment because of gastrointestinal side effects. These data suggest that many of the gastrointestinal side effects seen reflect a high background incidence of gastrointestinal complaints, rather than an alendronate-specific effect [73-75].

Risedronate — The risk of upper gastrointestinal side effects with risedronate also appears to be low.

In clinical trials, the incidence of gastrointestinal side effects was not different from placebo [28].

In an endoscopic study of 515 postmenopausal women receiving risedronate (5 mg/day) or alendronate (10 mg/day) for two weeks, significantly fewer patients in the risedronate group had gastric ulcers (4.1 percent versus 13.2 percent for alendronate) [76]. Another endoscopic trial confirmed these findings [77]. However, a third randomized endoscopy study comparing risedronate to alendronate found no difference in ulcerations between the two agents [78].

In a pooled analysis of nine clinical trials that included 10,068 patients randomly assigned to risedronate (5 mg/day) or placebo for up to three years, upper gastrointestinal tract adverse events were no different between the two groups (29.8 and 29.6 percent, respectively) [79]. Unlike clinical trials with alendronate, patients with active gastrointestinal disease were not excluded from the studies. (See "Medication-induced esophagitis").

Thus, the risk of esophageal adverse effects appears to be low with risedronate, even in patients with a history of esophageal disease.

Flu-like symptoms — Intravenous bisphosphonates are often associated with an acute-phase reaction within 24 to 72 hours of the infusion, characterized by low grade fever, myalgias, and arthralgias. Treatment with antipyretic agents (ibuprofen or acetaminophen) generally improves the symptoms, and the recurrence of symptoms decreases with subsequent infusions.

In the HORIZON trial, the most commonly reported side effects were fever, flu-like symptoms, myalgia, headache, and arthralgia, which occurred within three days after the first infusion in 32 percent of individuals in the ZA group [55]. Post-dose symptoms decreased in frequency in the ZA group after the second and third infusion (6.6 and 2.8 percent, respectively).

Other

Hypocalcemia — Treatment with an oral bisphosphonate lowers serum calcium concentrations, but clinically important hypocalcemia has been reported only in patients with hypoparathyroidism [80]. It might also be expected in patients with vitamin D or calcium deficiency.

In the HORIZON trial, hypocalcemia (calcium < 8.3 mg/dl [2.075 mmol/L]) occurred more commonly with intravenous ZA than with placebo (1.3 versus 0.02 percent) [55]. Hypocalcemia was noted nine to eleven days post infusion and was reported to be transient and asymptomatic. However, hypocalcemia may be more severe and prolonged in individuals who are vitamin D deficient at the time of IV treatment [81,82]. (See "IV regimen" above).

Ocular side effects — Ocular side effects including pain, blurred vision, conjunctivitis, uveitis, and scleritis have been reported with most bisphosphonates. However, these complications appear to be rare [55,83-85].

Musculoskeletal pain — Although rare, some patients have experienced severe musculoskeletal pain (bone, joint, and/or muscle pain) while taking oral bisphosphonates [86-88].

Osteonecrosis of the jaw — Osteonecrosis of the jaw (ONJ, avascular necrosis of the jaw), often associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw, has been described in patients receiving chronic bisphosphonate therapy. Risk factors for developing ONJ include intravenous bisphosphonates, cancer and anti-cancer therapy, duration of exposure, dental extractions, dental implants, poorly fitting dentures, glucocorticoids, smoking, and pre-existing dental disease [89,90]. (See "Risks of bisphosphonate therapy in patients with malignancy", section on Osteonecrosis of the jaw).

Although most cases have been in cancer patients or in patients with a compromised immune system (particularly multiple myeloma and metastatic breast cancer), who were treated with intravenous bisphosphonates, cases have been noted in patients with postmenopausal osteoporosis taking oral bisphosphonates [91,92]. It has been estimated that the risk of ONJ is approximately 1 in 10,000 to 1 in 100,000 patient-years in patients taking oral bisphosphonates for osteoporosis [89,93,94]. There is little data on the risk of ONJ in patients using intravenous bisphosphonates at doses recommended for the treatment of osteoporosis. In two clinical trials of zoledronic acid versus placebo for the treatment of osteoporosis, there were two potential cases of ONJ (one in each group). (See "Zoledronic acid" above).

In patients initiating or receiving treatment with oral bisphosphonates for the treatment of osteoporosis, the American Society of Bone and Mineral Research recommends that clinicians discuss the risk, signs, and symptoms of ONJ, and the risk factors for developing ONJ [89]. Although good oral hygiene and regular dental visits are encouraged, a dental visit prior to beginning oral bisphosphonates is not necessary.

In patients already receiving oral bisphosphonates, there is particular concern for patients scheduled for invasive dental procedures that involve the jaw, such as extractions or implants.

The American Association of Oral and Maxillofacial Surgeons suggest performing dentoalveolar surgery, such as extractions and implants, as usual in patients who have been treated with oral bisphosphonates for less than three years. However, if a patient has been treated for more than three years, they recommend discontinuing oral bisphosphonates for three months prior to performing the dental surgery and restarting when the bone has healed [95]. These criteria were chosen on the basis of clinical experience and observational data as to which patients are at higher risk for developing ONJ.

However, there are no data to suggest that this would lower ONJ risk. In addition, bisphosphonates stay in bone for years, not months. But if a patient chooses to stop the bisphosphonate, it is unlikely that there would be adverse consequences on BMD or fracture risk.

Potential complications and recommendations for patients receiving bisphosphonates for the treatment of malignancy are described in detail elsewhere. (See "Risks of bisphosphonate therapy in patients with malignancy", section on Osteonecrosis of the jaw).

Arrhythmia — Bisphosphonates in general have not been associated with atrial arrhythmias. However, in the HORIZON Pivotal Fracture Trial, the number of patients who had arrhythmia, including serious atrial fibrillation (AF), was greater in the ZA compared with placebo group (1.3 versus 0.5 percent) [55]. In contrast, an increase in atrial arrhythmia was not seen in the HORIZON Recurrent Fracture Trial, which included older individuals and identical dosing. Hypocalcemia may be related to AF. However, most of the events occurred more than 30 days after the infusion, at which time mild, transient hypocalcemia would have resolved. Whether the acute-phase reaction contributes to the risk of AF is unclear.

This finding in the HORIZON Pivotal Fracture Trial prompted additional review, as illustrated by the following:

In a retrospective review of the Fracture Intervention Trial data, there was a trend toward an increased risk of serious AF in the alendronate compared with placebo group (relative hazard 1.5, 95% CI 0.97-2.40) [96].

