Clinical Review

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

Prevalence of thrombophilias in women with normal pregnancy outcomes

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.

No need to screen women with abruptio placenta

The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.

It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.³ Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.

Kupferminc et al²⁸ found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al²⁹ found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.

A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.⁸ Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.

And no routine screening in cases of IUGR

Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al³⁰ found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.

A recent meta-analysis of case-control studies by Howley et al³¹ found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al⁸ found no association between thrombophilia and IUGR in asymptomatic gravidas.

TABLE 3

Incidence of thrombophilias in women with intrauterine growth restriction

Fetal loss is a complication of thrombophilia

One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.³² When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.^2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).

Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.³³ In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.³³

TABLE 4

Incidence of factor V Leiden mutation in women with recurrent pregnancy loss

History of adverse outcomes? Offer screening

It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.^3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.³ Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.^3,37

Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes^3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B₆ supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.

TABLE 5

How women with a previous adverse outcome fare on anticoagulation therapy

No randomized trials on prophylaxis

We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.

TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.

TABLE 6

Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia

Prophylaxis for APA syndrome and recurrent pregnancy loss

Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).^39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.⁴⁶

TABLE 7

Live births in women with APA and a history of fetal loss

Genetic thrombophilias

Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.^{3,9,38,44,45,47} These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).^{3,9,38,41,48,49}

Gris et al⁴⁷ performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.

In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.

History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.

Unresolved questions keep management experimental

What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?

There is a prevailing need for a double-blind placebo-controlled trial to address these questions and evaluate the benefit of heparin in pregnant women with a history of adverse pregnancy outcomes and thrombophilia. Until then, screening and treatment for thrombophilia remain experimental in these women.

The authors report no financial relationships relevant to this article.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

Prevalence of thrombophilias in women with normal pregnancy outcomes

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.

No need to screen women with abruptio placenta

The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.

It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.³ Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.

Kupferminc et al²⁸ found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al²⁹ found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.

A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.⁸ Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.

And no routine screening in cases of IUGR

Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al³⁰ found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.

A recent meta-analysis of case-control studies by Howley et al³¹ found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al⁸ found no association between thrombophilia and IUGR in asymptomatic gravidas.

TABLE 3

Incidence of thrombophilias in women with intrauterine growth restriction

Fetal loss is a complication of thrombophilia

One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.³² When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.^2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).

Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.³³ In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.³³

TABLE 4

Incidence of factor V Leiden mutation in women with recurrent pregnancy loss

History of adverse outcomes? Offer screening

It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.^3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.³ Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.^3,37

Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes^3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B₆ supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.

TABLE 5

How women with a previous adverse outcome fare on anticoagulation therapy

No randomized trials on prophylaxis

We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.

TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.

TABLE 6

Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia

Prophylaxis for APA syndrome and recurrent pregnancy loss

Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).^39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.⁴⁶

TABLE 7

Live births in women with APA and a history of fetal loss

Genetic thrombophilias

Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.^{3,9,38,44,45,47} These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).^{3,9,38,41,48,49}

Gris et al⁴⁷ performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.

In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.

History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.

Unresolved questions keep management experimental

What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?

There is a prevailing need for a double-blind placebo-controlled trial to address these questions and evaluate the benefit of heparin in pregnant women with a history of adverse pregnancy outcomes and thrombophilia. Until then, screening and treatment for thrombophilia remain experimental in these women.

The authors report no financial relationships relevant to this article.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

Prevalence of thrombophilias in women with normal pregnancy outcomes

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.

No need to screen women with abruptio placenta

The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.

It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.³ Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.

Kupferminc et al²⁸ found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al²⁹ found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.

A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.⁸ Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.

And no routine screening in cases of IUGR

Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al³⁰ found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.

A recent meta-analysis of case-control studies by Howley et al³¹ found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al⁸ found no association between thrombophilia and IUGR in asymptomatic gravidas.

TABLE 3

Incidence of thrombophilias in women with intrauterine growth restriction

Fetal loss is a complication of thrombophilia

One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.³² When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.^2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).

Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.³³ In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.³³

TABLE 4

Incidence of factor V Leiden mutation in women with recurrent pregnancy loss

History of adverse outcomes? Offer screening

It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.^3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.³ Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.^3,37

Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes^3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B₆ supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.

TABLE 5

How women with a previous adverse outcome fare on anticoagulation therapy

No randomized trials on prophylaxis

We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.

TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.

TABLE 6

Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia

Prophylaxis for APA syndrome and recurrent pregnancy loss

Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).^39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.⁴⁶

TABLE 7

Live births in women with APA and a history of fetal loss

Genetic thrombophilias

Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.^{3,9,38,44,45,47} These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).^{3,9,38,41,48,49}

Gris et al⁴⁷ performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.

In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.

History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.

Unresolved questions keep management experimental

What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?

There is a prevailing need for a double-blind placebo-controlled trial to address these questions and evaluate the benefit of heparin in pregnant women with a history of adverse pregnancy outcomes and thrombophilia. Until then, screening and treatment for thrombophilia remain experimental in these women.

The authors report no financial relationships relevant to this article.

Surgery for stress incontinence

A pain drug for OAB?

Does genetics affect risk?

Another year is drawing to a close and, looking back, what have we learned about urinary incontinence? A clear understanding of etiology stubbornly eludes us. How would a clear understanding of etiology affect management? It’s difficult to be specific until we actually do understand it, but generally:

The “multiple-hit” theory probably applies to urinary incontinence, too

The “multiple-hit” theory usually ascribed to cancer probably also fits the development of urinary incontinence, a likewise multifaceted condition. A woman begins life with genetic predisposition at some level that we cannot currently measure, but which is influenced by the environment (eg, nutrition, toxic exposures) and life events (eg, childbirth, aging)—all of which determine her likelihood of developing incontinence.

Until the time when we do have a clear understanding on which to base diagnosis, treatment, and prevention, of course, we must continue to manage incontinence with the tools of today.

A few pieces of the puzzle are slowly coming together.

Surgery for stress incontinence

Even as new surgical techniques or modifications continue to proliferate, evidence to guide clinical practice accumulates belatedly. MEDLINE lists 325 articles since 1996 (combining surgical mesh and urinary incontinence, limited to human females and published in English). Nonetheless, a consensus may be emerging that the safest synthetic material is monofilament polypropylene with pore size larger than 70 μm.

Unfortunately, by the time research reports are published showing higher complications with certain products, countless women have already been treated.

Mesh erosion (or exposure, extrusion), sometimes accompanied by infection, is a common complication when multifilament or small-pore meshes are used. Even worse, companies commonly withdraw products, modify them, and re-introduce them to the market, accompanied by intensive marketing but, as with the original product, without any real evidence of safety and effectiveness.

In an ideal world, clinicians (and patients) would insist on evidence before accepting new products and techniques. Failing that, clinicians (and patients!) should clearly understand that all new products and techniques are experimental until they are proven equal to or better than traditional techniques. As we have learned with the most subtle differences between synthetic materials, “almost the same” or “looks the same” is not the same.

Among the most important evidence on slings this year are reports of investigations that demonstrated what should not be done.

Are monofilament, large-pore mesh products safer?

Abdel-Fattah M, Sivanesan K, Ramsay I, Pringle S, Bjornsson S. How common are tape erosions? A comparison of two versions of the transobturator tension-free vaginal tape procedure. BJU Int. 2006;98:594–598.

Yamada BS, Govier FE, Stefanovic KB, Kobashi KC. High rate of vaginal erosions associated with the Mentor Obtape. J Urol. 2006;176:651–654.

Siegel AL, Kim M, Goldstein M, Levey S, Ilbeigi P. High incidence of vaginal mesh extrusion using the Intravaginal Slingplasty sling. J Urol. 2005;174:1308–1311.

The risk of vaginal erosion is much higher with synthetic meshes used for sling procedures when the mesh is multifilament and/or small-pore (<70 μm). In some cases, companies have replaced products (Mentor Obtape small-pore polypropylene sling product was replaced with macroporous Aris), whereas others continue to market products reported to have unacceptably high rates of vaginal erosion and mesh extrusion (Intravaginal Slingplasty multifilament mesh) (TABLE 1).

TABLE 1

Comparison of selected multifilament and small-pore mesh products

Avoid cadaveric fascia in sling procedures

Howden NS, Zyczynski HM, Moalli PA, Sagan ER, Meyn LA, Weber AM. Comparison of autologous rectus fascia and cadaveric fascia in pubovaginal sling continence outcomes. Am J Obstet Gynecol. 2006;194:1444–1449.

Evidence has accumulated that sling procedures performed with cadaveric fascia have substantially worse continence outcomes, compared with those using autologous fascia. In a retrospective cohort study of 150 women with cadaveric fascial slings and 153 women who had autologous rectus fascial slings, urinary incontinence (16 vs 5 per 100 women-years) and reoperation for stress incontinence (4 vs 1 per 100 women-years) occurred more frequently after cadaveric versus autologous rectus fascial slings.

Should xenograft materials be used in sling procedures?

Giri SK, Hickey JP, Sil D, et al. Long-term results of pubovaginal sling surgery using acellular cross-linked porcine dermis in the treatment of urodynamic stress incontinence. J Urol. 2006; 175:1788–1792.

Several companies market specific products integrated into sling techniques, such as In-First Ultra (porcine dermal matrix secured with bone anchors) and Stratasis (porcine small intestinal submucosa in urethral sling and tension-free versions). Other companies market only the xenograft for application in sling procedures, such as Pelvicol (acellular porcine collagen matrix). However, relatively little information is available to support or discourage use of xenograft materials in sling procedures.

Giri et al found worse outcomes using Pelvicol compared with autologous rectus fascia for pubovaginal slings. With 3-year follow-up, 54% (26 of 48 women) with Pelvicol were considered successfully cured or improved, compared with 80.4% (37 of 46 women) with rectus fascia. Of interest, women continued to report recurrent incontinence with Pelvicol through the 3-year period, whereas women with rectus fascia had recurrence within the first 9 months after surgery.

Midurethral slings: Retropubic or transobturator?

Waltregny D, Reul O, Mathantu B, Gaspar Y, Bonnet P, de Leval J. Inside out transobturator vaginal tape for the treatment of female stress urinary incontinence: interim results of a prospective study after a 1-year minimum followup. J Urol. 2006;175:2191–2195.

Morey AF, Medendorp AR, Noller MW, et al. Transobturator versus transabdominal midurethral slings: a multi-institutional comparison of obstructive voiding complications. J Urol. 2006;175:1014–1017.

Midurethral sling placement was modified from the retropubic to the obturator approach with the objective of reducing the risk of major bladder and urethral injury and vascular complications. Does the obturator approach actually have fewer intraoperative complications compared with the retropubic approach? Unknown. (As noted below, even within retropubic procedures, it is possible—although currently unknown—that vaginal and abdominal approaches have different complication rates.) This is a good news–bad news problem:

Results of the obturator approach are beginning to appear in the literature as case series and uncontrolled comparative studies. Waltregney et al reported cure of stress incontinence in 91% of 99 patients after 1 year of follow-up. Morey et al reported similar continence outcomes: 89% success for 154 patients after the obturator approach compared with 86% success for 350 patients after the abdominal approach, although follow-up in the abdominal group was substantially longer (mean 20 months, range 18–26) than in the obturator group (mean 9 months, range 6–16). Of interest, urethrolysis was performed more frequently in the abdominal group (2.3%) than in the obturator group (0%).

Randomized trials are necessary to obtain unbiased comparisons of techniques. Investigators in the NIH-sponsored Urinary Incontinence Treatment Network are currently performing a randomized trial comparing obturator and abdominal approaches with midurethral slings for women with stress and stress-predominant mixed incontinence. The primary outcome will compare objective and subjective treatment success between the 2 groups at 1 and 2 years after surgery. Enrollment is expected to be complete by early 2008, and 1-year follow-up by early 2009. Stay tuned for the results!

Retropubic midurethral slings: Which brand?

Gandhi S, Abramov Y, Kwon C, et al. TVT versus SPARC: comparison of outcomes for two midurethral tape procedures. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17:125–130.

Lord HE, Taylor JD, Finn JC, et al. A randomized controlled equivalence trial of short-term complications and efficacy of tension-free vaginal tape and suprapubic urethral support sling for treating stress incontinence. BJU Int. 2006;98:367–376.

As the first midurethral sling, the tension-free vaginal tape (Gynecare TVT) has the most evidence and longest follow-up available in the literature. It was originally described using the vaginal approach (“bottom-up”); the company now markets all 3 approaches: vaginal, abdominal (“top-down”), and obturator. Other companies market different products along the same lines, but it cannot be assumed that midurethral slings are interchangeable. Studies are starting to appear that compare different retropubic midurethral slings. In a retrospective case series (Gandhi et al) and a randomized trial (Lord et al), Gynecare TVT had better continence outcomes compared with SPARC (TABLE 2).

TABLE 2

Comparison of 2 retropubic midurethral slings

A pain drug for OAB?

Particularly for urge incontinence and associated symptoms falling under the heading of “overactive bladder,” new drugs are always being developed and existing drugs can be found to have a potentially new application. Drugs recently added to those FDA-approved for urge incontinence have relied primarily on their anticholinergic effects. In contrast, tramadol, a drug FDA-approved for pain relief (marketed in the United States as Ultram), was tested for this use. Although the mechanism of action is unknown, the authors proposed a possible change in dopamine receptor activation.

Treated group improved, placebo group did not

Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study. Br J Clin Pharmacol. 2006;61:456–463.

This randomized, placebo-controlled trial included 76 men and women with detrusor overactivity. The study population was relatively young, with mean ages of 39 and 37 years in the drug and placebo groups, respectively, and included about 2/3 women. At a sustained-release dose of 100 mg twice a day for 12 weeks of study, tramadol was effective for reducing the number of urge incontinence episodes per 24 hours from a baseline mean of 3.2 ±3.3 episodes to a mean of 1.6 ± 2.8 episodes. In addition, frequency of voiding per 24 hours was reduced (baseline mean 9.3 ± 3.2 episodes, to 5.1 ± 2.1) and the mean volume per void increased substantially (158 ± 32 mL, to 198 ± 76 mL) without an increase in postvoid residual urine volume.

In contrast to the results of many placebo-controlled drug trials and even with the use of 24-hour voiding diaries every 2 weeks for the 12-week study, the placebo group showed essentially no change in clinical and urodynamic outcomes. For example, the number of urge incontinence episodes per 24 hours was unchanged, from a baseline mean of 3.3 ± 3.1 episodes, to a mean of 3.1 ± 3.0 after 12 weeks. Nausea was the most commonly reported side effect (18% vs 5% in the drug and placebo groups, respectively); 2 of 35 participants in the tramadol group dropped out of the study due to nausea.

Confirmation of these results and further study may shed light on the complex control of normal voiding and the true etiology behind the symptoms that we call “detrusor overactivity,” and potentially open a new class of drugs for treatment.

Delivery mode and genetic influences on urinary incontinence

Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand. 2004;83:978–982.

Goldberg RP, Abramov Y, Botros S, et al. Delivery mode is a major environmental determinant of stress urinary incontinence: results of the Evanston–Northwestern Twin Sisters Study. Am J Obstet Gynecol. 2005;193:2149–2153.

The genetic predisposition for urinary incontinence, seen in clinical practice as clustering in families—mothers, daughters, sisters—has been long suspected, and has been supported in recent studies of nature’s gift to genetic research—twins. In a study of more than 1,000 Danish twins in 2 age groups, Rohr et al were able to quantitatively estimate the heritable component for urinary incontinence, which was categorized by questionnaire into urge, mixed, and stress incontinence. The study included 548 monozygotic twin pairs (who share identical genetic material) and 620 dizygotic twin pairs (who, on average, share 50% of their genes like ordinary sisters).

Urge incontinence, in both age groups, had a similar level of heritability: 42% for ages 46–68 and 49% for ages 70–94.

Mixed incontinence had a lower level of heritability: 27% in middle age and 55% in the older group.

Stress incontinence in the older group had a significant heritable component at 39%, but stress incontinence in the middle-aged group was more strongly associated with environmental factors than with heritability.

Another study focused on stress incontinence in a study of 271 monozygotic twin pairs with a mean age of 47 years. Within the 173 parous twin pairs, environmental factors associated with stress incontinence were identified: age, parity, obesity, and mode of delivery.

Childbirth and genetic factors. These data clarify an important area of (apparently) inconsistent epidemiologic literature on the role of childbirth, and particularly mode of delivery, in lifetime risk of urinary incontinence. The inconsistency resolves once age of the study cohort and type of incontinence are considered. Stress incontinence is influenced most strongly by mode of delivery in middle-aged women. Later in life, genetic factors play a more important role in risk of stress incontinence, and mode of delivery becomes less important. Urge incontinence, perhaps developing along a different etiologic path than stress incontinence, is strongly influenced by heritability in both middle-aged and older women; environmental factors influencing the development of urge incontinence are less important through the lifespan.