In a retrospective analysis of clinical trials of risedronate versus placebo for the treatment of osteoporosis, there was no difference in the incidence of AF (reported as an adverse or serious adverse event) [97].

In a population based case-control study from Denmark, which evaluated 13,586 patients with atrial arrhythmia and 68,054 population controls, current, former, or new use of bisphosphonates (etidronate and alendronate) was not associated with an increased risk of atrial fibrillation or flutter (adjusted RR for current use compared with non-use 0.95, 95% CI 0.84-1.07) [98].

In another case-control study from the US (719 women with AF, 966 control subjects), ever use of alendronate was associated with a higher risk of AF than never use (odds ratio [OR] 1.86, 95% CI 1.09-3.15) [99]. However, the risk of AF was increased in past (OR 3.27, 95% CI 1.43-7.47), not current users (OR 1.42, 95% CI 0.78-2.59). In addition, the risk was not temporally related to the interval since first prescription or dose of alendronate.

Thus, data on the potential increased risk of atrial fibrillation with bisphosphonates are conflicting. However, the large observational study from Denmark and the absence of an association between current use and AF in the US case-control study suggest that the risk of atrial fibrillation from oral bisphosphonates is small, if it exists at all.

The observed association between intravenous zoledronic acid and atrial fibrillation may be plausible, but the studies do not prove causality. Osteoporosis and atrial fibrillation are more common in the elderly and share similar risk factors, which may explain the reported findings. In the absence of more definitive data, the benefits of fracture prevention must be weighed against the potential risk of atrial fibrillation, and some caution should be employed when considering IV bisphosphonates for patients with serious underlying heart disease and/or a history of atrial fibrillation.

Theoretical risks — Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. Although clinical trial data clearly support the beneficial effect of bisphosphonates on the prevention of osteoporotic fracture, there is theoretical concern that prolonged therapy leads to oversuppression of bone turnover ("frozen bone") and increased skeletal fragility [100]. In animal studies, high-dose bisphosphonate accumulation results in microscopic damage [101]. Although similar findings do not appear to be common by histomorphometry in postmenopausal women on long-term bisphosphonates [102], individual cases of atypical fracture (particularly sub-trochanteric fractures) and severely suppressed bone turnover in the setting of prolonged bisphosphonate therapy have been reported [103,104].

The observed association in the case reports does not prove causality, and additional studies are required to determine if oversuppression of osteoclasts by prolonged bisphosphonate therapy can result in atypical fractures in selected individuals. Such data would also influence decisions on duration of therapy. Stopping bisphosphonate therapy after five years (with careful BMD and risk factor assessment follow-up) may be reasonable for some women (stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future), but concern about oversuppression of bone turnover is not a reason to stop bisphosphonate therapy in the vast majority of women. (See "How long to treat?" aboveSee "How long to treat?" above and see "Duration of therapy" belowsee "Duration of therapy" below).

DURATION OF THERAPY — There is currently no consensus on how long to continue bisphosphonate therapy. Alendronate and risedronate have demonstrated efficacy for 10 and 7 years, respectively. Stopping therapy after five years may be reasonable for some women, as there appears to be residual BMD and fracture benefit. (See "How long to treat?" aboveSee "How long to treat?" above).

Many practitioners give a drug "holiday" after five years of therapy in an attempt to reduce the risk of ONJ, an extremely rare complication. However, there are no data to suggest that this reduces ONJ risk. (See "Risks of bisphosphonate therapy in patients with malignancy", section on Osteonecrosis of the jaw).

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Osteoporosis prevention and treatment"). We encourage you to print or e-mail this topic, or to refer patients to our public web site www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS — Bisphosphonates, one of the available therapeutic options for the management of osteoporosis, inhibit bone resorption with relatively few side effects. As a result, they are widely used for the prevention and treatment of osteoporosis. Candidates for pharmacologic therapy for prevention and treatment are discussed elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on Candidates, and see "Prevention of osteoporosis").

Prevention — For most postmenopausal women, pharmacological therapy for prevention of osteoporosis is not necessary. However, it should be considered for women at high risk of fracture. (See "Prevention of osteoporosis").

For postmenopausal women who are candidates for and desire pharmacologic therapy for prevention of osteoporosis, we recommend bisphosphonates or raloxifene as first-line choices (Grade 2B). (See "Prevention of osteoporosis").

The dose for prevention for both alendronate and risedronate is 35 mg given once-weekly. (See "Alendronate" aboveSee "Alendronate" above, and see "Risedronate" abovesee "Risedronate" above).

Treatment

For postmenopausal women with established osteoporosis or fragility fracture, we recommend pharmacologic therapy (Grade 1A).
Additional information about candidates for pharmacologic therapy are found elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women").

For treatment of osteoporosis in postmenopausal women, we suggest bisphosphonates as first-line therapy (Grade 2B).

We favor bisphosphonates over raloxifene for osteoporosis treatment because they increase bone mineral density (BMD) more than raloxifene, and have documented hip fracture efficacy. (See "Overview of the management of osteoporosis in postmenopausal women", section on Recommendations).

Choice of bisphosphonate

For postmenopausal women with osteoporosis, we suggest either weekly alendronate or risedronate as the initial choice of bisphosphonate (Grade 2B). Alendronate is available in a liquid preparation for individuals who cannot swallow pills. Although oral ibandronate may be more convenient for patients, a reduction in hip fracture risk has not been established. (See "Ibandronate" above).

For women with a history of significant gastroesophageal reflux or peptic ulcer disease, we suggest initial therapy with risedronate over alendronate, to minimize adverse gastrointestinal side effects (Grade 2B). (See "Gastrointestinal" above).
We suggest an intravenous bisphosphonate formulation for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes (Grade 2B). Zoledronic acid is the only intravenous bisphosphonate that has demonstrated efficacy for fracture prevention in clinical trials and is therefore our agent of choice. However, long-term safety data in patients with osteoporosis is lacking. (See "Zoledronic Acid" above).

Dental procedures

For patients scheduled for invasive dental procedures, we suggest not stopping bisphosphonates (Grade 2C). However, the risk of developing ONJ as a rare complication of intravenous or oral therapy should be discussed with patients.
There are no data to suggest that discontinuing bisphosphonates for dental procedures would lower ONJ risk. In addition, bisphosphonates stay in bone for years, not months. However, if a patient chooses to stop the bisphosphonate, it is unlikely that there would be short term adverse consequences on BMD or fracture risk. (See "Osteonecrosis of the jaw" above).

Duration of therapy

For patients on bisphosphonates for five years who are at high risk of fracture (previous fractures, older age, frail, high risk for fall, etc), we suggest continuing therapy (Grade 2B).

Residual benefit after stopping therapy has not been demonstrated in this population. In addition, the benefits of continued therapy likely outweigh the risk of ONJ, an extremely rare complication.

For patients taking alendronate for five years who have a stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future, we suggest discontinuing the drug (Grade 2C). We then monitor BMD and urinary markers of resorption. The drug should then be resumed if BMD decreases or urinary markers of bone turnover increase.

Data demonstrating residual benefit after stopping risedronate after five years of use are not yet available. Until such studies are available, for patients taking risedronate for three years, we suggest continuing therapy (Grade 2C).



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REFERENCES

Androgen production and therapy in women

Androgen production and therapy in women

Author
Laurence Udoff, MD
Section Editor
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD



Last literature review version 16.2: May 2008 | This topic last updated: May 28, 2008 (More)


INTRODUCTION — All women produce some androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition and sexual behavior. This topic will review androgen production in pre- and postmenopausal women and the effects of androgen therapy in postmenopausal women. Female sexual dysfunction, including hypoactive sexual desire disorder, is discussed elsewhere. (See "Etiology and diagnosis of sexual dysfunction in women" and see "Treatment of sexual dysfunction in women").

ANDROGEN PRODUCTION

Premenopausal women — The major androgens in the serum of normal cycling women are dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT) in descending order of serum concentrations [1] .

Though abundant in the circulation, DHEA-S, DHEA, and A may be considered pro-hormones requiring conversion to T or DHT to express their androgenic effects. Androgens are mainly produced in the adrenal gland, the ovary and from the peripheral conversion of pro-hormones.

• DHEA-S is produced solely by the adrenal gland at a rate of 3.5 to 20 mg per day [2] . Circulating levels are in the range of 1 to 4 mcg/mL.
• DHEA is also produced in the adrenal gland (50 percent), the ovary (20 percent) and from peripheral conversion of DHEA-S (30 percent) with total production rates of 6 to 8 mg per day [3] . Circulating levels are in the range of 1 to 10 ng/mL.
• A production is split equally between the adrenal gland and the ovary. Daily rates of production are 1.4 to 6.2 mg/day and circulating levels are in the range of 0.5 to 2 ng/mL [4,5] .
• T is synthesized in the adrenal gland (25 percent), the ovary (25 percent) and from the peripheral conversion of A (50 percent). Daily production rates are in the range of 0.1 to 0.4 mg/day and circulating levels are between 0.2 and 0.7 ng/mL with the lowest levels found during the early follicular phase followed by a 20 percent increase at midcycle [3] . Nearly all (99 percent) of circulating T is protein-bound (mainly to sex-hormone binding globulin [SHBG]) [6] . Therefore, any impact on SHBG concentration (eg, oral estrogen-mediated increase in SHBG) affects the concentration of the free/active androgen.
• Lastly, DHT is mainly a peripheral product of T conversion and has very low circulating levels [7] .

All the major androgens are metabolized and excreted into the urine almost exclusively as 17-ketosteroids.

Natural history — In a report of normal women ages 18-75 years, serum androgen concentrations (total and free testosterone, DHEA-S, and androstenedione) gradually declined in women of reproductive age [8,9] , with no further decrease after clinical menopause [10] .

Putative roles for androgens — Androgens are essential precursors for estrogen synthesis. They also play an important role in follicular development. Maintenance of a precise balance of estrogens and androgens within ovarian follicles is a requirement for successful follicular maturation [11-13] . In addition, many tissues have androgen receptors, including the central nervous system [14] and bone [15] , which has led to speculation that androgens affect their function.

It has also been proposed that androgens play a role in sexual behavior. A woman's libido is dependent upon many factors, including psychological factors [16] . As an example, in a study of 341 peri- and postmenopausal women, common menopausal symptoms, including depression, sleep disturbances, and night sweats, were associated with diminished libido [17] .

A balance of estrogen and androgen also may be necessary for normal sexual desire and responsiveness, but the results of studies on the role of androgens in sexuality in normal premenopausal women are inconclusive [9,16] . As an example, a cross-sectional study of a population-based cohort of women ages 48 to 58 years suggested that most aspects of female sexual function were not affected by age, menopausal functioning, or serum sex hormone concentrations [9] . Additionally, a study comparing women with premature ovarian failure with normal premenopausal controls did not find an important role for circulating androgens in sexual functioning [18] .

The special case of adrenal insufficiency may be an exception, as data suggests that young women with this condition may show improvement in sexuality with the addition of DHEA to their replacement regimen. (See "Dehydroepiandrosterone and its sulfate", section on Adrenal insufficiency).

Androgens may also be important for the maintenance of normal affect, cognitive functioning and of skeletal homeostasis. (See "Cognitive function" below and see "Bone metabolism" below). Regarding the latter, a significant body of evidence exists implicating a role for androgens in the maintenance of bone health. Androgens may impact bone homeostasis directly (eg, all bone cells including osteoblasts, osteoclasts, and osteocytes have androgen receptors), or indirectly by conversion to estrogen, or by their effect on local and systemic factors that control the bone cells' microenvironment [15] .

Low serum androgen concentrations may be associated with lower bone density and fracture risk:

• Serum free androgen concentrations and bone mineral density have been positively correlated in several studies [19-21] .
• In another study, postmenopausal women with a history of vertebral crush fractures had lower serum free androgen concentrations (and similar serum estrogen values) when compared to women with no fractures [19] .
• Women with hypopituitarism (who are androgen deficiency) have low bone density [22] .


Postmenopausal women — The production rate and serum concentrations of androstenedione fall by 50 percent after the menopause (show figure 1) [23,24] . This change appears to result from decreased ovarian production of the hormone with the adrenal glands becoming the major site of androstenedione production. This hypothesis is based upon the following findings in postmenopausal women:

• Administration of corticotropin (ACTH), but not human chorionic gonadotropin (hCG), raises serum androstenedione concentrations.
• Serum androstenedione concentrations fall little after oophorectomy, but markedly after the administration of dexamethasone, which suppresses the release of ACTH.
• There is a diurnal variation in serum androstenedione concentrations that parallels the diurnal variation in serum cortisol concentrations.
• The ratio of androstenedione in ovarian venous blood to peripheral venous blood is decreased [24] .


The rate of testosterone production also falls in postmenopausal women (show figure 2) [25,26] , mostly because of a decline in the peripheral production of testosterone from androstenedione [27] . Ovarian testosterone production remains relatively constant, thereby increasing the relative ovarian contribution to overall testosterone production [27] . These observations are substantiated by the larger ovarian-to-peripheral serum gradient of testosterone in postmenopausal than in premenopausal women [24] , and by the 40 to 50 percent decrease in serum testosterone concentration seen after oophorectomy in postmenopausal women [28] , a change that persists over time [29] .