Nonetheless, indications of a genetic component do not begin to tell us what exactly is affected that increases the likelihood of urinary incontinence. Speculation is easy enough—perhaps the inherent strength, elasticity, or regeneration potential of critically important tissues in the urethra and pelvis is affected—but the details are not yet fully known.

Again, until we have a clearer understanding, we must continue to manage incontinence with the tools of today.

Surgery for stress incontinence

A pain drug for OAB?

Does genetics affect risk?

Another year is drawing to a close and, looking back, what have we learned about urinary incontinence? A clear understanding of etiology stubbornly eludes us. How would a clear understanding of etiology affect management? It’s difficult to be specific until we actually do understand it, but generally:

The “multiple-hit” theory probably applies to urinary incontinence, too

The “multiple-hit” theory usually ascribed to cancer probably also fits the development of urinary incontinence, a likewise multifaceted condition. A woman begins life with genetic predisposition at some level that we cannot currently measure, but which is influenced by the environment (eg, nutrition, toxic exposures) and life events (eg, childbirth, aging)—all of which determine her likelihood of developing incontinence.

Until the time when we do have a clear understanding on which to base diagnosis, treatment, and prevention, of course, we must continue to manage incontinence with the tools of today.

A few pieces of the puzzle are slowly coming together.

Surgery for stress incontinence

Even as new surgical techniques or modifications continue to proliferate, evidence to guide clinical practice accumulates belatedly. MEDLINE lists 325 articles since 1996 (combining surgical mesh and urinary incontinence, limited to human females and published in English). Nonetheless, a consensus may be emerging that the safest synthetic material is monofilament polypropylene with pore size larger than 70 μm.

Unfortunately, by the time research reports are published showing higher complications with certain products, countless women have already been treated.

Mesh erosion (or exposure, extrusion), sometimes accompanied by infection, is a common complication when multifilament or small-pore meshes are used. Even worse, companies commonly withdraw products, modify them, and re-introduce them to the market, accompanied by intensive marketing but, as with the original product, without any real evidence of safety and effectiveness.

In an ideal world, clinicians (and patients) would insist on evidence before accepting new products and techniques. Failing that, clinicians (and patients!) should clearly understand that all new products and techniques are experimental until they are proven equal to or better than traditional techniques. As we have learned with the most subtle differences between synthetic materials, “almost the same” or “looks the same” is not the same.

Among the most important evidence on slings this year are reports of investigations that demonstrated what should not be done.

Are monofilament, large-pore mesh products safer?

Abdel-Fattah M, Sivanesan K, Ramsay I, Pringle S, Bjornsson S. How common are tape erosions? A comparison of two versions of the transobturator tension-free vaginal tape procedure. BJU Int. 2006;98:594–598.

Yamada BS, Govier FE, Stefanovic KB, Kobashi KC. High rate of vaginal erosions associated with the Mentor Obtape. J Urol. 2006;176:651–654.

Siegel AL, Kim M, Goldstein M, Levey S, Ilbeigi P. High incidence of vaginal mesh extrusion using the Intravaginal Slingplasty sling. J Urol. 2005;174:1308–1311.

The risk of vaginal erosion is much higher with synthetic meshes used for sling procedures when the mesh is multifilament and/or small-pore (<70 μm). In some cases, companies have replaced products (Mentor Obtape small-pore polypropylene sling product was replaced with macroporous Aris), whereas others continue to market products reported to have unacceptably high rates of vaginal erosion and mesh extrusion (Intravaginal Slingplasty multifilament mesh) (TABLE 1).

TABLE 1

Comparison of selected multifilament and small-pore mesh products

Avoid cadaveric fascia in sling procedures

Howden NS, Zyczynski HM, Moalli PA, Sagan ER, Meyn LA, Weber AM. Comparison of autologous rectus fascia and cadaveric fascia in pubovaginal sling continence outcomes. Am J Obstet Gynecol. 2006;194:1444–1449.

Evidence has accumulated that sling procedures performed with cadaveric fascia have substantially worse continence outcomes, compared with those using autologous fascia. In a retrospective cohort study of 150 women with cadaveric fascial slings and 153 women who had autologous rectus fascial slings, urinary incontinence (16 vs 5 per 100 women-years) and reoperation for stress incontinence (4 vs 1 per 100 women-years) occurred more frequently after cadaveric versus autologous rectus fascial slings.

Should xenograft materials be used in sling procedures?

Giri SK, Hickey JP, Sil D, et al. Long-term results of pubovaginal sling surgery using acellular cross-linked porcine dermis in the treatment of urodynamic stress incontinence. J Urol. 2006; 175:1788–1792.

Several companies market specific products integrated into sling techniques, such as In-First Ultra (porcine dermal matrix secured with bone anchors) and Stratasis (porcine small intestinal submucosa in urethral sling and tension-free versions). Other companies market only the xenograft for application in sling procedures, such as Pelvicol (acellular porcine collagen matrix). However, relatively little information is available to support or discourage use of xenograft materials in sling procedures.

Giri et al found worse outcomes using Pelvicol compared with autologous rectus fascia for pubovaginal slings. With 3-year follow-up, 54% (26 of 48 women) with Pelvicol were considered successfully cured or improved, compared with 80.4% (37 of 46 women) with rectus fascia. Of interest, women continued to report recurrent incontinence with Pelvicol through the 3-year period, whereas women with rectus fascia had recurrence within the first 9 months after surgery.

Midurethral slings: Retropubic or transobturator?

Waltregny D, Reul O, Mathantu B, Gaspar Y, Bonnet P, de Leval J. Inside out transobturator vaginal tape for the treatment of female stress urinary incontinence: interim results of a prospective study after a 1-year minimum followup. J Urol. 2006;175:2191–2195.

Morey AF, Medendorp AR, Noller MW, et al. Transobturator versus transabdominal midurethral slings: a multi-institutional comparison of obstructive voiding complications. J Urol. 2006;175:1014–1017.

Midurethral sling placement was modified from the retropubic to the obturator approach with the objective of reducing the risk of major bladder and urethral injury and vascular complications. Does the obturator approach actually have fewer intraoperative complications compared with the retropubic approach? Unknown. (As noted below, even within retropubic procedures, it is possible—although currently unknown—that vaginal and abdominal approaches have different complication rates.) This is a good news–bad news problem:

Results of the obturator approach are beginning to appear in the literature as case series and uncontrolled comparative studies. Waltregney et al reported cure of stress incontinence in 91% of 99 patients after 1 year of follow-up. Morey et al reported similar continence outcomes: 89% success for 154 patients after the obturator approach compared with 86% success for 350 patients after the abdominal approach, although follow-up in the abdominal group was substantially longer (mean 20 months, range 18–26) than in the obturator group (mean 9 months, range 6–16). Of interest, urethrolysis was performed more frequently in the abdominal group (2.3%) than in the obturator group (0%).

Randomized trials are necessary to obtain unbiased comparisons of techniques. Investigators in the NIH-sponsored Urinary Incontinence Treatment Network are currently performing a randomized trial comparing obturator and abdominal approaches with midurethral slings for women with stress and stress-predominant mixed incontinence. The primary outcome will compare objective and subjective treatment success between the 2 groups at 1 and 2 years after surgery. Enrollment is expected to be complete by early 2008, and 1-year follow-up by early 2009. Stay tuned for the results!

Retropubic midurethral slings: Which brand?

Gandhi S, Abramov Y, Kwon C, et al. TVT versus SPARC: comparison of outcomes for two midurethral tape procedures. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17:125–130.

Lord HE, Taylor JD, Finn JC, et al. A randomized controlled equivalence trial of short-term complications and efficacy of tension-free vaginal tape and suprapubic urethral support sling for treating stress incontinence. BJU Int. 2006;98:367–376.

As the first midurethral sling, the tension-free vaginal tape (Gynecare TVT) has the most evidence and longest follow-up available in the literature. It was originally described using the vaginal approach (“bottom-up”); the company now markets all 3 approaches: vaginal, abdominal (“top-down”), and obturator. Other companies market different products along the same lines, but it cannot be assumed that midurethral slings are interchangeable. Studies are starting to appear that compare different retropubic midurethral slings. In a retrospective case series (Gandhi et al) and a randomized trial (Lord et al), Gynecare TVT had better continence outcomes compared with SPARC (TABLE 2).

TABLE 2

Comparison of 2 retropubic midurethral slings

A pain drug for OAB?

Particularly for urge incontinence and associated symptoms falling under the heading of “overactive bladder,” new drugs are always being developed and existing drugs can be found to have a potentially new application. Drugs recently added to those FDA-approved for urge incontinence have relied primarily on their anticholinergic effects. In contrast, tramadol, a drug FDA-approved for pain relief (marketed in the United States as Ultram), was tested for this use. Although the mechanism of action is unknown, the authors proposed a possible change in dopamine receptor activation.

Treated group improved, placebo group did not

Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study. Br J Clin Pharmacol. 2006;61:456–463.

This randomized, placebo-controlled trial included 76 men and women with detrusor overactivity. The study population was relatively young, with mean ages of 39 and 37 years in the drug and placebo groups, respectively, and included about 2/3 women. At a sustained-release dose of 100 mg twice a day for 12 weeks of study, tramadol was effective for reducing the number of urge incontinence episodes per 24 hours from a baseline mean of 3.2 ±3.3 episodes to a mean of 1.6 ± 2.8 episodes. In addition, frequency of voiding per 24 hours was reduced (baseline mean 9.3 ± 3.2 episodes, to 5.1 ± 2.1) and the mean volume per void increased substantially (158 ± 32 mL, to 198 ± 76 mL) without an increase in postvoid residual urine volume.

In contrast to the results of many placebo-controlled drug trials and even with the use of 24-hour voiding diaries every 2 weeks for the 12-week study, the placebo group showed essentially no change in clinical and urodynamic outcomes. For example, the number of urge incontinence episodes per 24 hours was unchanged, from a baseline mean of 3.3 ± 3.1 episodes, to a mean of 3.1 ± 3.0 after 12 weeks. Nausea was the most commonly reported side effect (18% vs 5% in the drug and placebo groups, respectively); 2 of 35 participants in the tramadol group dropped out of the study due to nausea.

Confirmation of these results and further study may shed light on the complex control of normal voiding and the true etiology behind the symptoms that we call “detrusor overactivity,” and potentially open a new class of drugs for treatment.

Delivery mode and genetic influences on urinary incontinence

Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand. 2004;83:978–982.

Goldberg RP, Abramov Y, Botros S, et al. Delivery mode is a major environmental determinant of stress urinary incontinence: results of the Evanston–Northwestern Twin Sisters Study. Am J Obstet Gynecol. 2005;193:2149–2153.

The genetic predisposition for urinary incontinence, seen in clinical practice as clustering in families—mothers, daughters, sisters—has been long suspected, and has been supported in recent studies of nature’s gift to genetic research—twins. In a study of more than 1,000 Danish twins in 2 age groups, Rohr et al were able to quantitatively estimate the heritable component for urinary incontinence, which was categorized by questionnaire into urge, mixed, and stress incontinence. The study included 548 monozygotic twin pairs (who share identical genetic material) and 620 dizygotic twin pairs (who, on average, share 50% of their genes like ordinary sisters).

Urge incontinence, in both age groups, had a similar level of heritability: 42% for ages 46–68 and 49% for ages 70–94.

Mixed incontinence had a lower level of heritability: 27% in middle age and 55% in the older group.

Stress incontinence in the older group had a significant heritable component at 39%, but stress incontinence in the middle-aged group was more strongly associated with environmental factors than with heritability.

Another study focused on stress incontinence in a study of 271 monozygotic twin pairs with a mean age of 47 years. Within the 173 parous twin pairs, environmental factors associated with stress incontinence were identified: age, parity, obesity, and mode of delivery.

Childbirth and genetic factors. These data clarify an important area of (apparently) inconsistent epidemiologic literature on the role of childbirth, and particularly mode of delivery, in lifetime risk of urinary incontinence. The inconsistency resolves once age of the study cohort and type of incontinence are considered. Stress incontinence is influenced most strongly by mode of delivery in middle-aged women. Later in life, genetic factors play a more important role in risk of stress incontinence, and mode of delivery becomes less important. Urge incontinence, perhaps developing along a different etiologic path than stress incontinence, is strongly influenced by heritability in both middle-aged and older women; environmental factors influencing the development of urge incontinence are less important through the lifespan.

Nonetheless, indications of a genetic component do not begin to tell us what exactly is affected that increases the likelihood of urinary incontinence. Speculation is easy enough—perhaps the inherent strength, elasticity, or regeneration potential of critically important tissues in the urethra and pelvis is affected—but the details are not yet fully known.

Again, until we have a clearer understanding, we must continue to manage incontinence with the tools of today.

Surgery for stress incontinence

A pain drug for OAB?

Does genetics affect risk?

Another year is drawing to a close and, looking back, what have we learned about urinary incontinence? A clear understanding of etiology stubbornly eludes us. How would a clear understanding of etiology affect management? It’s difficult to be specific until we actually do understand it, but generally:

The “multiple-hit” theory probably applies to urinary incontinence, too

The “multiple-hit” theory usually ascribed to cancer probably also fits the development of urinary incontinence, a likewise multifaceted condition. A woman begins life with genetic predisposition at some level that we cannot currently measure, but which is influenced by the environment (eg, nutrition, toxic exposures) and life events (eg, childbirth, aging)—all of which determine her likelihood of developing incontinence.

Until the time when we do have a clear understanding on which to base diagnosis, treatment, and prevention, of course, we must continue to manage incontinence with the tools of today.

A few pieces of the puzzle are slowly coming together.

Surgery for stress incontinence

Even as new surgical techniques or modifications continue to proliferate, evidence to guide clinical practice accumulates belatedly. MEDLINE lists 325 articles since 1996 (combining surgical mesh and urinary incontinence, limited to human females and published in English). Nonetheless, a consensus may be emerging that the safest synthetic material is monofilament polypropylene with pore size larger than 70 μm.

Unfortunately, by the time research reports are published showing higher complications with certain products, countless women have already been treated.

Mesh erosion (or exposure, extrusion), sometimes accompanied by infection, is a common complication when multifilament or small-pore meshes are used. Even worse, companies commonly withdraw products, modify them, and re-introduce them to the market, accompanied by intensive marketing but, as with the original product, without any real evidence of safety and effectiveness.

In an ideal world, clinicians (and patients) would insist on evidence before accepting new products and techniques. Failing that, clinicians (and patients!) should clearly understand that all new products and techniques are experimental until they are proven equal to or better than traditional techniques. As we have learned with the most subtle differences between synthetic materials, “almost the same” or “looks the same” is not the same.

Among the most important evidence on slings this year are reports of investigations that demonstrated what should not be done.

Are monofilament, large-pore mesh products safer?

Abdel-Fattah M, Sivanesan K, Ramsay I, Pringle S, Bjornsson S. How common are tape erosions? A comparison of two versions of the transobturator tension-free vaginal tape procedure. BJU Int. 2006;98:594–598.

Yamada BS, Govier FE, Stefanovic KB, Kobashi KC. High rate of vaginal erosions associated with the Mentor Obtape. J Urol. 2006;176:651–654.

Siegel AL, Kim M, Goldstein M, Levey S, Ilbeigi P. High incidence of vaginal mesh extrusion using the Intravaginal Slingplasty sling. J Urol. 2005;174:1308–1311.

The risk of vaginal erosion is much higher with synthetic meshes used for sling procedures when the mesh is multifilament and/or small-pore (<70 μm). In some cases, companies have replaced products (Mentor Obtape small-pore polypropylene sling product was replaced with macroporous Aris), whereas others continue to market products reported to have unacceptably high rates of vaginal erosion and mesh extrusion (Intravaginal Slingplasty multifilament mesh) (TABLE 1).

TABLE 1

Comparison of selected multifilament and small-pore mesh products

Avoid cadaveric fascia in sling procedures

Howden NS, Zyczynski HM, Moalli PA, Sagan ER, Meyn LA, Weber AM. Comparison of autologous rectus fascia and cadaveric fascia in pubovaginal sling continence outcomes. Am J Obstet Gynecol. 2006;194:1444–1449.

Evidence has accumulated that sling procedures performed with cadaveric fascia have substantially worse continence outcomes, compared with those using autologous fascia. In a retrospective cohort study of 150 women with cadaveric fascial slings and 153 women who had autologous rectus fascial slings, urinary incontinence (16 vs 5 per 100 women-years) and reoperation for stress incontinence (4 vs 1 per 100 women-years) occurred more frequently after cadaveric versus autologous rectus fascial slings.