In addition to this decline in ovarian androgen secretion, there is an age-related decline in the adrenal androgens dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S). As an example, in women ages 40 to 50, serum DHEA concentrations are approximately 50 percent of the peak concentrations seen in younger women [30] . (See "Dehydroepiandrosterone and its sulfate").

Serum androstenedione and testosterone concentrations fall little with advancing age after the menopause, despite a progressive fall in serum DHEA concentrations [31] . This difference suggests that little androstenedione and testosterone are derived from DHEA in older women, and that ovarian androstenedione and testosterone production increases or their clearance decreases with age [32] .

The decline in ovarian androgen production in postmenopausal women is much less than the decline in estrogen production; as a result, the ovaries become primarily androgen-producing glands. The relatively high rate of androgen production is due to the increase in gonadotropin secretion, which stimulates steroidogenesis in ovarian hilar cells or luteinized stromal cells [32] . Ovarian stromal tissue has receptors for both follicle-stimulating hormone and luteinizing hormone [30,33] , and chorionic gonadotropin (hCG) stimulates androstenedione, estradiol and progesterone secretion by isolated ovarian cortical stromal and hilar cells [34,35] . In addition, postmenopausal women given hCG have a small increase in serum testosterone concentrations [36] and hyperplasia of their ovarian hilar cells [37] ; in comparison, their serum estrogen concentrations do not increase [38] .

The vast majority of evidence suggests that the postmenopausal ovary is a major androgen-producing gland [27-38] , with the exception of one study [39] . In 10 postmenopausal women with adrenal insufficiency, women with natural and surgical menopause had undetectable serum androgen concentrations. In addition, ovarian stimulation with hCG did not increase circulating levels of androgens in the women with intact ovaries. Negligible levels of T and A were found in ovarian homogenates, and ovarian immunocytochemistry did not detect the presence of enzymes for androgen synthesis. These data have not been confirmed by other investigators.

ANDROGEN DEFICIENCY — Women with low levels of circulating androgens are said to have androgen deficiency or androgen insufficiency syndrome. However, there are no clear biochemical criteria for this syndrome; measurement of serum androgen concentrations, in particular, free testosterone, is problematic because of a lack of validated assays in the female range (much lower than the male range); there are no age-based normative data; and serum androgen concentrations do not appear to be an independent predictor of sexual function in women [40-44] .

An Endocrine Society Clinical Practice Guideline recommended against making a diagnosis of androgen deficiency because of the lack of both a well-defined clinical syndrome and age-based normative data for serum testosterone and free testosterone concentrations That said, there are a number of conditions that may represent androgen deficiency syndromes:

• Bilateral oophorectomy
• Primary adrenal insufficiency
• Hypopituitarism, particularly women with both ACTH and gonadotropin deficiency [45]


Medications including oral contraceptives and glucocorticoids may cause a relative androgen deficiency due to ovarian and adrenal androgen suppression, respectively. Oral estrogens, even at low doses (menopausal replacement) reduce serum free testosterone concentrations by increasing serum SHBG levels.

Women with anorexia nervosa have lower serum concentrations of total and free testosterone, but not DHEAS concentrations when compared to normal-weight women with hypothalamic amenorrhea or healthy controls [46] . In this report, women with anorexia nervosa who were taking oral contraceptives had the lowest concentrations of free testosterone and DHEAS.

EFFECTS OF EXOGENOUS ANDROGENS — Androgen replacement therapy has been advocated by some for postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause [47,48] . However, given the lack of a well-defined clinical syndrome, age-based normative data for serum testosterone concentrations, and long-term safety data for testosterone preparations, we agree with the Endocrine Society guidelines and currently do not suggest the routine use of androgen therapy in women [42] .

Exceptions to this may include women with hypopituitarism (ACTH and gonadotropin deficiency), bilateral oophorectomy and premature ovarian failure (POF). However, our ability to treat these women is limited by the lack of an approved testosterone preparation. Women with primary and secondary adrenal insufficiency are candidates for DHEA therapy. (See "Dehydroepiandrosterone and its sulfate").

Sexual function — Testosterone therapy in postmenopausal women may have a beneficial effect on sexual function in select women, but data are variable.

Replacement vs. supraphysiologic therapy — Studies of androgen therapy in women with androgen deficiency (eg, hypopituitarism, bilateral oophorectomy) should be considered separately from studies in women with sexual desire disorders who are not androgen deficient, as the former would be considered to be replacement therapy, and the latter, supraphysiologic therapy. However, in almost all trials reporting a beneficial effect of testosterone, including those considered to be "replacement" trials, serum testosterone concentrations are higher than the upper limit of normal for premenopausal women.

• Studies in heterogeneous populations - Many testosterone trials have been performed in heterogeneous populations of women (natural or surgical menopause, with normal or low libido) receiving variable types, doses, and routes of administration of estrogen and testosterone. One of these trials reported no effect of testosterone on sexual arousal [49] , while others reported an improvement in sexual function in women with normal [50,51] or low [52] libido at baseline.

A trial in naturally menopausal women diagnosed with hypoactive sexual desire disorder who were taking estrogen reported improved sexual function with the transdermal testosterone patch (dose 300 mcg/day) [53] .

• Women post-oophorectomy — The main evidence that testosterone has an effect on sexual function comes from trials that have examined a transdermal testosterone preparation combined with exogenous estrogen in women who have undergone bilateral oophorectomy and subsequently developed hypoactive sexual desire disorder (HSDD). Although there is a modest improvement in sexual function with testosterone in these trials, serum testosterone concentrations are typically in the high normal or supranormal range for younger premenopausal women.

In one study, 300 mcg/day of transdermal testosterone improved sexual function and psychological well-being, but mean serum free testosterone concentration increased to approximately twice the mean of premenopausal women [54] . A dose of testosterone (150 mcg/day) that increased the mean serum testosterone to a value similar to that of the mean in premenopausal women did not increase sexual function or psychological well-being.

In a second, larger, multicenter trial, 532 women with hypoactive sexual desire who had undergone hysterectomy with bilateral oophorectomy received either testosterone (300 mcg/day) or placebo patch twice per week (in addition to estrogen) for 24 weeks [55] . Sexual desire and frequency of sexual activity increased more in the testosterone group compared to placebo, but only by one additional episode per 2.5 week interval in the testosterone group versus one additional episode per 5.5 week interval with placebo. Serum testosterone levels and androgenic side effects increased with transdermal therapy; however, the side effects were considered mild. Although promising, the results of this trial do not address the safety of long-term testosterone administration.