Should xenograft materials be used in sling procedures?

Giri SK, Hickey JP, Sil D, et al. Long-term results of pubovaginal sling surgery using acellular cross-linked porcine dermis in the treatment of urodynamic stress incontinence. J Urol. 2006; 175:1788–1792.

Several companies market specific products integrated into sling techniques, such as In-First Ultra (porcine dermal matrix secured with bone anchors) and Stratasis (porcine small intestinal submucosa in urethral sling and tension-free versions). Other companies market only the xenograft for application in sling procedures, such as Pelvicol (acellular porcine collagen matrix). However, relatively little information is available to support or discourage use of xenograft materials in sling procedures.

Giri et al found worse outcomes using Pelvicol compared with autologous rectus fascia for pubovaginal slings. With 3-year follow-up, 54% (26 of 48 women) with Pelvicol were considered successfully cured or improved, compared with 80.4% (37 of 46 women) with rectus fascia. Of interest, women continued to report recurrent incontinence with Pelvicol through the 3-year period, whereas women with rectus fascia had recurrence within the first 9 months after surgery.

Midurethral slings: Retropubic or transobturator?

Waltregny D, Reul O, Mathantu B, Gaspar Y, Bonnet P, de Leval J. Inside out transobturator vaginal tape for the treatment of female stress urinary incontinence: interim results of a prospective study after a 1-year minimum followup. J Urol. 2006;175:2191–2195.

Morey AF, Medendorp AR, Noller MW, et al. Transobturator versus transabdominal midurethral slings: a multi-institutional comparison of obstructive voiding complications. J Urol. 2006;175:1014–1017.

Midurethral sling placement was modified from the retropubic to the obturator approach with the objective of reducing the risk of major bladder and urethral injury and vascular complications. Does the obturator approach actually have fewer intraoperative complications compared with the retropubic approach? Unknown. (As noted below, even within retropubic procedures, it is possible—although currently unknown—that vaginal and abdominal approaches have different complication rates.) This is a good news–bad news problem:

Results of the obturator approach are beginning to appear in the literature as case series and uncontrolled comparative studies. Waltregney et al reported cure of stress incontinence in 91% of 99 patients after 1 year of follow-up. Morey et al reported similar continence outcomes: 89% success for 154 patients after the obturator approach compared with 86% success for 350 patients after the abdominal approach, although follow-up in the abdominal group was substantially longer (mean 20 months, range 18–26) than in the obturator group (mean 9 months, range 6–16). Of interest, urethrolysis was performed more frequently in the abdominal group (2.3%) than in the obturator group (0%).

Randomized trials are necessary to obtain unbiased comparisons of techniques. Investigators in the NIH-sponsored Urinary Incontinence Treatment Network are currently performing a randomized trial comparing obturator and abdominal approaches with midurethral slings for women with stress and stress-predominant mixed incontinence. The primary outcome will compare objective and subjective treatment success between the 2 groups at 1 and 2 years after surgery. Enrollment is expected to be complete by early 2008, and 1-year follow-up by early 2009. Stay tuned for the results!

Retropubic midurethral slings: Which brand?

Gandhi S, Abramov Y, Kwon C, et al. TVT versus SPARC: comparison of outcomes for two midurethral tape procedures. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17:125–130.

Lord HE, Taylor JD, Finn JC, et al. A randomized controlled equivalence trial of short-term complications and efficacy of tension-free vaginal tape and suprapubic urethral support sling for treating stress incontinence. BJU Int. 2006;98:367–376.

As the first midurethral sling, the tension-free vaginal tape (Gynecare TVT) has the most evidence and longest follow-up available in the literature. It was originally described using the vaginal approach (“bottom-up”); the company now markets all 3 approaches: vaginal, abdominal (“top-down”), and obturator. Other companies market different products along the same lines, but it cannot be assumed that midurethral slings are interchangeable. Studies are starting to appear that compare different retropubic midurethral slings. In a retrospective case series (Gandhi et al) and a randomized trial (Lord et al), Gynecare TVT had better continence outcomes compared with SPARC (TABLE 2).

TABLE 2

Comparison of 2 retropubic midurethral slings

A pain drug for OAB?

Particularly for urge incontinence and associated symptoms falling under the heading of “overactive bladder,” new drugs are always being developed and existing drugs can be found to have a potentially new application. Drugs recently added to those FDA-approved for urge incontinence have relied primarily on their anticholinergic effects. In contrast, tramadol, a drug FDA-approved for pain relief (marketed in the United States as Ultram), was tested for this use. Although the mechanism of action is unknown, the authors proposed a possible change in dopamine receptor activation.

Treated group improved, placebo group did not

Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study. Br J Clin Pharmacol. 2006;61:456–463.

This randomized, placebo-controlled trial included 76 men and women with detrusor overactivity. The study population was relatively young, with mean ages of 39 and 37 years in the drug and placebo groups, respectively, and included about 2/3 women. At a sustained-release dose of 100 mg twice a day for 12 weeks of study, tramadol was effective for reducing the number of urge incontinence episodes per 24 hours from a baseline mean of 3.2 ±3.3 episodes to a mean of 1.6 ± 2.8 episodes. In addition, frequency of voiding per 24 hours was reduced (baseline mean 9.3 ± 3.2 episodes, to 5.1 ± 2.1) and the mean volume per void increased substantially (158 ± 32 mL, to 198 ± 76 mL) without an increase in postvoid residual urine volume.

In contrast to the results of many placebo-controlled drug trials and even with the use of 24-hour voiding diaries every 2 weeks for the 12-week study, the placebo group showed essentially no change in clinical and urodynamic outcomes. For example, the number of urge incontinence episodes per 24 hours was unchanged, from a baseline mean of 3.3 ± 3.1 episodes, to a mean of 3.1 ± 3.0 after 12 weeks. Nausea was the most commonly reported side effect (18% vs 5% in the drug and placebo groups, respectively); 2 of 35 participants in the tramadol group dropped out of the study due to nausea.

Confirmation of these results and further study may shed light on the complex control of normal voiding and the true etiology behind the symptoms that we call “detrusor overactivity,” and potentially open a new class of drugs for treatment.

Delivery mode and genetic influences on urinary incontinence

Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand. 2004;83:978–982.

Goldberg RP, Abramov Y, Botros S, et al. Delivery mode is a major environmental determinant of stress urinary incontinence: results of the Evanston–Northwestern Twin Sisters Study. Am J Obstet Gynecol. 2005;193:2149–2153.

The genetic predisposition for urinary incontinence, seen in clinical practice as clustering in families—mothers, daughters, sisters—has been long suspected, and has been supported in recent studies of nature’s gift to genetic research—twins. In a study of more than 1,000 Danish twins in 2 age groups, Rohr et al were able to quantitatively estimate the heritable component for urinary incontinence, which was categorized by questionnaire into urge, mixed, and stress incontinence. The study included 548 monozygotic twin pairs (who share identical genetic material) and 620 dizygotic twin pairs (who, on average, share 50% of their genes like ordinary sisters).

Urge incontinence, in both age groups, had a similar level of heritability: 42% for ages 46–68 and 49% for ages 70–94.

Mixed incontinence had a lower level of heritability: 27% in middle age and 55% in the older group.

Stress incontinence in the older group had a significant heritable component at 39%, but stress incontinence in the middle-aged group was more strongly associated with environmental factors than with heritability.

Another study focused on stress incontinence in a study of 271 monozygotic twin pairs with a mean age of 47 years. Within the 173 parous twin pairs, environmental factors associated with stress incontinence were identified: age, parity, obesity, and mode of delivery.

Childbirth and genetic factors. These data clarify an important area of (apparently) inconsistent epidemiologic literature on the role of childbirth, and particularly mode of delivery, in lifetime risk of urinary incontinence. The inconsistency resolves once age of the study cohort and type of incontinence are considered. Stress incontinence is influenced most strongly by mode of delivery in middle-aged women. Later in life, genetic factors play a more important role in risk of stress incontinence, and mode of delivery becomes less important. Urge incontinence, perhaps developing along a different etiologic path than stress incontinence, is strongly influenced by heritability in both middle-aged and older women; environmental factors influencing the development of urge incontinence are less important through the lifespan.

Nonetheless, indications of a genetic component do not begin to tell us what exactly is affected that increases the likelihood of urinary incontinence. Speculation is easy enough—perhaps the inherent strength, elasticity, or regeneration potential of critically important tissues in the urethra and pelvis is affected—but the details are not yet fully known.

Again, until we have a clearer understanding, we must continue to manage incontinence with the tools of today.

CASE Postmenopausal dyspareunia

A 60-year-old widow who recently remarried complains of dyspareunia. Examination of the vulva reveals firm but thin white skin over the periclitoral area and labia minora and shrinking of the vulvar skin.

What is the likely diagnosis?

Lichen sclerosus is the probable diagnosis, given her age and the appearance of the vulva, although it is impossible to assure the diagnosis without a biopsy. The preferred treatment is clobetasol, an ultrapotent steroid, applied daily.

True, powerful steroids can cause atrophy if applied regularly to other areas of the skin, but clobetasol does not cause atrophy of vulvar skin. After several weeks of nightly application, the skin should be softer and more pliable, and dyspareunia should be resolved. The patient can then reduce the clobetasol application to twice weekly—but she must continue the treatment indefinitely.

The vulva over the lifespan

The vulva is sensitive to both physiologic and pathologic changes, as well as to the sex hormones that govern the menstrual cycle. The mucosa on the inner aspects of the labia minora is very similar to the skin of the vagina and thus very sensitive to estrogen. The skin of the labia majora and the outer surface of the labia minora is more consistent with hair-bearing skin in the perineal area and more sensitive to androgens, which help thicken the skin. At menopause, the loss of estrogen leads to atrophy, and the vulvar epithelium is reduced to a few layers of mostly intermediate and parabasal cell types. The labia minora and majora as well as the clitoris gradually become less prominent with age.

The skin of the vulva consists of both dermis and epidermis, which interact with each other and respond to different nutritional and hormonal influences. For example, estrogen has little effect on vulvar epidermis, but considerable effect on the dermis, thickening the skin and preventing atrophy.

Postmenopausal atrophic changes can become a clinical problem when a woman resumes sexual intercourse after a long period of abstinence, as in the opening case. If atrophy is the main complaint, estrogen replacement therapy will alleviate symptoms of tightness, irritation, and dyspareunia, but it may take 6 weeks to 6 months to achieve optimal results. In the interim, women need to be reassured that reasonable function can be achieved.

Hygienic considerations

With any vulvar irritation, the patient should discontinue the use of synthetic undergarments in favor of cotton panties, which permit more adequate circulation and do not trap moisture.

Sitz baths often help relieve local discomfort, but should be followed by thorough drying.

Vulvar dystrophies: Think “white”

In the past, these diseases have been defined as non-neoplastic epithelial disorders of the vulva. Although there have been many attempts to more accurately define vulvar dystrophies, none have completely described the wide variety of clinical presentations.

In general, dystrophies are disorders of epithelial growth and nutrition that often result in a white surface color change. This definition includes intraepithelial neoplasia and Paget’s disease of the vulva. The International Society for the Study of Vulvovaginal Disease has proposed multiple classifications since 1975. I prefer the clarity of the 1987 classification system.¹ I also consider these terms out-of-date: lichen sclerosus et atrophicus, carcinoma simplex, leukoplakic vulvitis, leukoplakia, hyperplastic vulvitis, neurodermatitis, kraurosis vulvae, leukokeratosis, erythroplasia of Queyrat, and Bowen’s disease.

What makes the lesions white?

The white appearance of dystrophic lesions is due to excessive keratin, at times deep pigmentation, and relative avascularity. All 3 of these characteristics are present in the spectrum of vulvar dystrophies. Biopsy of the affected skin is the key to accurate diagnosis and successful therapy.

Lichen sclerosus

Does not raise risk of carcinoma

The most common of the 3 groups of white lesions described in the 1987 classification of dystrophies, lichen sclerosus usually occurs in postmenopausal women, but can appear at any age, including childhood (FIGURE 1). Despite claims to the contrary, there is no good evidence that women with lichen sclerosus face a higher risk for vulvar carcinoma.

FIGURE 1

Lichen sclerosus affects all ages

3-year-old child. Note the inflammation secondary to excoriations.

20-year-old woman. The glans clitoris has begun the hooding process.

70-year-old woman. The introitus has shrunk, making intercourse impossible.

Signs and symptoms

In lichen sclerosus, the skin of the vulva appears very thin, atrophic, and dry, resembling parchment. It is also white, with loss of pigmentation.

Pruritus is the most common symptom and is usually the presenting symptom. Scratching during sleep may create ulcerations and areas of ecchymosis, and there is generalized shrinking of the vulvar skin, with eventual loss of the labia minora.

The edema and shrinking that occur around the clitoris cause a “hooding” of the glans clitoris. If the process continues unchecked, it can involve the labia majora as well as the skin of the inner thigh and anal region.

Prescribe clobetasol ointment

The patient should be instructed to use clobetasol 0.05% ointment on a continuing basis. This drug is so successful it has eclipsed the use of testosterone propionate for this indication. Lorenz and colleagues² found very high success rates in 81 symptomatic patients with biopsy-proven disease who had failed previous therapy.

For reasons that are unknown, persistent use of this steroid on vulvar skin does not cause the atrophy commonly seen with prolonged use of high-potency steroids on other areas of the skin.

Start with twice-daily application and taper to less frequent use as the symptoms come under control. Most patients in remission can be maintained with twice-weekly application. Pruritus should disappear completely, and the skin itself will become less “leathery.”

Surgical treatment is not advised

Surgery does not appear to have a role because lichen sclerosus often recurs outside excised areas. Several reports have even described the return of disease in skin grafts used to replace large diseased areas.

I do not recommend surgery except in dire circumstances, when symptom relief is essential to the patient’s quality of life and all other therapies have failed.

Squamous cell hyperplasia

This disease is probably the same entity as lichen simplex chronicus. Changes in vulvar skin appear to result from chronic scratching secondary to intense pruritus. This complaint often involves a vicious cycle of scratching, increased pruritus, and more scratching, until excoriations occur. The aim of therapy is to eliminate the pruritus (FIGURE 2).

FIGURE 2

Squamous cell hyperplasia

75-year-old woman. The skin is thickened and may be leathery.

Intense pruritus and aggressive scratching lead to excoriations.

Signs and symptoms

Vulvar skin is typically white or pink. Biopsy will confirm the diagnosis, revealing a markedly thickened keratin layer (hyperkeratosis) and irregular thickening of the Malpighian ridges (acanthosis).

Inflammatory changes are also present, especially when there are areas of excoriation.

Treatment is similar to therapy for lichen sclerosus

Potent topical corticosteroids are the backbone of treatment; clobetasol is the preferred drug. The frequency of application is identical to that described for lichen sclerosus, and response to therapy usually takes 2 months. In the interim, it is advisable to prescribe other medications for the pruritus.

Lichen sclerosus and squamous cell hyperplasia sometimes coincide. Fortunately, the therapies are quite similar and both conditions tend to respond.

Vulvodynia

This disorder consists of chronic vulvar discomfort due to itching, burning, and/or pain that causes physical, sexual, and psychological distress.^3,4 Once referred to as essential vulvodynia, it now is defined as generalized vulvar dysesthesia.

Signs and symptoms

Women with this condition tend to have difficulty localizing their pain. They often present with a complaint of recurrent yeast infection or constant irritation at the introitus. Dyspareunia may or may not be a presenting symptom, although intercourse often triggers this condition. Tight pants or rough undergarments also may trigger symptoms.

Common symptoms. In a study by Sadownik,⁵ women with vulvar dysesthesia reported the following symptoms:

Women with vulvar dysesthesia who appear to have urinary tract symptoms should undergo a urine culture, though it will often be negative and antibiotic therapy will have little effect.

A diagnosis of exclusion

The pain of dysesthesia appears to be neuropathic in origin in that it mimics pain of the sensory nervous system. It may be diffuse or focal, unilateral or bilateral, constant or sporadic. Thus, it is a diagnosis of exclusion.

Recommended therapies

Vulvar dysesthesia should be regarded as a chronic pain syndrome and treated accordingly, with emphasis on generalized improvements in health and attitude rather than single-therapy approaches.

Potent topical corticosteroids are usually of no benefit. Nor does topical estrogen produce long-term relief.

Once all possible causes of symptoms are excluded, refer the patient for education, support, and treatment of depression, if present. Occasionally, topical anesthetics will provide short-term relief.

At least 2 vulvar pain societies—the National Vulvodynia Association and the Vulvar Pain Foundation—have newsletters, outreach programs, and Web sites.

Vulvar vestibulitis

A more readily definable condition in the same category as vulvodynia is so-called vulvar vestibulitis, also known as localized vulvodynia (as classified by the new ACOG Committee Opinion on vulvodynia).