Additional, phase-III trials reported similar results on sexual desire and sexual activity [56,57] . In one study, no additional benefits were observed with a testosterone patch delivering 400 mcg/day when compared to 300 mcg/day [56] .

• Hypopituitarism — Women with hypopituitarism, in particular those with both ACTH and gonadotropin deficiency, may also benefit from testosterone therapy. In a trial of women with androgen deficiency due to hypopituitarism, treatment with 150 to 300 mcg of testosterone transdermally daily for one year improved overall sexual function, as judged by a questionnaire, by a small but statistically significant amount [58] .
• Use of testosterone without estrogen — Preliminary data from a trial in postmenopausal women (both natural and surgical) with hypoactive sexual desire disorder receiving transdermal testosterone 300 mcg (without estrogen) suggest that sexual function may also be improved in this group of patients [59] .
• Meta-analysis — In a systematic review of 23 clinical trials (with 1957 participants) of testosterone plus hormone therapy versus hormone therapy alone in peri- or postmenopausal women, a significant decrease in serum HDL concentrations was observed, there was insufficient evidence of a treatment effect in perimenopausal women, and there appeared to be an improvement in sexual function scores in postmenopausal women [60] . However, only three trials were included in the sexual function analysis. In addition, this review was not limited to women who would be considered to be truly androgen-deficient (ie post-oophorectomy). (See "Androgen deficiency" above).


Other effects

Vasomotor symptoms — Testosterone therapy may be effective for postmenopausal women who remain symptomatic (eg, hot flashes) despite estrogen or estrogen-progestin treatment [61-63] . Because androgen production declines after the menopause, it is reasonable to assume that some postmenopausal symptoms could at least in part be due to androgen deficiency. However, we do not consider persistent vasomotor flushes to be an indication for routine androgen replacement.

Cognitive function — Some data from uncontrolled studies in which postmenopausal women were treated with estrogen alone or with androgen have suggested that androgen may improve affect and cognitive functioning. This issue was also addressed in a randomized double-blind, placebo-controlled trial in which postmenopausal women were treated for two months with either estrogen, estrogen plus testosterone, or placebo [64] . Both hormone treatments were associated with better scores on a self-rating scale of anxiety and depression than placebo, and there was a trend towards better scores in the estrogen plus testosterone group as compared with the estrogen group.

In another study of the effect of hormone treatment on energy, well-being and appetite, estrogen plus testosterone was superior to estrogen alone [65] . Androgen therapy has also resulted in increased well-being, improved energy levels, and less dysphoric mood in oophorectomized women [66] .

A common criticism of these studies is that the testosterone given is metabolized into estrogen and therefore that the results are mainly due to an estrogen effect. However, in the last report, there was no difference in the incidence of hot flashes between the treatment and placebo groups, suggesting a mode of action for testosterone distinct from aromatization to estrogen [66] .

Bone metabolism — A direct correlation between bone density and serum androgens has been noted in postmenopausal women [20,21] . The effects of androgen therapy on bone in postmenopausal women have been examined in studies of androgen alone and androgen in combination with estrogen; numerous observations are compatible with a beneficial effect of androgen in this setting [49,67-74] :

• In a study of biochemical markers of bone resorption and formation, women receiving either estrogen or estrogen plus androgen had evidence of increased bone formation, whereas bone resorption decreased only in the women receiving estrogen alone [67] . In another report, androgen monotherapy in postmenopausal women with osteoporosis reduced markers of bone turnover (serum alkaline phosphate concentrations and urinary calcium excretion) to the same extent as estrogen [75] .
• A number of reports have shown that nandrolone increased bone mineral density at the spine and radius when compared with no treatment [68-70] .
• In studies of the effect of androgen plus estrogen, the addition of androgen to a regimen of estrogen with or without progestin had a more beneficial effect on bone density [72-74] .
• In a study of women with clear androgen deficiency due to hypopituitarism, who were taking estrogen and had normal baseline bone density, physiologic testosterone replacement (150 to 300 mcg/day transdermally) increased serum testosterone into the normal range, and increased mean hip and radius, but not spine, bone mineral density [58] .

Taken together, these results suggest that androgen alone or in combination with estrogen may protect against osteoporosis. The putative mechanisms involve a decrease in bone resorption by either direct androgenic action or conversion of androgen to estrogen, or an increase in bone formation. However, there is no strong evidence that the addition of androgen to estrogen in postmenopausal women is more beneficial than estrogen alone.

Adrenal androgen replacement — DHEA replacement therapy appears to be effective in women with adrenal androgen deficiency, including those with primary adrenal insufficiency, hypopituitarism (ACTH deficiency), and chronic glucocorticoid use (for example, women with systemic lupus erythematosus). (See "Dehydroepiandrosterone and its sulfate", section on Adrenal insufficiency and see "Overview of the therapy and prognosis of systemic lupus erythematosus in adults", section on Dehydroepiandrosterone (DHEA)).

DHEA supplementation has also been proposed as adjunctive hormone replacement therapy for aging men and women. While there is a well-known decline in serum DHEA and DHEA-S concentrations with age, the role of adrenal androgen replacement in peri- and postmenopausal women is unclear. However, DHEA supplementation in otherwise healthy peri- or postmenopausal women does not appear to have clinical benefits. (See "Dehydroepiandrosterone and its sulfate").

Risks and side effects — One concern regarding androgen replacement therapy in postmenopausal women is the possible adverse effect on cardiovascular disease risk, because androgens have been thought to be atherogenic. This supposition is based mainly on the higher rates of cardiovascular disease in men as compared with women and the higher risk in women with androgen excess (eg, polycystic ovary syndrome) [76,77] . (See "Postmenopausal hormone therapy and cardiovascular risk").

One proposed mechanism by which androgens may adversely affect the risk of cardiovascular disease is through a decline in serum high-density lipoprotein (HDL) cholesterol concentrations. As compared with normal women, women with hyperandrogenism have lower serum HDL cholesterol concentrations [78] . In postmenopausal women, however, the results are less clear. One report found no strong correlation between serum androgen and HDL cholesterol concentrations [79] , but another study found that serum testosterone concentrations were inversely correlated with serum HDL cholesterol concentrations [80] . Confounding variables that could explain the disparity in the results include the effects of diet, body weight, exercise, and heredity, as well as methodological differences such as problems associated with the standardization of methods to measure serum lipids.

The more androgenic progestins (eg, norethindrone, levonorgestrel), when given as the progestin component of estrogen-progestin replacement therapy in postmenopausal women, tend to blunt the estrogen-related rise or even produce a treatment-related decline in serum HDL cholesterol concentrations [81] . However, the addition of testosterone to estrogen replacement therapy has produced conflicting results: it caused a decline in serum HDL cholesterol concentrations in studies using oral estrogen [52,74,82,83] , but not in others using non-oral routes of administration [54,62,84,85] .

One study suggests that testosterone administration might decrease cardiovascular risk in postmenopausal women on hormone replacement therapy (HRT) [86] . In 33 postmenopausal women on HRT compared with 15 controls, both endothelial-dependent and -independent brachial artery vasodilatation was improved by the addition of a testosterone implant (50 mg) for six weeks. Additionally, it has been shown in a group of sixty postmenopausal women that endogenous testosterone levels are positively correlated with brachial artery vasodilation [87] .

Other potential side effects of adding androgen to estrogen in postmenopausal women are acne, hirsutism, deepening of the voice, and clitoromegaly. Among women given testosterone implants, 15 to 20 percent had slight increase in downy facial hair after several years, but acne, voice changes and clitoromegaly were very rare [88] . Women given oral methyltestosterone doses (2.5 mg daily) may become mildly hirsute [74] . Androgen replacement therapy does not affect body weight or blood pressure [63,89] .

A possible association between testosterone administration and breast cancer risk has been reported. However, data are limited. (See "Postmenopausal hormone therapy and the risk of breast cancer", section on Effect of testosterone).

In a review of available testosterone clinical trials, hirsutism and acne appeared to be the major adverse reactions (both were dose- and duration-related and generally reversible). Virilization was rare, and oral, but not parental or transdermal, testosterone was associated with a decrease in serum HDL concentrations, which could have a negative impact on cardiovascular risk. However, there were no adverse effects on blood pressure, vascular reactivity, blood viscosity, hemoglogin concentration, coagulation factors or insulin sensitivity. All available trials are limited by their short duration (≤ two years) and the co-administration of estrogen or estrogen-progestin therapy [90] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women" and see "Patient information: Postmenopausal hormone therapy" and see "Patient information: Alternatives to postmenopausal hormone therapy"). We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.

SUMMARY — The use of androgens as an addition to estrogen or estrogen-progestin therapy for postmenopausal women is controversial.

• The clearest indication for androgen replacement therapy is in patients with symptomatic androgen insufficiency in association with hypopituitarism, adrenal insufficiency, premature ovarian failure, or in women who have undergone bilateral oophorectomy.
• Androgens may significantly improve sexual functioning in select postmenopausal women. (See "Sexual function" above).
• The data that androgens significantly improve cognitive function and affect are not compelling. (See "Cognitive function" above).
• Androgen may have a beneficial effect on bone, which may simply be due to the additional estrogen formed from the administered androgen; studies with nonaromatizable androgens could resolve this question. (See "Bone metabolism" above).
• Serum HDL cholesterol concentrations decline slightly in postmenopausal women receiving oral testosterone therapy, but it is not known if the change substantially affects overall cardiovascular risk. (See "Risks and side effects" above).
• Cosmetic side effects such as hirsutism and acne are usually mild and are well tolerated and irreversible virilizing changes are rare.

In conclusion, for highly selected postmenopausal women, especially those who have undergone bilateral oophorectomy, estrogen replacement alone may not be adequate therapy. Based upon the finding that endogenous androgen production declines after spontaneous menopause as well as oophorectomy, it may be logical to offer some women androgen therapy in conjunction with estrogen therapy. The practitioner and patient should realize, however that many questions remain to be answered regarding the efficacy and safety of this therapy. Most androgen preparations that have been used for this indication are not approved the United States Food and Drug Administration. (See "Treatment of sexual dysfunction in women").

Treatment of sexual dysfunction in women

Treatment of sexual dysfunction in women

Author
Alan Altman, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD



Last literature review version 16.2: May 2008 | This topic last updated: June 11, 2007 (More)


INTRODUCTION — A number of nonpharmacologic and pharmacologic therapies are available to treat sexual dysfunction in women. Prior to initiating treatment, however, it is important to emphasize that sexual activity or frequency is not necessarily correlated with sexual satisfaction. Sexual dysfunction only becomes a problem when the patient or her partner finds it to be a problem.

The management of sexual dysfunction in women is reviewed here. The etiology and diagnosis are discussed separately. (See "Etiology and diagnosis of sexual dysfunction in women").

NONPHARMACOLOGIC THERAPY — Treatment of sexual dysfunction can begin with any of a number of nonpharmacologic measures. Blood flow increases during sexual activity; thus, sexual activity begets better sexual function. Masters and Johnson demonstrated this in their early work; sexual activity maintained vaginal pH, pO2, and mucosal health and allowed successful function to continue. The same beneficial effects could be achieved with sexual activity of any kind, partnered or unpartnered, including masturbation or sexual fantasy alone.

A number of other nonpharmacologic interventions also may be helpful.

Communication — Communicating sexual likes and dislikes, in a nonthreatening manner, can reignite novelty and intensify satisfaction. This may be difficult if techniques of communication were never the couple's forte. Sex videos or erotic literature can assist in seeking out new directions. Communication also means giving attention to a partner's presence, discussions, and ideas, which can help validate their importance and self image.

Lifestyle changes — Changes in lifestyle such as smoking cessation, strength training exercises, and aerobic training, can all have positive impacts on sexuality. Strength training, with weights or resistance machines may enhance body image and therefore, indirectly enhance libido.

Vaginal weights — Vaginal weights can be used to strengthen the pelvic floor muscles. In some women with orgasmic disorders, this can improve awareness of sexual response and also potentially correct urine leakage, which might cause a problem during sexual activity [1] .

Vaginal weights are usually available in sets of five weights. The patient inserts the lightest weight and remains upright for 15 minutes, twice a day. With the weight in place, she should feel the urge to hold it in. After a number of days, she will no longer feel the urge to hold in the weight, because an improvement in muscle tone has occurred. She then moves up to the next weight in the progression. Once she no longer feels the urge to hold in the heaviest weight, a significant increase in muscle tone has taken place. Maintenance with the fifth weight should be carried out each month for five to seven consecutive days to preserve muscle tone.

Use of vaginal lubricants — Genitourinary atrophy symptoms, in particular vaginal dryness and dyspareunia, develop in a high percentage of postmenopausal women who are not taking estrogen. Vaginal estroggen is highly effective for treating these symptoms, but water soluble vaginal lubricants are also helpful for continued sexual activity. This topic is reviewed in detail separately. (See "Diagnosis and treatment of vaginal atrophy").