Signs and symptoms

The defining presentation is severe pain on vestibular touch (eg, entry at intercourse), with tenderness to pressure localized within the vulvar vestibule in a horseshoe distribution pattern encompassing 3, 6, and 9 o’clock on the vestibule. Erythema is often present, especially at the 5 and 7 o’clock positions (FIGURE 3).

Patients have no symptoms during normal daily activities, but complain of dyspareunia and an inability to use tampons.

FIGURE 3

Vestibular adenitis

Intense erythema at the 5 o’clock position in the vestibule.

Diagnostic strategies

Vulvar vestibulitis can be diagnosed using a moistened cotton-tip applicator. Pressure applied in the area of the urethral meatus will result in minimal discomfort, but pressure in the horseshoe area of the vestibule will cause exquisite discomfort.

Careful inspection at 5 and 7 o’clock in the vestibule usually uncovers intense erythema over an area of 4 or 5 mm. To distinguish vestibulitis from dysesthesia, see the comparison in TABLE 1.

TABLE 1

Distinguishing vulvar vestibulitis and dysesthesia

Recommended therapies

Treatment of vulvar vestibulitis is complex. It is important to see the patient often to ensure that this syndrome is truly present rather than vulvar dysesthesia. Xylocaine jelly should be given in an attempt to relieve symptoms; topical steroid ointments are another option.

Women with persistent symptoms are difficult to treat medically. Earlier theories pointing to infection as the cause of vestibulitis have been discounted.

Some experts believe that foods containing oxalates precipitate these symptoms. It may be advisable to have the patient reduce the content of oxalates in her diet in an effort to address all possible remedies.

For refractory cases, consider surgery

Consider surgical removal of the tender vestibule if all other therapies fail to provide adequate relief. Surgery for this indication has a high success rate (TABLE 2).⁷

Some surgeons have attempted treatment with laser ablation, but most have found excision more satisfactory, with faster recovery and excellent cosmesis.

Schneider and colleagues⁸ had 69 women complete a questionnaire 6 months after surgery, 54 (78%) of whom replied. Moderate to excellent improvement was reported by 45 women (83%); 7 had repeat surgery, after which 4 improved.

TABLE 2

Impressive track record for surgical treatment of vestibulitis

Pigmented lesions

Are they cancer precursors?

Precursors of malignant melanoma of the vulva have yet to be clearly defined. The majority of these melanomas appear to arise de novo; however, some are associated with precursor nevi, especially junctional nevi. The 3 most common types of nevi that appear on the vulva are:

Assessing malignant potential

Only a small number of dysplastic nevi progress to malignant melanoma, but the frequency increases when the dysplastic nevus is familial and not acquired.

In general, the more severe the dysplasia, the greater the likelihood it will progress to malignancy. In dysplastic nevi, the pattern and appearance of the melanocytic cells are atypical. Bridging of melanocytic clusters of atypical cells may occur. Often, the atypical melanocytes are varied in size and shape, increasing in cell and nuclear size as severity increases. In the most severe cases, nucleoli are very prominent.

Many pigmented lesions of the vulva are lentigines, similar to freckles. Distinguishing one pigmented lesion from another is difficult even with magnification, and the clinician often must decide whether or not to biopsy. One set of guidelines recommends excisional biopsy of vulvar nevi when there is a change in:

Note that a reddish lesion may be basal cell hyperplasia, which has been associated with the development of basal cell carcinoma (FIGURE 4).

FIGURE 4

Basal cell carcinoma

An uncommon type of vulvar cancer, this tumor rarely metastasizes.

Premalignant lesions of squamous epithelium

The variable appearance of vulvar intraepithelial neoplasia (VIN) necessitates the liberal use of diagnostic biopsies, particularly when lesions persist or recur. VIN can present as a white lesion, or as pseudopigmented, pink, or raised and eroded.

Cigarette smoking is a risk factor.

Clinical appearance

Macroscopically, VIN lesions are often multiple and appear slightly raised and papular. Hyper- or pseudopigmented lesions are seen in about 30% of cases.

A confluence of VIN can create an appearance of diffuse plaques. In VIN, as for CIN, carcinoma in situ involves a full-thickness abnormality.

Terminology

If the abnormal parabasal layer extends to one half to two thirds of the epithelium, moderate dysplasia is present. A lower degree of involvement is called mild dysplasia, and full-thickness involvement is severe dysplasia or carcinoma in situ.

High rate of persistence, recurrence

Herod and colleagues⁹ reported on a 15-year follow-up of VIN and found that disease persisted or recurred in 48% of women managed surgically, and 7% of patients progressed to frankly invasive carcinoma. These investigators used the following classification system:

Joura et al¹⁰ strongly suggested that the incidence of this condition is increasing, especially in women prior to the 7th decade of life. Whether this increase is due to better recognition or a true rise in prevalence has been debated.

Diagnostic strategies

Application of 5% acetic acid to the vulvar skin will, after 3 to 5 minutes, allow areas of involvement to be readily seen with a handheld magnifying glass. Colposcopy can be used, but is slower and not as efficient as a simple magnifying lens. Most clinicians have abandoned the use of toluidine blue to identify multicentric lesions, since acetic acid appears to be less cumbersome and just as efficient.

White or pseudopigmented lesions (FIGURE 5) can be seen anywhere on the vulva and represent 2 of the 3 presentations of VIN. Pink lesions (FIGURE 5) are usually seen on moist surfaces near mucous membranes, whereas the white or pseudopigmented lesions are usually seen on the drier, hair-bearing areas of the vulva. Biopsy reveals similar histology.

The cause of the pseudopigmented lesions is unclear, but is unrelated to a disturbance of the melanin cells. As with other vulvar lesions, biopsy is essential for a correct diagnosis.

FIGURE 5

VIN III lesions: A trio of presentations

White lesion.

Pseudopigmented lesions.

Pink lesion.

Recommended therapies

VIN is treated by destroying or excising the epithelium involved. When the area is limited in size, simple excision or laser vaporization is preferred. A 2- to 3-mm margin is adequate, because these lesions have sharp borders.

Laser therapy warrants extra care because the epithelium is rarely thicker than 0.5 mm. For this reason, vaporization of the vulva should be limited to the following depths:

These limits will speed healing and prevent the unnecessary destruction of dermis.

Also be aware that the depth of hair-follicle involvement rarely exceeds 1 mm. Vaporization of the full thickness of the dermis will lead to alopecia and vulvar dryness.

When disease is multifocal or confluent, treatment is more challenging. Several decades ago, simple vulvectomy was performed, but the patient was left a sexual cripple.

Since then, laser therapy has been attempted in these cases, and has proved to be effective when the area treated does not exceed 25% of the total area of the vulva. Extensive laser therapy leads to considerable postoperative pain and an unhappy result.

Extensive involvement may necessitate laser treatment by quadrant to achieve the best results. Another option is “skinning vulvectomy” using a skin graft. This procedure, first described by Felix Rutledge,¹¹ requires a 7- or 8-day hospitalization, but allows for complete therapy in 1 session.

Paget’s disease of the vulva

This disease is most frequently seen in the breast nipple (FIGURE 6), where it is usually associated with an underlying infiltrating ductal carcinoma. Extramammary sites include the vulvar, perianal, and axillary regions. The disease has also been seen in the ear canal.

Paget’s disease is an intraepithelial adenocarcinoma of eccrine or apocrine origin.

FIGURE 6

Paget disease: Not just a breast complaint

Paget disease of the nipple with underlying ductal adenocarcinoma.

Vulvar Paget disease: lesion (left) and photomicrograph of the lesion.

Clinical appearance

Paget’s disease of the vulva appears as a superficial, red to pink, velvety, eczematoid lesion (FIGURE 6), which is very pruritic and often associated with exfoliation. Margins are difficult to identify grossly.

On rare occasions, a nodular tumor can be found in the middle of the skin involvement, but in most cases no invasive malignancy is found at extramammary sites on the vulva.

Diagnostic strategies

Microscopic appearance of Paget cells (FIGURE 6) are pathognomonic of the disease.

Older textbooks suggest that 10% to 20% of patients have an associated, underlying, invasive carcinoma of a skin appendage, Bartholin’s gland, urinary tract, or bowel or rectal site, but later experience has not confirmed this. Rather, the likelihood of concomitant invasive disease is much lower than 10%.

Excision is the treatment of choice

Any attempt to achieve negative margins must utilize frozen section. Some studies have suggested that negative margins are not associated with a reduced rate of recurrence, but these findings have been inconsistent.

Recurrence is common

Paget’s disease of the vulva often recurs, especially when the initial lesion is large. Close monitoring will detect these recurrences when they’re quite small and easily removed via local excision. Occasionally, the initial disease is so extensive that skin grafting may be necessary to cover the defect.

The author reports no financial relationships relevant to this article.

CASE Postmenopausal dyspareunia

A 60-year-old widow who recently remarried complains of dyspareunia. Examination of the vulva reveals firm but thin white skin over the periclitoral area and labia minora and shrinking of the vulvar skin.

What is the likely diagnosis?

Lichen sclerosus is the probable diagnosis, given her age and the appearance of the vulva, although it is impossible to assure the diagnosis without a biopsy. The preferred treatment is clobetasol, an ultrapotent steroid, applied daily.

True, powerful steroids can cause atrophy if applied regularly to other areas of the skin, but clobetasol does not cause atrophy of vulvar skin. After several weeks of nightly application, the skin should be softer and more pliable, and dyspareunia should be resolved. The patient can then reduce the clobetasol application to twice weekly—but she must continue the treatment indefinitely.

The vulva over the lifespan

The vulva is sensitive to both physiologic and pathologic changes, as well as to the sex hormones that govern the menstrual cycle. The mucosa on the inner aspects of the labia minora is very similar to the skin of the vagina and thus very sensitive to estrogen. The skin of the labia majora and the outer surface of the labia minora is more consistent with hair-bearing skin in the perineal area and more sensitive to androgens, which help thicken the skin. At menopause, the loss of estrogen leads to atrophy, and the vulvar epithelium is reduced to a few layers of mostly intermediate and parabasal cell types. The labia minora and majora as well as the clitoris gradually become less prominent with age.

The skin of the vulva consists of both dermis and epidermis, which interact with each other and respond to different nutritional and hormonal influences. For example, estrogen has little effect on vulvar epidermis, but considerable effect on the dermis, thickening the skin and preventing atrophy.

Postmenopausal atrophic changes can become a clinical problem when a woman resumes sexual intercourse after a long period of abstinence, as in the opening case. If atrophy is the main complaint, estrogen replacement therapy will alleviate symptoms of tightness, irritation, and dyspareunia, but it may take 6 weeks to 6 months to achieve optimal results. In the interim, women need to be reassured that reasonable function can be achieved.

Hygienic considerations

With any vulvar irritation, the patient should discontinue the use of synthetic undergarments in favor of cotton panties, which permit more adequate circulation and do not trap moisture.

Sitz baths often help relieve local discomfort, but should be followed by thorough drying.

Vulvar dystrophies: Think “white”

In the past, these diseases have been defined as non-neoplastic epithelial disorders of the vulva. Although there have been many attempts to more accurately define vulvar dystrophies, none have completely described the wide variety of clinical presentations.

In general, dystrophies are disorders of epithelial growth and nutrition that often result in a white surface color change. This definition includes intraepithelial neoplasia and Paget’s disease of the vulva. The International Society for the Study of Vulvovaginal Disease has proposed multiple classifications since 1975. I prefer the clarity of the 1987 classification system.¹ I also consider these terms out-of-date: lichen sclerosus et atrophicus, carcinoma simplex, leukoplakic vulvitis, leukoplakia, hyperplastic vulvitis, neurodermatitis, kraurosis vulvae, leukokeratosis, erythroplasia of Queyrat, and Bowen’s disease.

What makes the lesions white?

The white appearance of dystrophic lesions is due to excessive keratin, at times deep pigmentation, and relative avascularity. All 3 of these characteristics are present in the spectrum of vulvar dystrophies. Biopsy of the affected skin is the key to accurate diagnosis and successful therapy.

Lichen sclerosus

Does not raise risk of carcinoma

The most common of the 3 groups of white lesions described in the 1987 classification of dystrophies, lichen sclerosus usually occurs in postmenopausal women, but can appear at any age, including childhood (FIGURE 1). Despite claims to the contrary, there is no good evidence that women with lichen sclerosus face a higher risk for vulvar carcinoma.

FIGURE 1

Lichen sclerosus affects all ages

3-year-old child. Note the inflammation secondary to excoriations.

20-year-old woman. The glans clitoris has begun the hooding process.

70-year-old woman. The introitus has shrunk, making intercourse impossible.

Signs and symptoms

In lichen sclerosus, the skin of the vulva appears very thin, atrophic, and dry, resembling parchment. It is also white, with loss of pigmentation.

Pruritus is the most common symptom and is usually the presenting symptom. Scratching during sleep may create ulcerations and areas of ecchymosis, and there is generalized shrinking of the vulvar skin, with eventual loss of the labia minora.

The edema and shrinking that occur around the clitoris cause a “hooding” of the glans clitoris. If the process continues unchecked, it can involve the labia majora as well as the skin of the inner thigh and anal region.

Prescribe clobetasol ointment

The patient should be instructed to use clobetasol 0.05% ointment on a continuing basis. This drug is so successful it has eclipsed the use of testosterone propionate for this indication. Lorenz and colleagues² found very high success rates in 81 symptomatic patients with biopsy-proven disease who had failed previous therapy.

For reasons that are unknown, persistent use of this steroid on vulvar skin does not cause the atrophy commonly seen with prolonged use of high-potency steroids on other areas of the skin.

Start with twice-daily application and taper to less frequent use as the symptoms come under control. Most patients in remission can be maintained with twice-weekly application. Pruritus should disappear completely, and the skin itself will become less “leathery.”

Surgical treatment is not advised

Surgery does not appear to have a role because lichen sclerosus often recurs outside excised areas. Several reports have even described the return of disease in skin grafts used to replace large diseased areas.

I do not recommend surgery except in dire circumstances, when symptom relief is essential to the patient’s quality of life and all other therapies have failed.

Squamous cell hyperplasia

This disease is probably the same entity as lichen simplex chronicus. Changes in vulvar skin appear to result from chronic scratching secondary to intense pruritus. This complaint often involves a vicious cycle of scratching, increased pruritus, and more scratching, until excoriations occur. The aim of therapy is to eliminate the pruritus (FIGURE 2).

FIGURE 2

Squamous cell hyperplasia

75-year-old woman. The skin is thickened and may be leathery.

Intense pruritus and aggressive scratching lead to excoriations.

Signs and symptoms

Vulvar skin is typically white or pink. Biopsy will confirm the diagnosis, revealing a markedly thickened keratin layer (hyperkeratosis) and irregular thickening of the Malpighian ridges (acanthosis).

Inflammatory changes are also present, especially when there are areas of excoriation.

Treatment is similar to therapy for lichen sclerosus

Potent topical corticosteroids are the backbone of treatment; clobetasol is the preferred drug. The frequency of application is identical to that described for lichen sclerosus, and response to therapy usually takes 2 months. In the interim, it is advisable to prescribe other medications for the pruritus.

Lichen sclerosus and squamous cell hyperplasia sometimes coincide. Fortunately, the therapies are quite similar and both conditions tend to respond.

Vulvodynia

This disorder consists of chronic vulvar discomfort due to itching, burning, and/or pain that causes physical, sexual, and psychological distress.^3,4 Once referred to as essential vulvodynia, it now is defined as generalized vulvar dysesthesia.

Signs and symptoms

Women with this condition tend to have difficulty localizing their pain. They often present with a complaint of recurrent yeast infection or constant irritation at the introitus. Dyspareunia may or may not be a presenting symptom, although intercourse often triggers this condition. Tight pants or rough undergarments also may trigger symptoms.

Common symptoms. In a study by Sadownik,⁵ women with vulvar dysesthesia reported the following symptoms:

Women with vulvar dysesthesia who appear to have urinary tract symptoms should undergo a urine culture, though it will often be negative and antibiotic therapy will have little effect.

A diagnosis of exclusion

The pain of dysesthesia appears to be neuropathic in origin in that it mimics pain of the sensory nervous system. It may be diffuse or focal, unilateral or bilateral, constant or sporadic. Thus, it is a diagnosis of exclusion.

Recommended therapies

Vulvar dysesthesia should be regarded as a chronic pain syndrome and treated accordingly, with emphasis on generalized improvements in health and attitude rather than single-therapy approaches.

Potent topical corticosteroids are usually of no benefit. Nor does topical estrogen produce long-term relief.

Once all possible causes of symptoms are excluded, refer the patient for education, support, and treatment of depression, if present. Occasionally, topical anesthetics will provide short-term relief.

At least 2 vulvar pain societies—the National Vulvodynia Association and the Vulvar Pain Foundation—have newsletters, outreach programs, and Web sites.

Vulvar vestibulitis

A more readily definable condition in the same category as vulvodynia is so-called vulvar vestibulitis, also known as localized vulvodynia (as classified by the new ACOG Committee Opinion on vulvodynia).

Signs and symptoms

The defining presentation is severe pain on vestibular touch (eg, entry at intercourse), with tenderness to pressure localized within the vulvar vestibule in a horseshoe distribution pattern encompassing 3, 6, and 9 o’clock on the vestibule. Erythema is often present, especially at the 5 and 7 o’clock positions (FIGURE 3).

Patients have no symptoms during normal daily activities, but complain of dyspareunia and an inability to use tampons.

FIGURE 3

Vestibular adenitis

Intense erythema at the 5 o’clock position in the vestibule.

Diagnostic strategies

Vulvar vestibulitis can be diagnosed using a moistened cotton-tip applicator. Pressure applied in the area of the urethral meatus will result in minimal discomfort, but pressure in the horseshoe area of the vestibule will cause exquisite discomfort.

Careful inspection at 5 and 7 o’clock in the vestibule usually uncovers intense erythema over an area of 4 or 5 mm. To distinguish vestibulitis from dysesthesia, see the comparison in TABLE 1.

TABLE 1

Distinguishing vulvar vestibulitis and dysesthesia

Recommended therapies

Treatment of vulvar vestibulitis is complex. It is important to see the patient often to ensure that this syndrome is truly present rather than vulvar dysesthesia. Xylocaine jelly should be given in an attempt to relieve symptoms; topical steroid ointments are another option.

Women with persistent symptoms are difficult to treat medically. Earlier theories pointing to infection as the cause of vestibulitis have been discounted.

Some experts believe that foods containing oxalates precipitate these symptoms. It may be advisable to have the patient reduce the content of oxalates in her diet in an effort to address all possible remedies.

For refractory cases, consider surgery

Consider surgical removal of the tender vestibule if all other therapies fail to provide adequate relief. Surgery for this indication has a high success rate (TABLE 2).⁷

Some surgeons have attempted treatment with laser ablation, but most have found excision more satisfactory, with faster recovery and excellent cosmesis.

Schneider and colleagues⁸ had 69 women complete a questionnaire 6 months after surgery, 54 (78%) of whom replied. Moderate to excellent improvement was reported by 45 women (83%); 7 had repeat surgery, after which 4 improved.

TABLE 2

Impressive track record for surgical treatment of vestibulitis

Pigmented lesions

Are they cancer precursors?

Precursors of malignant melanoma of the vulva have yet to be clearly defined. The majority of these melanomas appear to arise de novo; however, some are associated with precursor nevi, especially junctional nevi. The 3 most common types of nevi that appear on the vulva are:

Assessing malignant potential

Only a small number of dysplastic nevi progress to malignant melanoma, but the frequency increases when the dysplastic nevus is familial and not acquired.

In general, the more severe the dysplasia, the greater the likelihood it will progress to malignancy. In dysplastic nevi, the pattern and appearance of the melanocytic cells are atypical. Bridging of melanocytic clusters of atypical cells may occur. Often, the atypical melanocytes are varied in size and shape, increasing in cell and nuclear size as severity increases. In the most severe cases, nucleoli are very prominent.

Many pigmented lesions of the vulva are lentigines, similar to freckles. Distinguishing one pigmented lesion from another is difficult even with magnification, and the clinician often must decide whether or not to biopsy. One set of guidelines recommends excisional biopsy of vulvar nevi when there is a change in:

Note that a reddish lesion may be basal cell hyperplasia, which has been associated with the development of basal cell carcinoma (FIGURE 4).

FIGURE 4

Basal cell carcinoma

An uncommon type of vulvar cancer, this tumor rarely metastasizes.

Premalignant lesions of squamous epithelium

The variable appearance of vulvar intraepithelial neoplasia (VIN) necessitates the liberal use of diagnostic biopsies, particularly when lesions persist or recur. VIN can present as a white lesion, or as pseudopigmented, pink, or raised and eroded.

Cigarette smoking is a risk factor.

Clinical appearance

Macroscopically, VIN lesions are often multiple and appear slightly raised and papular. Hyper- or pseudopigmented lesions are seen in about 30% of cases.

A confluence of VIN can create an appearance of diffuse plaques. In VIN, as for CIN, carcinoma in situ involves a full-thickness abnormality.

Terminology

If the abnormal parabasal layer extends to one half to two thirds of the epithelium, moderate dysplasia is present. A lower degree of involvement is called mild dysplasia, and full-thickness involvement is severe dysplasia or carcinoma in situ.

High rate of persistence, recurrence

Herod and colleagues⁹ reported on a 15-year follow-up of VIN and found that disease persisted or recurred in 48% of women managed surgically, and 7% of patients progressed to frankly invasive carcinoma. These investigators used the following classification system:

Joura et al¹⁰ strongly suggested that the incidence of this condition is increasing, especially in women prior to the 7th decade of life. Whether this increase is due to better recognition or a true rise in prevalence has been debated.

Diagnostic strategies

Application of 5% acetic acid to the vulvar skin will, after 3 to 5 minutes, allow areas of involvement to be readily seen with a handheld magnifying glass. Colposcopy can be used, but is slower and not as efficient as a simple magnifying lens. Most clinicians have abandoned the use of toluidine blue to identify multicentric lesions, since acetic acid appears to be less cumbersome and just as efficient.

White or pseudopigmented lesions (FIGURE 5) can be seen anywhere on the vulva and represent 2 of the 3 presentations of VIN. Pink lesions (FIGURE 5) are usually seen on moist surfaces near mucous membranes, whereas the white or pseudopigmented lesions are usually seen on the drier, hair-bearing areas of the vulva. Biopsy reveals similar histology.

The cause of the pseudopigmented lesions is unclear, but is unrelated to a disturbance of the melanin cells. As with other vulvar lesions, biopsy is essential for a correct diagnosis.

FIGURE 5

VIN III lesions: A trio of presentations

White lesion.

Pseudopigmented lesions.

Pink lesion.

Recommended therapies

VIN is treated by destroying or excising the epithelium involved. When the area is limited in size, simple excision or laser vaporization is preferred. A 2- to 3-mm margin is adequate, because these lesions have sharp borders.

Laser therapy warrants extra care because the epithelium is rarely thicker than 0.5 mm. For this reason, vaporization of the vulva should be limited to the following depths:

These limits will speed healing and prevent the unnecessary destruction of dermis.

Also be aware that the depth of hair-follicle involvement rarely exceeds 1 mm. Vaporization of the full thickness of the dermis will lead to alopecia and vulvar dryness.

When disease is multifocal or confluent, treatment is more challenging. Several decades ago, simple vulvectomy was performed, but the patient was left a sexual cripple.

Since then, laser therapy has been attempted in these cases, and has proved to be effective when the area treated does not exceed 25% of the total area of the vulva. Extensive laser therapy leads to considerable postoperative pain and an unhappy result.

Extensive involvement may necessitate laser treatment by quadrant to achieve the best results. Another option is “skinning vulvectomy” using a skin graft. This procedure, first described by Felix Rutledge,¹¹ requires a 7- or 8-day hospitalization, but allows for complete therapy in 1 session.

Paget’s disease of the vulva

This disease is most frequently seen in the breast nipple (FIGURE 6), where it is usually associated with an underlying infiltrating ductal carcinoma. Extramammary sites include the vulvar, perianal, and axillary regions. The disease has also been seen in the ear canal.

Paget’s disease is an intraepithelial adenocarcinoma of eccrine or apocrine origin.

FIGURE 6

Paget disease: Not just a breast complaint

Paget disease of the nipple with underlying ductal adenocarcinoma.

Vulvar Paget disease: lesion (left) and photomicrograph of the lesion.

Clinical appearance

Paget’s disease of the vulva appears as a superficial, red to pink, velvety, eczematoid lesion (FIGURE 6), which is very pruritic and often associated with exfoliation. Margins are difficult to identify grossly.

On rare occasions, a nodular tumor can be found in the middle of the skin involvement, but in most cases no invasive malignancy is found at extramammary sites on the vulva.

Diagnostic strategies

Microscopic appearance of Paget cells (FIGURE 6) are pathognomonic of the disease.

Older textbooks suggest that 10% to 20% of patients have an associated, underlying, invasive carcinoma of a skin appendage, Bartholin’s gland, urinary tract, or bowel or rectal site, but later experience has not confirmed this. Rather, the likelihood of concomitant invasive disease is much lower than 10%.

Excision is the treatment of choice

Any attempt to achieve negative margins must utilize frozen section. Some studies have suggested that negative margins are not associated with a reduced rate of recurrence, but these findings have been inconsistent.

Recurrence is common

Paget’s disease of the vulva often recurs, especially when the initial lesion is large. Close monitoring will detect these recurrences when they’re quite small and easily removed via local excision. Occasionally, the initial disease is so extensive that skin grafting may be necessary to cover the defect.

The author reports no financial relationships relevant to this article.

CASE Postmenopausal dyspareunia

A 60-year-old widow who recently remarried complains of dyspareunia. Examination of the vulva reveals firm but thin white skin over the periclitoral area and labia minora and shrinking of the vulvar skin.

What is the likely diagnosis?

Lichen sclerosus is the probable diagnosis, given her age and the appearance of the vulva, although it is impossible to assure the diagnosis without a biopsy. The preferred treatment is clobetasol, an ultrapotent steroid, applied daily.

True, powerful steroids can cause atrophy if applied regularly to other areas of the skin, but clobetasol does not cause atrophy of vulvar skin. After several weeks of nightly application, the skin should be softer and more pliable, and dyspareunia should be resolved. The patient can then reduce the clobetasol application to twice weekly—but she must continue the treatment indefinitely.

The vulva over the lifespan

The vulva is sensitive to both physiologic and pathologic changes, as well as to the sex hormones that govern the menstrual cycle. The mucosa on the inner aspects of the labia minora is very similar to the skin of the vagina and thus very sensitive to estrogen. The skin of the labia majora and the outer surface of the labia minora is more consistent with hair-bearing skin in the perineal area and more sensitive to androgens, which help thicken the skin. At menopause, the loss of estrogen leads to atrophy, and the vulvar epithelium is reduced to a few layers of mostly intermediate and parabasal cell types. The labia minora and majora as well as the clitoris gradually become less prominent with age.

The skin of the vulva consists of both dermis and epidermis, which interact with each other and respond to different nutritional and hormonal influences. For example, estrogen has little effect on vulvar epidermis, but considerable effect on the dermis, thickening the skin and preventing atrophy.

Postmenopausal atrophic changes can become a clinical problem when a woman resumes sexual intercourse after a long period of abstinence, as in the opening case. If atrophy is the main complaint, estrogen replacement therapy will alleviate symptoms of tightness, irritation, and dyspareunia, but it may take 6 weeks to 6 months to achieve optimal results. In the interim, women need to be reassured that reasonable function can be achieved.

Hygienic considerations

With any vulvar irritation, the patient should discontinue the use of synthetic undergarments in favor of cotton panties, which permit more adequate circulation and do not trap moisture.

Sitz baths often help relieve local discomfort, but should be followed by thorough drying.

Vulvar dystrophies: Think “white”

In the past, these diseases have been defined as non-neoplastic epithelial disorders of the vulva. Although there have been many attempts to more accurately define vulvar dystrophies, none have completely described the wide variety of clinical presentations.

In general, dystrophies are disorders of epithelial growth and nutrition that often result in a white surface color change. This definition includes intraepithelial neoplasia and Paget’s disease of the vulva. The International Society for the Study of Vulvovaginal Disease has proposed multiple classifications since 1975. I prefer the clarity of the 1987 classification system.¹ I also consider these terms out-of-date: lichen sclerosus et atrophicus, carcinoma simplex, leukoplakic vulvitis, leukoplakia, hyperplastic vulvitis, neurodermatitis, kraurosis vulvae, leukokeratosis, erythroplasia of Queyrat, and Bowen’s disease.

What makes the lesions white?

The white appearance of dystrophic lesions is due to excessive keratin, at times deep pigmentation, and relative avascularity. All 3 of these characteristics are present in the spectrum of vulvar dystrophies. Biopsy of the affected skin is the key to accurate diagnosis and successful therapy.

Lichen sclerosus

Does not raise risk of carcinoma

The most common of the 3 groups of white lesions described in the 1987 classification of dystrophies, lichen sclerosus usually occurs in postmenopausal women, but can appear at any age, including childhood (FIGURE 1). Despite claims to the contrary, there is no good evidence that women with lichen sclerosus face a higher risk for vulvar carcinoma.

FIGURE 1

Lichen sclerosus affects all ages

3-year-old child. Note the inflammation secondary to excoriations.

20-year-old woman. The glans clitoris has begun the hooding process.

70-year-old woman. The introitus has shrunk, making intercourse impossible.

Signs and symptoms

In lichen sclerosus, the skin of the vulva appears very thin, atrophic, and dry, resembling parchment. It is also white, with loss of pigmentation.

Pruritus is the most common symptom and is usually the presenting symptom. Scratching during sleep may create ulcerations and areas of ecchymosis, and there is generalized shrinking of the vulvar skin, with eventual loss of the labia minora.

The edema and shrinking that occur around the clitoris cause a “hooding” of the glans clitoris. If the process continues unchecked, it can involve the labia majora as well as the skin of the inner thigh and anal region.

Prescribe clobetasol ointment

The patient should be instructed to use clobetasol 0.05% ointment on a continuing basis. This drug is so successful it has eclipsed the use of testosterone propionate for this indication. Lorenz and colleagues² found very high success rates in 81 symptomatic patients with biopsy-proven disease who had failed previous therapy.

For reasons that are unknown, persistent use of this steroid on vulvar skin does not cause the atrophy commonly seen with prolonged use of high-potency steroids on other areas of the skin.

Start with twice-daily application and taper to less frequent use as the symptoms come under control. Most patients in remission can be maintained with twice-weekly application. Pruritus should disappear completely, and the skin itself will become less “leathery.”

Surgical treatment is not advised

Surgery does not appear to have a role because lichen sclerosus often recurs outside excised areas. Several reports have even described the return of disease in skin grafts used to replace large diseased areas.

I do not recommend surgery except in dire circumstances, when symptom relief is essential to the patient’s quality of life and all other therapies have failed.

Squamous cell hyperplasia

This disease is probably the same entity as lichen simplex chronicus. Changes in vulvar skin appear to result from chronic scratching secondary to intense pruritus. This complaint often involves a vicious cycle of scratching, increased pruritus, and more scratching, until excoriations occur. The aim of therapy is to eliminate the pruritus (FIGURE 2).

FIGURE 2

Squamous cell hyperplasia

75-year-old woman. The skin is thickened and may be leathery.

Intense pruritus and aggressive scratching lead to excoriations.

Signs and symptoms

Vulvar skin is typically white or pink. Biopsy will confirm the diagnosis, revealing a markedly thickened keratin layer (hyperkeratosis) and irregular thickening of the Malpighian ridges (acanthosis).

Inflammatory changes are also present, especially when there are areas of excoriation.

Treatment is similar to therapy for lichen sclerosus

Potent topical corticosteroids are the backbone of treatment; clobetasol is the preferred drug. The frequency of application is identical to that described for lichen sclerosus, and response to therapy usually takes 2 months. In the interim, it is advisable to prescribe other medications for the pruritus.

Lichen sclerosus and squamous cell hyperplasia sometimes coincide. Fortunately, the therapies are quite similar and both conditions tend to respond.

Vulvodynia

This disorder consists of chronic vulvar discomfort due to itching, burning, and/or pain that causes physical, sexual, and psychological distress.^3,4 Once referred to as essential vulvodynia, it now is defined as generalized vulvar dysesthesia.

Signs and symptoms

Women with this condition tend to have difficulty localizing their pain. They often present with a complaint of recurrent yeast infection or constant irritation at the introitus. Dyspareunia may or may not be a presenting symptom, although intercourse often triggers this condition. Tight pants or rough undergarments also may trigger symptoms.

Common symptoms. In a study by Sadownik,⁵ women with vulvar dysesthesia reported the following symptoms:

Women with vulvar dysesthesia who appear to have urinary tract symptoms should undergo a urine culture, though it will often be negative and antibiotic therapy will have little effect.

A diagnosis of exclusion

The pain of dysesthesia appears to be neuropathic in origin in that it mimics pain of the sensory nervous system. It may be diffuse or focal, unilateral or bilateral, constant or sporadic. Thus, it is a diagnosis of exclusion.