Increased tactile stimulation of partner — Decreased vasocongestion during arousal can create the need for increased manual and/or oral stimulation in the male to help achieve or maintain an erection, and in the female to achieve adequate clitoral, labial, and vaginal response. Just providing an explanation of the need for more stimulation in both partners can have a positive effect, not only on sexual response, but also on the relationship.

Sexual frequency — How frequent is enough? Everyone has a different answer and that answer depends on multiple variables. Surveys are notoriously inaccurate due to their questionable ability to collect honest data. The bottom line has to remain what is comfortable for each individual pair of partners [2] .

PHARMACOLOGIC THERAPY — When education, lifestyle, communication, and behavioral changes do not achieve the desired level of success, pharmacological therapy can be utilized to treat sexual dysfunction in women. Treatment options focus on providing hormonal support and increasing genital blood flow. However, there are few randomized, placebo controlled trials of pharmacologic therapy in postmenopausal women upon which to base recommendations [3] .

Estrogen — Estrogen may positively affect sexual function in a number of ways. Estrogens rapidly restore the superficial cell layer of the vaginal epithelium, reestablish elasticity, restore the balance in vaginal pH, improve mood, and increase vaginal blood flow to enhance lubrication. (See "Postmenopausal hormone therapy: Benefits and risks"). In addition, their positive effect on neuronal growth and nerve transmission could help restore tactile perception and sensation, although treatment with estrogen alone is associated with inconsistent results with respect to sexual desire and arousal.

Short-term studies of estrogen replacement therapy (ERT) have confirmed a benefit in some postmenopausal women with sexual dysfunction:

• In a report of 93 women, 68 percent reported problems with sex, specifically vaginal dryness of at least moderate degree (58 percent); dyspareunia (39 percent); decrease in clitoral sensitivity (36 percent), decrease in orgasmic frequency (29 percent), decrease in orgasm intensity (35 percent), decrease in sexual desire (77 percent), and intercourse once a month or less (50 percent) [4] . Women reported vaginal dryness, pain with penetration, and burning sensation when the serum estradiol concentration dropped below 50 pg/mL. Symptoms decreased markedly when the estradiol concentration was above 50 pg/mL. Overall, oral estrogen therapy resulted in an improvement in clitoral sensitivity. Orgasm rates also improved. The most dramatic response was seen in the women who reported a lack of desire; after three to six months of treatment, 90 percent of these women had an increase in level of desire and increase in sexual activity with ERT.
• In a study of 242 women ages 45 to 65 requiring ERT for climacteric symptoms, women were randomly assigned to blinded treatment with transdermal estrogen or placebo for 12 weeks [5] . Answers to a questionnaire regarding satisfaction with frequency of sexual activity, sexual fantasies, degree of enjoyment, vaginal lubrication, and pain during intercourse were positively influenced by estrogen compared with placebo therapy, while the frequency of orgasm and sexual arousal were not affected.


However, not all studies have demonstrated positive results [6] , possibly because women most likely to respond are those with symptoms of hypoestrogenism. Furthermore, any short term positive effects of oral estrogen may diminish in the long term because of increasing sex hormone binding globulin (SHBG) levels, which lead to reduced estrogen and androgen bioavailability, and consequent decreased desire and activity [7] . The increase in SHBG appeared to be less significant in women who use nonoral delivery systems for ERT, suggesting improved bioavailability of estrogens and androgens [8] . (See "Etiology and diagnosis of sexual dysfunction in women", for a more complete discussion of the effects of SHBG.)

Progestins — Progestational agents down-regulate the estrogen receptor, a desired result in the endometrium, but potentially undesirable in the brain, heart, bone, and genitalia. They generally have an overall negative effect in the CNS with respect to depression and mood, and have been shown to decrease sexual desire and diminish vaginal blood flow [9,10] . Medroxyprogesterone acetate (MPA) is the most potent progestin available, therefore its ability to down-regulate the estrogen receptor and diminish estrogen effects may be particularly intense. Other available options include micronized progesterone (MP) and the 19 nortestosterone derivatives, norethindrone acetate (NA) and norgestimate (NGM). (See "Preparations for postmenopausal hormone therapy"). NA, the more androgenic progestin, has been shown to decrease SHBG and increase bone density.

A number of studies have evaluated the effect of progestins on sexual function:

• The effects of estrogen alone or with MPA on psychological functioning and sexual behavior were evaluated in a study of 48 healthy, naturally menopausal women [9] . The benefits of estrogen were diminished by MPA co-administration [9] .
• A second report comparing the use of estradiol alone or in combination with lynestrenol, a 19-norsteriod, revealed that women who used the combination therapy reported more negative mood symptoms than the estrogen only group [11] .
• In a single-arm, unblinded study, women who were intolerant of a conjugated equine estrogen (CEE)/MPA regimen were switched to CEE plus progesterone and reported better vasomotor, somatic, psychologic, cognitive, and sexual functioning [10] .


Progestins appear to produce a wide range of patient responsiveness and tolerability, suggesting that women who do not tolerate one regimen might be effectively switched to another and experience improvement. When estrogen is given with a progestin, the effect on SHBG depends upon the type of progestin used; 19-nortestosterone derived progestins, such as NA, decrease SHBG levels, a potential benefit while derivatives of C-21 progesterone, such as MPA, do not significantly influence them [12] . Newer studies in progress with more modern combinations of progestins with estrogens and androgens will provide better insight into the progestational effects on sexuality.

Androgens — Androgens play an important role in physiologic aspects of the female sexual response. (See "Etiology and diagnosis of sexual dysfunction in women"). However, the effect of androgen therapy on sexual function in women is controversial. Androgen replacement therapy for women with androgen deficiency (eg, bilateral oophorectomy) must be distinguished from pharmacologic androgen treatment of women with low libido who are not androgen deficient. (See "Androgen production and therapy in women").

Some studies have reported improvements in libido, sexual arousal, and the frequency of sexual fantasies with testosterone therapy in a variety of forms [4,13-15] , while others have been unable to detect a significant benefit from androgen therapy [6,7] . The observation that testosterone therapy may result in improvements in mood and well being [16] is felt by some researchers to be most important; the central sex steroid effect on mood may be what underlies sexual function in both women and men. (See "Androgen production and therapy in women")

Side effects — Potential adverse effects of androgens include a decline in serum high density lipoprotein (HDL) cholesterol with oral preparations, and mild cosmetic side effects such as hirsutism and acne; irreversible virilizing changes are rare. (See "Androgen production and therapy in women", section on Risks and side effects.) Hepatocellular damage is rare at the prescribed doses. The effect of testosterone on breast cancer risk is discussed separately. (See "Postmenopausal hormone therapy and the risk of breast cancer", section on Effect of testosterone).