Recommended therapies

Vulvar dysesthesia should be regarded as a chronic pain syndrome and treated accordingly, with emphasis on generalized improvements in health and attitude rather than single-therapy approaches.

Potent topical corticosteroids are usually of no benefit. Nor does topical estrogen produce long-term relief.

Once all possible causes of symptoms are excluded, refer the patient for education, support, and treatment of depression, if present. Occasionally, topical anesthetics will provide short-term relief.

At least 2 vulvar pain societies—the National Vulvodynia Association and the Vulvar Pain Foundation—have newsletters, outreach programs, and Web sites.

Vulvar vestibulitis

A more readily definable condition in the same category as vulvodynia is so-called vulvar vestibulitis, also known as localized vulvodynia (as classified by the new ACOG Committee Opinion on vulvodynia).

Signs and symptoms

The defining presentation is severe pain on vestibular touch (eg, entry at intercourse), with tenderness to pressure localized within the vulvar vestibule in a horseshoe distribution pattern encompassing 3, 6, and 9 o’clock on the vestibule. Erythema is often present, especially at the 5 and 7 o’clock positions (FIGURE 3).

Patients have no symptoms during normal daily activities, but complain of dyspareunia and an inability to use tampons.

FIGURE 3

Vestibular adenitis

Intense erythema at the 5 o’clock position in the vestibule.

Diagnostic strategies

Vulvar vestibulitis can be diagnosed using a moistened cotton-tip applicator. Pressure applied in the area of the urethral meatus will result in minimal discomfort, but pressure in the horseshoe area of the vestibule will cause exquisite discomfort.

Careful inspection at 5 and 7 o’clock in the vestibule usually uncovers intense erythema over an area of 4 or 5 mm. To distinguish vestibulitis from dysesthesia, see the comparison in TABLE 1.

TABLE 1

Distinguishing vulvar vestibulitis and dysesthesia

Recommended therapies

Treatment of vulvar vestibulitis is complex. It is important to see the patient often to ensure that this syndrome is truly present rather than vulvar dysesthesia. Xylocaine jelly should be given in an attempt to relieve symptoms; topical steroid ointments are another option.

Women with persistent symptoms are difficult to treat medically. Earlier theories pointing to infection as the cause of vestibulitis have been discounted.

Some experts believe that foods containing oxalates precipitate these symptoms. It may be advisable to have the patient reduce the content of oxalates in her diet in an effort to address all possible remedies.

For refractory cases, consider surgery

Consider surgical removal of the tender vestibule if all other therapies fail to provide adequate relief. Surgery for this indication has a high success rate (TABLE 2).⁷

Some surgeons have attempted treatment with laser ablation, but most have found excision more satisfactory, with faster recovery and excellent cosmesis.

Schneider and colleagues⁸ had 69 women complete a questionnaire 6 months after surgery, 54 (78%) of whom replied. Moderate to excellent improvement was reported by 45 women (83%); 7 had repeat surgery, after which 4 improved.

TABLE 2

Impressive track record for surgical treatment of vestibulitis

Pigmented lesions

Are they cancer precursors?

Precursors of malignant melanoma of the vulva have yet to be clearly defined. The majority of these melanomas appear to arise de novo; however, some are associated with precursor nevi, especially junctional nevi. The 3 most common types of nevi that appear on the vulva are:

Assessing malignant potential

Only a small number of dysplastic nevi progress to malignant melanoma, but the frequency increases when the dysplastic nevus is familial and not acquired.

In general, the more severe the dysplasia, the greater the likelihood it will progress to malignancy. In dysplastic nevi, the pattern and appearance of the melanocytic cells are atypical. Bridging of melanocytic clusters of atypical cells may occur. Often, the atypical melanocytes are varied in size and shape, increasing in cell and nuclear size as severity increases. In the most severe cases, nucleoli are very prominent.

Many pigmented lesions of the vulva are lentigines, similar to freckles. Distinguishing one pigmented lesion from another is difficult even with magnification, and the clinician often must decide whether or not to biopsy. One set of guidelines recommends excisional biopsy of vulvar nevi when there is a change in:

Note that a reddish lesion may be basal cell hyperplasia, which has been associated with the development of basal cell carcinoma (FIGURE 4).

FIGURE 4

Basal cell carcinoma

An uncommon type of vulvar cancer, this tumor rarely metastasizes.

Premalignant lesions of squamous epithelium

The variable appearance of vulvar intraepithelial neoplasia (VIN) necessitates the liberal use of diagnostic biopsies, particularly when lesions persist or recur. VIN can present as a white lesion, or as pseudopigmented, pink, or raised and eroded.

Cigarette smoking is a risk factor.

Clinical appearance

Macroscopically, VIN lesions are often multiple and appear slightly raised and papular. Hyper- or pseudopigmented lesions are seen in about 30% of cases.

A confluence of VIN can create an appearance of diffuse plaques. In VIN, as for CIN, carcinoma in situ involves a full-thickness abnormality.

Terminology

If the abnormal parabasal layer extends to one half to two thirds of the epithelium, moderate dysplasia is present. A lower degree of involvement is called mild dysplasia, and full-thickness involvement is severe dysplasia or carcinoma in situ.

High rate of persistence, recurrence

Herod and colleagues⁹ reported on a 15-year follow-up of VIN and found that disease persisted or recurred in 48% of women managed surgically, and 7% of patients progressed to frankly invasive carcinoma. These investigators used the following classification system:

Joura et al¹⁰ strongly suggested that the incidence of this condition is increasing, especially in women prior to the 7th decade of life. Whether this increase is due to better recognition or a true rise in prevalence has been debated.

Diagnostic strategies

Application of 5% acetic acid to the vulvar skin will, after 3 to 5 minutes, allow areas of involvement to be readily seen with a handheld magnifying glass. Colposcopy can be used, but is slower and not as efficient as a simple magnifying lens. Most clinicians have abandoned the use of toluidine blue to identify multicentric lesions, since acetic acid appears to be less cumbersome and just as efficient.

White or pseudopigmented lesions (FIGURE 5) can be seen anywhere on the vulva and represent 2 of the 3 presentations of VIN. Pink lesions (FIGURE 5) are usually seen on moist surfaces near mucous membranes, whereas the white or pseudopigmented lesions are usually seen on the drier, hair-bearing areas of the vulva. Biopsy reveals similar histology.

The cause of the pseudopigmented lesions is unclear, but is unrelated to a disturbance of the melanin cells. As with other vulvar lesions, biopsy is essential for a correct diagnosis.

FIGURE 5

VIN III lesions: A trio of presentations

White lesion.

Pseudopigmented lesions.

Pink lesion.

Recommended therapies

VIN is treated by destroying or excising the epithelium involved. When the area is limited in size, simple excision or laser vaporization is preferred. A 2- to 3-mm margin is adequate, because these lesions have sharp borders.

Laser therapy warrants extra care because the epithelium is rarely thicker than 0.5 mm. For this reason, vaporization of the vulva should be limited to the following depths:

These limits will speed healing and prevent the unnecessary destruction of dermis.

Also be aware that the depth of hair-follicle involvement rarely exceeds 1 mm. Vaporization of the full thickness of the dermis will lead to alopecia and vulvar dryness.

When disease is multifocal or confluent, treatment is more challenging. Several decades ago, simple vulvectomy was performed, but the patient was left a sexual cripple.

Since then, laser therapy has been attempted in these cases, and has proved to be effective when the area treated does not exceed 25% of the total area of the vulva. Extensive laser therapy leads to considerable postoperative pain and an unhappy result.

Extensive involvement may necessitate laser treatment by quadrant to achieve the best results. Another option is “skinning vulvectomy” using a skin graft. This procedure, first described by Felix Rutledge,¹¹ requires a 7- or 8-day hospitalization, but allows for complete therapy in 1 session.

Paget’s disease of the vulva

This disease is most frequently seen in the breast nipple (FIGURE 6), where it is usually associated with an underlying infiltrating ductal carcinoma. Extramammary sites include the vulvar, perianal, and axillary regions. The disease has also been seen in the ear canal.

Paget’s disease is an intraepithelial adenocarcinoma of eccrine or apocrine origin.

FIGURE 6

Paget disease: Not just a breast complaint

Paget disease of the nipple with underlying ductal adenocarcinoma.

Vulvar Paget disease: lesion (left) and photomicrograph of the lesion.

Clinical appearance

Paget’s disease of the vulva appears as a superficial, red to pink, velvety, eczematoid lesion (FIGURE 6), which is very pruritic and often associated with exfoliation. Margins are difficult to identify grossly.

On rare occasions, a nodular tumor can be found in the middle of the skin involvement, but in most cases no invasive malignancy is found at extramammary sites on the vulva.

Diagnostic strategies

Microscopic appearance of Paget cells (FIGURE 6) are pathognomonic of the disease.

Older textbooks suggest that 10% to 20% of patients have an associated, underlying, invasive carcinoma of a skin appendage, Bartholin’s gland, urinary tract, or bowel or rectal site, but later experience has not confirmed this. Rather, the likelihood of concomitant invasive disease is much lower than 10%.

Excision is the treatment of choice

Any attempt to achieve negative margins must utilize frozen section. Some studies have suggested that negative margins are not associated with a reduced rate of recurrence, but these findings have been inconsistent.

Recurrence is common

Paget’s disease of the vulva often recurs, especially when the initial lesion is large. Close monitoring will detect these recurrences when they’re quite small and easily removed via local excision. Occasionally, the initial disease is so extensive that skin grafting may be necessary to cover the defect.

The author reports no financial relationships relevant to this article.

With more women steering clear of estrogen in the wake of the Women’s Health Initiative and other trials,^{page 24). Nonetheless, many physicians and patients seek nonestrogen alternatives for this menopause-related symptom.}

Over-the-counter lubricants are a mixed lot

Although many lubricants are marketed today, clinical study has been limited because they are regulated by the FDA as cosmetics. Of these products, Replens, a bioadhesive vaginal lubricant, has been studied the most intensively.

A unique formulation. Replens, a polycarbophil-based polymer, attaches to the vaginal wall and can hold 60 times its weight in water. It remains against the vaginal epithelial surface for more than 24 hours before it is sloughed off. This mechanism provides longer relief and requires less frequent application than other lubricants.¹⁷

Replens vs estrogen. Thrice-weekly Replens was compared with 12 weeks of daily vaginal estrogen cream¹⁸ and with vaginal estrogen cream applied daily for 2 weeks and then 3 times weekly for a total of 3 months.¹⁹ The comparison of Replens with conjugated estrogen cream (Premarin) showed significant improvements in vaginal moisture, fluid volume, elasticity, and pH levels in both treatment groups.¹⁸ Vaginal atrophy (assessed via Papanicolaou smear) reversed in 100% of estrogen-treated patients and 60% of Replens-treated patients.

When Replens was compared with dienoestrol vaginal cream, both therapies produced significant improvement in the vaginal dryness index (a score based on vaginal moisture, fluid volume, elasticity, and mucosa) within the first week.¹⁹ However, dienoestrol-treated patients had greater improvement in mean vaginal dryness (21.78 vs 17.32) at 12 weeks of therapy (P=.0001), compared with baseline values of 13 (dienoestrol) and 13.45 (Replens). Vaginal symptoms and dyspareunia improved at similar rates in the 2 groups. Patient satisfaction also was high in both groups, with 60% of Replens-treated patients and 84% of dienoestrol-treated patients reporting good to excellent effects.

No serious side effects were reported.^18,19

Start with Replens for vaginal dryness, as it is a safe and effective alternative. If it is ineffective, vaginal estrogen may be more effective than vaginal lubricants.

The authors report no financial relationships relevant to this article

Is hormone-free treatment effective? 3 women’s stories

By Joann V. Pinkerton, MD, OBG Management Board of Editors, Professor of Obstetrics and Gynecology and Director, The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

CASE 1 Perimenopausal, daily hot flashes

THERAPY

Exercise, soy products, vitamin E, and black cohosh

THE PATIENT: “V.S.,” 51, has been a patient for some time. At her latest visit, she reports that her menstrual periods are irregular, occurring every 3 to 12 weeks. She also has as many as 5 hot flashes a day, wakes in the very early morning, and occasionally experiences mild night sweats. Because she underwent bilateral tubal ligation many years ago, there is no need for contraception. She has no family history of breast cancer, but prefers to avoid drugs and asks if there are any herbal remedies and/or lifestyle changes that will ease her transition through menopause. She has a body mass index (BMI) of 31.6, and her breast and pelvic examinations are negative.

INTERVENTION: We discuss several simple options. For example, regular exercise may reduce vasomotor symptoms, although intense exertion with sweating can provoke hot flashes. Soy products and soy extracts have had mixed results, but appear to have some benefit. I suggest adding 1 soy dietary product per day. Vitamin E also may reduce hot flashes very modestly. The most promising product is black cohosh; I advise V.S. to take 20 mg twice a day.

OUTCOME: V.S. begins exercising regularly and sets a weight loss goal of 10%. She also begins taking 400 IU of vitamin E daily, adds soy nuts to her diet, and starts taking black cohosh. Three months later, she reports that her hot flashes have decreased to about 3 per day and are tolerable. She has had 1 menstrual cycle in the interim. If her symptoms worsen, she will consider medical therapy.

CASE 2 Severe symptoms, mood effects

THERAPY

Venlafaxine and vaginal moisturizers

THE PATIENT: “A.B.,” 54, a cancer survivor, is menopausal and has 10 to 20 hot flashes a day and soaking night sweats. She also reports low mood, frequent crying, and irritability. Before her cancer diagnosis, A.B. took hormone therapy for 6 months for severe menopausal symptoms. She recently underwent lumpectomy, axillary node dissection, radiation, and chemotherapy for a 3-cm, grade 3, invasive lobular carcinoma that was estrogen- and progesterone-receptor positive, and she is about to begin an aromatase inhibitor for chemoprevention. She and her husband have attempted intercourse since her chemotherapy ended, but the experience was painful. She would prefer to restart hormone therapy, but is willing to try nonhormonal options first. Her examination is unremarkable except for significant atrophy, with a vaginal pH of 7.0.

INTERVENTION: After a discussion of the data on SSRIs, SNRIs, and gabapentin, A.B. decides to try venlafaxine, 37.5 mg daily. If she has no improvement after 2 weeks, she will increase the dosage to 75 mg daily. For the vulvovaginal atrophy, she will try both vaginal moisturizers and vaginal lubricants, recognizing that this will not rethicken the epithelium. She also will exercise 5 days per week.

OUTCOME: After 3 months and an increase to 75 mg daily venlafaxine, the patient reports a 50% decrease in hot flashes and a more stable mood. The dyspareunia remains a problem. She decides to try a small amount of estradiol cream—somewhere between the size of a pea and the size of a dime—applied externally around the introital opening. She will start by applying it daily for 2 weeks, then reduce to twice a week.

CASE 3 Severe symptoms after TAH/BSO

THERAPY

Unsatisfactory improvement, a return to estrogen

THE PATIENT: “A.G.,” 46, complains of severe vasomotor symptoms. Two months ago she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy for bilateral complex masses, which turned out to be endometriomas. At that time, endometriosis was observed along the left ureter, with residual peritoneal implants and a small nodule within the rectovaginal septum. A.G. was offered leuprolide acetate (Lupron Depot) postoperatively, but declined. She did well for about 2 months and then began having vasomotor symptoms. Her physician was hesitant to prescribe estrogen because of fear of reactivating endometriosis. A.G. toughed it out for 3 months, but now reports “misery.” She is moody, cries easily, and has not had sex with her husband since her surgery. An examination reveals a small, 8-mm nodule within the rectovaginal septum, decreased vulvar color, vaginal pallor, and levator ani spasm with exam. Vaginal pH is 6.5.

INTERVENTION: Although I suggest systemic progesterone therapy—oral, vaginal, or intramuscular—and explain that it would decrease any residual endometriosis and relieve the hot flashes, the patient does not want to take any hormonal therapy and is concerned about worsening her mood. Despite reassurance that hormone therapy would have less than a 5% chance of reactivating the endometriosis, A.G. decides to try an antidepressant first. Since she had taken paroxetine (Paxil) for postpartum depression, with no major side effects, she decides to try it again, starting with 10 mg daily.

OUTCOME: A.G. continues to have at least 5 bothersome hot flashes per day, which interrupt her work with profuse sweating. She also wakes at night for the same reason. However, she is less irritable. It has been 7 months since her surgery, and both she and her husband want her to try hormone therapy. She elects to begin a low-dose combined estrogen–progesterone product, as well as estradiol vaginal cream twice daily.

Three months later, she reports no pain, a gradual reduction in hot flashes, and significant improvement overall. Her vaginal color has returned, her pH is 5.5, and intercourse is no longer painful. She decides to continue taking oral hormone therapy at a low dose despite occasional vasomotor symptoms, and to keep using vaginal estrogen, but will stop the paroxetine.

EVIDENCE RECAP

How does one hot flash differ from another?

By Joann V. Pinkerton, MD, OBG Management Board of Editors, Professor of Obstetrics and Gynecology and Director of The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057–2071.

Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms. Arch Intern Med. 2006;166:1453–1465.

The hot flash, long synonymous with menopause, is the bane of many women facing the midlife transition. Despite the intensity of the sensation, hot flashes appear to be triggered by small elevations in core body temperature within a greatly reduced thermoneutral zone.^1-4 If the core temperature crosses the upper threshold, a hot flash with sweating and peripheral vasodilation occurs. If the lower threshold is crossed, shivering results. Core temperature elevations occur in both symptomatic and asymptomatic women.

The difference: In symptomatic women, the thermoneutral zone is narrowed.

2 randomized trials attest to mostly modest efficacy

In their rigorous study of nonhormonal therapies for hot flashes, Nelson et al reviewed MEDLINE, PsycINFO, and the Cochrane Clinical Trials Register Database for randomized, double-blind, placebo-controlled trials of oral nonhormonal treatments for hot flashes, ultimately selecting 43 trials. These included 10 trials of antidepressants, 10 trials of clonidine, 17 trials of isoflavones, and 6 trials of other prescription drugs. They found at least some evidence of efficacy for SSRIs, SNRIs, clonidine, and gabapentin, but all were considerably less effective than estrogen.

Nedrow and colleagues searched the same databases plus MANTIS and AMED, selecting 70 trials for inclusion. Overall, the data were insufficient to support the effectiveness of any complementary or alternative therapy. For example, a good-quality study enrolling breast cancer survivors compared 56 patients ingesting 90 mg daily of isoflavone soy drink with 55 patients who took placebo, with no differences reported between the groups in hot flash frequency or intensity, yet both groups improved over baseline.

The placebo effect and other challenges

Randomized, controlled trials of alternative medicines and nonhormonal prescription therapies have found a placebo effect that ranges from about 1% to as high as 77%.^5,6 In estrogen trials, the mean placebo response is 50.8%.⁷ The study of nonhormonal therapies involves several challenges, such as difficulty locating a proper control or placebo, and double-blinding is often impossible.

A big problem faced in both studies was the lack of consistency in inclusion criteria. Study samples differed in age range, menopausal status, type of menopause, inclusion of breast cancer survivors, or use of antiestrogen therapy such as tamoxifen, raloxifene, or aromatase inhibitors—drugs that are associated with hot flashes.

Studies also varied in the degree of hot-flash severity required for enrollment. Some studies of alternative therapies enrolled women with 1 or 2 hot flashes per day, or 14 per week, whereas the US FDA requires women in hormone-therapy trials to have at least 7 moderate to severe hot flashes daily, or 50 to 60 per week, with specific definitions of severity.

Moreover, botanical products may have milder effects overall or take longer to elicit a response. Most studies are of short duration with small numbers of women, increasing the potential for confounding by the placebo effect.

REFERENCES

With more women steering clear of estrogen in the wake of the Women’s Health Initiative and other trials,^{page 24). Nonetheless, many physicians and patients seek nonestrogen alternatives for this menopause-related symptom.}

Over-the-counter lubricants are a mixed lot

Although many lubricants are marketed today, clinical study has been limited because they are regulated by the FDA as cosmetics. Of these products, Replens, a bioadhesive vaginal lubricant, has been studied the most intensively.

A unique formulation. Replens, a polycarbophil-based polymer, attaches to the vaginal wall and can hold 60 times its weight in water. It remains against the vaginal epithelial surface for more than 24 hours before it is sloughed off. This mechanism provides longer relief and requires less frequent application than other lubricants.¹⁷

Replens vs estrogen. Thrice-weekly Replens was compared with 12 weeks of daily vaginal estrogen cream¹⁸ and with vaginal estrogen cream applied daily for 2 weeks and then 3 times weekly for a total of 3 months.¹⁹ The comparison of Replens with conjugated estrogen cream (Premarin) showed significant improvements in vaginal moisture, fluid volume, elasticity, and pH levels in both treatment groups.¹⁸ Vaginal atrophy (assessed via Papanicolaou smear) reversed in 100% of estrogen-treated patients and 60% of Replens-treated patients.

When Replens was compared with dienoestrol vaginal cream, both therapies produced significant improvement in the vaginal dryness index (a score based on vaginal moisture, fluid volume, elasticity, and mucosa) within the first week.¹⁹ However, dienoestrol-treated patients had greater improvement in mean vaginal dryness (21.78 vs 17.32) at 12 weeks of therapy (P=.0001), compared with baseline values of 13 (dienoestrol) and 13.45 (Replens). Vaginal symptoms and dyspareunia improved at similar rates in the 2 groups. Patient satisfaction also was high in both groups, with 60% of Replens-treated patients and 84% of dienoestrol-treated patients reporting good to excellent effects.

No serious side effects were reported.^18,19

Start with Replens for vaginal dryness, as it is a safe and effective alternative. If it is ineffective, vaginal estrogen may be more effective than vaginal lubricants.

The authors report no financial relationships relevant to this article

Is hormone-free treatment effective? 3 women’s stories

By Joann V. Pinkerton, MD, OBG Management Board of Editors, Professor of Obstetrics and Gynecology and Director, The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

CASE 1 Perimenopausal, daily hot flashes

THERAPY

Exercise, soy products, vitamin E, and black cohosh

THE PATIENT: “V.S.,” 51, has been a patient for some time. At her latest visit, she reports that her menstrual periods are irregular, occurring every 3 to 12 weeks. She also has as many as 5 hot flashes a day, wakes in the very early morning, and occasionally experiences mild night sweats. Because she underwent bilateral tubal ligation many years ago, there is no need for contraception. She has no family history of breast cancer, but prefers to avoid drugs and asks if there are any herbal remedies and/or lifestyle changes that will ease her transition through menopause. She has a body mass index (BMI) of 31.6, and her breast and pelvic examinations are negative.

INTERVENTION: We discuss several simple options. For example, regular exercise may reduce vasomotor symptoms, although intense exertion with sweating can provoke hot flashes. Soy products and soy extracts have had mixed results, but appear to have some benefit. I suggest adding 1 soy dietary product per day. Vitamin E also may reduce hot flashes very modestly. The most promising product is black cohosh; I advise V.S. to take 20 mg twice a day.

OUTCOME: V.S. begins exercising regularly and sets a weight loss goal of 10%. She also begins taking 400 IU of vitamin E daily, adds soy nuts to her diet, and starts taking black cohosh. Three months later, she reports that her hot flashes have decreased to about 3 per day and are tolerable. She has had 1 menstrual cycle in the interim. If her symptoms worsen, she will consider medical therapy.

CASE 2 Severe symptoms, mood effects

THERAPY

Venlafaxine and vaginal moisturizers

THE PATIENT: “A.B.,” 54, a cancer survivor, is menopausal and has 10 to 20 hot flashes a day and soaking night sweats. She also reports low mood, frequent crying, and irritability. Before her cancer diagnosis, A.B. took hormone therapy for 6 months for severe menopausal symptoms. She recently underwent lumpectomy, axillary node dissection, radiation, and chemotherapy for a 3-cm, grade 3, invasive lobular carcinoma that was estrogen- and progesterone-receptor positive, and she is about to begin an aromatase inhibitor for chemoprevention. She and her husband have attempted intercourse since her chemotherapy ended, but the experience was painful. She would prefer to restart hormone therapy, but is willing to try nonhormonal options first. Her examination is unremarkable except for significant atrophy, with a vaginal pH of 7.0.

INTERVENTION: After a discussion of the data on SSRIs, SNRIs, and gabapentin, A.B. decides to try venlafaxine, 37.5 mg daily. If she has no improvement after 2 weeks, she will increase the dosage to 75 mg daily. For the vulvovaginal atrophy, she will try both vaginal moisturizers and vaginal lubricants, recognizing that this will not rethicken the epithelium. She also will exercise 5 days per week.

OUTCOME: After 3 months and an increase to 75 mg daily venlafaxine, the patient reports a 50% decrease in hot flashes and a more stable mood. The dyspareunia remains a problem. She decides to try a small amount of estradiol cream—somewhere between the size of a pea and the size of a dime—applied externally around the introital opening. She will start by applying it daily for 2 weeks, then reduce to twice a week.

CASE 3 Severe symptoms after TAH/BSO

THERAPY

Unsatisfactory improvement, a return to estrogen

THE PATIENT: “A.G.,” 46, complains of severe vasomotor symptoms. Two months ago she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy for bilateral complex masses, which turned out to be endometriomas. At that time, endometriosis was observed along the left ureter, with residual peritoneal implants and a small nodule within the rectovaginal septum. A.G. was offered leuprolide acetate (Lupron Depot) postoperatively, but declined. She did well for about 2 months and then began having vasomotor symptoms. Her physician was hesitant to prescribe estrogen because of fear of reactivating endometriosis. A.G. toughed it out for 3 months, but now reports “misery.” She is moody, cries easily, and has not had sex with her husband since her surgery. An examination reveals a small, 8-mm nodule within the rectovaginal septum, decreased vulvar color, vaginal pallor, and levator ani spasm with exam. Vaginal pH is 6.5.

INTERVENTION: Although I suggest systemic progesterone therapy—oral, vaginal, or intramuscular—and explain that it would decrease any residual endometriosis and relieve the hot flashes, the patient does not want to take any hormonal therapy and is concerned about worsening her mood. Despite reassurance that hormone therapy would have less than a 5% chance of reactivating the endometriosis, A.G. decides to try an antidepressant first. Since she had taken paroxetine (Paxil) for postpartum depression, with no major side effects, she decides to try it again, starting with 10 mg daily.

OUTCOME: A.G. continues to have at least 5 bothersome hot flashes per day, which interrupt her work with profuse sweating. She also wakes at night for the same reason. However, she is less irritable. It has been 7 months since her surgery, and both she and her husband want her to try hormone therapy. She elects to begin a low-dose combined estrogen–progesterone product, as well as estradiol vaginal cream twice daily.

Three months later, she reports no pain, a gradual reduction in hot flashes, and significant improvement overall. Her vaginal color has returned, her pH is 5.5, and intercourse is no longer painful. She decides to continue taking oral hormone therapy at a low dose despite occasional vasomotor symptoms, and to keep using vaginal estrogen, but will stop the paroxetine.

EVIDENCE RECAP

How does one hot flash differ from another?

By Joann V. Pinkerton, MD, OBG Management Board of Editors, Professor of Obstetrics and Gynecology and Director of The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057–2071.

Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms. Arch Intern Med. 2006;166:1453–1465.

The hot flash, long synonymous with menopause, is the bane of many women facing the midlife transition. Despite the intensity of the sensation, hot flashes appear to be triggered by small elevations in core body temperature within a greatly reduced thermoneutral zone.^1-4 If the core temperature crosses the upper threshold, a hot flash with sweating and peripheral vasodilation occurs. If the lower threshold is crossed, shivering results. Core temperature elevations occur in both symptomatic and asymptomatic women.

The difference: In symptomatic women, the thermoneutral zone is narrowed.

2 randomized trials attest to mostly modest efficacy

In their rigorous study of nonhormonal therapies for hot flashes, Nelson et al reviewed MEDLINE, PsycINFO, and the Cochrane Clinical Trials Register Database for randomized, double-blind, placebo-controlled trials of oral nonhormonal treatments for hot flashes, ultimately selecting 43 trials. These included 10 trials of antidepressants, 10 trials of clonidine, 17 trials of isoflavones, and 6 trials of other prescription drugs. They found at least some evidence of efficacy for SSRIs, SNRIs, clonidine, and gabapentin, but all were considerably less effective than estrogen.

Nedrow and colleagues searched the same databases plus MANTIS and AMED, selecting 70 trials for inclusion. Overall, the data were insufficient to support the effectiveness of any complementary or alternative therapy. For example, a good-quality study enrolling breast cancer survivors compared 56 patients ingesting 90 mg daily of isoflavone soy drink with 55 patients who took placebo, with no differences reported between the groups in hot flash frequency or intensity, yet both groups improved over baseline.

The placebo effect and other challenges

Randomized, controlled trials of alternative medicines and nonhormonal prescription therapies have found a placebo effect that ranges from about 1% to as high as 77%.^5,6 In estrogen trials, the mean placebo response is 50.8%.⁷ The study of nonhormonal therapies involves several challenges, such as difficulty locating a proper control or placebo, and double-blinding is often impossible.

A big problem faced in both studies was the lack of consistency in inclusion criteria. Study samples differed in age range, menopausal status, type of menopause, inclusion of breast cancer survivors, or use of antiestrogen therapy such as tamoxifen, raloxifene, or aromatase inhibitors—drugs that are associated with hot flashes.

Studies also varied in the degree of hot-flash severity required for enrollment. Some studies of alternative therapies enrolled women with 1 or 2 hot flashes per day, or 14 per week, whereas the US FDA requires women in hormone-therapy trials to have at least 7 moderate to severe hot flashes daily, or 50 to 60 per week, with specific definitions of severity.

Moreover, botanical products may have milder effects overall or take longer to elicit a response. Most studies are of short duration with small numbers of women, increasing the potential for confounding by the placebo effect.

REFERENCES

With more women steering clear of estrogen in the wake of the Women’s Health Initiative and other trials,^{page 24). Nonetheless, many physicians and patients seek nonestrogen alternatives for this menopause-related symptom.}

Over-the-counter lubricants are a mixed lot

Although many lubricants are marketed today, clinical study has been limited because they are regulated by the FDA as cosmetics. Of these products, Replens, a bioadhesive vaginal lubricant, has been studied the most intensively.

A unique formulation. Replens, a polycarbophil-based polymer, attaches to the vaginal wall and can hold 60 times its weight in water. It remains against the vaginal epithelial surface for more than 24 hours before it is sloughed off. This mechanism provides longer relief and requires less frequent application than other lubricants.¹⁷

Replens vs estrogen. Thrice-weekly Replens was compared with 12 weeks of daily vaginal estrogen cream¹⁸ and with vaginal estrogen cream applied daily for 2 weeks and then 3 times weekly for a total of 3 months.¹⁹ The comparison of Replens with conjugated estrogen cream (Premarin) showed significant improvements in vaginal moisture, fluid volume, elasticity, and pH levels in both treatment groups.¹⁸ Vaginal atrophy (assessed via Papanicolaou smear) reversed in 100% of estrogen-treated patients and 60% of Replens-treated patients.

When Replens was compared with dienoestrol vaginal cream, both therapies produced significant improvement in the vaginal dryness index (a score based on vaginal moisture, fluid volume, elasticity, and mucosa) within the first week.¹⁹ However, dienoestrol-treated patients had greater improvement in mean vaginal dryness (21.78 vs 17.32) at 12 weeks of therapy (P=.0001), compared with baseline values of 13 (dienoestrol) and 13.45 (Replens). Vaginal symptoms and dyspareunia improved at similar rates in the 2 groups. Patient satisfaction also was high in both groups, with 60% of Replens-treated patients and 84% of dienoestrol-treated patients reporting good to excellent effects.

No serious side effects were reported.^18,19

Start with Replens for vaginal dryness, as it is a safe and effective alternative. If it is ineffective, vaginal estrogen may be more effective than vaginal lubricants.

The authors report no financial relationships relevant to this article

Is hormone-free treatment effective? 3 women’s stories

By Joann V. Pinkerton, MD, OBG Management Board of Editors, Professor of Obstetrics and Gynecology and Director, The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

CASE 1 Perimenopausal, daily hot flashes

THERAPY

Exercise, soy products, vitamin E, and black cohosh

THE PATIENT: “V.S.,” 51, has been a patient for some time. At her latest visit, she reports that her menstrual periods are irregular, occurring every 3 to 12 weeks. She also has as many as 5 hot flashes a day, wakes in the very early morning, and occasionally experiences mild night sweats. Because she underwent bilateral tubal ligation many years ago, there is no need for contraception. She has no family history of breast cancer, but prefers to avoid drugs and asks if there are any herbal remedies and/or lifestyle changes that will ease her transition through menopause. She has a body mass index (BMI) of 31.6, and her breast and pelvic examinations are negative.

INTERVENTION: We discuss several simple options. For example, regular exercise may reduce vasomotor symptoms, although intense exertion with sweating can provoke hot flashes. Soy products and soy extracts have had mixed results, but appear to have some benefit. I suggest adding 1 soy dietary product per day. Vitamin E also may reduce hot flashes very modestly. The most promising product is black cohosh; I advise V.S. to take 20 mg twice a day.