Preparations — Most early papers demonstrating a benefit of androgens on sexual function utilized injections or pellets. Since that time, compounding pharmacists have formulated testosterone creams, gels, and tablets that can be taken orally or used sublingually, but their production is not uniform, they are not approved by the United States Food and Drug Administration (FDA), and efficacy studies are lacking. Many clinicians have tried creams used for vulvar dystrophies made up with 2 percent testosterone propionate. Others tapered down the potency using micronized testosterone 0.5 percent up to 1 percent, and rarely 2 percent.

Creams were applied first on the inside of the forearms or thighs, while later paraclitoral use became common. Mixed results were common, and the effect of rubbing the cream into the clitoris prior to intercourse may have been nothing more than masturbatory prestimulation. Anecdotally, the creams seemed to work better paraclitorally in patients with sexual arousal disorder than in those with hypoactive sexual desire disorder (HSDD).

A transdermal testosterone preparation has also been studied in clinical trials of postmenopausal women (primarily women who are post-oophorectomy). These trials are discussed in detail elsewhere. (See "Androgen production and therapy in women").

Studies on the use of dehydroepiandrosterone (DHEA), which is available over-the-counter in the United States, have shown an increase in energy level, well-being, sexual satisfaction, and sexual function only in women with primary and secondary adrenal insufficiency [17,18] . There are no receptors for DHEA; side effects occur due to conversion to testosterone and then to estrogens [18] . (See "Dehydroepiandrosterone and its sulfate").

Combination therapy with oral estrogen and methyltestosterone also improved sexual interest/desire in postmenopausal women already taking estrogen who were experiencing hypoactive sexual desire. A double-blind trial randomly assigned such women to four months of therapy with 0.625 mg esterified estrogens alone (n = 111) or with 1.25 mg methyltestosterone (n = 107). Improvements in self-reported sexual desire were seen in the combined therapy group, which correlated with changes in bioavailable testosterone concentrations [19] . However, acne was more common and significant decreases in HDL cholesterol were seen with combined treatment. (See "Androgen production and therapy in women").

Thus, the data that androgen therapy significantly improves sexual functioning are suggestive but not conclusive. Many of the positive studies have been in women who had surgical menopause or who achieved supraphysiologic levels of testosterone with therapy [20] , suggesting that the clinical application may be limited. No guidelines for androgen therapy for female sexual dysfunction are available, and no androgen preparations have been approved for the treatment of sexual desire disorders, although the combination oral estrogen/methyltestosterone preparation described above is approved for management of persistent vasomotor symptoms not relieved by estrogen alone.

Women most likely to benefit from androgen therapy are probably those who have undergone bilateral oophorectomy with hysterectomy.

For any woman considering androgen therapy, the risks and benefits should be discussed prior to initiating treatment. Women with hepatic disease, a history of breast cancer, uncontrolled hyperlipidemia, acne, or hirsutism should not be treated.

Although there are no FDA-approved testosterone products for women presently available in the US, specialists utilize the following products off-label or compounded for women with sexual dysfunction after extensive history and counseling:

• Combination estrogen/methyltestosterone (Estratest or Estratest HS)
• Testim 1 percent testosterone Gel (one to two drops/day)
• Methyltestosterone (1.22 to 2.5 mg/day)
• Micronized oral testosterone (5 mg BID)
• Testosterone injectables/pellets
• Testosterone propionate 2 percent in petroleum applied QOD
• DHEA 50 mg per day

Non-oral estrogen should be administered in conjunction with testosterone therapy to avoid increasing SHBG and to negate any potential negative effects of either on lipoproteins. Baseline free and total testosterone levels, liver function tests, and a lipid profile should be obtained prior to initiating therapy, and women should be current on cervical and breast cancer screening. The lipid profile and liver function tests should be reevaluated along with a clinical evaluation for symptoms in three to four months, and the androgen tapered to the lowest dose possible. Some authors recommend that the serum testosterone concentration remain in the normal range for premenopausal women, but this is not universal. Liver function tests and lipids should be monitored every six months during therapy [1] .

Herbal therapies — The literature on herbal therapies for the treatment of sexual dysfunction in women is sparse. In general, St John's wort, ginseng, dong quai do not appear to be more effective than placebo for sexual dysfunction. Herbal products such as yohimbine have been reported to enhance desire, arousal, and orgasm in women with sexual dysfunction secondary to SSRIs, but results are inconsistent [21,22] .

L-arginine, an amino acid, has been touted as the natural Viagra due to the claimed ability to release nitric oxide, causing increased vasocongestion in the genitalia of both sexes [21,23] . More studies are necessary before conclusions can be drawn regarding any of these products.

Future therapies — A number of products are undergoing research and development for use in women with sexual dysfunction:

Tibolone — Tibolone, currently available in Europe and Australia, has not yet gained FDA approval in the United States. Taken orally, its metabolites have estrogenic, androgenic, and progestational effects. The level of androgenic activity and its potential use for sexual dysfunction is under evaluation. A small placebo controlled trial in postmenopausal women found tibolone increased vaginal lubrication, arousability, and sexual desire, but did not change frequency of sexual intercourse or orgasm compared to placebo [24] . Tibolone is effective for the management of osteoporosis, but may be associated with an increased risk of breast and endometrial cancer. Tibolone is discussed in more detail elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women").

Sildenafil — Preliminary findings on use of sildenafil demonstrated positive effects in the areas of sexual arousal and orgasm in appropriately selected women [25-28] . However, several large scale, placebo controlled studies including about 3000 women with female sexual arousal disorder yielded inconclusive results [29] . For this reason, the manufacturer has decided not to seek regulatory approval to use the drug for female sexual arousal disorder.

Other — Now available in the United States is a clitoral suction device modeled after a pump used before the advent of penile injections and sildenafil to produce and maintain erection in males, uses suction or negative pressure to increase vasocongestion and engorge the clitoris and paraclitoral tissues for enhanced arousal and orgasm [30] .

One placebo-controlled randomized study of daily apomorphine SL administered to premenopausal women suggested this drug may improve sexual desire and function in women with hypoactive sexual desire [31] . Apomorphine SL is not FDA approved for this indication and requires further investigation.

This growing pharmacopoeia should not overshadow the psychosocial, intimacy, and relationship issues that are equally, if not more involved in problems with midlife sexuality.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.