OUTCOME: V.S. begins exercising regularly and sets a weight loss goal of 10%. She also begins taking 400 IU of vitamin E daily, adds soy nuts to her diet, and starts taking black cohosh. Three months later, she reports that her hot flashes have decreased to about 3 per day and are tolerable. She has had 1 menstrual cycle in the interim. If her symptoms worsen, she will consider medical therapy.

CASE 2 Severe symptoms, mood effects

THERAPY

Venlafaxine and vaginal moisturizers

THE PATIENT: “A.B.,” 54, a cancer survivor, is menopausal and has 10 to 20 hot flashes a day and soaking night sweats. She also reports low mood, frequent crying, and irritability. Before her cancer diagnosis, A.B. took hormone therapy for 6 months for severe menopausal symptoms. She recently underwent lumpectomy, axillary node dissection, radiation, and chemotherapy for a 3-cm, grade 3, invasive lobular carcinoma that was estrogen- and progesterone-receptor positive, and she is about to begin an aromatase inhibitor for chemoprevention. She and her husband have attempted intercourse since her chemotherapy ended, but the experience was painful. She would prefer to restart hormone therapy, but is willing to try nonhormonal options first. Her examination is unremarkable except for significant atrophy, with a vaginal pH of 7.0.

INTERVENTION: After a discussion of the data on SSRIs, SNRIs, and gabapentin, A.B. decides to try venlafaxine, 37.5 mg daily. If she has no improvement after 2 weeks, she will increase the dosage to 75 mg daily. For the vulvovaginal atrophy, she will try both vaginal moisturizers and vaginal lubricants, recognizing that this will not rethicken the epithelium. She also will exercise 5 days per week.

OUTCOME: After 3 months and an increase to 75 mg daily venlafaxine, the patient reports a 50% decrease in hot flashes and a more stable mood. The dyspareunia remains a problem. She decides to try a small amount of estradiol cream—somewhere between the size of a pea and the size of a dime—applied externally around the introital opening. She will start by applying it daily for 2 weeks, then reduce to twice a week.

CASE 3 Severe symptoms after TAH/BSO

THERAPY

Unsatisfactory improvement, a return to estrogen

THE PATIENT: “A.G.,” 46, complains of severe vasomotor symptoms. Two months ago she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy for bilateral complex masses, which turned out to be endometriomas. At that time, endometriosis was observed along the left ureter, with residual peritoneal implants and a small nodule within the rectovaginal septum. A.G. was offered leuprolide acetate (Lupron Depot) postoperatively, but declined. She did well for about 2 months and then began having vasomotor symptoms. Her physician was hesitant to prescribe estrogen because of fear of reactivating endometriosis. A.G. toughed it out for 3 months, but now reports “misery.” She is moody, cries easily, and has not had sex with her husband since her surgery. An examination reveals a small, 8-mm nodule within the rectovaginal septum, decreased vulvar color, vaginal pallor, and levator ani spasm with exam. Vaginal pH is 6.5.

INTERVENTION: Although I suggest systemic progesterone therapy—oral, vaginal, or intramuscular—and explain that it would decrease any residual endometriosis and relieve the hot flashes, the patient does not want to take any hormonal therapy and is concerned about worsening her mood. Despite reassurance that hormone therapy would have less than a 5% chance of reactivating the endometriosis, A.G. decides to try an antidepressant first. Since she had taken paroxetine (Paxil) for postpartum depression, with no major side effects, she decides to try it again, starting with 10 mg daily.

OUTCOME: A.G. continues to have at least 5 bothersome hot flashes per day, which interrupt her work with profuse sweating. She also wakes at night for the same reason. However, she is less irritable. It has been 7 months since her surgery, and both she and her husband want her to try hormone therapy. She elects to begin a low-dose combined estrogen–progesterone product, as well as estradiol vaginal cream twice daily.

Three months later, she reports no pain, a gradual reduction in hot flashes, and significant improvement overall. Her vaginal color has returned, her pH is 5.5, and intercourse is no longer painful. She decides to continue taking oral hormone therapy at a low dose despite occasional vasomotor symptoms, and to keep using vaginal estrogen, but will stop the paroxetine.

EVIDENCE RECAP

How does one hot flash differ from another?

By Joann V. Pinkerton, MD, OBG Management Board of Editors, Professor of Obstetrics and Gynecology and Director of The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057–2071.

Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms. Arch Intern Med. 2006;166:1453–1465.

The hot flash, long synonymous with menopause, is the bane of many women facing the midlife transition. Despite the intensity of the sensation, hot flashes appear to be triggered by small elevations in core body temperature within a greatly reduced thermoneutral zone.^1-4 If the core temperature crosses the upper threshold, a hot flash with sweating and peripheral vasodilation occurs. If the lower threshold is crossed, shivering results. Core temperature elevations occur in both symptomatic and asymptomatic women.

The difference: In symptomatic women, the thermoneutral zone is narrowed.

2 randomized trials attest to mostly modest efficacy

In their rigorous study of nonhormonal therapies for hot flashes, Nelson et al reviewed MEDLINE, PsycINFO, and the Cochrane Clinical Trials Register Database for randomized, double-blind, placebo-controlled trials of oral nonhormonal treatments for hot flashes, ultimately selecting 43 trials. These included 10 trials of antidepressants, 10 trials of clonidine, 17 trials of isoflavones, and 6 trials of other prescription drugs. They found at least some evidence of efficacy for SSRIs, SNRIs, clonidine, and gabapentin, but all were considerably less effective than estrogen.

Nedrow and colleagues searched the same databases plus MANTIS and AMED, selecting 70 trials for inclusion. Overall, the data were insufficient to support the effectiveness of any complementary or alternative therapy. For example, a good-quality study enrolling breast cancer survivors compared 56 patients ingesting 90 mg daily of isoflavone soy drink with 55 patients who took placebo, with no differences reported between the groups in hot flash frequency or intensity, yet both groups improved over baseline.

The placebo effect and other challenges

Randomized, controlled trials of alternative medicines and nonhormonal prescription therapies have found a placebo effect that ranges from about 1% to as high as 77%.^5,6 In estrogen trials, the mean placebo response is 50.8%.⁷ The study of nonhormonal therapies involves several challenges, such as difficulty locating a proper control or placebo, and double-blinding is often impossible.

A big problem faced in both studies was the lack of consistency in inclusion criteria. Study samples differed in age range, menopausal status, type of menopause, inclusion of breast cancer survivors, or use of antiestrogen therapy such as tamoxifen, raloxifene, or aromatase inhibitors—drugs that are associated with hot flashes.

Studies also varied in the degree of hot-flash severity required for enrollment. Some studies of alternative therapies enrolled women with 1 or 2 hot flashes per day, or 14 per week, whereas the US FDA requires women in hormone-therapy trials to have at least 7 moderate to severe hot flashes daily, or 50 to 60 per week, with specific definitions of severity.

Moreover, botanical products may have milder effects overall or take longer to elicit a response. Most studies are of short duration with small numbers of women, increasing the potential for confounding by the placebo effect.

REFERENCES

It is all too easy to focus on T-scores and lose sight of why we check bone mass: we want to prevent fragility fractures—not osteoporosis per se. Fracture incidence is greater in women with osteoporosis, but the absolute number of fragility fractures is far greater in the women who have not yet reached that threshold. That was my main message last year. It still is, although I had hoped we would by now have in our hands a fracture risk assessment tool due from the World Health Organization. It will use age, DXA score, history, and other factors to project 5- and 10-year risk of fracture. Then we will simply have to decide at what level of risk, for an individual patient, drug therapy is indicated. Watch this space!

1 Osteonecrosis of the jaw: What clinicians need to know

Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753–761.

This was the year of massive media attention on bisphosphonate therapy and osteonecrosis of the jaw. A bone specialist I know said he got even more phone calls after this report was published than after the WHI blitz 4 years ago.

Patients started calling when the lay press limelight focused on a report by Woo et al, who reviewed all of the world’s literature published since 1966, and identified 368 reported cases of bisphosphonate-associated osteonecrosis of the jaw (ONJ).

Main findings

Of the 368 cases, 94% were being treated with intravenous bisphosphonate therapy; 85% of the patients had either multiple myeloma or metastatic cancer of the breast. More than half of all cases (60%) were preceded by tooth extraction or other dentoalveolar surgical procedure to treat infections, and the remaining 40% were related to infection, denture trauma, or other physical trauma.

The latter group of cases occurred spontaneously, although the patients affected often wore dentures. The mandible was more commonly affected than the maxilla by a ratio of 2:1.

Other studies have reported 75% of patients with ONJ were receiving chemotherapy at the time of diagnosis, and 38% were on corticosteroids.

Do these findings affect prescribing?

A small number of cases of ONJ in postmenopausal women taking oral bisphosphonates have occurred, though rarely—well under 1 per 100,000 patients treated. Realize that patients with myeloma or metastatic breast cancer are usually treated with high-dose, high-potency intravenous bisphosphonate.

There were no reports of ONJ in any of the controlled trials on use of bisphosphonates for osteoporosis; this represents more than 60,000 patients who in some cases were treated for more than 8 years.

Recommendations

The American Society for Bone and Mineral Research advises:

2 Raloxifene: An osteoporosis drug that reduces new onset breast cancer

Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA 2006;295:2727–2741.

Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–137.

Two large trials cause me to believe that raloxifene significantly reduces new onset breast cancer in virtually every group of women in which it has been studied.

Why you didn’t hear about this until now

Raloxifene was FDA-approved for prevention of osteoporosis in 1997 and for treatment of osteoporosis in 1999. There was a statistically significant 76% reduction in new onset breast cancer in raloxifene-treated patients versus placebo through 4 years of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, and this persisted at a 66% reduction through the additional years of the CORE (Continued Observation of Raloxifene Evaluation) trial.

Findings effectively buried. However, because of the wording of the FDA label, and, as a result of a $36 million fine from the Department of Justice, for promotional activities in the early years after its release, these findings were effectively buried and not well promulgated.

STAR and RUTH trials

Study of Tamoxifen and Raloxifene

The STAR trial reported by Vogel et al involved 19,747 postmenopausal women enrolled on the basis of their high risk for breast cancer. The patients were randomized to tamoxifen (already approved for breast cancer prevention) or raloxifene.

Over 5 years of study, the incidence of invasive breast cancer was virtually identical in both groups. However, the raloxifene group had statistically significant lower numbers of thromboembolic events, cataracts, hysterectomies performed, and endometrial hyperplasias. A 38% reduction in endometrial cancer in the raloxifene group had not reached statistical significance but was trending in that direction.

Studies of fracture reduction in populations with existing osteoporosis include the Fracture Intervention Trial, which enrolled women with low bone mass and existing vertebral fractures. Clinical vertebral and other fractures were substantially reduced in the treatment group

Raloxifene Use in The Heart

The RUTH trial reported by Barrett-Connor et al involved 10,101 post-menopausal women selected for multiple risks for coronary heart disease.

Although there was no reduction in coronary heart disease, there was no increase, unlike the estrogen and progesterone arm of the Women’s Health Initiative (WHI). Additionally, however, there was a 44% reduction in invasive breast cancer (95% CI 0.38–0.83). Remember, these women were chosen for their risk of heart disease. The rate of breast cancer in the placebo group was 2.7 cases per 1,000 women per year, and thus the 44% reduction means the rate in the treatment group was 1.5 cases per 1,000 women per year.

Consider the context

For comparison purposes, consider an average-risk group in the WHI, where the incidence of breast cancer was 3.3 cases per 1,000 women per year. Contrast this rate to that of a high-risk group, such as the placebo group in the original breast cancer prevention trial (BCPT), where the incidence was 6.8 cancers per 1,000 women per year.

A case in point

I believe that such information must be available to clinicians and must be factored into your decision when contemplating a bone drug. A recent anecdote underscores the problem.

4 out of 10 Caucasian women over age 50 will fracture a hip, spine, or wrist sooner or later

1 of every 5 who fracture a hip ends up in a nursing home

DXA T-score of -2.0 in the hip and atypical ductal hyperplasia

An internist called me to discuss a mutual patient whom I had placed on raloxifene 2 years earlier. His comment was that raloxifene does not work in the hip. Our mutual patient had a T-score on DXA in the hip of -2.0 and in the spine of -0.7 (falsely improved by some osteophytes). In addition, she had been diagnosed with atypical ductal hyperplasia of the breast 2 years earlier.

I pointed out to him that studies of hip fracture reduction with bisphosphonate were all performed in women with osteoporosis. Furthermore, after the NHANES III correction, a sizable number of women in the MORE trial were not osteoporotic. In fact, the fracture incidence in the MORE trial placebo group was 0.7%—an extremely low risk—compared with 2.2% in the treatment group in the Fracture Intervention Trial I, and 3.0% in the treatment group in the Hip Intervention Program.

Stated another way, the incidence of hip fracture in the MORE placebo group was less than that in the treated groups in the Fracture Intervention Trial I and the Hip Intervention Program.

But perhaps the most important point in my anecdotal case is that the woman had a diagnosis of atypical ductal hyperplasia of the breast, a lesion that significantly increases her risk of invasive breast cancer. For these reasons, raloxifene was a much better choice for her fracture reduction pharmacotherapy. Her internist was unaware of these breast effects and had not taken this into account.

3 Estrogen for bone protection: Time for a comeback?

Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647–1657.

Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res. 2006;6:817–828.

It may be time to revisit our initial reaction to the WHI. Although most estrogens are FDA-approved for treatment of osteoporosis, recommendations since the WHI have generally been that we should reserve hormone therapy or estrogen therapy for disruptive transitional symptoms (hot flashes, night sweats, etc.), and prescribe the lowest dose possible for the shortest time possible, consistent with the patient’s treatment goals.

Rethink therapy for 2 types of patients?

Recent reports, however, may cause us to rethink that approach, especially in 2 types of patients:

Stefanick et al reported on the 10,739 women aged 50–79 in the estrogen-only arm of the WHI, who received placebo or0.625 mg of conjugated equine estrogen. After a mean follow-up of 7.1 years, there were 104 cases of invasive breast cancer in this CEE group and 133 cases in the placebo group.

Stated another way, this represents a 20% reduction in breast cancer in women in the CEE group. Although this reduction was not statistically significant, it is in stark contrast with the increase in breast cancer seen in numerous studies of estrogen and progestogen together.

Statistically significant reductions in fracture, compared with placebo, in the WHI E2-only arm were:

wrist 42%

clinical vertebral 36%

hip 35%

total fractures 29%

Women in the WHI had all levels of fracture risk

Jackson et al also analyzed fracture incidence in the WHI E2-only arm, as assessed by semiannual questionnaires and verified by adjudication of radiology reports.

Women on CEE had statistically significant reductions in hip fracture (35%), clinical vertebral fracture (36%), wrist fracture (42%), and total fractures (29%), compared with placebo. This trend held across all levels of fracture, although the reductions were greatest in patients at highest risk.

This is notable, however, because the WHI was primarily studying the effect of CEE on coronary heart disease. Unlike virtually all osteoporosis studies, in which women with increased risk of fracture are studied, the women selected for the Women’s Health Initiative represent all levels of fracture risk—and this placebo-controlled, large, randomized study discovered that all fractures, across all levels of risk, were significantly reduced. And there was no increase in breast cancer.

This may well weigh in on many a clinician’s thought process about indications and real risks of estrogen therapy.

4 Risedronate: Not just for fracture prevention?

Buckland-Wright JC, Messent EA, Bingham CO III, et al. A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients. Rheumatology (Oxford). 2006 Jul 11; [Epub ahead of print].

Bone formation in osteoarthritic knees reversed disease-related bone loss while maintaining structural integrity within the subchondral cancellous bone in patients treated with risedronate, in this 2-year study. Patients with progressive knee osteoarthritis were enrolled in this double-blinded, multicenter, randomized, placebo-controlled trial.

The treatment groups included placebo, risedronate 5 mg/day, 15 mg/day, and 50 mg/week. Patients receiving risedronate 15 mg/day retained vertical trabecular structure and those receiving 50 mg/week increased vertical trabecular number, thereby preserving the structural integrity of the subchondral bone.

This is important because weakening and loss of vertical trabecular support, when combined with the biomechanical weakening of the bone due to disease-related reduction in mineral content, are believed to contribute to collapse of the tibial compartment in late-stage osteoarthritis. It has been suggested that bisphosphonates are associated with decreased bone formation as an expected consequence of suppressing the coupled bone remodeling process. This did not appear to be the case in this study. In fact, the study tends to agree with experimental work that shows that high doses of bisphosphonates, as well as repeated administration, may enhance bone accretion.

The author serves on the advisory boards for Eli Lilly, Merck, Pfizer, Procter & Gamble, and GlaxoSmithKline.